A Phase 3b, Randomized, Double-Blind, Switch Study to Evaluate F/TAF in HIV-1 Infected Subjects Who Are Virologically Suppressed on Regimens Containing ABC/3TC
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences

Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Sr. Clinical Program 
Manager: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b, Randomized, Double-Blind, Switch Study to Evaluate 
FITAF in HIV-1 Infected Subjects who are Virologically 
Suppressed on Regimens containing ABC/3TC 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 9440 
111851 
2015-000871-28 
Not Available 
HIV -1 Infection 
GS-US-311-1717 
Name: 
Telephone: 
Fax: 
PPD 
PPD 
PPD 
I 
Gilead Medical Monitor: 
Name: 
MouQali Das, MD, MPH 
PPD 
Telephone: 
Mobile: 
PPD 
Fax: 
PPD 
Protocol Version/Date: 
Original: 
11 March 2015 
CONFIDENTIALITY STATEMENT 
The inf01m ation contained in this document, pruiicularly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the infonnation to others without written authorization from Gilead 
Sciences, Inc., except to the extent necessruy to obtain infonned consent from those persons to 
whom the dmg may be administered. 

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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................15
1.1.
Background ............................................................................................................................................15
1.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF).....................................................................................16
1.3.
Tenofovir Alafenamide (TAF, GS 7340)...............................................................................................16
1.3.1.
General Information .............................................................................................................16
1.3.2.
Preclinical Pharmacology and Toxicology...........................................................................17
1.3.3.
Nonclinical Pharmacokinetics..............................................................................................17
1.3.4.
Nonclinical Toxicology........................................................................................................18
1.3.5.
Clinical Trials of Single Agent Tenofovir Alafenamide (TAF, GS-7340) 
or Fixed Dose Combination emtricitabine/tenofovir alafenamide (F/TAF).........................19
1.3.6.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF) ...................................................................................................21
1.3.7.
Clinical Trials of Darunavir/Cobicistat/Emtricitabine/TAF (D/C/F/TAF)...........................25
1.4.
Emtricitabine (FTC, Emtriva®) .............................................................................................................26
1.4.1.
General Information .............................................................................................................26
1.5.
Information about Fixed Dose Combination of Abacavir/Lamivudine (ABC/3TC, Epzicom, 
Kivexa).................................................................................................................................................27
1.6.
Rationale for This Study ........................................................................................................................27
1.7.
Rationale for Dose Selection..................................................................................................................28
1.8.
Compliance ............................................................................................................................................30
2.
OBJECTIVES.....................................................................................................................................................31
3.
STUDY DESIGN................................................................................................................................................32
3.1.
Endpoints ...............................................................................................................................................32
3.2.
Study Design..........................................................................................................................................32
3.3.
Study Treatments ...................................................................................................................................32
3.4.
Duration of Treatment............................................................................................................................33
3.5.
Biomarker Testing..................................................................................................................................34
3.5.1.
Samples for Optional Future Research.................................................................................34
4.
SUBJECT POPULATION..................................................................................................................................35
4.1.
Number of Subjects and Subject Selection ............................................................................................35
4.2.
Inclusion Criteria....................................................................................................................................35
4.3.
Exclusion Criteria...................................................................................................................................37
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................38
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................38
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................38
5.2.
Description and Handling.......................................................................................................................39
5.2.1.
Formulation..........................................................................................................................39
5.2.2.
Packaging and Labeling .......................................................................................................40
5.2.3.
Storage and Handling...........................................................................................................40
5.3.
Dosage and Administration....................................................................................................................41

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5.4.
Prior and Concomitant Medications.......................................................................................................42
5.5.
Changes in Antiretroviral Therapy.........................................................................................................43
5.6.
Dispensing and Accountability of Investigational Medicinal Product (IMP) ........................................43
5.7.
Investigational Medicinal Product Return or Disposal...........................................................................44
6.
STUDY PROCEDURES ....................................................................................................................................45
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................45
6.2.
Pretreatment Visit Assessments .............................................................................................................45
6.2.1.
Screening Visit .....................................................................................................................45
6.2.2.
Day 1 Visit ...........................................................................................................................46
6.3.
Treatment Assessments..........................................................................................................................48
6.3.1.
Treatment Visits (Weeks 4 – 48)..........................................................................................48
6.3.2.
Treatment Visits (Weeks 60-96) ..........................................................................................51
6.3.3.
Treatment Visits (Post Week 96 until the Unblinding Visit and post 
Unblinding Visit) .................................................................................................................53
6.3.4.
Unblinding Visit...................................................................................................................54
6.4.
Post-treatment Assessments ...................................................................................................................56
6.4.1.
Early Study Drug Discontinuation (ESDD) Visit.................................................................56
6.4.2.
30 Day Follow-Up Visit.......................................................................................................58
6.5.
Criteria for Discontinuation of Study Treatment....................................................................................59
6.6.
Bone Mineral Density Evaluations.........................................................................................................59
6.7.
Other Evaluations...................................................................................................................................60
6.7.1.
Markers of Bone Turnover...................................................................................................60
6.7.2.
Markers of Renal Tubular Function .....................................................................................60
6.7.3.
Markers of Inflammation......................................................................................................60
6.7.4.
Markers of Platelet Function ................................................................................................60
6.8.
Blood and Urine Storage........................................................................................................................60
6.9.
Virologic Failure....................................................................................................................................60
6.9.1.
Management of Virologic Failure ........................................................................................61
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 in the Absence of VR .........................................61
6.10.
Platelet Function Substudy.....................................................................................................................63
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................64
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................64
7.1.1.
Adverse Events.....................................................................................................................64
7.1.2.
Serious Adverse Events........................................................................................................64
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................65
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................65
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................65
7.2.2.
Assessment of Severity ........................................................................................................66
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................66
7.3.1.
Adverse Events.....................................................................................................................66
7.3.2.
Serious Adverse Events........................................................................................................66
7.4.
Gilead Reporting Requirements.............................................................................................................67
7.5.
Special Situations Reports......................................................................................................................68
7.5.1.
Definitions of Special Situations..........................................................................................68
7.5.2.
Instructions for Reporting Special Situations.......................................................................69
7.6.
Toxicity Management ............................................................................................................................70
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................70
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event ...........................................................70
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................71
7.6.4.
Management of Bone Evaluation.........................................................................................71

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7.6.5.
Management of Hyperbilirubinemia in Patients Receiving Atazanavir ...............................71
7.6.6.
Management of Possible Abacavir Hypersensitivity Reaction.............................................72
7.6.7.
Management of Changes in Estimated Glomerular Filtration Rate......................................73
8.
STATISTICAL CONSIDERATIONS................................................................................................................74
8.1.
Analysis Objectives and Endpoints........................................................................................................74
8.1.1.
Analysis Objectives..............................................................................................................74
8.1.2.
Primary Endpoint .................................................................................................................74
8.1.3.
Secondary Endpoint .............................................................................................................74
8.2.
Analysis Conventions.............................................................................................................................74
8.2.1.
Analysis Sets ........................................................................................................................74
8.3.
Data Handling Conventions ...................................................................................................................76
8.4.
Demographic Data and Baseline Characteristics ...................................................................................76
8.5.
Efficacy Analysis ...................................................................................................................................76
8.5.1.
Primary Analysis..................................................................................................................76
8.5.2.
Secondary Analyses .............................................................................................................76
8.6.
Safety Analysis.......................................................................................................................................76
8.6.1.
Extent of Exposure...............................................................................................................77
8.6.2.
Adverse Events.....................................................................................................................77
8.6.3.
Laboratory Evaluations ........................................................................................................77
8.6.4.
Bone Mineral Density ..........................................................................................................78
8.6.5.
Other Safety Evaluations......................................................................................................78
8.7.
Pharmacokinetic Analysis......................................................................................................................78
8.8.
Analysis of Evaluations of Bone Turnover, Renal Tubular Function, and Inflammation......................78
8.9.
Sample Size............................................................................................................................................79
8.10.
Independent Data Monitoring Committee..............................................................................................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.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................81
9.1.5.
Study Files and Retention of Records ..................................................................................81
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................83
9.1.8.
Inspections............................................................................................................................83
9.1.9.
Protocol Compliance............................................................................................................84
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
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..................................................................................85
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..........................................................................................................90

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Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................95
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............96
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations.........................................................................................119
Appendix 6.
Definitions of HIV-1 Related Disease (CDC Guidelines)....................................................122
LIST OF IN-TEXT TABLES
Table 1-1.
GS-US-311-0101, GS-US-120-0117, and GS-US-120-0118: Changes in TAF 
exposures when Coadministered with Third Agents ..............................................................20
Table 1-2.
Dose Recommendations for F/TAF with Potential Concomitant Antiretroviral Drugs..........29
Table 3-1.
Recommended F/TAF dose by co-administered third agent: .................................................33
Table 4-1.
Allowable Antiretroviral Agents of Pre-Existing Regimen....................................................36
Table 5-1.
Recommended F/TAF Dose by Co-administered Third Agent ..............................................41
Table 5-2.
Prior and Concomitant Medications.......................................................................................42
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................33
Figure 6-1.
Schema for Management of Virologic Failure .......................................................................62

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3b, Randomized, Double-Blind, Switch Study to Evaluate 
F/TAF in HIV-1 Infected Subjects who are Virologically Suppressed 
on Regimens containing ABC/3TC
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111851
2015-000871-28 
Not Available
Study Centers 
Planned:
Approximately 100 centers in Europe and North America 
Objectives:
The primary objective is:

To evaluate the efficacy of switching ABC/3TC to F/TAF versus 
maintaining ABC/3TC in HIV-1 infected subjects who are 
virologically suppressed on regimens containing ABC/3TC as 
determined by the proportion of subjects with HIV-1 RNA 
< 50 copies/mL at Week 48 
The secondary objectives are:

To evaluate the efficacy, safety and tolerability of two regimens
through Week 48 and Week 96

To evaluate the bone safety of two regimens as determined by the
percentage change from baseline in hip and spine bone mineral
density (BMD) through Week 48 and Week 96
Study Design:
Randomized, double-blind, multicenter, active-controlled study to 
evaluate the safety and efficacy of switching ABC/3TC fixed-dose 
combination (FDC) tablet to F/TAF FDC tablet versus continuing 
ABC/3TC in HIV-1 infected subjects who are virologically 
suppressed (HIV-1 RNA < 50 copies/mL) on a stable regimen 
containing ABC/3TC for 6 consecutive months prior to screening.
All subjects will be randomized, in a blinded fashion, in a 1:1 ratio to 
either switch from ABC/3TC to F/TAF + placebo-to-match ABC/3TC 
or maintain the ABC/3TC + placebo-to-match F/TAF while 
continuing the protocol allowed third agent (as prescribed by the 

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Investigator) in their antiretroviral (ARV) regimen. 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 arms:
Treatment Arm 1: F/TAF + Placebo-to-match ABC/3TC; third 
antiretroviral agent remains the same (n = 250)
Treatment Arm 2: ABC/3TC + Placebo-to-match F/TAF; third  
antiretroviral agent remains the same (n = 250)
Since different antiretroviral third agents require different doses of 
TAF, randomization will be stratified by the third agents: boosted 
protease inhibitors vs. other agents (see below for protocol allowed 
third agents). 
Number of Subjects 
Planned:
Approximately 500 subjects total with approximately 250 subjects 
each in Treatment Arm 1 and Treatment Arm 2.
Target Population:
HIV-1 infected adult subjects who are virologically suppressed 
(HIV-1 RNA < 50 copies/mL) on a stable regimen containing 
ABC/3TC for 6 consecutive months prior to screening.
Duration of 
Treatment:
Subjects will be treated for 96 weeks in the randomized phase. After 
Week 96, subjects will continue to take their blinded study drug and 
attend visits every 12 weeks until treatment assignments have been 
unblinded. After unblinding, in countries where F/TAF FDC is not 
commercially available, subjects will be given the option to receive 
the open-label F/TAF FDC and attend study visits every 12 weeks 
until it becomes commercially available, or until Gilead Sciences 
terminates the study in that country.   
Diagnosis and Main 
Eligibility Criteria:
HIV-1 infected adult subjects who meet the following criteria will be 
given the option to participate in the study:

Currently receiving an antiretroviral regimen containing 
ABC/3TC in combination with one third agent for 6 consecutive 
months prior to screening

Plasma HIV-1 RNA < 50 copies/mL for ≥ 6 months preceding the 
screening visit (measured at least twice using the same assay) and 
not experienced two consecutive HIV-1 RNA measurements
above detectable levels after achieving a confirmed (two 
consecutive) HIV-1 RNA measurement below detectable levels 
on the current regimen in the past year. Plasma HIV-1 RNA 
should be < 50 copies/mL at the screening visit

Estimated glomerular filtration rate 50 mL/min 
(Cockcroft - Gault formula)

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Study Procedures/
Frequency:
After screening, eligible subjects will be randomized to Treatment 
Arm 1 or 2 and treated for 96 weeks. Following the Screening and 
Day 1 visits, subjects will return for study visits at Weeks 4, 8, 12, 
and then every 12 weeks through Unblinding Visit.  
Laboratory analyses (hematology, chemistry, and urinalysis), HIV-1
RNA, CD4+ cell count, and complete or symptom directed physical 
examinations will be performed at the Screening, Day 1, and all 
subsequent study visits. 
For all subjects, dual energy x-ray absorptiometry (DXA) scans will 
be performed prior to study drug administration at Day 1 and every 
24 weeks until Week 96, at Unblinding Visit and at Early Study Drug 
Discontinuation (ESDD), if > 12 weeks since last scan. Scans will 
cover the spine and hip to measure changes in bone mineral density. 
Analyzed DXA scans will be provided to study sites when available.
Blood and urine for selected evaluations of renal tubular function and 
bone turnover will be collected at Day 1, Weeks 4, 12, 24, 48, 72, 96 
and ESDD (if applicable). In addition, blood will be collected and 
stored at Day 1, Weeks 4, 12, 24, 48, 72, and 96 and ESDD (if 
applicable) for possible evaluation of inflammation and immune 
activation, including cystatin-C, IL-6, hs-CRP, d-dimer, sCD14, and 
sCD163. Platelet function evaluations will also be assessed, including 
soluble glycoprotein VI (sGPVI), P-selectin, and soluble CD40 
ligand.
A single PK blood sample will be collected any time pre or post-dose 
at Weeks 8, 12, 24, and 36. At Weeks 4 and 48 the single PK blood 
sample will be collected between 15 minutes and 4 hours post-dose.
A whole blood sample will be collected at Week 4 visit for 
assessment of archived provirus in peripheral blood mononuclear 
cells (PBMCs).
In a subset of patients, platelet function will be assessed at Day 1 
visit, Weeks 4 and 12, and the Early Study Drug Discontinuation 
Visit (if applicable). 
Subjects who complete the study through the Unblinding Visit and do 
not wish to continue to participate will be required to return to the 
clinic 30 days after the completion of the study drug for a 30-Day 
Follow-up Visit.
Adverse events and concomitant medications will be assessed at each 
visit.

