A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Fixed Dose Combination of Bictegravir/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir + Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment Naïve, HIV-1 and Hepatitis B Co-Infected Adults
Phase: PHASE3
Conditions: HIV-1/HBV Co-Infection
Sponsor: Gilead Sciences



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6.2.
Pretreatment Assessments......................................................................................................................48
6.2.1.
Screening Visit .....................................................................................................................48
6.3.
Randomization .......................................................................................................................................49
6.4.
Day 1 Assessments.................................................................................................................................49
6.5.
Treatment Assessments (Week 4 – 96)..................................................................................................49
6.6.
Treatment Assessments (Post Week 96 until the End of Blinded Treatment Visit)...............................50
6.6.1.
Post Week 96 Assessments ..................................................................................................50
6.6.2.
End of Blinded Treatment Visit Assessments ......................................................................51
6.7.
Open-Label Rollover Extension Assessments........................................................................................51
6.8.
Post-Treatment Assessments..................................................................................................................52
6.8.1.
Early Study Drugs Discontinuation Assessments.................................................................52
6.8.2.
30 Day Follow-Up Visit.......................................................................................................53
6.9.
Criteria for Discontinuation of Study Treatment....................................................................................54
6.10.
Clinical Laboratory Assessments ...........................................................................................................54
6.10.1.
Blood Samples......................................................................................................................54
6.10.2.
Urine Samples ......................................................................................................................56
6.10.3.
Blood Storage Samples ........................................................................................................57
6.11.
Assessments for Premature Discontinuation from Study.......................................................................57
6.12.
End of Study...........................................................................................................................................57
6.13.
Post Study Care......................................................................................................................................57
6.14.
HIV-1 Virologic Failure.........................................................................................................................57
6.14.1.
Management of HIV-1 Virologic Rebound..........................................................................58
6.14.2.
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Discontinuation, 
Week 48 or 96......................................................................................................................59
6.15.
HBV Resistance Surveillance ................................................................................................................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.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................62
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................62
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................62
7.2.2.
Assessment of Severity ........................................................................................................63
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................63
7.4.
Gilead Reporting Requirements.............................................................................................................64
7.5.
Toxicity Management ............................................................................................................................65
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................65
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................65
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................66
7.5.4.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis B 
Management.........................................................................................................................66
7.5.5.
Management of Potential Nephrotoxicity.............................................................................67
7.6.
Special Situations Reports......................................................................................................................68
7.6.1.
Definitions of Special Situations..........................................................................................68
7.6.2.
Instructions for Reporting Special Situations.......................................................................69
8.
STATISTICAL CONSIDERATIONS................................................................................................................71
8.1.
Analysis Objectives and Endpoints........................................................................................................71
8.1.1.
Analysis Objectives..............................................................................................................71
8.1.2.
Primary Endpoints................................................................................................................71
8.1.3.
Secondary Endpoint .............................................................................................................72

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8.2.
Analysis Conventions.............................................................................................................................72
8.2.1.
Analysis Sets ........................................................................................................................72
8.3.
Data Handling Conventions ...................................................................................................................73
8.4.
Demographic Data and Baseline Characteristics ...................................................................................74
8.5.
Efficacy Analysis ...................................................................................................................................74
8.5.1.
Primary Analysis..................................................................................................................74
8.5.2.
Secondary Analyses .............................................................................................................76
8.6.
Safety Analysis.......................................................................................................................................77
8.6.1.
Extent of Exposure...............................................................................................................77
8.6.2.
Adverse Events.....................................................................................................................77
8.6.3.
Laboratory Evaluations ........................................................................................................78
8.6.4.
Other Safety Evaluations......................................................................................................78
8.7.
Pharmacokinetic Analysis......................................................................................................................78
8.8.
Sample Size............................................................................................................................................78
8.9.
Data Monitoring Committee ..................................................................................................................79
8.10.
Analysis Schedule ..................................................................................................................................79
9.
RESPONSIBILITIES..........................................................................................................................................80
9.1.
Investigator Responsibilities ..................................................................................................................80
9.1.1.
Good Clinical Practice..........................................................................................................80
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................80
9.1.3.
Informed Consent.................................................................................................................80
9.1.4.
Confidentiality......................................................................................................................81
9.1.5.
Study Files and Retention of Records ..................................................................................81
9.1.6.
Case Report Forms...............................................................................................................82
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................83
9.1.8.
Inspections............................................................................................................................83
9.1.9.
Protocol Compliance............................................................................................................83
9.2.
Sponsor Responsibilities ........................................................................................................................83
9.2.1.
Protocol Modifications.........................................................................................................83
9.2.2.
Study Report and Publications .............................................................................................84
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................84
9.3.1.
Payment Reporting...............................................................................................................84
9.3.2.
Access to Information for Monitoring..................................................................................84
9.3.3.
Access to Information for Auditing or Inspections ..............................................................85
9.3.4.
Study Discontinuation..........................................................................................................85
10.
REFERENCES ...................................................................................................................................................86
11.
APPENDICES ....................................................................................................................................................88
Appendix 1.
Investigator Signature Page....................................................................................................89
Appendix 2.
Study Procedures Table (Blinded Phase) ...............................................................................90
Appendix 3.
Study Procedures Table (Open Label Rollover Extension)....................................................94
Appendix 4.
Management of Clinical and Laboratory Adverse Events......................................................96
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............97
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................119
Appendix 7.
Definitions of Stage 3 Opportunistic Illnesses in HIV .........................................................122

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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)...................................................................................................................................23
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) ..................................................................................23
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)...............................................................................24
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) ...........................................................................25
Table 1-5.
GS-US-141-1475: Virologic Outcome at Week 48 Using the US FDA-Defined 
Snapshot Algorithm and HIV-1 RNA < 50 copies/mL (FAS) ...............................................28
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).......................................................................................26
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 3, Randomized, Double-Blind Study to Evaluate the Safety 
and Efficacy of  Fixed Dose Combination of 
Bictegravir/Emtricitabine/Tenofovir Alafenamide versus Dolutegravir 
+ Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment Naïve,
HIV-1 and Hepatitis B Co-Infected Adults 
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
125,589
2018-000926-79
NCT03547908
Study Centers 
Planned:
Approximately 70 centers worldwide
Objectives:
The primary objective of this study is:

To evaluate the efficacy of  fixed dose combination (FDC) of 
bictegravir /emtricitabine /tenofovir alafenamide (B/F/TAF) 
versus a regimen of dolutegravir (DTG) + emtricitabine/tenofovir 
disoproxil fumarate (F/TDF) in HIV and HBV treatment naïve, 
HIV-1 and HBV co-infected subjects as determined by the 
achievement of HIV-1 RNA 50 copies/mL at Week 48 

To evaluate the efficacy of  FDC of B/F/TAF versus DTG + 
F/TDF in HIV and HBV treatment naïve, HIV-1 and HBV 
co-infected subjects as determined by the proportion of subjects 
with plasma HBV DNA < 29 IU/mL at Week 48
The secondary objectives of this study are:

To evaluate the efficacy of FDC of B/F/TAF versus DTG + 
F/TDF as determined by the achievement of HIV-1 RNA  
50 copies/mL at Week 96

To evaluate the efficacy of FDC of  B/F/TAF versus DTG + 
F/TDF as determined by the proportion of subjects with plasma 
HBV DNA < 29 IU/mL at Week 96

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
To evaluate the efficacy of the FDC of  B/F/TAF versus DTG + 
F/TDF as determined by the proportion of subjects with ALT 
normalization at Weeks 48 and 96

To evaluate the efficacy of  FDC of  B/F/TAF versus DTG + 
F/TDF as determined by the proportion of subjects with HBsAg 
loss at Weeks 48 and 96

To evaluate the safety and tolerability of the two treatment groups 
through Week 96
Study Design:
Randomized, double-blind, multicenter, active-controlled study to 
evaluate the safety and efficacy of a FDC of B/F/TAF versus DTG + 
F/TDF in HIV and HBV treatment-naïve, HIV-1 and HBV 
co-infected adult subjects. Subjects who provide written consent and 
meet all eligibility criteria will be randomized in a 1:1 ratio to one of 
the following two treatment groups:
Treatment Group 1 (n=120): FDC of bictegravir 
50 mg/emtricitabine 200 mg/ tenofovir alafenamide 25 mg (B/F/TAF) 
+ placebo to match dolutegravir 50 mg and placebo to match FDC of 
emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (F/TDF) 
administered orally, once daily, without regard to food 
Treatment Group 2 (n=120): dolutegravir 50 mg (DTG) + FDC of 
emtricitabine 200 mg/TDF 300 mg (F/TDF) + placebo to match FDC 
of B/F/TAF administered orally, once daily, without regard to food 
Randomization will be stratified by HBeAg (positive vs. negative), 
HBV DNA (< 8 log10 IU/mL vs. ≥ 8 log10 IU/mL), CD4+ cell count 
(< 50 cells/μL vs.  ≥ 50 cells/μL) at Screening
Number of Subjects 
Planned:
Approximately 240 subjects
Target Population:
Antiviral HIV-1 and HBV treatment-naïve, HIV-1 and HBV 
co-infected adults 
Duration of 
Treatment:
After screening, eligible subjects will be treated for at least 96 weeks 
during the blinded treatment phase. Following the Screening and 
Day 1 visits, subjects will be required to return for study visits at 
Weeks 4, 8, 12 and every 12 weeks thereafter. 
Once all subjects complete their Week 96 visit and Gilead completes 
the Week 96 analysis, all subjects will return to the clinic (preferably 
within 30 days) for an End of Blinded Treatment Visit. At the End of 
Blinded Treatment Visit, if safety and efficacy of B/F/TAF FDC is 
demonstrated for the HIV-1 and HBV coinfected subjects following 

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review of unblinded data, subjects in a country where B/F/TAF FDC 
is not available will be given the option to receive B/F/TAF FDC in 
an open label (OL) extension phase or until the product becomes 
accessible to subjects through an access program, or until Gilead 
Sciences elects to discontinue the study in that country, whichever 
occurs first. 
All subjects participating in the OL extension phase, without regard 
to their blinded treatment regimen, will return for study visits at 
Week 12 OL and every 12 weeks thereafter.
Subjects who complete the study through the End of Blinded
Treatment Visit and do not continue on the open-label extension 
phase, will be required to return to the clinic 30 days after the End of 
Blinded Treatment Visit for a 30-Day Follow-Up Visit.
Treatment assignments will be provided to the investigators within
30 days of the last subject completing the End of Blinded Treatment
Visit.
Diagnosis and Main 
Eligibility Criteria:
Subjects must meet all of the following inclusion criteria to be 
eligible to participate in the study.

HIV-1 co-infection:
1) Must be HIV antiretroviral treatment naive with plasma 
HIV-1 RNA 500 copies/mL at Screening
2) ≤ 10 days of prior therapy with any antiretroviral agent, 
including lamivudine, entecavir and approved or experimental 
integrase inhibitors following a diagnosis of HIV-1 infection 
(except the use for PrEP or PEP, up to one month prior to 
screening)
3) Screening HIV-1 genotype report must show sensitivity to 
FTC (emtricitabine) and TFV (tenofovir). 

HBV co-infection:
4) Must be HBV treatment naïve (defined as < 12 weeks of oral 
antiviral treatment)
5) Screening HBV DNA ≥ 2,000  IU/mL

Estimated glomerular filtration rate (eGFR) 50 mL/min 
according to the Cockcroft-Gault (C-G) formula at the screening 
visit
Study Procedures/
Frequency:
After screening procedures, eligible subjects will be randomized 1:1 
to Treatment Group 1 or Treatment Group 2 and treated for 96 weeks. 
Following the Day 1 visit, subjects will be required to return for study 
visits at Weeks 4, 8, and 12, and then every 12 weeks from Week 12 

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though Week 96. After Week 96, all subjects will continue to take 
their blinded study drugs and attend study visit every 12 weeks until 
the End of Blinded Treatment Visit. 
Laboratory analyses (serum chemistry, liver function tests, 
hematology, urinalysis, pregnancy testing [for females of 
childbearing potential]), will be performed at the Screening, Day 1, 
and all subsequent study visits. HIV-1 RNA and CD4 + cell count 
will be performed at Screening, Day 1, and all subsequent study 
visits. HIV-1 genotype (RT and PR) will be determined at screening.  
Plasma HBV DNA levels, HBV serology (HBsAg and reflex 
anti-HBs Ab, and HBeAg and reflex anti-HBe Ab) will be performed 
at Screening, Day 1, and every 12 weeks thereafter. Plasma HBV 
DNA will be monitored at all study visits. 
Serum samples for potential sequence analysis of HBV 
polymerase/reverse transcriptase (pol/RT) should be collected at all 
time points except screening. Sequencing analysis of the HBV 
pol/RT will be attempted for all viremic subjects (HBV DNA 
> 69 IU/mL) at Weeks 48, 96 or early study drug discontinuation as
early as Week 8, as well as all subjects who meet virologic 
breakthrough criteria.
Trough PK blood sample will be obtained 20-28 hours following the 
last dose at Weeks 4, 12, and 36. Following an observed dose, one 
post-dose PK blood sample will be collected between 1 and 4 hours 
post-dose at Weeks 8 and 24. 
Adverse events and concomitant medications will be assessed at each 
visit.
Test Product, Dose, 
and Mode of 
Administration:
FDC of bictegravir 50 mg/emtricitabine 200 mg/tenofovir 
alafenamide 25 mg  administered orally, once daily, without regard to 
food
Reference Therapy, 
Dose, and Mode of 
Administration:
dolutegravir 50mg + FDC of emtricitabine 200mg /tenofovir 
disoproxil fumarate 300mg administered orally, once daily, without 
regard to food
Criteria for 
Evaluation:
Safety:
Adverse events and clinical laboratory tests to evaluate the safety and 
tolerability of the treatment regimens.  

