A Phase 3b, Multicenter, Open-Label Study to Evaluate Switching From an Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fixed-Dose Combination Regimen or a Tenofovir Disoproxil Fumarate Containing Regimen to Fixed-Dose Combination of Bictegravir/Emtricitabine/Tenofovir Alafenamide in Elderly, Virologically-Suppressed, HIV-1 Infected Subjects Aged ≥ 65 Years
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3b, Multicenter, Open-Label Study to Evaluate Switching from 
an Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
Fixed-Dose Combination Regimen or a Tenofovir Disoproxil Fumarate 
Containing Regimen to Fixed-Dose Combination of Bictegravir
/Emtricitabine/Tenofovir Alafenamide in Elderly, 
Virologically-Suppressed, HIV-1 Infected Subjects Aged ≥ 65 Years
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
125,589
2017-003428-61
NCT03405935
Indication:
HIV-1 Infection
Protocol ID:
GS-US-380-4449
Clinical Program 
Manager:
Name:
Telephone:
Mobile:
Gilead Study Director:
Name:
Telephone:
Mobile:
Gilead Medical 
Monitor:
Name:
Telephone:
Mobile:
Protocol Version/Date:
Original:
22 September 2017
Amendment 1:
03 January 2018
Amendment 2:
18 December 2018
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable Institutional Review 
Board or Independent Ethics Committee. The information is only to be used by you in connection 
with authorized clinical studies of the investigational drug described in the protocol. You will not 
disclose any of the information to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessary to obtain informed consent from those persons to whom the drug 
may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
(rJ GILEAiJ 

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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....................................................................11
1.
INTRODUCTION ..............................................................................................................................................14
1.1.
Background ............................................................................................................................................14
1.2.
Bictegravir..............................................................................................................................................15
1.2.1.
General Information .............................................................................................................15
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................15
1.2.3.
Clinical Trials of Bictegravir................................................................................................17
1.3.
Information about Emtricitabine (Emtriva®, F)......................................................................................30
1.4.
Information about tenofovir alafenamide (TAF, GS-7340) ...................................................................31
1.4.1.
Clinical Trials of Single Agent Tenofovir alafenamide (TAF, GS-7340) 
or Fixed Dose Combination emtricitabine/tenofovir alafenamide 
(FTC/TAF)...........................................................................................................................31
1.4.2.
Clinical Trials of FTC/TAF as part of 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) ...........................33
1.5.
Information about Bictegravir/emtricitabine/tenofovir alafenamide (Bictegravir/F/TAF) ....................35
1.5.1.
GS-US-141-1233: Study of the Relative Bioavailability of Bictegravir, 
FTC, and TAF between Bictegravir/F/TAF and Bictegravir + F/TAF ................................35
1.6.
Rationale for This Study ........................................................................................................................36
1.7.
Risk/Benefit Assessment for the Study..................................................................................................37
1.8.
Compliance ............................................................................................................................................37
2.
OBJECTIVES.....................................................................................................................................................38
3.
STUDY DESIGN................................................................................................................................................39
3.1.
Endpoints ...............................................................................................................................................39
3.2.
Study Design..........................................................................................................................................39
3.3.
Study Treatments ...................................................................................................................................40
3.4.
Duration of Treatment............................................................................................................................40
3.5.
End of Study...........................................................................................................................................40
3.6.
Post Study Care......................................................................................................................................40
3.7.
Biomarker Testing..................................................................................................................................40
3.7.1.
Biomarker Samples to Address the Study Objectives:.........................................................40
4.
SUBJECT POPULATION..................................................................................................................................42
4.1.
Number of Subjects and Subject Selection ............................................................................................42
4.2.
Inclusion Criteria....................................................................................................................................42
4.3.
Exclusion Criteria...................................................................................................................................43
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................45
5.1.
Subject Enrollment.................................................................................................................................45
5.2.
Description and Handling.......................................................................................................................45
5.2.1.
Formulation..........................................................................................................................45
5.2.2.
Packaging and Labeling .......................................................................................................45
5.2.3.
Storage and Handling...........................................................................................................46
5.3.
Dosage and Administration of B/F/TAF................................................................................................46

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5.4.
Prior and Concomitant Medications.......................................................................................................46
5.5.
Accountability for Investigational Medicinal Product (IMP).................................................................48
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Pretreatment Assessments......................................................................................................................49
6.2.1.
Screening Visit .....................................................................................................................49
6.2.2.
Day 1 Visit ...........................................................................................................................50
6.3.
Treatment Assessments..........................................................................................................................51
6.3.1.
Treatment Visits (Weeks 4-96) ............................................................................................51
6.4.
Treatment Assessments (Post Week 96 extension phase)......................................................................52
6.4.1.
Early Study Drug Discontinuation Visit...............................................................................53
6.4.2.
30 Day Follow-Up Visit.......................................................................................................54
6.5.
Assessments for Premature Discontinuation from Study.......................................................................55
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................55
6.7.
End of Study...........................................................................................................................................55
6.8.
Post Study Care......................................................................................................................................55
6.9.
Blood Samples .......................................................................................................................................56
6.10.
Urine Samples........................................................................................................................................57
6.11.
Blood and Urine Sample Storage...........................................................................................................57
6.12.
Virologic Failure....................................................................................................................................57
6.12.1.
Management of Virologic Rebound .....................................................................................57
6.12.2.
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Drug Discontinuation 
or at Week 48, Week 72 or Week 96 ...................................................................................60
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................61
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................61
7.1.1.
Adverse Events.....................................................................................................................61
7.1.2.
Serious Adverse Events........................................................................................................61
7.1.3.
Assessment of Causality for Study Drugs and Procedures...................................................62
7.1.4.
Assessment of Severity ........................................................................................................62
7.2.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................63
7.2.1.
Adverse Events.....................................................................................................................63
7.2.2.
Serious Adverse Events........................................................................................................63
7.3.
Gilead Reporting Requirements.............................................................................................................64
7.4.
Toxicity Management ............................................................................................................................65
7.4.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................65
7.4.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................65
7.4.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................65
7.4.4.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis B 
Management.........................................................................................................................66
7.4.5.
Management of Potential Hepatobiliary Toxicity ................................................................67
7.4.6.
Hepatitis C Management......................................................................................................67
7.5.
Special Situations Reports......................................................................................................................68
7.5.1.
Definitions of Special Situations..........................................................................................68
7.5.2.
Instructions for Reporting Special Situations.......................................................................68
8.
STATISTICAL CONSIDERATIONS................................................................................................................70
8.1.
Analysis Objectives and Endpoints........................................................................................................70
8.1.1.
Analysis Objectives..............................................................................................................70
8.1.2.
Primary Endpoint .................................................................................................................70
8.1.3.
Secondary Endpoints............................................................................................................70

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8.1.4.
Other Endpoints of Interest ..................................................................................................70
8.2.
Analysis Conventions.............................................................................................................................71
8.2.1.
Analysis Sets ........................................................................................................................71
8.3.
Data Handling Conventions ...................................................................................................................71
8.4.
Demographic Data and Baseline Characteristics ...................................................................................71
8.5.
Efficacy Analysis ...................................................................................................................................71
8.6.
Safety Analysis.......................................................................................................................................72
8.6.1.
Extent of Exposure...............................................................................................................72
8.6.2.
Adverse Events.....................................................................................................................72
8.6.3.
Laboratory Evaluations ........................................................................................................72
8.7.
Sample Size............................................................................................................................................72
9.
RESPONSIBILITIES..........................................................................................................................................73
9.1.
Investigator Responsibilities ..................................................................................................................73
9.1.1.
Good Clinical Practice..........................................................................................................73
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................73
9.1.3.
Informed Consent.................................................................................................................74
9.1.4.
Confidentiality......................................................................................................................74
9.1.5.
Study Files and Retention of Records ..................................................................................74
9.1.6.
Case Report Forms...............................................................................................................76
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................76
9.1.8.
Inspections............................................................................................................................76
9.1.9.
Protocol Compliance............................................................................................................77
9.2.
Sponsor Responsibilities ........................................................................................................................77
9.2.1.
Protocol Modifications.........................................................................................................77
9.2.2.
Study Report and Publications .............................................................................................77
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
9.3.1.
Payment Reporting...............................................................................................................77
9.3.2.
Access to Information for Monitoring..................................................................................78
9.3.3.
Access to Information for Auditing or Inspections ..............................................................78
9.3.4.
Study Discontinuation..........................................................................................................78
10.
REFERENCES ...................................................................................................................................................79
11.
APPENDICES ....................................................................................................................................................81
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table..........................................................................................................83
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................86
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............87
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, Definition 
of Male Fertility and Contraceptive Requirements...............................................................109
Appendix 6.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC Guidelines) ...........................110

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LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-141-1218: Bictegravir Mean (%CV) PK Parameters Following Single Doses 
of Bictegravir in Healthy Subjects (Bictegravir PK Analysis Set; Part A: Single 
Dosing)...................................................................................................................................21
Table 1-2.
GS-US-141-1218: Bictegravir Plasma Pharmacokinetic Parameters by Bictegravir 
Dose Following Multiple-Dose Administration of Bictegravir (Analysis Set: 
Bictegravir PK Part B: Multiple-Dose) ..................................................................................22
Table 1-3.
GS-US-141-1218: Statistical Comparison of Bictegravir Pharmacokinetic 
Parameters Following Single-Dose Administration of Bictegravir in the Fasted and 
Fed States (Bictegravir PK Analysis Set)...............................................................................23
Table 1-4.
Trough Bictegravir Plasma Concentrations at Steady State Following Bictegravir 
Administration Under Fasting Conditions and Corresponding Protein-Adjusted IQ95 
Values (Bictegravir PK Analysis Set) ....................................................................................24
Table 5-1.
Prior and Concomitant Medications.......................................................................................47
LIST OF IN-TEXT FIGURES
Figure 1-1.
GS-US-141-1219: Mean and 95% CIs of Change from Baseline in HIV-1 RNA 
(log10 copies/mL) (PP Analysis Set).......................................................................................24
Figure 6-1.
Virologic Rebound Schema....................................................................................................59

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3b, Multicenter, Open-Label Study to Evaluate Switching 
from an Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
Fixed-Dose Combination Regimen or a Tenofovir Disoproxil 
Fumarate Containing Regimen to Fixed-Dose Combination of 
Bictegravir/Emtricitabine/Tenofovir Alafenamide in Elderly, 
Virologically-Suppressed, HIV-1 Infected Subjects Aged ≥ 65 Years
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
125,589
2017-003428-61
NCT03405935
Study Centers 
Planned:
Approximately 30 centers in Europe
Objectives:
The primary objective of this study is:

To characterize the virologic efficacy of switching virologically 
suppressed subjects on an E/C/F/TAF FDC or TDF-containing 
regimen to B/F/TAF FDC defined by HIV-1 RNA <50 copies/mL 
at Week 24
The secondary objectives of this study are:

To characterize the safety and tolerability of switching to 
B/F/TAF FDC from an E/C/F/TAF FDC or TDF-containing 
regimen through Week 96

To characterize the virologic efficacy of switching to B/F/TAF 
FDC defined by HIV-1 RNA <50 copies/mL at Week 48, Week 
72 and Week 96.

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Study Design:
Open-label, multicenter, single arm study to evaluate switching from 
either E/C/F/TAF FDC, or TDF and FTC-containing ‘backbone’ 
regimen plus a third agent to bictegravir 50 mg / emtricitabine 
200 mg / tenofovir alafenamide 25 mg (B/F/TAF) FDC in 
virologically-suppressed, HIV-1 infected subjects aged ≥65 years.
All eligible subjects who complete GS-US-292-1826, Week 48 and 
are at least 65 years old at the screening visit will be allowed to enter. 
Subjects can proceed directly into the study after the 
GS-US-292-1826 study 30-day Follow-Up visit or the subject may 
enroll even if the subject has already completed and left the prior 
protocol, as long as the subject remains virologically suppressed on a 
stable regimen. A stable regimen is defined by no change in the ARV 
regimen for ≥3 months prior to the screening visit.
Subjects not previously participating in GS-US-292-1826 will be able 
to enroll as long as they meet all eligibility criteria.
The GS-US-292-1826 30-day Follow-Up visit may coincide with the 
Screening visit for this study. Labs drawn during this visit may be 
utilized for this study as long as the labs are within 30 days of the 
Day 1 visit.
Subjects will be treated for at least 96 weeks.
Number of Subjects 
Planned:
Approximately 80 subjects in total
Target Population:
All subjects ≥65 years old at the time of the screening visit who are 
currently receiving either E/C/F/TAF FDC or a TDF-based regimen 
are eligible to enroll as long as the subject meets all eligibility
criteria.
Duration of 
Treatment:
Treatment duration is at least 96 weeks.
At the Week 96 Visit, subjects in a country where B/F/TAF FDC is 
not yet commercially available, will be given the option to receive 
B/F/TAF FDC for up to an additional 48 weeks (up to week 144) and 
attend study visits every 12 weeks followed by 30 Day Follow-Up 
visit; or until Gilead Sciences elects to discontinue the study in that 
country, whichever occurs first. Subjects who complete the study 
through Week 96 Visit and do not further continue participation in the 
study, will be required to return to the clinic 30 days after the Week 
96 Visit for a 30-Day Follow-Up Visit.

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Diagnosis and Main 
Eligibility Criteria:
Medically stable HIV-1 infected subjects who meet the following
criteria:

Age years

Currently receiving an ARV regimen of E/C/F/TAF FDC (or 
FTC/TDF + 3rd agent if currently or previously participated in
GS-US-292-1826) for ≥3 months

Documented plasma HIV-1 RNA < 50 copies/mL during 
treatment with E/C/F/TAF (or FTC/TDF + 3rd agent if currently or 
previously participated in GS-US-292-1826) for the last 2 visits
preceding the Screening Visit (or undetectable HIV-1 RNA level 
according to the local assay being used if the limit of detection is 
≥ 50 copies/mL)
A) Unconfirmed virologic elevations of ≥ 50 copies/mL but 
< 400 copies/mL (transient detectable viremia, or “blip”) in the 
past are acceptable.
B) If the lower limit of detection of the local HIV-1 RNA assay is < 
50 copies/mL (e.g., 20 copies/mL), the plasma HIV-1 RNA level 
cannot exceed 50 copies/mL on two consecutive HIV-1 RNA 
tests after < 50 copies/mL has been achieved.

Adequate renal function, an eGFR ≥ 30 mL/min according to the 
Cockcroft-Gault formula for creatinine clearance
Study Procedures/
Frequency:
After Screening procedures, study visits will occur at Day 1, Weeks 
4, 12, 24, 36, 48, 60, 72, 84 and 96.
Laboratory analyses (chemistry, hematology, and urinalysis), HIV-1 
RNA, CD4+ cell count, assessment of adverse events and 
concomitant medications, and complete or symptom directed physical 
examinations will be performed at all study visits.
Subjects screening visit should be performed within 30 days from the 
Day 1 visit to determine eligibility for this study. The 
GS-US-292-1826, 30 Day Follow-Up visit may be utilized for this 
study’s Screening visit if Day 1 is within 30 days. Any assessments 
that are over 30 days prior to Day 1will need to be repeated for the 
current study.
Blood and urine for selected evaluations of renal safety, 
inflammation, and platelet and coagulation function will be collected 
at Day 1, Weeks 4, 12, 24, 48, 60, 72, 84 and 96. A portion of the 
biomarker blood sample obtained at Day 1, Weeks 4, 12, 24, 48, 60, 
72, 84 and 96 may be utilized to assess study drug PK. This will be a 
random sample with the date and time of the subject’s last medication 
dose recorded
Adverse events and concomitant medications will be assessed at each 
visit.

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Test Product, Dose, 
and Mode of 
Administration:
bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 
25 mg (B/F/TAF) FDC administered orally, once daily, without 
regard to food
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:

Adverse events through Week 24

Adverse events through Week 48

Adverse events through Week 72

Adverse events through Week 96
Efficacy:
Primary Endpoint:

HIV-1 RNA <50 copies/mL at Week 24 - defined by the Food and 
Drug Administration (FDA) snapshot algorithm.
Secondary Endpoints:

HIV-1 RNA <50 copies/mL at Week 48 - defined by the Food and 
Drug Administration (FDA) snapshot algorithm.

HIV-1 RNA <50 copies/mL at Week 72 - defined by the Food and 
Drug Administration (FDA ) snapshot algorithm.

HIV-1 RNA <50 copies/mL at Week 96 - defined by the Food and 
Drug Administration (FDA) snapshot algorithm.
Patient reported 
outcomes:
Health related questionnaires will be administered, including the 
Visual Analogue Scale (VAS), HIV Treatment Satisfaction 
(HIVTSQ), EQ-5D, Short Form 36 Health Survey (SF-36), and 
Functional Assessment of Chronic Illness Therapy − Fatigue 
(FACIT-F).

