A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD Versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the Treatment of HBeAg-Negative, Chronic Hepatitis B
Phase: PHASE3
Conditions: HBV, Chronic HBV Infection
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
ClinicalT rials.gov 
Identifier: 
Indication: 
Protocol ID: 
Gilead Sciences 
Study Director: 
Gilead Sciences 
Medical Monitor: 
Protocol Version/Date: 
(!') GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind Study to Evaluate the 
Safety and Efficacy ofTenofovir Alafenamide (TAF) 25 mg QD 
versus Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment ofHBeAg-Negative, Chronic Hepatitis B 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
115, 561 
2013-000626-63 
NCT01940341 
HBeAg-negative Chronic Hepatitis B 
GS-US-320-0108 
Name: 
Telephone: 
Fax: 
Mobile: 
Email: 
Name: 
Telephone: 
Fax (paper): 
Mobile: 
Email: 
Amendment 3.1: 
John Flaherty, Phatm D 
PPD 
PPD 
PPD 
PPD 
Benedetta Massetto, MD, PhD 
[PPD 
PPD 
PPD 
PPD 
I 
23 Febmmy 2016 
CONFIDENTIALITY STATEMENT 
The inf01mation contained in this document, pmiiculm·ly unpublished data, is the propetiy or 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 Bom·d or Independent Ethics Committee. The inf01m ation is only to be used 
by you in connection with authorized clinical studies of the investigational dmg described in the 
protocol. You will not disclose any of the inf01m ation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessmy to obtain inf01m ed consent from those 
persons to whom the dmg may be administered. 

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Protocol GS-US-320-0108
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Gilead Sciences, Inc.
Amendment 3.1
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Background ............................................................................................................................................23
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................25
1.2.1.
General Information .............................................................................................................25
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................26
1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340).................................................29
1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF).........................................................................................................................41
1.3.
Rationale for This Study ........................................................................................................................49
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B .................................49
1.3.2.
Rationale for the Current Study............................................................................................50
1.3.3.
Rationale for Dose Selection................................................................................................52
1.4.
Compliance ............................................................................................................................................53
2.
OBJECTIVES.....................................................................................................................................................54
3.
STUDY DESIGN................................................................................................................................................56
3.1.
Treatment Plan and Regimen .................................................................................................................56
3.2.
Biomarker Testing..................................................................................................................................57
3.2.1.
Biomarker Samples to Address the Study Objectives:.........................................................57
3.2.2.
Biomarker Samples for Optional Pharmacogenomic Research............................................58
3.3.
Intensive PK Substudy (Optional)..........................................................................................................58
3.4.
Ophthalmologic Substudy (Optional) ....................................................................................................59
4.
SUBJECT POPULATION..................................................................................................................................60
4.1.
Number of Subjects and Subject Selection ............................................................................................60
4.2.
Inclusion Criteria....................................................................................................................................60
4.3.
Exclusion Criteria...................................................................................................................................61
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................63
5.1.
Randomization and Blinding..................................................................................................................63
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................63
5.2.
Description and Handling of Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate 
(TDF) and Matched Placebos.................................................................................................................64
5.2.1.
Formulation..........................................................................................................................64
5.2.2.
Packaging and Labeling .......................................................................................................65
5.2.3.
Storage and Handling...........................................................................................................65
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos ...................................................65
5.4.
Prior and Concomitant Medications.......................................................................................................66
5.5.
Accountability for Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF) and 
Matched Placebos...................................................................................................................................68
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................68
6.
STUDY PROCEDURES ....................................................................................................................................69

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6.1.
Subject Enrollment and Treatment Assignment.....................................................................................69
6.2.
Pretreatment Assessments......................................................................................................................69
6.2.1.
Screening Visit .....................................................................................................................69
6.2.2.
Baseline Assessments...........................................................................................................70
6.3.
Treatment Assessments..........................................................................................................................71
6.3.1.
Double Blind Visits (Including Amendment 2.1 Open Label Visits 
Weeks 108 through 144) ......................................................................................................71
6.3.2.
Open Label Visits.................................................................................................................81
6.4.
Post-treatment Assessments ...................................................................................................................83
6.4.1.
HBsAg Loss and Seroconversion Subjects ..........................................................................83
6.4.2.
All other subjects who discontinue study drug.....................................................................83
6.4.3.
Follow up visit assessments (all subjects)............................................................................83
6.5.
Early Discontinuation (ED) from Study.................................................................................................84
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................84
6.7.
Intensive Pharmacokinetic Substudy (Optional)....................................................................................85
6.8.
Urine, Serum and Plasma for Storage ....................................................................................................85
6.9.
Resistance Surveillance..........................................................................................................................86
6.10.
Hepatic Ultrasound for Hepatocellular Carcinoma Surveillance ...........................................................86
6.11.
End of Study...........................................................................................................................................86
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................87
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................87
7.1.1.
Adverse Events.....................................................................................................................87
7.1.2.
Serious Adverse Events........................................................................................................87
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................88
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................88
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................88
7.2.2.
Assessment of Severity ........................................................................................................89
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................89
7.4.
Gilead Reporting Requirements.............................................................................................................92
7.5.
Toxicity Management ............................................................................................................................92
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................93
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................93
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................93
7.5.4.
Management of Bone Evaluation.........................................................................................94
7.5.5.
Management of Potential Nephrotoxicity.............................................................................94
7.5.6.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis 
Management.........................................................................................................................95
7.5.7.
Management of Potential Posterior Uveitis Cases................................................................97
7.6.
Special Situations Reports......................................................................................................................97
7.6.1.
Definitions of Special Situations..........................................................................................97
7.6.2.
Instructions for Reporting Special Situations.......................................................................98
8.
STATISTICAL CONSIDERATIONS..............................................................................................................100
8.1.
Analysis Objectives and Endpoints......................................................................................................100
8.1.1.
Analysis Objectives............................................................................................................100
8.1.2.
Primary Endpoint ...............................................................................................................101
8.1.3.
Secondary Endpoints..........................................................................................................101
8.1.4.
Other Endpoints of Interest ................................................................................................101
8.2.
Analysis Conventions...........................................................................................................................102
8.2.1.
Analysis Sets ......................................................................................................................102
8.2.2.
Data Handling Conventions ...............................................................................................103

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8.3.
Multiplicity Adjustments......................................................................................................................103
8.4.
Demographic Data and Baseline Characteristics .................................................................................104
8.5.
Efficacy Analysis .................................................................................................................................104
8.5.1.
Primary Analysis................................................................................................................104
8.5.2.
Analyses of Other Endpoints of Interest.............................................................................105
8.6.
Safety Analysis.....................................................................................................................................105
8.6.1.
Key Secondary Safety Analyses.........................................................................................105
8.6.2.
Extent of Exposure.............................................................................................................105
8.6.3.
Adverse Events...................................................................................................................106
8.6.4.
Laboratory Evaluations ......................................................................................................106
8.7.
Pharmacokinetic Analysis....................................................................................................................107
8.7.1.
Biomarker Analysis............................................................................................................107
8.8.
Sample Size..........................................................................................................................................107
8.9.
Data Monitoring Committee ................................................................................................................108
9.
RESPONSIBILITIES........................................................................................................................................109
9.1.
Investigator Responsibilities ................................................................................................................109
9.1.1.
Good Clinical Practice........................................................................................................109
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval.........................................................................................................109
9.1.3.
Informed Consent...............................................................................................................109
9.1.4.
Confidentiality....................................................................................................................110
9.1.5.
Study Files and Retention of Records ................................................................................110
9.1.6.
Case Report Forms.............................................................................................................111
9.1.7.
Investigational Medicinal Product Accountability and Return...........................................112
9.1.8.
Inspections..........................................................................................................................112
9.1.9.
Protocol Compliance..........................................................................................................112
9.2.
Sponsor Responsibilities ......................................................................................................................113
9.2.1.
Protocol Modifications.......................................................................................................113
9.2.2.
Study Report and Publications ...........................................................................................113
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................113
9.3.1.
Access to Information for Monitoring................................................................................113
9.3.2.
Access to Information for Auditing or Inspections ............................................................114
9.3.3.
Study Discontinuation........................................................................................................114
10.
REFERENCES .................................................................................................................................................115
11.
APPENDICES ..................................................................................................................................................117
Appendix 1.
Investigator Signature Page..................................................................................................118
Appendix 2.
Study Procedures Table........................................................................................................119
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])............................................................................125
Appendix 4.
Management of Clinical and Laboratory Adverse Events....................................................126
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities.............127
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations.........................................................................................149

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LIST OF IN-TEXT TABLES
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection......................................30
Table 1-2.
GS-US-320-0101: Baseline Demographics and Disease Characteristics ...............................33
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and Laboratory 
Abnormalities: Overall Summary, Safety Analysis Set..........................................................34
Table 1-4.
GS-US-320-0101: HBV DNA Results: Median Change from Baseline at Day 15 
and Day 29 by Treatment Group ............................................................................................37
Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on Day 1 ........................39
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on Day 1 ........................40
Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: Overall Summary, Safety 
Analysis Set............................................................................................................................44
Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities, 
Safety Analysis Set.................................................................................................................45
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine and Hip Bone 
Mineral Density at Week 24, DXA Analysis Set ...................................................................47
Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by Gradation at Week 
24, DXA Analysis Set ............................................................................................................48
Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover Markers, 
Safety Analysis Set.................................................................................................................49
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution Due to the 
Potential for Drug-Drug Interaction with Study Medication..................................................67
LIST OF IN-TEXT FIGURES
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance (Cockcroft-Gault 
Method) in GS-US-320-0101.................................................................................................35
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV DNA (Log10
IU/mL) by Treatment Group ..................................................................................................36
Figure 1-3.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on Day 1: TAF (GS-
7340), Linear Scale.................................................................................................................38
Figure 1-4.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on Day 1: 
Tenofovir, Linear Scale..........................................................................................................39
Figure 1-5.
GS-US-292-0102: Median (Q1, Q3) of Change from Baseline in Estimated GFR by 
Cockcroft-Gault by Visit, Safety Analysis Set.......................................................................46
Figure 3-1.
Study Schema.........................................................................................................................57

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Title of Study:
A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety 
and Efficacy of Tenofovir Alafenamide (TAF) 25 mg QD versus 
Tenofovir Disoproxil Fumarate (TDF) 300 mg QD for the 
Treatment of HBeAg-Negative, Chronic Hepatitis B
IND Number:
EudraCT Number:
ClinicalTrials.gov 
Identifier:
115,561
2013-000626-63
NCT01940341
Study Centers Planned:
Approximately 160 centers worldwide
Objectives:
The primary objectives of this study are as follows:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg 
QD versus tenofovir disoproxil fumarate (TDF) 300 mg QD for 
the treatment of HBeAg-negative, chronic hepatitis B at 
Week 48 in treatment-naïve and treatment-experienced subjects. 
The primary efficacy parameter is the proportion of subjects 
with plasma HBV DNA levels below 29 IU/mL. 

To compare the safety and tolerability of TAF 25 mg QD versus 
TDF 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows:

To compare the safety of TAF 25 mg QD versus TDF 300 mg 
QD as determined by the percent change from baseline in hip 
and spine bone mineral density (BMD) at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg 
QD as determined by the change from baseline in serum 
creatinine at Week 48

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Amendment 3.1
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Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg
QD for the treatment of HBeAg-negative, chronic hepatitis B in 
regard to the proportion of subjects with plasma HBV DNA 
levels below 29 IU/mL at Weeks 96 and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg 
QD for the treatment of HBeAg-negative, chronic hepatitis B in 
regard to the proportion of subjects with plasma HBV DNA 
levels below 29 IU/mL (target not detected) at 
Weeks 48, 96, and 144

To compare the biochemical (ALT normalization) response of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with 
seroconversion to anti-HBs) of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144

To compare the change in fibrosis as assessed by FibroTest® of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B at Weeks 48, 96, and 144

To compare the incidence of drug resistant mutations of TAF 
25 mg QD versus TDF 300 mg QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic 
findings by fundoscopic examination of TAF 25 mg QD versus 
TDF 300 mg QD at Weeks 24, 48, 72, 96, and 144 in a subset 
of subjects 

To characterize the pharmacokinetics of TAF and tenofovir 
(TFV) and determine intracellular concentrations of tenofovir 
diphosphate (TFV-DP) within peripheral blood mononuclear 
cells (PBMCs) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy , safety, and 
incidence of drug resistance mutations of TAF 25 mg QD in 
subjects initially randomized to TAF 25 mg QD and in subjects 
sequentially treated with TDF 300 mg QD and then switched to 
open-label TAF 25 mg QD

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Study Design:
This is a randomized, double-blind, non-inferiority study to 
compare the antiviral activity of TAF 25 mg QD versus TDF 
300 mg QD. Approximately 390 subjects will be randomized in 
a 2:1 ratio (A:B) to the treatment arms and will be 
stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
> 7 log10 IU/mL −< 8 log10 IU/mL, > 8 log10 IU/mL) and oral 
antiviral treatment status (treatment-naïve vs. 
treatment-experienced).
Treatment Arm A: 260 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched 
placebo of TAF 25 mg QD
For China, approximately 150 additional subjects 
(100 in Treatment Arm A and 50 in Treatment Arm B) will be 
enrolled for local registration purposes.
The duration of double-blind treatment is 144 weeks (96 weeks 
under Amendment 2.1). All subjects who complete the double-blind 
period of treatment are eligible for participation in the open label 
TAF 25 mg QD extension period for an additional 240 weeks 
(through Week 384/ED). Subjects already assigned to open-label
TAF 25 mg QD at Week 96 per Amendment 2.1 will continue on 
open-label TAF 25 mg QD through Week 384/ED. For the entire 
duration of the study, subjects and investigators will remain blinded 
to the initial treatment regimen to which they were randomized.  
Subjects with a confirmed creatinine clearance (CLCr) 
< 50 mL/min, and > 20 % decline in eGFR by CKD-EPI 
(cystatin C), at any time during the double blind period of the study 
will be required to undergo dose modification to every other day 
dosing of study drug. Subjects with confirmed creatinine clearance 
< 30 mL/min at any time during the study will have the study drug 
permanently discontinued.
The primary analysis will occur at Week 48 with the primary 
efficacy endpoint being the proportion of subjects with complete 
viral suppression, i.e., plasma HBV DNA level below 29 IU/mL.
Subjects who permanently discontinue study drug 
(either prematurely or at the end of study [Week 384]) for reasons 
other than HBsAg loss with confirmed seroconversion to anti-HBs 
will be followed every 4 weeks for 24 weeks off treatment or until 
initiation of alternative, commercially available, HBV therapy, 
whichever occurs first. Use of commercial therapy is strongly 
encouraged.

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Subjects with HBsAg loss with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of seroconversion to anti-HBs. Subjects 
with HBsAg loss with confirmed seroconversion to anti-HBs prior 
to Week 48 are not permitted to discontinue study drug prior to the 
Week 48 visit. Subjects who discontinue study drug for confirmed 
seroconversion to anti-HBs will be followed off treatment every 
4 weeks for 12 weeks and then per the study visit schedule 
(Appendix 2) through Week 384/ED. Discontinuation of study drug 
for subjects experiencing HBsAg loss with confirmed 
seroconversion, who have known bridging fibrosis or cirrhosis, 
should be considered on a case by case basis.
An external, independent, multidisciplinary Data Monitoring 
Committee (DMC) will review the progress and safety of this study 
approximately every 24 weeks following the time of randomization 
of the first subject during the double blind period of the study. 
During the open-label duration of the study (Weeks 144 to 384), the 
DMC will convene approximately every 48 weeks. At each 
meeting, the DMC will review routine safety and dual energy X-ray 
absorptiometry (DXA) data and will make recommendations 
regarding modification of the study treatment.
Number of Subjects 
Planned:
390 subjects (260 subjects TAF 25 mg QD and matched placebo of 
TDF 300 mg QD, and 130 subjects TDF 300 mg QD and matched 
placebo of TAF 25 mg QD)
For China, approximately 150 additional subjects (100 subjects 
TAF 25 mg QD and matched placebo of TDF 300 mg QD, and 
50 subjects TDF 300 mg QD and matched placebo of 
TAF 25 mg QD) will be enrolled.
Target Population:
Subjects, who are 18 years of age and older, with HBeAg-negative, 
chronic hepatitis B
Duration of Treatment:
The duration of the double-blind treatment is 144 weeks (96 weeks 
under Amendment 2.1). After completing the double-blind period 
of treatment, all subjects remaining on treatment will be eligible to 
receive open label TAF 25 mg QD for up to an additional 
240 weeks (Week 144 through Week 384). Subjects already 
assigned to open-label TAF 25 mg QD at Week 96 per Amendment 
2.1 will continue on open-label TAF through Week 384/ED. 
Subjects who lose HBsAg with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of seroconversion to anti-HBs, or after 
Week 48, if seroconversion occurs prior to this visit. 

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Amendment 3.1
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Diagnosis and Main 
Eligibility 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, which must be obtained prior to initiation of 
study procedures.
2) Male and non-pregnant, non-lactating female subjects, 18 years 
of age and older, based on the date of the screening visit. 
A negative serum pregnancy test at Screening is required for 
female subjects of childbearing potential (as defined in 
Appendix 6).
3) Documented evidence of chronic HBV infection 
(e.g. HBsAg positive for more than 6 months)
4) HBeAg-negative, chronic hepatitis B with all of the following:

HBeAg-negative and HBeAb positive at Screening (if the 
subject is deemed ineligible for this study by HBV serology 
[i.e. HBeAg positive CHB], this information may be used to 
determine eligibility for GS-US-320-0110 
[another Gilead Sciences Phase 3 study in HBeAg-positive, 
CHB subjects; this study must also be IRB/EC approved at 
the participating center])

Screening HBV DNA ≥ 2 × 104 IU/mL 

Screening serum ALT level > 60 U/L (males) or > 38 U/L 
(females) and ≤10 × ULN (by central laboratory range)
5) Treatment-naïve subjects (defined as < 12 weeks of oral 
antiviral treatment with any nucleoside or nucleotide analogue), 
OR 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) will be eligible for enrollment. 
Treatment-experienced subjects receiving oral antiviral 
treatment at Screening must continue their treatment regimen 
until the time of randomization, when it will be discontinued.
6) Any previous treatment with interferon (pegylated or 
non-pegylated) must have ended at least 6 months prior to the 
baseline visit.

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7) Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the 
Cockcroft-Gault method) based on serum creatinine and actual 
body weight as measured at the Screening evaluation, as 
follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8) Normal ECG (or if abnormal, determined by the investigator
not to be clinically significant)
9) Must be willing and able to comply with all study requirements.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in the study.
1) Pregnant women, women who are breastfeeding or who believe 
they may wish to become pregnant during the course of the 
study.
2) Males and females of reproductive potential who are unwilling 
to use an “effective”, protocol-specified method(s) of 
contraception during the study. For a list of protocol-specified 
contraceptive methods, refer to Appendix 6.
3) Co-infection with HCV, HIV, or HDV
4) Evidence of hepatocellular carcinoma (e.g. as evidenced by 
recent imaging)
5) Any history of, or current evidence of, clinical hepatic 
decompensation (e.g., ascites, encephalopathy or 
variceal hemorrhage).
6) Abnormal hematological and biochemical parameters, 
including:

Hemoglobin < 10 g/dL 

Absolute neutrophil count < 750/mm3

Platelets ≤50,000/mm3

AST or ALT > 10 × ULN

Total bilirubin > 2.5 × ULN

Albumin < 3.0 g/dL

INR > 1.5 × ULN (unless stable on anticoagulant regimen)

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7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological 
disease in the opinion of the investigator
9) Significant bone disease (eg, osteomalacia, chronic 
osteomyelitis, osteogenesis imperfecta, osteochrondroses), or 
multiple bone fractures
10) Malignancy within 5 years prior to screening, with the 
exception of specific cancers that are cured by surgical resection 
(basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible
11) Currently receiving therapy with immunomodulators 
(e.g. corticosteroids), investigational agents, nephrotoxic agents, 
or agents capable of modifying renal excretion
12) Known hypersensitivity to study drugs, metabolites, or 
formulation excipients
13) Current alcohol or substance abuse judged by the investigator to 
potentially interfere with subject compliance
14) Any other clinical condition or prior therapy that, in the opinion 
of the investigator, would make the subject unsuitable for the 
study or unable to comply with dosing requirements.
15) Subjects on prohibited concomitant medications 
(See Table 5-1). Subjects on prohibited medications, otherwise 
eligible, will need a wash out period of at least 30 days.
Study Procedures/
Frequency:
Laboratory analyses (serum chemistry, liver tests, hematology, 
urinalysis, plasma HBV DNA levels, pregnancy testing [for females 
of childbearing potential]), vital signs, adverse events and 
concomitant medications will be performed at Screening, Baseline, 
and every 4 weeks thereafter through Week 48, every 8 weeks 
through Week 96, every 12 weeks through Week 144, and every 
24 weeks through Week 384/Early Discontinuation (ED) visit. 
HBV serology (HBeAg and HBeAb, HBsAg and reflex HBsAb 
[anti-HBs]) will be performed at Screening and Baseline, HBsAg 
and reflex HBsAb will be performed every 12-16 weeks until 
Week 144, every 24 weeks until Week 384/ED and at Follow Up
Weeks 12 and 24. Quantitative serum HBsAg will be assessed at 
Screening, Baseline, and every 12-16 weeks until Week 144, every 
24 weeks until Week 384/ED, and at Follow Up visits. Bone and 
renal biomarker testing will be performed at Baseline and then at 
defined intervals (see Schedule of Assessments, Appendix 2)
throughout the study. IL28B polymorphism genotype, HBV 
genotyping and vitamin D level will be performed at Baseline only. 
Fibrotest® will be performed at Baseline and every 48 weeks until 

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Week 384/ED. Fasting metabolic assessments (fasting glucose and 
lipid panel) will be conducted at Baseline, every 24 weeks until 
Week 240, and every 48 weeks until Week 384/ED visit.
Complete physical examinations will be performed at Screening, 
Baseline, and Weeks 24, 48, 72, 96, 144, 240 and Week 384/ED. 
Height assessment will be conducted at Screening only. Symptom 
directed physical exams with body weight assessment will be 
conducted at all other visits. ECG will be performed at Screening 
and every 48 weeks thereafter. At sites in China with the capability 
only, DXA scans of the hip and spine will be conducted during the 
screening period, and should be conducted at least 14 days prior to 
the first dose of study drug, and will be subsequently conducted at 
Weeks 24, 48, 72, 120, 96, 144, every 48 weeks until Week 384, 
and the ED visit, if not done within the last 24 weeks. Hepatic 
ultrasound for surveillance of hepatocellular carcinoma will be 
performed starting at Week 96 and then every 24 weeks until 
Week 384/ED.  
Genotypic analysis of the HBV polymerase/reverse transcriptase 
(pol/RT) for resistance surveillance will be performed at Baseline 
for all subjects and attempted for all viremic subjects (HBV DNA 
≥69 IU/mL) at Weeks 48, 96, 144 and every 48 weeks until 
Week 384/ED. 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. Plasma, serum, and urine will be 
collected at Baseline and at every visit thereafter for storage. 
A single pharmacokinetic (PK) blood sample will be collected at all 
study visits from Weeks 4 through 48 for all subjects. At the 
Week 4 and 12 visits, dosing will occur in-clinic and a single PK 
blood sample will be collected between 15 minutes and 4 hours 
post-dose. It is preferred that subjects take their study drug 
according to a morning dosing schedule; however, evening dosing 
is allowable. Subjects who elect to dose in evening are not required 
to have in-clinic dosing and the single PK blood sample collection 
performed at the Week 4 and 12 visits.
Pharmacokinetic Substudy
For subjects who provide a separate informed consent (n=16 and up 
to n=32), an intensive PK substudy will be conducted once at either 
of the Week 4, 8 or 12 visits at select sites. Blood (plasma) samples 
will be collected at 0 (≤30 minutes pre-dose), at 5, 15 , 30, 
45 minutes, and at 1, 1.5, 2, 3, 4, 5, 8, 12, and 24 hours post dose. 
Subjects will be dosed in-clinic and should be in a fasted state 
(no food or drinks 8 hours prior except water up to 1 hr) prior to the

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intensive PK visit. The subjects will then be provided a 
standardized meal 4 hours post dose. Subjects participating in the 
PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the time of the intensive 
PK substudy. Please refer to the PK manual for specific restrictions 
on food and water intake.
Ophthalmologic Substudy
For subjects who provide a separate informed consent (n = 30, at 
select sites), a substudy will be conducted to assess ophthalmologic 
findings, including fundoscopic examination with slit lamp and 
retinal photographs (both eyes), anytime during the screening 
period, but must be completed prior to the first dose of study drug, 
and at Weeks 24, 48, 72, 96, and 144. An exam should be 
performed at the ED visit, if prior to Week 144 and not done within 
the last 24 weeks of this visit.
Pharmacogenomic Substudy
An optional blood sample may be obtained for exploratory 
biomarker and pharmacogenomic discovery research. This sample 
may only be collected following approval of the national and local 
regulatory bodies and Ethical Committees. This sample should be
collected at Baseline, prior to the first dose of study drug, but may 
be collected at any time during the study or at a separate 
unscheduled study visit, if necessary. Subjects who agree to have 
blood drawn for these purposes will sign a separate informed
consent form prior to obtaining this sample.
Subjects who receive at least one dose of study drug and 
permanently discontinue study drug for reasons other than HBsAg 
loss and seroconversion to anti-HBs, either prematurely or at the 
end of the study (Week 384), will be followed every 4 weeks for 
24 weeks post-treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. The 
following evaluations will occur every 4 weeks: vital signs, 
hematology, serum chemistry, liver function tests, and plasma HBV 
DNA. Plasma, serum, and urine will be collected for storage. 
HBsAg and reflex HBsAb will be evaluated at Follow up 
Weeks 12 and 24. 
Subjects who lose HBsAg with confirmed seroconversion to 
anti-HBs should discontinue study drug within 3-6 months 
following confirmation of HBsAg loss and seroconversion to 
anti-HBs or after Week 48, if seroconversion occurs prior to this 
visit. These subjects will be followed off treatment every 4 weeks 
for 12 weeks and then per the study visit schedule (Appendix 2) 
through Week 384/ED.