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Test Product, Dose, 
and Mode of 
Administration:
F/TAF FDC tablet administered orally once a day (QD). 
Recommended F/TAF dose by co-administered third agent:
Treatment Arm 1
Allowed Third Agents
F/TAF (200/10 mg)
LPV/r, ATV+RTV, ATV+COBI (or ATV/COBI 
FDC),  DRV+RTV, DRV+COBI (or DRV/COBI 
FDC)
F/TAF (200/25 mg)
EFV, RPV, RAL, DTG, MVC, NVP
Reference Therapy, 
Dose, and Mode of 
Administration:
ABC/3TC (600/300 mg) FDC tablet administered orally once a day 
(QD)
Criteria for 
Evaluation:
Safety:
Adverse events, clinical laboratory tests (including selected 
evaluations of renal tubular function, bone turnover, and 
inflammation ), and DXA to evaluate the safety and tolerability of the 
two regimens
Efficacy:
The primary efficacy endpoint is the proportion of subjects with 
HIV-1 RNA < 50 copies/mL at Week 48 as defined by the Food and 
Drug Administration (FDA) snapshot algorithm.
Other secondary endpoints include: 

The proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Weeks 96 as defined by the FDA snapshot algorithm

The percent change from baseline in hip and spine BMD at 
Week 48 and Week 96
Pharmacokinetics:
The PK of individual analytes may be explored.
Statistical Methods:
The primary analysis will consist of a non-inferiority evaluation of 
switching to F/TAF versus maintaining ABC/3TC, with respect to the 
proportion of subjects with HIV-1 RNA less than 50 copies/mL at 
Week 48 (as defined by the FDA snapshot algorithm). It will be 
concluded that F/TAF is non-inferior to the ABC/3TC if the lower 
bound of the two-sided 95% confidence interval of the difference 
between treatment arms (F/TAF – ABC/3TC) in the response rate is 
greater than −10% (i.e. a margin of 10% is applied to non- inferiority  
assessment). The 95% confidence interval will be constructed using 
the normal approximation method based on stratified 
Mantel-Haenszel proportions, where the stratification factor is the 
third agents (boosted protease inhibitors vs. other agents).

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The secondary analysis evaluating switching to F/TAF versus 
maintaining ABC/3TC, with respect to the percent change from 
baseline in hip and spine BMD will be conducted using Analysis of 
Variance (ANOVA), including the third agent stratum as a fixed 
effect.
The adverse events and clinical laboratory data will be summarized 
using descriptive statistics.
Sample Size:
A total of approximately 500 HIV-1 infected subjects, randomized in 
a 1:1 ratio to two arms (250 subjects per arm), achieves at least 90%
power to detect a non-inferiority margin of 10% in Week 48 response 
rate (HIV-1 RNA < 50 copies/mL as defined by the FDA snapshot 
algorithm) difference between the two groups. For sample size and 
power computation, it is assumed that both treatment arms have a 
response rate of 0.87, that a non-inferiority margin is 0.10, 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
3TC
lamivudine 
ABC
abacavir
AE
adverse event
AIDS
Acquired Immune Deficiency Syndrome
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ANOVA
analysis of variance
ARV
antiretroviral
AST
aspartate aminotransferase
ATR
Atripla®; EFV/FTC/TDF
ATV
atazanavir 
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration 
versus time curve
AUClast
area under the plasma concentration-time curve from time 0 to the last 
measurable concentration
AUCtau
area under the plasma concentration-time curve at the end of the dosing 
interval
AV
atrioventricular
BMD
bone mineral density
BUN
blood urea nitrogen
CBC
complete blood count
CK
creatine kinase
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CNS
central nervous system
COBI, /co
cobicistat 
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CSR
clinical study report
CTX
type 1 collagen crosslinked C-telopeptide
CYP
cytochrome P450
DDI
drug-drug interaction
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
DRV
darunavir
DSPH
Drug Safety and Public Health
DTG
dolutegravir
DXA
dual-energy X-ray absorptiometry
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
EFV
efavirenz
EVG
elvitegravir 
E/C/F/TDF
elvitegravir (EVG) 150 mg/cobicistat (COBI) 150 mg/emtricitabine (FTC) 
200 mg/tenofovir disoproxil fumarate (TDF) 300 mg single tablet regimen
E/C/F/TAF
elvitegravir (EVG) 150 mg/cobicistat (COBI) 150 mg/emtricitabine (FTC) 
200 mg/tenofovir alafenamide (TAF) 10 mg single tablet regimen
ESDD
early study drug discontinuation
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
FTC
emtricitabine
F/TAF
emtricitabine/tenofovir alafenamide
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GSI
Gilead Sciences, Inc.
GS-7340  
tenofovir alafenamide, TAF, L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-
9-yl)-1-methylethoxy]methyl]/ phenoxyphosphinyl]-, 1-methylethyl ester
HAART
highly active antiretroviral therapy
HBsAg
hepatitis B virus surface antigen serology
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus serology
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HLGT
high-level group term
HLT
high-level term
HSP
hysterosalpingogram
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IEC
Independent Ethics Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor
IMP
Investigational Medicinal Product
IRB
institutional review board
IUD
intrauterine device
IWRS
interactive web response system
KS
Kaposi’s sarcoma
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
LLT
low-level term
LPV
lopinavir
MedDRA
Medical Dictionary for Regulatory Activities
Mg
milligram
Min
minute
mmHg
millimeters mercury
MVC
maraviroc
NNRTI
non-nucleoside reverse transcriptase inhibitor
N[t]RTI
nucleos(t)ide reverse transcriptase inhibitor
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
NVP
nevirapine
P1NP
procollagen Type 1 N-terminal propeptide
PBMCs
peripheral blood mononuclear cells
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term 
QD
once daily 
RAL
raltegravir
RBC
Red blood cells
RNA
ribonucleic acid
RPV
rilpivirine
RTV, /r
ritonavir
SADR
serious adverse drug reaction
SAE
serious adverse event
SOC
system organ class
SOP
standard operating procedure
STB
Stribild®, EVG/COBI/FTC/TDF (E/C/F/TDF) STR

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SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TDF
tenofovir disoproxil fumarate
TFV
tenofovir
TFV-DP
tenofovir diphosphate (TFVpp)
Tmax
the time (observed time point) of Cmax
UGT
uridine glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
WBC
white blood cells
z
terminal elimination rate constant, estimated by linear regression of the 
terminal elimination phase of the serum, plasma concentration of drug versus 
time curve

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1.
INTRODUCTION
1.1.
Background
HIV-1 infection is a life-threatening and serious disease of major public health significance, with 
approximately 35 million people infected worldwide {27071}. Standard of care for the treatment 
of HIV-1 infection uses combination antiretroviral therapy (ART) to suppress viral replication to 
below detectable limits, increase CD4 cell counts, and stop disease progression. 
The success of potent and well-tolerated ART means that morbidity and mortality in the 
HIV-infected population is increasingly driven by non-AIDS–associated comorbidities. Clinical 
attention has become more focused on optimizing tolerability, long-term safety, and adherence
{29705}.There remains a significant medical need for safe and effective new therapies that take 
into consideration the aging patient population, non-HIV–related comorbidities, virologic 
resistance, and regimen simplification.
For ART-naive HIV-infected patients, treatment guidelines recommend that initial therapy 
consist of 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) and either a nonnucleoside 
reverse transcriptase inhibitor (NNRTI), a boosted protease inhibitor (PI), or an integrase 
strand-transfer inhibitor (INSTI). Virologically suppressed, HIV-infected patients can benefit by 
switching from their current regimen to improve safety or tolerability or to simplify the regimen 
{32519}, {27621}.
Tenofovir (TFV) is a nucleotide analog with limited oral bioavailability that inhibits HIV-1 
reverse transcription. Tenofovir disoproxil fumarate (TDF) is an oral prodrug of TFV. While 
TDF is used broadly in the treatment of HIV-1 infection, nephrotoxicity is an identified risk, and 
reductions in bone mineral density (BMD) have been shown that are larger than those seen with 
other NRTIs {26885}.
TDF in combination with emtricitabine (FTC) forms a guideline-recommended N(t)RTI 
backbone for ART-naive HIV-infected patients that can be combined with different third agents. 
The combination of FTC and TDF is used within several once-daily fixed-dose combinations 
(FDCs) (Truvada® [FTC/TDF], Atripla® [efavirenz/FTC/TDF], Complera® or Eviplera®
[rilpivirine/FTC/TDF], and Stribild® [elvitegravir/cobicistat/FTC/TDF]). Availability of a 
stand-alone NRTI backbone is important when there is a medical need to use a third agent that is 
not part of an FDC (eg, ritonavir-boosted PIs), and particularly to provide a range of treatment 
options in patients with virologic resistance to their third agent but not to the backbone.
Tenofovir alafenamide (TAF) is an investigational oral prodrug of TFV. TAF is more stable in 
plasma than TDF. It provides higher intracellular levels of the active phosphorylated metabolite 
tenofovir diphosphate (TFV-DP), and approximately 90% lower circulating levels of TFV 
relative to TDF. The distinct metabolism of TAF offers the potential for an improved clinical 
profile compared with TDF.

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Gilead Sciences (Gilead) has coformulated TAF (as TAF fumarate) with FTC into an FDC 
tablet. 
1.2.
Emtricitabine/Tenofovir Alafenamide (F/TAF)
F/TAF is a fixed-dose combination (FDC) tablet containing two medications: emtricitabine 
(FTC) and tenofovir alafenamide (TAF).  
The safety of F/TAF FDC is based on two year-long clinical studies (GS-US-292-0104 and 
GS-US-292-0111) in which 866 treatment-naïve subjects received E/C/F/TAF FDC. The 
following adverse drug reactions have been identified for F/TAF: 

Very common (more than or equal to 10%): headache, diarrhea, and nausea

Common (≥ 1% and < 10%): vomiting, abdominal pain, dyspepsia , flatulence, rash, and 
fatigue
Across all Phase 2 and Phase 3 studies in which 2,394 subjects received E/C/F/TAF FDC, eye 
disorders were uncommon, balanced between treatment arms, and most were considered by the 
investigator as unrelated to the study drugs. None were definitive for posterior uveitis, and none 
resulted in permanent discontinuation of study drugs. One subject in Study GS-US-292-0106 had 
an adverse reaction of intermediate uveitis (inflammation in the middle of the eye) that was 
considered related to study drug by the investigator but resolved while the subject continued on 
study drug without interruption.
For further information on F/TAF, refer to the current version of the investigator’s brochure for 
F/TAF.
1.3.
Tenofovir Alafenamide (TAF, GS 7340)
1.3.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-Alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-
1-methylethoxy]methyl]/phenoxyphosphinyl]-, 1-methylethyl ester) is a second generation oral 
prodrug of tenofovir (TFV), a nucleotide analog that inhibits HIV-1 reverse transcription. 
Tenofovir is metabolized intracellularly to the active metabolite, tenofovir diphosphate 
(TFV-DP), a competitive inhibitor of HIV-1 reverse transcriptase (RT) that terminates the 
elongation of the viral DNA chain. In the development of TAF, three forms of the drug substance
have been used in various studies: GS-7340, synonym for GS-7340 as the free base; 
GS-7340-02, synonym for TAF monofumarate (1:1); and GS-7340-03 as the hemifumarate (2:1). 
GS 7340 03, also known as TAF fumarate, is considered comparable based on physical/chemical 
properties to GS-7340-02 that has been used in previous studies and a number of ongoing 
studies. GS-7340-03 was also used in the Phase 2 study GS US 292-0102 and is being used in 
several ongoing Phase 3 studies (for example: GS-US-292-0104 and GS-US-292-0111). 
GS-7340-03 and GS-7340-02 exist as the free base, TAF (GS-7340), in blood and biological 
fluids.

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1.3.2.
Preclinical Pharmacology and Toxicology
1.3.2.1.
Primary Pharmacodynamics
TAF is metabolized to TFV, a nucleotide analog (i.e., a nucleoside monophosphate analog) 
which is not dependent on an intracellular nucleoside kinase activity for the first step in the 
conversion to the active metabolite, TFV diphosphate (TFV-DP). The cellular enzymes 
responsible for TFV metabolism to the active diphosphorylated form are adenylate kinase (AK) 
{13} and nucleotide diphosphate kinase, which are highly active and ubiquitous. AK exists as 
multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most efficiently by 
AK2.
The intracellular metabolism of TAF and TFV are consistent with the 600 fold enhancement in 
anti-HIV activity in cell culture of TAF over TFV. Metabolism of TAF was also studied in 
different human blood lymphocyte subpopulations, CD4+ and CD8+ T cells, NK cells, B cells 
and macrophages/monocytes. TAF is metabolized inside host cells to the active metabolite TFV 
DP. Concentration of the active metabolite TFV-DP was substantial in all cell populations.
1.3.2.2.
Safety Pharmacology
TAF monofumarate (GS-7430-02) has been evaluated to determine potential effects on the 
central nervous system (R990188), renal system (R990186), cardiovascular (D2000006) and 
gastrointestinal systems (R990187). Single doses did not induce pharmacologic effects on the 
central nervous system of the rat (1000 mg/kg), the renal system of the rat (1000 mg/kg), or the 
cardiovascular system of the dog (100 mg/kg). TAF monofumarate (at 1000 mg/kg reduced 
distal transit and increased stomach weights starting 2 hours postdosing with reversibility 
beginning by 6 hours after dosing. The NOEL for gastrointestinal motility was 100 mg/kg. The 
IC50 for the inhibitory effect of TAF fumarate (GS-7340-03) on hERG potassium current was 
estimated to be greater than 10 μM.
1.3.3.
Nonclinical Pharmacokinetics
All nonclinical pharmacokinetic experiments in this section were performed using TAF 
monofumarate (GS-7340-02), and all study data described in this section reflect the dosage of the 
monofumarate. For reference, 100 mg of TAF monofumarate is equivalent to 80 mg of the 
GS-7340 free base (TAF).
Plasma pharmacokinetics of the intact prodrug, TAF, following oral administration of 
GS-7340-02 in dogs and monkeys demonstrated rapid absorption with peak plasma 
concentrations between 0.25 and 0.5 hours. 
Peak TFV plasma concentrations occurred following TAF absorption, with TFV Tmax values 
between 0.25 to 1.7 hours in rats, dogs, and monkeys. TFV plasma concentrations declined with 
a terminal half-life of 11.2 to 16.4 hours in rats (fasted), > 24 hours in dogs (fasted) and 8.1 to 
12.5 hours in rhesus monkeys. 