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Statistical Methods:
The primary efficacy analysis will consist of a non-inferiority test of 
FDC of B/F/TAF versus DTG + F/TDF, with respect to the 
proportion of subjects who achieve HIV-1 RNA < 50 copies/mL at 
Week 48 as defined by the US FDA-defined snapshot algorithm. It 
will be concluded that B/F/TAF is non-inferior to DTG + F/TDF if 
the lower bound of the 2-sided 95% confidence interval (CI) of the 
difference (B/F/TAF – DTG + F/TDF) in the response rate (HIV-1 
RNA < 50 copies/mL as defined by the US FDA-defined snapshot 
algorithm) is greater than -12%; ie, a margin of 12% is applied to 
non-inferiority assessment. The 95% CI will be constructed using a 
normal approximation method based on stratified Mantel-Haenszel 
proportions, where stratification factor includes baseline HIV-1 RNA 
(≤ 100,000 copies/mL vs. > 100,000 copies/mL).
The co-primary efficacy analysis will consist of a non-inferiority test 
of FDC of B/F/TAF versus DTG + F/TDF, with respect to the 
proportion of subjects with plasma HBV DNA < 29 IU/mL at 
Week 48 by Missing = Failure approach. It will be analyzed in a 
similar manner as described for the primary efficacy endpoint, except 
that the stratification factors include HBeAg status (positive vs. 
negative) and baseline HBV DNA (< 8 log10 IU/mL vs. 
≥8 og10 IU/mL).
To control type I error for the assessment of the primary and the 
co-primary efficacy endpoints, the hypothesis testing will be 
performed using the fallback procedure {Wiens 2005} in the sequential 
order with pre-specified 1-sided alpha level. The primary hypothesis 
of noninferiority of B/F/TAF relative to DTG + F/TDF, with respect 
to the proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Week 48 (as defined by the FDA snapshot analysis) will be tested 
first. Non-inferiority test will be performed at one-sided, 0.025 alpha 
level. If non-inferiority is established, the co-primary hypothesis of 
noninferiority of B/F/TAF relative to DTG + F/TDF, with respect to 
the proportion of subjects with plasma HBV DNA < 29 IU/mL at 
Week 48 using Missing = Failure approach will be tested second at 
one-sided, 0.025 alpha level. Otherwise, the co-primary endpoint will 
not be tested at all.
The secondary anti-HIV efficacy endpoints include:
1) the proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Week 96 as defined by the US FDA-defined snapshot algorithm,
which will be analyzed in a similar manner as described for the 
primary efficacy endpoint.

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2) the change from baseline in CD4 and CD4% at Weeks 48 and 96, 
which will be summarized by treatment using descriptive 
statistics. The differences and the associated 2-sided 95% CIs will 
be constructed using an Analysis of Variance (ANOVA) model, 
including treatment (B/F/TAF vs. DTG + F/TDF), HIV-1 RNA 
(≤100,000 copies/mL vs. > 100,000 copies/mL) as fixed effects 
in the model.  
The secondary anti-HBV efficacy endpoints include:
1) the proportion of subjects with plasma HBV DNA < 29 IU/mL at 
Week 96  
2) the proportion of subjects with ALT normalization at Weeks 48 
and 96
3) the proportion of subjects with HBsAg loss at Weeks 48 and 96.  
Each of these secondary anti-HBV efficacy endpoints will be 
analyzed in the same manner as described for the primary efficacy 
endpoint, except that stratification factors for the secondary efficacy 
endpoints include HBeAg status (positive vs. negative) and baseline 
HBV DNA (< 8 log10 IU/mL vs. ≥ 8 log10 IU/mL).   
The adverse events and clinical laboratory data will be summarized 
using descriptive statistics.
A total of approximately 240 HIV and HBV naïve, HIV-1 and HBV 
co-infected subjects, randomized in a 1:1 ratio to 2 treatment groups 
(120 subjects per treatment group), achieves 90% power to detect a 
non-inferiority margin of 12% in Week 48 response rate (HIV-1 RNA 
< 50 copies/mL as defined by the US FDA-defined snapshot 
algorithm) difference between the 2 treatment groups. For the sample 
size and power computation, it is assumed that both treatment groups 
have a response rate of 91% (based on Gilead Studies 
GS-US-380-1489 and GS-US-380-1490), that the non-inferiority 
margin is 12%, and that the significance level of the test is at a 
one-sided 0.025 level.
A total of approximately 240 subjects also provides 81% power to 
detect a non-inferiority margin of 12% with respect to the co-primary 
efficacy endpoint of the proportion of subjects with plasma HBV 
DNA < 29 IU/mL at Week 48. This assumes that both treatment 
groups have a response rate of 88% (based on Gilead Studies 
GS-US-320-0108 and GS-US-320-0110), that the non-inferiority 
margin is 12%, and that the significance level of the test is at a 
one-sided 0.025 level.
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
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ANOVA
Analysis of Variance
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time 
curve
BIC
bictegravir, B
B/F/TAF
bictegravir/emtricitabine/ tenofovir alafenamide, Bictarvy
BID
twice a day 
BUN
blood urea nitrogen
CBC
complete blood count
CHB
chronic hepatitis B
CPT
Child-Pugh-Turcotte
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
COBI, /C
cobicistat
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
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DTG
dolutegravir, Tivicay
ECG
electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
FAS
full analysis set
EVG
elvitegravir, E
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Genvoya
E/C/F/TDF
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, Stribild
FAS
full analysis set
FDA
(United States) Food and Drug Administration

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FDC
fixed dose combination
FTC/TAF 
emtricitabine/tenofovir alafenamide , Descovy
F/TDF
emtricitabine/tenofovir desoproxil fumarate, Truvada
FSH
follicle-stimulating hormone
FTC, F
emtricitabine, Emtriva
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GLSM
geometric least squares mean
GSI
Gilead Sciences, Inc.
GS-9883
bictegravir, B
GS-9883/F/TAF
GS-9883/emtricitabine/tenofovir alafenamide
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HBeAb
hepatitis B e-antibody
HBeAg
hepatitis B e-antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high-density polyethylene
HCC
hepatocellular carcinoma
hERG
human Ether-à-go-go-Related Gene
HIV
human immunodeficiency virus
HIV Sx
HIV Symptoms  Distress Module
HLA
human leukocyte antigen
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INSTI
integrase strand-transfer inhibitors
IRB
institutional review board
IWRS
interactive web response system
KS
Kaposi’s sarcoma
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MH
Mantel-Haenszel
min
minute

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mmHg
millimeters mercury
nM
nanoMolar
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOEL
no observed effect level
OL
Open Label
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
PEP
post-exposure prophxylaxis
P-gp
P-glycoprotein
PI
protease inhibitor
PK
Pharmacokinetic
PT
preferred term 
PT
prothrombin time 
PTM
placebo-to-match
PVE
Pharmacovigilance and Epidemiology
QD
once daily 
RAL
raltegravir
RNA
ribonucleic acid
SA
single agent
SAE
serious adverse event
SmPC
Summary of Product Characteristics
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
TSH
thyroid stimulating hormone
UGT1A1
uridine 5'-diphospho-glucuronosyltransferase 
UGT
uridine glucuronosyltransferase
ULN
upper limit of the normal range
US
United States

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1.
INTRODUCTION
1.1.
Background
There is an urgent need to address HIV and HBV coinfection worldwide. Both HIV and HBV 
infection can lead to chronic disease, with attendant morbidity and mortality that is 
synergistically exacerbated by coinfection with both viruses. 
Over 2 billion people are infected, 400 million chronically with Hepatitis B Virus, (HBV), which 
is a primary cause of chronic liver disease and a major contributor to mortality, contributing to 
half the burden of cirrhosis and hepatocellular carcinoma (HCC). HBV is endemic in parts of 
Asia and Africa, with 70% of the population showing serologic evidence of current or prior 
infection and approximately 8-15% with chronic hepatitis B infection {Kalayjian 2003}, {Drake 
2004}, {Kourtis 2012}.
There are estimated to be 35 million people living with HIV/AIDS, with the majority in Asia and 
Africa; estimates ranging for a total of approximately 3-6 million individuals coinfected with 
HIV and HBV, coinfection rates are as high as 25% in areas where both viruses are endemic 
{Kourtis 2012}. 
Coinfection worsens morbidity and mortality synergistically; HIV-HBV coinfected patients have 
higher HBV DNA levels and progress to chronic hepatitis B five times more quickly than HBV 
monoinfected patients and have higher risk of cirrhosis and HCC.
In HIV-positive patients co-infected with HBV, F/TDF or F/TAF are the preferred NRTI 
backbone of a fully suppressive antiretroviral regimen {Panel on Antiretroviral Guidelines for 
Adults and Adolescents 2016}. For the majority of monoinfected chronic hepatitis B (CHB) 
subjects, life-long treatment is required as only a small percentage (< 10%) of subjects 
experience sustained loss of hepatitis B surface antigen (HBsAg), and as a consequence, achieve 
an effective cure of the disease. However, data in HIV/HBV coinfected patients are limited 
{Charpentier 2015}. 
Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), has the potential to advance 
treatment of chronic hepatitis B infection, including those who are coinfected with HIV. In 
contrast to TDF, an oral prodrug that is rapidly cleaved by esterases in the intestines and plasma 
to TFV, TAF has been specifically synthesized to resist early enzymatic cleavage following oral 
administration and remain mostly intact until penetrating target cells. By virtue of this key 
distinguishing property, TAF when administered at a lower dose than TDF, is capable of 
efficiently delivering active drug (e.g. tenofovir diphosphate [TFV-DP]) to the cells where it is 
needed (e.g. HBV-infected hepatocytes, HIV-infected lymphoid cells) while systemic exposures 
of TFV are greatly reduced in comparison to oral administration of TDF 300 mg. In support of 
the concept of enhanced delivery of active drug for treatment of HBV, a study in dogs showed 
70% of the orally administered TAF dose is extracted by the liver during first pass metabolism. 
Additionally, TAF has in vitro been shown to be efficiently taken up by hepatocytes where 
intracellular concentrations of TFV-DP are 120-fold higher with TAF compared with TFV, and 

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5-fold higher with TAF compared to TDF. These features are hypothesized to translate into the 
potential for effective suppression of viral replication and an improved tolerability and safety 
profile. 
Bictegravir (GS-9883) is a potent inhibitor of HIV-1 integrase that is being evaluated for the 
treatment of HIV-1 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, non-nucleoside reverse-transcriptase inhibitors 
(NNRTIs), and protease inhibitors (PIs).  Integrase mutant viruses that are resistant to the INSTIs 
raltegravir (RAL) and elvitegravir (EVG) remain largely sensitive to bictegravir.
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 B/F/TAF FDC may provide a potent, convenient, tolerable, and practical regimen for the 
long-term treatment of patients with HBV and HIV co-infection.
1.2.
Bictegravir (GS-9883, B)
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.

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Bictegravir is mainly metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT1A1) 
and 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 
(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 B/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, 

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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.  
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 B/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 
GS-9883 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 GS-9883 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 GS-9883 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 
GS-9883/Emtricitabine/Tenofovir Alafenamide (75/200/25 mg and 50/200/25 mg) Fixed-Dose 
Combination Tablets Versus a GS-9883 (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 GS-9883, Emtricitabine and Tenofovir 
Alafenamide When Administered as GS-9883/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 GS-9883 in Subjects with Normal and Impaired Hepatic 
Function (completed)

GS-US-141-1479, a Phase 1, open-label, parallel-group, adaptive single-dose study to 
evaluate the PK of GS-9883 in subjects with normal and impaired renal function (completed)

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
GS-US-141-1480, a Phase 1 partially-blinded, randomized, placebo- and positive-controlled 
study to evaluate the effect of GS-9883 on the QT/QTc interval in healthy subjects 
(completed)

GS-US-141-1481, a Phase 1 study to evaluate the pharmacokinetics, metabolism, and 
excretion of GS-9883 in healthy subjects (completed)

GS-US-141-1485, a Phase 1 adaptive study to evaluate transporter, CYP-mediated and 
UGT1A1 drug-drug interactions between GS-9883 and probe drugs (completed)

GS-US-141-1487, a Phase 1 randomized, Blinded, Placebo-Controlled Phase 1 Study 
Evaluating the Effect of GS-9883 on Renal Function as Assessed by Markers of Glomerular 
Filtration Rate (completed)

GS-US-311-1790, a Phase 1 Randomized, Open Label, Drug Interaction Study Evaluating 
the Effect of F/TAF FDC Tablet or GS-9883 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 GS-9883/Emtricitabine/Tenofovir Alafenamide Fumarate 
(GS-9883/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 GS-9883/Emtricitabine/Tenofovir Alafenamide 
Fumarate (GS-9883/FTC/TAF) in Healthy Japanese and Caucasian Subjects (completed)

GS-US-380-1999, a Phase 1 Multiple Dose Study to Evaluate the Pharmacokinetic 
Drug-Drug Interaction Potential between GS-9883/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 GS-9883/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 GS-9883 Pharmacokinetics (completed)

GS-US-141-1475, a Phase 2 Randomized, Double-Blinded Study of the Safety and Efficacy 
of GS-9883 + Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir + 
Emtricitabine/Tenofovir Alafenamide in HIV-1 Infected, Antiretroviral Treatment-Naive 
Adults (ongoing)

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
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)

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 Adults (ongoing)

GS-US-380-4449: 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 (ongoing)
Please refer to the B/F/TAF Investigators’ Brochure for further information about these studies.

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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 F/TAF 
FDC tablet and bictegravir in healthy subjects.
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 F/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 F/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 + F/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).
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)

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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 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.
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. 

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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.   
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.

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Week 48 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 B+F/TAF 
group and 33 subjects in the DTG+F/TAF group. At the time of the Week 48 data analysis, 
5 subjects (5.1%) had prematurely discontinued study drug, 3 in the B+F/TAF group and 2 in the 
DTG+F/TAF group. The reasons for study drug discontinuation were as follows (one subject 
each): AE, withdrawal of consent, and lost to follow-up in the B+F/TAF group, and
noncompliance with study drug and lost to follow up in the DTG+F/TAF group.
Demographic and baseline characteristics were similar between the 2 treatment groups. Key 
baseline disease characteristics (ie, viral load, CD4+ cell count, and estimated glomerular 
filtration rate [eGFR]CG) were similar between the 2 treatment groups.
Median (Q1, Q3) baseline HIV-1 RNA was 4.45 (3.96, 4.79) log10 copies/mL, with 82.7% 
having ≤ 100,000 copies/mL at baseline. Five subjects (5.1%) had > 400,000 copies/mL at 
baseline; of these, 4 subjects were randomized to B+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.
Efficacy Results
The primary efficacy endpoint was the proportion of subjects with HIV-1 RNA 50 copies/mL 
at Week 24 as determined by the United States (US) Food and Drug Administration 
(FDA)-defined snapshot algorithm. The percentages of subjects with HIV-1 RNA 
< 50 copies/mL at Week 24 was high in both groups, as follows: BIC+F/TAF 96.9%; 
DTG+F/TAF 93.9%; difference in percentages: 2.9%, 95% CI: −8.5% to 14.2%. Because the 
lower bound of the 95% CI for the difference in response rate (B+F/TAF – DTG+F/TAF) was 
greater than the prespecified −12% margin, B+F/TAF was determined to be noninferior to 
DTG+F/TAF.
The percentages of subjects with HIV-1 RNA < 50 copies/mL at Week 48 were similar between 
the 2 treatment groups when assessed using the US FDA-defined snapshot algorithm based on 
the full analysis set (FAS) (Table 1-5), as follows: B+F/TAF 96.9%; DTG+F/TAF 90.9%; 
difference in percentages: 6.4%, 95% CI: −6.0% to 18.8%.
As expected for an INSTI-containing regimen, HIV-1 RNA levels decreased rapidly in the 
first 4 weeks following initiation of study drug in both treatment groups. After Week 4, HIV-1 
RNA values were stable and similar between the 2 treatment groups through Week 48; mean 
(SD) decreases from baseline at Week 48 using the FAS were as follows: B+F/TAF 
−3.09 (0.752) log10copies/mL; DTG+F/TAF −3.11 (0.852) log10copies/mL; difference in 
least-squares mean (LSM): −0.06 log10copies/mL, 95% CI: −0.32 to 0.20 log10 copies/mL.