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Test Product, Dose, and 
Mode of Administration:
Double-Blind Treatment: 

Tenofovir alafenamide (TAF) 25 mg QD, oral administration 
and matched placebo of Tenofovir DF (TDF) 300 mg QD, 
oral administration
Open-Label Treatment: 

Tenofovir alafenamide (TAF) 25 mg QD, oral administration 
Reference Therapy, 
Dose, and Mode of 
Administration:
Double-blind Treatment: 

Tenofovir DF 300 mg QD, oral administration and matched 
placebo of Tenofovir alafenamide (TAF) 25 mg QD, 
oral administration
Open-label Treatment: NA
Criteria for Evaluation:
Safety:
Key secondary safety endpoints include the percent change from 
baseline at Week 48 in hip and spine BMD, and change from 
baseline at Week 48 in serum creatinine.
If a subject has confirmed creatinine clearance (CLCr) < 50 mL/min, 
and > 20% decline in eGFR by CKD-EPI (cystatin C), at any time 
during the double-blind period of the study, the subject will be 
required to undergo dose modification to every other day dosing of 
study drug. Subjects with confirmed creatinine clearance 
< 30 mL/min at any time during the study will have the study drug 
permanently discontinued.
The proportion of subjects in each treatment arm with tolerability 
failure (defined as an adverse event [AE] leading to permanent 
discontinuation of study drug) at Weeks 48, 96, 144, 240, and 384
will be summarized. Change from baseline in serum creatinine will 
be assessed at every visit and summarized through Week 384/ED. 
Change from baseline in BMD by DXA of the spine and hip will be 
assessed at Weeks 24, 48, 72, 96, 120, and 144, and every 48 weeks 
until Week 384/ED. Fracture Risk Assessment will be evaluated at 
Baseline.
Ophthalmologic changes from baseline by fundoscopic examination 
at Weeks 24, 48, 72, 96, and 144 (or ED if prior to Week 144 and 
more than 24 weeks since the last exam) will be summarized for a 
subset of subjects (n = 30). In addition, for any subject who 
develops signs or symptoms of posterior uveitis, the investigator 
should contact the Gilead Medical Monitor to discuss the need for 
additional ophthalmologic evaluation including dilated fundoscopy 
and optical coherence tomography (OCT).

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Adverse events and clinical laboratory tests will be collected at
every visit and summarized through Week144. Additionally, 
summaries of AEs, discontinuations due to AEs, and laboratory 
data including BMD measurements (via DXA scans, serum 
creatinine and creatinine clearance by Cockcroft-Gault) by original 
treatment arms (TAF versus TDF) will continue through Week 384. 
Fracture risk assessment will be evaluated at Baseline. In China, 
this fracture risk assessment will be evaluated at sites with DXA 
capability only.
Efficacy:
The primary efficacy endpoint is the proportion of subjects with 
plasma HBV DNA levels below 29 IU/mL at Week 48. 
Other secondary efficacy endpoints are:

The proportion of subjects with plasma HBV DNA < 29 IU/mL 
at Weeks 96, 144, 240, and 384

The proportion of subjects with plasma HBV DNA < 29 IU/mL
(target not detected) at Weeks 48, 96, 144, 240, and 384

The proportion of subjects with ALT normalization (by central 
laboratory and American Association for the Study of Liver 
Diseases [AASLD] criteria) at Weeks 48, 96, 144, 240, and 384

The proportion of subjects with HBsAg loss at 
Weeks 48, 96, 144, 240, and 384

The proportion of subjects with HBsAg seroconversion to 
anti-HBs at Weeks 48, 96, 144, 240, and 384

The change from baseline in fibrosis as assessed by FibroTest®
at Weeks 48, 96, 144, 240, and 384

The incidence of drug resistant mutations at 
Weeks 48, 96, 144, 240, and 384
Pharmacokinetics:
The following TAF and TFV plasma pharmacokinetic parameters 
will be calculated for the substudy population (n = 30): 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½
Single PK plasma samples collected at Weeks 4-48 may be used for 
estimation of population pharmacokinetics of TAF and TFV.
Single PBMC samples at selected PK substudy sites collected at the 
intensive PK substudy visit will be used for TFV-DP concentration 
determination

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Statistical Methods:
The primary analysis will be performed when approximately 
390 subjects complete 48 weeks of the double-blind treatment 
period or discontinue prematurely. The analysis will compare the 
TAF arm to the TDF arm.
Analysis Methods:
A two-sided 95% confidence interval, based on large sample 
theory, adjusted for the randomization stratification factors, for the 
difference (TAF-TDF) between treatments will be evaluated to 
compare treatment groups with respect to the primary efficacy 
endpoint. A missing equals failure approach will be employed for 
the primary analysis. Non-inferiority will be declared if the lower 
bound of this confidence interval exceeds −0.10 (i.e., 10% 
non-inferiority margin). If non-inferiority is established, the lower 
bound of the 95% confidence interval (CI) will be compared to 0; if 
the lower bound of the 95% CI is greater than 0, then superiority of 
TAF over TDF will be established using the same CI.
The percent change from baseline in hip and spine BMD at 
Week 48 will be analyzed using an analysis of variance (ANOVA)
model. The model will include treatment group as a fixed effect. 
The details are provided in the Statistical Analysis Plan (SAP).
The change from baseline in serum creatinine at Week 48 will be 
analyzed using an analysis of covariance (ANCOVA) model with 
baseline serum creatinine as a covariate, and treatment group as a 
fixed effect. The details are provided in the SAP.
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:
With respect to the primary efficacy endpoint of proportion of 
subjects with plasma HBV DNA levels below 29 IU/mL at 
Week 48, when the sample sizes are 260 (TAF 25 mg arm) and 
130 (TDF 300 mg arm), a two-group, large-sample normal 
approximation test of proportions with a one-sided 0.025 
significance level will have 90% power to reject the null 
hypothesis, that the TAF 25 mg arm is inferior to the TDF 300 mg 
arm (the difference in proportions [TAF-TDF] having a lower 
bound of the one-sided 97.5% confidence interval of less than 
−0.10, i.e., 10%) in favor of the alternative hypothesis that the TAF 
25 mg arm is not inferior to the TDF 300 mg arm. This assumes the 
expected difference (TAF-TDF) in proportion of subjects with 
HBV DNA < 29 IU/mL is 0 and the proportion of subjects with 
HBV DNA < 29 IU/mL in the TDF 300 mg arm is 0.91. 

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The TDF virologic rate of 0.91 was calculated using the observed 
rate in Study GS-US-174-0102. 
This sample size also provides 90% power to detect a 1% difference 
in the percentage change from baseline in hip BMD at Week 48 
(assuming a −1.17% change from baseline in TDF 300 mg arm and 
−0.17% change in TAF 25 mg arm, with a common standard 
deviation of 2.20% and a two-sided α = 0.025); a 77% power to 
detect a 1% difference in the percentage change from baseline in 
spine BMD at Week 48 (assuming a −1.69% change from baseline 
in the TDF 300 mg arm and −0.69% change in the TAF 25 mg arm, 
with a common standard deviation of 3.08% and a two-sided 
α = 0.025); a 52% power to detect a 0.03 mg/dL difference in the 
change from baseline in serum creatinine at Week 48 (assuming a 
0.04 mg/dL change from baseline in the TDF 300 mg arm and 
0.01 mg/dL change from baseline in the TAF 25 mg arm, with a 
common standard deviation of 0.12). These assumptions were 
derived from studies GS-98-437, GS-98-438, GS-US-174-0102, 
GS-US-174-0103, and GS-US-174-0121.
For China, approximately 150 additional subjects (100 subjects 
TAF 25 mg QD and matched placebo of TDF 300 mg QD, and 
50 subjects TDF 300 mg QD and matched placebo of TAF 25 mg 
QD) will be enrolled.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
°C
Degrees Celsius
°F
Degrees Fahrenheit
AASLD
American Association for the Study of Liver Diseases
ADV
Adefovir dipivoxil
AE
Adverse event
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
CKF-EPI
Chronic kidney disease epidemiology collaboration
CL/F
Apparent oral clearance after administration of the drug
CLCr
Creatinine clearance
Cmax
The maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
COBI / C
Cobicistat
CRF/eCRF
Case report form(s)/electronic case report form(s)
CRO
Contract (or clinical) research organization
CTX
C-type collagen sequence
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSPH
Drug Safety and Public Health
DXA
Dual energy x-ray absorptiometry

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E2
Estradiol
EC
Ethics committee
EudraCT
European clinical trials database
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)

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

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STR
Single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
Tenofovir Alafenamide, GS-7340
TAF Fumarate
Tenofovir Alafenamide Fumarate, GS-7340-03
TDF
Tenofovir Disoproxil Fumarate
TFV
Tenofovir
TFV-DP
Tenofovir diphosphate
TLOVR
Time to loss of virologic response
Tmax
The time (observed time point) of Cmax
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
T3
Triiodothyronine
TSH
Thyroid stimulating hormone
UACR
Urine albumin-to-creatinine ratio
UGT1A1
Uridine glucuronosyltransferase 1 family, polypeptide A1 
ULN
Upper limit of the normal range
UPCR
Urine protein-to-creatinine ratio
US
United States
WHO
World Health Organization

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1.
INTRODUCTION
1.1.
Background
Chronic hepatitis B (CHB) is a serious global health care problem and one of the principal causes 
of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Of the estimated 
2 billion people worldwide who have been acutely infected with the hepatitis B virus (HBV), 
approximately 400 million have developed CHB, and approximately 1 million people die 
annually from complications of CHB {World Health Organization (WHO) 2000}. Despite the 
availability of HBV vaccine programs in many countries, new HBV infections are still common 
even in areas of low endemicity. For example, approximately 80,000 people in the United States 
(US) become acutely infected each year, according to an estimate from the Centers for Disease 
Control and Prevention {Centers for Disease Control and Prevention (CDC) 2003}. Following 
acute HBV infection, approximately 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}.
Chronic hepatitis B has a broad clinical spectrum, ranging from asymptomatic, slowly 
progressive illness to severe, and more rapidly progressive liver disease. Chronic hepatitis B may 
remain quiescent for many years and represent a risk factor for progression to cirrhosis, liver 
failure, and death within a few years. Approximately 25% of subjects with CHB will ultimately 
develop serious liver disease such as hepatic decompensation, cirrhosis, or HCC 
{Zuckerman 1996}. The development of nucleos(t)ide analogues has been a major breakthrough 
for the treatment of CHB, providing effective suppression of viral replication and reducing the 
risk of long term complications. However, if viral replication resumes as a result of resistance 
mutation development, the clinical benefit is lost. The rate of resistance development in 
treatment-naive subjects varies depending on the treatment: up to 70% after 4 years with 
lamivudine (LAM), up to 29% after 5 years with adefovir dipivoxil (ADV), 25%/11% in 
hepatitis B e antigen positive/negative (hepatitis B e antigen [HBeAg]+/) subjects after 2 years 
with telbivudine (LdT), and 1.2% after 5 years with entecavir (ETV). To date, resistance to TDF 
has not been documented {Marcellin et al 2011}.
Tenofovir DF (Viread®) 300 mg once daily was first approved for the treatment of CHB in 
Turkey on 28 March 2008, and is currently approved in 101 countries, including the US, Canada, 
and Europe. Approval of TDF for CHB was based primarily on 48 week data from 375 adult 
subjects with HBeAg− CHB and 266 subjects with HBeAg+ CHB who enrolled in the similarly 
designed pivotal studies GS-US-174-0102 (HBeAg− subjects) and GS-US-174-0103 
(HBeAg+ subjects). In study GS-US-174-0102, TDF 300 mg once daily was shown to be 
superior to ADV 10 mg once daily for the treatment of HBeAg/antibody to hepatitis B e antigen 
(anti-HBe)-positive (presumed precore mutant) chronic HBV infection. At 48 weeks, 
70.8% of subjects in the TDF group (n = 250) had a complete response (plasma HBV 
deoxyribonucleic acid [DNA] < 69 IU/mL [400 copies/mL] and histologic improvement 
characterized by ≥2 point reduction in the Knodell necroinflammatory score and no worsening 
of Knodell fibrosis), compared to 48.8% of subjects in the ADV group (n = 125; p < 0.001) 
{Marcellin et al 2007}. In study GS-US-174-0103 (HBeAg+ subjects), at 48 weeks, 

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66.5% of subjects in the TDF group (n = 176) had a complete response, compared to 12.2% in 
the ADV group (n = 90; p < 0.001) {Heathcote et al 2007}. Subjects in both studies who 
completed the 48-week double-blind treatment period (including the end-of-blinded-treatment 
biopsy) were eligible to continue in an open-label (OL) extension phase consisting of treatment 
with TDF up to Week 480 (Year 10). 
In both Phase 3 studies, for viremic subjects originally randomized to ADV who rolled over to 
open-label TDF at Week 48, HBV DNA values decreased sharply during the first 16 weeks of 
TDF therapy. At Week 96, the percentages of subjects with plasma HBV DNA < 400 copies/mL 
were not significantly different between treatment groups in both studies. Viral suppression was 
maintained through Week 240 of these 2 pivotal studies in those subjects receiving continued 
treatment with TDF for 240 weeks (TDFTDF group), and in those subjects who received 
192 weeks of TDF treatment following an initial 48 weeks of treatment with ADV 
(ADVTDF group). Based on results from a pooled histology analysis at Year 5 for these 
2 studies, 96.2% of subjects on open-label TDF experienced either improvement or no change in 
fibrosis (by Ishak fibrosis scoring). Further, of the 96 subjects with cirrhosis at baseline 
(Ishak fibrosis score 5-6), 25% experienced no change in Ishak fibrosis score while 73% 
experienced reversal of cirrhosis by Week 240 with a reduction in Ishak fibrosis score of at least 
2 points (missing = excluded [M = E], data after addition of emtricitabine [FTC] included) 
{Marcellin et al 2013}. Importantly, viral suppression (HBV DNA < 69 IU/mL or 
< 400 copies/mL was documented in 330/334 (99%) of subjects with available histology who 
were maintained on therapy with an available HBV DNA measurement at Week 240. No 
mutations associated with TDF resistance developed in subjects treated with TDF for up to 
5 years in the pivotal studies {Marcellin et al 2013}. No phenotypic resistance to TDF has been 
observed among subjects with virologic breakthrough or who developed conserved-site changes 
in the HBV polymerase (pol)/reverse transcriptase (RT) during TDF treatment for up to 5 years. 
Continued treatment with TDF for 5 years revealed no new adverse reactions inconsistent with 
the known safety profile of TDF. Importantly, these results demonstrate that achievement and 
maintenance of long term viral suppression with TDF translates into a histological benefit 
(i.e. fibrosis regression) in the majority of subjects.
While liver biopsy provides important information regarding severity of necroinflammatory 
activity and fibrosis in diseases such as CHB, it is no longer considered routine in clinical 
practice for ongoing disease monitoring, and the procedure itself is challenging to perform within 
the context of clinical trials. Additionally, liver biopsy is costly and limited by sampling error as 
well as patient reluctance to undergo this invasive procedure. With the availability of 
non-invasive tests, including FibroTest® (also known as FibroSURE in the U.S.) and Fibroscan®, 
which have been shown to correlate with histology in liver diseases such hepatitis B 
{Poynard et al 2005}, hepatitis C {Ngo et al 2006}, and non-alcoholic fatty liver disease 
{Poynard et al 2007}, the need for liver biopsy has been largely replaced, particularly for 
ongoing monitoring of changes in fibrosis.
Tenofovir DF is also approved worldwide in many markets for administration in combination 
with other antiretroviral agents for treatment of human immunodeficiency virus (HIV)-1 
infection (first approval in 2001). Tenofovir DF is also a component of Truvada®
(FTC 200 mg/TDF 300 mg), a marketed fixed-dose combination product for treatment of HIV-1 

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infection in combination with other antiretroviral agents. More recently, TDF has been included 
in single tablet regimens (STRs) for treatment of HIV infection. Three STRs are currently 
approved for once-daily administration in the treatment of HIV-1 infection, efavirenz 
(EFV)/FTC/TDF (Atripla®), FTC/rilpivirine (RPV)/TDF (Complera®/Eviplera), and more 
recently, elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TDF (Stribild™). The newly approved 
Stribild™STR tablet, which contains a fixed-dose combination of E/C/F/TDF 
(150/150/200/300 mg), has been approved in the United States by the Food and Drug 
Administration (FDA) for the treatment of HIV-1 infection in treatment-naïve adults. E/C/F/TDF 
is the first approved STR that combines an integrase strand transfer inhibitor (elvitegravir) with a
nucleoside reverse transcriptase inhibitor (NRTI) backbone into a once-daily tablet. Since 
Viread® was first marketed on 31 October 2001, the overall exposure to TDF up to 31 May 2013 
from branded Viread®, Truvada®, Atripla®, Complera® and Stribild®, combined up to 
31 May 2013, is estimated to be in excess of 6 million patient years
TDF is a preferred oral N(t)RTIs for treatment of CHB infection by all current treatment 
guidelines. For the majority of CHB subjects, life-long treatment is required as only a small 
percentage (< 10%) of subjects experience sustained loss of hepatitis B surface antigen (HBsAg), 
and as a consequence, achieve an effective cure of the disease. Though highly effective, long 
term use of TDF is associated with nephrotoxicity and reduced bone mineral density in some 
subjects {Panel on Antiretroviral Guidelines for Adults and Adolescents 2012}. Thus, alternative 
therapies with high antiviral potency, a high genetic barrier to resistance development, and 
improved long term safety and tolerability are needed in order to further advance treatment of 
chronic HBV infection worldwide.
Tenofovir alafenamide (TAF), a novel “intracellular” prodrug of tenofovir (TFV), has the 
potential to advance treatment of chronic HBV infection. In contrast to TDF, an oral prodrug that 
is rapidly cleaved by esterases in the intestines and plasma to TFV, TAF has been specifically 
synthesized to be more stable in resisting early enzymatic cleavage following oral administration 
and remain mostly intact until penetrating target cells. By virtue of this key distinguishing 
property, TAF when administered at a lower dose than TDF, is capable of efficiently delivering 
active drug (e.g. tenofovir diphosphate [TFV-DP]) to the cells where it is needed 
(e.g. HBV-infected hepatocytes, HIV-infected lymphoid cells) while systemic exposures of TFV 
are greatly reduced in comparison to oral administration of TDF 300 mg. These features are 
hypothesized to translate into the potential for effective suppression of viral replication and an 
improved tolerability and safety profile.
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) is a next generation oral 
prodrug of TFV, a nucleotide analog that inhibits reverse transcription in HIV-1 and HBV. TFV
is metabolized intracellularly to the active metabolite, tenofovir diphosphate (TFV-DP), a 
competitive inhibitor of HIV-1 reverse transcriptase (RT) and HBV pol/RT that terminates the 
elongation of the viral DNA chain. In the development of TAF, three forms of the drug substance 

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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, the form being used in GS-US-292-0102 
(Phase 2 study in HIV subjects) and GS-US-320-0101 (Phase 1b study in HBV subjects), is 
considered comparable to GS-7340-02 based on physical/chemical properties of GS-7340-02, the 
form that has been used in previous studies and a number of currently ongoing studies. 
Importantly, both 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), please refer to the latest Investigator’s Brochure for 
GS-7340.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Primary Pharmacodynamics
TAF is converted intracellularly by cathepsin A (CatA) and carboxylesterase-1 (Ces1) to form 
TFV (i.e, a nucleoside monophosphate analog) which is not dependent on an intracellular 
nucleoside kinase activity for the first step in the conversion to the active metabolite, and is 
subsequently converted to TFV-DP by cellular kinases. The cellular enzymes responsible for 
TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{Robbins et al 1995} and nucleotide diphosphate kinase, which are highly active and ubiquitous. 
AK exists as multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most 
efficiently by AK2. Analysis of primary cells showed that CatA activity varied minimally in both 
human cluster of differentiation 4 (CD4+) T-lymphocytes and macrophages. CatA activity was 
equivalent in resting and activated CD4s and approximately 2-fold higher in macrophages.
Intracellular metabolites of TAF were similar among individual donors in both CD4+ T-cells and 
macrophages. Carboxylesterease-1 (Ces1) which is highly expressed in liver, contributes to TAF 
conversion to TFV, particularly in hepatocytes {Bam et al 2012, Birkus et al 2012}.
The intracellular metabolism of TAF and TFV are consistent with the 600-fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T-cells, NK cells, B-cells 
and macrophages/monocytes. TAF is metabolized inside host cells to the active metabolite 
TFV-DP. Concentration of the active metabolite TFV-DP was substantial in all cell populations. 
Additionally, a 24-hour continuous incubation of TAF in primary human hepatocytes in vitro 
resulted in approximately 120- or 5-fold higher levels of TFV-DP compared to incubation of 
TFV or TDF, respectively (AD-120-2017).
1.2.2.2.
Safety Pharmacology
TAF monofumarate (GS-7340-02) has been evaluated to determine potential 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). GS-7340-02 (at 1000 mg/kg) reduced 
distal transit and increased stomach weights starting 2 hours post dosing with reversibility 

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beginning by 6 hours after dosing. The NOEL for gastrointestinal motility was 100 mg/kg. The 
IC50 for the inhibitory effect of TAF fumarate (GS-7340-03) on hERG potassium current was 
estimated to be greater than 10 μM.
1.2.2.3.
Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments in this section were performed using TAF 
monofumarate (GS-7340-02), and all study data described in this section reflect the dosage of the 
monofumarate. For reference, 100 mg of GS-7340-02 is equivalent to 80 mg of the GS-7340 free 
base (TAF).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. 
Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. TFV plasma concentrations declined with 
a terminal half-life of 11.2 to 16.4 hours in rats (fasted), > 24 hours in dogs (fasted), and 8.1 to
12.5 hours in rhesus monkeys. 
The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in beagle 
dogs. Radioactivity was detected in all tissues except brain, with the majority present in the 
contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations 
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV-related radioactive material were observed in lymph nodes from all 4 sites, suggesting that
TAF may be selectively cleaved to TFV in the cells of the lymphoreticular system.
The primary route of elimination of TFV is renal excretion of unchanged drug based on 
IV studies of TFV. Following oral administration of GS-7340-02, approximately 15% of a 
radiolabeled dose is recovered in dog urine in 24 hrs. TFV was the major species present in the 
urine (90%), with about 3.4% of TAF also present. Biliary excretion of TFV in dogs and fecal 
elimination of TFV in rats and dogs are negligible.
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.
The hepatic extraction of TAF was estimated to be 70% suggesting that TAF was rapidly cleaved 
by hepatic hydrolases including Ces1 and CatA {Babusis et al 2013}. An in vitro study to 
evaluate effects of inhibitors of CatA or Ces1 on TAF metabolism in primary human hepatocytes 
is ongoing. Single and repeat dose dog liver pharmacokinetic studies are planned.