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The tissue distribution and recovery of [14C] radiolabeled GS-7340-02 was examined in beagle 
dogs. Radioactivity was detected in all tissues except brain, with the majority present in the 
contents of the gastrointestinal tract, liver, kidney, and large intestine. Tissue concentrations 
were the highest in kidney, PBMCs, liver, large intestine, and bile. Significant concentrations of 
TFV related radioactive material were observed in lymph nodes suggesting that TAF may be 
selectively cleaved to tenofovir in the cells of the lymphoreticular system.
The primary route of elimination of tenofovir is renal excretion of unchanged drug based on IV 
studies of tenofovir. Following oral administration of GS-7340-02, approximately 15% of a 
radiolabeled dose is recovered in dog urine in 24 hrs. Tenofovir was the major species present in 
the urine (90%), with about 3.4% of TAF also present. Biliary excretion of tenofovir in dogs and 
fecal elimination of tenofovir in rats and dogs are negligible.
Tenofovir was the only species found in the intestinal contents and feces. In human systems, 
TAF is metabolized by hydrolytic cleavage and, to a lesser extent, by CYP3A4 catalyzed 
oxidation (AD-120-2004). As a result of the limited metabolism of TAF by CYP3A4 inhibition 
or induction of this enzyme should have little consequence on TAF exposure in vivo. TAF has 
limited potential to alter CYP enzyme activity through inhibition and does not inhibit UGT1A1 
function. In addition, TAF is not an activator of either the aryl hydrocarbon receptor (AhR) or 
human pregnane-X-receptor (PXR). These features combined with the relatively low plasma 
exposures of TAF in humans suggest that the potential of TAF to cause or be affected by 
clinically relevant drug-drug interactions is very low.
1.3.4.
Nonclinical Toxicology
TAF monofumarate (GS-7340-02) was evaluated in mice, rats, dogs, and monkeys for treatment 
periods up to 9 months and was negative in genetic toxicology studies.
In chronic studies in rats, bone (atrophy of metaphyseal cancellous bone) and kidneys 
(karyomegaly) were the primary target organs after 26 weeks of treatment. GS-7340-02 also 
appeared to increase biochemical markers of bone turnover and decrease serum 1,25 dihydroxy  
and 25 hydroxyvitamin D3 at doses of 25 mg/kg/day and above.  In chronic studies in dogs after 
9 months of treatment with GS-7340-02, the primary target organs were kidney and bone. This 
chronic toxicity study of TAF in beagle dogs given 2mg/kg/day, 6 mg/kg/day or 12-18 
mg/kg/day for 9 months found non-specific mononuclear cell infiltrates seen on histopathology 
in the lungs, spleen and posterior uvea (eye) of animals in the 12 18 mg/kg group. This group of 
animals experienced generalized debility at the 18 mg/kg/day dose, so the dose was decreased 
after Week 6. The histopathologic changes were felt to be due to the overall condition of the 
animals and not specific TAF-related toxicity. There were no findings in the eyes of dogs treated 
with lower doses (2 mg/kg and 6 mg/kg), and it was concluded that the NOAEL in beagle dogs 
was 2 mg/kg/day.
TAF monofumarate had no discernible electrocardiograph effect at the low dose of 2 mg/kg/day 
and slightly prolong PR intervals at 6 and 12-18 mg/kg/day. Additionally, at Week 39, TAF 
monofumarate appeared to reversibly reduce heart rate with an associated mild QT prolongation. 
At Week 39, decreases in serum T3 were noted for animals receiving 18/12 mg/kg/day but was 

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reversible at the 3-month recovery period. Minor hematological and biochemistry parameters 
changes were observed but remained within normal historical ranges with the following 
exceptions: AST (~ 100% increase) and total bilirubin (~ 40% increase). There were no clear 
treatment-related effects observed in monkeys following 28 days of treatment including no 
changes in mitochondrial function.
The data from the 6-month rat study determined a NOAEL of 25 mg/kg/day (tenofovir 
AUC = 3758 ng·h/mL); the 9-month dog study defined a NOAEL of 2 mg/kg/day (tenofovir 
AUC = 1180 ng·h/mL), and the 28-day nonhuman primate study defined a NOAEL of 
30 mg/kg/day (tenofovir AUC = 5870 ng·h/mL). In conjunction with the nonclinical data with 
TDF and the clinical experience with TDF and TAF, these toxicology studies support studies in 
humans of doses up to 150 mg/day (120 mg free base, the highest anticipated human dose) for 
chronic treatment.
At the time of the rodent toxicity studies, the bioassay could not detect plasma TAF, possibly due 
to instability in the matrix.
Because of the lack of exposure to the prodrug in mice and rats and achievable tenofovir 
exposures less than previously tested in chronic and carcinogenicity studies with TDF, 
carcinogenicity studies in mice and rats with TAF are not required per agreement with the FDA. 
Also, TAF does not need to be evaluated in perinatal-postnatal reproductive toxicology studies 
per agreement with the FDA. Reproductive tissues were examined in repeat-dose toxicology 
studies in the rat, dog, and monkey. There were no clearly treatment-related histologic alterations 
or changes in organ weights in the rat and the dog following chronic daily dosing, or in the 
monkey. 
The TAF fumarate (GS-7340-03) oral rat fertility study is ongoing (Report No. TX-120-2012, 
report in progress). 
1.3.5.
Clinical Trials of Single Agent Tenofovir Alafenamide (TAF, GS-7340) or 
Fixed Dose Combination emtricitabine/tenofovir alafenamide (F/TAF)
A proof-of-concept study, GS-US-120-0104, evaluated monotherapy, with three lower doses of 
TAF or TDF 300 mg, or placebo, administered in a fasted state for 10 days. Potent antiviral 
activity was achieved in treatment-naïve HIV-1 infected patients, with mean (± SD) change from 
baseline in HIV-1 RNA of -0.98 ± 0.46, -1.50 ± 0.41, -1.74 ± 0.19, and  0.81± 0.58 log10 
copies/ml at 8 mg, 25 mg, 40 mg dose of TAF, and TDF 300 mg, respectively. Mean viral load 
declines for both the 25 mg and 40 mg doses were statistically greater than the 8 mg dose. TAF 
exposure (AUC) was best associated with antiviral activity despite its short plasma half-life 
(~ 30 min). TFV AUC were 97%, 87%, and 80% lower at 8 mg, 25 mg, and 40 mg TAF 
compared to TDF administration. When compared to 40 mg and historical 120 mg data, 25 mg 
TAF provides near maximal activity (predicted to be ~ 1.7 to1.8 log10 c/mL). From this PK-PD 
analysis, a target dose of 20 25 mg TAF monotherapy is expected to provide near maximal 
activity and ~ 90% reduction in circulating TFV.

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The drug interaction potential of F/TAF with other antiretroviral agents was evaluated in 
GS-US-311-0101 (EFV, DRV/co, COBI), GS-US-120-0117 (RPV), and GS-US-120-0118 
(ATV/r, LPV/r, DRV/r, and DTG). The effect of third agents on TAF exposures are summarized 
in Table 1-1.
Table 1-1.
GS-US-311-0101, GS-US-120-0117, and GS-US-120-0118: Changes in 
TAF exposures when Coadministered with Third Agents
Coadministered Third Agent
TAF AUC (% change)
(90% CI)
EFV
↓14
(↓28 to ↑2)
DRV/co
↓2
(↓20 to ↑19)
COBI
↑165
(↑129 to ↑207)
RPV
↓4
(↓17 to ↑10)
ATV/r
↑91
(↑55 to ↑135)
LPV/r
↑47
(↑17 to ↑85)
DRV/r
↑6
(↓16 to ↑35)
DTG
↑19
(↓4 to ↑48)
In Study GS-US-311-1386, the effect of food (high-calorie, high-fat meal) on the PK of the TAF 
component of the F/TAF FDC was evaluated. The GLSM ratio of the AUClast of TAF when 
administered with a high-fat meal was 177% (90% CI: 166% to 188%), and the TAF Cmax
GLSM ratio was 84.5% (90% CI: 74.9% to 95.4%). This ~75% increase in TAF plasma 
exposure and ~15% decrease in TAF plasma Cmax when administered with food was 
accompanied by a delay in Tmax (increase from 1.00 hour under fasted conditions to 2.00 hours 
under fed conditions). The exposures of TAF observed under fed or fasted conditions in this 
study are within the range of exposures observed in the E/C/F/TAF clinical development 
program and are commensurate with safe and effective plasma levels of TAF (see investigator 
brochure for further details). Therefore, the changes in TAF exposures when F/TAF is 
administered with food should not result in differences in efficacy and thus are not clinically 
relevant. TAF can be administered without regard for food and these findings can be 
extrapolated to F/TAF (as FTC can be taken without regard to food). 
Dose selection considerations for F/TAF that rely on these analyses are outlined in Table 1-2. 
Further details for the above clinical studies and other clinical studies of TAF or F/TAF 
(e.g. TAF in subjects with renal impairment or hepatic impairment) are provided in the F/TAF 
investigator brochure. 

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1.3.6.
Clinical Trials of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir 
Alafenamide (E/C/F/TAF)
The individual components of F/TAF (ie, FTC and TAF) have been combined with the integrase 
inhibitor EVG and its pharmacoenhancer cobicistat (COBI, C) in the FDC product E/C/F/TAF, 
which has been designed to be a complete treatment regimen for HIV-1 infection. The interim 
data of the 2 clinical studies in ART-naïve patients (GS-US-292-0104 and GS-US-292-0111) and 
1 in virologically suppressed patients (GS-US-292-0111) are summarized below. 
GS-US-292-0104 
This is a randomized, double-blind, multicenter, active-controlled study to evaluate the efficacy 
and safety of E/C/F/TAF FDC vs STB in HIV-infected, ART-naive adult subjects.
Eligible subjects were ART-naive (excluding pre exposure prophylaxis [PREP] or post exposure 
prophylaxis [PEP], as admissible, up to 6 months prior to screening), HIV-infected adults with 
plasma HIV-1 RNA ≥ 1,000 copies/mL, a screening genotype showing sensitivity to EVG, FTC, 
and TDF, and an eGFR calculated using the Cockcroft Gault method ( eGFRCG) ≥ 50 mL/min at 
screening.
Subjects were randomized in a 1:1 ratio to one of the following 2 treatment groups:

Treatment Group 1: E/C/F/TAF FDC once daily + placebo-to-match STB once daily

Treatment Group 2: STB once daily + placebo-to-match E/C/F/TAF FDC once daily
This summary describes the results of the study through a data cutoff performed when all 
randomized subjects had completed the Week 48 visit, or had discontinued study treatment 
before their Week 48 visit:

The Safety Analysis Set and FAS included 867 (99.4%) subjects (E/C/F/TAF: 435 [99.3%] 
subjects, STB: 432 [99.5%] subjects).

For the primary efficacy endpoint analysis (percentage of subjects with HIV-1 RNA 
< 50 copies/mL at Week 48 using the FDA snapshot algorithm) using the FAS, virologic 
success rates were as follows: E/C/F/TAF 93.1%, STB 92.4%; difference in percentages 
(95.002% CI): 1.0% (2.6% to 4.5%). Because the lower bound of the 2-sided 95.002% CI of 
the difference in the response rate (E/C/F/TAF – STB) was greater than the prespecified 12% 
noninferiority margin, E/C/F/TAF was determined to be noninferior to STB. Noninferiority 
was confirmed using the Week 48 PP Analysis Set.

Overall, the steady state plasma exposure of TAF and TFV, and intracellular exposure of 
TFV-DP, were in the range of historical data and concurrent study data from the ongoing 
Phase 3 program. Compared with STB, administration of E/C/F/TAF led to an approximately 
90% reduction in mean systemic TFV AUCtau and a higher mean PBMC TFV-DP AUCtau.

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
The 48-week AE profile of E/C/F/TAF was generally similar to that of STB with 
396 (91.0%) vs 392 (90.7%) subjects reporting any AE, and 36 (8.3%) vs 26 (6.0%) subjects 
reporting any Grade 3 or 4 AE. The most commonly reported AEs (≥10% of subjects in 
either treatment group) were diarrhea, nausea, upper respiratory tract infection, and 
headache. There were no clinically relevant differences in AE incidence between treatment 
groups.

As noninferiority of E/C/F/TAF to STB was established, multiplicity adjustments were 
performed for the 4 key safety endpoints at Week 48 in sequential order using a fallback 
procedure with pre specified 2 sided alpha levels. Based on the adjusted alpha levels, there 
were statistically significant differences favoring E/C/F/TAF over STB at Week 48 for all 
4 safety endpoints: mean percentage changes from baseline in hip BMD (p < 0.001) and 
spine BMD (p < 0.001), mean change from baseline in serum creatinine (p < 0.001), and 
incidence of treatment-emergent proteinuria (p = 0.034). Other findings of note regarding 
bone and renal safety included the following:
— The percentage of subjects with > 3% decrease from baseline to Week 48 in hip or spine 
BMD was lower in the E/C/F/TAF group than in the STB group (19.0% vs 54.7% for hip 
and 25.1% vs 45.4% for spine), with statistically significant differences between groups 
in the categorical distribution of percentage change from baseline to Week 48 in hip or 
spine BMD (p < 0.001).
— Decreases from baseline in median eGFRCG were smaller in the E/C/F/TAF group than in 
the STB group (p < 0.001), and changes from baseline to Week 48 in eGFRCKD-EPI, creatinine 
were consistent with those observed in eGFRCG.
— There were no AEs of proximal renal tubulopathy (including Fanconi Syndrome) or 
laboratory findings consistent with subclinical renal tubulopathy in either treatment 
group.

There were no relevant differences in reported eye findings for the study. No eye disorder 
AEs resulted in discontinuation of study drug. There were no AEs of posterior uveitis during 
the study.

Although laboratory abnormalities were common in both treatment groups, the incidence of 
Grade 3 or 4 abnormalities was balanced between treatment groups. Increases from baseline 
to Week 48 in total cholesterol, LDL, HDL, total cholesterol to HDL ratio, triglycerides, and 
serum glucose were larger in the E/C/F/TAF group than in the STB group (p ≤ 0.032), most 
likely representing a smaller protective TFV effect with E/C/F/TAF.
GS-US-292-0111
This is a randomized, double-blind, multicenter, active-controlled study to evaluate the efficacy 
and safety of E/C/F/TAF FDC vs STB in HIV-infected, ART-naive adult subjects. This study has 
the same study objectives and an identical study design to those of Study GS-US-292-0104, with 
the following exception:

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
While both studies have sites in North America and Europe, Study GS-US-292-0104 
includes additional sites in Asia Pacific while Study GS-US-292-0111 includes additional 
sites in Latin America.
This summary describes the results of the study through a data cutoff performed when all 
randomized subjects had completed the Week 48 visit, or had discontinued study treatment 
before their Week 48 visit:

The Safety Analysis Set and FAS included 866 (99.3%) subjects (E/C/F/TAF: 431 [99.1%] 
subjects, STB: 435 [99.5%] subjects).

For the primary efficacy endpoint analysis (percentage of subjects with HIV-1 RNA 
< 50 copies/mL at Week 48 using the FDA snapshot algorithm) using the FAS, virologic 
success rates were as follows: E/C/F/TAF 91.6%, STB 88.5%; difference in percentages 
(95.002% CI): 3.1% (1.0% to 7.1%). Because the lower bound of the 2-sided 95.002% CI of 
the difference in the response rate (E/C/F/TAF – STB) was greater than the prespecified 12% 
noninferiority margin, E/C/F/TAF was determined to be noninferior to STB. Noninferiority 
was confirmed using the Week 48 PP Analysis Set.

Overall, the 48-week safety profile of E/C/F/TAF was generally similar to that of 
GS-US-292-0104.
GS-US-292-0109 
Study GS-US-292-0109 is a randomized, open-label, multicenter, active-controlled study to 
evaluate the efficacy, safety, and tolerability of switching to E/C/F/TAF from regimens 
containing FTC/TDF in virologically suppressed HIV-infected adult subjects. All subjects were 
drawn from a predefined set of Gilead clinical studies and were virologically suppressed for at 
least 48 weeks with one of the following FTC/TDF-based regimens:

STB (Stribild®; EVG/COBI/FTC/TDF)

ATR (Atripla®; efavirenz (EFV)/FTC/TDF)

COBI boosted atazanavir (ATV/co)+FTC/TDF (Truvada®; TVD)

ritonavir boosted atazanavir (ATV/r)+TVD
Subjects enrolled in this study were HIV-infected adults receiving ART regimens for at 
least 6 consecutive months. All subjects were required to have plasma HIV-1 RNA levels at 
undetectable levels for at least 6 consecutive months prior to the screening visit; HIV-1 RNA 
< 50 copies/mL at the screening visit; and an eGFRCG 50 mL/min at screening. Subjects must 
have completed the Week 144 visit in Studies GS-US-236-0102 (US only study), 
GS-US-236-0103, or GS-US-216-0114; must have completed the Week 96 visit in 
Study GS-US-264-0110 (subjects taking the EFV-based regimen only); or must have completed 
the primary endpoint assessment visit in Studies GS-US-236-0104 or GS-US-216-0105.

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Subjects were randomized in a 2:1 ratio to one of the following 2 treatment groups:

Treatment Group 1: Switch to E/C/F/TAF FDC once daily

Treatment Group 2: Stay on preexisting FTC/TDF+3rd Agent regimen (STB, ATR, 
ATV/co+TVD, or ATV/r+TVD)
Randomization was stratified by prior treatment regimen (ie, STB, ATR, ATV/boosted+TVD) at 
screening.
This data cutoff was performed when all subjects randomized by 31 October 2013 had been 
followed through the lower limit of Week 48 analysis window (Week 42, or calendar date 
28 August 2014) or had discontinued study treatment before this time.