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Statistical Methods:
The sample size is based on feasibility of conducting a study with 
≥65 years old subjects.
The efficacy endpoints will be characterized by a point estimate and 
95% confidence intervals.
Descriptive statistics will summarize baseline characteristics, 
efficacy, safety, and patient reported outcomes data.
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
ABC/3TC
abacavir/lamivudine, Epzicom, Kivexa
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ARV
Antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time curve
BUN
blood urea nitrogen
B/F/TAF
bictegravir/emtricitabine/tenofovir alafenamide, GS-9883/F/TAF, Biktarvy
CBC
complete blood count
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) concentration of 
drug
CNS
central nervous system
COBI, /co
cobicistat, C, (GS-9350)
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization
CYP
cytochrome P450
DNA
deoxyribonucleic acid
DRV
Darunavir
PV&E
Pharmacovigilance and Epidemiology
DTG
dolutegravir, Tivicay
ECG
Electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
eGFRCG
Estimated glomerular filtration rate according to the Cockcroft-Gault formula
EVG
elvitegravir, E
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Genvoya
E/C/F/TDF
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, Stribild
EQ-5D
EuroQol 5D patient questionnaire
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination

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FTC/TAF
emtricitabine/tenofovir alafenamide, F/TAF, Descovy
FTC, F
emtricitabine, Emtriva
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GLSM
geometric least squares mean
GSI
Gilead Sciences, Inc.
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high-density polyethylene
hERG
human Ether-à-go-go-Related Gene
HIV
human immunodeficiency virus
HIV TSQ
HIV Treatment Satisfaction Status Questionnaire
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IND
Investigational New Drug (Application)
INSTI
integrase strand-transfer inhibitors
IRB
institutional review board
IWRS
interactive web response system
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MH
Mantel-Haenszel
min
Minute
mmHg
millimeters mercury
nM
nanoMolar
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
P-gp
P-glycoprotein
PI
protease inhibitor
PK
Pharmacokinetic
PT
preferred term
PT
prothrombin time
QD
once daily
RAL
raltegravir
RNA
ribonucleic acid
SA
single agent

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SAE
serious adverse event
SF-36
Short Form 36 Health Survey
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate, Viread
TFV-DP
tenofovir diphosphate (TFVpp)
tmax
the time (observed time point) of Cmax
UGT1A1
uridine 5'-diphospho-glucuronosyltransferase
UGT
uridine glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
VAS
Visual analog scale

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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 (HIV-1) infection is a life-threatening and serious disease that
is of major public health interest around the world. There are approximately 2.4 million people in
North America and Western and Central Europe living with HIV-1 and 37 million people
worldwide {UNAIDS 2016}. The infection, if left untreated or suboptimally treated, is 
characterized by deterioration in immune function, ultimately resulting in death. Therapeutic 
strategies for the treatment of HIV-1 disease have been significantly advanced by the availability 
of highly active antiretroviral therapy (HAART); the introduction of HAART was associated 
with a dramatic decrease in acquired immune deficiency syndrome (AIDS)-related morbidity and 
mortality {Palella 1998}, {Mocroft 1998}, {Sterne 2005}.
The success of potent and well-tolerated ART means that morbidity and mortality in the
HIV-infected population is increasingly driven by non-AIDS–associated comorbidities. Clinical
attention has become more focused on the optimization of tolerability, long-term safety, and
adherence of potent ART regimens {Costagliola 2014}. In addition, there remains a significant 
medical need for new, effective therapies that take into consideration HIV genetic variability, the 
aging HIV-infected population, ARV resistance, non-HIV comorbidities, and regimen 
simplification. For ART-naive HIV-infected patients, current treatment guidelines suggest that 
initial therapy consist of 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) and either an 
integrase strand transfer inhibitor (INSTI), the nonnucleoside reverse transcriptase inhibitor 
(NNRTI), rilpivirine, or the boosted protease inhibitor (PI), darunavir (DRV) {European AIDS 
Clinical Society (EACS) 2017}.Virologically suppressed, HIV-infected patients may switch 
from their current regimen because of safety or tolerability concerns or for regimen 
simplification. All patient populations may benefit from once-daily fixed-dose combination 
(FDC) regimens as these have been shown to provide increased adherence and improved clinical 
and virologic outcomes {Sterrantino 2012}, {Aldir 2014}
Tenofovir (TFV) is a nucleotide analog that inhibits HIV-1 reverse transcription. While tenofovir
disoproxil fumarate (TDF), an oral prodrug of TFV, is a preferred NtRTI for initial therapy,
nephrotoxicity is an identified risk, and reductions in bone mineral density (BMD) have been
shown that are larger than those seen with other NRTIs. Tenofovir alafenamide (TAF) is also an
oral prodrug of TFV. TAF is more stable in plasma than TDF, provides higher intracellular
levels of the active phosphorylated metabolite tenofovir diphosphate (TFV-DP), and
approximately 90% lower circulating levels of TFV relative to TDF at the clinical doses. The 
distinct metabolism of TAF offers the potential for an improved clinical profile compared with 
TDF.
Bictegravir is a potent inhibitor of HIV-1 integrase that is being evaluated for the treatment of 
HIV-1 infection {Gallant 2016}. Antiviral testing has shown that bictegravir is active against a 
broad panel of HIV-1 viral lab strains and clinical isolates. Bictegravir (BIC; B) is a potent 
INSTI that is being evaluated for the treatment of HIV-1 infection {Gallant 2016} and that has 
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In a Phase 2 study of ART-naive HIV-infected subjects, BIC was compared with the 
guideline-recommended INSTI, dolutegravir (DTG) {Sax 2017}. When coadministered with the 
guideline-recommended N(t)RTI backbone, emtricitabine (FTC; F) and tenofovir alafenamide 
(TAF), each INSTI demonstrated high ARV activity, with no virologic failures due to resistance, 
and both treatments were safe and well tolerated.
Gilead Sciences (Gilead) has coformulated bictegravir with the NRTI emtricitabine (FTC; F) and
the NtRTI tenofovir alafenamide (TAF) into an FDC tablet that is suitable for once-daily use.
This bictegravir/F/TAF FDC may provide a potent, convenient, tolerable, and practical regimen
for the long-term treatment of patients with HIV infection. Phase 3 studies of the FDC are 
currently underway and Week 48 results are described in section 1.2.3.4.
1.2.
Bictegravir
1.2.1.
General Information
Bictegravir, a potent inhibitor of HIV-1 integrase is being evaluated for the treatment of HIV
infection. Antiviral testing has shown that bictegravir is active against a broad panel of HIV-1 
viral lab strains and clinical isolates. Bictegravir is fully active against a panel of mutant viruses 
with resistance to NRTIs, NNRTIs, and PIs. Integrase mutant viruses that are resistant to the 
INSTIs RAL and EVG remain largely sensitive to bictegravir.
1.2.2.
Preclinical Pharmacology and Toxicology
A core battery of safety pharmacology studies have been conducted with bictegravir. These
include assessments of cytotoxicity, off-target receptor and ion-channel binding, effects on, 
human Ether-à-go-go-Related Gene (hERG) potassium current and papillary muscle action
potential, and in vivo studies in rats and dogs that evaluated effects of bictegravir on all major
organ systems. The volume of distribution of bictegravir ranged between 0.09 and 0.22 L/kg in 
the preclinical species, which indicates that the distribution of bictegravir is limited to the 
extracellular compartment due to its high binding to plasma proteins. The projected half-life of 
bictegravir in humans is approximately 20 hours based upon the estimates of clearance and 
volume of distribution.
1.2.2.1.
Pharmacology
Bictegravir has IC50 values ranging from 1.5 to 2.4 nM, similar to the inhibitory effect of DTG 
and EVG. Bictegravir is highly potent against HIV replication in MT4 cells with an EC50 
(50% effective inhibitory concentration) value of 1.9 nM and a protein adjusted EC95 value of 
361 nM. Bictegravir does not show significant cytotoxicity against dividing and non-dividing 
human PBMCs, primary human hepatocytes and various non-target human cell lines. Bictegravir
is mainly metabolized by uridine 5'-diphospho-glucuronosyltransferase UGT1A1 and
secondarily by CYP3A. Bictegravir does not inhibit major human CYP isoforms or UGT1A1 at
concentrations up to 25 M. Consequently, Bictegravir is unlikely to be a clinically relevant
inhibitor of these enzymes, and is not expected to inhibit the metabolic clearance of drugs
metabolized by these enzymes. Bictegravir only modestly inhibits renal transporter OCT2

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(IC50 = 0.42 M). As a result, bictegravir is not expected to significantly interfere with the key
transporter responsible for creatinine tubular elimination at the clinically projected Cmax.
Additionally, the risk that bictegravir will affect the OCT2-mediated excretion of 
co-administered drugs is considered to be low.
Bictegravir does not activate AhR and only weakly activates PXR at concentrations up to 50 M
(less than 5% and 40% of activation, respectively, compared to positive control compound).
Therefore, bictegravir is not expected to act as an inducer through PXR- or AhR-mediated
pathways at the doses and exposure levels projected in clinical use.
1.2.2.2.
Toxicology
Single oral doses of bictegravir up to 1000 mg/kg were well-tolerated in rats (AD-141-2286). 
The increase in exposure was limited (< 2-fold) between 100 and 300 mg/kg and similar 
exposure was observed between 300 and 1000 mg/kg suggesting saturation of absorption at 
300 mg/kg (AUC0-24 2205 gh/mL and 1931 gh/mL, respectively). In monkeys, single oral 
doses of bictegravir up to 1000 mg/kg were well-tolerated (AD-141-2284). The increase in 
exposure was limited (< 2-fold) between 300 to 1000 mg/kg (AUC0-24 803 gh/mL and 
1078 g h/mL, respectively).
In 2-week (TX-141-2029) and 26-week (TX-141-2031) oral toxicity studies in rats at doses up to
300 mg/kg/day, bictegravir was well-tolerated with no bictegravir-related effects on clinical
observations, body weight, food consumption, ophthalmic examinations, and anatomic
pathology. The high dose of 300 mg/kg/day was considered the maximum feasible dose based
upon saturation of absorption. The no observed effect level (NOEL) in the 26-week study was
considered to be the high dose of 300 mg/kg/day. At the NOEL, bictegravir exposures in the rat
were considered to be approximately 12-/31-fold higher (males/females) than the projected
steady state human exposure of bictegravir following administration of bictegravir/F/TAF
(50/200/25 mg) QD under fed conditions.
In a 39-week study in monkeys (TX-141-2032), following administration of 1000 mg/kg/day
(high dose) of bictegravir for 39 weeks, pathology data indicated minimal to marked bile duct
hyperplasia and minimal or moderate hepatocyte hypertrophy in both sexes, and minimal
regenerative hyperplasia and minimal or slight neutrophil infiltrate in males. The macroscopic
finding of rough surface on the liver in one male administered 1000 mg/kg/day correlated with
moderate hepatocyte hypertrophy and marked bile duct hyperplasia. After a 4-week recovery
period, bictegravir-related microscopic liver findings included marked bile duct hyperplasia, 
slight hepatocyte hypertrophy, minimal regenerative hyperplasia, and slight lymphocyte infiltrate 
in one male and slight bile duct hyperplasia in one female administered 1000 mg/kg/day, while 
the other two animals in the high dose group had no hepatobiliary findings. Minimally to mildly
increased ALT activities (≤ 3.5-fold versus baseline values), likely associated with liver findings,
exhibited reversibility. There were no other adverse findings in the study, including clinical
observations, or effects on body weight, body weight change, food consumption, ECGs,
hematology, coagulation, clinical chemistry, urinalysis, and ophthalmoscopy.

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No bictegravir-related effects were observed in the mid-dose group (200 mg/kg/day) which was
considered the no-observed-effect-level (NOEL). The estimated margin of exposure at the NOEL 
was approximately 5.1-fold based on expected human exposure with the once daily dosing of the 
bictegravir/F/TAF (50/200/25 mg) tablet.
A standard battery of in vitro and in vivo studies was performed to assess the genotoxic potential
of bictegravir. There was no evidence of mutagenic or clastogenic activity in an in vitro bacterial
reverse mutation assay (Study TX-141-2026), a chromosomal aberration assay in human
lymphocytes (Study TX-141-2027), or in a rat micronucleus test (Study TX-141-2029).
1.2.3.
Clinical Trials of Bictegravir
Clinical trials entailing the use of bictegravir include:

GS-US-141-1218, a Phase 1 double blind, randomized, placebo-controlled, first-in-human,
single- and multiple-ascending dose study evaluating the safety, tolerability, and PK of oral
bictegravir in healthy subjects and a randomized, open-label, 2-cohort, 3-period, crossover, 
PK study evaluating the drug interaction potential between F/TAF FDC tablet and bictegravir
in healthy subjects (completed)

GS-US-141-1219, a Phase 1b randomized, double-blinded, sequential cohort
placebo-controlled study of the safety, PK, and antiviral activity of Bictegravir in HIV-1
infected subjects (5 mg, 25 mg,50 mg, 100 mg) (completed)

GS-US-141-1233, a Phase 1,Open-label, Two-Cohort, Multiple-Period, Fixed-Sequence,
Crossover Study to Evaluate 1) the Relative Bioavailability of Two 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (75/200/25 mg and 50/200/25 mg)
Fixed-Dose Combination Tablets Versus a Bictegravir (75 mg) Tablet and a
Emtricitabine/Tenofovir Alafenamide (200/25 mg) Fixed-Dose Combination Tablet
Administered Simultaneously and 2) the Effect of Food on the Pharmacokinetics of
Bictegravir, Emtricitabine and Tenofovir Alafenamide When Administered as
Bictegravir/Emtricitabine/Tenofovir Alafenamide (75/200/25 mg and 50/200/25 mg)
Fixed-Dose Combination Tablets (completed)

GS-US-141-1478, a Phase 1, Open Label, Parallel Group, Adaptive, Single-Dose Study to
Evaluate the Pharmacokinetics of Bictegravir in Subjects with Normal and Impaired Hepatic
Function (in life portion completed)

GS-US-141-1479, a Phase 1, open-label, parallel-group, adaptive single-dose study to
evaluate the PK of Bictegravir in subjects with normal and impaired renal function 
(completed)

GS-US-141-1480, a Phase 1 partially-blinded, randomized, placebo- and positive-controlled
study to evaluate the effect of Bictegravir on the QT/QTc interval in healthy subjects
(completed)

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
GS-US-141-1481, a Phase 1 study to evaluate the pharmacokinetics, metabolism, and
excretion of Bictegravir in healthy subjects (completed)

GS-US-141-1485, a Phase 1 adaptive study to evaluate transporter, CYP-mediated and
UGT1A1 drug-drug interactions between Bictegravir and probe drugs (completed)

GS-US-141-1487, a Phase 1 randomized, Blinded, Placebo-Controlled Phase 1 Study
Evaluating the Effect of Bictegravir on Renal Function as Assessed by Markers of 
Glomerular Filtration Rate (completed)

GS-US-311-1790, a Phase 1Randomized, Open Label, Drug Interaction Study Evaluating the
Effect of F/TAF FDC Tablet or Bictegravir on the Pharmacokinetics of a Representative
Hormonal Contraceptive Medication, Norgestimate/Ethinyl Estradiol (completed)

GS-US-380-1761, a Phase 1 Study to Evaluate Pharmacokinetic Drug-Drug Interaction
Potential between Bictegravir/Emtricitabine/Tenofovir Alafenamide Fumarate
(Bictegravir/F/TAF) and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC)
Tablets (completed)

GS-US-380-1991, a Phase I Single and Multiple Dose Study Evaluating the
Pharmacokinetics, Safety, and Tolerability of Bictegravir/Emtricitabine/Tenofovir 
Alafenamide Fumarate (Bictegravir/FTC/TAF) in Healthy Japanese and Caucasian Subjects 
(ongoing)

GS-US-380-1999, a Phase 1 Multiple Dose Study to Evaluate the Pharmacokinetic 
Drug-Drug Interaction Potential between Bictegravir/Emtricitabine/Tenofovir Alafenamide 
Fumarate and Sofosbuvir/Velpatasvir/GS-9857 in Healthy Subjects (completed)

GS-US-380-3908, a Phase 1, Blinded, Placebo-controlled, Two-period Crossover Drug
Interaction Study to Assess the Effect of Bictegravir/F/TAF on Metformin Pharmacokinetics 
in Healthy Subjects (completed)

GS-US-380-3909, a Phase 1, Open Label, Multiple-Cohort, Multiple-Period,
Fixed-Sequence, Drug Interaction Study to Evaluate the Effect of Antacid and Mineral
Supplements on Bictegravir Pharmacokinetics (completed)

GS-US-141-1475, a Phase 2 Randomized, Double-Blinded Study of the Safety and Efficacy
of Bictegravir + Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir + 
Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected, Antiretroviral Treatment-Naive 
Adults (ongoing)

GS-US-380-1489, a Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of GS-9883/Emtricitabine/Tenofovir Alafenamide Versus 
Abacavir/Dolutegravir/Lamivudine in HIV-1 Infected, Antiretroviral Treatment-Naïve 
Adults (ongoing)

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
GS-US-380-1490, a Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of GS-9883/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir + 
Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected, Antiretroviral Treatment-Naïve 
Adults (ongoing)

GS-US-380-1844, A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of Switching from a Regimen of Dolutegravir and ABC/3TC, or a Fixed Dose 
Combination (FDC) of ABC/DTG/3TC to a FDC of GS-9883/F/TAF in HIV-1 Infected 
Subjects who are Virologically Suppressed (ongoing)

GS-US-380-1878, a Phase 3, Randomized, Open-Label Study to Evaluate the Safety and 
Efficacy of Switching from Regimens Consisting of Boosted Atazanavir or Darunavir plus 
either Emtricitabine/Tenofovir or Abacavir/Lamivudine to GS-9883/Emtricitabine/Tenofovir 
Alafenamide in Virologically Suppressed HIV-1 Infected Adults (ongoing)

GS-US-380-1961, A Phase 3, Randomized, Open Label Study to Evaluate the Safety and 
Efficacy of Switching to a Fixed Dose Combination (FDC) of 
GS-9883/Emtricitabine/Tenofovir Alafenamide (GS-9883/F/TAF) from 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF), 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (E/C/F/TDF) or 
Atazanavir + Ritonavir + Emtricitabine/Tenofovir Disoproxil Fumarate 
(ATV+RTV+FTC/TDF) in Virologically Suppressed HIV-1 Infected Women (ongoing)

GS-US-380-1474, A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and 
Antiviral Activity of the GS-9883/Emtricitabine/Tenofovir Alafenamide (GS-9883/F/TAF) 
Fixed Dose Combination (FDC) in HIV-1 Infected Virologically Suppressed Adolescents 
and Children (ongoing)

GS-US-380-4030, A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and 
Efficacy of Switching from a Regimen of Dolutegravir and Either Emtricitabine/Tenofovir 
Alafenamide or Emtricitabine/Tenofovir Disoproxil Fumarate to a Fixed Dose Combination 
of Bictegravir/ Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected Subjects who are 
Virologically Suppressed (ongoing)
Please refer to the B/F/TAF Investigators’ Brochure for further information about these studies.
1.2.3.1.
Phase 1 Safety and Pharmacokinetics
Study GS-US-141-1218 was a four part, first-in-human study. Parts A and B were randomized,
double-blind, placebo-controlled, single and multiple ascending dose studies of bictegravir in
healthy male and female subjects. Part C was an open label, fixed sequence food effect study
evaluating the effect of food on the PK of bictegravir. Part D was a randomized, open-label,
2-cohort, 3-period, crossover PK study evaluating the drug interaction potential between
FTC/TAF FDC tablet and bictegravir in healthy subjects.