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1.2.2.4.
Nonclinical Toxicology
TAF monofumarate (GS-7340-02) was evaluated in mice, rats, dogs, and monkeys for treatment 
periods up to 9 months and was negative in genetic toxicology studies.
In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment. GS-7340-02 also 
appeared to increase biochemical markers of bone turnover and decrease serum 
1,25-dihydroxy- and 25-hydroxyvitamin D3 at doses of 25 mg/kg/day and above. In chronic 
studies in dogs after 9 months of treatment with GS-7340-02, the primary target organs were 
kidney and bone.  
GS-7340-02 had no discernible electrocardiograph (ECG/EKG) effect at the low dose of 
2 mg/kg/day and slightly prolonged PR intervals at 6 and 18/12 mg/kg/day (started at 
18 mg/kg/day, then reduced to 12 mg/kg/day at Weeks 7-8). Additionally, at Week 39, 
GS-7340-02 appeared to reversibly reduce heart rate with an associated mild QT prolongation. 
At Week 39, decreases in serum T3 were noted for animals receiving 18/12 mg/kg/day but was 
reversible at the 3 month recovery period. Minor hematological and biochemistry parameters 
changes were observed but remained within normal historical ranges with the following 
exceptions: AST (~ 100% increase) and total bilirubin (~ 40% increase). There were no clear 
treatment-related effects observed in monkeys following 28 days of treatment, including no 
changes in mitochondrial function.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day 
(tenofovir AUC = 3758 ng•h/mL); the 9-month dog study defined a NOAEL of 2 mg/kg/day 
(tenofovir AUC = 1180 ng•h/mL), and the 28-day nonhuman primate study defined a NOAEL of 
30 mg/kg/day (tenofovir AUC = 5870 ng•h/mL). In conjunction with the nonclinical data with 
TDF and the clinical experience with TDF and TAF, these toxicology studies support studies in 
humans of doses up to 150 mg/day (equivalent to 120 mg free base, the highest anticipated 
human dose) for chronic treatment.
At the time of the rodent toxicity studies, the bioassay could not detect plasma TAF, possibly due 
to instability in the matrix.
Because of the lack of exposure to the prodrug in mice and rats and achievable TFV exposures 
less than previously tested in chronic and carcinogenicity studies with TDF, carcinogenicity 
studies in mice and rats with TAF are currently not required per agreement with FDA and EMA.
Also, TAF does not need to be evaluated in perinatal-postnatal reproductive toxicology studies
per agreement with FDA and EMA. Reproductive tissues were examined in repeat-dose 
toxicology studies in the rat, dog, and monkey. There were no clearly treatment-related 
histologic alterations or changes in organ weights in the rat and the dog following chronic daily 
dosing, or in the monkey. 
The TAF fumarate (GS-7340-03) oral rat fertility study is ongoing (Report No. TX-120-2012;
report in progress). 

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1.2.3.
Clinical Trials of Tenofovir Alafenamide (TAF, GS-7340)
To date, a total of 8 Phase 1 and Phase 1/2, or Phase 2, clinical trials of tenofovir alafenamide 
(TAF) have been conducted or are ongoing in 528 subjects. This includes seven HIV studies 
(total of 477 subjects; 2 completed Phase 1/2 studies [68 subjects], 3 completed Phase 1 studies 
[83 subjects], and 2 ongoing Phase 2 studies [326 subjects]), and 1 Phase 1b HBV study 
(completed enrollment; 51 subjects). TAF is presently in Phase 3 for treatment of HIV-1 
infection in combination with E, C and F, and a Phase 1b study has completed enrollment and 
dosing for treatment of chronic HBV. 
Clinical trials entailing the use of TAF (dose[s] studied) for HIV-1 infection and other Phase 1 
studies include:

GS-120-1101, a Phase 1/2 study of the pharmacokinetics and antiviral activity of TAF 
(GS-7340 [50 mg and 150 mg]) in HIV infected subjects (completed)

GS-US-120-0104, a Phase 1b study of the pharmacokinetics and antiviral activity of 
GS-7340 (8 mg, 25 mg, 40 mg) in HIV infected subjects (completed)

GS-US-120-0107, a Phase 1, partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-7340 (25 mg and 150 mg) on the QT/QTc interval in 
healthy subjects (completed)

GS-US-120-0108, A Phase 1, Open-Label, Parallel-Design Study to Evaluate the 
Pharmacokinetics of GS-7340 (25 mg) in Subjects with Severe Renal Impairment 
(completed)

GS-US-120-0109, A Phase 1 Study to Evaluate the Pharmacokinetics, Metabolism and 
Excretion of GS-7340 (25 mg [completed])
Further details regarding these studies are provided in the table below (Table 1-1). In Phase 1/2 
studies in HIV-infected subjects (Studies 120-1101 and 120-0104), the short-term 
safety/tolerability, PK, and antiviral activity of TAF when given as a stand alone agent (SA) 
were evaluated over a range of doses. In Study 120-0104, at TAF doses of 25 mg or higher, 
near-maximal HIV RNA suppression was observed at Day 10, and importantly, single dose PK 
assessments of TAF (8 mg, 25 mg, or 40 mg) and TDF (300 mg) demonstrated that the 
TAF-generated TFV systemic exposures (AUCinf) were markedly lower (approximately 90% 
lower at TAF 25 mg) than the TFV exposure generated with TDF 300 mg. For HIV Phase 2 
(and Phase 3) studies, however, a 10 mg dose of TAF was selected for inclusion as a component 
of the elvitegravir (E)/ cobicistat (COBI, or “C”)/emtricitabine(F)/TAF single tablet regimen 
(STR) in comparison to the E/C/F/TDF STR control arm. A reduction in dose from 25 mg to
10 mg of TAF in the E/C/F/TAF STR is required based on a drug-drug interaction between TAF 
and COBI resulting in increased exposures of both TAF and TFV which is likely a consequence 
of Pgp-mediated inhibition of TAF and TFV efflux within the gut by COBI. Importantly, the 
resultant TFV exposures when TAF is dosed at 10 mg with COBI in the E/C/F/TAF STR 
formulation are similar to TFV exposures generated with TAF 25 mg given as a SA. Given that 
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10 mg are comparable to those with TAF given alone, safety results in HIV trials using this 
formulation are being assessed at a TAF dose that is considered therapeutically equivalent to 
TAF 25 mg. Thus, HIV studies conducted at TAF exposures similar to those expected in HBV 
provide the basis for supporting safety data for the TAF HBV development program.
Table 1-1.
Summary of TAF Phase 1 and Phase 1/2 Studies for HIV Infection
Study #
Population
Design
Dosing/Duration
Rationale
HIV Studies (Phase 1/2)
120-1101
N = 30
Treatment naïve
Dose escalation
3 treatment cohorts
TAF 50 mg, 150 mg, TDF 
300 mg; multiple dosing 
for 14 days
Short-term proof of 
concept study;
safety, PK, and antiviral 
efficacy
120-0104
N = 38
Treatment naïve
(no ARV within 
90 days of screening)
Randomized 
(2:2:2:1:2) 
partially blinded
TAF 8 mg, 25 mg, 40 mg, 
TDF 300 mg, or placebo 
(PBO) for 10 days; off 
treatment follow up to 
Day 21
Confirmatory study for 
Study 1101 using a TAF 
reformulation; more 
rigorous design, evaluate 
lower TAF doses
Ongoing Supportive Phase 1 Studies
120-0107
N = 48
Males/females, 
age 18-45
Thorough QT 
(TQT)
TAF 25 mg, 125 mg;
each subject dosed 3 times 
for 37 days (with 10 day 
wash-out period)
Regulatory requirement
120-0108
N = 27 
(14 with severe renal 
impairment [CrCL 
15-29 mL/min] and 
13 matched controls 
[CrCL ≥90 mL/min])
PK in Renal 
impairment
TAF 25 mg single dose 
with 14 days of follow up
Characterizing TAF and 
TFV PK in severe renal 
impairment 
(to demonstrate no need 
for TAF dose adjustment)
120-0109
N = 8
healthy volunteer, 
male subjects
Mass Balance
Single radio-labeled TAF 
25 mg dose with 21 days 
of follow up
Regulatory requirement
Clinical trials entailing the use of TAF for the treatment of CHB virus:

GS-US-320-0101 A Phase 1b Randomized, Open Label, Active-Controlled Study to Assess 
the Safety, Viral Kinetics and Anti-HBV Activity of GS-7340 in Treatment-Naïve Adults 
with Chronic Hepatitis B (CHB) Infection (enrollment and dosing completed)
The two proof-of concept studies, GS-120-1101 and GS-US-120-0104, as well as 
GS-US-292-0101, a STR bioequivalence study, were performed using TAF monofumarate
(GS-7340-02). All subsequent studies discussed herein were performed using TAF fumarate 
(GS-7340-03). 
GS-120-1101 was a Phase 1/2 randomized double-blind, active-controlled, dose escalation study 
of the safety, tolerance, pharmacokinetics, and antiviral activity of TAF in antiretroviral-naïve 
subjects who are chronically infected with HIV-1. The subjects were randomized to receive 

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14 days of monotherapy, fasting, with GS-7340-02 50 mg (40 mg GS-7340 [free base]
equivalent) QD, 150 mg (120 mg GS-7340 [free base] equivalent) QD, or tenofovir DF 300 mg 
QD (n = 10 per group). TAF was rapidly absorbed into the systemic circulation, and 
subsequently following attainment of Cmax, was eliminated rapidly with a short plasma half-life 
(20-40 minutes). Compared with TDF, GS-7340-02 50 mg provided a ~16-fold lower TFV Cmax
(207 ng/mL vs 13 ng/mL), about 2-fold longer elimination half-life (26 hours vs 48 hours) and 
lower overall systemic tenofovir exposure (AUCinf: 1814 ng.h/mL vs 383 ng.h/ml). TAF 
monofumarate 150 mg provided lower Cmax (42 ng/mL), but comparable AUCinf: (1740 ng.h/mL) 
as TDF. In PBMCs, TFV was detected earlier, more frequently, and in higher concentrations 
following dosing of TAF monofumarate as compared to TDF. The intracellular delivery of TFV
is approximately 30-fold greater for GS-7340-02 versus TDF. The decrease from Baseline to 
Day 14 in plasma HIV-RNA levels was greater for groups treated with GS-7340-02 50 mg 
(p = 0.02757) or 150 mg (p = 0.0010) than the group that received TDF 300 mg. The median 
changes from baseline in plasma HIV-1 RNA after 14 days of monotherapy were 
−0.96 log10 copies/mL for TDF 300 mg, −1.65 log10 copies/mL for GS-7340-02 50 mg, and 
−1.68 for GS-7340-02 150 mg. 
A second proof-of-concept study, GS-US-120-0104, evaluated monotherapy, fasting, with three 
lower doses of TAF compared with TDF 300 mg, or placebo, administered for 10 days. Potent 
antiviral activity was achieved with TAF in treatment-naïve HIV-1 infected subjects; mean viral 
load declines for both the 25 mg and 40 mg doses were statistically better than the 8 mg dose. 
TAF exposure (AUC) was best associated with antiviral activity despite its short plasma half-life 
(~ 30 min). TFV AUC values were 97%, 87%, and 80% lower at 8 mg, 25 mg, and 40 mg TAF
respectively, compared to TDF administration. When compared to 40 mg and historical 120 mg 
data, 25 mg TAF provides near maximal anti-HIV-1 activity. From this PK-PD analysis, a target 
exposure of a dose of 25 mg TAF monotherapy is expected to provide near maximal antiviral 
activity and ~ 90% reduction in circulating TFV. 
Study GS-US-120-0107 is a Phase 1, partially-blinded, randomized, placebo- and 
positive-controlled study to evaluate the effect of TAF on the QT/QTc interval in healthy 
subjects. This was a negative thorough-QTc study. No effect of TAF was observed on the QTcF 
interval (ie, no QTc interval prolongation > 10 msec at any time point post-dose and assay 
sensitivity was confirmed via the positive control [moxifloxacin]). As such, these findings satisfy 
the guidelines set forth in the International Conference on Harmonization (ICH) E14 guidance 
and support the conclusion that there is no significant effect of TAF on the QT/QTc interval.
Study GS-US-120-0108 is a Phase 1, open-label, parallel-design study to evaluate the PK of TAF 
in subjects with severe renal impairment. TAF was well tolerated in the study. Subjects with 
severe renal impairment had < 2-fold higher TAF and 5-6 fold higher TFV systemic exposures as 
assessed by AUC relative to subjects with normal renal function. TFV exposures in subjects with 
severe renal impairment are comparable to those with normal renal function receiving 300 mg 
TDF QD. Given the extensive safety data available for TDF at a dose of 300 mg, TFV exposures 
in severely renally impaired subjects similar to those associated with TDF 300 mg are deemed 
appropriate for further study of TAF in HIV-infected subjects without TAF dose modification.

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Preliminary results from Study GS-US-120-0109, a Phase 1 PK, metabolism and excretion study 
demonstrated that TAF is eliminated in both feces and urine. TAF and its metabolites are 
eliminated in both feces and urine. The predominant species detected in feces and urine is TFV, 
accounting for 31.4% ± 10.4% and 22.2% ± 4.47% respectively of the total radioactive dose.
These human data are consistent with the established preclinical profile of TAF. Following
administration of TAF, plasma [14C] radioactivity showed a time dependent profile with TAF as 
the most abundant species in the initial few hours and uric acid, a byproduct of TAF metabolism, 
in the remaining period. The whole blood-to-plasma concentration ratio of [14C] radioactivity 
increased from 0.511 at 0.25 hours post dose to 2.32 at 216 hours post dose, suggesting a 
relatively slower clearance of [14C] radioactivity from blood cells relative to the plasma 
[14C] radioactivity time-course. In addition to TFV and uric acid, additional low quantities of 
metabolites were formed, including xanthine, hypoxanthine, and adenine. They are identical to 
the endogenous products of purine metabolism and therefore should not cause any safety risk. 
TAF 25 mg tablets administered together with tracer dose of [14C] radiolabeled TAF as a single 
oral tablet, were well tolerated.
HBV Study – GS-US-320-0101
In HBV subjects, a 28 day Phase 1b study (GS-US-320-0101), was conducted to evaluate 
safety/tolerability, pharmacokinetics, and antiviral activity of TAF at doses of 8 mg, 25 mg, 
40 mg, and 120 mg compared to TDF 300 mg control in 50 subjects (10/cohort). As of 
April 2, 2013, enrollment was completed (n = 51) and all subjects have completed study drug 
dosing through Day 29.
Preliminary data suggest that all treatment groups were generally well matched (Table 1-2) and 
representative of the chronic HBV population. Overall, the majority of subjects were male 
(66.7%), and of Asian descent (56.9%). Of the 51 randomized subjects, 27 (53%) and 24 (47%) 
were HBeAg-negative and HBeAg-positive, respectively. Median age ranged among groups 
from 34 years in the 8 mg and 25 mg TAF groups to 40 and 42 years in the 40 mg and 120 mg 
TAF groups, respectively; median age in the TDF group was 34 years. The most common HBV 
genotype at enrollment was genotype C (16/51; 31%), the proportions of other genotypes were: 
A (7/51; 14%), B (10/51; 20%), D (9/51; 18%), and E (9/51; 18%). The distribution of HBV 
genotypes was similar within groups, with the exception of a higher proportion (5 of 11 [45.5%]) 
of subjects in the 40 mg TAF group having genotype B.

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2 subjects in the TAF 120 mg group (1 subject each with elevated transaminases [both AST and 
ALT occurring during treatment follow-up], and amylase elevation), and in 1 subject in the TDF 
arm (amylase elevation). The subject with Grade 3 glycosuria in the TAF 40 mg group, 
experienced this abnormality at Day 29 which was associated with a corresponding serum 
glucose elevation (212 mg/dL); the subject also had a history of diabetes mellitus.
Table 1-3.
GS-US-320-0101: Treatment-Emergent Adverse Events and 
Laboratory Abnormalities: Overall Summary, Safety Analysis Set
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(n = 11)
TAF 120 mg
(N = 10)
TDF 300 mg
(N = 10)
Subjects Experiencing Any 
Treatment-Emergent Adverse Event
7 (70%)
6 (60%)
6 (55%)
8 (80%)
5 (50%)
Subjects Experiencing Any 
Treatment-Emergent 
Study Drug-Related Adverse Event
2 (20%)
4 (40%)
3 (27%)
4 (40%)
5 (50%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-Emergent 
Adverse Event
1 (10%)
1 (10%)
0
4 (40%)
2 (20%)
Subjects Experiencing Any 
Grade 2, 3 or 4 Treatment-Emergent 
Study Drug-Related Adverse Event
0
0
0
3 (30%)
1 (10%)
Subjects Experiencing Any 
Grade 3 or 4 Treatment-Emergent 
Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Grade 3 or 4 Treatment-Emergent 
Laboratory Abnormality
0
0
3 (27%)
2 (20%)
1 (10%)
Subjects Experiencing Any 
Treatment-Emergent 
Serious Adverse Event
0
0
0
0
0
Subjects Experiencing Any 
Treatment-Emergent Adverse Event 
Leading to Premature Study Drug 
Discontinuation
0
0
0
0
0
Given the significantly smaller declines in creatinine clearance (CLCr) observed at Week 24 with 
TAF relative to TDF in the HIV Phase 2 study (GS-US-209-0102; Section 1.2.4), changes in 
CLCr were also assessed in HBV subjects participating in GS-US-320-0101. After 4 weeks of 
dosing, numerically smaller changes in CLCr at Day 29 were seen in HBV subjects receiving 
TAF compared with TDF (Figure 1-1). At Day 29, median (range) change from baseline in CLCr
was −2.0 (−13.2, 9.6) mL/min for the TAF 25 mg group compared with a change of 
−10.4 (−35.7, 13.0) mL/min in the TDF group. Further, there were no notable differences in CLCr
change among the two lowest dose groups (TAF 8 mg and TAF 25 mg), and the highest dose 

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group (120 mg). An early decline in CLCr, similar to that observed in the TDF group was noted 
in the TAF 40 mg group; however, by Day 29 the change in CLCr was similar to the other TAF 
groups. These results are consistent with findings in HIV subjects receiving the E/C/F/TAF 
10 mg STR and provide additional evidence to support the concept that lower TFV exposures 
with TAF relative to TFV exposures with TDF are associated with notable differences in renal 
function as determined by estimated CLCr.
Figure 1-1.
Median Change (Q1, Q3) from Baseline in Creatinine Clearance 
(Cockcroft-Gault Method) in GS-US-320-0101
Baseline is defined as Day 1.
Over 28 days of study drug treatment, similar median declines in HBV DNA levels were 
observed among treatment groups (Figure 1-2). Overall, viral decay results among subjects who 
received treatment with TAF demonstrated the absence of a dose effect. In addition, the HBV 
DNA declines with TAF (n = 41) over 28 days of dosing were similar to HBV DNA declines 
observed in the TDF 300 mg group (n = 10). A summary of change from baseline in HBV DNA 
results at Day 15 and Day 29 is provided in the table below (Table 1-4) below. Among TAF 
groups, median change from baseline in HBV DNA at Day 29 ranged from −1.98 log10 IU/mL
for the TAF 40 mg group to −2.76 log10 IU/mL for the TAF 8 mg group. For TAF 25 mg, the 
change from baseline in HBV DNA at Day 29 was −2.67 log10 IU/mL. Consistently smaller 
declines in HBV DNA over time, and slightly lower median change from baseline in HBV DNA
were observed in the TAF 40 mg group at Day 29. The reason for this is unclear and possibly 

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related to a lower median HBV DNA value at Baseline (Table 1-4). In this group, 
5/11 (45.5%) subjects had a baseline HBV DNA value below 5.0 log10 IU/mL. In comparison to 
TAF groups, the change from baseline in HBV DNA at Day 29 was −2.60 log10 IU/mL with 
TDF 300 mg. 
Figure 1-2.
GS-US-320-0101: Median Change (Q1, Q3) from Baseline in HBV 
DNA (Log10 IU/mL) by Treatment Group
Baseline is defined as Day 1/pre-dose.