The Safety Analysis Set included 1436 (99.5%) subjects (E/C/F/TAF: 959 [99.6%] subjects, 
FTC/TDF+3rd Agent: 477 [99.4%] subjects), and the Week 48 FAS included 1196 (82.9%) 
subjects (E/C/F/TAF: 799 [83.0%] subjects, FTC/TDF+3rd Agent: 397 [82.7%] subjects).

For the primary efficacy endpoint analysis (percentage of subjects with HIV-1 RNA 
< 50 copies/mL at Week 48 using the FDA snapshot algorithm) using the FAS, virologic 
success rates were as follows: E/C/F/TAF 95.6%, FTC/TDF+3rd Agent 92.9%; difference in 
percentages (95% CI): 2.7% (-0.3% to 5.6%). Because the lower bound of the 2-sided 95% 
CI of the difference in the response rate (E/C/F/TAF – FTC/TDF+3rd Agent) was greater 
than the prespecified  12% noninferiority margin, E/C/F/TAF was determined to be 
noninferior to FTC/TDF+3rd Agent.

The incidence and severity of all AEs, and the incidence of SAEs, AEs leading to premature 
study drug discontinuation, and deaths was similar between treatment groups. The incidence
of any study-drug related AE was higher in the E/C/F/TAF group (185 [19.3%] subjects) 
than in the FTC/TDF+3rd Agent group (61 [12.8%] subjects); however, the incidence of 
Grade 2, 3, or 4 study drug-related AEs was similar between treatment groups (E/C/F/TAF: 
46 [4.8%] subjects, FTC/TDF+3rd Agent: 20 [4.2%] subjects).

In this study, 4 key secondary safety endpoints were defined and tested in sequential order 
using a fallback procedure at Week 48. Overall, there were statistically significant 
differences favoring E/C/F/TAF over FTC/TDF+3rd Agent at Week 48 for all 4 key 
secondary safety endpoints: mean percentage changes from baseline in hip BMD (p < 0.001) 
and spine BMD (p < 0.001), mean change from baseline in serum creatinine (p < 0.001), and 
change from baseline in EFV-related symptom assessment composite score (p < 0.001). 
Other findings of note regarding bone and renal safety included the following:
— The percentage of subjects with > 3% increase from baseline to Week 48 in hip or spine 
BMD was greater in the E/C/F/TAF group than in the FTC/TDF+3rd Agent group 
(25.2% vs 8.6% for hip and 33.6% vs13.8% for spine), with statistically significant 
differences between treatment groups in the categorical distribution of percentage change 
from baseline to Week 48 in hip or spine BMD (p < 0.001).

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— Median (Q1, Q3) changes from baseline to Week 48 in eGFRCG in the E/C/F/TAF and 
FTC/TDF+3rd Agent groups were 1.8 (-6.6, 9.7) and -3.7 (-11.1, 3.6) mL/min, 
respectively (p < 0.001), and differences between treatment groups in change from 
baseline to Week 48 in eGFRCKD-EPI, creatinine were consistent with those observed in 
eGFRCG (p < 0.001). The difference between treatment groups in the distribution of 
proteinuria by urinalysis (dipstick) adjusted for baseline status was statistically significant 
at Week 48 (p = 0.004).
— One subject in the FTC/TDF+3rd Agent group had a nonserious AE of acquired Fanconi 
syndrome; the event was considered related to the study drug by the investigator and 
resulted in discontinuation of study drug. Otherwise, there were no AEs of proximal renal 
tubulopathy (including Fanconi Syndrome) or laboratory findings consistent with 
subclinical renal tubulopathy in either treatment group.

There were no relevant differences in eye findings for the study. No eye disorder AEs 
resulted in discontinuation of study drug. There were no AEs of posterior uveitis during the 
study. Among subjects who participated in the ophthalmologic substudy (E/C/F/TAF: 
32 subjects; FTC/TDF+3rd Agent: 15 subjects), only 1 subject (E/C/F/TAF) with available 
postbaseline data had a treatment-emergent abnormality, specifically, the detection of a 
retinal hemorrhage in the left eye. All other subjects had no new abnormalities relative to 
their baseline fundoscopic examination.

The incidence of laboratory abnormalities of any grade was balanced between treatment 
groups for most chemistry, hematology, and urinalysis parameters. Increases from baseline to 
Week 48 in total cholesterol, LDL, HDL, total cholesterol to HDL ratio, and triglycerides 
were larger in the E/C/F/TAF group than in the FTC/TDF+3rd Agent group (p ≤ 0.025), most 
likely representing a decrease in the protective TFV effect.
Further details for the above clinical studies and other clinical studies of E/C/F/TAF 
(e.g. E/C/F/TAF in HIV-infected subjects with renal impairment) are provided in the F/TAF 
investigator brochure.
1.3.7.
Clinical Trials of Darunavir/Cobicistat/Emtricitabine/TAF (D/C/F/TAF)
The individual components of F/TAF (ie, FTC and TAF) have been combined with COBI 
boosted DRV in the FDC product D/C/F/TAF for treatment of HIV-1 infection.
Bioavailability studies demonstrated that when administered as the D/C/F/TAF FDC (TAF 
10 mg), TAF exposures were comparable (and corresponding TFV exposures ~ 3 fold higher) to 
TAF 10-mg exposures, which is consistent with a mixed inhibitory/inductive effect of DRV and 
COBI on TAF absorption. TAF at 10-mg exposures was deemed appropriate for further 
evaluation due to the high antiviral activity of TAF at the 8-mg dose, similar to that of 
TDF-300 mg as monotherapy and given the potency of this regimen.
A randomized, active-controlled Phase 2 Study GS-US-299-0102 compared D/C/F/TAF versus 
DRV+COBI+FTC/TDF in ART-naive, HIV-infected subjects. 

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Results from the final analysis demonstrated the following:

The proportion of subjects with plasma HIV-1 RNA < 50 copies/mL using the Food and 
Drug Administration (FDA) snapshot algorithm was similar between treatment groups at 
Week 24 (primary efficacy endpoint) (74.8% in the D/C/F/TAF group and 74.0% in the 
DRV+COBI+TVD group), but numerically lower in the D/C/F/TAF group at Week 48 
(76.7% in the D/C/F/TAF group and 84.0% in the DRV+COBI+TVD group).

At Week 48, the difference in rates of virologic success between treatment groups was 
primarily due to a difference in the numbers of subjects who discontinued study drug due to 
other reasons and had the last available HIV-1 RNA ≥50 copies/mL (D/C/F/TAF: 8.7%; 
DRV+COBI+TVD: 4.0%) or < 50 copies/mL (D/C/F/TAF: 6.8%; DRV+COBI+TVD: 
2.0%). 

Importantly, D/C/F/TAF demonstrated a potential benefit over DRV+COBI+FTC/TDF in 
terms of renal and bone safety: smaller median decreases in eGFRCG (mL/min) (at Week 48, 
D/C/F/TAF -2.9 vs DRV+COBI+FTC/TDF -10.6 [p = 0.017]) and smaller mean percentage 
decreases in BMD (at Week 48, spine D/C/F/TAF -1.57% vs DRV+COBI+FTC/TDF -3.62% 
[p = 0.003], hip -0.84% vs -3.82% [p < 0.001]). These mean percentage changes from 
baseline to Week 48 in spine and hip BMD with D/C/F/TAF are both lower than all 
published studies of Week 48 BMD data in ART-naive subjects receiving an 
NRTI-containing ART regimen {25124}, {25126}, {16658}, {21057}. 

Treatment with D/C/F/TAF or DRV+COBI+TVD was generally well tolerated during this 
study. No unexpected AEs were associated with the use of D/C/F/TAF through 48 weeks of 
treatment. Most treatment-emergent AEs were assessed as Grade 1 or Grade 2 in severity. 
The incidence of Grade 3 AEs was comparable between the 2 groups (D/C/F/TAF 6.8%, 
DRV+COBI+TVD 8.0%). No Grade 4 AEs were reported during the study. Similar 
percentages of subjects in each treatment group had SAEs (D/C/F/TAF 4.9% vs. 
DRV+COBI+TVD 4.0%), most of which were unrelated to study drug.
1.4.
Emtricitabine (FTC, Emtriva®)
Further information regarding Emtrivais available in the current investigator’s brochure and 
local label; an overview is provided below.
1.4.1.
General Information
Emtricitabine (5-fluoro-1-[(2R, 5S)-2-(hydroxymethyl)-[1, 3]-oxathiolan-5-yl] cytosine, FTC) is 
a NRTI that has demonstrated potent and selective inhibition of the HIV. In HIV infected adults, 
FTC is administered as a 200 mg QD dose concurrently with other ARVdrugs. The 200 mg FTC 
capsule formulation was approved by the US Food and Drug Administration (FDA) for 
marketing on 2 July 2003 and is available under the name Emtriva®. In the European Union 
(EU), marketing authorization was granted for both the 200 mg Emtriva® capsule formulation 
and a 10 mg/mL Emtriva® oral Solution formulation on 24 October 2003, with indications for the 
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pediatric patients. In pediatric patients, the recommended dose of Emtriva® is 6 mg/kg QD, up to 
a maximum of 200 mg QD when administered using the capsule formulation (for children 
weighing > 33 kg) or up to a maximum of 240 mg when administered using the oral solution 
formulation.
1.5.
Information about Fixed Dose Combination of Abacavir/Lamivudine 
(ABC/3TC, Epzicom, Kivexa)
Epzicomor Kivexais the brand name for the fixed dose combination of abacavir 
300 mg/lamivudine 600 mg (ABC/3TC). Epzicomor Kivexais recommended for use once 
daily in adults. 
Please refer to the latest version of the SmPC and/or Prescribing Information for Epzicomor 
Kivexafor additional information.
1.6.
Rationale for This Study
Gilead is developing the fixed-dose combination (FDC) product emtricitabine/tenofovir
alafenamide (F/TAF) for the treatment of HIV-1 infection in combination with other 
antiretroviral agents. TAF, one component of F/TAF is an improved prodrug for tenofovir, and 
for clinicians, F/TAF can provide flexibility in constructing an effective antiretroviral regimen 
for patients.
The Phase 1 study (GS-US-120-0104) demonstrated that TAF has an improved pharmacokinetic
profile relative to TDF (longer plasma half-life, lower plasma TFV exposure, and higher
intracellular TFV-DP exposure) with greater antiviral activity at 25 mg dose.
As a nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) backbone, F/TAF is being 
evaluated as part of E/C/F/TAF FDC (150/150/200/10 mg) in several Phase 3 studies across 
broad patient populations. The interim data from these studies demonstrated potent efficacy of 
E/C/F/TAF with improved renal and bone safety profile relative to STB in ART-naive patients 
(GS-US-292-0104 and GS-US-292-0111) and to TDF-containing regimens (including 
E/C/F/TDF) in virologically suppressed patients (GS-US-292-0109). In addition, the efficacy and 
safety of F/TAF FDC (200/10 and 200/25 mg) is being evaluated in Study GS-US-311-1089, an 
ongoing, Phase 3, randomized, double-blind study in HIV-infected subjects who are virologically 
suppressed on regimens containing FTC/TDF. 
As ABC/3TC is another N[t]RTIs backbone for the treatment of HIV-1 infection in combination 
with other antiretroviral agents, it is of interest to conduct a randomized controlled study in 
patients who are virologically suppressed on a ABC/3TC containing regimen that compares 
efficacy and safety between patients who switch to F/TAF vs. those who maintain ABC/3TC 
while continuing the same third agent.

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1.7.
Rationale for Dose Selection
The 200 mg dose of FTC represents the marketed dose for this agent that is currently available as 
single agent capsules (Emtriva) and as a component of a number of fixed-dose combination 
tablets, including: Truvada, Atripla, Complera/Eviplera, and Stribild.
The recommended dose of F/TAF (200/10 mg or 200/25 mg) per third ARV agent is based on 
ensuring that patients have a TAF systemic exposure that is comparable to the TAF 25 mg
exposure, the common reference exposure for which an extensive E/C/F/TAF safety and efficacy 
database exists.
The different TAF dose (10 or 25 mg) is generally based on whether or not the coadministered 
third agent has any clinically relevant effect on TAF (eg, via inhibition of intestinal Pgp, termed 
as “boosting” for simplicity).
Specifically, F/TAF (200/10 mg) will be used with third agents that substantially increase TAF 
exposure (ATV/r, LPV/r), and F/TAF (200/25 mg) will be used with third agents that do not 
have clinically relevant effect on TAF exposure (EFV, RPV, DTG). Although DRV/r did not 
demonstrate any clinically relevant “boosting” effect on TAF, clinical data from a Phase 2, 
randomized, double-blind, active-controlled study evaluating efficacy and safety of a regimen 
containing D/C/F/TAF compared with DRV+COBI+FTC/TDF in HIV-1 infected, ART-naïve 
subjects provides support for using F/TAF 200/10 mg with DRV/r. In that study, D/C/F/TAF was 
noninferior to DRV+COBI+TVD when administered for 24 weeks using the FDA snapshot
algorithm with HIV-1 RNA cutoff at 50 copies/mL, in accordance with the primary objective of 
this study. 
Based on these considerations, the proposed dose of F/TAF FDC tablets per third ARV agent is 
listed in Table 1-2, which presents the TAF-equivalent dose achieved based on systemic TAF 
exposure resulting from administration of the recommended F/TAF dose with each 
coadministered third ARV agent.

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Table 1-2.
Dose Recommendations for F/TAF with Potential Concomitant 
Antiretroviral Drugs
ARV Drug
Recommended F/TAF Dose
(mg)
TAF-Equivalent Dosea
(mg)
EFV
12b
RPV
24
DTGc
200/25
17b/30
RAL
—d
MVC
—d
NVP
—d
ATV+COBI
—e
ATV+RTV
19
DRV+COBI
200/10
11
DRV+RTV
11
LPV/r
15
TAF-Equivalent Dose calculated based on percentage change in TAF AUC with/without coadministered drug.
a
Expected exposure in fed state unless otherwise noted.
b
Expected exposure in fasted state.
c
Because DTG may be administered without regard to food, expected exposures are provided for both the fed and fasted 
states.
d
No DDI study performed. Dosing recommendation based on the nonclinical profiles of TAF and the specified ARV.
e
No DDI study performed. Dosing recommendation extrapolated based on nonclinical information and the DDI study 
between TAF and ATV+RTV.
While no clinical drug-drug interaction studies of TAF were conducted with raltegravir (RAL), 
MVC and NVP, no clinically relevant drug-drug interaction is expected based upon nonclinical 
and clinical information.
Taken together, F/TAF (200/10 or 200/25 mg) in combination with the appropriate third agent 
can achieve plasma TAF exposure that is associated with potent antiviral activity and with lower 
plasma TFV exposure than that seen with TDF 300 mg.
The complete list of allowed third agents and the corresponding F/TAF dose are presented in 
Table 3-1. 
Lastly, the food effect on TAF was evaluated when administered as part of E/C/F/TAF FDC 
(GS-US-292-0110) and as F/TAF FDC (GS-US-311-1386). Under fed conditions (high fat 
meal), TAF exposures increased by 17% with E/C/F/TAF FDC and 77% with F/TAF FDC 
However, these TAF exposures observed under fed or fasted conditions in this study are within 
the range of exposures observed in the E/C/F/TAF FDC clinical development program and are 
commensurate with safe and effective TAF exposure. Therefore, these data support the 
administration of F/TAF without regard to food.