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There was no difference in the overall incidence or type of AEs when bictegravir was 
administered in the fasted and fed states. There was no difference in the overall incidence of AEs 
when bictegravir or FTC/TAF was each administered alone or in combination.
No deaths or pregnancies were reported. No Grade 3 or 4 AEs or SAEs, were reported in any
cohort. Changes in serum creatinine were observed in this study, presumably via inhibition of the 
renal transporter OCT2. In the MAD cohorts (fasted), serum creatinine change at Day 14 ranged 
from 0.05 mg/dL for the 5 mg cohort to 0.18 mg/dL for the 300 mg/dL cohort. In Part D (DDI),
conducted in the fed state (regular meal), subjects received 100 mg bictegravir monotherapy for
7 days and 100 mg bictegravir with FTC/TAF for 7 days, the mean serum creatinine change at
Day 7 was 0.14 mg/dL following bictegravir and 0.17 mg/dL following bictegravir + FTC/TAF. 
All changes returned to baseline after discontinuation of bictegravir.
The majority of laboratory abnormalities were Grade 1 or Grade 2 in severity. Grade 3 laboratory
abnormalities included 10 subjects with Grade 3 urine dipstick tests for blood. All of these
subjects were female, none of the labs were considered by the Investigator to be clinically
significant, and all were associated with menstruation. No other Grade 3 or 4 laboratory
abnormalities were observed.
Based on results in study GS-US-141-1218, pharmacokinetic profile of bictegravir was
characterized by rapid absorption with time to peak plasma concentrations (median Tmax of
cohorts) ranging between 1 and 4 hours following administration under fasted conditions.
bictegravir exposures were appropriately dose proportional following single dose 25-100 mg 
dose administration, with decreasing dose proportional at higher doses. The half-life of 
bictegravir was approximately 18 hours, with no changes observed across studied dose range as 
evidenced by parallel terminal phase slopes. A high-fat meal increased AUCinf and Cmax 
(geometric mean, 84% and 101%, respectively) following 100 mg single dose administration. 
Steady state was achieved after 4-6 days of once daily dosing of bictegravir with average 
accumulation ratios for AUC24hr of 1.6.

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Table 1-1.
GS-US-141-1218: Bictegravir Mean (%CV) PK Parameters Following 
Single Doses of Bictegravir in Healthy Subjects (Bictegravir PK 
Analysis Set; Part A: Single Dosing)
Bictegravir
PK 
Parameter
Mean 
(%CV)
5mg
(N=6)
25 mg
(N=6)
50 mg
(N=6)
100 mg
(N=6)
300 mg
(N=6)
600 mg
(N=6)
Cmax (ng/mL)
691.2
(22.1)
1618.3
(26.7)
3965.0
(40.1)
6998.3
(36.1)
14605.0 
(27.1)
20050.0
(7.5)
Tmax (hr)
1.25 
(1.00-1.50)
2.00
(1.00-3.00)
3.00
(1.50-4.00)
2.25
(1.50-3.00)
3.50
(2.00-6.00)
3.5
(2.00-4.00)
AUCinf 
(ng.hr/mL)
13059.7
(25.1)
35718.2 
(21.3)
78399.5 
(29.7)
163028.2 
(24.3)
355917.3 
(32.9)
454446.8 
(19.9)
T1/2 (hr)
18.51
(16.81-19.99)
18.08
(16.63-19.64)
16.72
(15.77-17.11)
18.90
(17.96-20.05)
18.14
(17.86-20.53)
17.89
(16.38-19.52)
T1/2 and Tmax: Median (Q1, Q3)
Table 1-2 presents bictegravir plasma PK parameters following administration of bictegravir
(5, 25, 50, 100, and 300 mg) once daily for 7 days. Following administration of either bictegravir
(5, 25, 50, 100, or 300 mg) once daily for 7 days, the PK absorption profile observed on Days 1 
and 7 was similar to that observed in Part A (SAD). The median Tmax values ranged from 1.5 to 
2.5 hours on Day 1 and 1.5 to 4.0 hours on Day 7. Linearity was observed comparing bictegravir
AUC and Cmax on Days 1 and 7 over the dose range of 25 to 50 mg. Steady state levels of 
bictegravir were achieved between Study Days 4 to 6 of dosing and maintained through Day 14. 
Accumulation is approximately 1.6-fold, which is consistent with the observed half-life of the 
bictegravir (approximately 18 hours).

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Table 1-2.
GS-US-141-1218: Bictegravir Plasma Pharmacokinetic Parameters by 
Bictegravir Dose Following Multiple-Dose Administration of 
Bictegravir (Analysis Set: Bictegravir PK Part B: Multiple-Dose)
Bictegravir PK Parameter Mean
(%CV)a
Multiple-Dose Bictegravir
5 mg
(N = 6)
25 mg
(N = 6)
50 mg
(N = 6)
100 mg
(N = 6)
300 mg
(N = 6)
Day 1
AUC0-24 (hr*ng/mL)
9033.6
(8.2)
27,775.1
(28.3)
58,371.4
(18.9)
79,773.8
(18.9)
180,714.3
(17.6)
Cmax (ng/mL)
709.7
(9.5)
2220.0
(35.6)
4648.3
(18.7)
6248.3
(26.8)
13,716.7
(19.1)
Tmax (hr)
1.50
(1.50, 
1.50)
1.75
(1.00, 3.00)
1.50
(1.00, 2.00)
2.50
(2.00, 3.00)
2.50
(2.00, 
4.00)
Day 7
AUCtau (hr*ng/mL)
14,392.0
(16.7)
50,008.2
(26.6)
89,710.1
(22.7)
126,785.8 
(23.7)
277,200.2 
(16.7)
Cmax (ng/mL)
982.5
(7.9)
3455.0
(24.1)
6538.3
(17.6)
9396.7
(20.8)
19,900.0 
(21.2)
Ctau (ng/mL)
400.83
(26.9)
1322.00
(27.8)
2241.67
(28.2)
3145.00 
(26.1)
6758.33 
(21.6)
Tmax (hr)
1.50
(1.00, 
2.00)
3.00
(2.00, 3.00)
1.75
(1.50, 2.00)
1.75
(1.50, 3.00)
4.00
(2.00, 
4.00)
Accumulation Ratio of AUC (%)
160.5
(19.0)
182.2
(17.1)
154.0
(15.9)
158.5
(12.1)
157.5
(22.6)
a
Data are presented as mean (%CV), except for Tmax, and t½, which are presented as median (Q1, Q3)
Table 1-3 presents the GLSM ratios and associated 90% CIs for the test (fed) versus reference 
(fasted) treatments for the primary plasma PK parameters of bictegravir. Administration of a 
single dose of bictegravir 100 mg with food (high-calorie/high-fat breakfast) increased the 
GLSM values of Cmax and AUCinf 101% (90% CI of GLSM ratio 165.93% to 242.74%) and 84% 
(90% CI of GLSM ratio 152.05% to 222.59%), respectively. There were no apparent changes in 
clearance and T1/2 following administration with food, indicating that food enhanced the 
bioavailability of bictegravir by improving its solubility and/or absorption.

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Table 1-3.
GS-US-141-1218: Statistical Comparison of Bictegravir
Pharmacokinetic Parameters Following Single-Dose Administration 
of Bictegravir in the Fasted and Fed States (Bictegravir PK 
Analysis Set)
Bictegravir PK Parameter 
Mean (%CV)
% GLSM Ratio
(90% CI)
Test
Bictegravir 100 mg Fed
(n=8)
Reference
Bictegravir 100 mg Fasted
(n=8)
AUCinf (hr*ng/mL)
214,146.3 (15.9)
117,777.1 (23.3)
183.97 (152.05, 222.59)
AUClast (hr*ng/mL)
209,259.9 (15.1)
115,681.7 (24.0)
183.58 (151.91, 221.86)
Cmax (ng/mL)
11,268.8 (15.1)
5885.0 (34.9)
200.69 (165.93, 242.74)
CI = confidence interval; GLSM = geometric least squares mean
1.2.3.2.
Phase 1b Proof of Concept
The first HIV-1 positive human subjects were dosed in the fasted state with 10 days of 
Bictegravir in study (GS-US-141-1219). Four cohorts of 5 subjects each were randomized 4:1 to 
receive Bictegravir or placebo to match at doses of 5 mg, 25 mg, 50 mg, and 100 mg once daily 
for 10 days.
Bictegravir was generally well tolerated at the doses evaluated. A total of 9 of 20 subjects had an 
AE in this study. The most frequently reported AEs across all subjects were diarrhea (2 subjects), 
and headache (3 subjects). No other AE was reported in more than 1 subject. There was no 
increase in the incidence of AEs with increasing doses of bictegravir.
The majority of AEs were considered by the investigator to be not related to study drug. A total 
of 2 subjects experienced mild diarrhea that was considered related to study drug (1 in the 5 mg 
cohort, 1 in the 100 mg cohort).
No deaths or pregnancies were reported. No Grade 3 or 4 AEs, SAEs, or AEs leading to 
discontinuation of study drug were reported in any cohort.
The majority of laboratory abnormalities were Grade 1 or Grade 2 in severity. No Grade 3 
treatment emergent laboratory abnormalities were observed. Median serum creatinine changes at 
Day 10 were: 0.05 mg/dL (5 mg), 0.04 mg/dL (25 mg), 0.06 mg/dL (50 mg), and 0.15 mg/dL 
(100 mg). These changes in serum creatinine appeared to be transient and returned close to
baseline values on discontinuation of study drug. One Grade 4 new onset laboratory abnormality 
was seen in 1 subject who received 5 mg bictegravir. This was a Grade 4 CPK seen on Day 17, 
7 days following his last dose of study medication. The subject was asymptomatic. The 
Investigator felt that this was unrelated to study medication and was due to resumption of crystal 
methamphetamine use by the subject. An adverse event of elevated CK was reported unrelated to 
study medication.

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Based on PK information collected in study GS-US-141-1219, which was in line with PK 
observed in study GS-US-141-1218, the median IQ for each dose were calculated and are 
presented in Table 1-4 below.
Table 1-4.
Trough Bictegravir Plasma Concentrations at Steady State Following 
Bictegravir Administration Under Fasting Conditions and 
Corresponding Protein-Adjusted IQ95 Values
(Bictegravir PK Analysis Set)
Bictegravir dose
n
Median (range) Ctau, SS (ng/mL)
Median (range) paIQ95a
5 mg
4
206.5 (146.0 to 342.0)
1.3 (0.9 to 2.1)
25 mg
4
797.5 (714.0 to 1900.0)
4.9 (4.4 to 11.7)
50 mg
4
2170.0 (852.0 to 3020.0)
13.4 (5.3 to 18.6)
100 mg
4
4190.0 (3730.0 to 5970.0)
25.9 (23.0 to 36.9)
a
The protein adjusted IQ95 (paIQ95) value is estimated based on steady-state Ctau values and the in vitro paIC95 value for 
wild-type HIV-1 (162 ng/ml).
The mean and 95% CIs of change from baseline in HIV-1 RNA (log10 copies/mL) are presented 
in Figure 1-1.
Figure 1-1.
GS-US-141-1219: Mean and 95% CIs of Change from Baseline in 
HIV-1 RNA (log10 copies/mL) (PP Analysis Set)
NOTE: Baseline value was the last available value collected prior to the time of the first dose of study drug.
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Mean viral load change on Day 11 was -2.08 log10 in the 25 mg cohort, -2.06 log10 in the 50 mg 
cohort, and -2.43 log10 in the 100 mg cohort. Time weighted average change from baseline at 
Day 11 (DAVG11) was -0.92 log10 in the 5 mg cohort, -1.33 log10 in the 25 mg 
cohort, -1.37 log10 in the 50 mg cohort and -1.61 log10 in the 100 mg cohort. Viral suppression 
(HIV-1 RNA < 50 copies/mL) was ever achieved by the end of the study (Day 17) by 1 subject 
(25.0%) in the bictegravir 50 mg group and 2 subjects (50%) in the bictegravir 100 mg group.
1.2.3.3.
Summary of Phase 2 Study (GS-US-141-1475)
Study GS-US-141-1475 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of a regimen containing 
bictegravir+F/TAF versus dolutegravir (DTG)+F/TAF in HIV-infected, ART-naive adult 
subjects.
Eligible subjects were randomized in a 2:1 ratio to one of the following treatment groups, 
stratified by HIV-1 RNA level (≤ 100,000 copies/mL, 100,000 copies/mL to 
400,000 copies/mL, or > 400,000 copies/mL) at screening:

Treatment Group 1: Bictegravir 75 mg + F/TAF (200/25 mg) + placebo-to-match DTG 
50 mg once daily

Treatment Group 2: DTG 50 mg + F/TAF (200/25 mg) + placebo-to-match bictegravir 75 mg 
once daily
Week 24 interim data are summarized below.
Subject Disposition and Baseline Characteristics
A total of 98 subjects were randomized and treated in the study: 65 subjects in the 
bictegravir+F/TAF group and 33 subjects in the DTG+F/TAF group. At the time of the Week 24 
data analysis, 2 subjects (2.0%) had prematurely discontinued from the study, 1 in each treatment 
group; both subjects were lost to follow-up.
Demographic and baseline characteristics were similar between the 2 treatment groups.
Key baseline disease characteristics (ie, viral load, CD4 cell count, and eGFRCG) were similar 
between the 2 treatment groups.
Median (first quartile [Q1], third quartile [Q3]) baseline HIV-1 RNA was 4.45 (3.96, 
4.79) log10 copies/mL, with 82.7% of subjects having ≤ 100,000 copies/mL at baseline; 
5 subjects had > 400,000 copies/mL at baseline; 4 of these subjects were randomized to 
bictegravir+F/TAF and 1 subject was randomized to DTG+F/TAF.
Median (Q1, Q3) baseline CD4 cell count was 444 (316, 595) cells/μL, with 41.8% of subjects 
having ≥ 500 cells/μL at baseline. Median (Q1, Q3) baseline eGFRCG was 125.3 (105.7, 
147.0) mL/min.

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Efficacy Results
Virologic success at Weeks 12 and 24 was assessed using the US FDA-defined snapshot 
algorithm, defined as plasma HIV-1 RNA < 50 copies/mL. At Weeks 12 and 24, virologic 
success was high and similar between the 2 treatment groups as follows: Week 12 
bictegravir+F/TAF 93.8%, DTG+F/TAF 93.9% (stratum-adjusted difference in percentages: 
−1.3%; 95% CI: −12.9% to 10.2%; p = 0.79); Week 24 bictegravir+F/TAF 95.4%, DTG+F/TAF 
93.9% (1.0%; 95% CI: −10.7% to 12.7%; p = 0.84).
Of the 5 subjects with baseline viral load > 400,000 copies/mL, 4 had HIV-1 RNA 
< 50 copies/mL at Week 24, and 1 had 60 copies/mL.
Following initiation of study drug, the increases from baseline in CD4 cell count were similar 
between treatment groups. Mean (SD) baseline CD4 cell counts were as follows: 
Bictegravir+F/TAF 471 (190.9) cells/μL; DTG+F/TAF 507 (271.0) cells/μL; p = 0.35. The mean 
(SD) change in CD4 cell count from baseline to Week 12 was similar between the 2 treatment 
groups as follows: Bictegravir+F/TAF, +170 (150.0) cells/μL; DTG+F/TAF, +173 
(220.5) cells/μL (difference in least squares mean [LSM]: 0; 95% CI: −76 to 76; p = 1.00). There 
were similar increases in the mean (SD) CD4 cell count in both treatment groups Week 24: 
Bictegravir+F/TAF, +189 (177.8) cells/μL; DTG+F/TAF, +157 (163.2) cells/μL (difference in 
LSM: 39; 95% CI: −35 to 113; p = 0.30).
Interim Virology Resistance Data
Through Week 24, no emergent drug resistance was detected.
Safety Results
Adverse Events
The overall incidence of treatment-emergent AEs was balanced between treatment groups as 
follows: Bictegravir+F/TAF 66.2%, 43 subjects; DTG+F/TAF 57.6%, 19 subjects. The most 
common treatment-emergent AEs (occurring in > 2 subjects) by treatment group were as 
follows:

Bictegravir+F/TAF: diarrhea and headache (7.7%, 5 subjects each); and nausea, decreased 
appetite, arthralgia, and cough (4.6%, 3 subjects each)

DTG+F/TAF: nausea (12.1%, 4 subjects); diarrhea (9.1%, 3 subjects)
Most treatment-emergent AEs were Grade 1 in severity. Grade 3 or 4 AEs were reported in only 
1 subject (Grade 3 diabetic ketoacidosis), in the bictegravir+F/TAF group; this event was also 
reported as an SAE. One other SAE (appendicitis), also in the bictegravir+F/TAF group, was 
reported. Neither SAE was considered related to study drug by the investigator or resulted in 
study drug discontinuation or interruption, and both SAEs resolved.