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Figure 1-3.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on 
Day 1: TAF (GS-7340), Linear Scale
TAF plasma pharmacokinetic parameters are summarized in Table 1-5. Day 1 pharmacokinetic 
results in CHB subjects participating in GS-US-320-0101 are consistent with previously reported 
results in the HIV Phase 1/2 study GS-US-120-0104, which evaluated TAF single-dose 
pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 40 mg (n=8), versus TDF 
300 mg (n=6). In GS-US-120-0104, mean (%CV) AUC0-last was 38.4 (80.6) ng∙h/mL, 
139.7 (57.8) ng∙h/mL, and 322.1 (42.0) ng∙h/mL after single doses of TAF 8 mg, 25 mg, and 
40 mg, respectively. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to the results generated in GS-US-120-0104.
Similar findings to the present study were also observed when TAF pharmacokinetic parameters 
were assessed after multiple doses at steady-state in the ongoing Phase 2 study, 
GS-US-292-0102, which compares STRs of E/C/F/TAF 10 mg to E/C/F/TDF 300 mg in HIV-1 
infected, treatment-naive subjects. Mean (%CV) AUClast, and Cmax values for TAF at the 10 mg 
dose in combination with COBI were 230.4 (47.3) ng∙h/mL and 232.8 (64.6) ng/mL, 
respectively. As TAF exposures at the 10 mg dose, when included as a component of the 
E/C/F/TAF STR, have been shown to be comparable to those with TAF 25 mg given as the 
stand-alone agent, these results indicate similar TAF exposures in both subjects infected with 
HIV and those infected with HBV.  

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Table 1-5.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TAF on 
Day 1
TAF PK Parameter
TAF 8 mg
(N = 10)
TAF 25 mg
(N = 10)
TAF 40 mg
(N = 11)
TAF 120 mg
(N = 10)
AUC0-last (ngh/mL)
59.2 (54.1)
153.0 (41.1)
328.1 (58.4)
832.4 (39.1)
AUCinf (ngh/mL)
60.6 (52.8)
154.4 (41.0)
329.8 (58.1)
834.6 (38.9)
Cmax (ng/mL))
83.2 (46.3)
249.5 (45.9)
527.4 (50.6)
1128.7 (33.7)
Tmax (h) median
0.5
0.5
0.5
0.5
T1/2 (h)
0.36 (23.8)
0.51 (32.6)
0.59 (30.7)
0.76 (30.8)
All results expressed as mean (%CV) unless otherwise stated
TFV Pharmacokinetic Results
Mean (SD) plasma concentration versus time profiles for TFV following single dose 
administration of ascending doses of TAF and TDF 300 mg are shown in Figure 1-4. At each 
TAF dose evaluated, plasma TFV concentrations resulting from TAF administration were lower 
than plasma TFV concentrations following TDF administration. The TFV concentrations 
achieved from all TAF dose levels in HBV subjects in GS-US-320-0101 are comparable to TFV 
concentrations achieved after TAF administration in the HIV program.
Figure 1-4.
GS-US-320-0101: Mean (SD) Plasma Concentrations vs. Time on 
Day 1: Tenofovir, Linear Scale

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Tenofovir (TFV) plasma pharmacokinetic parameters are summarized in Table 1-6. As with 
TAF, Day 1 TFV pharmacokinetic results in CHB subjects participating in GS-US-320-0101 are 
consistent with those previously reported in the HIV Phase 1/2 study GS-US-120-0104, which 
evaluated TAF single-dose pharmacokinetics following doses of 8 mg (n=9), 25 mg (n=8), and 
40 mg (n=8), versus TDF 300 mg (n=6). In GS-US-120-0104, mean (%CV) AUCinf for TFV 
were 49.4 (30.3) ng∙h/mL, 195.9 (27.2) ng∙h/mL, and 287.3 (33.7) ng∙h/mL after single doses of 
TAF 8 mg, 25 mg, and 40 mg, respectively. Mean (%CV) AUCinf for TFV following TDF 
300 mg was 1719.2 ng∙h/mL. Other parameters assessed on Day 1 (Cmax, Tmax, and t1/2) in 
GS-US-320-0101 were similar to results seen in HIV subjects in GS-US-120-0104. As stated 
earlier, When TAF is included as a component of the E/C/F/TAF STR, a reduced dose (10 mg) is
required due to a drug-drug interaction (inhibition of P-gp in the gut by cobicistat) that results in
increased exposures of both TAF and TFV (see Section 1.2.4).
Table 1-6.
GS-US-320-0101: Single Dose Pharmacokinetic Results for TFV on 
Day 1
TFV PK Parameter
TAF 8 mg
(n=10)
TAF 25 mg
(n=10)
TAF 40 mg
(n=11)
TAF 120 mg
(n=10)
TDF 300 mg
(n=10)
AUC0-last (ngh/mL)
32.9 (35.0)
90.6 (25.8)
213.4 (40.2)
607.7 (35.4)
1682.1 (28.0)
AUCinf (ngh/mL),
74.0 (41.2)
171.4 (29.9)
444.6 (43.0)
1572.0 (47.2)
2309.8 (27.9)
Reduction in AUCinf, 
TAF/TDF (%)
97
93
81
32
N/A
Cmax (ng/mL),
3.0 (34.5)
8.3 (41.6)
20.3 (43.2)
61.0 (33.5)
306.8 (24.5)
Reduction in Cmax, 
TAF/TDF (%)
99
97
93
80
N/A
Tmax (h) median
1.25
1.0
1.0
1.0
1.0
t1/2 (h)
26.7 (23.4)
20.7 (39.6)
26.3 (33.8)
31.4 (38.6)
10.8 (17.4)
The following Section (1.2.4) provides a summary of experience with TAF in HIV-1 infection, 
including the final Week 24 analysis results for TAF when used as a component of the 
E/C/F/TAF STR in the HIV Phase 2 study GS-US-292-0102. Because TAF exposures in this 
ongoing trial are similar to those expected in the TAF HBV development program, these results 
provide important supporting safety data.

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1.2.4.
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF)
Phase 1 and 2 clinical trials using TAF, coformulated into the E/C/F/TAF STR for the treatment 
of HIV-1 infection include:

GS-US-292-0101, a Phase 1 healthy volunteer study evaluating the relative bioavailability of 
EVG, FTC, TFV, and COBI when administered as E/C/F/TAF STR relative to E/C/F/TDF or 
TAF (completed)

GS-US-292-0103, a Phase 1 healthy volunteer study to evaluate the pharmacokinetics and 
relative bioavailability of the E/C/F/TAF STR relative to the individual components at 
GS-7340 doses of 10 mg (STR) or 25 mg SA (completed)

GS-US-292-0102, a Phase 2 randomized, double-blinded study of the safety and efficacy of 
E/C/F/TAF STR versus E/C/F/TDF STR in HIV-1 infected, antiretroviral treatment-naive 
adults (ongoing)
1.2.4.1.
Summary of Phase 1 Studies (Study GS-US-292-0102, GS-US-292-0103)
Study GS-US-292-0101 is a completed Phase 1 study of 40 subjects evaluating the relative 
bioavailability of two different formulations of E/C/F/TAF STR, each with TAF dose of 25 mg 
or 40 mg, versus E/C/F/TDF STR or TAF 25 mg alone. Exposures of EVG, COBI, and FTC 
were comparable between E/C/F/TAF vs E/C/F/TDF regardless of formulation (monolayer or 
bi-layer). In contrast, TAF exposures were ~2.2-fold higher (and corresponding tenofovir 
exposures ~ 3-fold higher) when administered as E/C/F/TAF (25 mg) vs TAF SA 25 mg for both 
formulations of the E/C/F/TAF. This is likely mediated by inhibition of Pgp-mediated intestinal 
secretion of TAF by COBI and consistent with data from Study GS-US-311-0101 described 
below. 
Study GS-US-292-0103 is a completed Phase 1 healthy volunteer study which evaluated the PK 
and relative bioavailability of the E/C/F/TAF STR relative to the individual components at TAF 
doses of 10 mg (as STR) or 25 mg SA. Results indicate that when dosed as the E/C/F/TAF 
10 mg STR, TAF and TFV exposures were comparable to those observed with TAF 25 mg dosed 
alone. Exposures of EVG, COBI, and FTC were also comparable between the STR and 
individually dosed formulations. 
1.2.4.2.
Week 24 Summary of Phase 2 Study (Study GS-US-292-0102)
GS-US-292-0102 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of E/C/F/TAF STR versus E/C/F/TDF in 
HIV-1 infected, antiretroviral treatment-naive adults with plasma HIV-1 RNA levels 
≥5,000 copies/mL at Screening. 

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Eligible subjects were randomized in a 2:1 ratio to 1 of the following 2 treatment arms and 
randomization was stratified by HIV-1 RNA level (≤ 100,000 copies/mL or > 100,000 copies/mL) 
at Screening:

Treatment Arm 1: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TAF 10 mg 
(E/C/F/TAF) + placebo-to-match STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ 
TDF 300 mg (E/C/F/TDF) once daily (n = 100)

Treatment Arm 2: STR of EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ TDF 300 mg 
(E/C/F/TDF) + placebo-to-match STR EVG 150 mg/ COBI 150 mg/ FTC 200 mg/ 
TAF 10 mg (E/C/F/TAF) once daily (n = 50)
The Independent Data Monitoring Committee (IDMC) reviewed the safety and study conduct at 
Week 12 and determined that no changes were required for study GS-US-292-0102. Interim data 
at Week 24 is presented below.
1.2.4.3.
Week 24 Subject Disposition and Demographics
A total of 170 subjects were randomized and treated in this study: 112 subjects in the E/C/F/TAF 
group and 58 subjects in the E/C/F/TDF group. The full analysis set (FAS) and safety analysis 
set (SAS) each included all randomized and treated subjects from each group. A total of 
24 subjects were included in the pharmacokinetic substudy analysis set. At the time of the 
Week 24 data analysis, 6 subjects (2.4%) had been discontinued from treatment and 4 subjects 
(2.4%) had been discontinued from study. 
Of the 170 subjects in the FAS and SAS, 165 (97.1%) were male; 115 (67.6%) were white and 
50 (29.49%) were black; and the mean age was 36 years (range: 18 to 71 years). Demographic 
and baseline disease characteristics were similar between the 2 treatment groups.
1.2.4.4.
Week 24 Efficacy Results
Proportion of Subjects with Plasma HIV-1 RNA < 50 copies/mL at Week 24
The proportion of subjects who achieved HIV-1 RNA < 50 copies/mL at Week 24 was 86.6% in 
the E/C/F/TAF group and 89.7% in the E/C/F/TDF group, with a stratum-adjusted difference in 
the response rate between the 2 treatment groups of −4.9% (95% CI: −15.7% to 5.9%; p = 0.36).
Results of the secondary efficacy endpoint confirmed those of the primary analysis. The 
proportion of subjects with suppression of plasma HIV-1 RNA < 50 copies/mL at Week 24 
(time-to-loss of virologic-response [TLOVR] analysis) was 88.4% (99/112) in the E/C/F/TAF 
group and 84.5% (49/58) in the E/C/F/TDF group. The stratum-adjusted difference in the 
response rate between the 2 treatment groups was −0.1% (95% CI: −10.4% to 10.2%; p = 0.99).
The mean increase in CD4 cell count from baseline to Week 24 was 163 cells/μL in the 
E/C/F/TAF group and 177 cells/μL in the E/C/F/TDF group (-6 difference in LSM, 95% CI 
−44 to 33).

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1.2.4.5.
Week 24 Pharmacokinetic Results
Results from the intensive pharmacokinetic substudy demonstrated that, consistent with data in 
healthy subjects and HIV-infected subjects treated with TAF monotherapy, E/C/F/TAF (10 mg) 
produced substantially lower tenofovir systemic exposures than E/C/F/TDF (TDF 300 mg). TAF 
exhibited a short median (min-max) plasma half-life of 0.47 (0.37 to 0.87) hours with no 
detectable drug after 8 hours post-administration. Steady-state mean (CV%) AUCtau was 
230 ng•hr/mL (47%). PK results for the other components EVG, COBI and FTC were similar to 
historical data for these agents when administered as E/C/F/TDF (data not shown). In addition, 
TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) in subjects in the 
E/C/F/TAF group showed that TFV-DP was detectable within PBMCs at greater exposures 
(approximately 5-fold) after administration of E/C/F/TAF than with E/C/F/TDF.
1.2.4.6.
Week 24 Safety Results
1.2.4.6.1.
Overall Safety
At the time of the 24-week interim analysis, 112 subjects had been treated with E/C/F/TAF for a 
median duration of 21.1 weeks and 58 subjects had been treated with E/C/F/TDF for a median 
duration of 21.3 weeks. The overall subject incidence of treatment-emergent adverse events 
(AEs) was balanced between treatment groups (81.3% E/C/F/TAF, 81.0% E/C/F/TDF) 
(Table 1-7). The most frequent treatment-emergent AEs (> 10% in either treatment group) were 
(17.9% E/C/F/TAF, 12.1% E/C/F/TDF) nausea, diarrhea (11.6% E/C/F/TAF, 12.1%
E/C/F/TDF), fatigue (11.6% E/C/F/TAF, 8.6% E/C/F/TDF), upper respiratory tract infection 
(7.1% E/C/F/TAF, 12.1% E/C/F/TDF), and headache (9.8% E/C/F/TAF, 10.3% E/C/F/TDF), 
respectively.  
Most treatment-emergent AEs were assessed as Grade 1 or Grade 2 in severity. The incidence of 
Grade 3 or 4 AEs was higher in the E/C/F/TAF group (7.1%) compared to the E/C/F/TDF group 
(3.4%). No Grade 3 or 4 event occurred in > 1 subject; the system organ class (SOC) with the 
highest subject incidence of Grade 3 or 4 events was Nervous System Disorders 
(2.7% E/C/F/TAF, 0% E/C/F/TDF). The only Grade 3 or 4 event that was considered by the 
investigator to be related to investigational product was Grade 3 diarrhea in 1 subject (0.9%) in 
the E/C/F/TAF group; there were no treatment-related Grade 3 or 4 AEs in the E/C/F/TDF 
group. Based on these data, there do not appear to be any signature, higher grade AEs associated 
with the use of E/C/F/TAF through 24 weeks of treatment.
More subjects in the E/C/F/TAF group compared to the E/C/F/TDF group also had 
treatment-emergent serious AEs (SAEs) (5.4% vs 3.4%) or AEs leading to premature treatment 
discontinuation (3.6% vs 0). None of these events occurred in > 1 subject, and none of the SAEs 
were considered by the investigator to be related to treatment with investigational product. The 
system organ class (SOC) with the highest subject incidence of treatment-emergent SAEs was 
Infections and Infestations (4.5% E/C/F/TAF, 0% E/C/F/TDF). No deaths or pregnancies 
occurred.

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Table 1-7.
GS-US-292-0102: Treatment-Emergent Adverse Events: 
Overall Summary, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Subjects Experiencing Any Treatment-Emergent Adverse Event
91 (81.3%)
47 (81.0%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent Adverse Event
42 (37.5%)
17 (29.3%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent Adverse Event
8 (7.1%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-Related Adverse Event
38 (33.9%)
15 (25.9%)
Subjects Experiencing Any Grade 2, 3, or 4 Treatment-Emergent Study-Drug-Related 
Adverse Event
6 (5.4%)
1 (1.7%)
Subjects Experiencing Any Grade 3 or 4 Treatment-Emergent Study-Drug-Related 
Adverse Event
1 (0.9%)
0
Subjects Experiencing Any Treatment-Emergent Serious Adverse Event
6 (5.4%)
2 (3.4%)
Subjects Experiencing Any Treatment-Emergent Study-Drug-Related 
Serious Adverse Event
0
0
Subjects Experiencing Any Treatment-Emergent Adverse Event Leading to 
Premature Study Drug Discontinuation
4 (3.6%)
0
Subjects who had Treatment-Emergent Death
0
0
Treatment-emergent death refers to a death occurring between the first dose date and the last dose date plus 30 days (inclusive).
At least 1 treatment-emergent laboratory abnormality (ie, at least 1 grade level increase in graded 
abnormality) was reported for 103/111 subjects (92.8%) in the E/C/F/TAF group and 
46/58 subjects (79.3%) in the E/C/F/TDF group. The majority of laboratory abnormalities were 
Grade 1 or 2 in severity. Subject incidence of Grade 3 or 4 treatment-emergent laboratory 
abnormalities is summarized in Table 1-8.

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Table 1-8.
GS-US-292-0102: Treatment-Emergent Grade 3 or 4 Laboratory 
Abnormalities, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
Maximum Post-Baseline Toxicity Grade 3 or 4
19 (17.1%)
8 (13.8%)
Neutrophils
5 (4.5%)
1 (1.7%)
WBC
1 (0.9%)
0
Amylase
2 (1.8%)
1 (1.7%)
Creatine Kinase (CK)
6 (5.4%)
2 (3.4%)
Lipase
0
1 (12.5%)
Serum Glucose (Hyperglycemia)
0
1 (1.7%)
Total Cholesterol (Fasting, Hypercholesterolemia)
1 (0.9%)
0
Triglycerides (Fasting)
1 (0.9%)
1 (1.7%)
LDL (Fasting)
7 (6.4%)
2 (3.4%)
Urine Protein (Proteinuria)
1 (0.9%)
0
Urine RBC (Hematuria, Quantitative)
1 (0.9%)
0
Denominator for percentage is the number of subjects in the SAS with at least 1 post-baseline laboratory value (for the test).
Subjects were counted once for the maximum postbaseline severity for each laboratory test.
Lipase test was only performed for subjects with serum amylase > 1.5 × upper limit of normal.
Urine RBC (hematuria, quantitative) was graded based on DAIDS grading scale (with the modification of urine RBC
> 75 cells/HPF as Grade 3).
For Urinalysis (i.e., urine glucose, urine protein, and urine RBC), the highest grade is up to Grade 3.
No clinically significant changes in mean thyroid function tests (TSH, free T3, free T4) or serum 
immunoglobulins (IgG and IgM) were observed.
1.2.4.6.2.
Renal Safety
On multiple objective laboratory tests of renal function, subjects receiving E/C/F/TAF had a 
lower magnitude of change than subjects receiving E/C/F/TDF through 24 weeks.  
The change from baseline in serum creatinine (sCr) was lower in the E/C/F/TAF group compared 
to the E/C/F/TDF group at most assessments through Week 24. At Week 24, median change 
from baseline in serum creatinine was 0.07 mg/dL (range through Week 24: 
0.05 mg/dL to 0.08 mg/dL) for the E/C/F/TAF group and 0.11 mg/dL (range through Week 24: 
0.08 mg/dL to 0.11 mg/dL) for the E/C/F/TDF group (Week 24 p = 0.016).
Accordingly, the decrease from baseline in estimated glomerular filtration rate (GFR) by 
Cockcroft-Gault formula for CLCr was lower in the E/C/F/TAF group compared to the 
E/C/F/TDF group at most assessments through Week 24 (Figure 1-5). At baseline, the mean 
(SD) estimated GFRC-G was similar between groups (120.1 [30.22] (mL/min) for subjects in the 
E/C/F/TAF group and 114.7 [21.68] (mL/min) for subjects in the E/C/F/TDF group. At Week 24, 

Tenofovir Alafenamide (TAF) 
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median change from baseline estimated GFR.c-G was - 6.6 mL/min for the E/C/F/TAF group and 
-10.6 mL/min for the E/C/F/TDF group (p = 0.009). At Week 24, 3 (5.2%) subjects in the 
E/C/F/TDF group would be classified as new Stage 3 CKD (eGFR 30-59 mL/mi.n) vs. 
1 (1.0%) subjects in the E/C/F/TAF group, and 15 (14.4%) subjects in the E/C/F/TAF group 
would be classified as new Stage 2 CKD (eGFR 60-89 mL/min) vs. 20 (34.5%) subjects in the 
EICIFITDF group. 
Figure 1-5. 
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Bl 
112 
109 
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54 
4 
109 
58 
8 
110 
58 
12 
107 
58 
16 
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58 
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At Week 24, a trend towards reduced proteinuria was observed in the E/C/F/TAF group. By 
urine dipstick, the frequency of maximmn post -baseline proteinuria (any grade) was 13.5% in 
E/C/F/TAF vs. 20.7% in E/C/F/TDF. The median change from baseline in urine albumin to 
creatinine ratio (UACR) was - 0.84 mg/g in E/C/F/TAF vs - 0.07 in E/C/F/TDF. The median 
change fi·om baseline in urine protein to creatinine ratio (UPCR) was - 5.6 mg/ g and 1.6 mg/g in 
the E/C/F IT AF and E/C/F /TDF groups, respectively. Explorat01y biomarkers of tubular 
proteinuria were also assessed, and demonstrated a statistically significant reduction in tubular 
proteinuria in the E/C/F/TAF group. At Week 24, median change fi·om baseline 
beta-2-microglobulin to creatinine ratio was - 35.9 f.!g/g for E/C/F/TAF vs - 1.1 f.!g/g for 
E/C/F/TDF (p = 0.004), and median change fi·om baseline in retinol binding protein to creatinine 
ratio was - 0.7 ~tg/g for E/C/F/TAF vs 11.9 ~tg/g for E/C/F/TDF (p = 0.006). 
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A treatment difference for other laboratory markers of kidney function were not observed, 
including median change from baseline for serum phosphate and fractional excretion of 
phosphate (fractional excretion of phosphate [FEPO4] using adjusted sCr).
1.2.4.6.3.
Bone Safety
DXA scans of the spine and hip were performed at the Baseline and Week 24 visits (and at the 
early study drug discontinuation visit, if applicable) to measure changes from baseline in BMD. 
The percent changes from baseline in BMD values in the lumbar spine and hip are summarized 
in Table 1-9. The median percentage decrease from baseline was significantly less for subjects in 
the E/C/F/TAF group compared with that for subjects in the E/C/F/TDF group for both spine 
(p = 0.002) and hip (p < 0.001) BMD. 
The categorical distribution of subjects in each treatment group with percentage changes in BMD 
from baseline within specified ranges at Week 24 is summarized for spine and hip in Table 1-10. 
At Week 24, a significantly higher proportion of subjects in the E/C/F/TAF group than in the 
E/C/F/TDF group had no decreases in BMD at the hip (40.6% vs 22.8%; p < 0.001) and spine 
(37.5% vs 12.1%; p = 0.003). Substantially fewer subjects in the E/C/F/TAF group had decreases 
in BMD of >3% at the hip than in the E/C/F/TDF group (3.0% vs 31.6%) at Week 24.
Table 1-9.
GS-US-292-0102: Percent Change from Baseline in Lumbar Spine 
and Hip Bone Mineral Density at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Change at Week 24
Spine
N
104
58
0.002
Mean (SD)
-0.84 (3.411)
-2.48 (2.519)
Median (Q1, Q3)
-0.92 (-3.00, 0.99)
-2.34 (-3.65, -0.33)
Min, Max
-8.49, 17.12
-10.37, 2.43
Hip
N
101
57
< 0.001
Mean (SD)
-0.30 (1.774)
-2.103 (2.677)
Median (Q1, Q3)
-0.42 (-1.44, 0.71)
-2.08 (-3.60, -0.48)
Min, Max
-4.68, 7.84
-8.55, 4.86
P-values were from the Wilcoxon rank sum test.
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 E/C/F/TDF post baseline visit were 
included in the DXA substudy analysis set.