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The mean (SD) increases from baseline in CD4+ cell counts were similar between the 
2 treatment groups through Week 48 using the FAS, as follows: B+F/TAF 258 (221.7) cells/μL; 
DTG+F/TAF 192 (242.0) cells/μL; difference in LSM: 72 cells/μL, 95% CI: −30 to 174 cells/μL.
Table 1-5.
GS-US-141-1475: Virologic Outcome at Week 48 Using the US 
FDA-Defined Snapshot Algorithm and HIV-1 RNA < 50 copies/mL 
(FAS)
B+F/TAF
(N = 65)
DTG+F/TAF
(N = 33)
B+F/TAF vs DTG+F/TAF
p-valuea
Difference in 
Percentages 
(95% CI)b
HIV-1 RNA < 50 copies/mL
63 (96.9%)
30 (90.9%)
0.17
6.4% 
(−6.0% to 18.8%)
HIV-1 RNA ≥ 50 copies/mL
1 (1.5%)
2 (6.1%)
HIV-1 RNA ≥ 50 copies/mL in Week 48 
window
0
1 (3.0%)
Discontinued study drug due to lack of efficacy
0
0
Discontinued study drug due to other reasons 
and last available HIV-1 RNA ≥50 copies/mLc
1 (1.5%)
1 (3.0%)
No virologic data in Week 48 window
1 (1.5%)
1 (3.0%)
Discontinued study drug due to AE/death
1 (1.5%)
0
Discontinued study drug due to other reasons 
and last available HIV-1 RNA < 50 copies/mLc
0
1 (3.0%)
Missing data during window but on study drug
0
0
Week 48 window was between Day 295 and 378 (inclusive).
a
p-value for the superiority test comparing the percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment 
groups was from the Cochran-Mantel-Haenszel test stratified by baseline HIV-1 RNA stratum (≤100,000 vs 
> 100,000 copies/mL).
b
Difference in percentages of subjects with HIV-1 RNA < 50 copies/mL between treatment groups and its 95% CI were 
calculated based on the baseline HIV-1 RNA stratum-adjusted Mantel-Haenszel proportion.
c
Discontinuation due to other reasons included subjects who prematurely discontinued study drug due to investigator’s 
discretion, withdrew consent, lost to follow-up, noncompliance with study drug, protocol violation, pregnancy, and study 
termination by sponsor.
Interim Virology Resistance Data
Through Week 48, no emergent drug resistance was detected in the B+F/TAF group.

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Safety Results
Adverse Events
Adverse events were reported in 84.6% (55 of 65 subjects) in the B+F/TAF group and 66.7% 
(22 of 33 subjects) in the DTG+F/TAF group. The most commonly reported AEs by treatment 
group were as follows:

B+F/TAF group—diarrhea (12.3%, 8 of 65 subjects); and headache, nausea, and upper 
respiratory tract infection (each 7.7%, 5 subjects)

DTG+F/TAF group—diarrhea and nausea (each 12.1%, 4 of 33 subjects); and arthralgia, 
fatigue, flatulence, furuncle, gastroenteritis, costochondritis, hemorrhoids, and pruritus 
(each 6.1%, 2 subjects)
The majority of AEs were Grade 1 in severity, with similar incidence of Grade 2, 3, or 4 AEs 
between the 2 treatment groups. Grade 3 AEs were uncommon, with all Grade 3 AEs reported in 
the B+F/TAF group (6.2%, 4 subjects); only 1 Grade 3 AE was considered related to study drug 
by the investigator (urticaria in a B+F/TAF subject). No individual Grade 3 AE was reported for 
> 1 subject. No Grade 4 AEs were reported.
Serious AEs were uncommon, with all reported SAEs occurring in the B+F/TAF group 
(4.6%, 3 subjects). No SAE was considered related to study drug by the investigator. The SAEs 
reported were appendicitis, psychotic disorder/suicidal ideation, and diabetic ketoacidosis.
The incidence of AEs considered related to study drug by the investigator was similar between 
the 2 treatment groups (B+F/TAF 20.0%, 13 subjects; DTG+F/TAF 21.2%, 7 subjects). Nearly 
all study drug-related AEs were Grade 1 in severity, with similar incidence of Grade 2, 3, or 4 
study drug-related AEs between the 2 treatment groups (B+F/TAF 3.1%, 2 subjects; 
DTG+F/TAF 3.0%, 1 subject). The only Grade 3 study drug-related AE reported (urticaria in a 
B+F/TAF subject) was also the only AE leading to premature study drug discontinuation; the 
event began on Day 130 and led to discontinuation of study drug on Day 162.
No deaths or pregnancies were reported in either treatment group.
Clinical Laboratory Evaluations
Most subjects in both treatment groups had at least 1 laboratory abnormality (B+F/TAF 84.4%, 
54 of 64 subjects; DTG+F/TAF 87.5%, 28 of 32 subjects). Most of the reported laboratory 
abnormalities were Grade 1 or 2 in severity. The incidence of Grade 3 or 4 laboratory 
abnormalities was similar between the 2 treatment groups (B+F/TAF 25.0%, 16 subjects; 
DTG+F/TAF 21.9%, 7 subjects). 
Graded laboratory abnormalities in ALT and aspartate aminotransferase (AST) were reported 
more frequently and with greater severity in the B+F/TAF group than in the DTG+F/TAF group. 
Graded ALT abnormalities were reported in 23.4% (15 of 64 subjects) in the B+F/TAF group 
and 9.4% (3 of 32 subjects) in the DTG+F/TAF group, and graded AST abnormalities were 

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reported in 20.3% (13 of 64 subjects) in the B+F/TAF group and 9.4% (3 of 32 subjects) in the 
DTG+F/TAF group. Grade 3 ALT elevations occurred in 1 subject in the B+F/TAF group and 
none in the DTG+F/TAF group. Grade 3 AST elevations were seen in 3 subjects in the B+F/TAF 
group (one of whom also had a Grade 3 ALT elevation) and none in the DTG+F/TAF group. Of 
the 3 subjects who had Grade 3 transaminase elevations, 2 were associated with simultaneous 
Grade 4 CK elevations, were transient, and resolved rapidly without any associated AEs. One 
participant had both Grade 3 AST and ALT persistent elevations that were attributed to ongoing 
alcohol use. No Grade 4 transaminase elevations were observed in either treatment group.
Grade 3 or 4 CK elevations were seen in 9.4% (6 of 64 subjects) in the B+F/TAF group and in 
3.1% (1 of 32 subjects) in the DTG+F/TAF group. All of the Grade 3 or 4 CK elevations 
occurred in young men (age range, 24 to 31 years), were transient, and resolved without 
treatment interruption, and none of these laboratory abnormalities were associated with AEs.
There were similar increases from baseline in median (Q1, Q3) serum creatinine in both 
treatment groups at Week 48: B+F/TAF 0.08 (0.02, 0.15) mg/dL; DTG+F/TAF 0.12 (0.02, 0.20) 
mg/dL. There were decreases in median (Q1, Q3) eGFRCG at Week 48, which were smaller in 
the B+F/TAF than in the DTG+F/TAF group: B+F/TAF −7.0 (−18.7, 1.6) mL/min; DTG+F/TAF 
−11.3 (−24.5, −0.8) mL/min.
There were no clinically significant changes from baseline or differences between treatment 
groups in the median values for hematology, chemistry, or metabolic parameters. 
Conclusions
Key conclusions from Study GS-US-141-1475 at Week 48 include the following:

The percentages of subjects with HIV-1 RNA < 50 copies/mL at Week 48 were similar 
between the 2 treatment groups when assessed using the US FDA-defined snapshot algorithm 
based on the FAS, as follows: B+F/TAF 96.9%; DTG+F/TAF 90.9%; difference in 
percentages: 6.4%, 95% CI: −6.0% to 18.8%. There was a similar increase in the mean (SD) 
CD4+ cell count between the 2 treatment groups: B+F/TAF 258 (221.7) cells/μL; 
DTG+F/TAF 192 (242.0) cells/μL; difference in LSM: 72 cells/μL, 
95% CI: −30 to 174 cells/μL.

No resistance to any INSTIs, NRTIs, NNRTIs, or PIs was detected through Week 48 in the 
B+F/TAF group.

Both B+F/TAF and DTG+F/TAF were generally well tolerated through 48 weeks of 
treatment. 
The most commonly reported AEs were diarrhea (12.3%, 8 of 65 subjects); and 
headache, nausea, and upper respiratory tract infection (each 7.7%, 5 subjects) in the 
B+F/TAF group, and diarrhea and nausea (each 12.1%, 4 of 33 subjects); and arthralgia, 
fatigue, flatulence, furuncle, gastroenteritis, costochondritis, hemorrhoids, and pruritus 
(each 6.1%, 2 subjects) in the DTG+F/TAF group. 

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One subject discontinued study drug due to AE: Grade 3 urticaria beginning on Day 130 
in a B+F/TAF subject. There were SAEs in 3 subjects, none of which were considered 
related to study drug by the investigator, or led to study drug discontinuation. 
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. Graded laboratory abnormalities in ALT and 
AST were reported more frequently and with greater severity in the B+F/TAF group than 
in the DTG+F/TAF group. 
There were similar increases from baseline in serum creatinine in both treatment groups at 
Week 48. The decrease from baseline in eGFRCG was smaller in the B+F/TAF group than in the 
DTG+F/TAF group.
1.2.3.4.
Summary of Phase 3 Studies
GS-US-380-1489
Results from a blinded phase 3 study were reported that compared B/F/TAF FDC to
co-formulated abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC, Triumeq®) {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 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.

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GS-US-380-1490
A second phase 3 study compared bictegravir and DTG, each with F/TAF, utilizing a single-pill
co-formulation 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 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 + F/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 + F/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 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.

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1.3.
Information about Emtricitabine/Tenofovir Disoproxil Fumarate (Truvada®, 
(F/TDF))
Further information is available in the current Prescribing Information for Truvada®
1.4.
Information about Dolutegravir (DTG, Tivicay®)
An ongoing observational study in Botswana identified neural tube defects (NTDs) in infants 
born to four of 426 women who started DTG prior to pregnancy, and were on it at the time of 
conception. The incidence rate for NTDs in these infants was 0.9%, while the reported rate of 
NTDs for HIV-infected women on non-DTG-containing regimen was 0.1%. These preliminary 
results suggest that women who received DTG at the time of becoming pregnant or early in the 
first trimester appear to be at higher risk for these embryonic defects.
The following guidance has been issued regarding the use of DTG in women who are pregnant, 
who become pregnant, or are of child bearing potential. 

FDA statement: https://www.fda.gov/Drugs/DrugSafety/ucm608112.htm

U.S. DHHS Recommendations Regarding the Use of Dolutegravir in Adults and Adolescents 
with HIV who are Pregnant or of Child-Bearing Potential: 
https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-
adults-and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential

European Medicines Agency (EMA): 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/05/news_
detail_002956.jsp&mid=WC0b01ac058004d5c1
For more detailed information, refer to the current Prescribing Information and local product 
labeling for DTG.
1.5.
Rationale for This Study
B/F/TAF has demonstrated efficacy and safety in Phase 2 and Phase 3 studies in 
HIV-monoinfected patients.  TAF 25 mg has been evaluated in two global Phase 3 HBV 
monoinfection studies – one each in treatment naïve and experienced HBeAg-negative subjects 
(GS-US-320-0108) and HBeAg-positive subjects (GS-US-320-0110) and is approved for the 
treatment of hepatitis B infection. 
Currently, TAF and TDF are approved by the US FDA for treatment of HBV- infected patients. 
This study will examine the efficacy and safety of B/F/TAF versus DTG +F/TDF in HBV and 
HIV-co-infected patients. Current guidelines for treatment of HBV in HIV co-infected patients 
emphasize the need to treat co-infected patients due to higher rates of liver disease progression. 
Both TDF and TAF containing regimens are recommended in multiple guidelines for treatment 
of HBV in HIV-1 infected patients {Gunthard 2016}, {Gorden 2007}, {Terrault 2016}, 
{European Association for the Study of the Liver 2017}, {European AIDS Clinical Society 
(EACS) 2016}, and {Sarin 2016}. The evaluation of the safety and tolerability of B/F/TAF in 
HIV and HBV coinfected patients is highly clinically relevant. 