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The overall incidence of study drug-related treatment-emergent AEs was balanced between 
treatment groups as follows: Bictegravir+F/TAF 15.4%, 10 subjects; DTG+F/TAF 18.2%, 
6 subjects. Most study drug-related treatment-emergent AEs were Grade 1 in severity. Grade 2 
study drug-related treatment-emergent AEs were reported in 1 subject in the bictegravir+F/TAF 
group (somnolence and headache) and 1 subject in the DTG+F/TAF group (vomiting). There 
were no Grade 3 or 4 treatment-emergent AEs or SAEs reported that were considered related to 
study drug.
No Grade 4 AEs, deaths, pregnancies, or AEs leading to premature study drug discontinuation 
were reported in either treatment group.
Clinical Laboratory Evaluations
The percentage of subjects with at least 1 treatment-emergent laboratory abnormality (ie, at least 
1 grade level increase from baseline in graded abnormality) was similar between treatment 
groups as follows: Bictegravir+F/TAF 76.6%, 49 subjects; DTG+F/TAF 78.1%, 25 subjects. The 
majority of treatment-emergent laboratory abnormalities were Grade 1 or 2 in severity. The 
percentage of subjects with at least 1 Grade 3 or 4 treatment-emergent laboratory abnormality 
was similar between treatment groups as follows: Bictegravir+F/TAF 17.2%, 11 subjects; 
DTG+F/TAF 12.5%, 4 subjects. Grade 3 or 4 laboratory abnormalities occurring in at least 
2 subjects in either treatment group were as follows: creatine kinase (bictegravir+F/TAF, 7.8% 
[5 subjects]), fasting serum glucose (DTG+F/TAF, 6.3% [2 subjects]), aspartate 
aminotransferase (AST) (bictegravir+F/TAF, 3.1% [2 subjects]), and fasting low-density 
lipoprotein (LDL) (bictegravir+F/TAF, 3.1% [2 subjects]). The only Grade 4 laboratory 
abnormalities were for creatine kinase, reported in 2 subjects (3.1%) in the bictegravir+F/TAF 
group. All increased creatine kinase values appeared to be transient, and none were associated 
with AEs. Of the 2 subjects with increased AST, 1 subject had Grade 3 AST and Grade 3 ALT at 
Week 24 in the setting of alcohol abuse; the other subject had Grade 3 AST at Week 8 that 
returned to normal by Week 24.
There were no clinically significant changes from baseline or differences between treatment 
groups in the median values for hematology, chemistry, or metabolic parameters. There were 
similar increases from baseline in median (Q1, Q3) serum creatinine in both treatment groups at 
Week 24: Bictegravir+F/TAF 0.12 (0.06, 0.18) mg/dL; DTG+F/TAF 0.13 (0.05, 0.21) mg/dL. 
There were decreases in median (Q1, Q3) eGFRCG at Week 24, which were smaller in the 
bictegravir+F/TAF compared with the DTG+F/TAF group: Bictegravir+F/TAF 
−13.3 (−19.9, −4.0) mL/min; DTG+F/TAF −17.2 (−25.7, −6.9) mL/min.

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Conclusions
Key Week 24 conclusions from Study GS-US-141-1475 include the following:

Virologic success at Week 24 when assessed using the US FDA-defined snapshot algorithm, 
defined as plasma HIV-1 RNA < 50 copies/mL, was similar between the 2 treatment groups 
as follows: Bictegravir+F/TAF 95.4%; DTG+F/TAF 93.9%; stratum-adjusted difference in 
percentages: 1.0%; 95% CI: −10.7% to 12.7%; p = 0.84. There was a similar increase in the 
mean (SD) CD4 cell count between the 2 treatment groups, bictegravir+F/TAF,
+189 (177.8) cells/μL; DTG+F/TAF, +157 (163.2) cells/μL (difference in LSM: 39; 95% CI: 
−35 to 113; p = 0.30).

No resistance to any INSTIs, NRTIs, NNRTIs, or PIs was detected through Week 24.

No AEs led to study drug discontinuation in either treatment group.

Both bictegravir+F/TAF and DTG+F/TAF were generally well tolerated through 24 weeks of 
treatment. The most commonly reported treatment-emergent AEs were diarrhea and 
headache (7.7% each) in the bictegravir+F/TAF group and nausea (12.1%) and diarrhea 
(9.1%) in the DTG+F/TAF group. There were 2 SAEs, 1 of which was also a Grade 3 AE; 
neither of these events was considered related to study drug by the investigator, or led to 
study drug discontinuation. There were no other Grade 3 or 4 AEs, and no deaths, 
pregnancies, or AEs leading to premature study drug discontinuation reported. The 
percentage of subjects with at least 1 treatment-emergent laboratory abnormality was similar 
between treatment groups. The majority of treatment-emergent laboratory abnormalities were 
Grade 1 or 2 in severity. There were similar increases from baseline in serum creatinine in 
both treatment groups at Week 24.
1.2.3.4.
Summary of B/F/TAF Phase 3 Studies
Summary of Phase 3 Study (GS-US-380-1489)
Results from a blinded phase 3 study were reported that compared B/F/TAF FDC to 
coformulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC) {Gallant 2017}. 
HIV-infected, treatment-naïve, HLA-B*5701-negative, HBV-uninfected adults with estimated 
glomerular filtration rate (eGFR) ≥50 mL/min were randomized 1:1 to receive blinded treatment 
with fixed-dose combination B/F/TAF (50/200/25 mg) or ABC/DTG/3TC (600/50/300 mg) with 
matching placebos once daily. The primary endpoint was proportion of participants with HIV-1 
RNA (VL) < 50 c/mL at W48 (FDA snapshot). Noninferiority was assessed through 95.002% 
confidence intervals (CI) (12% margin). Secondary endpoints were safety (adverse events [AEs] 
and laboratory abnormalities) and pre-defined analyses of changes from baseline in bone mineral 
density (BMD) and measures of renal function, including eGFR and proteinuria. Six hundred and 
twenty nine participants were randomized and treated (314 B/F/TAF, 315 ABC/DTG/3TC): 
10% women, 36% Black, 16% VL >100,000 c/mL, 11% CD4 < 200 cells/mL. Median baseline 
characteristics: age 32 yrs, CD4 count 444 cells/µL, and VL 4.47 log10 c/mL. At W48, B/F/TAF 
was noninferior to ABC/DTG/3TC, with 92.4% on B/F/TAF and 93.0% on ABC/DTG/3TC 

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achieving HIV-1 RNA < 50 c/mL (difference -0.6%; 95.002%CI -4.8% to 3.6%, p=0.78). No 
resistance mutations emerged in either group. Comparing B/F/TAF to ABC/DTG/3TC 
throughout, the most common AEs were diarrhea (13%, 13%), headache (11%, 14%), and 
nausea (10%, 23%). Few participants (0 vs 4 [1%]) had any AEs leading to premature study drug 
discontinuation. At W48, mean % changes from baseline in BMD were -0.83% vs. -0.60% 
(p=0.39) [lumbar spine] and -0.78% vs. -1.02% (p=0.23) [total hip]. No differences between 
treatments were noted in changes from baseline for eGFR and proteinuria at W48. At W48, 
B/F/TAF achieved virologic suppression in 92.4% of treatment-naïve adults and was noninferior 
to ABC/DTG/3TC, with no emergent resistance. B/F/TAF was safe and well tolerated with less 
nausea than ABC/DTG/3TC. Bone and renal safety profiles were similar between groups.
Summary of Phase 3 Study (GS-US-380-1490)
A second phase 3 study compared BIC and DTG, each with F/TAF, utilizing a single-pill 
coformulation of B/F/TAF {Sax 2017}. Treatment-naïve, HIV-infected adults with estimated 
glomerular filtration rate (eGFR) ≥30 mL/min were randomized 1:1 to receive blinded treatment 
with fixed dose combination B/F/TAF (50/200/25 mg) or DTG (50 mg) + F/TAF (200/25 mg) 
with matching placebos once daily through W48. Chronic hepatitis B and/or C infection was 
allowed. The primary endpoint was the proportion of participants with HIV-1 RNA 
< 50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% 
confidence intervals (CI) using a margin of 12%. Secondary endpoints were safety measures 
(adverse events [AEs] and laboratory results). There were 645 participants randomized and 
treated (320 B/F/TAF, 325 DTG + F/TAF): 12% women, 31% Black, 19% viral load (VL) 
>100,000 c/mL, 12% CD4 < 200 cells/µL, median age 34 yrs, CD4 count 440 cells/µL, and VL 
4.44 log10 c/mL. At W48, B/F/TAF was noninferior to DTG + F/TAF, with 89.4% on B/F/TAF 
and 92.9% on DTG + F/TAF achieving HIV-1 RNA < 50 c/mL (difference -3.5%; 
95.002%CI -7.9% to 1.0%, p=0.12). Six subjects discontinued treatment and had no post 
baseline HIV-1 RNA data for the following reasons: patient decision-3, protocol violation due to 
incarceration-1, lost to follow-up-1 and investigator discretion-1. Both the Missing=Excluded 
(M=E) and Missing=Failure (M=F) sensitivity analyses were pre-specified M=E analysis 
(B/F/TAF vs DTG + FTC/TAF, % treatment difference (95% CI); p-value): 99.0% (288/291) vs. 
99.3% (304/306), -0.4% (-2.3, 1.6); p=0.63 Missing values represent a potential source of bias in 
a clinical trial. Therefore, the study protocol pre-specified the M=E analysis as one imputation 
method for missing data The M=E population analysis excludes subjects in the full analysis set 
who do not have HIV-1 RNA data at the efficacy analysis time point. Of note, the M=E analysis 
set includes subjects with HIV-1 RNA data at the efficacy analysis time point, even if the subject 
has discontinued study antiretroviral medications but remained “in the study” on non-study 
antiretroviral medications (for the treatment of HIV). M=F analysis (B/F/TAF vs DTG + 
FTC/TAF, % treatment difference (95% CI); p-value): 90.0% (288/320) vs. 93.5% (304/325), -
3.4% (-7.7, 0.9); p=0.12. The study protocol pre-specified the M=F analysis as a 2nd imputation 
method for missing data. The M=F population considers subjects in the full analysis set who do 
not have HIV-1 RNA data at the efficacy analysis time point as having HIV-1 RNA ≥ 50 
copies/mL. Of note, the M=F analysis set includes subjects with HIV-1 RNA data at the efficacy 
analysis time point, even if the subjects has discontinued study antiretroviral medications but 
remained “in the study” on non-study antiretroviral medications (for the treatment of HIV). At 

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W48, proportion of participants with HIV-1 RNA ≥50 c/mL was < 1% in each arm. No study 
subject in either treatment arm developed resistance to any of the study drugs. The most common 
AEs were headache (13% B/F/TAF, 12% DTG + F/TAF) and diarrhea (12% for both). Few 
participants (5 [2%], 1 [< 1%]) had AEs leading to premature study discontinuation. Lipid 
changes were not significantly different between study arms. No renal discontinuations and no 
cases of proximal renal tubulopathy were reported. After 48 weeks, B/F/TAF achieved virologic 
suppression in 89.4% of treatment- naïve adults and was noninferior to DTG + F/TAF. B/F/TAF 
was safe and well tolerated.
Summary of Phase 3 Studies (GS-US-380-1844 and 1878)
One of the ongoing studies is designed to explore the efficacy and safety of B/F/TAF compared 
to regimens containing dolutegravir (50mg) (DTG) among virologically suppressed patients 
switching from an existing antiretroviral regimen (Study 1844). The other ongoing study in 
virologically suppressed patients compares switching to B/F/TAF versus remaining on a 
suppressive regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and a boosted 
protease inhibitor (Study 1878). In study 1844, patients (n=520) who were virologically 
suppressed (HIV-1 RNA levels <50 copies/mL) on a regimen of ABC/DTG/3TC or 
DTG+ABC/3TC were randomized 1:1 to stay on their existing regimen or switch to B/F/TAF in 
a blinded manner. Study 1878 is an open-label study in which patients (n=520) who were 
virologically suppressed on a boosted protease inhibitor of darunavir (800mg) or atazanavir 
(300mg) plus a nucleoside/nucleotide backbone of ABC/3TC or emtricitabine/tenofovir 
disoproxil fumarate (200/300mg) were randomized 1:1 to either maintain their current regimen 
or switch to B/F/TAF. The primary endpoint in these studies is the proportion of patients with 
HIV-1 RNA ≥50 copies/mL at Week 48, and the lower bound of the 95 percent CI for 
noninferiority is 4 percent. Both studies were randomized through 48 weeks, after which point 
patients continuing in the studies enter an open-label extension receiving B/F/TAF. B/F/TAF met 
the definition of non-inferiority in all four studies, with comparable proportions of patients 
having HIV1 RNA ≥50 copies/mL (Studies 1844 and 1878). In all studies B/F/TAF was well 
tolerated and no patients discontinued study medication due to renal events. No patients 
randomized to the bictegravir or dolutegravir arms developed treatment-emergent resistance. 
One patient randomized to the protease inhibitor arm in Study 1878 developed an abacavir 
resistance mutation (L74V).{Gilead Sciences Inc 2017}
1.3.
Information about Emtricitabine (Emtriva®, F)
Emtricitabine (5-fluoro-1-[(2R, 5S)-2-(hydroxymethyl)-[1, 3]-oxathiolan-5-yl] cytosine, FTC) is 
a NRTI that has demonstrated potent and selective inhibition of the HIV. In HIV-infected adults, 
FTC is administered as a 200 mg QD dose concurrently with other ARVdrugs. The 200 mg FTC 
capsule formulation was approved by the US Food and Drug Administration (FDA) for 
marketing on 2 July 2003 and is available under the name Emtriva®. In the European Union 
(EU), marketing authorization was granted for both the 200 mg Emtrivacapsule formulation 
and a 10 mg/mL Emtrivaoral Solution formulation on 24 October 2003, with indications for 
the treatment of HIV infection concurrently with other antiretroviral drugs in both adult and 
pediatric patients.
Further information is available in the current Prescribing Information for Emtriva®.

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1.4.
Information about tenofovir alafenamide (TAF, GS-7340)
Tenofovir alafenamide (GS-7340, TAF) is an oral prodrug of tenofovir (TFV), a nucleotide 
analog that inhibits HIV-1 reverse transcription. Tenofovir is metabolized intracellularly to the 
active metabolite, tenofovir diphosphate (TFV-DP), a competitive inhibitor of HIV-1 reverse 
transcriptase (RT) that terminates the elongation of the viral DNA chain. 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.
Please refer to the B/F/TAF Investigator’s Brochure for further information.
1.4.1.
Clinical Trials of Single Agent Tenofovir alafenamide (TAF, GS-7340) or 
Fixed Dose Combination emtricitabine/tenofovir alafenamide (FTC/TAF)
Clinical trials entailing the use of tenofovir alafenamide include:

GS-US-120-1101, a Phase 1/2 study of the pharmacokinetics and antiviral activity of 
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 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 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 (completed)

GS-US-120-0114, a Phase 1, open-label, parallel-group, single dose study to evaluate the 
pharmacokinetics of tenofovir alafenamide in subjects with normal and impaired hepatic 
function (completed)

GS-US-120-0117, a Phase 1 single-dose study evaluating the pharmacokinetic drug 
interaction potential between rilpivirine and tenofovir alafenamide (completed)

GS-US-120-0118, a Pharmacokinetic study evaluating the drug interaction potential of 
tenofovir alafenamide with a boosted protease inhibitor or unboosted integrase inhibitor in 
healthy subjects (completed)

GS-US-120-1538, a Fixed-Sequence, Open-Label, Study Evaluating the Pharmacokinetics 
and Drug Interaction Potential between Tenofovir Alafenamide and Midazolam (Oral and 
Intravenous) in Healthy Volunteers (completed)

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
GS-US-120-1554, a Fixed-Sequence, Randomized, Open-Label, 2-Cohort, 2-Period, 
Multiple-Dose Study Evaluating the Pharmacokinetics and Drug Interaction Potential 
between Tenofovir Alafenamide and Rilpivirine in Healthy Subjects (completed)

GS-US-311-1386, a Phase 1 study to determine the effect of food on the pharmacokinetics of 
tenofovir alafenamide when administered as F/TAF FDC in healthy volunteers (completed)

GS-US-311-0101, a Phase 1 healthy volunteer study evaluating the drug interaction potential 
between once-daily FTC/GS-7340 fixed-dose combination and efavirenz (EFV) or 
COBI-boosted darunavir (DRV) (completed)

GS-US-311-1088, a Phase 1, Relative Bioavailability Study of Emtricitabine/Tenofovir 
Alafenamide Fixed Dose Combination Tablet to evaluate the formulation performance of 
emtricitabine (FTC) and tenofovir alafenamide (TAF) fixed dose combination tablets relative 
to co-administration of individual agents (completed).

GS-US-311-1089, a Phase 3 study of the safety and efficacy of FTC/TAF in HIV infected, 
virologically suppressed patients (ongoing).

GS-US-311-1717, a Phase 3b, Randomized, Double-Blind, Switch Study to Evaluate F/TAF 
in HIV-1 Positive Subjects who are Virologically Suppressed on Regimens containing 
ABC/3TC (ongoing).
In Study GS-US-311-1386, the effect of food (high-calorie, high-fat meal) on the PK of the TAF 
component of the F/TAF FDC was evaluated. The GLSM ratio of the AUClast of TAF when 
administered with a high-fat meal was 177% (90% CI: 166% to 188%), and the TAF Cmax 
GLSM ratio was 84.5% (90% CI: 74.9% to 95.4%). This ~75% increase in TAF plasma 
exposure and ~15% decrease in TAF plasma Cmax when administered with food was 
accompanied by a delay in Tmax (increase from 1.00 hour under fasted conditions to 2.00 hours 
under fed conditions). The exposures of TAF observed under fed or fasted conditions in this 
study are within the range of exposures observed in the E/C/F/TAF clinical development 
program and are commensurate with safe and effective plasma levels of TAF (see investigator 
brochure for further details). Therefore, the changes in TAF exposures when F/TAF is 
administered with food should not result in differences in efficacy and thus are not clinically 
relevant. TAF can be administered without regard for food and these findings can be 
extrapolated to F/TAF (as FTC can be taken without regard to food).