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1.8.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objective of this study is:

To evaluate the efficacy of switching ABC/3TC to F/TAF versus maintaining ABC/3TC in 
HIV-1 infected subjects who are virologically suppressed on regimens containing ABC/3TC 
as determined by the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 
The secondary objectives of this study are:

To evaluate the efficacy, safety and tolerability of two regimens through Week 48 and 
Week 96

To evaluate the bone safety of two regimens as determined by the percentage change from 
baseline in hip and spine bone mineral density (BMD) through Week 48 and Week 96

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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 as defined by the 
FDA snapshot algorithm
The secondary endpoints of this study are:

The proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 96 as defined by the 
FDA snapshot algorithm

The percent change from baseline in hip and spine BMD at Week 48 and Week 96
3.2.
Study Design
This protocol describes a randomized, double-blind, multicenter, active-controlled study to 
evaluate the safety and efficacy of switching ABC/3TC to F/TAF fixed-dose combination (FDC) 
tablet versus continuing ABC/3TC in HIV-1 infected subjects who are virologically suppressed 
(HIV-1 RNA < 50 copies/mL) on a stable regimen containing ABC/3TC for 6 consecutive 
months prior to screening.
All subjects will be randomized, in a blinded fashion, in a 1:1 ratio to either switch from 
ABC/3TC to F/TAF + placebo-to-match ABC/3TC or maintain the ABC/3TC + placebo-to-
match F/TAF while continuing the protocol allowed third agent (as prescribed by the 
Investigator) in their antiretroviral (ARV) regimen.
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 arms:
Treatment Arm 1: F/TAF + Placebo-to-match ABC/3TC; third antiretroviral agent remains the 
same (n = 250)
Treatment Arm 2: ABC/3TC + Placebo-to-match F/TAF; third antiretroviral agent remains the 
same (n = 250)
Since different antiretroviral third agents require different doses of TAF, randomization will be 
stratified by the third agents: boosted protease inhibitors vs. other agents. 

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Table 3-1. 
Recommended F/TAF dose by co-administered third agent: 
TI·eatment Arm 1 
Allowed Third Agents 
FffAF (200/10 mg) 
LPV/r, ATV+RTV, ATV+COBI (or ATVICOBI FDC), DRV+RTV, 
DRV+COBI (or DRV/COBI FDC) 
FffAF (200/25 mg) 
EFV, RPV, RAL, DTG, MVC, NVP 
Figure 3-1. 
Study Schema 
Day 1• 
Week48 
(Primary Endpoint) 
Screening: 
~ 30 days 
prior to 
Day 1 
Treatment Arm 1: 
F/TAF +placebo-to-match ABC/3TC (n= 250) 
Treatment Arm 2: 
ABC/3TC + Placebo-to-match FffAF (n= 250) 
Week 
96 
Unblinding 
V .. b,c 
lSlt 
30 
Day 
a 
Following the Day 1 visit, subjects will rettu11 for study visits at Weeks 4, 8, 12, and then evety 12 weeks tlu·ough Week 96. 
b 
Aftet· Unblinding visit, in cotmtries whet·e FIT AF FDC is not conuuercially available, subjeds (except in certain cotmtries 
such as UK) will be given the option to receive the open-label F/TAF FDC and attend study visits every 12 weeks tultil it 
bec.omes conuuercially available, or until Gilead Sciences temlinates the study in that countJ.y. Subjects who complete the 
study tlu·ough Unblinding and do not wish to continue to participate (including all subjects in certain cotmtries such as UK) 
will be required to rettu11 to tl1e clinic 30 days after the completion of the study drug for a 30-Day follow-up visit. 
c 
Subjects who have discontinued stt1dy drug before Week 96 will not be eligible for the extension phase of the study; these 
subjects will be asked to continue attending the scheduled stt1dy visits tlu-ough Unblinding. 
3.4. 
Duration of Treatment 
The treatment dmation is 96 weeks. After screening, eligible subjects will be randomized to 
Treatment Aim 1 or 2 and treated for 96 weeks. Following the Screening and Day 1 visits, 
subjects will retum for study visits at Weeks 4, 8, 12, and then eve1y 12 weeks through Week 96. 
Subjects will be treated for 96 weeks in the randomized phase. After Week 96, subjects will 
continue to take their blinded study drug and attend visits eve1y 12 weeks until treatment 
assignments have been unblinded. After unblinding, in countries where F/TAF FDC is not 
commercially available, subjects (except in ce1tain countries such as UK) will be given the 
option to receive the open-label F/TAF FDC and attend study visits every 12 weeks until it 
becomes commercially available, or until Gilead Sciences te1minates the study in that country. 
Subjects who complete the study through Unblinding Visit and do not wish to receive open-label 
FITAF FDC will be required to retmn to the clinic for a 30-Day Follow Up visit. 
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After the Unblinding Visit, subjects in certain countries (eg UK) per requirement must stop 
taking study drug and complete a 30-Day Follow Up visit.
3.5.
Biomarker Testing
3.5.1.
Samples for Optional Future Research
In addition to the study-specific informed consent to be signed by each subject participating in 
the study, a separate, specific signature will be required to document a subject's agreement to 
provide additional samples or to allow the use of the remainder of their already collected PK 
specimens for optional future research, once approved by local authorities as applicable 
according to specific local regulations. 
The specimens collected for optional future research will be used to increase our knowledge and 
understanding of the biology of the study disease and related diseases and to study the 
association of biomarkers with disease pathogenesis, progression and/or treatment outcomes, 
including efficacy, adverse events, and the processes of drug absorption and disposition. These 
specimens may be used also to develop biomarker or diagnostic assays and establish the 
performance characteristics of these assays. The collection and analysis of optional future 
research specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for patients in 
the future.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 500 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. Currently receiving antiretroviral regimen containing ABC/3TC FDC in combination with 
one third agent for 6 consecutive months prior to Screening. Refer to Table 4-1  for 
allowed third agents of the pre-existing regimen; ABC/3TC/DTG (Triumeq® FDC) is not an 
allowed pre-existing regimen
4. Plasma HIV-1 RNA levels < 50 copies/mL for ≥ 6 months preceding the screening visit 
(measured at least twice using the same assay) and not experienced two consecutive HIV-1 
RNA above detectable levels after achieving a confirmed (two consecutive) HIV-1 RNA 
below detectable levels on the current regimen in the past year
To determine virologic suppression in the preceding 6 months prior to screening, the lower 
limit of quantification (LLOQ) by the local HIV-1 RNA assay may be used, only if its LLOQ 
is greater than 50 copies/mL (e.g. LLOQ of 75 copies/mL)
5. Plasma HIV-1 RNA levels < 50 copies/mL at Screening Visit
6. Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
7. Estimated GFR ≥ 50 mL/min according to the Cockcroft Gault formula for creatinine 
clearance {2202}:
Male:
(140 – age in years) (wt in kg) CLcr (mL/min)
72 (serum creatinine in mg/dL)
Female:
(140 – age in years) (wt in kg) 0.85 CLcr (mL/min)
72 (serum creatinine in mg/dL)
8. Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)

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9. Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin (subjects with documented Gilbert’s 
syndrome or with atazanavir-associated hyperbilirubinemia may have total bilirubin up to 5 x 
ULN)
10. Adequate hematologic function (absolute neutrophil count ≥1,000/mm3; platelets 
≥50,000/mm3; hemoglobin ≥ 8.5 g/dL)
11. Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if 
serum lipase is ≤5 × ULN)
12. A female subject is eligible to enter the study if it is confirmed that she is:
a.
Not pregnant or nursing
b. Of non-childbearing potential (e.g., women who have had a hysterectomy, have had both 
ovaries removed or medically documented ovarian failure, or are postmenopausal women 
> 54 years of age with cessation (for 12 months) of previously occurring menses).
c.
Of childbearing potential (as defined in Appendix 5) and agrees to utilize highly effective 
contraception methods or be non-heterosexually active or practice sexual abstinence 
(as defined in Appendix 5) from screening throughout the duration of study treatment and 
for 30 days following discontinuation of study drugs. 
d. Female subjects who utilize hormonal contraceptive as one of their birth control methods 
must have used the same method for at least three months prior to study dosing.
13. Male subjects must agree to utilize a highly effective method of contraception (as defined in 
Appendix 5) during heterosexual intercourse or be non-heterosexually active, or practice 
sexual abstinence from first dose throughout the study period and for 30 days following the 
last study drug dose.
a.
Male subjects must agree to refrain from sperm donation from first dose until at least 
30 days after the last study drug dose.
Table 4-1.
Allowable Antiretroviral Agents of Pre-Existing Regimen
Antiretroviral Class
Agents
Boosted PI
LPV/r, ATV+RTV, ATV+COBI (or ATV/COBI FDC),  
DRV+RTV, DRV+COBI (or DRV/COBI FDC)
NNRTI
EFVa, RPVa, NVP
INSTI
RAL, DTGa
CCR5 inhibitor
MVC
a
DTG is allowed only when administered as an individual agent, but not as part of single tablet regimen (i.e. ABC/3TC/DTG)
b
Change of pharmacoenhancer between RTV and COBI in itself, including change from PI+RTV to PI/COBI, is not 
considered as change of regimen

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4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. A new AIDS-defining condition diagnosed within the 30 days prior to screening 
(except CD4 cell count and/or percentage criteria) (refer to Appendix 6)
2. Hepatitis B surface antigen (HBsAg) positive
3. Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)
4. Subjects receiving ongoing treatment with bisphosphonate to treat bone disease 
(e.g. osteoporosis)
5. Females who are breastfeeding
6. Positive serum pregnancy test 
7. Have an implanted defibrillator or pacemaker
8. Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
9. A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy 
other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive 
cutaneous squamous carcinoma. Subjects with cutaneous KS are eligible, but must not have 
received any systemic therapy for KS within 30 days of Day 1 Visit and must not be 
anticipated to require systemic therapy during the study
10. Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1 Visit
11. Any other clinical condition or prior therapy that, in the opinion of the Investigator, would 
make the subject unsuitable for the study or unable to comply with dosing requirements
12. Participation in any other clinical trial (including observational trials) without prior approval 
from the sponsor is prohibited while participating in this trial
13. Medications excluded due to the potential for interaction with FTC, TAF, ABC or 3TC 
(Table 5-2). Administration of any Prohibited Medication (Table 5-2) must be discontinued 
at least 30 days prior to the Day 1 visit and for the duration of the study. Use of Medications 
to Be Used With Caution (Table 5-2) are allowed and are at the discretion of the Principal 
Investigator.

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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 visit cannot occur until subject eligibility has been confirmed. 
Once eligibility has been confirmed, each subject will be assigned a unique subject number using 
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 7 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 Arm 1 or Treatment Arm 2. 
Randomization will be stratified by the third agents (boosted protease inhibitors vs. any other 
protocol allowed third agents) in a subject’s existing regimen.
Treatment Arm 1: F/TAF + Placebo-to-match ABC/3TC; the third ARV agent (as prescribed 
by the Investigator) of the subjects’ regimen should remain the same during the subjects’ 
participation in the study (n = 250)
Treatment Arm 2: ABC/3TC + Placebo-to-match F/TAF; the third ARV agent (as prescribed 
by the Investigator) of the subjects’ regimen should remain the same during the subjects’ 
participation in the study (n = 250)
IWRS will assign blinded study drug bottle numbers at each study visit until the Unblinding 
Visit. Study drug will be dispensed to the subject in a blinded fashion. All Day 1 visit tests and 
procedures must be completed prior to the administration of the first dose of the study 
drug. Initiation of treatment with the study drug must take place within 24 hours after the Day 1 
visit. 
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS 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. 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.

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Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling
5.2.1.
Formulation
5.2.1.1.
Emtricitabine/Tenofovir Alafenamide (F/TAF) Tablets and matching placebo
For subjects randomized to Treatment Arm 1, F/TAF and placebo-to-match F/TAF tablets will 
be provided by the Sponsor. Emtricitabine /Tenofovir Alafenamide 200/25 mg tablets are 
rectangular-shaped, film-coated blue tablets and are debossed with "GSI" on one side of the 
tablet and "225" on the other side of the tablet. The F/TAF tablet cores contain 200 mg of 
emtricitabine and 25 mg of tenofovir alafenamide. In addition to the active ingredients, the 
F/TAF tablets contain croscarmellose sodium, magnesium stearate, and microcrystalline 
cellulose. The tablet cores are film-coated with Blue #2/indigo carmine aluminum lake, 
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Emtricitabine /Tenofovir Alafenamide 200/10 mg tablets are rectangular-shaped, film-coated 
gray tablets and are debossed with "GSI" on one side of the tablet and "210" on the other side of 
the tablet. The F/TAF tablet cores contain 200 mg of emtricitabine and 10 mg of tenofovir 
alafenamide. In addition to the active ingredients, the F/TAF tablets contain croscarmellose 
sodium, magnesium stearate, and microcrystalline cellulose. The tablet cores are film-coated 
with iron oxide black, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Placebo-to-match F/TAF 200/25 mg tablets are rectangular-shaped, film-coated blue tablets and 
are debossed with "GSI" on one side of the tablet and "225" on the other side of the tablet. 
Placebo tablets contain croscarmellose sodium, magnesium stearate, lactose and microcrystalline 
cellulose. The tablet cores are film-coated with Blue #2/indigo carmine aluminum lake, 
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Placebo-to-match F/TAF 200/10 mg tablets are rectangular-shaped, film-coated gray tablets and 
are debossed with "GSI" on one side of the tablet and "210" on the other side of the tablet. 
Placebo tablets contain croscarmellose sodium, magnesium stearate, lactose and microcrystalline 
cellulose. The tablet cores are film-coated with iron oxide black, polyethylene glycol, polyvinyl 
alcohol, talc, and titanium dioxide.

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5.2.1.2.
Abacavir/Lamivudine (ABC/3TC) and matching placebo
Abacavir/Lamivudine (ABC/3TC) tablets are commercially sourced. Information regarding the 
formulation of commercially available Abacavir/Lamivudine (ABC/3TC) can be found in the 
current prescribing information. 
Placebo-to-match Abacavir/Lamivudine (ABC/3TC) tablets are capsule-shaped, film-coated 
orange tablets and are debossed with “GS FC2” on one side of the tablet and plain faced on the 
other side of the tablet. Placebo tablets are identical in appearance to the active tablets. Placebo 
tablets contain croscarmellose sodium, magnesium stearate, lactose and microcrystalline 
cellulose. The tablet cores are film-coated with Yellow #6/sunset yellow FCF aluminum lake,
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
5.2.2.
Packaging and Labeling
Emtricitabine/Tenofovir Alafenamide (F/TAF) tablets and placebo-to-match F/TAF tablets are 
packaged in a white high density polyethylene (HDPE) bottle. 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 fitted with an induction-sealed and 
aluminum-faced liner.
Abacavir/Lamivudine (ABC/3TC) tablets and placebo-to-match ABC/3TC tablets are packaged 
in a white high density polyethylene (HDPE) bottle. Each bottle contains 30 tablets. Each bottle 
is enclosed with a white, continuous thread, child-resistant polypropylene screw cap fitted with 
an induction-sealed and aluminum-faced liner.To ensure stability of the tablets and proper 
product identification, the drug should not be stored in a container other than the container in 
which it is supplied.
Study drug(s) bottles to be distributed to centers in the US and EU shall be labeled to meet all 
applicable requirements of the US Food and Drug Administration (FDA), EU Guideline to Good 
Manufacturing Practice- Annex 13 (Investigational Medicinal Products), and/or other local 
regulations as applicable.
5.2.3.
Storage and Handling
Emtricitabine /Tenofovir Alafenamide  and the placebo-to-match Emtricitabine/Tenofovir 
Alafenamide tablets should be stored at a controlled room temperature of 25 °C (77 °F); 
excursions are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are 
specified on the label. 
Abacavir/Lamivudine (ABC/3TC) and the placebo-to-match Abacavir/Lamivudine (ABC/3TC) 
tablets should be stored at a controlled room temperature of 25 °C (77 °F); excursions are 
permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are specified on the 
label.