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1.6.
Risk/Benefit Assessment for the Study
HIV and HBV co-infection worsens morbidity and mortality synergistically; co-infected patients 
have higher risk of cirrhosis and hepatocellular carcinoma. In HIV-positive patients co-infected 
with HBV, F/TDF or F/TAF are the preferred NRTI backbone of a fully suppressive 
antiretroviral regimen {Panel on Antiretroviral Guidelines for Adults and Adolescents 2016}. 
This study seeks to generate safety and efficacy data of B/F/TAF FDC in this population by 
enrolling treatment naïve patients.  The comparator regimen contains DTG and F/TDF, a fully 
suppressive regimen. 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 
to patient population that 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.
In summary, the risk/benefit for this study is acceptable due to the following considerations: 

Treatment of HBV is indicated and important in all HIV co-infected patients due to 
accelerated progression of liver disease

TDF and TAF are approved for the treatment of HBV infection

B/F/TAF has been proven to be safe, well tolerated and effective in the treatment of
HIV-infected patients

Hepatic flares, defined by an increase in ALT of five-fold above upper limit of normal, are 
not uncommon early in treatment initiation and will be closely monitored (refer to 
Section 7.5.4)  

Risk of nephrotoxicity, defined as a decreased in eGFR < 50ml/min is considered to be low 
and will be closely monitored (refer to Section 7.5.5)
The benefit-risk assessment for this study is favorable at this time.
1.7.
Rational for Dose Selection
B/F/TAF
The B/F/TAF FDC containing B (50 mg), F (200 mg), and TAF (25 mg), has been approved by 
the US-FDA for use once daily for the treatment of human immunodeficiency virus type 1 
(HIV-1) infection in adults. B/F/TAF contains 25 mg of TAF, the approved and recommended 
dosage for the treatment of HBV infection with other ARVs for treatment of HIV/HBV 
coinfection {Gunthard 2016}, {Panel on Antiretroviral Guidelines for Adults and Adolescents 
2016}, {Terrault 2016}, {European Association for the Study of the Liver 2017}, {European 
AIDS Clinical Society (EACS) 2016}, and {Sarin 2016}.

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DTG + F/TDF
The 50 mg dose of DTG represents the approved, marketed dose for this agent that is currently 
available as a single agent, Tivicay® and as a component of the FDC, Triumeq®.  Within the 
FDC, F/TDF, the 200 mg dose of FTC and the 300 mg dose of TDF represent the approved 
marketed doses for these agents that are currently available as single agents (EMTRIVA and 
VIREAD) and as a component of a number of FDCs, including: ATRIPLA, COMPLERA 
(EVIPLERA), and STRIBILD. 300 mg dose of TDF in Truvada® is the dose approved for the 
treatment of HBV monoinfection, and is the dose recommended for the treatment of HIV/HBV 
coinfection by multiple treatment guidelines {Gunthard 2016}, {Panel on Antiretroviral 
Guidelines for Adults and Adolescents 2016}, {Terrault 2016}, {European Association for the 
Study of the Liver 2017}, {European AIDS Clinical Society (EACS) 2016}, and {Sarin 2016}.
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 objectives of this study are:

To evaluate the efficacy of  FDC of B/F/TAF versus DTG + F/TDF in HIV and HBV 
treatment naïve, HIV-1 and HBV co-infected subjects as determined by the achievement of 
HIV-1 RNA 50 copies/mL at Week 48 

To evaluate the efficacy of  FDC of B/F/TAF versus DTG + F/TDF in HIV and HBV 
treatment naïve, HIV-1 and HBV co-infected subjects as determined by the proportion of 
subjects with plasma HBV DNA < 29 IU/mL at Week 48
The secondary objectives of this study are:

To evaluate the efficacy of FDC of B/F/TAF versus DTG + F/TDF as determined by the 
achievement of HIV-1 RNA  50 copies/mL at Week 96

To evaluate the efficacy of FDC of  B/F/TAF versus DTG + F/TDF as determined by the 
proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 96

To evaluate the efficacy of the FDC of  B/F/TAF versus DTG + F/TDF as determined by the 
proportion of subjects with ALT normalization at Weeks 48 and 96

To evaluate the efficacy of the FDC of  B/F/TAF versus DTG + F/TDF as determined by the 
proportion of subjects with HBsAg loss at Weeks 48 and 96

To evaluate the safety and tolerability of the two treatment groups through Week 96

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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoints are:

The proportion of subjects that have HIV-1 RNA < 50 copies/mL at Week 48 as defined by 
the US FDA-defined snapshot algorithm

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 48 by Missing = 
Failure approach
The secondary anti-HIV efficacy endpoints are:

The proportion of subjects that have HIV-1 RNA < 50 copies/mL at Week 96

The change from baseline in CD4 cell count and CD4% at Weeks 48 and 96
The secondary anti-HBV efficacy endpoints are:

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 96

The proportion of subjects with ALT normalization at Weeks 48 and 96

The proportion of subjects with HBsAg loss at Weeks 48 and 96
3.2.
Study Design
This protocol describes a randomized, double-blind, multicenter, active-controlled study to 
evaluate the safety and efficacy of B/F/TAF FDC versus DTG + F/TDF FDC in treatment-naïve 
HIV-1 and HBV co-infected adult subjects. 
3.3.
Study Treatments
Subjects who provide written consent and meet all eligibility criteria will be randomized in a 
1:1 ratio to one of the following two treatment groups:
Treatment Group 1 (n=120): FDC of bictegravir 50 mg/emtricitabine 200 mg/ tenofovir 
alafenamide 25 mg (B/F/TAF) + placebo to match dolutegravir 50 mg (DTG) and placebo to 
match FDC of emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (F/TDF) administered 
orally, once daily, without regard to food
Treatment Group 2 (n=120): dolutegravir 50 mg (DTG) + FDC of emtricitabine 200 mg/
tenofovir disoproxil fumarate 300 mg (F/TDF) + Placebo to match FDC of bictegravir 
50 mg/emtricitabine 200 mg/ tenofovir alafenamide 25 mg (B/F/TAF) administered orally, once 
daily, without regard to food
Randomization will be stratified by HBeAg (positive vs. negative), HBV DNA (< 8 log10 IU/mL 
vs. ≥ 8 log10 IU/mL), CD4+ cell count (< 50 cells/L vs. ≥ 50 cells/μL) at Screening.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 240 subjects who meet the eligibility criteria will be enrolled. 
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 18 years
3) HIV-1 co-infection:
a) Must be HIV antiretroviral treatment naive with plasma HIV-1 RNA 500 copies/mL at 
screening
b) ≤ 10 days of prior therapy with any antiretroviral agent, including lamivudine and 
entecavir, following a diagnosis of HIV-1 infection (except the use for PrEP or PEP, up 
to one month prior to screening)
c) Screening genotype report must show sensitivity to FTC and TFV. This report will be 
provided by Gilead Sciences. Alternatively, if genotype results from a local laboratory 
obtained ≤ 90 days prior to screening visit date show sensitivity to these drugs, this 
genotype will be acceptable to fulfill this inclusion criterion in the event that the genotype 
obtained at screening is not yet available and all other inclusion/exclusion criteria have 
been confirmed
4) HBV co-infection:
a) Must be HBV treatment naïve (defined as < 12 weeks of oral antiviral treatment)
b) Screening HBV DNA ≥ 2000 IU/mL
5) Normal ECG (or if abnormal, determined by the investigator not to be clinically significant) 

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6) Estimated glomerular filtration rate (eGFR) 50 mL/min according to the Cockcroft-Gault 
(C-G) formula  {Cockcroft 1976}:
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  
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
7) Hepatic transaminases (AST and ALT) 10 upper limit of normal (ULN)
8) Total bilirubin 2.5 upper limit of normal (ULN)
9) 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))
10) Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if 
serum lipase is ≤5 × ULN)
11) Female subjects of childbearing potential and male subjects who are fertile who engage in 
heterosexual intercourse must agree to utilize protocol specified method(s) of contraception 
as described in Appendix 6.
12) Male subjects must agree to refrain from sperm donation from first study drug dose until at 
least 90 days following the last study drug dose
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Hepatitis C Virus (HCV) antibody positive and HCV RNA detectable
2) Previous use of any approved or experimental HIV integrase inhibitor
3) An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to 
screening (refer to Appendix 7)
4) Subjects experiencing decompensated cirrhosis (eg, ascites, encephalopathy, or variceal 
bleeding) or with Child-Pugh-Turcotte (CPT) C impairment

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5) Have been treated with immunosuppressant therapies or chemotherapeutic agents within 
3 months of study screening, or expected to receive these agents or ongoing systemic steroids 
during the study (e.g., corticosteroids, immunoglobulins, and other immune- or 
cytokine-based therapies)
6) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
7) 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
8) Active, serious infections (other than HIV-1 and HBV infection) requiring parenteral 
antibiotic or antifungal therapy within 30 days prior to Day 1
9) Participation in any other clinical trial, including observational studies, without prior 
approval from the sponsor is prohibited while participating in this trial
10) 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
11) Any known allergies to the excipients of B/F/TAF FDC or DTG + F/TDF FDC tablets
12) Females who are pregnant (as confirmed by positive serum pregnancy test)
13) Females who are breastfeeding
14) Subjects receiving ongoing therapy with any of the following medications in the table below, 
including drugs not to be used with FTC, TAF, TDF, bictegravir and DTG
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
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, echinacea
*
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.
15) Acute hepatitis in the 30 days prior to study entry
16) Active tuberculosis infection

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Subjects will be assigned a screening number at the time of consent. Randomization and Day 1 
visits cannot occur until the Investigator has received the results of the screening genotype 
report and subject eligibility has been confirmed.
Once eligibility has been confirmed and prior to or during the Day 1 visit, the Investigator or 
designee will randomize 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 and randomization 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.
Subjects will be randomized in a 1:1 ratio to Treatment Group 1 or Treatment Group 2. 
Randomization will be stratified by HBeAg (positive vs. negative), HBV DNA (< 8 log10 IU/mL 
vs. ≥ 8 log10 IU/mL), CD4+ cell count (< 50 cells/L vs. ≥ 50 cells/μL) at screening.
The IWRS will assign study drug bottle numbers of blinded FDC of B/F/TAF + placebo to 
match DTG + placebo to match F/TDF FDC, or DTG + F/TDF FDC + placebo to match FDC of 
B/F/TAF at each study visit for each subject. 
At the End of Blinded Treatment Visit the IWRS will assign open label FDC of B/F/TAF.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, or in the case of pregnancy that occurs while on study drug, the investigator may 
obtain treatment assignment directly from the IXRS system for that subject. Gilead recommends 
but does not require that the investigator contact the Gilead medical monitor before breaking the 
blind. Treatment assignment should remain blinded unless that knowledge is necessary to 
determine subject emergency medical care or in the event of a pregnancy that occurs while on
study drug. The rationale for unblinding must be clearly explained in source documentation and 
on the electronic case report form (eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Pharmacovigilance and Epidemiology (PVE) may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).

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5.2.
Description and Handling of Study Drug
5.2.1.
Formulation
5.2.1.1.
Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF) 50/200/25 mg and 
Placebo to Match Tablets
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. Each tablet core contains 50 mg of 
bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. In addition to the 
active ingredients, the B/F/TAF tablets contain croscarmellose sodium, magnesium stearate, and 
microcrystalline cellulose. The tablet cores are film-coated with iron oxide red, iron oxide black, 
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
The placebo to match (PTM) 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 and are identical in 
physical appearance to B/F/TAF tablets. The placebo tablets contain microcrystalline cellulose, 
lactose monohydrate, croscarmellose sodium and magnesium stearate. The tablet cores are 
film-coated with iron oxide red, iron oxide black, polyethylene glycol, polyvinyl alcohol, talc, 
and titanium dioxide.
5.2.1.2.
Dolutegravir (DTG) 50 mg and Placebo to Match Tablets
DTG tablets are round, film-coated yellow, debossed with “50” on one side and debossed with 
“SV 572” on the other side. Each tablet core contains 50 mg of dolutegravir. In addition to the 
active ingredient, DTG tablets contain D-mannitol, microcrystalline cellulose, povidone K29/32, 
sodium starch glycolate and sodium stearyl fumarate. The tablet cores are film-coated with iron 
oxide yellow, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
The placebo to match (PTM) DTG tablets are round, film coated yellow, debossed with “50” on 
one side and debossed with “SV 572” on the other side.  PTM DTG tablets are identical in 
physical appearance to DTG 50 mg tablets. The placebo tablet cores contain microcrystalline 
cellulose, lactose monohydrate, croscarmellose sodium and magnesium stearate. The tablet cores 
are film-coated with iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc and titanium 
dioxide.
5.2.1.3.
Emtricitabine/Tenofovir disoproxil fumarate (F/TDF) 200 mg/300 mg and 
Placebo to Match Tablets
F/TDF tablets are capsule-shaped, film-coated blue, debossed with "GILEAD" on one side of the 
tablet and plain-faced on the other side of the tablet. Each tablet core contains 200 mg of 
emtricitabine, and 300 mg of tenofovir disoproxil fumarate. In addition to the active ingredients, 
the F/TDF tablets contain croscarmellose sodium, lactose monohydrate, magnesium stearate, 
microcrystalline cellulose, and pregelatinized starch. The tablet cores are film-coated with 
lactose monohydrate, hypromellose, triacetin, titanium dioxide, and FD&C Blue#2. 

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The placebo to match F/TDF tablets are capsule-shaped, film-coated blue, debossed with 
"GILEAD" on one side of the tablet and plain-faced on the other side of the tablet. PTM F/TDF 
tablets are identical in physical appearance to F/TDF tablets. The placebo tablet cores contain 
lactose monohydrate, croscarmellose sodium, pregelatinized starch, denatonium benzoate, and 
magnesium stearate. The tablet cores are film-coated with lactose monohydrate, hypromellose, 
triacetin, titanium dioxide, and FD&C Blue#2. 
5.2.2.
Packaging and Labeling
5.2.2.1.
Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF) 50/200/25 mg and 
Placebo to Match Tablets
B/F/TAF tablets and PTM B/F/TAF 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(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice - Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
5.2.2.2.
Dolutegravir (DTG) 50 mg and Placebo to Match Tablets
DTG tablets and PTM DTG tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 30 tablets.  Each bottle is enclosed with a white, continuous thread, 
child-resistant polypropylene screw cap with an induction-sealed and aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US FDA, EU Guideline to Good Manufacturing 
Practice - Annex 13 (Investigational Medicinal Products), and/or other local regulations.
5.2.2.3.
Emtricitabine/Tenofovir Disoproxil Fumarate (F/TDF) 200 mg/300 mg and 
Placebo to Match Tablets
F/TDF tablets and PTM F/TDF tablets are packaged in white, high density polyethylene (HDPE) 
bottles. Each bottle contains 30 tablets and silica gel desiccant.  Each bottle is enclosed with a 
white, continuous thread, child-resistant polypropylene screw cap with an induction-sealed and 
aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the US 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 drugs 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 through inhalation when handling.
5.3.
Dosage and Administration of Bictegravir/Emtricitabine/Tenofovir 
alafenamide and Dolutegravir + Emtricitabine/Tenofovir Disoproxil 
Fumarate
Study drugs B/F/TAF FDC, DTG + F/TDF FDC and placebo-to-match tablets will be provided 
by Gilead Sciences.
Treatment Group 1: FDC of bictegravir 50 mg/emtricitabine 200 mg/ tenofovir alafenamide 
25 mg (B/F/TAF) + placebo to match dolutegravir 50 mg (DTG) and placebo to match FDC of 
emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (F/TDF) administered orally, once 
daily, without regard to food 
Treatment Group 2: dolutegravir 50 mg (DTG) + FDC of emtricitabine 200 mg/tenofovir 
disoproxil fumarate 300 mg (F/TDF) + placebo to match FDC of bictegravir 50 mg/emtricitabine 
200 mg/tenofovir alafenamide 25 mg (B/F/TAF) administered orally, once daily, without regard 
to food. 
After the End of Blinded Treatment Visit, all subjects who choose to participate in the open-label 
extension will receive B/F/TAF FDC once daily.
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.  