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1.4.2.
Clinical Trials of FTC/TAF as part of 
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF)
Clinical trials using tenofovir alafenamide, coformulated into the E/C/F/TAF STR include:

GS-US-292-0101, a Phase 1 healthy volunteer study evaluating the relative bioavailability of 
EVG, FTC, TFV, and COBI 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 Single Agent (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)

GS-US-292-0104 and GS-US-292-0111, Phase 3 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)

GS-US-292-0109, a Phase 3 open-label study to evaluate switching from a TDF-containing 
combination regimen to a TAF-containing combination single tablet regimen (STR) in 
virologically-suppressed, HIV-1 positive subjects (ongoing)

GS-US-292-0112, a Phase 3 Open-label Safety Study of 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide single-tablet Regimen in HIV-1 
positive patients with mild to moderate renal impairment (ongoing)

GS-US-292-0117, a Phase 3, two-part study to evaluate the efficacy of Tenofovir 
Alafenamide versus placebo added to a failing regimen followed by treatment with 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in HIV-1 positive, 
antiretroviral treatment-experienced adults (ongoing)

GS-US-292-0119, a Phase 3 open-label study to evaluate switching from optimized stable 
antiretroviral regimens containing darunavir to 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) single tablet 
regimen (STR) plus darunavir (DRV) in treatment experienced HIV-1 positive adults 
(ongoing)

GS-US-292-0106, a Phase 2/3, open-label study of the pharmacokinetics, safety, and 
antiviral activity of the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) single tablet regimen (STR) in HIV-1 infected antiretroviral treatment-naive 
adolescents (ongoing)

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Study GS-US-292-0101 is a 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 single agent (SA) 25 mg for both 
formulations of the E/C/F/TAF, likely mediated by inhibition of P-gp-mediated intestinal 
secretion of TAF by COBI.
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 (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.
Study GS-US-292-0102 is an ongoing, randomized, active-controlled Phase 2 study, compares 
E/C/F/TAF (10 mg) versus Stribild® (STB, E/C/F/TDF) in treatment-naïve, HIV-1 infected 
subjects. At Week 48, the E/C/F/TAF demonstrated potent antiviral efficacy (HIV-1 RNA 
< 50 copies/mL) similar to STB (88.4% [99/112] vs 87.9% [51/58] using the US FDA-defined 
snapshot algorithm); in the E/C/F/TAF group, no patient had emergent resistance to 1 or more 
components of the E/C/F/TAF. Importantly, E/C/F/TAF demonstrated a potential benefit over 
E/C/F/TDF in terms of renal and bone safety: smaller median decreases in eGFR (mL/min) 
(at Week 48, E/C/F/TAF -5.5 vs E/C/F/TDF -10.0 [P<0.001) and smaller median percentage 
decreases in BMD (at Week 48, spine E/C/F/TAF -1.00 vs E/C/F/TDF -3.37 [p<0.001], 
hip -0.62 vs -2.39 [p<0.001]).
Studies GS-US-292-0104 and GS-US-292-0111 are ongoing, Phase 3 randomized, 
double-blinded studies of the safety and efficacy of E/C/F/TAF versus E/C/F/TDF in HIV-1 
infected, antiretroviral treatment-naive adults. The interim Week 48 key conclusions from pooled 
data showed that E/C/F/TAF once daily was noninferior to STB once daily when administered 
for 48 weeks to HIV-infected, ART-naive adults, as assessed using the US FDA-defined 
snapshot algorithm with HIV-1 RNA < 50 copies/mL (E/C/F/TAF 92.4%; STB 90.4%; 
difference in percentages: 2.0%, 95% CI: -0.7% to 4.7%). Administration of E/C/F/TAF resulted 
in > 90% lower plasma TFV and higher intracellular TFV-DP relative to STB. E/C/F/TAF 
showed an improved renal and bone safety profile with significantly less decline in hip and spine 
BMD, less increase in serum creatinine and reduction in estimated glomerular filtration rate 
(eGFR).

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1.5.
Information about Bictegravir/emtricitabine/tenofovir alafenamide 
(Bictegravir/F/TAF)
Please refer to the Bictegravir/F/TAF Investigator’s Brochure for further information.
1.5.1.
GS-US-141-1233: Study of the Relative Bioavailability of Bictegravir, FTC, 
and TAF between Bictegravir/F/TAF and Bictegravir + F/TAF
Study GS-US-141-1233 is an ongoing Phase 1, open-label, 2-cohort, multiple-period,
fixed-sequence, crossover study conducted at a single center in the US to evaluate 1) the relative 
bioavailability (BA) of 2 B/F/TAF (75/200/25 mg and 50/200/25 mg) FDC tablets compared 
with the bictegravir (75 mg) tablet and the F/TAF (200/25 mg) FDC tablet administered 
simultaneously and 2) the effect of food on the PK of bictegravir, FTC, and TAF when 
administered as B/F/TAF (75/200/25 mg and 50/200/25 mg) FDC tablets.
Cohort 1 evaluated the relative BA and food effect of bictegravir/F/TAF (75/200/25 mg) FDC 
tablet in a 3-period sequence. Following review of preliminary data from Cohort 1, Cohort 2 was 
added to the study via protocol amendment. Cohort 2 evaluated the relative BA and food effect 
of B/F/TAF (50/200/25 mg) FDC tablet in a 4-period sequence.
The in-life portion of Cohorts 1 and 2 are complete. Preliminary results are summarized below.
Cohort 1 Results:
Pharmacokinetic Results
Under fasted conditions, bictegravir AUCinf and Cmax were 27% and 31% higher, respectively, 
following B/F/TAF (75/200/25 mg) FDC administration than following administration of 
single-agent bictegravir (75 mg ) with the F/TAF (200/25 mg) FDC. FTC and TAF exposure was 
similar following administration of B/F/TAF FDC (75/200/25 mg) or single-agent bictegravir
(75 mg) with the F/TAF (200/25 mg) FDC.
Compared with administration under fasted conditions, administration of the B/F/TAF 
(75/200/25 mg) FDC with a high-fat meal resulted in a 46% higher bictegravir AUCinf and a 27% 
higher bictegravir Cmax. The impact of food on TAF and FTC exposure was similar to that 
previously observed for F/TAF (Study GS-US-311-1386). B/F/TAF may be taken without regard 
to food. Based on these results, Cohort 2 was added to the study via protocol amendment to 
evaluate the relative BA of the B/F/TAF (50/200/25 mg) FDC tablet compared with the 
single-agent bictegravir (75 mg) tablet and the F/TAF (200/25 mg) FDC tablet administered 
simultaneously.
Safety Results
Of the 28 subjects included in the Safety Analysis Set for Cohort 1, 12 subjects (43%) had at 
least 1 treatment-emergent AE. All treatment emergent AEs were assessed as Grade 1 or 2 in 
severity. No deaths or other SAEs occurred during this study, and no subject discontinued the 
study due to an AE.

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Cohort 2 Results:
Pharmacokinetic Results
The PK results from Study GS-US-141-1233 demonstrated that the bictegravir AUCinf and Cmax
following administration of the 50mg bictegravir FDC tablets was 79% and 78%, respectively of 
those observed in the same study following co-administration of bictegravir 75 mg single agent 
with F/TAF (200/25 mg) under fasted conditions. The bictegravir exposures of 50 and 75 mg 
fixed dose combination tablets were approximately dose proportional under fasted and fed 
conditions and a high fat and moderate fat meal had similar impact on bictegravir with AUCinf
increasing by 24%. The steady state paIQ95 of bictegravir/F/TAF (50/200/25 mg) was predicted to 
be 17 (fasted)-23 (fed). The exposures of TAF and FTC of the 50 mg bictegravir FDC were 
similar to those of bictegravir 75 mg single agent with F/TAF FDC, and the food effect on TAF 
and FTC was similar to the historical results.
Safety Results
Of the 28 subjects included in the Safety Analysis Set for Cohort 2, 12 subjects (43%) had at 
least 1 treatment-emergent AE. All treatment emergent AEs were assessed as Grade 1 or 2 in 
severity. No deaths or other SAEs occurred during this study, and no subject discontinued the 
study due to an AE.
1.6.
Rationale for This Study
HIV standard of care has relied upon nucleos(t)ide backbones for effective and durable virologic
suppression, but nucleos(t)ide-associated toxicities are increasingly important as HIV-infected
patients are often diagnosed earlier, initiate therapy earlier, and look toward lifelong therapy 
(often greater than 50 years). Where patients have access to treatment, morbidity and mortality 
are driven by non–AIDS-associated comorbidities, which are observed earlier than in 
HIV-uninfected age-matched controls despite the best available ART. The contribution of 
specific nucleos(t)ides, such as tenofovir disoproxil fumarate, to long-term morbidity and 
mortality is increasingly important in this context.
B/F/TAF FDC has the potential to offer a simple, once-daily regimen containing a INSTI that 
provides a high barrier to resistance, does not require a boosting agent, and offers an effective 
and safer alternative to standard nucleos(t)ide based regimens, without the need for HLA testing 
or close monitoring of renal or bone toxicities. It could provide a FDC treatment that avoids the 
risk of hypersensitivity reactions, would not contribute to an increased risk of cardiovascular 
events, could be used in patients with chronic hepatitis B or C infection or renal impairment, and 
that could be continued as patients age and confront non-HIV-related comorbidities. In the 
current Phase 3 studies of B/F/TAF, sparse data are available on the efficacy and safety in
HIV-infected subjects who are 65 years and older. As the population of people living with HIV
infection continues to age (median age approaches 50 years in many locations), the urgency of 
obtaining B/F/TAF safety and efficacy data in older populations is critical. The study provides 
the opportunity to evaluate the potential benefits of switching from E/C/F/TAF to B/F/TAF FDC 
in men and women, as an ongoing study of this switch is underway solely in women.

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The objective of this study is to characterize the virologic efficacy of switching virologically 
suppressed subjects on an E/C/F/TAF FDC or TDF-containing regimen (if currently or 
previously participated in GS-US-292-1826) to B/F/TAF FDC defined by HIV-1 RNA 
<50 copies/mL at Week 24.
1.7.
Risk/Benefit Assessment for the Study
All patients with HIV-1 infection should receive effective anti-retroviral therapy. With the aging 
of the HIV-infected population such that half of the population is now over the age of 50 years, 
there is a need for efficacy and safety data in this population. This study seeks to address this gap 
by enrolling subjects 65 years or older in order to generate data on the efficacy and safety of 
B/F/TAF FDC in this population. Potential risks associated with all classes of ARVs include 
immune reconstitution syndrome, lipodystrophy, and lactic acidosis with steatosis. The risk of 
class effects is considered to be low. Potential benefits may include provision of a new ARV 
therapy that is not currently available and which may have fewer side effects than alternative 
therapies. Other potential benefits include provisions of fixed dose combination therapy, and the 
knowledge that patient participation will contribute to the body of knowledge of HIV therapies. 
Following a chronic 39 week study in monkeys, animals administered the highest dose of BIC 
(1000 mg/kg/day) had bile duct hyperplasia (increased cell growth) and hypertrophy (increased 
cell size), and some increased cell growth and inflammation in nearby liver cells. These effects 
were not seen in monkeys administered the mid-level dose (200 mg/kg/day), and these animals 
had plasma BIC exposures that were approximately 5-fold above human exposures when given 
the B/F/TAF FDC. No adverse drug reactions associated with liver or bile duct problems has 
been identified in humans treated with BIC. Potential hepatobiliary toxicity is appropriately 
managed by study inclusion/exclusion criteria, close clinical and laboratory monitoring, as well 
as specific toxicity management guidance to investigators (Refer to Section 7.4). As Phase 3 data 
have clearly shown the benefits of B/F/TAF FDC outweigh the risks in treatment naïve subjects 
as well as in ongoing studies in virologically suppressed subjects that switch to B/F/TAF FDC
and the potential risk of the study will be mitigated by follow up and monitoring of overall 
health, the overall benefit-risk assessment for B/F/TAF FDC is favorable. {Gilead Sciences Inc 
2017}
1.8.
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 objective of this study is:

To characterize the virologic efficacy of switching virologically suppressed subjects on an 
E/C/F/TAF FDC or TDF-containing regimen to B/F/TAF FDC defined by HIV-1 RNA 
<50 copies/mL at Week 24.
The secondary objectives of this study are as follows:

To characterize the safety and tolerability of switching to B/F/TAF FDC from an E/C/F/TAF 
FDC or TDF-containing regimen through Week 96.

To characterize the virologic efficacy of switching to B/F/TAF FDC defined by HIV-1 RNA 
<50 copies/mL at Week 48, Week 72 and Week 96.

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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

HIV-1 RNA <50 copies/mL at Week 24 - defined by the Food and Drug Administration 
(FDA) snapshot algorithm
The secondary endpoints of this study are:

Adverse events through Week 24

Adverse events through Week 48

Adverse events through Week 72

Adverse events through Week 96

HIV-1 RNA <50 copies/mL at Week 48 - defined by the Food and Drug Administration 
(FDA) snapshot algorithm

HIV-1 RNA <50 copies/mL at Week 72 - defined by the Food and Drug Administration 
(FDA) snapshot algorithm

HIV-1 RNA <50 copies/mL at Week 96 - defined by the Food and Drug Administration 
(FDA) snapshot algorithm
3.2.
Study Design
Open-label, multicenter, single arm study to evaluate switching from either E/C/F/TAF FDC or 
TDF-containing regimen (if currently or previously participated in GS-US-292-1826) to 
bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 25 mg (B/F/TAF) FDC in 
virologically-suppressed, HIV-1 infected subjects aged ≥ 65 years.
All eligible subjects who complete GS-US-292-1826, Week 48 and are at least 65 years old at 
the screening visit will be allowed to enter. Subjects can proceed directly into the study after the 
GS-US-292-1826 study 30 day Follow-Up visit; additionally if the subject has already completed 
and left the study, subject may enroll as long as the subject remains virologically suppressed on a 
stable regimen. A stable regimen is defined by no change in the ARV regimen for ≥3 months 
prior to the screening visit.
Subjects not previously enrolled into GS-US-292-1826 will be eligible to enroll as long as they 
meet all eligibility criteria.

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The GS-US-292-1826 30-day Follow-Up visit may coincide with the screening visit for this 
study. Labs drawn during this visit may be utilized for this study as long as the labs are within 
30 days of the Day 1 visit.
Subjects will be treated for at least 96 weeks.
3.3.
Study Treatments
Subjects who provide written informed consent and meet all eligibility criteria will receive 
bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 25 mg (B/F/TAF) FDC 
administered orally, once daily, without regard to food.
3.4.
Duration of Treatment
The treatment duration is at least 96 Weeks.
At the Week 96 Visit, subjects in a country where B/F/TAF FDC is not yet commercially 
available will be given the option to receive B/F/TAF FDC for up to additional 48 weeks (up to 
Week 144) and attend study visits every 12 weeks, or until Gilead Sciences elects to discontinue 
the study in that country, whichever occurs first.
3.5.
End of Study
End of study, for purposes of the primary and secondary analyses, is defined as completion of the 
96 weeks of treatment and the 30 Day Follow-Up visit. Subjects who are still on B/F/TAF FDC 
at Week 96 and continue to attend visits after Week 96, will have the Week 96 study visit, and 
then attend study visits every 12 weeks for up to additional 48 weeks (up to Week 144) followed 
by a 30 day Follow-Up visit, or until Gilead Sciences elects to discontinue the study in that 
country, whichever occurs first.
3.6.
Post Study Care
After a subject has completed/terminated their participation in the study, long-term care for the 
subject will remain the responsibility of their primary treating physician.
3.7.
Biomarker Testing
3.7.1.
Biomarker Samples to Address the Study Objectives:
Blood and urine will be collected for selected evaluations of bone and renal safety, inflammation, 
and platelet and coagulation function at Day 1, Weeks 4, 12, 24, 48, 60, 72, 84 and 96. Because 
biomarker science is a rapidly evolving area of investigation, it is not possible to specify 
prospectively all tests that will be done on the specimens provided. The testing outlined is based 
upon the current state of scientific knowledge. Specific testing 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.