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Table 1-10.
GS-US-292-0102: Percent Change in Bone Mineral Density by 
Gradation at Week 24, DXA Analysis Set
E/C/F/TAFa
(N = 101-104)
E/C/F/TDFa
(N = 57-58)
E/C/F/TAF vs E/C/F/TDF
p-value
Percentage Change at Week 24
Spine
No Decrease
39/104 (37.5%)
7/58 (12.1%)
0.003
> 0 to < = 1% Decrease
14/104 (13.5%)
11/58 (19.0%)
> 1 to < = 3% Decrease
25/104 (24.0%)
17/58 (29.3%)
> 3 to < = 5% Decrease
18/104 (17.3%)
15/58 (25.9%)
> 5% Decrease
8/104 (7.7%)
8/58 (13.8%)
Hip
No Decrease
41/101 (40.6%)
13/57 (22.8%)
< 0.001
> 0 to < = 1% Decrease
23/101 (22.8%)
7/57 (12.3%)
> 1 to < = 3% Decrease
34/101 (33.7%)
19/57 (33.3%)
> 3 to < = 5% Decrease
3/101 (3.0%)
12/57 (21.1%)
> 5% Decrease
0/101
6/57 (10.5%)
P-value was from the CMH test for ordinal data (row mean scores differ statistic was used).
a
Only subjects with nonmissing spine or hip BMD for the baseline visit and at least 1 postbaseline visit were included in 
DXA substudy analysis set.
Clinical BMD status was assessed using BMD T-scores. Changes from baseline in BMD status 
at Week 24 were determined using T-scores. At Week 24, 6 of 99 subjects (6.1%) in the 
E/C/F/TAF group and 2 of 58 subjects (3.4%) in the E/C/F/TDF group showed a deterioration 
from baseline in spine BMD T-score category, and 1 of 99 subjects (1.1%) in the E/C/F/TAF 
group and 5 of 54 subjects (9.3%) in the E/C/F/TDF group showed a deterioration from baseline 
in hip BMD T-score category. In the E/C/F/TAF group at Week 24, 5 subjects had improvement 
in spine BMD T-score category and 1 subject had improvement in hip BMD T-score category. 
One subject in the E/C/F/TDF group showed improvement in the hip BMD T-score category. As 
a continuous variable, median decrease from baseline BMD T-score was significantly less for 
E/C/F/TAF vs E/C/F/TDF at both spine (-0.08 vs. −0.22, p = 0.005) and hip (−0.03 vs −0.14, 
p < 0.001).
Bone turnover markers, including one for bone resorption (C-type collagen sequence [CTX]) and 
three for formation (bone specific alkaline phosphatase [bsAP], osteocalcin [OC], and 
procollagen type 1 N-terminal propeptide [P1NP]), were assessed to support the BMD data. 
Comparisons of percent change from baseline for each bone turnover marker at Weeks 12 and 24 
demonstrated statistically significantly less change in the E/C/F/TAF arm, and provide evidence 
of less bone turnover at both timepoints in the E/C/F/TAF arm vs the E/C/F/TDF arm 
(Table 1-11). These results are consistent with the observations made in the BMD analyses.

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Table 1-11.
GS-US-292-0102: Percentage Change from Baseline in Bone Turnover 
Markers, Safety Analysis Set
E/C/F/TAF
(N = 112)
E/C/F/TDF
(N = 58)
E/C/F/TAF vs E/C/F/TDF
p-value
Week 12
CTx, % change in mean (SD)
37.9 (62.0)
103.7 (109.1)
<0.001
bsAP, % change in mean (SD)
-13.4 (16.0)
2.0 (16.3)
<0.001
OC, % change in mean (SD)
22.0 (32.5)
46.9 (49.1)
<0.001
P1NP, % change in mean (SD)
2.6 (32.2)
30.1 (36.1)
<0.001
Week 24
CTx, % change in mean (SD)
39.2 (79.2)
94.8 (107.9)
<0.001
bsAP, % change in mean (SD)
4.1 (17.2)
25.3 (24.9)
<0.001
OC, % change in mean (SD)
30.3 (43.5)
71.0 (74.3)
<0.001
P1NP, % change in mean (SD)
10.6 (38.7)
58.8 (61.4)
<0.001
P-values were from the Wilcoxon rank sum test; CTx = Type 1 collagen crosslinked C-telopeptide; 
bsAP = serum bone specific alkaline phosphatase; OC = osteocalcin; P1NP = procollagen Type 1 N-terminal propeptide.
1.2.4.6.4.
Week 24 Conclusions
Key conclusions from the Week 24 analysis of Study GS-US-292-0102 included the following:

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL at Week 24 was similar 
between treatment groups

Treatment was generally well tolerated as most AEs were mild and not associated with 
treatment discontinuation. No new or unexpected adverse events occurred.

The data shows that subjects taking E/C/F/TAF had more modest changes in creatinine and 
in bone mineral density than subjects taking E/C/F/TDF. The differences were statistically 
significant and may have important clinical relevance for individual subjects.
Other than renal lab abnormalities and biomarkers and bone biomarkers, the frequency and type 
of laboratory abnormalities was comparable between the two treatment arms.
1.3.
Rationale for This Study
1.3.1.
Tenofovir Alafenamide (TAF) for Treatment of Chronic Hepatitis B
Approximately one-third of the world’s population has serological evidence of past or present 
HBV infection with over 350 million people globally who are chronic HBV surface antigen 
(HBsAg) carriers. The disease burden for HBV varies regionally, with greater than 50% of all 
subjects residing in Asian countries with the highest prevalence (e.g. China, India, Vietnam, 
Indonesia, South Korea, Taiwan, the Philippines, and Pakistan). The primary goal of treatment is 
to achieve and maintain virologic suppression, without resistance, which has been shown to 

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translate to improvement in liver disease outcomes. Current guidelines recommend treatment for 
subjects with evidence of ongoing viral replication along with liver injury based on elevated 
levels of serum ALT. 
TDF and ETV are highly potent first line therapies for CHB; however, each has specific 
limitations. TDF has a potential to cause renal- and bone-related toxicities in a subset of subjects. 
ETV has reduced activity in drug-treated populations, specifically 
lamivudine-experienced/resistant subjects {Baldick et al 2008, Tenney et al 2009}. The latter is a 
key limitation for ETV use as LAM remains one of the most commonly prescribed HBV 
treatments in most regions of the world. Thus, despite the availability of effective treatments 
there remains a clear need for newer oral HBV agents that are safe and well tolerated for long 
term use, and capable of achieving high rates of viral suppression with little or no potential for 
resistance development. 
Tenofovir alafenamide (TAF), a novel prodrug of TFV, has the potential to further advance the 
treatment of chronic HBV infection. In contrast to TDF, an agent that is rapidly and completely 
cleaved by intestinal and plasma esterases to TFV, TAF is a more stable prodrug that efficiently 
resists early enzymatic cleavage following oral administration and remains more fully intact until 
it is taken up by target cells. As a consequence, TAF, when given at a lower dose than TDF, is 
capable of efficiently delivering active drug (e.g. TFV-DP) to the virally-infected cells 
(e.g. HBV-infected hepatocytes and HIV-infected lymphoid cells) while systemic exposures of 
TFV are reduced compared with oral administration of TDF 300 mg. These features are 
hypothesized to translate into the potential for effective suppression of viral replication, and an 
improved tolerability and safety profile.
Results from GS-US-320-0101, a Phase 1b study evaluating the short-term (28 day) safety, 
efficacy (HBV DNA suppression), and PK of TAF at 4 dose levels (8 mg, 25 mg, 40 mg, 
and 120 mg) compared to TDF 300 mg, has shown no dose effect in regard to viral suppression, 
and similar short-term safety and tolerability compared with TDF. Intensive PK results show 
93% or greater reductions in TFV exposures with doses of TAF 25 mg or lower compared to the 
TFV exposures generated with TDF 300 mg. These results, taken together with 24 weeks safety 
results from the HIV Phase 2 study GS-US-292-0102, which directly compares TAF to TDF 
(each included as a component of an STR), suggest that TAF is safe and well tolerated and may 
have a lower potential for renal- and bone-related AEs compared to TDF. Importantly, TFV 
exposures for E/C/F/TAF 10 mg are comparable to TFV exposures generated with TAF 25 mg 
given as a stand alone agent.
1.3.2.
Rationale for the Current Study
TDF and ETV are highly potent first line therapies for chronic HBV; however, each has specific 
limitations. TDF has a potential to cause renal- and bone-related toxicities in a subset of subjects. 
ETV has reduced activity in drug-treated populations, specifically lamivudine 
(LAM)-experienced/resistant subjects. Thus, despite the availability of effective treatments there 
remains a clear need for newer oral HBV agents that are safe and well tolerated for long term 
use, and capable of achieving high rates of viral suppression with little or no potential for 
resistance development. TAF has the potential to address each of these requirements. 

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The current study is designed to evaluate non-inferiority of TAF compared to TDF in regard to 
the proportion of subjects with HBV DNA levels below 29 IU/mL at Week 48. The durability of 
TAF compared to TDF in regard to the proportion of subjects with HBV DNA < 29 IU/mL at 
Weeks 96 and 144 will also be assessed in a double blind fashion. In addition to treatment naïve 
subjects, treatment experienced CHB subjects who are viremic and with elevated ALT levels at 
screening are included. This is based on given results from GS-US-174-0106 (ADV suboptimal 
responders) and GS-US-174-0121 (LAM-resistant subjects) which demonstrated in viremic 
patients comparable rates of HBV DNA suppression, as described below, in comparison to 
results in mostly treatment naïve subjects participating in pivotal studies GS-US-174-0102 
(HBeAg-negative subjects) and GS-US-174-0103 (HBeAg-positive subjects). Given the unique 
properties of TAF (efficient delivery of the active moiety, TFV-DP, to HBV-infected 
hepatocytes with reduced systemic TFV exposures), this study will also evaluate the potential 
safety differences (e.g. renal- and bone-related complications) of TAF relative to TDF at
Week 48 and long term comparative safety at Week 96 and 144, after which subjects will be 
further evaluated for longer-term safety and efficacy of TAF in an open-label TAF 25 mg QD 
extension phase through Week 384. The extension phase is important as it will enable the 
evaluation of subjects treated for the entire 384 week period with TAF as well as those who 
received 144 weeks of TDF initially in a double-blinded fashion followed by an additional 
240 weeks of open-label TAF. The latter group will allow an ongoing assessment, including 
possible resolution, of any potential bone- and/or renal-related (or other) complications during 
TAF treatment that might have arisen under initial treatment with TDF.
The primary endpoint of this study is the proportion of subjects with HBV DNA < 29 IU/mL at 
Week 48; the lowest limit of susceptibility of the polymerase chain reaction (PCR) assay to be 
employed (Roche COBAS® Taqman® HBV test for use with the High Pure System). A
histological component of treatment response is not included. Alternatively, non-invasive means 
(i.e. Fibrotest®) will be used to assess the degree of fibrosis at baseline and the change in fibrosis 
on an annual basis for all subjects participating in the trial. In support of this, 48 week results 
from studies, GS-US-174-0102 and GS-US-174-0103, which formed the basis for TDF approval 
for CHB, showed TDF to be superior to ADV based on a “complete response” to treatment 
(a composite endpoint of HBV DNA suppression and histologic improvement based on repeat 
liver biopsy). In GS-US-174-0102, conducted in HBeAg-negative (presumed pre-core mutant) 
subjects, 70.8% and 48.8% of subjects randomized to TDF and ADV, respectively, achieved a 
complete response at Week 48 (treatment difference: 23.5%; p < 0.001). Of the components, 
HBV DNA suppression (< 69 IU/mL) was achieved in 94.4% and 64.0% (treatment difference: 
30.3%; p < 0.001), while histologic improvement was achieved in 74.2% and 68.8% 
(treatment difference: 5.2%; p = 0.292) of TDF- and ADV-treated subjects, respectively. Thus, 
the greater potency of TDF relative to ADV resulting in a significantly higher rate of viral 
suppression was the primary element associated with the superior treatment response at 48 weeks
{Marcellin et al 2007, Marcellin et al 2008}. Similar findings were observed in HBeAg-positive 
subjects in GS-US-174-0103.
After 48 weeks, subjects in GS-US-174-0102 and GS-US-174-0103 were eligible to continue 
open-label treatment with TDF. At Year 5 (Week 240), 331/641 (52%) of subjects on TDF 
(without addition of FTC) underwent a repeat liver biopsy, and regression of fibrosis 

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(improvement in Ishak fibrosis score of ≥1 point) was seen in 52% (172/331) of subjects. 
Furthermore, in 94/331 (28%) subjects with cirrhosis (Ishak score ≥5) at baseline, 73% (69/94) 
were no longer cirrhotic at year 5 (≥1 unit decrease in Ishak score). These results confirm the 
benefits of long term viral suppression with TDF in terms of regression of fibrosis and reversal 
of cirrhosis in the majority of TDF-treated subjects {Marcellin et al 2013}.
The efficacy of TDF in viremic treatment experienced CHB populations has been shown to be 
similar to treatment naïve subjects. In a prospective, randomized (1:1), double-blind, Phase 3b 
study (GS-US-174-0121) which compared TDF alone to the combination of FTC/TDF in 
280 HBeAg-positive and HBeAg-negative subjects receiving treatment with LAM and having 
HBV DNA > 3 log10 IU/mL with documented LAM-resistance (rtM204I/V ± rtL180M 
mutation[s]), 89.4% of TDF-treated subjects vs. 86.3% treated with FTC/TDF had HBV DNA 
< 69 IU/mL at Week 96 (primary endpoint, missing equals failure analysis; p = 0.43). BMD was 
also assessed in GS-US-174-0121, and small declines in BMD (< 2%) of both hip and spine were 
seen with equal frequency in both groups which occurred by Week 24 (spine) and Week 72 
(hip). In another prospective, randomized, double-blind study of TDF vs. FTC/TDF in 
105 HBeAg-positive and HBeAg-negative subjects with a prior suboptimal response to ADV 
(GS-US-174-0106), no differences in HBV DNA suppression (proportion less than 69 IU/mL) 
were seen between treatment groups (82.4% TDF vs. 84.0% FTC/TDF; ITT, non-completer 
equals failure; p = 0.78). Taken together, these studies support the efficacy of TDF in treatment 
experienced subjects as being similar to results seen in treatment naïve subjects.
1.3.3.
Rationale for Dose Selection
In the Phase 1b study, GS-US-320-0101, which has completed enrollment, 4 doses 
(8, 25, 40, and 120 mg) of TAF monotherapy, and TDF 300 mg were evaluated in 
51 treatment naïve CHB subjects. To date, all subjects have completed the 28 day dosing period. 
Results demonstrate that TAF when given in doses over a range of 8 to 120 mg results in similar 
HBV DNA declines over 28 days. Furthermore, HBV DNA suppression with TAF is comparable 
to that of TDF 300 mg. In GS-US-320-0101, increased rates of viral suppression were not 
observed with higher TAF doses (40 mg, 120 mg) relative to lower TAF doses 
(8 mg and 25 mg), and similar safety profiles were observed among TAF treatment groups. PK 
results demonstrate a 93% reduction in TFV exposures relative to TDF 300 mg when TAF is 
dosed at 25 mg. These results in CHB subjects are consistent with data in healthy volunteers and 
HIV-infected subjects given TAF 25 mg as a stand alone agent. Importantly, as previously 
stated, the TFV exposures seen with TAF 25 mg in CHB subjects are therapeutically comparable 
to those in HIV patients receiving E/C/F/TAF 10 mg (due to an inhibitory drug-drug interaction 
between TAF and COBI when these agents are included in the E/C/F/TAF STR) which provide 
safety data (from Phase 2 study GS-US-292-0102) supporting the development of TAF for 
hepatitis B at the 25 mg dose level. Further, in CHB subjects participating in the Phase 1b study 
who were dosed at the lowest TAF dose (8 mg), a 97% reduction in TFV exposures relative to 
TDF 300 mg was observed, representing an incremental reduction in TFV exposure of only 
5% at this dose level relative to TAF 25 mg.

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Importantly, the TFV exposures at a 25 mg dose when given alone are consistent with TAF 
exposures generated with the E/C/F/TAF 10 mg STR currently in Phase 3 development for 
treatment of HIV infection. Thus, the efficacy and safety of TAF in HIV is also being evaluated 
at a dose level that is therapeutically equivalent to the dose selected for study GS-US-320-0108.
Final Week 24 results from GS-US-292-0102, a phase 2 study being conducted in HIV-1 
treatment naïve subjects, demonstrated similar safety and tolerability of TAF vs. TDF when each 
is included as a component of STRs containing elvitegravir, cobicistat, and emtricitabine. At 
Week 24, significant differences were noted between arms in regard to smaller declines in hip 
BMD, estimated CLCr (Cockcroft-Gault), and changes in various biomarkers of bone and renal 
function which are suggestive of differences in bone and renal tolerability of TAF vs. TDF. 
Similar assessments are included in the present trial in HBeAg-negative, chronic HBV subjects, 
and the study is sufficiently powered to demonstrate a potentially superior safety profile for TAF 
relative to TDF in regard to these bone and renal parameters.
In summary, a 25 mg dose was selected for TAF for use in this non-inferiority trial based upon 
the safety profile for TAF in treatment naïve HIV-1-infected subjects from GS-US-292-0102, 
which utilizes a therapeutically equivalent TAF dose (10 mg as a component of the E/C/F/TAF 
STR), the viral suppression results in chronic HBV subjects in GS-US-320-0101 showing 
comparable rates of HBV DNA decline for a TAF 25 mg dose compared to TDF 300 mg 
(the approved dose for treatment of HBV), and the reduced systemic TFV exposures (~93%) 
seen with TAF relative to TDF 300 mg, when dosed at this level.
1.4.
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 compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus 
tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative,
chronic hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL 

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment naïve and 
treatment experienced subjects
The key secondary safety objectives of the study are:

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96 and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144

To compare the biochemical (ALT normalization by central laboratory and AASLD criteria) 
response of TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144

To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

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
To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72 , 96, and 144 
(or ED visit if prior to Week 144 and more than 24 weeks since prior exam) in a subset of 
subjects

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, safety, and the incidence of drug resistance 
mutations of TAF 25 mg QD in subjects initially randomized to TAF 25 mg QD and in 
subjects sequentially treated with TDF 300 mg QD and then switched to open-label 
TAF 25 mg QD

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3.
STUDY DESIGN
3.1.
Treatment Plan and Regimen
This is a randomized, double-blind, non-inferiority study to compare the antiviral activity of 
TAF 25 mg QD versus TDF 300 mg QD. Approximately three hundred ninety (390) subjects 
will be randomized in a 2:1 ratio (A:B) to the treatment arms for 144 weeks (96 weeks under 
Amendment 2.1), and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced).
For China, approximately 150 additional subjects will be randomized in a 2:1 ratio (A: B) to the 
treatment arms for 96 weeks, and will be stratified by plasma HBV DNA level (< 7 log10 IU/mL, 
≥ 7 log10 IU/mL - < 8 log10 IU/mL, ≥8 log10 IU/mL) and oral antiviral treatment status 
(treatment-naïve vs. treatment-experienced). 
If the subject is deemed ineligible for this study by HBV serology (i.e. HBeAg positive CHB), 
this information may be used to determine eligibility for GS-US-320-0110 
(another Gilead Sciences Phase 3 study in HBeAg positive, CHB subjects; this study must also 
be IRB/EC approved at the participating center). 
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD
For China, approximately 150 additional subjects (100 in Treatment Arm A and 50 in 
Treatment Arm B) will be enrolled for local registration purposes.
Subjects with a history of or current diagnosis of compensated cirrhosis are eligible for 
enrollment. Acceptable diagnostic criteria for cirrhosis include a Metavir or Knodell fibrosis 
score ≥4 or Ishak fibrosis score ≥ 5 by liver biopsy, or previous Fibroscan result > 12kPa 
(in countries where locally approved). Available information regarding the presence or absence 
of cirrhosis by these criteria will be captured in the electronic case report forms at Baseline, and 
any other time during the trial should an investigator opt to undertake additional studies. 
Importantly, the change in fibrosis as assessed by Fibrotest® will be performed in all subjects 
participating in the trial at Baseline, and annually thereafter through Week 384/ED.
The duration of double-blind treatment is 144 weeks (96 weeks under Amendments 2.1). At 
Week 144, all subjects remaining on blinded treatment will be switched to the open-label TAF 
25 mg QD extension period for up to an additional 240 weeks (Week 144 through 
Week 384/ED). Subjects already assigned to open-label TAF 25 mg QD at Week 96 per 
Amendment 2.1 will continue on open-label TAF 25 mg QD through Week 384/ED. All subjects 
who complete the double-blind period of treatment are eligible for participation in the open label 
TAF 25 mg QD extension period. Subjects who permanently discontinue study drug 
(either prematurely [ED] or at the end of study [Week 384]) for reasons other than HBsAg loss 
with confirmed seroconversion to anti-HBs, will be followed every 4 weeks for 24 weeks off 
treatment or until initiation of alternative, commercially available HBV therapy, whichever 
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Subjects with HBsAg loss with confirmed seroconversion to anti-HBs should discontinue study 
drug within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion to anti-HBs prior to Week 48 are not permitted to 
discontinue study drug prior to the Week 48 visit. After Week 48, these subjects who discontinue 
study drug will be followed off treatment every 4 weeks for 12 weeks and then per the study visit 
schedule (Appendix 2) through Week 384/ED. 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.
Figure 3-1.
Study Schema
3.2.
Biomarker Testing
3.2.1.
Biomarker Samples to Address the Study Objectives:
The following biological specimens will be collected in this study and will be used to evaluate 
the association of 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 biomarkers and assays listed below. Because biomarker science is a rapidly evolving area 

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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. 

Blood sample for bone biomarkers – including, but not limited to, C-type collagen sequence 
(CTX) and procollagen type 1 N-terminal propeptide (P1NP)

Urine sample for renal biomarkers −including, but not limited to, retinol binding protein and
beta-2-microglobulin
These specimens will be collected from all subjects in a fasted state.
3.2.2.
Biomarker Samples for Optional Pharmacogenomic Research
A separate, specific consent form will be required to document a subject’s agreement to provide 
additional samples for optional pharmacogenomic research. From subjects who agree to 
participate and provide their additional specific consent, a blood sample will be obtained. This
sample should be collected at the Baseline visit, prior to the first dose of study drug, but may be 
collected at any time during the study or at a separate unscheduled study visit, if necessary. The 
specimens collected for optional pharmacogenomic research will be used to identify or validate 
genetic markers that may increase our knowledge and understanding of the biology of the study 
disease and related diseases and to study the association of genetic markers with disease 
pathogenesis, progression and/or treatment outcomes, including efficacy, adverse events, and the 
processes of drug absorption and disposition. These specimens may be used also to develop 
biomarker or diagnostic assays and establish the performance characteristics of these assays. The 
collection and analysis of optional future research specimens will facilitate the rational design of 
new pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for subjects in the future.
3.3.
Intensive PK Substudy (Optional)
For subjects who provide a separate informed consent (n=16 and up to n=32), an intensive 
pharmacokinetic substudy will be performed once at either of the Week 4, 8 or 12 visits, at select 
sites to assess intensive PK profiling in plasma. 
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the intensive PK substudy visit. This will be used to 
evaluate PBMC concentrations of tenofovir diphosphate (TFV-DP), the active form of tenofovir 
(TFV).