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Table 5-1.
Prior and Concomitant Medications
Drug Class
Agents Disallowed*
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Buffered medications
Concentration of study drug may decrease with 
antacids. Administer study drug 2 hours before or 
6 hours after taking antacids (e.g., Tums or Rolaids); 
the ulcer medication sucralfate (Carafate); or vitamins
or mineral supplements that contain calcium, iron or 
zinc.
Antiarrhythmic Agent
Dofetilide
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, Oxcarbazepine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin
Antiretrovirals
Any antiretroviral drug that is 
not part of the study regimen
GI Motility Agents
Cisapride
Herbal/Natural 
Supplements
St. John’s Wort, Echinacea
Oral Hypoglycemic 
Agent
Close monitoring of metformin use is recommended. A 
dose adjustment of Metformin may be necessary.  
Limit total daily doses of metformin to 1000 mg when 
initiating study medication or if initiating metformin 
while on study drug.
5.5.
Accountability for Investigational Medical 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.
Study Drug 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
Study drug return and disposal 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 this 
section and in tabular form in Appendix 2 and Appendix 3.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible for study prior to 
enrollment. Please refer to Section 6.3 for details about randomization and treatment 
assignments.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30-days before Day 1 to determine eligibility for participation in 
the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history including history of HIV-1 disease-related events and prior 
medications within 30 days of the screening visit

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

12-lead ECG performed supine

Height 

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Review of adverse events and concomitant medications
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30-days after screening for the Day 1 Visit.
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 

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(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
(Section 7).
6.3.
Randomization
Once eligibility has been confirmed and prior to or during the Day 1 visit, the Investigator or 
designee will randomize 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 and randomization 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.
6.4.
Day 1 Assessments 
The following evaluations are to be completed at the Day 1 Visit. The Investigator must have 
received the results from the screening genotype report and confirmed eligibility before 
proceeding with the Day 1 visit. The subject must complete all study procedures before being 
administered the study drug:

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 (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Provide subject dosing diary to all subjects for PK collection

Dispense study drug  

Observed first dose administration of the assigned study drugs as described in Section 5.3.

Subjects should be instructed to take study drugs without regard to food. The subject should 
be counseled regarding the importance of adherence and taking their study medications at 
approximately the same time each day as directed by the Investigator.
6.5.
Treatment Assessments (Week 4 – 96)
The following evaluations are to be completed at the end of Weeks 4, 8, 12, 24, 36, 48, 60, 72, 
84 and 96 unless otherwise specified.  

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Study visits are to be completed within ± 2 days of the protocol-specified visit date (based on the 
Day 1 visit) through Week 12 and completed within ± 6 days of the protocol-specified visit date 
through Week 96, unless otherwise specified. The visit window at Weeks 48 and 96 will be 
± 6 weeks of the protocol-specified visit date, and this clinical visit window coincides with the 
Weeks 48 and 96 statistical analysis window for HIV-1 RNA.
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

Complete physical examination (Weeks 24, 48, 96) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator) or symptom-directed physical examination as 
needed 

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Provide subject dosing diary to all subjects (Weeks 4, 8, 12 and 24)

Dosing diaries will be collected from subjects for the trough and post-dose PK blood sample 
collection as noted in Section 6.10. If a dosing diary is not returned the site may ask the 
subject for the time of the last dose and if it was taken with or without food.

Document study drug dispensation and accountability for all study drugs dispensed.
6.6.
Treatment Assessments (Post Week 96 until the End of Blinded Treatment 
Visit)
6.6.1.
Post Week 96 Assessments
After Week 96, all subjects will continue to take their blinded study drugs and attend visits every 
12 weeks until the last subject completes the Week 96 visit of the blinded phase. Study visits are 
to be completed within 6 days of the protocol-specified visit date unless otherwise specified. 

Review of AEs and changes in concomitant medications

Complete physical examination (every 48 weeks) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator) or symptom-directed physical examination as 
needed

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Document study drug dispensation and accountability for all study drugs dispensed.

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6.6.2.
End of Blinded Treatment Visit Assessments
Once the last subject completes their Week 96 visit and Gilead completes the Week 96 analysis, 
all subjects will return to the clinic (preferably within 30 days) for an End of Blinded Treatment 
Visit. At the End of Blinded Treatment Visit, if safety and efficacy of B/F/TAF FDC is 
demonstrated for the HIV-1 and HBV coinfected subjects following review of unblinded data, 
subjects in a country where B/F/TAF FDC is not available will be given the option to receive 
B/F/TAF FDC in an open label extension phase for up to 48 weeks, or until the product becomes 
accessible to subjects through an access program, or until Gilead Sciences elects to discontinue 
the study in that country, whichever occurs first. 
Subjects who receive the open-label B/F/TAF FDC will return for study visits every 12 weeks.
Subjects who complete the study through the End of Blinded Treatment Visit and do not 
continue on the open label B/F/TAF FDC extension will be required to return to the clinic for a 
30-Day Follow-up visit. Subjects who have discontinued drug study prior to the End of Blinded 
Treatment Visit will not be eligible for the open-label rollover extension; these subjects will be 
asked to continue attending the scheduled study visits through the End of Blinded Treatment 
Visit and discontinue the study after the End of Blinded Treatment Visit. 
Treatment assignments will be provided to the investigators within 30 days of the last subject 
completing the End of Blinded Treatment Visit.
The following will be performed at the End of Blinded Treatment 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 (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Document study drug dispensation, if applicable, and accountability for all study drugs 
dispensed

Subjects who wish to continue in the Open-Label Rollover extension study will receive open 
label B/F/TAF.
6.7.
Open-Label Rollover Extension Assessments
For purposes of study visit identification during the open-label rollover extension, study visits 
will be identified by the number of weeks that have elapsed between the End of Blinded 
Treatment Visit and the corresponding open-label study visit, and labeled with “OL” (Week 12 
OL, Week 24 OL, Week 36 OL, etc.).

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All subjects participating in the open label extension phase, without regard to their blinded 
treatment regimen, will return for study visits at Week 12 OL and every 12 weeks thereafter.
Study visits are to be completed within ± 2 days of the protocol-specified visit date based on the 
End of Blinded Treatment Visit through Week 12 OL and completed ± 6 days of the 
protocol-specified visit date every 12 weeks thereafter, unless otherwise specified.
The following will be performed at the Open-Label Extension Visits:

Review of AEs and changes in concomitant medications

Complete physical examination (every 48 weeks) (urogenital/anorectal exams will be
performed at the discretion of the Investigator) or symptom-directed physical examination as 
needed

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Document study drug dispensation and accountability for all study drugs dispensed.
6.8.
Post-Treatment Assessments
6.8.1.
Early Study Drugs Discontinuation Assessments
If the subject discontinues study drug prior to the End of Blinded Treatment Visit, the subject 
will be asked to return to the clinic within 72 hours of stopping study drugs for the Early Study 
Drugs Discontinuation Visit. The subject will be asked if they wish to continue attending the 
scheduled study visits through the End of Blinded Treatment Visit.
If the subject discontinues study drug during the Open Label rollover extension, the subject will 
be asked to return to the clinic within 72 hours of stopping the study drug for the Early Study 
Drugs Discontinuation Visit.
At the Early Study Drugs Discontinuation 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 the Early Study Drugs Discontinuation Visit:

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

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
Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood and urine samples as described in Section 6.10

Drug accountability
6.8.2.
30 Day Follow-Up Visit
Subjects who prematurely discontinue study drug during the blinded phase and refuse to 
continue in the study through the End of Blinded Treatment Visit will be asked to return to the 
clinic 30 days after the completion of the Early Study Drugs Discontinuation Visit for the 30 Day 
Follow-Up Visit.
Those subjects who prematurely discontinue study drug during the blinded phase 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.
Subjects who complete the study through the End of Blinded Treatment Visit, and refuse to 
participate in the open-label rollover extension will be required to return to the clinic 30 days 
after the completion of study drug for the 30 Day Follow-Up Visit.
Subjects who prematurely discontinue study drug during the Open Label rollover extension will 
be asked to return to the clinic 30 days after the completion of the Early Study Drugs 
Discontinuation Visit for the 30 Day Follow-Up Visit. The subject will not continue attending 
the scheduled study visits.
Subjects who complete the Open Label rollover extension will be asked to return to the clinic 
30 days after the completion of the study drugs 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 (blood pressure, pulse, respiration rate, and temperature), including 
weight 

Obtain blood and urine samples as described in Section 6.10
At the 30 Day Follow-Up Visit, any evaluations showing abnormal results believed to be a 
reasonable possibility of a causal relationship with the study drugs 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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6.9.
Criteria for Discontinuation of Study Treatment
Study medication will be discontinued in the following instances:

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

Subject request to discontinue for any reason

Pregnancy during the study; refer to Appendix 6
Note: Female subjects who become pregnant during the study will be discontinued from the 
study and their study treatment assignment will be unblinded by the investigator and shared with 
the subject.

Development of active tuberculosis infection
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

Lack of efficacy

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)
6.10.
Clinical Laboratory Assessments
Blood and urine samples will be collected throughout the study as outlined below and in 
Appendix 2 and Appendix 3.
6.10.1.
Blood Samples
Blood samples will be collected at all study visits (including the open-label rollover extension 
phase), unless otherwise noted for the below noted laboratory analyses: 

Serum pregnancy test at the Screening Visit (females of childbearing potential only). If the 
test is positive, the subject will not be enrolled. At all subsequent study visits, serum 
pregnancy test will be performed if urine pregnancy test is positive. 

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
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
phosphorus, magnesium, potassium, sodium, uric acid, amylase (reflex lipase testing is 
performed in subjects with total amylase 1.5 ULN)
At Day 1, Weeks 24, 48, 72, 96, every 24 weeks after Week 96, End of Blinded 
Treatment Visit, and every 24 weeks after the End of Blinded Treatment Visit in the open 
label extension phase glucose will be done as part of the fasting metabolic assessments 
and not part of the chemistry profile. 
PT/INR (prothrombin time/international normalized ratio) will be analyzed at Screening 
and Day 1 Visits.

Metabolic assessments: Fasting (no food or drinks, except water, at least 8 hours prior to 
blood collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, and 
triglycerides) at Day 1, Weeks 24, 48, 72, 96, every 24 weeks after Week 96, End of Blinded 
Treatment Visit, and every 24 weeks after End of Blinded Treatment Visit in the open label 
rollover extension phase. 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 to draw blood for the metabolic 
assessments.

Estimated glomerular filtration rate according to the Cockcroft-Gault formula
If eGFR is < 50 mL/min at Day 1 visit, Cystatin C will be measured

Hematology profile: complete blood count (CBC) with differential and platelet count

CD4+ cell count and CD4% 

Plasma HIV-1 RNA 

Hepatitis B Virus (HBV) blood panel: 
HBV serologies: HBsAg, reflex anti-HBs Ab, HBeAg, reflex anti-HBe Ab
(Screening, Day 1 and Weeks 12, 24, 36, 48, 60, 72, 84, 96 and every 24 weeks after 
Week 96 until the End of Blinded Treatment Visit. In the open-label extension phase, 
testing will be completed every 48 weeks)

Plasma HBV DNA will be monitored at all study visits.

Plasma sample for HBV Genotyping (A-H) at Day 1 visit.

Serum samples for potential sequence analysis of HBV polymerase/reverse transcriptase 
(pol/RT) should be collected at all time points except screening. Sequencing analysis of the 
HBV pol/RT will be attempted for all subjects who remain viremic (HBV DNA 69 IU/mL) 
at Weeks 48, 96 and Early Study Drug Discontinuation Visit as early as Week 8 and 
according to Section 6.15. 

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
Urine pregnancy testing for females of childbearing potential only (not collected at Screening 
and 30 Day-Follow-up Visit). Positive urine pregnancy tests will be confirmed with a serum 
test. If the serum test is positive, the subject will be discontinued.

Markers of renal dysfunction (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 state to provide 
a urine sample for markers of renal dysfunction at Day 1 Visit, Weeks 24, 48, 96 and ESDD (if 
applicable).
6.10.3.
Blood Storage Samples
Any residual blood samples from the samples collected will be frozen and stored. These stored 
blood samples may be used by the Sponsor or its research partners for HIV-1 and/or HBV or 
related diseases, genotyping/phenotyping assays or their development, for retesting the amount 
of HIV-1 and/or HBV in the blood, for measurement of antiviral drug levels in the blood, or for 
testing to learn more about how the study drug has worked against HIV-1 and/or HBV or related 
diseases, or clinical laboratory testing to provide additional safety data. No human genetic testing 
will be performed without expressed consent of study subjects. At the conclusion of this study, 
these samples may be retained in storage by Gilead Sciences for a period up to 15 years.
6.11.
Assessments for Premature Discontinuation from Study
If a subject discontinues study drug in the blinded phase of the study (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 procedures until the End of Blinded Treatment Visit. If this is not possible or 
acceptable to the subject or investigator, the subject may be withdrawn from the study.
6.12.
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 extension phase will complete study visits every 12 weeks until the 
product becomes accessible to subjects through an access program, or until Gilead Sciences 
elects to discontinue the study in that country, whichever occurs first. 
6.13.
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.
6.14.
HIV-1 Virologic Failure
HIV-1 virologic failure is defined as confirmed virologic rebound or HIV-1 RNA 
≥50 copies/mL at study drug discontinuation, Week 48, or 96.