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Biomarkers to be analyzed will include but will not be limited to soluble: glycoprotein VI 
(sGPVI), P-selectin, soluble CD40 ligand, and d-dimer. Inflammation evaluations may include: 
cystatin-C, IL 6, hs CRP, sCD14, sCD163, sTNF-R1, and Lp-PLA2. Specimens will be collected 
from all subjects.
Samples may be stored for a period of 15 years.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 80 subjects who meet the eligibility criteria will be enrolled in the study.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) The ability to understand and sign a written informed consent form, which must be obtained 
prior to initiation of study procedures
2) Age years
3) Currently receiving an ARV regimen of E/C/F/TAF FDC (or FTC/TDF + 3rd agent if 
currently or previously participated in GS-US-292-1826) for ≥ 3 months
4) Documented plasma HIV-1 RNA < 50 copies/mL during treatment with E/C/F/TAF 
(or FTC/TDF + 3rd agent if currently or previously participated in GS-US-292-1826) for the 
last 2 visits preceding the Screening Visit (or undetectable HIV-1 RNA level according to the 
local assay being used if the limit of detection is ≥ 50 copies/mL)
a) Unconfirmed virologic elevations of ≥ 50 copies/mL but < 400 copies/mL (transient 
detectable viremia, or “blip”) in the past are acceptable.
b) If the lower limit of detection of the local HIV-1 RNA assay is < 50 copies/mL 
(e.g., < 20 copies/mL), the plasma HIV-1 RNA level cannot exceed 50 copies/mL on 
two consecutive HIV-1 RNA tests after < 50 copies/mL has been achieved.
5) Plasma HIV-1 RNA levels < 50 copies/mL at Screening Visit
6) Have no documented or suspected resistance to FTC, TFV, or BIC including, but not limited, 
to the reverse transcriptase resistance mutations K65R and M184V/I
7) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)

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8) Adequate renal function:
eGFR ≥ 30 mL/min according to the Cockcroft-Gault formula for creatinine clearance
{Cockcroft 1976}:
a) Male: 
(140 – age in years) (wt in kg) CLcr (mL/min)
72 (serum creatinine in mg/dL)
(140 – age in years) (wt in kg) 
CLcr (mL/sec)
72 (serum creatinine in umol/L) 0.6786
b) Female: 
(140 – age in years) (wt in kg) 0.85 CLcr (mL/min)
72 (serum creatinine in mg/dL)
(140 – age in years) (wt in kg) 0.85 
CLcr (mL/sec)
72 (serum creatinine in umol/L) 0.6786
9) Male subjects who are fertile and engage in heterosexual intercourse with women who are of 
child-bearing potential must agree to use protocol specified method(s) of contraception as 
described in Appendix 5.
10) Male subjects must agree to refrain from sperm donation from first study drug dose until 
after the end of relevant systemic exposure
11) Life expectancy >1 year
12) Hepatic transaminases (AST and ALT) 5 upper limit of normal (ULN)
13) Total bilirubin ≤ 1.5X ULN or normal direct bilirubin
14) Adequate hematologic function (absolute neutrophil count ≥ 750/mm3 (≥ 0.75 GI/L);
platelets ≥ 50,000/mm3 (≥ 50 GI/L); hemoglobin ≥ 8.5 g/dL (≥ 85 g/L))
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to 
screening (refer to Appendix 6)
2) Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, or variceal 
bleeding)
3) Have been treated with immunosuppressant therapies or chemotherapeutic agents within 
3 months of study screening, or expected to receive these agents or systemic steroids
(e.g. prednisone doses > 10 mg daily or equivalent) during the study (e.g., corticosteroids, 
immunoglobulins, and other immune- or cytokine-based therapies)

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4) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
5) Malignancy within 5 years of screening other than cutaneous Kaposi’s sarcoma, completely 
resected non-melanoma skin cancer (basal cell carcinoma or non-invasive cutaneous 
squamous carcinoma), or completely resected carcinoma in-situ of the cervix (CIN 3) or anus 
(AIN 3). A prior malignancy treated with curative therapy and for which there has been no 
evidence of disease for at least five years prior to screening is allowed.
6) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1
7) Participation in any other clinical trial, including observational studies, without prior 
approval from the Medical Monitor
8) 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 the dosing requirements
9) Known hypersensitivity to B/F/TAF FDC tablets, their metabolites, or formulation excipient
10) Subjects receiving ongoing therapy with any of the following medications in the table below,
including drugs not to be used with BIC, FTC, TAF:
Drug Class
Agents Disallowed*
Antiarrhythmic Agent
Dofetilide**
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antiretrovirals
Any antiretroviral drug that is not part of the study regimen
Herbal/Natural Supplements
St. John’s Wort
*
Administration of any of the above medications must be discontinued at least 30 days prior to the Day 1 visit and for the
duration of the study.
**
Dofetilde was withdrawn from the EU in 2009.
11) Acute hepatitis in the 30 days prior to study entry
12) Active tuberculosis infection

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Subject Enrollment
Subjects will be assigned a screening number at the time of consent. Day 1 visit cannot occur 
until subject eligibility has been confirmed.
Once eligibility has been confirmed and prior to or during the Day 1 visit the Investigator or 
designee will enroll the subject using the Interactive Web Response System (IWRS). Once a 
subject number has been assigned to a subject, it will not be reassigned to any other subject. The 
subject number assignment may be performed up to 3 days prior to the in-clinic Day 1 visit 
provided that all screening procedures have been completed and subject eligibility has been 
confirmed.
Subject enrolled will be assigned study drug bottle numbers of B/F/TAF FDC at study visits by 
IWRS.
The study procedures to be conducted for each subject enrolled in the study are also presented in 
tabular form in Appendix 2 and described in the text that follows.
5.2.
Description and Handling
5.2.1.
Formulation
B/F/TAF tablets are capsule-shaped, film-coated purplish-brown, debossed with “GSI” on one 
side of the tablet and “9883” on the other side of the tablet. B/F/TAF tablets contain 50 mg of 
bictegravir (B, BIC), 200 mg of emtricitabine (F, FTC), and 25 mg of tenofovir alafenamide 
(TAF). In addition, of the active ingredients, active B/F/TAF tablets contain croscarmellose
sodium, microcrystalline cellulose, magnesium stearate, polyvinyl alcohol, polyethylene glycol, 
titanium dioxide, talc, iron oxide red, and iron oxide black.
5.2.2.
Packaging and Labeling
B/F/TAF (50/200/25 mg) tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 30 tablets, silica gel desiccant and polyester packing material. Each 
bottle is enclosed with a white, continuous thread, child-resistant polypropylene screw cap with 
an induction-sealed and aluminum-faced liner.
Study drug to be distributed to centers in the participating countries shall be labeled to meet 
applicable requirements of the United States Food and Drug Administration (FDA), EU 
Guideline to Good Manufacturing Practice - Annex 13 (Investigational Medicinal Products), 
and/or other local regulations.

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5.2.3.
Storage and Handling
Study drug (B/F/TAF) should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the subjects, all bottles of study drugs should be stored 
in a securely locked area, accessible only to authorized site personnel. To ensure the stability and 
proper identification, study drug(s) should not be stored in a container other than the container in 
which they were supplied. Keep the bottle tightly closed to protect from moisture. Consideration 
should be given to handling, preparation, and disposal through measures that minimize drug 
contact with the body. Appropriate precautions should be followed to avoid direct eye contact or 
exposure when handling.
5.3.
Dosage and Administration of B/F/TAF
B/F/TAF tablets will be provided by Gilead Sciences.
Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) 50 mg/200 mg/25 mg FDC will be 
administered orally, once daily without regard to food at approximately the same time each day.
Subjects will be instructed to bring all study medication in the original container at each clinic 
visit for drug accountability. The Investigator will be responsible for maintaining accurate 
records for all study drug bottles dispensed and tablets returned. The inventory and dispensing 
logs must be available for inspection by the study monitor. Study medication supplies, including 
partially used or empty bottles, must be accounted for by the study monitor prior to destruction 
or return.
5.4.
Prior and Concomitant Medications

The use of medications for the treatment of HIV, other than study drug, is prohibited.
Medications listed in the following table and use of herbal/natural supplements are excluded or 
should be used with caution while subjects are participating in the study, depending on subject’s 
treatment regimen.

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Table 5-1.
Prior and Concomitant Medications
Drug Class
Agents Disallowed*
Use Discouraged and To Be Used With 
Caution
Medications or oral 
supplements containing 
polyvalent cations (e.g., 
Mg, Al, Ca, Fe):
Calcium or iron 
supplements
Cation-containing antacids 
or laxatives
Buffered medications
Antacids containing Al/Mg or Calcium:
B/F/TAF can be taken under fasting 
conditions 2 hours before antacids containing 
Al/Mg or calcium.
Routine administration of B/F/TAF 
simultaneously with, or 2 hours after, 
antacids containing Al/Mg or calcium is not 
recommended.
Supplements containing Calcium or Iron:
B/F/TAF and supplements containing 
calcium or iron can be taken together with 
food.
Routine administration of B/F/TAF under 
fasting conditions simultaneously with, or 
2 hours after, supplements containing 
calcium or iron is not recommended.
Antiarrhythmic Agent
Dofetilide**
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Antiretrovirals
Any antiretroviral drug that is not 
part of the study regimen
Hypoglicemic agent
Refer to the prescribing information of 
Metformin for assessing the benefit and risk 
of concomitant use of BIKTARVY and 
metformin.
Herbal/Natural 
Supplements
St. John’s Wort
*
Administration of any of the above medications must be discontinued at least 30 days prior to the Day 1 visit and for the 
duration of the study.
**
Dofetilde was withdrawn from the EU in 2009.
Should subjects have a need to initiate treatment with any excluded concomitant medication, 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.

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5.5.
Accountability for Investigational Medicinal Product (IMP)
The investigator is responsible for ensuring adequate accountability of all used and unused IMP.
This includes acknowledgement of receipt of each shipment of IMP (quantity and condition). 
All used and unused IMP dispensed to subjects must be returned to the site.
B/F/TAF accountability records will be provided to each study site to:

Record the date received and quantity of IMP kits

Record the date, subject number, subject initials, the IMP kit number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information
5.5.1.
Investigational Medicinal Product Return or Disposal
Return and disposal of study drug B/F/TAF will be performed as outlined in Section 9.1.7.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
Entry into Screening does not guarantee enrollment into the study. Please refer to section 5.1 for 
details about treatment assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before the Day 1 visit to determine eligibility for 
participation in the study. The GS-US-292-1826 30 Day Follow-Up visit may be utilized for this 
study’s Screening visit if Day 1 is within 30 days. Any assessments that are over 30 days prior to 
Day 1 will need to be repeated for the current study.
The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history, including: HIV-1 disease-related events, cigarette smoking 
(including current or previous smoker), history of fractures, family history of myocardial 
infarction or stroke, and prior medications within 30 days of screening visit

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator); if available, obtain historical genotype(s) (not required for 
entry to study)

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Height

12-lead ECG performed supine

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
Obtain blood and urine samples as described in Sections 6.9 and 6.10
eGFRCG
Male: 
(140 – age in years) × (wt in kg) = CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female: 
(140 – age in years) × (wt in kg) × 0.85 = CLcr (mL/min)
72 × (serum creatinine in mg/dL)

Whole blood sample for virology

Review of adverse events and concomitant medications
Subjects will be screened within 30 days before study entry to determine eligibility for 
participation in the study.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for Day 1 of the study.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events electronic case report form 
(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 eCRF. See 
Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Visit
The following evaluations are to be completed at the Day 1 visit. The Investigator must have 
confirmed subject’s eligibility before proceeding with the Day 1 visit. The subject must 
complete all evaluations before being dispensed the study drug. Initiation of treatment with the 
study drug must take place within 24 hours after this visit.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs measurement, including weight

Obtain blood and urine samples as described in sections 6.9 and 6.10
eGFRCG

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
Cystatin-C

Whole blood sample for virology

Patient reported outcomes: Subject is to read questionnaires by her/himself and write/mark 
answers directly onto questionnaires prior being administered study drug.
Visual Analog Scale (VAS)
HIV Treatment Satisfaction Status (HIVTSQs)
EQ-5D
Short Form 36 Health Survey (SF-36)
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F)

Dispense study drug

Subjects must initiate dosing of study drug or current regimen within 24 hours after the Day 
1 visit.

Subjects should also be counseled regarding the importance of adherence and taking their 
study drug once daily at approximately the same time each day
6.3.
Treatment Assessments
6.3.1.
Treatment Visits (Weeks 4-96)
The following assessments are to be completed at the end of Weeks 4, 12, 24, 36, 48, 60, 72, 84, 
and 96 unless otherwise specified.
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the visit date through Week 12 and completed within ± 6 days of 
the visit date through Week 96. The visit window at Week 24, Week 48, Week 72 and Week 96
may be ± 6 weeks of the visit date, if notified by Gilead. Unless notified by Gilead, the Week 24, 
Week 48, Week 72 and Week 96 visits should be completed within ± 6 days of the visit date.
Regularly scheduled evaluations will be made on all subjects whether or not they continue to 
receive study drug.

Review of AEs and changes in concomitant medications (all visits)

Complete physical examination (Weeks 48 and 96) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator)

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
Symptom-directed physical examination (Weeks 4, 12, 24, 36, 60, 72, and 84)

Vital signs measurement, including weight (all visits)

12-lead ECG (Weeks 48 and 96 only)

Obtain blood and urine samples as described in Sections 6.9 and 6.10
eGFRCG (all visits)

Subjects who meet the criteria for virologic rebound should be managed according to 
Section 6.12, Virologic Failure

HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic 
rebound with HIV-1 RNA value ≥ 200 copies/mL (Weeks 48, 72 and 96 only)

Patient reported outcomes: Subject is to read questionnaires by her/himself and write/mark 
answers directly onto questionnaires.
Visual Analog Scale (VAS) (all visits)
HIV Treatment Satisfaction Change (HIVTSQc) (Weeks 4, 24, and 48)
EQ-5D (Weeks 24 and 48)
SF-36 (Weeks 24 and 48)
FACIT-F (Weeks 24 and 48)

Document study drug dispensation and accountability for B/F/TAF study drug (all visits)
6.4.
Treatment Assessments (Post Week 96 extension phase)
At the Week 96 Visit, subjects in a country where B/F/TAF FDC is not yet commercially 
available will be given the option to receive B/F/TAF FDC for up to additional 48 weeks (up to 
week 144) and attend study visits every 12 weeks, or until Gilead Sciences elects to discontinue 
the study in that country, whichever occurs first.
Subjects who further continue participation in the study and receive B/F/TAF FDC will return 
for study visits every 12 weeks. Study visits are to be completed within ±6 days of the 
protocol-specified visit date unless otherwise specified.
Subjects participating in the study post Week 96 extension phase will be required to return for 
study visits according to the schedule present in Appendix 2 and described in the text below:

Review of AEs and changes in concomitant medications

Symptom-directed physical examination

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
Vital signs measurement, including weight

Obtain blood and urine samples as described in Sections 6.9 and 6.10
eGFRCG (all visits)

Subjects who meet the criteria for virologic rebound should be managed according to 
Section 6.12, Virologic Failure

Document study drug dispensation and accountability
6.4.1.
Early Study Drug Discontinuation Visit
If a subject discontinues study drug prior to Week 96, the subject will be asked to return to the 
clinic within 72 hours for the ESDD visit. The subject will be asked to continue attending the 
scheduled study visits through Week 96.
If a subject discontinues study drug before the completion of post Week 96 extension phase, the 
subject will be asked to return to the clinic within 72 hours for the ESDD Visit.
Subjects who complete the study drug through Week 96, and who do not continue participation 
in the post Week 96 extension phase, will not be required to complete the Early Study Drug 
Discontinuation Visit.
At the ESDD visit, any evaluations showing abnormal results indicating that there is a possible 
or probable causal relationship with the study drug will be repeated weekly (or as often as 
deemed prudent by the Investigator) until the abnormality is resolved, returns to baseline, or is 
otherwise explained.
The following evaluations are to be completed at this visit:

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the
discretion of the Investigator)

Vital signs measurement, including weight

12-lead ECG

Obtain blood and urine samples as described in Sections 6.9 and 6.10
eGFRCG

Patient reported outcomes: Subject is to read questionnaire by her/himself and write/mark 
answers directly onto questionnaire.
VAS
HIVTSQc

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
HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic 
rebound with HIV-1 RNA value ≥ 200 copies/mL

Document study drug accountability
6.4.2.
30 Day Follow-Up Visit

For subjects discontinuing study between Day 1 – Week 96
If the subject discontinues study drug and does not continue in the study, the subject will be 
required to return to the clinic 30 days after the completion of the Early Study Drug 
Discontinuation Visit for the 30-Day Follow-Up visit.
If the subject discontinues study drug and continues in the study through at least one 
subsequent visit after the Early Study Drug Discontinuation Visit, the subject will not be 
required to complete the 30-Day Follow-Up Visit.
If the subject completes the study drug through Week 96 and does not continue participation 
in the post Week 96 extension phase, the subject will be required to return to the clinic 
30 days after the completion of study drug for the 30-Day Follow-Up visit.

For subjects discontinuing study post Week 96 extension phase
If the subject discontinues study drug before the completion of post Week 96 extension 
phase, the subject will be required to return to the clinic 30 days after the completion of the
Early Study Drug Discontinuation Visit for the 30-Day Follow-Up visit
If the subject continues participation in the extension phase post Week 96, the subject will be 
required to return to the clinic 30 days after the completion of the extension phase for the 
30-Day Follow-Up visit.
For the purpose of scheduling a 30-Day Follow-Up Visit, a 6 days window may be used. 
The following evaluations are to be completed at the 30-Day Follow-Up Visit:

Review of AEs and changes in concomitant medications

Symptom-directed physical examination

Vital signs measurement, including weight

Obtain blood and urine samples as described in Sections 6.9 and 6.10
At the 30 Day Follow-Up visit any evaluations showing abnormal results indicating that there is 
a possible or probable causal relationship with the study drug will be repeated weekly (or as 
often as deemed prudent by the Investigator) until the abnormality is resolved, returns to 
baseline, or is otherwise explained.

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6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.6, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
6.6.
Criteria for Discontinuation of Study Treatment
Study medication will be discontinued in the following instances:

Development of active tuberculosis infection

Unacceptable toxicity, 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

Lack of efficacy

Subject request to discontinue for any reason
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

Subject noncompliance

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.7.
End of Study
End of study is defined as completion of the 96 weeks of treatment and the 30 Day Follow-Up 
visit. Subjects that enter the post Week 96 extension phase will have the week 96 study visit, 
then up to 48 weeks on the extension phase and the 30 Day Follow-Up visit.
6.8.
Post Study Care
After a subject has completed/terminated their participation in the study, long-term care for the 
subject will remain the responsibility of their primary treating physician.