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3.4.
Ophthalmologic Substudy (Optional)
For subjects who provide a separate informed consent (n = 30), a substudy will be conducted to 
assess ophthalmologic findings, including fundoscopic examination with retinal photographs 
(both eyes), anytime during the screening period, and must be completed prior to the first dose of 
study drug, and at Weeks 24, 48, 72, 96 and 144/ visits at select sites. An exam should be 
performed at the ED visit if prior to Week 144 and not done within the past 24 weeks.
An examination of the full retinal field should be conducted noting changes or abnormalities. 
Photographs of the retina must be taken at each exam and filed in the subject’s source medical 
records. A central vendor will be used to assess the retinal photographs.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 390 subjects, who are 18 years of age and older, with HBeAg-negative chronic 
hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 300 mg 
matched placebo (n = 260) or TDF 300 mg and TAF 25 mg matched placebo (n = 130) for 
144 weeks (96 weeks under Amendment 2.1).
For China, approximately 150 subjects, who are 18 years of age and older, with HBeAg-negative 
chronic hepatitis B will be randomized 2:1 to receive either blinded TAF 25 mg and TDF 
300 mg matched placebo (n = 100) or TDF 300 mg and TAF 25 mg matched placebo (n = 50) 
for 96 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, which must be 
obtained prior to initiation of study procedures.
2. Male and non-pregnant, non-lactating female subjects, 18 years of age and older, based on 
the date of the screening visit. A negative serum pregnancy test at Screening is required for 
female subjects of childbearing potential (as defined in Appendix 6).
3. Documented evidence of chronic HBV infection (e.g. HBsAg positive for more than 
6 months).
4. HBeAg-negative, chronic hepatitis B with all of the following:

HBeAg-negative and HBeAb-positive at Screening (if the subject is deemed ineligible for 
this study by HBV serology [i.e. HBeAg-positive CHB], this information may be used to 
determine eligibility for GS-US-320-0110 [another Gilead Sciences Phase 3 study in 
HBeAg-positive, CHB subjects; this study must also be IRB/EC approved at the 
participating center])

Screening HBV DNA ≥ 2 × 104 IU/mL

Screening serum ALT level 60 U/L (males) or > 38 U/L (females) and ≤10 × ULN 
(by central laboratory range)

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5. Treatment-naïve subjects (defined as < 12 weeks of oral antiviral treatment with any 
nucleoside or nucleotide analogue), OR 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) will be 
eligible for enrollment. Treatment-experienced subjects receiving oral antiviral treatment at 
Screening must continue their treatment regimen until the time of randomization, when it will 
be discontinued.
6. Any previous treatment with interferon (pegylated or non-pegylated) must have ended at 
least 6 months prior to the baseline visit. 
7. Estimated creatinine clearance (CLCr) ≥ 50 mL/min (using the Cockcroft-Gault method) 
based on serum creatinine and actual body weight as measured at the Screening evaluation, 
as follows:
(140 – age in years) (body weight [kg])
(72) (serum creatinine [mg/dL])
[Note: multiply estimated rate by 0.85 for women]
8. Normal ECG (or if abnormal, determined by the investigator not to be clinically significant)
9. Must be willing and able to comply with all study requirements.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Pregnant women, women who are breastfeeding or who believe they may wish to become 
pregnant during the course of the study.
2. Males and females of reproductive potential who are unwilling to use an “effective”, 
protocol-specified method(s) of contraception during the study. For a list of 
protocol-specified contraceptive methods, refer to Appendix 6. 
3. Co-infection with HCV, HIV, or HDV.
4. Evidence of hepatocellular carcinoma (e.g. as evidenced by recent imaging)
5. Any history of, or current evidence of, clinical hepatic decompensation 
(e.g., ascites, encephalopathy or variceal hemorrhage).  
6. Abnormal hematological and biochemical parameters, including:

Hemoglobin < 10 g/dL

Absolute neutrophil count < 750/mm3

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
Platelets ≤50,000/mm3

AST or ALT > 10 × ULN

Total Bilirubin > 2.5 × ULN

Albumin < 3.0 g/dL

INR > 1.5 × ULN (unless stable on anticoagulant regimen)
7. Received solid organ or bone marrow transplant.
8. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the 
investigator.
9. Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, 
osteochrondroses), or multiple bone fractures.
10. Malignancy within the 5 years prior to screening, with the exception of specific cancers that 
are cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for 
possible malignancy are not eligible.
11. Currently receiving therapy with immunomodulators (e.g. corticosteroids), investigational 
agents, nephrotoxic agents, or agents capable of modifying renal excretion.
12. Known hypersensitivity to study drugs, metabolites, or formulation excipients.
13. Current alcohol or substance abuse judged by the investigator to potentially interfere with 
subject compliance.
14. Any other clinical condition or prior therapy that, in the opinion of the investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements.
15. Subjects on prohibited concomitant medications (See Table 5-1). Subjects on prohibited 
medications, otherwise eligible, will need a wash out period of at least 30 days.

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization and Blinding
A centralized randomization procedure via an Interactive Voice/Web Response System 
(IVRS/IWRS) will be used for this study, whereby study treatment will be assigned to subjects 
according to the randomization schedule. A unique subject number will be provided during 
randomization. If the subject is deemed ineligible for this study by HBV serology 
(i.e. HBeAg-positive CHB), this information may be used to determine eligibility for 
GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg-positive, CHB subjects; this 
study must also be IRB/EC approved at the participating center). Eligible subjects will be 
randomized 2:1 to receive either blinded TAF 25 mg and TDF matched placebo or TDF 300 mg 
and TAF matched placebo for 144 weeks (96 weeks under Amendment 2.1). Subjects will be 
stratified by plasma HBV DNA level (< 7 log10 IU/mL, ≥7 log10 IU/mL - < 8 log10 IU/mL, 
≥8 log10 IU/mL) and oral antiviral treatment status (treatment-naïve vs. treatment-experienced). 
At Week 144, all subjects will be switched to open label TAF 25 mg QD up to an additional
240 weeks (Week 144 through Week 384/ED). Subjects already assigned to open-label 
TAF 25 mg QD at Week 96 per Amendment 2.1 will continue on TAF through Week 384/ED.
For the entire duration of the study, subjects and investigator will remain blinded to the initial 
treatment regimen to which the subjects were randomized.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IVRS/IWRS
for that subject. Gilead recommends, but does not require that the investigator contact the 
Gilead Medical Monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report form/ 
electronic case report form (CRF/eCRF), along with the date on which the treatment assignment 
was obtained. The investigator is requested to contact the Gilead Medical Monitor promptly in 
case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).

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5.2.
Description and Handling of Tenofovir Alafenamide (TAF), 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
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. 
5.2.1.2.
Placebo to match TAF Tablets
Placebo tablets to match TAF 25 mg are yellow, round-shaped, and film-coated. The tablets are 
debossed with “GSI” on one side and “25” on the other side. Each 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. 
5.2.1.3.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF)
TDF 300 mg tablets contain 300 mg of tenofovir disoproxil fumarate (TDF), which is equivalent 
to 245 mg of tenofovir disoproxil. The tablets are light blue, almond-shaped, plain-faced, and
film-coated. Each tablet contains the following inactive ingredients: microcrystalline cellulose, 
lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The 
film coating contains lactose monohydrate, hypromellose (hydroxypropyl methylcellulose), 
glycerol triacetate, titanium dioxide, and indigo carmine aluminum lake.
5.2.1.4.
Tenofovir Disoproxil Fumarate (Viread®, Tenofovir DF, TDF) to be Used in 
Developing Markets
TDF 300 mg tablets to be used in developing markets contain 300 mg of tenofovir disoproxil 
fumarate (TDF), which is equivalent to 245 mg of tenofovir disoproxil. The tablets are white, 
almond-shaped, film-coated, debossed with “GILEAD” and “4331” on one side and plain-faced 
on the other side. Each tablet contains the following inactive ingredients: microcrystalline 
cellulose, lactose monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium 
stearate. The film coating contains lactose monohydrate, hypromellose, triacetin and titanium 
dioxide.

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5.2.1.5.
Placebo to match TDF Tablets
Placebo tablets to match TDF 300 mg are light blue, almond-shaped, plain-faced, film-coated 
tablets. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose 
(hydroxypropyl methylcellulose), triacetin, titanium dioxide, and indigo carmine aluminum lake. 
5.2.1.6.
Placebo to Match TDF Tablets to be Used in Developing Markets
Placebo tablets to match TDF 300 mg for developing markets are white, almond-shaped, 
film-coated tablets, debossed with “GILEAD” and “4331” on one side and plain-faced on the 
other side. Each tablet contains the following inactive ingredients: denatonium benzoate, lactose 
monohydrate, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The film 
coating contains the following inactive ingredients: lactose monohydrate, hypromellose, 
triacetin, and titanium dioxide.
5.2.2.
Packaging and Labeling
TAF, TDF, and their matched placebo tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 30 tablets and a silica gel desiccant and polyester coil. Each 
bottle is enclosed with a white, continuous-thread, child-resistant polypropylene screw cap fitted 
with an induction-sealed, aluminum-faced liner. 
To ensure stability of the tablets and proper product identification, the drug should not be stored 
in a container other than the container in which it is supplied.
All labels for study drug bottles to be distributed to centers in the US, EU and the rest of the 
countries will meet all applicable requirements of the US Food and Drug Administration (FDA) 
and Annex 13 of Good Manufacturing Practices: Manufacture of Investigational Medicinal 
Products (July 2010) and/or other local regulations as applicable.
5.2.3.
Storage and Handling
TAF, TDF, and their matched placebo tablets should be stored at a controlled room temperature 
of 25 °C (77 °F); excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F), inclusive. 
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures.
5.3.
Dosage and Administration of TAF and TDF and Matched Placebos
Subjects will be randomly assigned (2:1) to receive one of the following treatments in a blinded 
fashion:
Treatment Arm A: 260 subjects TAF 25 mg QD and matched placebo of TDF 300 mg QD
Treatment Arm B: 130 subjects TDF 300 mg QD and matched placebo of TAF 25 mg QD

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For China, approximately 150 additional subjects will be randomized 2:1 to receive either 
Treatment A (n = 100) or Treatment B (n = 50) for 144 weeks.
After 144 weeks of blinded randomized treatment (96 weeks under Amendment 2.1), each 
subject will switch to open-label TAF 25 mg QD for up to an additional 240 weeks
(Week 144 through Week 384/ED). Subjects already assigned to open-label TAF 25 mg QD at 
Week 96 per Amendment 2.1 will continue on TAF through Week 384/ED. 
It is preferred that subjects take their study drug according to a morning dosing schedule; 
however, evening dosing is allowable.
All study drugs should be taken at approximately the same time each day with food.
Observed in-clinic study drug dosing is required at Weeks 4 and 12 visits. Subjects who elect to 
dose in evening are not required to have in-clinic dosing and the single PK blood sample 
collection at the Week 4 and 12 visits.
Study drug should be administered after assessing adverse events and concomitant medication(s).
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.
Concomitant use of some medications including herbal/natural products/therapies and over the 
counter medications with TAF may result in PK interactions.
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.
The following medications are excluded while subjects are participating in the study. These 
medications are prohibited during the screening period and for a minimum of 30 days prior 
to the Baseline/Day 1 visit through the end of treatment:

Nephrotoxic agents (e.g., aminoglycosides, amphoterecin B, vancomycin, cidofovir, 
foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus)

Probenecid

Agents that reduce renal function or compete for active tubular secretion with tenofovir (e.g., 
cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir)

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
Systemic chemotherapeutic agents, systemic corticosteroids (except short-term use of 
prednisone as a steroid burst [ ≤ 1 week of use], immunosuppressant, or 
immunomodulating agents

Bisphosphonates

Investigational agents (unless approved by Gilead Sciences)

Medications excluded due to the potential for drug-drug interaction with TAF (Table 5-1)
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.
Table 5-1.
List of Medications That Are Prohibited or to Be Used with Caution 
Due to the Potential for Drug-Drug Interaction with Study 
Medication
Medication Class
Prohibited Medications
Medications to be used with caution
Analeptic
Modafinil
Antiarrhythmics
Amiodarone, Quinidine: may increase 
concentration of TAF and/or TFV
Antibacterials
Clarithromycin: may increase concentration of 
TAF and/or TFV
Anticonvulsants
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin
Antifungals
Voriconazole
Itraconazole, Ketoconazole: may increase 
concentration of TAF and/or TFV
Antimycobacterials
Rifapentine, Rifabutin, Rifampin
Calcium channel blockers
Diltiazem, Felodipine, Verapamil: may increase 
concentration of TAF and/or TFV
Digoxin
Digoxin: concomitant use may result in an 
increased or decreased level; use with caution 
and with appropriate monitoring of serum 
digoxin levels. Digoxin therapy should be 
initiated at the lowest dose, and the dose should 
be titrated to clinical response.
Herbal/Natural Supplements
St. John’s Wort, Echinacea, 
Milk thistle (i.e., silymarin), 
Chinese herb sho-saiko-to 
(or Xiao-Shai-Hu-Tang)

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5.5.
Accountability for Tenofovir Alafenamide (TAF), 
Tenofovir Disoproxil Fumarate (TDF) and Matched Placebos
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product (IMP) kits and/or bottles. This includes 
acknowledgement of receipt of each shipment of IMP (quantity and condition). All used and 
unused IMP kits and/or bottles dispensed to subjects must be returned to the site.
Investigational product accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits and/or bottles

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP kits 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 each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has an appropriate Standard Operating Procedure (SOP) for drug destruction, 
the site may destroy used and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. If the site does not have acceptable procedures in place for 
drug destruction, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. A copy of the site’s 
SOP will be obtained for central files. Where possible, study drug will be destroyed at the site. 
Upon study completion, a copy of the Investigational Drug Accountability records must be filed 
at the site. Another copy will be returned to Gilead Sciences. If drug is destroyed on site, the 
investigator must maintain accurate records for all study drug 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. 
Any deviation from protocol procedures should be documented and the sponsor or the contract 
research organization (CRO) should be notified.
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 5.1. Candidates who fail to meet eligibility criteria by 
screening evaluations may be re-screened once after the initial screen if there is a reasonable 
expectation that the candidate will be eligible after repeat screening.
Retesting of an exclusionary laboratory value during the Screening period is permitted only if in 
the Principal Investigator’s opinion, the retest value will be within accepted parameters; if the 
initial value was deemed to be inaccurate, inconsistent with the subject’s previous result(s); in 
error (e.g. mishandled sample); or due to an extenuating circumstance.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 45 days before Baseline to determine eligibility for participation 
in the study. The following will be performed and documented during the screening period:

Obtain written informed consent

Review of inclusion/exclusion criteria

Obtain medical history, including HBV history

Review concomitant medications

Record any serious adverse events and all adverse events related to protocol mandated 
procedures occurring after signing of the consent form

Complete physical examination including vital signs (blood pressure, pulse, respiration rate 
and temperature), body weight, and height

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
ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (at sites in China with capability only). 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

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required) 
– to be performed at any time during the Screening period and prior to the first dose of the 
study drug 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HIV-1, HDV, HCV, serum pregnancy test (for females of child-bearing potential), 
α-fetoprotein (AFP) and INR. An AFP > 50 ng/mL at Screening must have an appropriate 
evaluation (e.g. CT scan) in order to rule out HCC prior to being permitted to enter the study

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 45 days for randomization into the study. If the subject is deemed ineligible for this 
study by HBV serology (i.e. HBeAg-positive CHB), this information may be used to determine 
eligibility for GS-US-320-0110 (another Gilead Sciences Phase 3 study in HBeAg positive, CHB 
subjects; this study must also be IRB/EC approved at the participating center).
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all SAEs, as well as any AEs related to protocol-mandated procedures 
on the adverse events case report form (CRF/eCRF). All other untoward medical occurrences 
observed during the screening period, including exacerbation or changes in medical history are to 
be captured on the medical history CRF/eCRF. See Section 7, Adverse Events and Toxicity 
Management for additional details.
6.2.2.
Baseline Assessments
All baseline tests and procedures must be completed prior to the receipt of the first dose of study 
drug. Subjects screened within 45 days before Baseline will be eligible to participate in the 
study. Initiation of treatment with study drug should take place on the day of the Baseline visit. 
The following will be performed at the Baseline visit:

Review of inclusion/exclusion criteria and confirm medical history

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

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
Review concomitant medications

Review adverse events 

Assess future risk of bone fracture using the Fracture Risk Assessment tool (FRAX®; at sites 
in China with DXA capability only)

Randomization

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBeAg, HBeAb, HBsAg and reflex HBsAb), 
HBV genotyping (A-H), virology (resistance surveillance), serum and plasma for storage, 
IL28B genotype, and vitamin D assessment

Cystatin C testing for estimated glomerular filtration rate (eGFR) by CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration)

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Optional blood sample for biomarker/pharmacogenomics (separate consent required prior to 
obtaining sample)
6.3.
Treatment Assessments
6.3.1.
Double Blind Visits (Including Amendment 2.1 Open Label Visits 
Weeks 108 through 144)
Study visits Weeks 4 – 44 and Week 56 - 88 should be completed ± 3 days of the protocol 
specified visit date, based on the Baseline Visit.
Study visit Week 48 should be completed −14 days of the protocol specified visit date, based on 
the Baseline Visit.
Study visits Weeks 96, 108, 120, and 132, and 144 should be completed ± 14 days of the 
protocol specified visit date, based on the Baseline Visit.

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6.3.1.1.
Week 4

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

Fasting urine sample for renal biomarkers

Intensive PK Substudy only at select sites (separate consent required prior to 
obtaining samples) – Can also be done at Weeks 8 or 12 
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours, except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs

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 and provide the single PK sample) 

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
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.2.
Week 8

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Intensive PK Substudy only at select sites (separate consent required prior to 
obtaining samples) – If not done at Week 4; can also be done at Week 12
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

Dispense blinded study drugs

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
Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and storage
6.3.1.3.
Week 12

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers

Fasting urine sample for renal biomarkers

Intensive PK Substudy only at select sites (separate consent required prior to 
obtaining samples) – If not done at Weeks 4 or 8, must be completed by this visit.
Subjects dosing in the evening will need to switch to a morning dosing regimen at least 
10 days prior to the intensive PK visit 
Subject should fast overnight (no food or drinks for a minimum of 8 hours except water 
for up to 1 hour) prior to the scheduled intensive PK visit
Collect pre-dose sample PK sample 
Collect pre-dose PBMC sample (at sites which can process PBMCs)
Provide subject with a standardized, moderate fat meal (refer to PK Manual)
Within 5 minutes of consuming the meal, dose subject in-clinic in the morning 
Collect blood (plasma) samples at defined intervals as per Appendix 3
Subject should not drink water until 2 hours or eat any food until 4 hours post dose

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
Dispense blinded study drugs

Dose in clinic and collect single plasma PK sample 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 and provide the single PK sample)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.4.
Weeks 16, 20, 28, 32, 40, and 44

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
plasma PK, virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.5.
Week 24

Complete physical examination including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

DXA scan of spine and hip (within ± 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

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
Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.6.
Week 36

Symptom directed physical exam

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

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6.3.1.7.
Week 48

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate 
and temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip (within −14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events 

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), plasma PK, 
virology (resistance surveillance), and serum and plasma for storage

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.8.
Weeks 56 and 88

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

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
Review concomitant medications

Review adverse events 

Perform study drug accountability

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.1.9.
Weeks 64, 80, 108, and 132

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability

Dispense blinded study drugs (subjects already assigned to open-label TAF 25 mg QD at 
Week 96 per Protocol Amendment 2.1 will be dispensed open-label TAF at all 
subsequent visits)

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

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6.3.1.10.
Week 72

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

DXA scan of spine and hip (within ± 14 days of the expected visit date; at sites in China with 
capability only)

Review concomitant medications

Review adverse events

Perform study drug accountability

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Dispense blinded study drugs

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
virology (resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.3.1.11.
Weeks 96 and 120

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording) [Week 96 only]

Hepatic ultrasound for surveillance of hepatocellular carcinoma

DXA scan of spine and hip to be performed (within ± 14 days of the expected visit date; at 
sites in China with capability only)

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
Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability

Dispense blinded study drugs (For Week 120, subjects already assigned to open-label TAF 
25 mg QD at Week 96 per Protocol Amendment 2.1 will be dispensed open-label TAF)

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest® [Week 96 only]

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
[Week 96 only]
6.3.1.12.
Week 144

Complete physical exam including, vital signs (blood pressure, pulse, respiration rate and 
temperature), and body weight

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within ± 14 days of the expected Week 144 visit 
date; at sites in China with capability only)

Hepatic ultrasound for surveillance of hepatocellular carcinoma

Review concomitant medications

Review adverse events 

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
Retrieve study drug and perform study drug accountability

Dispense open label TAF 

Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
At ED visit, ophthalmologic assessment should be performed only if not done within the 
last 12 weeks
6.3.2.
Open Label Visits
Study visits Weeks 168 through 384/ED should be completed ± 28 days of the protocol specified 
visit date, based on the Baseline Visit.
6.3.2.1.
Weeks 168, 216, 264, 312, and 360

Symptom directed physical exam

Hepatic ultrasound for surveillance of hepatocellular carcinoma

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature

Review concomitant medications

Review adverse events 

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
Perform open-label study drug accountability

Dispense open-label TAF

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAg and reflex HBsAb), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage
6.3.2.2.
Weeks 192, 240, 288, 336, and 384/ED
The ED Visit should be performed within 72 hours (i.e., visit window is within 3 days) of 
the last study drug dose.

Symptom directed physical exam (At Week 240 and 384/ED, a complete physical exam 
should be performed) 

Hepatic ultrasound for surveillance of hepatocellular carcinoma
At ED visit, Hepatic ultrasound should be performed only if not done within the prior 
24 weeks

Body weight

Vital signs: blood pressure, pulse, respiration rate, and temperature

ECG (subjects must rest quietly in the supine position for a minimum of 5 minutes prior to 
the recording)

DXA scan of spine and hip to be performed (within ±28 days of the expected visit date; at 
sites in China with DXA capability only)
At ED visit, DXA scan should be performed only if not done within the prior 24 weeks

Review concomitant medications

Review adverse events 

Retrieve study drug and perform study drug accountability 

Dispense Open Label TAF (no study drug will be dispensed at Week 384/ ED visit)

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
Fasting blood sample for bone biomarkers and metabolic assessment (glucose and lipid panel 
[total cholesterol, HDL, direct LDL, and triglycerides]) - no food or drinks, except water, at 
least 8 hours prior to blood collection 

Fasting urine sample for renal biomarkers

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA, 
serum HBsAg (quantitative), HBV serology (HBsAb and reflex HBsAg), virology 
(resistance surveillance), and serum and plasma for storage 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Blood sample for Fibrotest®

Urine sample for urinalysis, pregnancy test (for females of child-bearing potential; in case of 
a positive urine test, a serum pregnancy test will be done), and for storage

For ED visit prior to Week 144 only, if not performed within the prior 24 weeks:
Ophthalmologic assessment, including fundoscopic examination with slit lamp and retinal 
photographs (both eyes) (substudy subjects only at select sites - separate consent required)
6.4.
Post-treatment Assessments
6.4.1.
HBsAg Loss and Seroconversion Subjects
Subjects who discontinue study drug due to HBsAg loss with confirmed seroconversion to 
anti-HBs on or after the Week 48 visit, will be followed off treatment every 4 weeks for 
12 weeks and then per the study visit schedule through Week 384/ED (excluding drug 
dispensation and accountability).
6.4.2.
All other subjects who discontinue study drug
Subjects who have received at least one dose of study drug and permanently discontinue study 
drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be 
followed every 4 weeks for 24 weeks off treatment or up to initiation of alternative, 
commercially available HBV therapy, whichever occurs first. 
6.4.3.
Follow up visit assessments (all subjects)
Treatment-free Follow Up Visits should be completed ±7 days from the protocol-specified visit 
date, determined by the date the subject discontinued the study drug.