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6.14.1.
Management of HIV-1 Virologic Rebound
Subjects who meet the criteria listed below will be considered to have HIV-1 virologic rebound:

At any visit, after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 RNA 
≥50 copies/mL, which is subsequently confirmed at the following scheduled or unscheduled 
visit; OR

At any visit, a 1 log10 increase in HIV-1 RNA from the nadir which is subsequently 
confirmed at the following scheduled or unscheduled visit
At any visit after achieving HIV-1 RNA < 50 copies/mL, if the HIV-1 RNA is ≥50 and
< 200 copies/mL, a reflex HIV-1 RNA repeat test will be conducted on stored plasma if 
available. If the repeat result is < 50 copies/mL, no further action is required. If the repeat result 
is ≥ 50 copies/mL subjects will be asked to return to the clinic for a scheduled or unscheduled 
blood draw (2 to 3 weeks after the date of the original test that resulted in HIV-1 RNA virologic 
rebound) for confirmation of virologic rebound. If virologic rebound is confirmed at the 
scheduled or unscheduled visit and the HIV-1 RNA is ≥200 copies/mL, the blood sample from 
the confirmation visit will be the primary sample used for HIV-1 genotypic and phenotypic 
testing.  
All subjects with post-baseline resistance analyses will also be analyzed for their HIV-1 RT, PR, 
and IN genotypes and phenotypes from stored baseline samples. After a subject’s first post-
baseline 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 HIV-1 resistance is detected from the genotype or phenotype, the subject may remain on 
study drugs and a repeat HIV-1 RNA should be performed (2 to 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
a
If virologic rebound is not confirmed, the subject will remain on their current regimen.
b
If virologic rebound is confirmed and the HIV-1 RNA is ≥ 200 copies/mL, the HIV-1 genotype and phenotype (reverse 
transcriptase, protease, and integrase) will be analyzed.
c
Based on the results of the genotypic and phenotypic assays, the subject will remain on study drugs or study drugs will be 
discontinued. If genotyping or phenotyping assay fails, a new ARV regimen may be configured at the discretion of the 
Investigator.
d
If no resistance is detected, HIV-1 RNA will be repeated (2-3 weeks later).  Investigator reviews study drug 
continuation/discontinuation options and discusses with the Medical Monitor prior to study drug discontinuation
e
A new ARV regimen will be configured, at the Investigator’s discretion, and the subject will remain in the study.
6.14.2.
Subjects with HIV-1 RNA ≥ 50 copies/mL at Study Discontinuation, Week 48
or 96
Subjects with HIV-1 RNA ≥ 50 copies/mL at study discontinuation (at or after Week 8) or last 
visit will be considered virologic failures. However, if the HIV-1 RNA is ≥50 and
< 200 copies/mL, a reflex HIV-1 RNA repeat test will be conducted on stored plasma if 
available. If the repeat result is < 50 copies/mL, the subject will not be considered a virologic 
failure. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  

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Subjects with HIV-1 RNA ≥ 50 copies/mL at Week 48 and/or Week 96 will be asked to return 
for an unscheduled visit within the visit window for a retest. If the HIV-1 RNA is ≥50 and
< 200 copies/mL, a reflex HIV-1 RNA repeat test will be conducted on stored plasma if 
available. If the repeat result is < 50 copies/mL, the subject will not be considered a virologic 
failure and no further action is needed.
Subjects with HIV-1 RNA ≥ 200 copies/mL at study drug discontinuation, last visit, Week 48,
and/or Week 96 will also have resistance testing conducted. 
6.15.
HBV Resistance Surveillance
Sequencing analysis of the HBV pol/RT will be attempted for all subjects who remain viremic 
(HBV DNA 69 IU/mL) at Weeks 48 and 96 (or Early Study Drug Discontinuation Visit as 
early as Week 8), and for those with virologic breakthrough defined as: 

Two consecutive HBV DNA values 69 IU/mL after achieving < 69 IU/mL, or

Two consecutive 1.0 Log10 increases in HBV DNA from nadir for those who did not 
achieve a result < 69 IU/mL 
Sequencing of the corresponding Day 1 sample will also be conducted for any subject who 
remains viremic or experiences virologic breakthrough. As it may not be known at the time of 
the visit whether a patient is viremic or if it will be their last study visit, a separate virology
sample for potential resistance surveillance will be collected at each study visit. Phenotypic 
analysis will be performed for adherent subjects that are subjected to sequence analysis.

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

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

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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, (eg, venipuncture)
7.2.2.
Assessment of Severity
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the case report form (eCRF): all SAEs and adverse events related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Pharmacovigilance and Epidemiology (PVE) 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 PVE.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.

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All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 4 and as outlined below.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(Appendix 5). 

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational medicinal 
product discontinuation, unless such a delay is not consistent with good medical practice

Any questions regarding toxicity management should be directed to the Gilead Medical 
Monitor.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the Investigator.
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product will be withheld until the toxicity returns to Grade 2. When 
restarting investigational medicinal product following resolution of the adverse event, the 
investigational medicinal product should be restarted at full dose upon discussion with the 
Gilead Sciences Medical Monitor.

If a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product will be permanently discontinued and the subject managed 
according to local practice. Recurrence of laboratory abnormalities considered unrelated to 
investigational medicinal product may not require permanent discontinuation but requires 
discussion with the Gilead Sciences Medical Monitor.

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7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product will be permanently discontinued and the subject managed 
according to local practice. The subject should be followed as clinically indicated until the 
laboratory abnormality returns to baseline or is otherwise explained, whichever occurs first. 
A clinically significant Grade 4 laboratory abnormality that is not confirmed by repeat testing 
should be managed according to the algorithm for the new toxicity grade.

Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 4 laboratory abnormality (eg, Grade 4 CK after strenuous exercise, or 
triglyceride elevation that is nonfasting or that can be medically managed) or a clinical event 
considered unrelated to investigational medicinal product requires discussion with the Gilead 
Sciences Medical Monitor.
7.5.4.
On-Treatment ALT Flare and Post-Treatment Exacerbation of Hepatitis B 
Management
In 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.
7.5.4.1.
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 PT/INR, plasma HBV DNA, HBV serology (HBsAg, HBsAb, HBeAg and 
HBeAb), 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 (ie, 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.  

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Elevated Liver Enzymes, Elevated Liver Function Tests
If ALT values are elevated (ie, 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.
7.5.4.2.
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,HBsAb, HBeAg, HBeAb), HDV, HAV IgM and 
HCV. If plasma HBV DNA is increasing, the investigator should consider immediate 
initiation of approved therapy.

The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) return 
to normal or Day 1 up to a maximum of 6 months after the initial occurrence of the event.
7.5.5.
Management of Potential Nephrotoxicity
Estimated glomerular filtration rate (eGFR), according to the Cockcroft-Gault formula for 
creatinine clearance, will be followed post-baseline during the study. All subjects with estimated 
eGFR < 50 mL/min must have serum creatinine measured again within 3 calendar days of receipt 
of results.
At the time of this repeat serum creatinine assessment, Cystatin C will also be measured and the 
eGFR by CKD-EPI (cystatin C) will be calculated and compared with the baseline 
measurement. 

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Any subjects who have an eGFR < 50 mL/min that also experience > 20% reduction in eGFR by 
CKD-EPI (cystatin C) from baseline or who have other clinical and/or laboratory evidence of 
acute renal failure will be discussed with the Medical Monitor and potentially discontinue from 
study drugs. 
For subjects with eGFR < 50 mL/min who are not discontinued based on toxicity management 
procedures above and considered to have stable renal function per Principal Investigator and 
Medical Monitor, it is not mandatory to repeat eGFR assessments within 3 days.
CKD-EPI (cystatin C) formula adjusted for age and sex: 
eGFR (mL/min/1.73m2) = 133 x min(Scys/0.8,1)-0.499 × max(Scys/0.8,1)-1.328 ×
0.996Age [× 0.932 if female] 
Where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of 
Scys/0.8 or 1, and max (Scys/0.8,1) indicates the maximum of Scys/0.8 or 1.
Once an individual subject has developed any of these renal changes and followed the 
management guidelines above, it is not necessary to have repeat evaluations if it is determined 
that it is safe for that subject to continue on treatment with standard follow-up visits as described 
in the protocol.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.  
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  

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7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead PVE using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
The subject’s treatment assignment will be unblinded by the Investigator as described in Protocol 
Section 5.1.1.
Refer to Section 7.3 and the eCRF completion guidelines for full instructions on the mechanism 
of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.3. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead PVE.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead PVE using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead PVE. Gilead PVE contact information is as follows: 
Email: 
 and Fax: 
 
Refer to Appendix 6 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE 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 do 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. 
PPD
PPD

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Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to Section 7.6.1 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.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:

To evaluate the efficacy of  FDC B/F/TAF versus a regimen of DTG + F/TDF in HIV-1 and 
HBV treatment naïve, HIV-1 and HBV co-infected subjects as determined by the 
achievement of HIV-1 RNA 50 copies/mL at Week 48

To evaluate the efficacy of  FDC B/F/TAF versus a regimen of DTG + F/TDF in HIV-1 and 
HBV treatment naïve, HIV-1 and HBV co-infected subjects as determined by the proportion 
of subjects with plasma HBV DNA < 29 IU/mL at Week 48
The secondary objectives of this study are:

To evaluate the efficacy of FDC of B/F/TAF versus DTG + F/TDF as determined by the 
achievement of  HIV-1 RNA  50 copies/mL at Week 96

To evaluate the efficacy of FDC of  B/F/TAF versus DTG + F/TDF as determined by the 
proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 96

To evaluate the efficacy of the FDC of  B/F/TAF versus DTG + F/TDF as determined by the 
proportion of subjects with ALT normalization at Weeks 48 and 96

To evaluate the efficacy of the FDC of  B/F/TAF versus DTG + F/TDF as determined by the 
proportion of subjects with HBsAg loss at Weeks 48 and 96

To evaluate the safety and tolerability  of the two treatment groups through Week 96 
8.1.2.
Primary Endpoints
The primary efficacy endpoint is the proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Week 48 as defined by the US FDA-defined snapshot algorithm.
The co-primary efficacy endpoint is the proportion of subjects with plasma HBV DNA 
< 29 IU/mL at Week 48 as defined by Missing = Failure approach. 

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8.1.3.
Secondary Endpoint
The secondary efficacy endpoints are

The proportion of subjects that have HIV-1 RNA < 50 copies/mL at Week 96 as defined by 
the US FDA-defined snapshot algorithm.

The change from baseline in CD4 and at Weeks 48 and 96. 

The proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 96.

The proportion of subjects with ALT normalization at Weeks 48 and 96.

The proportion of subjects with HBsAg loss at Weeks 48 and 96
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
All Randomized 
The randomized analysis set includes all subjects who are randomized into the study. This is the 
primary analysis set for by-subject listings.
8.2.1.2.
Efficacy
8.2.1.2.1.
Full Analysis Set (FAS)
The primary analysis set for efficacy analyses is defined as full analysis set (FAS), which will 
include all subjects who (1) are randomized into the study, (2) have received at least 1 dose of 
study drug, and (3) have at least 1 post baseline HIV-1 RNA or HBV DNA results while on 
study drug. Subjects will be grouped according to the treatment to which they were randomized.
8.2.1.2.2.
Per-Protocol (PP) Analysis Set for anti-HIV Efficacy Analysis
The secondary analysis set for anti-HIV efficacy analyses is defined as per-protocol (PP) 
analysis set for anti-HIV efficacy analysis, which will include all subjects who (1) are 
randomized into the study, (2) have received at least 1 dose of study drug, and (3) have not 
committed any major protocol violation, including the violation of key entry criteria. Subjects 
will be grouped according to the treatment they actually received.
Subjects meeting any of the following criteria will be excluded from the Week 48 PP analysis set
for anti-HIV efficacy analysis:

Subjects who do not have on-treatment HIV-1 RNA in the Week 48 analysis window, except 
when missing due to discontinuation of study drug for lack of efficacy. 

Subjects who do not meet the inclusion criterion that the screening genotype report must 
show sensitivity to FTC and TFV.

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
Subjects who meet the exclusion criterion for receiving ongoing therapy with any of the 
medications listed in the table in protocol Section 4.3 including drugs not to be used with 
bictegravir, FTC, DTG, TAF, and TDF.

Nonadherence to study drug: subjects with adherence rate for active study drug up to the 
Week 48 Visit below the 2.5th percentile
8.2.1.2.3.
Per-Protocol (PP) Analysis Set for anti-HBV Efficacy Analysis
The secondary analysis set for anti-HBV efficacy analyses is defined as per-protocol (PP) 
analysis set for anti-HBV efficacy analysis, which will include all subjects who (1) are 
randomized into the study, (2) have received at least 1 dose of study drug, and (3) have not 
committed any major protocol violation, including the violation of key entry criteria. Subjects 
will be grouped according to the treatment they actually received.
Subjects meeting any of the following criteria will be excluded from the Week 48 PP analysis set 
for anti-HBV efficacy analysis:

Subjects who do not have on-treatment HBV DNA in the Week 48 analysis window, except 
when missing due to discontinuation of study drug for lack of efficacy. 

Subjects who do not meet the inclusion criterion that the screening genotype report must 
show sensitivity to FTC and TFV.

Subjects who meet the exclusion criterion for receiving ongoing therapy with any of the 
medications listed in the table in protocol Section 4.3 including drugs not to be used with 
bictegravir, FTC, DTG, TAF, and TDF.

Nonadherence to study drug: subjects with adherence rate for active study drug up to the 
Week 48 Visit below the 2.5th percentile
8.2.1.3.
Safety
The primary analysis set for safety analyses is defined as safety analysis set, which will include 
all subjects who (1) are randomized into the study and (2) have received at least 1 dose of study 
drug. All the data collected up to 30 days after subjects permanently discontinue their study drug 
will be included in the safety summaries, unless specified otherwise. Subjects will be grouped 
according to the treatment they actually received.
8.3.
Data Handling Conventions
HIV-1 RNA results of ‘No HIV-1 RNA detected’ and “< 20 cp/mL HIV-1 RNA Detected” will 
be imputed as 19 copies/mL for analysis purposes. HBV DNA results of “<20 IU/mL HBV DNA 
detected” or “No HBV DNA detected” will be imputed as 19 IU/mL for analysis purposes.  
Logarithm (base 10) transformation will be applied to HIV-1 RNA and HBV DNA data for 
efficacy analysis.