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6.9.
Blood Samples
Blood sample collection for the following laboratory analyses:

Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
potassium, sodium (all visits)

Hematology profile: complete blood count (CBC) with differential and platelet count (all 
visits)

CD4+ cell count (all visits)

Plasma HIV-1 RNA (TaqMan® v2.0) (all visits)

Hepatitis B virus surface antigen (HBsAg), Hepatitis B virus surface antibody (HBsAb) and 
Hepatitis B virus core antibody (HBcAb). The following tests will be conducted by the 
central laboratory if the following criteria are met (Screening visit)
If positive HBsAg: reflex testing for plasma HBV DNA, Hepatitis B virus e-antigen
(HBeAg) (if negative, reflex Hepatitis B virus e-Antibody [HBeAb]), and quantitative
HBsAg
If positive HBcAb with negative HBsAg and negative HBsAb: reflex testing for plasma 
HBV DNA (if positive, reflex HBeAg). If HBeAg is performed and found to be negative, 
reflex HBeAb

Hepatitis C virus (HCV Ab) serology (reflex HCV RNA is performed in subjects with 
positive HCV Ab serology) (Screening Visit)

Metabolic assessments: Fasting (no food or drink, except water, at least 8 hours prior to 
blood collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, and 
triglycerides) (Day 1, Weeks 24, 48 and 96); metabolic assessments will not be collected 
after Week 96.

If the subject has not fasted prior to the visit, the visit may proceed, but the subject must 
return within 72 hours in a fasted state.

Biomarkers to be analyzed may include but will not be limited to: soluble glycoprotein VI 
(sGPVI), P-selectin, soluble CD40 ligand, and d-dimer (Day 1, Weeks 4, 12, 24, 48, 60, 72, 
84, and 96); Biomarkers will not be collected after Week 96. A portion of the biomarker 
blood sample obtained at Day 1, Weeks 4, 12, 24, 48, 60, 72, 84, and 96 may be utilized to 
assess study drug PK. This will be a random sample with the date and time of the subject’s 
last medication dose recorded.

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
Inflammation evaluations may include: cystatin-C, IL 6, hs CRP, sCD14, sCD163, sTNF-R1, 
and Lp-PLA2. Specimens will be collected from all subjects (Day 1, Weeks 4, 12, 24, 48, 60, 
72, 84, and 96). Inflammation markers will not be collected after Week 96.

Plasma storage sample for safety and/or virology testing (all visits)

Whole blood sample for virology (Screening and Day 1)
6.10.
Urine Samples
Urine collection for the following laboratory analyses:

Urinalysis (all visits)

Urine chemistry (all visits)

Renal safety evaluations: Fasting (no food or drink, except water, at least 8 hours prior to 
blood collection) retinol binding protein and beta-2 microglobulin (Day 1, Weeks 4, 12, 24,
48, 60, 72, 84, and 96). Renal safety evaluations will not be done after Week 96.
6.11.
Blood and Urine Sample Storage
Residual blood and urine samples taken throughout the study (including the post Week 96
extension phase) will be stored. Stored samples may be used by the Sponsor or its research 
partners to help answer questions about the study drug, and HIV disease and its associated 
conditions, or to provide additional safety data. These samples will be stored until the completion 
of all visits for all subjects and the final study analysis.
6.12.
Virologic Failure
Virologic failure is defined as confirmed virologic rebound of HIV-1 RNA ≥50 copies/mL at 
2 consecutive visits, or having HIV-1 RNA ≥50 copies/mL at study drug discontinuation or at
Week 48, Week 72 or Week 96.
6.12.1.
Management of Virologic Rebound
Subjects who meet the criteria listed below will be considered to have virologic rebound:

At any post Day 1 visit, a rebound in HIV-1 RNA ≥ 50 copies/mL
Following the virologic rebound, subjects will be asked to return to the clinic for a scheduled or 
unscheduled blood draw (within 2-3 weeks after the date of the original test that resulted in 
HIV-1 RNA ≥50 copies/mL). Subjects with HIV-1 RNA values between 50-200 copies/mL 
should follow the algorithm in Figure 6-1. If virologic rebound is confirmed at the scheduled or 
unscheduled visit and the HIV-1 RNA is ≥200 copies/mL, the plasma sample from the 
confirmation visit will be the primary sample used for HIV-1 genotypic and phenotypic testing. 

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After a subject’s first post-Day 1 resistance test, additional testing will be conducted on a 
case-by-case basis. Any subject may be discontinued at Investigator’s discretion or per local 
treatment guidelines.
If no resistance to study drugs is detected from the genotype or phenotype, the subject may 
remain on study drugs and HIV-1 RNA test should be analyzed at a new visit (within 2-3 weeks
after date of test with HIV-1 RNA ≥50 copies/mL). Investigators should carefully evaluate the 
benefits and risks of remaining on study drug for each individual subject and document this 
assessment in the on-site medical record.
Subjects who are noncompliant on an ongoing basis will be considered for discontinuation per 
the Investigator’s discretion or local treatment guidelines. Investigators who opt to discontinue 
study drugs for an individual subject must discuss with the Medical Monitor prior to study drug 
discontinuation.
For subjects who are off study drug but remain on study, it will be the Investigator’s discretion to 
manage virologic rebound.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
rebound.

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Figure 6-1. 
Virologic Rebound Schema 
Final 
Amendment2 
Screening 
Treatment Period 
30 Day Follow-Up 
+ 
At Any Post-Day 1 Visit, 
an HIV-1 RNA::: 50 copies/mLa 
+ 
Return for scheduled or unscheduled visit (2-3 weeks after 
preceding visit) for HIV-1 RNA and collect sample for potential 
genotype/phenotype samplingb 
+ 
HIV-1 RNA ::: 200 copies/mL 
Confmned Viral Load Rebound 
Genotype and Phenotype Test 
Orderedc 
II 
l 
... 
If resistance to 
If no resistance to 
FTC, TAF, or BIC, 
FTC, TAF, or BIC, 
discontinue study 
may continue on 
drng and construct 
study drugd 
anew ARV 
regimene 
.~ 
·-
I Remain in Study I 
a 
If the HIV-I RNA is bet\veen 50 and 200 copies/mL, a reflex HIV-I RNA repeat test will be conducted on stored plasma if 
available. If the repeat result is < 50 copies/mL, then no further action is required. If the repeat result is 2: 50 copies/mL then 
proceed to the scheduled or llllScheduled visit 2 - 3 weeks later. 
b 
If the HIV-I RNA is < 50 copies/mL then no further action is required. If the HIV-I RNA is betwe.en 50 and 200 copies/mL, 
a reflex HIV-I RNA repeat test will be conducted on stored plasma if available. If the repeat result is < 50 copies/mL, then no 
fut1her action is required. If the repeat result is between 50 and 200 copies/mL this is protocol defined confirmed virologic failure 
and the Medical Monitor should be consulted. If the repeat result is 2: 200 copies/mL, then a Genotype and Phenotype test will be 
ordered. 
c 
Ifvirnlogic rebound is confumed and the last HIV-I RNA is 2: 200 copies/mL, the HIV-I genotype and phenotype (reverse 
t:ranscriptase protease and integrase) will be analyzed. If the genotype and phenotype assay fails, Investigator reviews sh1dy dmg 
continuation/disc.ontinuation options and discus with the Medical Monitor prior to sh1dy dmg discontinuation. 
d 
If no resistance to study drug is detected, HIV-I RNA w-ill be repeated 2 - 3 weeks later. Investigator re'\1-iews study dmg 
continuation/discontinuation options and discuss with the Medical Monitor prior to study drug discontinuation. The subject will 
remain in the study. 
e 
A new ARV regimen will be configtu-ed, at the Investigator's discretion and the subje-et will remain in the shldy. 
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6.12.2.
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Drug Discontinuation or 
at Week 48, Week 72 or Week 96
Subjects with HIV-1 RNA ≥ 50 copies/mL at study drug discontinuation or last visit will be 
considered virologic failures. Subjects with HIV-1 RNA ≥ 50 copies/mL at Weeks 48, 72 or 96 
will be asked to return for an unscheduled visit within the visit window for a retest.
Subjects with HIV-1 RNA ≥ 200 copies/mL at study drug discontinuation, last visit, or last 
measurement in the Weeks 48, 72 or 96 window, will also have resistance testing conducted.

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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

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.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (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.
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)
7.1.4.
Assessment of Severity
AE severity should be recorded and graded according to the Gilead Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 4). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
The distinction between the seriousness and the severity of an adverse event should be noted.

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Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events.
7.2.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and adverse events related to protocol-mandated 
procedures.
7.2.1.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.2.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance and Epidemiology (PV&E) as instructed. This 
also includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30-days of the 
last dose of study IMP, regardless of causality, should also be reported.
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period ; 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead PV&E.
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 PV&E within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

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
If it is not possible to record and submit the SAE information electronically, because the 
eCRF database cannot be accessed or is not available (including at study start), record the 
SAE on the paper serious adverse event report form and submit by e-mail or fax within 
24 hours of the investigator’s knowledge of the event to:
Gilead PV&E:
Fax:
E-mail:

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.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline.

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 and the event description section of the SAE form.
7.3.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable.
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
PPD
PPD

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7.4.
Toxicity Management
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 3, and as outlined below.
Refer to Section 6.6, Criteria for Study Drug Interruption or Discontinuation, for additional 
specific discontinuation criteria. For Specific toxicity discontinuation criteria please refer to 
Section 7.4. The Gilead Medical Monitor should be consulted prior to study drug discontinuation 
when medically feasible.
7.4.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the investigator.
7.4.2.
Grades 3 Laboratory Abnormality or Clinical Event

For a Grade 3 clinically significant laboratory abnormality or clinical event, IMP may be 
continued if the event is considered to be unrelated to IMP.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to IMP, IMP should be withheld until the 
toxicity returns to ≤ Grade 2.

If a laboratory abnormality recurs to ≥ Grade 3 following re-challenge with IMP and is 
considered related to IMP, then IMP should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to IMP may not require permanent discontinuation.
7.4.3.
Grade 4 Laboratory Abnormality or Clinical Event
For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality that is 
considered related to IMP, IMP 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.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (e.g., Grade 4 creatine kinase [CK] after 
strenuous exercise or triglyceride elevation that is nonfasting or that can be medically managed)
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead medical monitor, who will have a discussion with the investigator and decide the 
appropriate course of action. Whether or not considered treatment-related, all subjects 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or they are considered irreversible, 
or until there is a satisfactory explanation for the changes observed.
Any questions regarding toxicity management should be directed to the Gilead Medical Monitor.

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7.4.4.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis B 
Management
A On-Treatment ALT Flare is defined as:

Confirmed (within 3 days of receipt of initial laboratory results) serum ALT > 2 × Day 1 
value and >10 × ULN, with or without associated symptoms
7.4.4.1.
Management of ALT Flare in Subjects Receiving Study Medication
If laboratory results indicate elevation of ALT 2 × Day 1 value 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.

If the ALT elevation is confirmed, request the central clinical laboratory to conduct reflex 
testing for plasma HBV DNA, HBV serology (HBsAg and HBsAb), HDV, HAV IgM, and 
HCV serology
Check the following laboratory parameters: serum ALT and AST, total bilirubin, INR, and serum 
albumin. Based on the results of the confirmatory tests, the following treatment modifications are 
recommended:
Elevated Liver Enzymes, Normal or Stable relative to Day 1 Liver Function Tests
If ALT levels are elevated (i.e., 2 × Day 1 and 10 × ULN) with normal or stable total 
bilirubin and INR relative to Day 1, the subject may remain on study medication and should be 
monitored weekly as long as ALT levels return to normal or Day 1 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.
Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (i.e., 2 × Day 1 and 10 × ULN), and total bilirubin is confirmed to 
be 2 x Day 1 value, and INR is 0.5 above Day 1, provided both are > ULN, the investigator 
should consider discontinuing study medication (upon discussion with the Gilead Medical 
Monitor, unless the safety of the patient is of immediate concern). The subject should be 
monitored weekly as long as ALT, total bilirubin, and INR values remain elevated or above 
Day 1 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.

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7.4.4.2.
Management of Exacerbation of Hepatitis B in Subjects who have Discontinued 
Study Medication
If laboratory results indicate (1) an ALT elevation 2 × Day 1 and 10 × ULN alone OR 
associated with (2) abnormal laboratory parameters suggestive of worsening hepatic function 
(total bilirubin 2 × Day 1, INR 0.5 above Day 1, provided both are > ULN) and the subject is on 
no post-study therapy for HBV, the following is recommended:

Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 days 
after the initial laboratory values were drawn). During the visit, perform a clinical assessment 
of the subject.

Check the following laboratory parameters: serum ALT and AST, bilirubin, INR, and 
albumin.

If the ALT elevation is confirmed, request the clinical laboratory to conduct reflex testing for 
plasma HBV DNA, HBV serology (HBsAg and HBsAb), HDV, HAV IgM and HCV. If 
serum 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 Day 1 up to a maximum of 6 months after the initial occurrence of the event.
7.4.5.
Management of Potential Hepatobiliary Toxicity
Monkeys given a high dose (1000 mg/kg/day) for 39 weeks had evidence of biliary hyperplasia 
and hepatocyte hypertrophy on histopathologic examination. The risk to humans given the 
clinical dose of bictegravir (50 mg/day) is unknown. Investigators should be aware of this 
potential toxicity. Any study subject exhibiting signs/symptoms or laboratory abnormalities 
suggestive of possible hepatobiliary toxicity should undergo thorough examination and clinical 
workup as deemed appropriate by the Investigator, and the Investigator must communicate 
promptly with the Gilead Medical Monitor. Consideration should be given to appropriate 
imaging studies (for example, ultrasound of the liver and biliary tree) and potential consultation 
with a gastroenterologist with specialty training in hepatobiliary diseases. Management of graded 
laboratory and clinical abnormalities will be managed as outlined in Section 7.4.
7.4.6.
Hepatitis C Management
If a subject tests positive for HCV RNA at screening or develops signs or symptoms of active
Hepatitis C virus Gilead recommends that local medical practice is followed at the discretion of
the Investigator. Study drug may be continued without dose interruption. Should the Investigator 
decide to initiate Hepatitis C treatment, the Investigator must contact the Gilead Medical Monitor 
to confirm that no drug-drug interactions with Hepatitis C medications are expected. Subjects 
should return to the clinic for scheduled or unscheduled follow up visit(s) according to local 
medical practice for laboratory evaluations. If Hepatitis C treatment is initiated, Investigators 
should use the Gilead provided retest laboratory kits to manage the active Hepatitis C.

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7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, and 
AE in an infant following exposure from breastfeeding.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
Occupational exposure is defined as exposure to a medicinal product as a result of one’s 
professional or non-professional occupation.
7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Reporting Special Situations
All special situation reports must be reported on the special situations report form and forwarded 
to Gilead PV&E within 24 hours of the investigator becoming aware of the situation. These 
reports must consist of situations that involve study IMP and/or Gilead concomitant medications, 
but do not apply to non-Gilead concomitant medications.
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.

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Refer to Section 7.3 and the 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 eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
Gilead PV&E contact information is as follows:
Email: 
 and
Fax: 
PPD
PPD

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives

To characterize the virologic efficacy of switching virologically suppressed subjects on an 
E/C/F/TAF FDC or TDF-containing regimen (if currently or previously participated in 
GS-US-292-1826) to B/F/TAF FDC defined by HIV-1 RNA <50 copies/mL at Week 24.

The secondary objectives of the study are to characterize the safety and tolerability of 
switching to B/F/TAF FDC from an E/C/F/TAF FDC or TDF-containing regimen (if 
currently or previously participated in GS-US-292-1826) and to characterize the virologic 
efficacy of switching to B/F/TAF FDC defined by HIV-RNA <50 copies/mL at Week 48, 
Week 72, and Week 96.
8.1.2.
Primary Endpoint
The primary endpoint is HIV-1 RNA <50 copies/mL at Week 24 as defined by the Food and 
Drug Administration (FDA) snapshot algorithm
8.1.3.
Secondary Endpoints
Secondary endpoints to be evaluated are

adverse events through Week 24

adverse events through Week 48

adverse events through Week 72

adverse events through Week 96

HIV-1 RNA <50 copies/mL at Week 48 as defined by the Food and Drug Administration 
(FDA) snapshot algorithm

HIV-1 RNA <50 copies/mL at Week 72 as defined by the Food and Drug Administration 
(FDA) snapshot algorithm

HIV-1 RNA <50 copies/mL at Week 96 as defined by the Food and Drug Administration 
(FDA) snapshot algorithm
8.1.4.
Other Endpoints of Interest
Other endpoints of interest are:

Subject satisfaction after switching to B/F/TAF FDC

Number of potentially interacting medications

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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
The Full Analysis Set will include all the subjects who received at least one dose of study drug. 
The FAS will exclude subjects with major protocol violations (e.g., not having the correct 
background HIV therapy at study entry). The FAS analysis set is the primary analysis set for the 
efficacy analyses.
8.2.1.2.
Safety
The primary analysis set for safety analyses is defined as all subjects who received at least one 
dose of study drug.
All data collected during treatment up to 30 days after the last dose of study drug will be 
included in the safety summaries.
8.2.1.3.
Biomarkers
All subjects with available biomarkers data will be included in the Biomarker dataset.
8.3.
Data Handling Conventions
In general, baseline value is defined as the last value measured on or prior to Day 1 of the study.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity and age.
Baseline data will include a summary of body weight, height, body mass index, risk factors for 
HIV-1 infection, and background HIV therapy at study entry (E/C/F/TAF vs TDF containing 
regimen).
8.5.
Efficacy Analysis
The proportion of subjects maintaining HIV-1 RNA < 50 copies/mL (as defined by the FDA 
snapshot analysis) at Week 24 and its 95% confidence interval will be estimated. Additionally, 
the 95% CI for the proportion of subjects with HIV-1 RNA ≥ 50 copies/mL (per snapshot 
analysis) at Week 24 will be calculated and presented.
Similar summary tables will be provided to characterize the efficacy of study drug at Week 48, 
Week 72, and Week 96.