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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 of the tablets and proper product identification, the drug product should 
not be stored in a container other than the container in which it is supplied. Measures that 
minimize drug contact with the body should always be considered during handling, preparation, 
and disposal procedures.
The third ARV agent of the subjects’ pre-existing regimen should be stored according to the 
approved product labeling for each particular component.
5.3.
Dosage and Administration
F/TAF, placebo-to-match F/TAF, ABC/3TC and placebo-to-match ABC/3TC fixed-dose 
combination tablets will be provided by Gilead Sciences. The third antiretroviral agent of the 
subjects’ pre-existing regimen will be prescribed by the Investigator, and the subject is 
responsible for obtaining the third ARV agent prior to Day 1 visit. As both F/TAF and ABC/3TC 
can be taken without regard to food, subjects should be instructed to comply with the food or 
fasting requirements of the third agent, if any.
Treatment Arm 1: F/TAF FDC tablet (200/10 mg or 200/25 mg) + placebo-to-match ABC/3TC
FDC tablet in combination with a third antiretroviral agent administered orally once daily (QD) 
(at approximately the same time every day) with the recommended dose by co-administered third 
agent as summarized below.
Table 5-1.
Recommended F/TAF Dose by Co-administered Third Agent
Treatment Arm 1
Allowed Third Agents
F/TAF (200/10 mg)
LPV/r, ATV+RTV, ATV+COBI (or ATV/COBI FDC),  
DRV+RTV, DRV+COBI (or DRV/COBI FDC)
F/TAF (200/25 mg)
EFV, RPV, RAL, DTG, MVC, NVP
Treatment Arm 2: Current antiretroviral drug regimen containing ABC/3TC + placebo-to-match 
F/TAF FDC tablet in combination with a third antiretroviral agent administered orally, QD (at 
approximately the same time each day)
Subjects will be instructed to bring all study medication in the original container at each clinic 
visit for drug accountability (unless otherwise specified in the study procedures sections of this 
protocol). 
Antiretroviral agents that are not specified in Table 5-1 will be prohibited. 

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5.4.
Prior and Concomitant Medications
The use of medications for the treatment of HIV, other than the study treatment (i.e. F/TAF or 
ABC/3TC) and baseline third agent 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 due to potential drug-drug interactions with the study drugs.
Table 5-2.
Prior and Concomitant Medications
Medications to be avoided and medications to be used with caution due to the potential for 
drug-drug interaction with FTC, TAF, ABC or 3TC are as follows:
Medication Class
Prohibited Medications
Medications to be used with caution
Antiarrhythmics
amiodarone, quinidine: May increase 
concentration of TAF and/or TFV
Antibacterials
Trimethoprim/Sulfamethoxazole
(160/800 mg):
TMP/SMX increases the exposure of 
lamivudine.
Anticonvulsants
carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin
Antifungals
itraconazole, ketoconazole, voriconazole:
may increase concentration of TAF and/or
TFV
Antimycobacterials
rifabutin, rifampin, rifapentine
clarithromycin: may increase concentration
of TAF and/or TFV
Bisphosphonate
Any agent in this class (for example:
alendronate, ibandronate, risedronate,
zoledronate, pamidronate, teriparatide)
Calcium channel 
blockers
diltiazem, felodipine, verapamil: may
increase concentration of TAF and/or TFV
Digoxin
Concomitant use may result in an increased
or decreased digoxin concentration; use with 
caution and with appropriate monitoring of 
serum digoxin concentrations.
Ethanol
Ethanol:
Ethanol decreases the elimination of abacavir 
causing an increase in overall ABC exposure
Herbal/Natural 
Supplements
St. John’s wort (Hypericum perforatum), 
Echinacea, Milk thistle (i.e. silymarin), 
Chinese herb sho-saiko-to (or Xiao-Shai-Hu-
Tang)

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Medication Class
Prohibited Medications
Medications to be used with caution
Methadone
Methadone:
Coadministration of ABC with methadone 
increases oral methadone clearance
This alteration will not result in a methadone 
dose modification in the majority of patients; 
however, an increased methadone dose may 
be required in a small number of patients.
Other
probenecid
Should subjects have a need to initiate treatment with any excluded concomitant medication, the 
Gilead Medical Monitor must be consulted prior to initiation of the new medication. In instances 
where an excluded medication is initiated prior to discussion with the Sponsor, the Investigator 
must notify Gilead Sciences as soon as he/she is aware of the use of the excluded medication.
Additionally, Investigators should refer to the product/package inserts of the other antiretroviral 
medications for contraindications related to their use.
5.5.
Changes in Antiretroviral Therapy
Prior to the Unblinding Visit and during the open-label extension phase of the study, subjects and 
Investigators are not permitted from changing the third agent.
5.6.
Dispensing and Accountability of Investigational Medicinal Product (IMP)
The Investigator is responsible for ensuring adequate accountability of all used and unused IMP.
The Investigator [or designee (e.g., study center pharmacist)] will acknowledge receipt of the 
study drugs from Gilead Sciences (or designee) after reviewing the shipment’s content and 
condition. The Investigator (or designee) will be responsible for maintaining an accurate 
inventory (on IMP accountability records) of the dates and quantities of all study drugs received, 
dispensed, and returned. Each dose of the study drug administered at the study center will be 
administered by qualified study center personnel. All doses of study drug administered to 
subjects in the clinic under the supervision of staff will be accurately recorded on the 
Investigational Product Inventory Logs provided by Gilead Sciences (or on equivalent 
documentation maintained by the study center), which indicates the date and quantity of all doses 
of study drug(s) dispensed to individual subjects. The requirements of all applicable Federal and 
State drug dispensing laws will apply to all doses of study drugs dispensed by the Investigator 
(or designee). 
The IMP 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.

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IMP 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.
5.7.
Investigational Medicinal Product Return or Disposal
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. 
Any deviation from protocol procedures should be noted in the subject’s clinical chart and 
appropriate eCRFs. In addition, the Sponsor or Contract Research Organization (CRO) should be 
promptly notified of any protocol deviations.
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 5 for details about randomization and treatment assignment.
6.2.
Pretreatment Visit Assessments
6.2.1.
Screening Visit
Subjects will be screened within 30 days before Day 1 visit to determine eligibility for 
participation in the study. The following will be performed and documented at screening:
6.2.1.1.
Obtain written informed consent
6.2.1.2.
Obtain medical history including history of HIV-1 disease-related events and 
prior medications within 30 days of the Screening visit
6.2.1.3.
Complete physical examination (urogenital/anorectal exams will be performed at 
the discretion of the Investigator)
6.2.1.4.
Vital signs (blood pressure, pulse, respiration rate, and temperature), body weight, 
and height
6.2.1.5.
12-lead ECG performed supine
6.2.1.6.
Urine collection for the following laboratory procedures:
6.2.1.6.1.
Urinalysis and urine chemistry
6.2.1.7.
Blood sample collection for the following laboratory analyses:
6.2.1.7.1.
Serum pregnancy test (females of childbearing potential only). If the test is 
positive, the subject will not be enrolled.
6.2.1.7.2.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN)

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6.2.1.7.3.
Estimated GFR according to the Cockcroft Gault formula for creatinine clearance:
i. Male: (140 – age in years) (wt in kg) = CLcr (mL/min)
72 (serum creatinine in mg/dL)
ii. Female: (140 – age in years) (wt in kg) 0.85 = CLcr (mL/min)
72 (serum creatinine in mg/dL)
6.2.1.7.4.
Hematology profile: complete blood count (CBC) with differential and platelet 
count
6.2.1.7.5.
CD4+ cell count
6.2.1.7.6.
Plasma HIV-1 RNA 
6.2.1.7.7.
Hepatitis B surface antigen (HBsAg) serology
6.2.1.8.
Record any serious adverse events and all adverse events related to protocol 
mandated procedures occurring after signing of the consent form.
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 30 days after screening for the Day 1 assessments.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events electronic case report form 
(eCRF).  All other untoward medical occurrences observed during the screening period, 
including exacerbation or changes in medical history are to be captured on the medical history 
eCRF.  See Section 7 Adverse Events and Toxicity Management for additional details.
6.2.2.
Day 1 Visit
The following evaluations are to be completed at the Day 1 Visit. The subject must complete all 
Day 1 assessments before being dispensed the study drug. Initiation of treatment with the study 
drug must take place within 24 hours after the Day 1 visit.
6.2.2.1.
DXA Scan (spine and hip)
6.2.2.1.1.
The DXA scan will be performed on subjects once eligibility is confirmed and 
prior to study drug administration at the Day 1 Visit.  The scan may be performed 
prior to or on the Day 1 Visit so long as it occurs before dosing
6.2.2.2.
Review of AEs and changes in concomitant medications
6.2.2.3.
Complete physical examination (urogenital/anorectal exams will be performed at 
the discretion of the Investigator)
6.2.2.4.
Vital signs (blood pressure, pulse, respiration rate, and temperature), including 
weight

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6.2.2.5.
Urine collection for the following laboratory procedures:
6.2.2.5.1.
Urinalysis and urine chemistry 
6.2.2.5.2.
Evaluations of renal tubular function (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 these evaluations.
6.2.2.5.3.
Urine pregnancy test (females of childbearing potential only). If the urine 
pregnancy test is positive at Day 1 visit, study drug will not be dispensed. The 
positive result will be confirmed with a serum pregnancy test. If the serum 
pregnancy test is positive, the subject will not be able to participate.
6.2.2.5.4.
Urine sample storage for possible additional clinical testing
6.2.2.6.
Blood sample collection for the following laboratory analyses:
6.2.2.6.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN)
6.2.2.6.2.
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). 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.
6.2.2.6.3.
Estimated GFR, according to the Cockcroft Gault formula for creatinine clearance
6.2.2.6.4.
Hematology profile: CBC with differential and platelet count
6.2.2.6.5.
Plasma HIV-1 RNA 
6.2.2.6.6.
CD4+ cell count
6.2.2.6.7.
Hepatitis C virus antibody (HCVAb) serology. If the antibody test result is 
positive, HCV RNA test will be performed to confirm HCV viremia
6.2.2.6.8.
Plasma sample storage for virology, safety, and/or PK testing 
6.2.2.6.9.
Serum sample storage for possible additional clinical testing (for subjects who 
provide consent)
6.2.2.6.10.
Evaluations of bone turnover (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 draw blood for these evaluations

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6.2.2.6.11.
Evaluations of inflammation, including but not limited to cystatin-C, IL 6, hs 
CRP, d-dimer, sCD14, and sCD163
6.2.2.6.12.
Evaluations of platelet function, including but not limited to soluble glycoprotein 
VI (sGPVI), P-selectin, and soluble CD40 ligand
6.2.2.6.13.
Platelet function for substudy subjects (only at selected sites)
6.2.2.6.14.
Whole blood sample storage for virology analyses
6.2.2.7.
Obtain subject number and randomize the subject via the IWRS. The subject 
number assignment may be performed up to 7 days prior to the in clinic Day 1 
visit provided that all screening procedures have been completed and subject 
eligibility has been confirmed
6.2.2.8.
Study drug dispensation: Investigators must provide a prescription to the subjects 
for the third ARV agent in their pre-existing regimen. The subject is responsible 
for obtaining the third ARV prior to or during the study visit
6.2.2.8.1.
Study drug will be dispensed in a blinded fashion
6.2.2.8.2.
All subjects will take 2 tablets daily, in addition to the third ARV agent
6.2.2.8.3.
Subjects must initiate dosing of study drug within 24 hours after the Day 1 visit
6.2.2.9.
Subjects should also be counseled regarding the importance of adherence and 
taking their study medications in the morning at approximately the same time 
each day
For subjects in Germany, DXA scans will not be performed at any study visit.
6.3.
Treatment Assessments
6.3.1.
Treatment Visits (Weeks 4 – 48)
The following evaluations are to be completed at the end of Weeks 4, 8, 12, 24, 36 and 48 unless 
otherwise specified.
All study visits are to be scheduled relative to the Day 1 visit date. Study visits are to be 
completed within ± 2 days of the 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 36,
unless otherwise specified.  The visit window at Week 48 will be ± 6 weeks of the 
protocol-specified visit date, and this clinical visit window coincides with the Week 48 statistical 
analysis window for HIV RNA.
Regularly scheduled evaluations will be made on all subjects whether or not they continue to 
receive study drug.

F/TAF
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6.3.2.1.
DXA Scans (spine and hip) (Weeks 24 and 48; can be performed ≤10 days 
before study visit)
6.3.2.2.
Review of AEs and changes in concomitant medications
6.3.2.3.
Complete physical examination (Weeks 24 and 48) (urogenital/anorectal exams 
will be performed at the discretion of the Investigator)
6.3.2.4.
Symptom-directed physical examination as needed (Weeks 4, 8, 12, 36)
6.3.2.5.
12-lead ECG performed supine (Week 48 only)
6.3.2.6.
Vital signs (blood pressure, pulse, respiration rate, and temperature), including 
weight
6.3.2.7.
Urine collection for the following laboratory procedures:
6.3.2.7.1.
Urinalysis and urine chemistry 
6.3.2.7.2.
Evaluations of renal tubular function (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 these evaluations. 
(Weeks 4, 12, 24 and 48)
6.3.2.7.3.
Urine pregnancy test (females of childbearing potential only); positive urine 
pregnancy tests will be confirmed with a serum test. If the test is positive, the 
subject will be discontinued.
6.3.2.7.4.
Urine sample storage for possible additional clinical testing
6.3.2.8.
Blood sample collection for the following laboratory analyses:
6.3.2.8.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN). At Weeks 24 and 48, analyses of glucose will be done as part of 
the fasting metabolic assessments and not as part of the chemistry profile. 
6.3.2.8.2.
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). 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 (Weeks 24 and 48 only)

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6.3.2.8.3.
Estimated GFR, according to the Cockcroft Gault formula for creatinine clearance
6.3.2.8.4.
Hematology profile: CBC with differential and platelet count
6.3.2.8.5.
Plasma HIV-1 RNA 
6.3.2.8.6.
CD4+ cell count
6.3.2.8.7.
Plasma sample storage for virology, safety and/or PK testing 
6.3.2.8.8.
Serum sample storage for possible additional clinical testing (for subjects who 
provide consent)
6.3.2.8.9.
Evaluations of bone turnover (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 draw blood for these evaluations. (Weeks 4, 12, 24 and 48)
6.3.2.8.10.
Evaluations of inflammation, including but not limited to cystatin-C, IL 6, hs 
CRP, d-dimer, sCD14, and sCD163 (Weeks 4, 12, 24 and 48)
6.3.2.8.11.
Evaluations of platelet function, including but not limited to soluble glycoprotein 
VI (sGPVI), P-selectin, and soluble CD40 ligand (Weeks 4, 12, 24 and 48)
6.3.2.8.12
Platelet function for substudy subjects (only at selected sites) (Weeks 4 and 12)
6.3.2.8.13
Single whole blood sample collection (Week 4 only): PBMC sample processing 
will be performed by the central laboratory; TFV-DP concentrations in PBMCs 
will be determined. 
6.3.2.9.
Pharmacokinetic Blood Collection:
6.3.2.9.1.
A single PK blood sample should be collected as part of the safety laboratory 
blood draws at any time pre-or post-dose (Weeks 8, 12, 24 and 36)
6.3.2.9.2.
A single PK blood sample will be collected after an observed in-clinic dose 
15 minutes to 4 hours post dose (Weeks 4 and 48 only).

Subjects may take their previous day’s dose at their regular dosing time.  