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Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit plus 
or minus one significant digit, respectively (e.g. if the result of a continuous laboratory test is 
< 20, a value of 19 will be assigned).
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. However, a missing pre-treatment laboratory result would be 
treated as normal (i.e., no toxicity grade) for the laboratory abnormality summary.
All available data for subjects that do not complete the study will be included in data listings.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods including sample size, mean, SD, median, Q1, Q3, minimum, and maximum for 
continuous variables and frequency and percentages for categorical variables.
Demographic data will include sex, race, ethnicity, and age. 
Baseline characteristics will include body weight, height, body mass index, eGFR, HIV-1 
infection, HBV infection, and enrollment distribution by randomization stratum will be 
summarized.
For categorical demographic and baseline characteristics, the Cochran–Mantel–Haenszel (CMH)
test will be used to compare treatment groups. For continuous demographic and baseline 
characteristics, the Wilcoxon rank sum test will be used to compare treatment groups.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is the proportion of subjects who achieve HIV-1 RNA 
50 copies/mL at Week 48 as determined by the US FDA-defined snapshot algorithm. The 
primary analysis of the efficacy endpoint will be based on the FAS.
The co-primary efficacy endpoint is the proportion of subjects with plasma HBV DNA
< 29 IU/mL at Week 48 as determined by Missing=Failure approach. The primary analysis of 
this efficacy endpoint will be based on the FAS.
8.5.1.1.
The US FDA-defined Snapshot Algorithm for HIV-1
The analysis window at Week 48 is defined as from Study Day 295 to Study Day 378, inclusive. 
All HIV-1 RNA data collected on-treatment (ie, including data collected up to 1 day after the last 
dose date of study drug) will be used in the snapshot algorithm. Virologic outcome will be 
defined as the following categories:

HIV-1 RNA < 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA < 50 copies/mL in the Week 48 analysis window

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
HIV-1 RNA 50 copies/mL: this includes subjects
a) Who have the last available on-treatment HIV-1 RNA 50 copies/mL in the Week 48 
analysis window, or
b) Who do not have on-treatment HIV-1 RNA data in the Week 48 analysis window and
i)
Who discontinue study drug prior to or in the Week 48 analysis window due to lack 
of efficacy, or
ii) Who discontinue study drug prior to or in the Week 48 analysis window due to 
reasons other than adverse event (AE), death, or lack of efficacy and have the last 
available on-treatment HIV-1 RNA 50 copies/mL

No Virologic Data in the Week 48 analysis window: this includes subjects who do not 
have on-treatment HIV-1 RNA data in the Week 48 analysis window because of the 
following: 
a) Discontinuation of study drug prior to or in the Week 48 analysis window due to AE or 
death (regardless of whether the last available on-treatment HIV-1 RNA < 50 copies/mL 
or not) or,
b) Discontinuation of study drug prior to or in the Week 48 analysis window due to reasons 
other than AE, death, or lack of efficacy and the last available on-treatment HIV-1 RNA 
< 50 copies/mL or,
c) Missing data during the window but on study drug.
8.5.1.2.
Analysis of Primary Efficacy Endpoint
The null hypothesis is that the proportion of subjects achieving HIV-1 RNA < 50 copies/mL 
(as defined by the US FDA-defined snapshot algorithm) at Week 48 in B/F/TAF is at least 
12% lower than the response rate in DTG + F/TDF; the alternative hypothesis is that the 
response rate in B/F/TAF is less than 12% lower than that in DTG + F/TDF.
Non-inferiority will be assessed using the conventional confidence interval approach. The point 
estimate of treatment difference (B/F/TAF – DTG+F/TDF) and the associated 2-sided 95% 
confidence interval will be constructed using a normal approximation method based on stratified 
Mantel-Haenszel proportions, where stratification factor include baseline HIV-1 RNA 
(≤100,000 copies/mL vs. > 100,000 copies/mL).
It will be concluded that B/F/TAF is non-inferior to DTG + F/TDF if the lower bound of the 
2-sided 95% CI of the difference (B/F/TAF – DTG+F/TDF) in the response rate is greater 
than -12%.

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If non-inferiority of B/F/TAF to DTG+F/TDF is established, the lower bound of the 95% CI will 
be compared to 0; if the lower bound of the 95% CI is greater than 0, then superiority of 
B/F/TAF to DTG+F/TDF will be established.
8.5.1.3.
Analysis of Co-Primary Efficacy Endpoint for HBV
The null hypothesis is that the proportion of subjects with plasma HBV DNA < 29 IU/mL at 
Week 48 as determined by Missing=Failure approach in B/F/TAF is at least 12% lower than the 
response rate in DTG + F/TDF; the alternative hypothesis is that the response rate in B/F/TAF is 
less than 12% lower than that in DTG + F/TDF. For Missing = Failure approach, all missing data 
will be treated as HBV DNA ≥ 29 IU/mL.
Non-inferiority will be assessed similarly as for the primary efficacy endpoint, except the 
stratification factors include HBeAg status (positive vs. negative) and baseline HBV DNA 
(< 8 log10 IU/mL vs. ≥ 8 log10 IU/mL). To control type I error for the assessment of the primary 
and the co-primary efficacy endpoints, the hypothesis testing will be performed using the 
fallback procedure {Wiens 2005} in the sequential order with pre-specified 1-sided alpha level. 
The primary hypothesis of non-inferiority of B/F/TAF relative to DTG + F/TDF, with respect to 
the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 (as defined by the FDA 
snapshot analysis) will be tested first. Non-inferiority test will be performed at one-sided, 
0.025 alpha level. If non-inferiority is established, the co-primary hypothesis of non-inferiority 
of B/F/TAF relative to DTG + F/TDF, with respect to the proportion of subjects with plasma 
HBV DNA < 29 IU/mL at Week 48 will be tested second at one-sided, 0.025 alpha level. 
Otherwise, the co-primary endpoint will not be tested at all. 
8.5.2.
Secondary Analyses
8.5.2.1.
Secondary anti-HIV Efficacy Analysis 
The proportion of subjects who achieve HIV-1 RNA < 50 copies/mL at Week 96 as defined by 
the US FDA-defined snapshot algorithm, will be analyzed using the same method as for the 
primary efficacy endpoint.
The changes from baseline in CD4 cell count and CD4% at Weeks 48 and 96 will be 
summarized by treatment using descriptive statistics. The differences in changes from baseline in 
CD4 cell count and CD4% between 2 treatment groups and the associated 95% confidence 
intervals will be constructed using ANOVA models, including treatment (B/F/TAF vs. DTG + 
F/TDF) and baseline HIV-1 RNA (≤ 100,000 copies/mL vs. > 100,000 copies/mL) as fixed 
effects in the model.
In addition, missing CD4 cell count will be imputed using Last Observation Carried Forward 
(LOCF) method and analyzed similarly.

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8.5.2.2.
Secondary anti-HBV Efficacy Analysis 
The secondary anti-HBV efficacy endpoints include: (1) the proportion of subjects with HBV 
DNA < 29 copies/mL at Week 96, (2) the proportion of subjects with ALT normalization (i.e., 
subjects had ALT > ULN at baseline and a ALT ≤ ULN at the given post-baseline) at Weeks 48 
and 96, and (3) the proportion of subjects with HBsAg loss at Weeks 48 and 96. 
All these three anti-HBV efficacy endpoints will be analyzed using both Missing = Failure and 
Missing = Excluded approach. The 95% CIs will be constructed in the similar manner as 
described for the primary efficacy endpoint with stratification factors of HBeAg status (positive 
vs. negative) and baseline HBV DNA (< 8 log10 IU/mL vs. ≥ 8 log10 IU/mL).
8.6.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
All safety data collected on or after the date that the study drug was first administered up to the 
date of the last dose of study drug plus 30 days, unless specified otherwise will be summarized 
for subjects in the safety analysis set according to the study drug received.
Data for the pretreatment period and the period post the date of last dose of study drug plus 
30 days will be included in data listings for all enrolled subjects.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration page in eCRF. Exposure data will be summarized by treatment.
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 by treatment.
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.

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Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC, 
HLT [if applicable], and PT) will be provided by treatment. Additional summaries will include 
summaries for adverse events by grade, Investigator’s assessment of relationship to study drug, 
and effect on study drug dosing.
On an ongoing basis adverse events will be reviewed for events that might meet the definition of 
Stage 3 Opportunistic Illnesses in HIV are indicative of an AIDS-Defining Diagnoses. The 
Gilead medical personnel will review the possible Stage 3 events and approve the events that 
meet the definition. Those events that do meet the Stage 3 Opportunistic Illness definition of an 
AIDS-Defining Diagnosis will be listed.
A listing of Stage 3 Opportunistic Illnesses in HIV can be found in Appendix 7
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Absolute values and changes from baseline at all scheduled visits will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme defined in Grading of 
laboratory abnormalities attached 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 by treatment.  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 study drug or after the last dose of 
study drug plus 30 days will be included in a data listing.
8.6.4.
Other Safety Evaluations
Vital signs will be summarized as appropriate.
8.7.
Pharmacokinetic Analysis
Pharmacokinetic concentration data will be listed.
8.8.
Sample Size
A total of approximately 240 HIV-1 and HBV co-infected subjects, randomized in a 1:1 ratio to 
2 treatment groups (120 subjects per treatment group), achieves  90% power to detect a 
non-inferiority margin of 12% in Week 48 response rate (HIV-1 RNA < 50 copies/mL as defined 
by the US FDA-defined snapshot algorithm) difference between the 2 treatment groups. For the 
sample size and power computation, it is assumed that both treatment groups have a response 
rate of 91% (based on Gilead Studies GS-US-380-1489 and GS-US-380-1490), that the 
non-inferiority margin is 12%, and that the significance level of the test is at a one-sided 
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A total of approximately 240 subjects also provides 81% power to detect a non-inferiority 
margin of 12% with respect to the co-primary efficacy endpoint of the proportion of subjects 
with plasma HBV DNA < 29 IU/mL at Week 48. It was assumed that both treatment groups have
a response rate of 88% (based on Gilead Studies GS-US-320-0108 and GS-US-320-0110, with
an assumption that 80% enrolled subjects were HBeAg negative and 20% were HBeAg positive), 
that the non-inferiority margin is 12%, and that the significance level of the test is at a one-sided 
0.025 level.
8.9.
Data Monitoring Committee
An external Independent Data Monitoring Committee (IDMC) will review the progress, efficacy, 
and safety data of this study while the study is ongoing. The committee will convene after all
subjects enrolled have completed their Week 24 visit or prematurely discontinued from the study 
drug. However, Gilead will defer to the IDMC for any decision to convene earlier or more 
frequently. The IDMC will examine the safety results of the trial and also focus on logistical 
issues such as accrual, retention, quality of clinical and laboratory data, and implications of 
results of external studies. Blinding will be preserved during the conduct of the study and access 
to unblinded data will be limited to designated parties.
No formal stopping rules will be used by the IDMC for safety outcomes. Rather, a clinical 
assessment will be made to determine if the nature, frequency, and severity of adverse events 
associated with a study regimen warrant the early termination of the study in the best interest of
the participants.
For each IDMC analysis performed prior to the analysis of the primary efficacy endpoint, an 
alpha penalty of 0.00001 will be applied for the primary analysis of the primary endpoint.
8.10.
Analysis Schedule
The Weeks 48 and 96 analyses will be conducted after all subjects either complete their Week 48 
and 96 visits or prematurely discontinue from the study drug, respectively. The final analysis will 
be performed after all subjects complete the study or prematurely discontinue from the study.

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

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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by 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.
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

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

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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, IRBs/IECs and/or regulatory/health authority inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or] 
IEC in accordance with local requirements and receive documented approval before 
modifications can be implemented.

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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the below conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
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.

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9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.

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10.
REFERENCES
Charpentier C, Le MP, Joly V, Visseaux B, Lariven S, Phung B, et al. Use of PCR Signal and 
Therapeutic Drug Monitoring in a Switch Cohort Study to 
Tenofovir/Emtricitabine/Rilpivirine: A W96 Follow-Up. PLoS ONE 2015;10 
(7):e0134430.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Drake A, Nijch A, Sasadeusz J. Immune reconstitution hepatitis in HIV and hepatitis B 
coinfection, despite lamivudine therapy as part of HAART. Clin Infect Dis 
2004;39 (1):129-32.
European AIDS Clinical Society (EACS). Guidelines Version 8.1 English.  October, 2016.
European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the 
Management of Hepatitis B Virus Infection. J Hepatol 2017;67 (2):370-98.
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. 
Gorden DL, Fingleton B, Crawford HC, Jansen DE, Lepage M, Matrisian LM. Resident stromal 
cell-derived MMP-9 promotes the growth of colorectal metastases in the liver 
microenvironment. Int J Cancer 2007;121 (3):495-500.
Gunthard HF, Saag MS, Benson CA, del Rio C, Eron JJ, Gallant JE, et al. Antiretroviral Drugs 
for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations 
of the International Antiviral Society-USA Panel. JAMA 2016;316 (2):191-210.
Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, et al. Age-related 
immune dysfunction in health and in human immunodeficiency virus (HIV) 
disease: association of age and HIV infection with naive CD8+ cell depletion, 
reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect 
Dis 2003;187 (12):1924-33.
Kourtis AP, Bulterys M, Hu DJ, Jamieson DJ. HIV-HBV coinfection--a global challenge. N Engl 
J Med 2012;366 (19):1749-52.

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Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Developed by 
the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A 
Working Group of the Office of AIDS Research Advisory Council (OARAC) 
Available at: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Last Updated 14 July.  2016.
Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice 
guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10 
(1):1-98.
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.
Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines 
for treatment of chronic hepatitis B. Hepatology 2016;63 (1):261-83.
Wiens BL, Dmitrienko A. The fallback procedure for evaluating a single family of hypotheses. J 
Biopharm Stat 2005;15 (6):929-42.