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8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to 30 days 
after the date of last dose of IMP will be summarized. Data for the pretreatment period and post 
the date of last dose plus 30 days will be included in data listings.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the IMP administration data. 
Exposure data will be summarized.
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug 
administration, and summarized. Dosing information for individual subjects will be listed.
8.6.2.
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 with onset date on or after the study drug start 
date and no later than 30 days after the study drug stop date; or any adverse event leading to 
study drug discontinuation.
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
and PT) will be provided. Additional summaries may include summaries for adverse events by 
grade, Investigator’s assessment of relationship to study drug, and effect on study drug dosing.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Data and change from 
baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 4.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post baseline up to, and including, the date of last dose 
of study drug plus 30 days will be summarized. If baseline data are missing, then any graded 
abnormality (ie, at least a Grade 1) will be considered treatment emergent. The maximum post
baseline toxicity grade will be summarized by laboratory parameter.
Laboratory abnormalities that occur before the first dose of IMP or after the subject has been 
discontinued from treatment for 30 days will be included in a data listing.
8.7.
Sample Size
The sample size is based on feasibility of conducting a study with ≥65 year old subjects.

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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 subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.

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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB- 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/IEC or 
local requirements.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, , or laboratory. Laboratory specimens must 
be labeled in such a way as to protect subject identity while allowing the results to be recorded to 
the proper subject. Refer to specific laboratory instructions. NOTE: The investigator must keep a 
screening log showing codes, names, and addresses for all subjects screened and for all subjects 
enrolled in the trial. Subject data will be processed in accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the IMP, and any other study information, remain the 
sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.

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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);

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.

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9.1.6.
Case Report Forms
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 
capture the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Subsequent to data entry, a study monitor will perform 
source data verification within the EDC system. 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). Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to any interim time points or database lock (as 
instructed by Gilead), 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. At the conclusion of the trial, Gilead will provide the site with a read-only archive 
copy of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files.
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IECs, or to regulatory authority or health authority 
inspectors.

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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IEC in 
accordance with local requirements and receive documented IEC approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation.
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.2.2).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.

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

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10.
REFERENCES
Aldir I, Horta A, Serrado M. Single-tablet regimens in HIV: does it really make a difference? 
Curr Med Res Opin 2014;30 (1):89-97.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Costagliola D. Demographics of HIV and aging. Curr Opin HIV AIDS 2014;9 (4):294-301.
European AIDS Clinical Society (EACS). European AIDS Clinical Society (EACS) Guidelines 
Version 8.2 January, 2017.
Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al. A Phase 3 Randomized 
Controlled Clinical Trial of Bictegravir in a Fixed Dose Combination, B/F/TAF, 
vs DTG/ABC/3TC in Treatment-Naïve Adults at Week 48 [Presentation W48]. 
9th IAS Conference on HIV Science; 2017 23–26 July; Paris, France. 
Gallant J, Thompson M, DeJesus E, Voskuhl G, Wei X, Zack J, et al. Novel Integrase Strand 
Transfer Inhibitor Bictegravir 10 Day Monotherapy in HIV-1–Infected Patients 
[Poster PW-030]. ASM Microbe; 2016 16-20 June; Boston, MA. 
Gilead Sciences Inc. Gilead's Investigational Fixed-Dose Combination of Bictegravir, 
Emtricitabine and Tenofovir Alafenamide for the Treatment of HIV-1 Meets 
Primary Endpoint in Four Phase 3 Studies. U.S. NDA Submission Planned for Q2 
2017; EU MAA Filing Planned for Q3 2017.  2017.
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of 
mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. 
Lancet 1998;352 (9142):1725-30.
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining 
Morbidity and Mortality Among Patients With Advanced Human 
Immunodeficiency Virus Infection. N Eng J Med 1998;338 (13):853-60.
Sax PE, Pozniak A, Arribas J, Koenig E, DeJesus E, Stellbrink HJ, et al. Phase 3 Randomized, 
Controlled, Clinical Trial of Bictegravir Coformulated With FTC/TAF in a Fixed-
Dose Combination vs Dolutegravir + FTC/TAF in Treatment-Naïve HIV-1-
Positive Adults: Week 48 Results [Poster TUPDB0201LB]. 9th IAS Conference 
on HIV Science; 2017 23–26 July; Paris, France. 
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.

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Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
cohort study. Lancet 2005;366 (9483):378-84.
Sterrantino G, Santoro L, Bartolozzi D, Trotta M, Zaccarelli M. Self-reported adherence supports 
patient preference for the single tablet regimen (STR) in the current cART era. 
Patient preference and adherence 2012;6:427-33.
UNAIDS. Fact Sheet 2016: Global Statistics-2015. Available at: 
http://www.unaids.org/en/resources/documents/2016/UNAIDS_FactSheet.  2016.

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11.
APPENDICES
Appendix 1.
Investigator Signature Page....................................................................................................82
Appendix 2.
Study Procedures Table..........................................................................................................83
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................86
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............87
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, Definition 
of Male Fertility and Contraceptive Requirements...............................................................109
Appendix 6.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC Guidelines) ...........................110

PPD
PPD
PPD
B/F/TAF 
Protocol GS-US-380-4449 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b, Multicenter, Open-LabeJ Study to Evaluate Switching from an 
Elvitegravir/Cobicistat/Emtricitabine/fenofovir AJafenamide Fixed-Dose Combination 
Regimen or a Tenofovir Disoproxil Fumarate Containing Regimen to Fixed-Dose Combination 
of Bictegravir /Emtricitabine/Tenofovir Alafenamide in Elderly, Virologically-Suppressed, 
HIV-1 Infected Subjects Aged~ 65 Years 
GS-US-380-4449 Amendment 2, 18 December 2018 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. l will conduct this study as 
outlined herein and wil1 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 82 
18 December 20 I 8 

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Appendix 2.
Study Procedures Table
Study Procedure
Screeninga
Day 1b
End of Weekc
Post Week 96
extension phase
Early Study 
Drug 
Discontinuation 
(ESDD)d
30-Day
Follow-up
4
12
24
36
48
60
72
84
96
Every 12 weeks for 
48 weeks (until 
Week 144)
Informed Consent
X
Medical History
X
Concomitant Medications
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
Complete Physical Exame
X
X
X
X
X
Symptom-Directed 
Physical Exam
X
X
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-lead ECG
X
X
X
X
Urinalysis and Urine 
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
Renal Safety Evaluations 
– Urinef
X
X
X
X
X
X
X
X
X
Biomarkers: 
inflammation, platelet, 
renalg
X
X
X
X
X
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry Profileh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology Profilei
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAj
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV and HCV 
Serologiesk
X
Cystatin-C
X
Estimated GFRCGl
X
X
X
X
X
X
X
X
X
X
X
X
X
Whole Blood Samplem
X
X

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Study Procedure
Screeninga
Day 1b
End of Weekc
Post Week 96
extension phase
Early Study 
Drug 
Discontinuation 
(ESDD)d
30-Day
Follow-up
4
12
24
36
48
60
72
84
96
Every 12 weeks for 
48 weeks (until 
Week 144)
Metabolic Assessmentsn
X
X
X
X
Plasma Storage Sampleo
X
X
X
X
X
X
X
X
X
X
X
X
Patient reported outcomes: 
VAS
X
X
X
X
X
X
X
X
X
X
X
Patient reported outcome: 
HIVTSQs
X
Patient reported outcome: 
HIVTSQc
X
X
X
X
Patient reported outcome: 
EQ-5D
X
X
X
Patient reported outcome: 
SF-36
X
X
X
Patient reported outcome: 
FACIT-F
X
X
X
HIV-1 
Genotype/Phenotypeq
X
X
X
X
Study Drug Dispensation 
and Accountability
X
X
X
X
X
X
X
X
X
X
X
Xr
a
Evaluations to be completed within 30 days prior to Day 1 visit.
b
Subjects will be dispensed study drug at the Day 1 visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 visit.
c
All study visits are to be scheduled relative to the Day 1 visit date. Visit windows are ± 2 days of the protocol specified date through Week 12, ± 6 days of the protocol
specified date through Week 96. The Week 24, 48 and 96 visits window is ± 6 weeks of the visit date, if notified by Gilead. Unless notified by Gilead, the Week 24,, 48 and 
96 visits should be completed within ± 6 days of the visit date. For the purpose of scheduling a 30-Day Follow-Up Visit, a +/- 6 days window may be used. Those subjects 
who prematurely discontinue study drug and continue in the study through at least one subsequent visit after the Early Study Drug Discontinuation Visit will not be required 
to complete the 30 Day Follow Up Visit.
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through the
Week 96 visit even as the subject discontinues study drug.
e
Complete physical examination (urogenital/anorectal exams will be performed at the discretion of the investigator).
f
Urine for renal safety, including retinol binding protein, and beta-2-microglobulin, will be collected. Samples for renal safety will be collected fasted. If the subject has not 
fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted.
g
Inflammation may include cystatin-C, IL-6, hs-CRP, sCD14, sCD163, sTNF-1R, and Lp-PLA2; Platelet and coagulation function may include soluble glycoprotein VI 
(sGPVI), P-selectin, soluble CD40 ligand, and D-dimer will be collected. Urine for renal safety, including retinol binding protein, and beta-2-microglobulin, will be collected.
Samples for renal safety will be collected fasted. If the subject has not fasted prior to the visit, the visit may proceed, but the subject must return within 72 hours in a fasted 

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state. A portion of the biomarker blood sample obtained at Day 1, Weeks 4, 12, 24, 48, 60, 72, 84 and 96may be utilized to assess study drug PK. This will be a random 
sample with the date and time of the subject’s last medication dose recorded.
h
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium, and sodium. At Day 1, Weeks 24, 48 and 96 analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry
profile.
i
CBC with differential and platelet count.
j
For the management of virologic rebound please refer to section 6.12.
k
Hepatitis B virus surface antigen (HBsAg), Hepatitis B virus surface antibody (HBsAb) and Hepatitis B virus core antibody (HBcAb).
l
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance.
m
Whole blood sample for virology analysis.
n
Metabolic Assessments: Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). If the subject has not fasted prior to the visit, the visit may 
proceed, but the subject must return within 72 hours in a fasted state.
o
Plasma storage sample for safety and/or virology (Day 1, Weeks 4-96, and ESDD).
p
Urinalysis only.
q
The geno/pheno is only done if the last HIV-1 RNA is > 200 copies/mL.
r
Drug accountability only; study drug will not be dispensed at this visit.

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Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade I 
Grade 2 
I 
I 
! 
! 
i 
Repeat lab to 
May continue dosing 
at the discretion of 
confinn toxicity 
the investigator 
grade 
' 
If confinned and possibly and/or probably related to investigational 
medicinal products: 
I. 
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 confinned and possibly or probably 
related to investigational medicinal products, discontinue all 
investigational medicinal products dosing permanently 
Grade 3 
I I 
i 
Repeat lab to 
confinn toxicity 
grade 
l 
l 
If confinned and unrelated to 
investigational medicinal products, 
dosing may continue at the discretion 
of the investigator 
Grade 4 
If confinned and 
possibly or probably 
----+ related to 
investigational 
medicinal products, 
discontinue 
investigational 
medicinal products 
dosing permanently and 
follow at periodic 
intervals at least weekly 
until a return to 
baseline or is otherwise 
explained 
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator 

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

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 88
18 December 2018
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product 
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN 
1.50 to 3.00 ULN 
3.00 ULN 
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin 
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
# An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 89
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia
>ULN to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia
Adult and Pediatric
1 Year
3.0 to <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 90
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 91
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric 1 Year–14 Years
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN
5.0 ULN
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL
10.0 to 12.0 mg/dL
12.0 to 15.0 mg/dL
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
Adult and Pediatric
≥1 year
Infant < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine**
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L
Bicarbonate
Adult and Pediatric
≥ 4 Years
16.0 mEq/L to LLN
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 92
18 December 2018
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects >70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 93
18 December 2018
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT)
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 94
18 December 2018
URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria (Dipstick)
1
2
3-4+
NA
Hematuria (Quantitative)
See Note below
Females
>ULN - 10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Males
6-10 RBC/HPF
10-75 RBC/HPF
> 75 RBC/HPF
NA
Proteinuria (Dipstick)
1
2–3
4
NA
Proteinuria, 24 Hour Collection
Adult and Pediatric
10 Years
200 to 999 mg/24 h
>999 to 1999 mg/24 h
>1999 to 3500 mg/24 h
3500 mg/24 h
Pediatric 3 Mo to 
< 10 Years
201 to 499 mg/m2/24 h
>499 to 799 mg/m2/24 h
>799 to 1000 mg/m2/24 h
1000 mg/ m2/24 h
Glycosuria (Dipstick)
1+
2-3
4
NA
Notes:
*
Toxicity grades for Quantitative and Dipstick Hematuria will be assigned by Covance Laboratory, however for other laboratories, toxicity grades will only be assigned to 
Dipstick Hematuria.
*
With the exception of lipid tests, any graded laboratory test with a result that is between the LLN and ULN should be assigned Grade 0.
*
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for 
the AE.

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 95
18 December 2018
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND No 
intervention indicated
Asymptomatic AND Non-
urgent medical intervention 
indicated
Symptomatic, non-life-
threatening AND Non-
urgent medical intervention 
indicated
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia
(stable angina) OR Testing 
consistent with ischemia
Unstable angina OR Acute 
myocardial infarction
Hemorrhage (significant acute 
blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated (for 
children 10 cc/kg) indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic
OR
90–99 mmHg diastolic
159–179 mmHg systolic
OR
99–109 mmHg diastolic
179 mmHg systolic
OR
109 mmHg diastolic
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years (with 
repeat testing at same visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
Life-threatening consequences 
(eg, malignant hypertension) 
OR Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with non-life-
threatening physiologic 
consequences OR Effusion 
with nonurgent intervention 
indicated
Life-threatening consequences 
(eg, tamponade) OR Urgent 
intervention indicated

B/F/TAF
Protocol GS-US-380-4449
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 96
18 December 2018
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Prolonged PR Interval
PR interval 
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV 
block OR Ventricular pause 
3.0 sec
Complete AV block
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block
Type II 2nd degree AV 
block
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec
Asymptomatic, QTc interval 
0.465 to 0.479 sec
Asymptomatic, QTc interval 
0.480 sec
Life-threatening 
consequences, eg, Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)
Deep vein thrombosis AND 
Intervention indicated (eg, 
anticoagulation, lysis filter, 
invasive procedure)
Embolic event (eg, pulmonary 
embolism, life-threatening 
thrombus)
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness
Present with transient loss of 
consciousness
NA
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF

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

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

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

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

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

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NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Developmental delay –
Pediatric 16 Years
Mild developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate 
for the setting
Moderate developmental 
delay, either motor or 
cognitive, as determined by 
comparison with a 
developmental screening tool 
appropriate for the setting
Severe developmental delay, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Developmental regression, 
either motor or cognitive, as 
determined by comparison 
with a developmental 
screening tool appropriate for 
the setting
Headache 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities
Symptoms causing inability to 
perform usual social & 
functional activities
Symptoms causing inability to 
perform basic self-care 
functions OR Hospitalization 
indicated (other than ER visit) 
OR Headache with significant 
impairment of alertness or 
other neurologic function
Insomnia
NA
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social/functional activities
Difficulty sleeping causing 
inability to perform usual 
social & functional activities
Disabling insomnia causing 
inability to perform basic 
self-care functions
Neuromuscular Weakness 
(including myopathy & 
neuropathy)
Asymptomatic with 
decreased strength on exam 
OR Minimal muscle weak-
ness causing no or minimal 
interference with usual 
social & functional activities
Muscle weakness causing 
greater than minimal 
interference with usual social 
& functional activities
Muscle weakness causing 
inability to perform usual
social & functional activities
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle weakness 
impairing ventilation
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy)
Asymptomatic with sensory 
alteration on exam or 
minimal paresthesia causing 
no or minimal interference 
with usual social & 
functional activities
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities
Sensory alteration or 
paresthesia causing inability to 
perform usual social & 
functional activities
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care 
functions

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

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

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

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

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

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

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, Definition of Male Fertility and Contraceptive 
Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered to be fertile after the initiation 
of puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential.
Male subjects must agree to refrain from sperm donation from first study drug dose until after the 
end of relevant systemic exposure.
3) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.

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Appendix 6.
Definitions of Stage 3 Opportunistic Illnesses in HIV 
(CDC Guidelines)
1. Candidiasis of bronchi, trachea, or lungs
2. Candidiasis of esophagus
3. Cervical cancer, invasive
4. Coccidioidomycosis, disseminated or extrapulmonary
5. Cryptococcosis, extrapulmonary
6. Cryptosporidiosis, chronic intestinal (1 month duration)
7. Cytomegalovirus disease (other than liver, spleen or nodes)
8. Cytomegalovirus retinitis (with loss of vision)
9. Encephalopathy, HIV-related
10. Herpes simplex: chronic ulcer(s) (1 month duration); or bronchitis, pneumonitis or 
esophagitis
11. Histoplasmosis, disseminated or extrapulmonary
12. Isosporiasis, chronic intestinal (1 month duration)
13. Kaposi’s sarcoma
14. Lymphoma, Burkitt’s (or equivalent term)
15. Lymphoma, immunoblastic (or equivalent term)
16. Lymphoma, primary, of brain
17. Mycobacterium avium complex or Myobacterium kansasii, disseminated or extrapulmonary
18. Mycobacterium tuberculosis, of any site, pulmonary, disseminated or extrapulmonary
19. Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
20. Pneumocystis jirovecii (previously known as “Pneumocystis carinii) pneumonia
21. Pneumonia, recurrent
22. Progressive multifocal leukoencephalopathy

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23. Salmonella septicemia, recurrent
24. Toxoplasmosis of brain
25. Wasting syndrome attributed to HIV infection
CDC Stage-3-Defining Opportunistic Illnesses in HIV Infection - 2014 {Selik 2014}