Symptom directed physical exam

Body weight 

Vital signs: blood pressure, pulse, respiration rate, and temperature 

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
Review concomitant medications

Review adverse events 

Blood sample for serum chemistry and liver function tests, hematology, plasma HBV DNA,
serum for storage, HBV serology (HBsAg and reflex HBsAb at Follow Up visits 
Weeks 12 and 24), and serum HBsAg (quantitative) 

Estimated creatinine clearance (using the Cockcroft-Gault method)

Urine sample for urinalysis
6.5.
Early Discontinuation (ED) from Study
If a subject discontinues study medication dosing for reasons other than HBsAg loss with 
confirmed seroconversion to anti-HBs (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 visits 
and procedures. If this is not possible or acceptable to the subject or investigator, the subject may 
be withdrawn from the study. Early Discontinuation Assessments are described in 
Section 6.3.2.2.
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

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest

Subjects with confirmed creatinine clearance of < 30 mL/min at any time during the study 
will have their study drug permanently discontinued

Lack of efficacy (virologic failure)

HBsAg loss with seroconversion to anti-HBs. These subjects should discontinue study drug 
within 3-6 months following confirmation of seroconversion to anti-HBs. Subjects with 
HBsAg loss with confirmed seroconversion before Week 48 are not permitted to discontinue 
study drug prior to the Week 48 visit

Discontinuation of study drug for subjects experiencing HBsAg loss with confirmed 
seroconversion to anti-HBs, who have known bridging fibrosis or cirrhosis, should be 
considered on a case by case basis

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
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 Sciences, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.7.
Intensive Pharmacokinetic Substudy (Optional)
A PK substudy will be performed in a subset of subjects (n=16 and up to n=32) at selected study 
sites. Separate consent for the PK substudy is required. The substudy will include intensive PK 
profiling in plasma and will be conducted once at either of the Weeks 4, 8 or 12 visits. 
Blood samples will be collected at 0 (≤30 minutes pre-dose), 5 minutes, 15 minutes, 30 minutes, 
45 minutes, 1 hour, 1.5 hours, 2, 3, 4, 5, 8, 12 and 24 hours post-dose. 
Subjects participating in the PK substudy should not take their dose on the morning of the PK 
visit. Study medication will be administered in clinic on the morning of intensive PK. Subjects 
who have been routinely dosing in the evening will need to switch to a morning dosing regimen 
at least 10 days prior to the intensive PK visit. In addition, subjects should fast (no food or drinks 
for a minimum of 8 hours except water for up to 1 hour) prior to the scheduled intensive PK visit
After collection of the pre-dose sample, subjects will be provided a standardized, moderate fat 
meal (approximately 600 cal, 27% fat; Details can be found in the PK Manual). Within 
5 minutes after consuming the standardized meal, subjects will be dosed with TAF. Intensive 
PK sampling at the following time points will occur: 5, 15, 30, 45 minutes, 1, 1.5, 2, 3, 4, 5, 8, 12 
and 24 hours post-dose. Subjects will be restricted from further water intake until 2 hours after 
and food intake until 4 hours after dosing. The date and time of the subject’s previous dose will 
need to be collected in addition to the data at the PK substudy visit.
Details of pharmacokinetic blood sampling procedures and sample management will be 
documented in the Pharmacokinetic Sample Collection, Processing, Storage, and Shipment 
Manual.
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked 
to provide a PBMC (pre-dose) sample at the time of the intensive PK substudy.
6.8.
Urine, Serum and Plasma for Storage
A portion of the blood samples collected at each visit starting at Baseline will be frozen and 
stored. These stored blood samples may be used by the Sponsor or its research partners for HBV 
genotyping/phenotyping assays or their development, for retesting the amount of HBV in the 
blood, for measurement of antiviral drug levels in the blood, or for future testing to learn more 
about how the study drug has worked against HBV or clinical laboratory testing to provide 
additional safety data. No human genetic testing on this sample will be performed. 

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A portion of the urine samples collected at each visit starting at Baseline will be frozen and 
stored. These stored urine samples may be used by Sponsor for future renal and bone biomarker 
testing (in addition to the tests planned for the study).
At the conclusion of this study, these samples may be retained in storage by Gilead Sciences, 
Inc. for a period up to 15 years.
6.9.
Resistance Surveillance
Genotypic sequence analysis of the HBV polymerase/reverse transcriptase (pol/RT) for 
resistance mutations will be conducted at Baseline for all subjects, and attempted for all viremic 
subjects (HBV DNA 69 IU/mL) at Week 48 and every 48 weeks until Week 384/ED visit. 
At Baseline, resistance surveillance will be conducted by INNO-LiPA Multi-DR v3 
(Innogenetics), which will determine the presence of HBV pol/RT mutations known to confer 
resistance to lamivudine, adefovir, entecavir, clevudine and/or telbivudine.  
Every 48 weeks post Baseline (if viremic), resistance surveillance will be conducted by 
population sequencing of the HBV pol/RT.
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.
Hepatic Ultrasound for Hepatocellular Carcinoma Surveillance
Subjects will undergo hepatic ultrasound assessments for HCC surveillance, beginning at 
Week 96, at 24 week intervals. Subjects who have completed the Week 96 visit 
(under Amendment 2.1) should begin ultrasound assessments at the next visit at which an 
ultrasound assessment is included (see Appendix 2 and Section 6 of the Protocol).
6.11.
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

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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that require medical or 
surgical intervention or lead to IMP interruption, modification, or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (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 (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigators 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 7.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
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 serious adverse events (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 4-weeks 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 AE 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 occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. Any SAEs and deaths, regardless of causality, that occur during the post 
treatment follow-up period or within 30 days of the last dose of study drug, when subject 
transitions to alternative, commercially available HBV therapy, should also be reported.

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Investigators are not obligated to actively seek SAEs after the protocol defined follow up 30-day 
period. However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document
and report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 

At the time of study start, SAEs may be reported using a paper serious adverse event 
reporting form, but sites will transition to an electronic SAE (eSAE) system. Gilead will 
notify sites in writing and provide training and account information prior to implementing an 
eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
or emailing the report form within 24 hours of the investigator’s knowledge of the event to 
the attention of Gilead DSPH or to the designated CRO.
Electronic Serious Adverse Event (eSAE) Reporting Process 

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours as described above.

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.

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Safety: 
Medical Monitor: 
CONFIDENTIAL 
North America- PRA 
Email: CHOsafety@praintl.com, 
Final 
Amendment 3. 1 
Fax: 1-888-772-6919 
Europe (including Russian Federation), Asia Pacific - PRA 
Email: MHGSafety@PRAintl.com, 
Fax: +49-621-878-2181 
!wll! - KlinEra 
Email: safetyreporting@klinera.com, 
Fax: +91-22-25004588 
China, Vietnam - Quintiles 
Email: Ph V _ Gilead@quintiles.com 
Fax: 4001-206110 
Japan- CMIC 
Email: GPV _ GileadHB@cmic.co.jp 
Fax: +81-3-3493-5523 
North America- PRA 
Tel: 1.866.326.5053(toll-free) 
Tel: 1.434.951.4082 (direct) 
Fax: 1.800.280.7035 (toll-free) 
Fax: 1.913.307.5751 (direct) 
Email: Gilead320-08@prahs.com 
Europe (including Russian Federation), Asia Pacific- PRA 
Phone: +44 179 252 5608 
Fax: +49 621 878 2181 
Email: MedicEU@PRAintl.com 
India - KlinEra 
Vikram Vora, MD 
Phone: PPD 
Fax:IPPD 
Emml: PPD 
...._ _____ ..... 
China, Vietnam - Quintiles 
Ian Escudero 
Phone: '-P ... P"'D...----
Mobile: PPD 
Fax: PPD 
Email: PPD 
~--------~ 
Japan- CMIC 
Mistuhiro Omine 
Phone:PPD 
EmailP PD 
...._ ________ 
~ 
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
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.
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. 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.

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
Any recurrence of the investigational medicinal product-related Grade 3 or 4 clinical or 
clinically significant laboratory adverse event following dose interruption mandates 
permanent discontinuation of investigational medicinal product.

Administration of study drug may be discontinued due to a clinical or laboratory event. The 
Gilead Medical Monitor should be consulted prior to dose discontinuation of study drug 
unless the investigator believes that immediate action is warranted to ensure the continued 
safety of subject.

Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor.
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.

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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.
7.5.5.
Management of Potential Nephrotoxicity
Creatinine clearance (CLCr), estimated according to the Cockcroft-Gault formula, will be 
followed post-baseline during the study. All subjects with estimated CLCr < 50 mL/min must 
have serum creatinine measured again within 3 calendar days of receipt of results. At the time of 
this repeat serum creatinine assessment, 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. During the double-blind period, any subject, who 
has a confirmed CLCr estimated by the Cockroft-Gault formula < 50 mL/min and also 
experiences a > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline, will be 
managed as described below:
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499× max (Scys/0.8, 1)−1.328 ×
0.996Age [× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of
Scys/0.8 or 1, and max (Scys/0.8,1) indicates the maximum of Scys/0.8 or 1.
Subjects meeting the above eGFR criteria (i.e. confirmed CLCr < 50 mL/min by Cockcroft-Gault 
equation and > 20% reduction from baseline in eGFR by CKD-EPI equation) will be managed as 
follows:

If the CLCr is confirmed to be ≥ 30 mL/min and < 50 mL/min, the subject will be required to 
undergo dose modification to every other day dosing of study drug during the double blind 
period only.

If the CLCr is confirmed ≥ 30 mL/min to < 50 mL/min and the subject has undergone dose 
modification to every other day dosing of study drug and subsequently develops a confirmed 
CLCr ≥50 mL/min, the subject may revert to once daily dosing of study drug after discussion 
with the Gilead Medical Monitor.

If the CLCr is confirmed to be < 30 mL/min at any time during the study, the subject will be 
required to permanently discontinue study drug.

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
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. The following management will be required dependent upon the 
corresponding creatinine clearance value:
If creatinine clearance is < 50 ml/min, or the subject has other clinical and/or laboratory 
evidence of acute renal failure, the subject will be managed according to the guidance 
described above.
If creatinine clearance is ≥ 50 ml/min and the repeat testing of serum creatinine confirms 
a Grade 1 or Grade 2 serum creatinine elevation, it is recommended that subject be 
monitored weekly until the serum creatinine level returns to a value within the normal 
laboratory range.

All subjects with negative or trace proteinuria at baseline that develop ≥1+ proteinuria on 
urinalysis must have a urinalysis repeated, with a concurrent urinalysis and urine chemistry, 
within two weeks of receipt of results. Upon confirmation of new proteinuria, subjects will 
be asked to return to the clinic for a scheduled or unscheduled follow up visit for evaluation. 
It is recommended that the investigator contact the Gilead Medical Monitor to discuss if 
further consultation with a nephrologist is clinically warranted.
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.

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Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable relative to baseline Liver Function Tests
If ALT levels are elevated (i.e., > 2 × baseline and > 10 × ULN) with normal or stable total 
bilirubin and INR relative to baseline, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or baseline level. 
During monitoring, if the ALT values remain persistently elevated, the investigator should 
discuss with the Gilead Medical Monitor whether the study drug should be discontinued.
For subjects with bridging fibrosis or cirrhosis, study drug discontinuation with treatment-free 
follow-up is to be avoided due to the potential risk of exacerbation of hepatitis in the setting of 
low hepatic reserve which could lead to decompensation. Subjects with bridging fibrosis or 
cirrhosis should be placed on commercially available HBV therapy following study drug 
discontinuation.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., > 2 × baseline and > 10 × ULN), and total bilirubin is confirmed 
to be 2 × baseline value, and INR is 0.5 above baseline, provided both are > ULN, the 
investigator should consider discontinuing study medication (upon discussion with the 
Gilead Medical Monitor, unless the safety of the subject is of immediate concern). 
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:

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
Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject. 

Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and 
albumin.

If the ALT elevation is confirmed, the central clinical laboratory will conduct reflex testing 
for plasma HBV DNA, serology for HBV (HBsAg and HBsAb), HDV, HAV IgM, HCV and 
HEV. If Plasma HBV DNA is increasing, the investigator should consider immediate 
initiation of approved therapy. 

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or baseline up to a maximum of 6 months after the initial occurrence of the event. 
7.5.7.
Management of Potential Posterior Uveitis Cases
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. This pre-clinical finding has also not been 
observed in humans where the dose administered is lower than that given in the dog study, nor 
have there been reports of posterior uveitis in human clinical studies thus far. Nonetheless, if any 
subject 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, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
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 or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.

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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).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product. 
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. Refer to Section 7.3 and the CRF/eCRF completion guidelines for full 
instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to the CRO Safety Dept. using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information is as 
follows: Email: Safety_FC@gilead.com and Fax: +1 (650) 522-5477. 
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.

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7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the CRO Safety Dept within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Special situations involving non-Gilead concomitant medications does 
not need to be reported on the special situations report form, however, for special situations that 
result in AEs due to a non-Gilead concomitant medication, the AE should be reported on the AE 
form. Any inappropriate use of concomitant medications prohibited by this protocol should not 
be reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus 
tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative, 
chronic hepatitis B at Week 48 in treatment-naïve and treatment-experienced subjects. The 
primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 
29 IU/mL.

To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the 
treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment-naïve and 
treatment-experienced subjects
The key secondary safety objectives of this study are as follows: 

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
percent change from baseline in hip and spine BMD at Week 48

To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the 
change from baseline in serum creatinine at Week 48
Other secondary objectives of this study are as follows:

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL at Weeks 96, and 144

To compare the efficacy of TAF 25 mg QD versus TDF 300 mg QD for the treatment of 
HBeAg-negative, chronic hepatitis B in regard to the proportion of subjects with plasma 
HBV DNA levels below 29 IU/mL (target not detected) at Weeks 48, 96, and 144

To compare the biochemical (ALT normalization) response of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

To compare the serological response (loss of HBsAg with seroconversion to anti-HBs) of 
TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic 
hepatitis B at Weeks 48, 96, and 144

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
To compare the change in fibrosis as assessed by FibroTest® of TAF 25 mg QD versus TDF 
300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at 
Weeks 48, 96, and 144

To compare the incidence of drug resistant mutations of TAF 25 mg QD versus TDF 300 mg 
QD at Weeks 48, 96, and 144

To compare the change from baseline in ophthalmologic findings by fundoscopic 
examination of TAF 25 mg QD versus TDF 300 mg QD at Weeks 24, 48, 72, 96, and 144 in 
a subset of subjects 

To characterize the pharmacokinetics of TAF and tenofovir (TFV) and determine 
intracellular concentrations of tenofovir diphosphate (TFV-DP) within peripheral blood 
mononuclear cells (PBMC) in a subset of subjects receiving TAF or TDF

To evaluate the comparative open-label efficacy, safety, and incidence of drug resistance 
mutations of TAF 25 mg QD from Week 144 through Week 384 in subjects initially 
randomized to TAF 25 mg QD and in subjects sequentially treated with TDF 300 mg QD and 
then switched to open-label TAF
8.1.2.
Primary Endpoint
The primary efficacy endpoint is the proportion of subjects with plasma HBV DNA < 29 IU/mL 
at Week 48.
8.1.3.
Secondary Endpoints
The key secondary safety endpoints are:

The percent change from baseline at Week 48 in hip BMD 

The percent change from baseline at Week 48 in spine BMD 

The change from baseline at Week 48 in serum creatinine 
8.1.4.
Other Endpoints of Interest

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Weeks 96 and 144

The proportion of subjects with plasma HBV DNA < 29 IU/mL (target not detected) at 
Weeks 48, 96, and 144

The proportion of subjects with ALT normalization (by central laboratory and AASLD 
criteria) at Weeks 48, 96, and 144

The proportion of subjects with HBsAg loss at Weeks 48, 96, 144, 240, and 384

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
The proportion of subjects with HBsAg seroconversion to anti-HBs at Weeks 48, 96, 144, 
240, and 384

The change from baseline in fibrosis as assessed by FibroTest® at Weeks 48, 96, 144, 240 
and 384

The incidence of drug resistant mutations at Weeks 48, 96, 144, 240, and 384

The change from baseline in ophthalmologic findings by fundoscopic examination at 
Weeks 24, 48, 72, 96, and 144 in a subset of subjects

The proportion of subjects with treatment-emergent proteinuria (by dipstick) at 
Weeks 48, 96, 144, 240, and 384
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The primary analysis set for efficacy analysis 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 treatment free follow up 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 general 
pharmacokinetics.
The PK substudy analysis set will include all subjects who are randomized and have received at 
least one dose of study medication and for whom steady-state PK parameters of analytes TAF 
and TFV are available. The PK substudy analysis set will be used for detailed pharmacokinetics 
analyses.
8.2.1.4.
Biomarkers
The Biomarker analysis set will include all subjects who have evaluable biomarkers data.

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8.2.2.
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, missing data will be handled via a Last Observation Carried 
Forward (LOCF) method.
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.
8.3.
Multiplicity Adjustments
The primary hypothesis of non-inferiority between TAF 25 mg QD and TDF 300 mg QD with 
respect to the proportion of subjects with HBV DNA < 29 IU/mL will be tested first. If 
non-inferiority is established, then multiplicity adjustments will be performed for the secondary 
endpoints with a fallback procedure using the following weights:
a) Hip BMD (weight = 0.4)
b) Spine BMD (weight = 0.2)
c) Serum creatinine (weight = 0.4)

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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, geographical region, randomization 
stratification group, 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 approximately 390 randomized subjects
complete 48 weeks of the double-blind treatment period or discontinue prematurely. A two-sided 
95% confidence interval, based on the large sample theory adjusted for the randomization 
stratification factors (the adjusted Mantel-Haenszel proportions), for the difference (TAF – TDF) 
in the proportion of subjects who achieved HBV DNA < 29 IU/mL will be used to compare the 
treatment groups. A non-inferiority will be declared if the lower bound of this confidence 
interval exceeds a non-inferiority margin of –0.10. If non-inferiority is established, the lower 
bound of the 95% CI will be compared to 0; if the lower bound of the 95% CI is greater than 0, 
then superiority of TAF over TDF will be established using the same confidence interval. Details 
will be provided in the statistical analysis plan.
8.5.1.1.
Justification of the non-inferiority margin
At Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA < 29 IU/mL 
in the TDF arm was 91.2%. At Week 48 in study GS-98-438, the proportion of subjects with
HBV DNA < 29 IU/mL in the placebo was 0%. The non-inferiority margin of 10% would 
preserve more than 88% of the lower bound of the 95% confidence interval of the difference 
between TDF and placebo.
NTDF
NPBO
Response rate 
in TDF
Response rate 
in PBO
Difference
95% confidence interval 
lower bound
250
61
91.2%
0%
91.2%
87.7%
Preserve at least 88% 
of lower bound
10%
Furthermore, at Week 48 in study GS-US-174-0102, the proportion of subjects with HBV DNA 
< 29 IU/mL in the TDF arm was 91.2% and the proportion of subjects with HBV DNA 
< 29 IU/mL in adefovir (ADV) arm was 56.0%. The non-inferiority margin of 10% would 
preserve more than 60% of the lower bound of the 95% confidence interval of the difference 
between TDF and adefovir (ADV).

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NTDF
NADV
Response rate 
in TDF
Response rate 
in ADV
Difference
95% confidence interval 
lower bound
Study 174-0102
250
125
91.2%
56.0%
35.2%
25.8%
Preserve at least 60% 
of lower bound
10%
8.5.2.
Analyses of Other Endpoints of Interest
Continuous secondary endpoints will be summarized using conventional descriptive statistics 
(n, mean, standard deviation, median, Q1, Q3, minimum, and maximum) by treatment group and 
overall. A Wilcoxon rank sum test will be used to compare the treatment groups, in an 
exploratory manner.
Categorical secondary endpoints will be summarized by number and percentage of subjects that 
meet the endpoint. A two-sided Mantel-Haenszel test, controlling for the randomization strata,
will be used to compare the treatment groups, in an exploratory manner. Missing data will be 
handled by the missing = failure approach.
For the incidence of drug resistant mutations, the missing = excluded approach will be employed.
An analysis of the China subpopulation will also be conducted when approximately 
150 randomized and treated China subjects complete 48 weeks of double-blind treatment or 
discontinue prematurely to examine the consistency of the responses between the China 
subpopulation and the overall population.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose will be summarized by treatment group (according to the drug received). Data for the 
pretreatment and treatment-free follow-up periods will be included in data listings. 
8.6.1.
Key Secondary Safety Analyses
The percent change from baseline in hip and spine BMD at Week 48 will be analyzed using an
ANOVA model. The model will include treatment group as fixed effect. The details are provided 
in the Statistical Analysis Plan (SAP).
The change from baseline in serum creatinine at Week 48 will be analyzed using an ANCOVA 
model with baseline serum creatinine as a covariate, and treatment group as a fixed effect. The 
details are provided in the SAP.
8.6.2.
Extent of Exposure
A subject’s extent of exposure to drug data will be generated from the drug administration data. 
Exposure data will be summarized by treatment group. 

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8.6.3.
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:

Treatment-emergent adverse events

Treatment-emergent study drug-related adverse events

Grade 3 or 4 treatment-emergent adverse event

Grade 3 or 4 treatment-emergent study drug-related adverse event

Grade 2, 3, or 4 treatment-emergent adverse event

Grade 2, 3, or 4 treatment-emergent study drug-related adverse event

AE that caused permanent discontinuation from study drug

AE that caused change in dose or temporary interruption of study drug

Treatment-emergent serious adverse event

Treatment-emergent study drug-related serious adverse event
8.6.4.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 5.