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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table (Blinded Phase)
Appendix 3.
Study Procedures Table (Open Label Rollover Extension)
Appendix 4.
Management of Clinical and Laboratory Adverse Events
Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 7.
Definitions of Stage 3 Opportunistic Illnesses in HIV

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Appendix 2.
Study Procedures Table (Blinded Phase)
Study Procedures
Screeninga
Day 1b
End of Weeke, q
Post-Week 
96e, r
End of 
Blinded 
Treatment 
Visit
30-Day 
Follow-
upp
Early 
Study 
Drugs 
DCc
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Informed Consent
X
Medical History
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
Xf
Complete/Symptom-
Directed Physical 
Exam
X
X
Xd
Xd
Xd
X
Xd
X
Xd
Xd
Xd
X
Xd
X
Xd,f
Xf
12-Lead ECG 
(performed supine)
X
Height
X
Vital signs (blood 
pressure, pulse, 
respiration rate, and 
temperature), and
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
Xf
Urine Sample for 
Markers of Renal 
Dysfunction
X
X
X
X
X
Pregnancy Testg
X
X
X
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
Xf
Xf
Metabolic 
Assessmentsi
X
X
X
X
X
Xi
X

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Study Procedures
Screeninga
Day 1b
End of Weeke, q
Post-Week 
96e, r
End of 
Blinded 
Treatment 
Visit
30-Day 
Follow-
upp
Early 
Study 
Drugs 
DCc
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Estimated Glomerular 
Filtration Rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
X
Hematology Profilej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xf
Xf
Plasma HIV-1 RNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ Cell Count 
and CD4%
X
X
X
X
X
X
X
X
X
X
X
X
Xn
X
X
X
Blood Storage 
Sampleso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCV Serologyu
X
X
X
X
HIV-1 Genotypek
X
HIV-1 
Genotype/Phenotypee
Xe
Xe
Xe
HBV Blood panelt
X
X
X
X
X
X
X
X
X
X
Xt
HBV Genotyping 
(A-H)
X
Plasma HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum sample HBV 
Resistance 
Surveillancew
X
X
X
X
X
X
Xw
X
X
X
X
Xw
X
X
Xw
Trough PK Blood 
Samplel
X
X
X
Post-Dose PK Blood 
Samplem
X
X

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Study Procedures
Screeninga
Day 1b
End of Weeke, q
Post-Week 
96e, r
End of 
Blinded 
Treatment 
Visit
30-Day 
Follow-
upp
Early 
Study 
Drugs 
DCc
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
Randomizationv
X
Provide subject 
dosing diary to 
subjects
X
X
X
X
X
Study Drug 
Dispensation
Xb
X
X
X
X
X
X
X
X
X
X
X
Xs
Study Drug 
Accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Evaluations to be completed within 30 days prior to Day 1. 
b.
Administration of the first dose of study drug is to take place in-clinic following completion of study procedures at the Day 1 visit.
c.
Early Study Drugs 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 
End of Blinded Treatment Visit even if the subject discontinues study drug during the blinded phase.
d.
Symptom-directed physical examination as needed. After Week 96 visit, complete physical exam to be completed every 48 weeks. 
e.
HIV-1 genotype and phenotype of protease, reverse transcriptase, and integrase testing will be completed for subjects with virologic failure. Following virologic rebound, 
subjects will be asked to return to the clinic (2-3 weeks later) prior to the next scheduled visit or at the next scheduled study visit, for a HIV-1 RNA and HIV-1 genotype and 
phenotype blood draw. Based on the results of this testing, subjects should be managed according to the Virologic Rebound Schema (Section 6.14). Subjects with HIV-1 RNA 
≥ 50 copies/mL at Week 48 and 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, Week 48 or 96 will also have resistance testing conducted.
f.
Any adverse event or test showing abnormal results that is believed to have 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. 
g.
Females of childbearing potential only. Serum pregnancy testing will be performed at the Screening visit. Urine pregnancy testing will be performed at Day 1 and all 
subsequent study visits (except the 30 Day-Follow-up Visit). Positive urine pregnancy tests will be confirmed with a serum test.
h.
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid and amylase (reflex lipase testing is performed in subjects with total amylase 1.5 ULN). At Day 1, 
Weeks 24, 48, 72, 96, every 24 weeks post Week 96, and End of Blinded Treatment Visit, analyses of glucose will be done as part of the fasting metabolic assessments every 
24 weeks and not as part of the chemistry profile. PT/INR will be performed at Screening and Day 1.
CCI

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i.
Fasting (no food or drinks, except water, at least 8 hours prior to blood collection) 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 to draw blood for the metabolic assessments. After Week 96 
Visit, metabolic assessments will be completed every 24 weeks. 
j.
Complete blood count with differential and platelet count.
k.
The Investigator must have received the results from the screening HIV-1 genotype report before proceeding with the Day 1 visit.  Screening HIV-1 genotype report must 
show sensitivity to TFV and FTC. If genotype results from a local laboratory obtained ≤ 90 days prior to screening visit date show sensitivity to these drugs, this genotype 
will be acceptable to fulfill this inclusion criterion in the event that the genotype obtained at screening is not yet available and all other inclusion/exclusion criteria have been 
confirmed.
l.
Trough PK blood sample will be obtained 20-28 hours following the last dose at Weeks 4, 12 and 36. 
m.
Following an observed dose, one post-dose PK blood sample will be collected between 1 and 4 hours post-dose at Weeks 8 and 24. 
n.
CD4+ cell count and CD4% to be completed at all study visits. 
o.
Plasma and serum blood storage samples will be collected for safety, virology or PK testing. Whole blood storage samples will be collected for safety, virology or PK testing 
at Day 1, Week 48 and Week 96 visits. 
p.
Only required for those subjects who complete an End of Blinded Treatment Visit and do not wish to enroll in the open-label rollover extension or those subjects who 
prematurely discontinue study drugs prior to the End of Blinded Treatment Visit and do not continue in the study through at least one subsequent visit after the Early Study 
Drugs Discontinuation Visit. For the purpose of scheduling a 30-Day Follow-Up Visit, a 6 days window may be used.
q.
Study visits are to be completed within ± 2 days of the protocol-specified visit date based on the Day 1 visit through Week 12 and completed within ± 6 days through to 
Week 96, unless otherwise specified. The visit window at Weeks 48 and 96 will be ± 6 weeks of the protocol-specified visit date. 
r.
After Week 96, all subjects will continue to take their blinded study drug and attend visits every 12 weeks until the End of Blinded Treatment Visit.  Visit window of 6 days 
for study visits post Week 96.  
s.
Open label study drug, B/F/TAF FDC will be dispensed to subjects participating in the Open-Label Rollover extension.
t.
HBV serology (HBsAg and reflex anti-HBs Ab, and HBeAg and reflex anti-HBe Ab). After Week 96, HBV serology will be performed every 24 weeks.
u.
Hepatitis C virus (HCVAb) serology. Subjects who are HCVAb positive will have a HCV RNA test performed. After Week 96 visit, testing to be performed every 48 weeks 
v.
Randomization 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.
w.
Genotypic analysis of HBV polymerase/reverse transcriptase (pol/RT) for resistance surveillance will be attempted for all subjects who remain viremic (HBV 69 IU/mL) at 
Week 48 and 96 (or early study drug discontinuation visit as early as Week 8) and for those with virologic breakthrough as defined in Section 6.15.

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Amendment 2
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Appendix 3.
Study Procedures Table (Open Label Rollover Extension)
Study Procedures
Post End of Blinded Treatment 
Visit (every 12 weeks)a,e, l
30-Day Follow-upk
Early Study 
Drugs DCc
Adverse Events
X
Xf
Xf
Concomitant Medications
X
X
X
Complete/Symptom-Directed Physical Exam
Xd
Xd,f
Xf
Vital signs (blood pressure, pulse, respiration rate, and temperature) and Weight
X
X
X
Urinalysis
X
Xf
Xf
Urine Pregnancy Testg
X
X
Chemistry Profileh
X
Xf
Xf
Metabolic Assessmentsi
X
Estimated Glomerular Filtration Rate
X
Xf
X
Hematology Profilej
X
Xf
Xf
Plasma HIV-1 RNA
X
X
X
CD4+ Cell Count and CD4%
X
X
X
Blood Storage Sampleo
X
X
HBV Blood Panelm
X m
Plasma HBV DNA
X
HCV Serologyn
Xn
HIV-1 Genotype/Phenotypee
Xe
Study Drug Dispensationb
X
Study Drug Accountability
X
X
a.
Once the last subject completes the Week 96 visit and Gilead completes the Week 96 analysis, all subjects will return to the clinic (within 30 days ± 6 days) for an End of 
Blinded Treatment Visit. At the End of Blinded Treatment Visit, if safety and efficacy of B/F/TAF FDC is demonstrated for the HIV-1 and HBV coinfected subjects
following review of unblinded data, subjects in a country where B/F/TAF FDC is not available, will be given the option to receive B/F/TAF FDC in an open label extension 
phase until the product becomes accessible to subjects through an access program, or until Gilead Sciences elects to discontinue the study in that country, whichever occurs 
first.

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Amendment 2
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b.
Open label study drug, B/F/TAF FDC will be dispensed to subjects participating in the Open-Label Rollover extension.
c.
Subjects who discontinue study drug during the open label rollover extension portion of the study will be asked to return to the clinic within 72 hours of stopping study drugs 
for the Early Study Drugs Discontinuation Visit followed by a 30-Day Follow-Up Visit.  The subject will not continue attending the scheduled study visits.
d.
Symptom-directed physical examination as needed.
e.
HIV-1 genotype and phenotype testing for subjects with virologic failure. Following virologic rebound, subjects will be asked to return to the clinic (2-3 weeks later) prior to 
the next scheduled visit or at the next scheduled study visit, for a HIV-1 RNA and HIV-1 genotype and phenotype (reverse transcriptase, protease, and integrase genotype and 
phenotype) blood draw. Based on the results of this testing, subjects should be managed according to the Virologic Rebound Schema (Section 6.14). 
f.
Any adverse event or test showing abnormal results that is believed to have 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 Day 1, or is otherwise explained. 
g.
Females of childbearing potential only. Positive urine pregnancy tests will be confirmed with a serum test.
h.
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid and amylase (reflex lipase testing is performed in subjects with total amylase 1.5 ULN). At End of Blinded 
Treatment Visit and every 24 weeks after the End of Blinded Treatment Visit, analyses of glucose will be done as part of the fasting metabolic assessments and not as part of 
the chemistry profile. 
i.
Fasting (no food or drinks, except water, at least 8 hours prior to blood collection) glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides) every 24 weeks. 
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 to draw blood for the metabolic assessments.
j.
Complete blood count with differential and platelet count.
k.
Subjects who complete the open-label rollover extension will be required to return to the clinic 30 days after the completion of study drugs for the 30-Day Follow-Up Visit. 
Subjects who permanently discontinue study drugs during the open-label rollover extension will be asked to return to the clinic 30 days after the completion of the Early 
Study Drugs Discontinuation Visit 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.
l.
Study visits are to be completed within ± 2 days of the protocol-specified visit date based on the End of Blinded Treatment Visit date through Week 12 OL and completed 
within ± 6 days of the protocol-specified visit date every 12 weeks thereafter, unless otherwise specified
m.
HBV serology (HBsAg and reflex anti-HBs Ab, and HBeAg and reflex anti-HBe Ab will be performed every 48 weeks.. 
n.
Hepatitis C virus (HCVAb) serology will be performed every 48 weeks. Subjects who are HCVAb positive will have a HCV RNA test performed.
o.
Plasma and serum blood storage samples will be collected for safety, virology or PK testing..

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Amendment 2
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Appendix 4.
Management of Clinical and Laboratory Adverse Events
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 

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Appendix 5.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count  
(ANC)
Adult and Pediatric, 
≥ 7 Months# 
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL

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Amendment 2
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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.  

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Final
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Amendment 2
CONFIDENTIAL
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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 t o <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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered to be fertile after the initiation 
of puberty unless permanently sterile by bilateral orchiectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a.
Study Drug Effects on Pregnancy and Hormonal Contraception
The data on B/F/TAF in pregnant women is limited. There is no suspicion of human 
teratogenicity based on class effects or genotoxic potential. Relevant non-clinical reproductive 
studies for human pregnancy do not indicate a strong suspicion of human 
teratogenicity/fetotoxicity. Data from clinical pharmacokinetic interaction studies of bictegravir
and F/TAF have demonstrated that there is no reduction in the clinical efficacy of hormonal
contraception or that the effect on hormonal contraception is insignificant. Please refer to the 
latest versions of the B/F/TAF investigator’s brochure and F/TDF and DTG prescribing labels
for additional information.
Serious cases of neural tube birth defects involving the brain, spine, and spinal cord have been 
reported in babies born to women treated with dolutegravir. Preliminary results from an ongoing 
observational study in Botswana found that women who received dolutegravir at the time of 
becoming pregnant or early in the first trimester appear to be at higher risk for these defects.
Please refer to the latest local product labeling for DTG for additional information.
b.
Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must have a negative serum pregnancy test at Screening and a 
negative pregnancy test on the Baseline/Day 1 visit prior to randomization.  At minimum, a 
pregnancy test will be performed 7 days after the last study drug dose.  In the event of a delayed 
menstrual period (over one month between menstruations), a pregnancy test must be performed 

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to rule out pregnancy.  This is true even for women of childbearing potential with infrequent or 
irregular periods.  Female subjects must also agree to one of the following from Screening until 
30 days after the last dose of study drug. 

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle. 
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success by hysterosalpingogram 
three months after procedure and where permitted and used per local prescribing label)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects who wish to use a hormonally based method must use it in conjunction with a 
barrier method, preferably a male condom.  Female subjects who utilize a hormonal 
contraceptive as one of their birth control methods must have consistently used the same method 
for at least three months prior to study dosing.   Hormonally-based contraceptives and barrier 
methods permitted for use in this protocol are as follows:
Barrier methods (each method must be used with a hormonal method)
■
Male condom (with or without spermicide)
■
Female condom (with or without spermicide)
■
Diaphragm with spermicide
■
Cervical cap with spermicide
■
Sponge with spermicide
Hormonal methods (each method must be used with a barrier method, preferably male 
condom)
■
Oral contraceptives (either combined or progesterone only)

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■
Injectable progesterone
■
Subdermal contraceptive implant
■
Transdermal contraceptive patch
■
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3)
Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential.
4)
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).  Female condom and male condom should not be used 
together.
5)
Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant, or are concerned 
they may be pregnant at any time during the study, or if they become pregnant within 30 days of 
last study drug dose. Subjects who become pregnant or who suspect that they are pregnant during 
the study must report the information to the investigator and discontinue study drug immediately.  
Subjects who become pregnant will be discontinued from the study and their study treatment 
assignment will be unblinded by the Investigator and provided to the subject. 
Subjects who become pregnant while on study should receive appropriate monitoring and care 
until the conclusion of the pregnancy. Subjects who become pregnant while on study who are not 
engaged in pre-natal care that includes a routine second trimester ultrasound will be referred for 
ultrasonography as part of study follow-up. Instructions for reporting pregnancy and pregnancy 
outcome are outlined in Section 7.6.2.1.

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Appendix 7.
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}