Subjects should be reminded not to take their dose of study medication prior 
to their clinic visit; instead, subjects should bring their dose of study 
medication to the clinic

If the subject has taken their dose of study drugs prior to the visit, the visit 
may proceed, but the subject must return with 72 hours in a fasted state for the
observed dose and post-dose PK collection

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6.3.2.10.
Subjects who meet the criteria for virologic rebound should be managed 
according to Management of Virologic Failure (Section 6.9)
6.3.2.11.
Document study drug dispensation and accountability for all study drugs 
dispensed
6.3.2.
Treatment Visits (Weeks 60-96)
The following evaluations are to be completed at the end of Weeks 60, 72, 84, and 96 unless 
otherwise specified.
Study visits are to be completed within ± 6 days of the protocol-specified visit date through 
Week 84 unless otherwise specified. The visit window at Week 96 will be ± 6 weeks of the 
protocol-specified visit date, and this clinical visit window coincides with the Week 96 statistical 
analysis window for HIV RNA. 
Regularly scheduled evaluations will be made on all subjects whether or not they continue to 
receive study drug.
6.3.3.1.
DXA Scans (spine and hip) (Weeks 72 and 96; can be performed ≤10 days 
before study visit) 
6.3.3.2.
Review of AEs and changes in concomitant medications
6.3.3.3.
Complete physical examination (Weeks 72 and 96) (urogenital/anorectal exams 
will be performed at the discretion of the Investigator)
6.3.3.4.
Symptom-directed physical examination as needed (Weeks 60 and 84)
6.3.3.5.
12 lead ECG performed supine (Week 96)
6.3.3.6.
Vital signs (blood pressure, pulse, respiration rate, and temperature), including 
weight
6.3.3.7.
Urine collection for the following laboratory procedures:
6.3.3.7.1.
Urinalysis and urine chemistry 
6.3.3.7.2.
Evaluations of renal tubular function (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 these evaluations. 
(Week 72 and 96)
6.3.3.7.3.
Urine pregnancy test (females of childbearing potential only); positive urine 
pregnancy tests will be confirmed with a serum test. If the test is positive, the 
subject will be discontinued.

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6.3.3.7.4.
Urine sample storage for possible additional clinical testing
6.3.3.8.
Blood sample collection for the following laboratory analyses:
6.3.3.8.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN). At Weeks 72 and 96, analyses of glucose will be done as part of 
the fasting metabolic assessments and not as part of the chemistry profile
6.3.3.8.2.
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). 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 (Weeks 72 and 96)
6.3.3.8.3.
Estimated GFR, according to the Cockcroft-Gault formula for creatinine clearance
6.3.3.8.4.
Hematology profile: CBC with differential and platelet count
6.3.3.8.5.
Plasma HIV-1 RNA 
6.3.3.8.6.
CD4+ cell count
6.3.3.8.7.
Plasma sample storage for virology, safety and/or PK testing 
6.3.3.8.8.
Serum sample storage for possible additional clinical testing (for subjects who 
provide consent)
6.3.3.8.9.
Evaluations of bone turnover (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 draw blood for these evaluations. (Weeks 72 and 96)
6.3.3.8.10.
Evaluations of inflammation, including but not limited to cystatin-C, IL 6, hs 
CRP, d-dimer, sCD14, and sCD163 (Weeks 72 and 96)
6.3.3.8.11
Evaluations of platelet function, including but not limited to soluble glycoprotein 
VI (sGPVI), P-selectin, and soluble CD40 ligand (Weeks 72 and 96)
6.3.3.9.
Subjects who meet the criteria for virologic rebound should be managed 
according to Management of Virologic Failure Section 6.9
6.3.3.10.
Document study drug dispensation and accountability for all study drugs 
dispensed

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6.3.3.
Treatment Visits (Post Week 96 until the Unblinding Visit and post 
Unblinding Visit)
After the Week 96 visit, all subjects will continue to take their blinded study drug and attend 
visits every 12 weeks until treatment assignments have been unblinded, at which point they will 
return for an Unblinding Visit and will be given the option to receive open-label F/TAF. Study 
visits are to be completed within ±6 days of the protocol specified visit date unless otherwise 
specified.
Subjects participating post Week 96 will be required to return for study visits according to the 
schedule presented in Appendix 2 Study Procedures Table and described in the text below.
6.3.4.1.
The following evaluations are to be completed unless otherwise specified: DXA 
Scans (spine and hip) (every 24 weeks; can be performed ≤10 days before study
visit) 
6.3.4.2.
Review of AEs and changes in concomitant medications
6.3.4.3.
Completed physical examination (every 48 weeks) (urogenital/anorectal exams 
will be performed at the discretion of the Investigator) or symptom-directed 
physical examination as needed (at all other visits)
6.3.4.4.
Vital signs (blood pressure, pulse, respiration rate, and temperature), including 
weight
6.3.4.5.
12 lead ECG performed supine (every 48 weeks)
6.3.4.6.
Urine collection for the following laboratory procedures:
6.3.4.6.1.
Urinalysis and urine chemistry 
6.3.4.6.2.
Urine pregnancy test (females of childbearing potential only); positive urine 
pregnancy tests will be confirmed with a serum test. If the test is positive, the 
subject will be discontinued
6.3.4.6.3.
Urine storage sample for possible additional clinical testing
6.3.4.7.
Blood sample collection for the following laboratory analyses:
6.3.4.7.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN). At visits post-Week 96 in which metabolic assessment is to be 
conducted, analyses of glucose will be done as part of the fasting metabolic 
assessments and not as part of the chemistry profile

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6.3.4.7.2.
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). 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 (every 24 weeks).
6.3.4.7.3.
Estimated GFR, according to the Cockcroft Gault formula for creatinine clearance
6.3.4.7.4.
Hematology profile: complete blood count (CBC) with differential and platelet 
count
6.3.4.7.5.
Plasma HIV-1 RNA
6.3.4.7.6.
CD4+ cell count
6.3.4.7.7.
Plasma storage samples for virology, safety, and/or PK testing 
6.3.4.7.8.
Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
6.3.4.8.
Subjects who meet the criteria for virologic rebound will be managed according to 
the Management of Virologic Failure Section 6.9
6.3.4.9.
Document study drug dispensation and accountability for all study drugs 
dispensed 
6.3.4.
Unblinding Visit
Once Gilead Sciences provides unblinded treatment assignments to the Investigators, all subjects 
will return to the clinic (preferably within 30 days) for an Unblinding Visit. At the Unblinding 
Visit all subjects will discontinue their blinded study drug and will be given the option to receive 
open-label F/TAF. 
If the F/TAF FDC is not commercially available in a country in which the study is being 
conducted, subjects who complete the 96 weeks of the study on randomly assigned treatment 
will be given the option to receive the open- label F/TAF FDC and attend study visits every 
12 weeks until it becomes commercially available, or until Gilead Sciences terminates the study 
in that country.
Subjects who do not wish to receive open-label F/TAF will discontinue their blinded study drug 
and will return for a 30-Day Follow-up visit following the Unblinding Visit.
Subjects who have discontinued study drug prior to the Unblinding Visit will not be eligible to 
receive open-label F/TAF; these subjects will be asked to continue attending the scheduled study 
visits through the Unblinding Visit.

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Subjects in certain countries (such as the UK) will stop taking study drug after the Unblinding 
Visit and return to the clinic 30 days after the completion of study drugs for a 30-day Follow-Up 
Visit.
The following will be performed at the Unblinding Visit:
6.3.5.1.
DXA Scan (spine and hip) required if last scan was acquired > 12 weeks from the 
date of the Unblinding Visit (can be performed ≤10 days before study visit) 
6.3.5.1.1.
The DXA scan will be performed once unblinded treatment assignments have 
been provided and prior to administration of open-label study drug (F/TAF) at the 
Unblinding Visit. The scan may be performed on the morning of the Unblinding 
Visit so long as it occurs before open-label study drug dosing
6.3.5.2.
Review of AEs and changes in concomitant medications
6.3.5.3.
Complete physical examination (urogenital/anorectal exams will be performed at 
the discretion of the Investigator) 
6.3.5.4.
Vital signs (blood pressure, pulse, respiration rate, and temperature), including 
weight
6.3.5.5.
12-lead ECG performed supine
6.3.5.6.
Urine collection for the following laboratory procedures:
6.3.5.6.1.
Urinalysis and urine chemistry
6.3.5.6.2.
Urine pregnancy test (females of childbearing potential only); positive urine 
pregnancy tests will be confirmed with a serum test. If the test is positive, the 
subject will not be able to participate in the open-label rollover study
6.3.5.6.3.
Urine storage sample for possible additional clinical testing
6.3.5.7.
Blood sample collection for the following laboratory analyses:
6.3.5.7.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, phosphorus, magnesium, potassium, sodium, uric acid, and 
amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN)
6.3.5.7.2.
Estimated GFR, according to the Cockcroft-Gault formula for creatinine clearance
6.3.5.7.3.
Hematology profile: CBC with differential and platelet count
6.3.5.7.4.
Plasma HIV-1 RNA

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6.3.5.7.5.
CD4+ cell count
6.3.5.7.6.
Plasma storage samples for virology, safety and/or PK testing 
6.3.5.7.7.
Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
6.3.5.8.
Document study drug dispensation and accountability for all study drugs 
dispensed
6.3.5.8.1.
Subjects who wish to receive F/TAF will receive F/TAF (200/10 mg or 
200/25 mg) based on the third ARV agent in their pre-existing regimen (see 
Table 5-1). 
6.4.
Post-treatment Assessments
6.4.1.
Early Study Drug Discontinuation (ESDD) Visit
If a subject discontinues study drug prior to the Unblinding Visit,  the subject will be asked to 
return to the clinic within 72 hours of stopping study drug for the Early Study Drug 
Discontinuation (ESDD) visit. The subject will be asked to continue attending the scheduled 
study visits through the Unblinding Visit.
At the Early Study Drug 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 Drug Discontinuation Visit:
6.4.1.1.
Review of AEs and changes in concomitant medications
6.4.1.2.
Complete physical examination (urogenital/anorectal exams will be performed at 
the discretion of the Investigator) 
6.4.1.3.
12-lead ECG performed supine
6.4.1.4.
Vital signs (blood pressure, pulse, respiration rate, and temperature), including 
weight
6.4.1.5.
Urine collection for the following laboratory procedures:
6.4.1.5.1.
Urinalysis and urine chemistry
6.4.1.5.2.
Urine pregnancy test (females of childbearing potential only); positive urine 
pregnancy tests will be confirmed with a serum test

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6.4.1.5.3.
Urine storage sample for possible additional clinical testing
6.4.1.5.4.
Evaluations of renal tubular function required if last test was acquired > 12 weeks 
from the date of the ESDD Visit (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 these evaluations
6.4.1.6.
Blood sample collection for the following laboratory analyses:
6.4.1.6.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN)
6.4.1.6.2.
Estimated GFR, according to the Cockcroft Gault formula for creatinine clearance
6.4.1.6.3.
Hematology profile: complete blood count (CBC) with differential and platelet
count
6.4.1.6.4.
Plasma HIV-1 RNA
6.4.1.6.5.
CD4+ cell count
6.4.1.6.6.
Plasma storage samples for virology, safety and/or PK testing 
6.4.1.6.7.
Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
6.4.1.6.8.
HIV-1 genotype/phenotype resistance testing for subjects with confirmed 
virologic rebound with HIV-1 RNA value ≥ 400 copies/mL
6.4.1.6.9.
Evaluations of bone turnover required if last test was acquired > 12 weeks from 
the date of the ESDD Visit (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 blood sample for these evaluations
6.4.1.6.10.
Evaluations of inflammation required if last test was acquired > 12 weeks from 
the date of the ESDD Visit, including but not limited to cystatin-C, IL 6, hs CRP, 
d-dimer, sCD14, and sCD163
6.4.1.6.11
Evaluations of platelet function required if last test was acquired > 12 weeks from 
the date of the ESDD Visit, including but not limited to soluble glycoprotein VI 
(sGPVI), P-selectin, and soluble CD40 ligand
6.4.1.6.12
Platelet function for substudy subjects (only at selected sites)

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6.4.1.7.
DXA scan (spine and hip) required if last scan was acquired > 12 weeks from the 
date of the ESDD Visit. DXA scan can occur up to 10 days after the ESDD Visit
6.4.1.8.
Drug accountability
6.4.2.
30 Day Follow-Up Visit
Subjects who complete the study through the Unblinding Visit and who do not wish to receive 
the open-label F/TAF (including subjects in countries such as the UK) 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 drug during the blinded phase and refuse to 
continue in the study through the Unblinding Visit will be asked to return to the clinic 30 days 
after the completion of the Early Study Drug Discontinuation Visit for the 30-Day Follow-Up 
Visit.
Those subjects who permanently discontinue study drug and continue in the study through 
at least one subsequent visit after the Early Study Drug Discontinuation Visit will not be 
required to complete the 30-Day Follow-Up Visit.
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:
6.4.2.1.
Review of AEs and changes in concomitant medications
6.4.2.2.
Symptom-directed physical examination
6.4.2.3.
Vital signs (blood pressure, pulse, respiration rate, and temperature) including 
weight 
6.4.2.4.
Urine collection for the following laboratory procedures:
6.4.2.4.1.
Urinalysis
6.4.2.4.2.
Urine pregnancy test (females of childbearing potential only); positive urine 
pregnancy tests will be confirmed with a serum test
6.4.2.4.3.
Urine storage sample for possible additional clinical testing
6.4.2.5.
Blood sample collection for the following laboratory analyses:
6.4.2.5.1.
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and 
indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, 
chloride, creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric 
acid, and amylase (reflex lipase testing is performed in subjects with total amylase 
1.5 ULN)

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6.4.2.5.2.
Hematology profile: complete blood count (CBC) with differential and platelet 
count
6.4.2.5.3.
Plasma HIV-1 RNA
6.4.2.5.4.
CD4+ cell count
6.4.2.5.5.
Serum storage sample for possible additional clinical testing (for subjects who 
provide consent)
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 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.
6.5.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degreeFollowing resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator.

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

Therapeutic failure 

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.6.
Bone Mineral Density Evaluations
For all subjects excluding those in Germany, dual energy x-ray absorptiometry (DXA) scans will 
be performed prior to study drug administration at the Day 1, every 24 weeks, Unblinding Visit 
and the Early Study Drug Discontinuation Visit (if applicable). Scans will cover the spine and 
hip to measure changes in bone mineral density. DXA scan results will be provided to study 
sites.

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A complete description of the procedures performed for the DXA scans will be provided in a 
DXA manual.
6.7.
Other Evaluations 
6.7.1.
Markers of Bone Turnover
For all subjects, blood will be collected for selected evaluations of bone turnover, including 
C-type collagen sequence (CTX) and procollagen type 1 N-terminal propeptide (P1NP) at Day 1 
Visit, Weeks 4, 12, 24, 48, 72, 96 and ESDD (if applicable).
6.7.2.
Markers of Renal Tubular Function
For all subjects, urine will be collected for selected evaluations of renal tubular function, 
including retinol binding protein and beta 2 microglobulin at the Day 1 Visit, Weeks 4, 12, 24, 
48, 72, 96 and ESDD (if applicable).
6.7.3.
Markers of Inflammation
For all subjects, blood will be collected at Day 1 Visit, Weeks 4, 12, 24, 48, 72, 96 and ESDD (if 
applicable) for selected evaluations of inflammation, including but not limited to cystatin-C, IL 
6, hs CRP, d-dimer, sCD14, and sCD163.
6.7.4.
Markers of Platelet Function
For all subjects, blood will be collected at Day 1 Visit, Weeks 4, 12, 24, 48, 72, 96 and ESDD (if 
applicable) for selected evaluations of platelet function, including but not limited to soluble 
glycoprotein VI (sGPVI), P-selectin, and soluble CD40 ligand. In addition, a subset of subjects 
will be evaluated for the platelet function (see Section 6.10). 
6.8.
Blood and Urine Storage
From subjects who provide additional consent, a portion of the blood drawn at all visits (except 
the Screening Visit and Unscheduled Visits) will be frozen and stored. A portion of urine 
samples drawn from all subjects at all visits (except the Screening Visit and Unscheduled Visits) 
will be frozen and stored. These stored blood and urine samples may be used by the Sponsor or 
its research partners for future testing to learn more about how the study drug has worked against 
HIV-1 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, Inc. for a period up to 10 years.
6.9.
Virologic Failure 
Subjects who experience virologic rebound (VR), as defined below, will be considered to have 
virologic failure.  