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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.
For the PK intensive substudy, the following pharmacokinetic parameters will be calculated: 
Cmax, Tmax, Clast, Tlast, Ctau, AUCtau, AUClast, CL/F, V/F, z and t½.
8.7.1.
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. The difference in change from baseline in these biomarkers between two 
treatment arms will be tested using Wilcoxon rank sum test.
8.8.
Sample Size
With respect to the primary efficacy endpoint, a sample size of 130 for the TDF 300 mg group 
and 260 for the TAF 25 mg group will have 90% power to rule out the non-inferiority margin of 
10% at a one-sided significance level of 0.025. This assumes a rate of 91% in the TDF 300 mg 
group and 91% in the TAF 25 mg group in the proportion of subjects with HBV DNA 
< 29 IU/mL. A similar response rate in the TDF group was observed in GS-US-174-0102
{Marcellin et al 2007, Marcellin et al 2008}.
This sample size (n=260 for the TAF 25 mg arm, n=130 for the TDF 300 mg arm) also provides 
at least 90% power to detect a 1% difference in the percentage change from baseline in hip BMD 
at Week 48 (assuming a −1.17% change from baseline in TDF 300 mg arm and −0.17% change 
from baseline in the TAF 25 mg arm, with a common standard deviation of 2.20% and a 
two-sided α = 0.025); a 77% power to detect a 1% difference in the percentage change from 
baseline in spine BMD at Week 48 (assuming a −1.69% change from baseline in the TDF 
300 mg arm and −0.69% change in the TAF 25 mg arm, with a common standard deviation of 
3.08% and a two-sided α = 0.025); a 52% power to detect a 0.03 mg/dL difference in the change 
from baseline in serum creatinine at Week 48 (assuming a 0.04 mg/dL change from baseline in 
the TDF 300 mg arm and 0.01 mg/dL change from baseline in the TAF 25 mg arm, with a 
common standard deviation of 0.12). These assumptions were derived from studies GS-98-437, 
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For China, approximately 150 additional subjects (100 subjects TAF 25 mg QD and matched 
placebo of TDF 300 mg QD, and 50 subjects TDF 300 mg QD and matched placebo of TAF 
25 mg QD) will be enrolled.
8.9.
Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data 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
The DMC will convene approximately every 24 weeks following the time of randomization of 
the first subject during the blinded portion of the protocol and approximately every 48 weeks 
during the open-label period.
The DMC’s specific activities will be defined by a mutually agreed upon charter, which will
define the DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable sub-investigators 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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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 

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

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

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

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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC 
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.

Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.1
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9.3.2.
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.
9.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority (ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.

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10.
REFERENCES
Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for Effective Lymphoid Cell 
and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-
7340. Mol Pharm 2013;10 (2):459-66.
Baldick CJ, Eggers BJ, Fang J, Levine SM, Pokornowski KA, Rose RE, et al. Hepatitis B virus 
quasispecies susceptibility to entecavir confirms the relationship between 
genotypic resistance and patient virologic response. J Hepatol 2008;48 (6):895-
902.
Bam RA, Birkus G, Babusis D, Yant SR, Cihlar T. Minimal Donor Variation in Cathepsin A 
Expression and Antiviral Activity of GS-7340 in Primary Human CD4+ T Cells 
and Macrophages [Poster Number TUPE016]. XIX International AIDS 
Conference; 2012 July 22-27; Washington, D.C. . 
Birkus G, Bam R, Frey C, Tsai L, Stray K, Yant S, et al. Intracellular activation pathways for 
GS-7340 and the effect of antiviral protease inhibitors [Poster #577]. Presented 
at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); 2012 
March 5-8; Seattle, WA. 
Centers for Disease Control and Prevention (CDC). Hepatitis B Fact Sheet.  Available at:  
http://www.cdc.gov/ncidod/diseases/hepatitis/b/fact.htm. Accessed August 6, 
2003, 
Heathcote EJ, Gane E, DeMan R, Lee S, Flisiak R, Manns MP, et al. A Randomized, Double-
Blind Comparison of Tenofovir DF (TDF) Versus Adefovir Dipivoxil (ADV) for 
the Treatment of HBEAG-Positive Chronic Hepatitis B (CHB): Study GS-US-
174-0103 [AASLD Abstracts]. Hepatology 2007;46 (4 Supp1):861A.
Marcellin P, Buti M, Kraslev Z, Germanidis G, Kaita K, Kotzev I, et al. A Randomized, Double-
Blind Comparison of Tenofovir DF (TDF) Versus Adefovir Dipivoxil (ADV) for 
the Treatment of HBEAG-Negative Chronic Hepatitis B (CHB): Study GS-US-
174-0102 [AASLD Abstracts]. Hepatology 2007;46 (4 Suppl 1):290A-1A.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis 
during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-
year open-label follow-up study. Lancet 2013;381 (9865):468-75.
Marcellin P, Heathcote E, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil 
for chronic hepatitis B. N Engl J Med 2008;359 (23):2442-55.

Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Amendment 3.1
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Marcellin PE, Heathcote EJ, Corsa A, et al. No detectable resistance to tenofovir disoproxil 
fumarate (TDF) following up to 240 weeks of treatment in patients with 
HBEAG+ and HBEAG- chronic hepatitis B virus infection [Abstract 238]. 
Hepatology 2011;54 (4 Suppl.):480A.
Ngo Y, Munteanu M, Messous D, Charlotte F, Imbert-Bismut F, Thabut D, et al. A prospective 
analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic 
hepatitis C. Clin Chem 2006;52 (10):1887-96.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. 1–239. Available at  
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 
August 22.  2012.
Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of 
FibroTest diagnostic value in chronic liver disease. BMC gastroenterology 
2007;7:40.
Poynard T, Zoulim F, Ratziu V, Degos F, Imbert-Bismut F, Deny P, et al. Longitudinal 
assessment of histology surrogate markers (FibroTest-ActiTest) during 
lamivudine therapy in patients with chronic hepatitis B infection. Am J 
Gastroenterol 2005;100 (9):1970-80.
Robbins BL, Greenhaw JJ, Connelly MC, Fridland A. Metabolic pathways for activation of the 
antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. 
Antimicrob Agents Chemother 1995;39 (10):2304-8.
Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term 
monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive 
patients is rare through 5 years of therapy. Hepatology 2009;49 (5):1503-14.
World Health Organization (WHO). Fact Sheet WHO/204.  October, 2000.
Zuckerman AJ. Progress towards the comprehensive control of hepatitis B. Gut 1996;38 (2):S1.

Tenofovir Alafenamide (TAF)
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Gilead Sciences, Inc.
Amendment 3.1
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected sites in a 
subset of subjects [n=16 and up to n=32])
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 Recommendations

Teoofovir Alafenamide (TAF) 
Protocol GS-US-320-0 I 08 
Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER OTY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment 3.1 
A Phase 3, Randomjzed, Double-Blind Study to Evaluate the Safety and Efficacy of 
Tenofovir Alafcnamide (TAF) 25 mg QD versus Tenofovir Disoproxil Fumarate (TDF) 300 mg 
QD for the Treatment ofHBeAg-Negative, Chronic Hepatitis B 
GS-US-320-0108, Amendment 3.1, 23 February 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Jolm Flaherty, Pharm D 
Study Director 
Date 
PPD 
INVESTIGATOR STATEMENT 
J have read the protocol, including aU appendices; and I agree that it contains all necessary 
details for me and my stair to conduct this study as described. l 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 118 
23 February 2016 

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Appendix 2.
Study Procedures Table
Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Informed Consent 
X
Review of Inclusion/ Exclusion 
Criteria 
X
X
Medical History, including HBV 
history
X
Review Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Examination 
including vital signs, and weight 
X
X
X
X
X
X
X
X
Height
X
Symptom-directed Physical 
Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization 
X
DXAd (spine & hip ) 
X
X
X
X
X
X
X
Fracture Risk Assessmentq
X
Study Drug Accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensed/Retrievede
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dosing in-clinicf
X
X

Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
Amendment 3.1
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Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Serum Chemistry and Liver 
Function Testsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Estimated Creatinine Clearance 
(by Cockcroft-Gault Method)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cystatin C (for estimated eGFR)
X
Plasma HBV DNA Levels 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum HBsAg (quantitative)  
X
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyh
X
X
X
X
X
X
X
X
X
X
X
X
HBV Genotyping (A-H) 
X
Virology (resistance surveillance)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV-1, HDV, HCV
X
α-fetoprotein 
X
Fibrotest®
X
X
X
X
IL28B Genotype
X
Vitamin D
X
Plasma PK 
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood for Bone 
Biomarkersi
X
X
X
X
X
X
X
X
X
Fasting Urine for Renal 
Biomarkersi
X
X
X
X
X
X
X
X
X
Fasting Metabolic Panelj
X
X
X
X
X
X
X
Serum Pregnancy Testk
X

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Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
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Screening 
(45 days)
BL
Week
4
8
12
16
20
24
28
32
36
40
44
48a
56
64
72
80
88
96a,e
108
132e
120
144e
Visit 
Window
± 3 days
-14
days
±3 days
± 14 days
Urine Pregnancy Testk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Optional Intensive PK substudyl
X
Optional PBMCm
X
Serum and plasma for storage 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for Storage
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ophthalmologic substudyn –
fundoscopic examination with 
slit lamp
X
X
X
X
X
X
Hepatic Ultrasoundr
X
X
X
Optional Biomarker/ 
Pharmacogenomic Sample
For subjects who provide a separate informed consent, a blood sample should be collected at Baseline, prior to first dose of 
study drug, but may be collected at any time during the study.

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Amendment 3.1
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Visit windows
Week
168
192
216
240
264
288
312
336
360
384/EDo
FUp
±28 days
±7 days
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
Complete Physical Examination including vital signs, and weight 
X
X
Symptom-directed Physical Exam
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
ECGb
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
DXA (spine & hip)d
X
X
X
X
X
Study Drug Accountability  
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensed/Retrievede
X
X
X
X
X
X
X
X
X
Xe
Serum Chemistry and Liver Function Testsg
X
X
X
X
X
X
X
X
X
X
X
Est Creatinine Clearance (Cockcroft-Gault) 
X
X
X
X
X
X
X
X
X
X
X
Hematology 
X
X
X
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 (quantitative)  
X
X
X
X
X
X
X
X
X
X
X
HBV Serologyh
X
X
X
X
X
X
X
X
X
X
X
Virology (resistance surveillance)
X
X
X
X
X
X
X
X
X
X
Fibrotest®
X
X
X
X
X
Fasting Blood for Bone Biomarkersi
X
X
X
X
X
Fasting Urine for Renal Biomarkersi
X
X
X
X
X
Fasting Metabolic Panelj
X
X
X
X
X
Urine Pregnancy Testk
X
X
X
X
X
X
X
X
X
X

Tenofovir Alafenamide (TAF)
Protocol GS-US-320-0108
Final
Gilead Sciences, Inc.
Amendment 3.1
CONFIDENTIAL
Page 123
23 February 2016
Visit windows
Week
168
192
216
240
264
288
312
336
360
384/EDo
FUp
±28 days
±7 days
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
Serum and plasma for storage 
X
X
X
X
X
X
X
X
X
X
X (serum only)
Urine for Storage
X
X
X
X
X
X
X
X
X
X
Ophthalmologic substudyn −fundoscopic examination with slit lamp
Xn
Hepatic Ultrasoundr
X
X
X
X
X
X
X
X
X
X
a
The visit window for Week 48 visit is −14 days. The visit window for Week 96 is ±14 days.
b
Subjects must rest quietly in the supine position for a minimum of 5 minutes prior to the recording
c
Vital signs include blood pressure, pulse, respiration rate, and temperature 
d
DXA scans will be performed only at sites in China with capability. The initial (baseline) 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 −14 days only. DXA is required for Early Discontinuation (ED) visit if not done within the last 24 weeks.
e
Subjects already assigned to open-label TAF 25 mg QD per Amend 2.1 continue on open-label TAF 25 mg QD. Otherwise, blinded study drug will be dispensed until 
Week 144 visit. Open label TAF will be dispensed from Week 144 through Week 360. At Week 384/ED, study drug will not be dispensed
f
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 12 visits.
g
Serum chemistry and Liver Function Tests : alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, LDH, CPK, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in subjects 
with total amylase > 1.5 × ULN), and PTH. PTH analyzed at all visits except for Screening through Week 96, and then at Weeks 120, 144, and then every 48 weeks through 
Week 384/ED. At Baseline, Weeks 24, 48, 72, 96, 120, 144, 192, 240, 288, 336 and 384/ED, subject will be fasting for serum and glucose and metabolic panel. Coagulation 
panel will be done at Screening and then as a reflex only test for ALT flares.
h
HBeAg and HBeAb will be done at Screening and Baseline visits. HBsAg and reflex HBsAb will be done at Screening and Baseline visits, and every 12 to 16 weeks until 
week 144, every 24 weeks untile Week 384/ED and at Follow Up visits Weeks 12 and 24.  
i
Blood for selected bone biomarkers and 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
Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). 
k
For female subjects of childbearing potential. In the event of a positive urine test, a serum pregnancy test will be done
l
The optional intensive PK substudy will be conducted once at either of the Weeks 4,8 or 12 visits in a subset (n=16 and up to n= 32) of subjects who provide a separate 
consent form, at select sites. Subjects should fast (no food or drinks for a minimum of 8 hours except water for up to 1 hour) prior to the scheduled intensive PK visit. Subjects 
participating in the PK substudy should not take their dose on the morning of the PK visit. Study medication will be administered in clinic on the morning of intensive PK. 
Subjects who have been routinely dosing in the evening will need to switch to a morning dosing regimen at least 10 days prior to the intensive PK visit. After collection of the 
pre-dose sample and the PBMC sample (at sites which can process PBMCs), subjects will be provided a standardized meal (approximately 600 kcal, 27% fat; details can be 
found in the PK Manual). Within 5 minutes after consuming the standardized meal, subjects will be dosed with TAF. Intensive PK sampling will then occur. Subjects will be 
restricted from further water intake for until 2 hours after and food intake until 4 hours after dosing. 
m
Subjects participating in the PK substudy (at sites which can process PBMCs), will also be asked to provide a PBMC (pre-dose) sample at the intensive PK substudy visit to 
assess intracellular TFV-DP concentration in PBMCs

Tenofovir Alafenamide (TAF)
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CONFIDENTIAL
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n
For a subset of subjects (n = 30), who provide a separate consent form, a substudy will be conducted to assess ophthalmologic findings, including fundoscopic examination 
with retinal photographs (both eyes). The examination can be conducted anytime during the screening period, but must be completed prior to the first dose of the study drug,
and will be conducted at Weeks 24, 48, 72, 96, and 144 at select sites. Required for Early Discontinuation (ED) visit if prior to Week 144 and not done within the last 
24 weeks. An examination of the full retinal field should be conducted noting changes or abnormalities. Photographs of the retina must be taken at each exam and filed in the 
subject’s source medical records. A central vendor will be used to assess the retinal photographs.
o
The Early Discontinuation (ED) visit should be performed within 72 hours of the last study drug dose (+ 3 days)
p
Subjects who discontinue study drug for reasons other than HBsAg loss with confirmed seroconversion to anti-HBs will be followed every 4 weeks for 24 weeks or up to 
initiation of alternative, commercially available HBV therapy, whichever occurs first. Subjects who lose HBsAg with confirmed seroconversion to anti-HBs should 
discontinue study drug within 3-6 months following confirmation of HBsAg loss and seroconversion to anti-HBs or after Week 48, if seroconversion occurs prior to this visit. 
These subjects will be followed off treatment every 4 weeks for 12 weeks and then per the study visit schedule through Week 384/ED.
q
Complete the Fracture Risk Assessment specific eCRF at sites in China with DXA capability only.
r
Hepatic ultrasound for HCC surveillance

Tenofovir Alafenamide (TAF)
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Final
Gilead Sciences, Inc.
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CONFIDENTIAL
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Appendix 3.
Intensive Pharmacokinetic Substudy Assessment Schedule (at selected 
sites in a subset of subjects [n=16 and up to n=32])
Time Point (Once at either of the Week 4, 8 or 12 visits)
0 (within 30 minutes of dose)*
5 minutes post dose
15 minutes post dose
30 minutes post dose
45 minutes post dose
1 hour post dose
1.5 hours post dose
2 hours post dose
3 hours post dose
4 hours post dose
5 hours post dose
8 hours post dose
12 hours post dose
24 hours post dose
*
Subjects participating in the PK substudy (at sites which can process PBMCs), will also be asked to provide a PBMC 
(pre-dose) sample at the intensive PK substudy visit to assess intracellular TFV-DP concentration in PBMCs

Tenofovir Alafenamide (TAP) 
Protocol GS-US-320-0108 
Gilead Sciences, Inc. 
Final 
Amendment 3.1 
Appendix 4. 
Management of Clinical and Laboratory Adverse Events 
Grade 1 
L------G-ra_d_e_2----~~ 
Ll ------G-ra_d_e_3----~~ 
LI _________ G_r_ad_e_4--------~ 
May continue 
Repeat lab to 
dosing at the 
confirm toxicity 
discretion of the 
grade 
investigator 
lf confirmed and possibly and/or probably related to 
investigational medicinal products: 
l. Withhold investigational medicinal products until~ Grade 2 
2. 
Restart all investigational medicinal products at full dose 
l 
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 
l 
If c 
Repeat lab to 
confirm toxicity 
grade 
l 
inve 
onfirmed and unrelated to 
stigational medicinal products, 
ng may continue at the 
dosi 
disc retion of the investigator 
If confirmed and 
possibly or probably 
-.. related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently 
and follow at pe1iodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained 
Ir Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 
CONFIDENTIAL 
Page 126 
23 February 2016 

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Amendment 3.1
CONFIDENTIAL
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Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18 June 2012
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

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
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
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 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
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
100.0 to 125.0 GI/L
50,000 to 100,000/mm3
50.0 to 100.0 GI/L
25,000 to 50,000/mm3
25.0 to 50.0 GI/L
25,000/mm3
25.0 GI/L
WBCs 
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.0 GI/L to 2.5 GI/L
1.5 to 2.0 GI/L
1.0 to 1.5 GI/L
1.0 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
—
—

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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% 

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 mEq/L to LLN
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 mmol/L to LLN
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
146 to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146 to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
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
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4 mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 mg/dL to LLN
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63 mmol/L to LLN 
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 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 4.5 mg/dL
1.12 to 1.46 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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol /L to LLN
57 to 87 μmol /L
27 to 57 μmol /L
27 μmol /L
Creatinine 
1.50 to 2.0 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol /L
177 to 265 μmol /L
265 to 530 μmol /L
530 μmol /L
Bicarbonate
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
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L
LDL
(Fasting)
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
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

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
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
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
3.0 g/dL to LLN
2.0 to 3.0 g/dL
2.0 g/dL
NA
30 g/L to LLN
20 to 30 g/L
20 g/L

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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
Note: 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 
(e.g., 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 
(e.g., 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 (e.g., 
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, e.g., 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, e.g., Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event 
(e.g., 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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RESPIRATION
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 Respiration 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 
Respiration failure with 
ventilatory support indicated
Pediatric 14 Years
Wheezing OR minimal 
increase in respiration 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%
Respiration 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 [e.g., tube feeding 
or total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated 
(e.g., 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 (e.g., sepsis or 
perforation) 
Constipation 
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences (e.g., 
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 
(e.g., 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 
(e.g., 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 
(e.g., IV fluids)
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening 
consequences 
(e.g., 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 
(e.g., 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 
(e.g., hypotensive shock)

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

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

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

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

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

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

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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (e.g., 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 
(e.g., 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 
(e.g., 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
(e.g., myxedema coma)
Lipoatrophy (e.g., fat loss from 
the face, extremities, buttocks)
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults)
Detectable on physical exam 
by health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA

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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding (IMB)
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding 
greater in duration or amount 
than usual menstrual cycle
Hemorrhage with 
life-threatening hypotension 
OR Operative intervention 
indicated
Urinary Tract obstruction 
(e.g., 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 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual social 
& functional activities
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference 
with usual social & 
functional activities
Systemic antimicrobial 
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 
(e.g., septic shock)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.

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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations
1. Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential
The risks of treatment with study drug have not been evaluated. If females are using hormonal 
agents for contraception, the safety and/or efficacy may be affected by possible drug-drug 
interaction. However, it is recommended that the hormonal agent be continued and that a 
non-hormonal method(s) be used concurrently. If females utilize hormonal agents as one of their 
contraceptive methods, it is required that the same hormonal method be used for at least 
3 months before study dosing. Please refer to the latest version of the Investigator’s Brochure for 
GS-7340 for additional information
2. Definition of Female of Childbearing Potential

For the purposes of this study, a female subject of childbearing potential is a nonmenopausal 
female who has not had a hysterectomy, bilateral oophorectomy, or medically documented 
ovarian failure. This definition includes a pubertal female who has not yet started 
menstruating. A woman who has had a tubal sterilization is considered to be of childbearing 
potential.

A female subject ≤54 years in age, with the absence of normal menses is considered to be of 
childbearing potential. Exceptions must be discussed with the medical monitor.
A female subject may be considered menopausal in either of the following conditions:

Surgical menopause: Appropriate medical documentation of prior complete bilateral 
oophorectomy (ie, surgical removal of the ovaries and occurring at the age at which the 
procedure was performed)

Age > 54 years, with the cessation (for > 12 months) of previously occurring menses due to 
ovarian failure, will not be considered to be childbearing potential. 
3. Contraceptive Requirements for Female Subjects
Female subjects of childbearing potential who engage in intercourse must agree to utilize 
protocol specified methods of contraception from the screening visit throughout the study period 
and for 30 days following the last dose of study drug. Female study subjects who are not 
heterosexually active must provide periodic confirmation of continued abstinence from 
heterosexual intercourse and regular pregnancy testing while participating in the study. The 
investigator will counsel subjects on the protocol specified method(s) for avoiding pregnancy in 
case the subject chooses to engage in heterosexual intercourse.
Protocol specified contraceptive methods are as follows: (1) a combination of one hormonal 
method and one barrier method; (2) two barrier methods where one method is the male condom; 
or (3) use of an intrauterine device (IUD) or tubal sterilization; see Appendix Table 1 below; or 
(4) complete abstinence from intercourse. Periodic abstinence from intercourse (e.g. calendar, 
ovulation, sumptothermal, post-ovulation methods) is not permitted.

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Acceptable hormonal methods include injectable progesterone, progesterone implants, 
combination oral contraceptives, transdermal contraceptive patch, and vaginal ring. Acceptable 
barrier methods include diaphragm with spermicide, cervical cap with spermicide, and the male 
condom. The use of spermicide is not recommended if the subject or subject’s partner is infected 
with HIV. Female subjects must use either a hormonal method or a barrier method if the partner 
has a vasectomy. If a subject has undergone tubal sterilization or has had a Copper T 380A IUD 
or LNg 20 IUD inserted, no other contraception is needed.  
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and the 
contraception methods described below must be used. Female subjects who utilize hormonal 
contraceptives as one of their birth control methods must have used the same method for at least 
3 months before study dosing.
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline (Day 1) prior to receiving the first dose of study 
drug. Lactating females must discontinue nursing before IMP administration.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Methods to Use by Themselves
Combination Methods
Hormone Methods
(choose one and use with 
a barrier method)
Barrier Methods
(use both OR choose one and use with 
a hormone method)
Intrauterine Devices (IUDs)

Copper T 380A IUD

LNg 20 IUD
Tubal Sterilization
Estrogen and Progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicide
OR

Cervical cap with spermicide

Male condom (with or without 
spermicide)
Partner’s vasectomy must be used with a hormone or barrier method.
The investigator will counsel all subjects on the most effective method(s) for avoiding pregnancy 
during the study.
4. Contraceptive Requirements for Male Subjects
Male subjects must agree to use protocol specified method of contraception during heterosexual 
intercourse and avoid sperm donation from the time of the first dose of study drug and 
throughout the study period, and for at least 30 days after administration of the last dose of study 
medication 

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Use of condoms, except for lambskin, has been proven to decrease the risk of transmission of 
HIV and other sexually transmitted diseases. The use of spermicide is not recommended if the 
subject or subject’s partner is infected with HIV.
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. 
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.6.2.1.