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Subjects will be considered to have virologic rebound if they have confirmed HIV-1 RNA 
≥50 copies/mL (two consecutive tests) at a scheduled or unscheduled visit.
6.9.1.
Management of Virologic Failure

If the viral load is ≥ 50 copies/mL, HIV-1 RNA should be repeated at a scheduled or 
unscheduled visit (2-4 weeks after the date of the original test with HIV-1 RNA 
≥50 copies/mL).

Upon confirmation of HIV-1 RNA ≥ 50 copies/mL, potential causes of virologic failure 
should be documented.  Assessments should include:
— Adherence
— Concomitant medication
— Comorbidities (for example: active substance abuse, depression, other intercurrent 
illnesses)

If virologic failure is confirmed at the scheduled or unscheduled visit and HIV-1 RNA value 
is ≥ 400 copies/mL, the blood samples from the confirmation visit will be used for HIV-1 
genotype/phenotype testing.

If genotype/phenotype resistance to study drug is documented, study drugs should be 
discontinued. 

If no resistance is detected from genotype/phenotype testing, subject may remain on study 
drug and a repeat HIV-1 RNA should be repeated (2-4 weeks from the date of confirmed test 
with viral load ≥ 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.  Investigators who opt to discontinue study drugs for an individual 
subject must discuss with the Medical Monitor prior to study drug discontinuation.
6.9.2.
Subjects with ≥ 400 copies/mL of HIV-1 in the Absence of VR
Subjects with HIV-1 RNA < 50 copies/mL could subsequently experience unconfirmed blips of 
HIV-1 RNA ≥ 400 copies/mL. Such subjects will be analyzed for resistance if the unconfirmed 
rebound happens at Week 48, or at the last visit while receiving study drugs (or within 72 hours 
of discontinuation of study treatment).
Please refer to Figure 6-1 for the management of subjects who meet the criteria for virologic 
failure.

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Figure 6-1. 
Schema for Management of Virologic Failure 
Screening 
Treatment Period 
30-Day Follow-up 
Day I 
~ 
At any visit, a rebound in HIV-1 RNA to:?; 50 copies/mL 
I 
Unconfirmed 
v:h-ologic 
Retum for scheduled/unscheduled HIV-1 
rebound: remain 
Rl'JA and potential genotype/phenotype 
on current 
(2-4 weeks later) 
a 
regimen 
~ 
I 
Confirmed virologic 
rebound b 
I 
Remain on study 
, 
I 
HIV-1 genotype/phenotype c I 
... 
... 
If no reve1·se transcriptase resistance 
If reverse transcriptase, protease, or 
detected, continue on study dmgs. 
integrase resistance detec.ted, 
Repeat HIV-1 RNA b, d 
discontinue study dmgs and 
construct a new ARV regimen e 
a 
If virologic rebotmd is not confmned, the subject will remain on their cturent. regin1en. 
b 
If virologic rebotmd is confmned, and the HIV -1 RNA is :;:: 400 copies/mL, the HIV -1 genotype and phenotype (reverse 
transcriptase, protease, and, if applicable, integrase resistance) will be analyzed. 
c 
Based on the results of the genotype/phenotype assays, the subject will remain on study dtugs or study dt·ugs will be 
discontinued. If genotyping/phenotyping assay fails, a new ARV regimen may be configured at the discretion of the 
Investigator. 
d 
If no resistanc.e detected, HIV-1 RNA will be repeated (2-4 weeks later). Investigator reviews study dtug 
c.ontinuation/disc.ontinuation options and discuss with 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 
CONFIDENTIAL 
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6.10.
Platelet Function Substudy
In a subset of patients, platelet function (i.e. reactivity) will be assessed at Day 1 Visit, Weeks 4, 
12, and the Early Study Drug Discontinuation Visit (if applicable). The assay to assess platelet 
function will measure platelet aggregation in response to agonist(s). 
In addition, the expression of certain platelet receptors (e.g. glycoprotein VI) may be assessed 
using flow cytometry. The target sample size for the substudy is up to 80 subjects. 
The results will not be provided to the study sites. 
A complete description of the procedure performed for the evaluation of platelet reactivity will 
be provided in a separate laboratory manual. 

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
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 7.6.
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 (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.

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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, 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
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (Appendix 4). For adverse events associated with 
laboratory abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the grading of 
the laboratory abnormality.
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 electronic case report form (eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
7.3.1.
Adverse Events
Following initiation of study medication, all AEs, regardless of cause or relationship, until 
30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.3.2.
Serious Adverse Events 
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be 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 DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead Drug Safety and 
Public Health (DSPH):
Fax:
+1 650 522 5477
E-mail:
safety_fc@gilead.com

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. All AEs and SAEs will be recorded in the eCRF database within 
the timelines outlined in the eCRF completion guideline. 

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 

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other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.5.
Special Situations Reports
7.5.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, 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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7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to the Gilead DSPH using the pregnancy report form within 24 hours of becoming aware 
of the pregnancy. 
Refer to 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 
Section 7.3.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post study 
must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. 
Gilead DSPH contact information is as follows: 
Email: Safety_FC@gilead.com
Fax: +1 (650) 522-5477
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 

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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 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.
7.6.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix 3 as outlined below.

All clinically significant Grade 3 and 4 laboratory abnormalities should be repeated within 
3 calendar days to confirm toxicity grade. Confirmation of toxicity grade is required prior to 
the next dose of investigational medicinal product for any Grade 3 and 4 laboratory 
abnormality that in the opinion of the Investigator is clinically significant and may pose a 
risk to the subject’s safety.

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(Refer to Appendix 4).

Any questions regarding toxicity management should be directed to the Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue investigational medicinal product at the discretion of the Investigator.
7.6.2.
Grades 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, investigational 
medicinal product may be continued if the event is considered to be unrelated to 
investigational medicinal product.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to investigational medicinal product, 
investigational medicinal product should be withheld until the toxicity returns to Grade 2.

If a laboratory abnormality recurs to Grade 3 following rechallenge with investigational 
medicinal product and is considered related to investigational medicinal product, then 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. Recurrence of laboratory abnormalities considered 
unrelated to investigational medicinal product may not require permanent discontinuation.

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7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to investigational medicinal product, 
investigational medicinal product should be permanently discontinued and the subject 
managed according to local practice. The subject should be followed as clinically indicated 
until the laboratory abnormality returns to baseline or is otherwise explained, whichever 
occurs first. A clinically significant Grade 4 laboratory abnormality that is not confirmed by 
repeat testing should be managed according to the algorithm for the new toxicity grade.
Investigational medicinal product may be continued without dose interruption for a clinically 
non-significant Grade 3-4 laboratory abnormality (e.g., CK elevation after strenuous exercise, or 
triglyceride elevation that is nonfasting or that can be medically managed) or a Grade 3-4 clinical 
event considered unrelated to investigational medicinal product.
7.6.4.
Management of Bone Evaluation
As there is uncertainty surrounding the clinical significance and management of decreases in 
bone mineral density for HIV-1 infected patients, Gilead recommends that any subject who has a 
DXA scan that demonstrates a decrease from baseline of > 5% in the spine region or > 7% in the 
hip region be followed per local medical practice at the discretion of the investigator.
7.6.5.
Management of Hyperbilirubinemia in Patients Receiving Atazanavir
Most patients taking atazanavir sulfate experience asymptomatic elevations in indirect 
(unconjugated) bilirubin related to inhibition of UDP-glucuronyl transferase (UGT). 
As subjects on ATV-containing regimen are expected to have atazanavir-associated 
hyperbilirubinemia, occasionally up to Grade 4 (> 5 x ULN), the management of graded 
laboratory abnormality described above in Section 7.6 is not applicable for the management of 
graded hyperbilirubinemia in these subjects. 
However, repeat testing should be done and alternative etiologies (e.g. acute hepatitis B or C) be 
sought in the following subjects:
1. In those with elevation in conjugated (direct) bilirubin > 1.5 x ULN (i.e. direct 
hyperbilirubinemia), regardless of the hyperbilirubinemia grade, liver labs (total bilirubin, 
direct bilirubin, AST, ALT) should be repeated within 7 days of the Investigator being 
notified of the elevated bilirubin level and be discussed with the Medical Monitor. 
Thereafter, the management of a subject who continues to have direct bilirubin > 1.5 X ULN, 
which is deemed as clinically not significant, should be followed according to the clinical 
judgment of the Investigator.
2. In those with hepatic transaminase elevation, the graded AST or ALT abnormalities should 
be managed according to Section 7.6.

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Dose modification of atazanavir sulfate is not permitted. Subjects who experience unacceptable 
jaundice/scleral icterus due to atazanavir-associated hyperbilirubinemia can be discontinued 
from study at the discretion of the Investigator.
7.6.6.
Management of Possible Abacavir Hypersensitivity Reaction
Abacavir should not be used in patients known to carry the HLA-B*5701 allele due to increased 
risk of hypersensitivity reaction, unless no other therapeutic option is available based on the 
treatment history and resistance testing.
In a clinical study, 3.4 % of subjects with a negative HLA-B*5701 status receiving abacavir 
developed a hypersensitivity reaction. Therefore, even in the absence of HLA-B*5701 allele, it is 
important to permanently discontinue abacavir and not rechallenge with abacavir if a 
hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe 
or even fatal reaction.
Hypersensitivity reactions are characterized by the appearance of symptoms indicating multi 
organ system involvement. Almost all hypersensitivity reactions will have fever and/or rash as 
part of the syndrome. Other signs and symptoms may include respiratory signs and symptoms 
such as dyspnoea, sore throat, cough, and abnormal chest x-ray findings (predominantly 
infiltrates, which can be localized), gastrointestinal symptoms, such as nausea, vomiting, 
diarrhea, or abdominal pain, and may lead to misdiagnosis of hypersensitivity as respiratory 
disease (pneumonia, bronchitis, pharyngitis), or gastroenteritis. Other frequently observed signs 
or symptoms of the hypersensitivity reaction may include lethargy or malaise and 
musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia). The symptoms related to this 
hypersensitivity reaction worsen with continued therapy and can be life- threatening. These 
symptoms usually resolve upon discontinuation of abacavir.
Hypersensitivity reaction symptoms usually appear within the first six weeks of initiation of 
treatment with abacavir, although these reactions may occur at any time during therapy. Patients 
should be monitored closely, especially during the first two months of treatment with abacavir.
Regardless of their HLA-B*5701 status, patients who are diagnosed with a hypersensitivity 
reaction whilst on therapy MUST discontinue study drug immediately and MUST NEVER be 
restarted. Restarting study drug following a hypersensitivity reaction will result in a prompt 
return of symptoms within hours. This recurrence is usually more severe than on initial 
presentation, and may include life-threatening hypotension and death. To avoid a delay in 
diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, study drug must 
be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses 
are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medicinal 
products) {25149}.

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7.6.7.
Management of Changes in Estimated Glomerular Filtration Rate
Estimated glomerular filtration rate (GFR), according to the Cockcroft Gault formula, will be 
followed post-baseline during the study. All subjects with estimated GFR < 50 mL/min must 
have serum creatinine and subject’s weight measured again within 3 calendar days of receipt of 
results. If a subject has confirmed estimated GFR < 50 mL/min, the Medical Monitor should be 
notified and discontinuation of investigational medicinal product should be discussed.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective is:

To evaluate the efficacy of switching ABC/3TC to F/TAF versus maintaining ABC/3TC in 
HIV-1 infected subjects who are virologically suppressed on regimens containing ABC/3TC 
as determined by the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 
The secondary objectives are:

To evaluate the efficacy, safety and tolerability of two regimens through Week 48 and 
Week 96

To evaluate the bone safety of two regimens as determined by the percentage change from 
baseline in hip and spine bone mineral density (BMD) at Week 48 and Week 96
8.1.2.
Primary Endpoint
The primary endpoint is the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 
as defined by the FDA snapshot algorithm.
8.1.3.
Secondary Endpoint
Secondary endpoints include:

The proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 96 as defined by the 
FDA snapshot analysis

The percent change from baseline in hip and spine BMD at Week 48 and Week 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.

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8.2.1.2.
Efficacy
8.2.1.2.1.
Full Analysis Set (FAS)
The full analysis set (FAS) will include all subjects who (1) are randomized into the study and 
(2) have received at least one dose of study medication. Subjects will be grouped according to 
the treatment to which they were randomized.
8.2.1.2.2.
Per-Protocol (PP) Analysis Set
The Per-Protocol analysis set will include all subjects who (1) are randomized into the study, 
(2) have received at least one dose of study medication, 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.
8.2.1.3.
Safety
8.2.1.3.1.
Full analysis Set (FAS)
The safety analysis set will include all randomized subjects who (1) are randomized into the 
study and (2) have received at least one dose of study medication. All the data collected up to 
30 days after subjects permanently discontinue their study regimen will be included in the safety 
summaries. Subjects will be grouped according to the treatment they actually received.
8.2.1.4.
DXA
8.2.1.4.1.
Hip DXA Analysis Set
The Hip DXA analysis set will include all subjects who were randomized and received at least 
one dose of study medication, and had nonmissing hip BMD value for the Day 1 visit. Subjects 
will be grouped according to the treatment they actually received.
8.2.1.4.2.
Spine DXA Analysis Set
The Spine DXA analysis set will include all subjects who were randomized and received at least 
one dose of study medication, and had nonmissing spine BMD value for the Day 1 visit. Subjects 
will be grouped according to the treatment they actually received.
8.2.1.5.
Pharmacokinetics
The Pharmacokinetic (PK) analysis set will include all subjects who are randomized and have 
received at least one dose of study medication and for whom concentration data of any analytes 
of interest is available. The PK analysis set will be used for analyses of general 
pharmacokinetics.

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8.3.
Data Handling Conventions
Appropriate transformations may be applied prior to data summarization and analysis.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data including body weight, height, body mass index, HIV-1 infection, and enrollment 
distribution by randomization stratum will be summarized.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The primary efficacy endpoint is the proportion of subjects with HIV-1 RNA < 50 copies/mL at 
Week 48 as defined by the FDA snapshot algorithm. The primary analysis of the efficacy will be 
based on the full analysis set (FAS).
The null hypothesis is that the proportion of subjects with HIV-1 RNA < 50 copies/mL 
(as defined by the FDA snapshot algorithm) at Week 48 in the Treatment Arm 1 is at least 
10 percentage points lower than the response rate in the Treatment Arm 2; the alternative 
hypothesis is that the response rate in Treatment Arm 1 is less than 10% lower than that in 
Treatment Arm 2.  
Non-inferiority will be assessed using the conventional confidence interval approach. The point 
estimate of treatment difference (F/TAF arm – FTC/TDF arm) and the associated two-sided 95% 
confidence interval will be constructed using normal approximation method based on stratum-
stratified Mantel-Haenszel proportions, where the stratification factor is the third agents (boosted 
protease inhibitors vs. other agents). 
Once non-inferiority of F/TAF treatment regimen to FTC/TDF treatment regimen 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 F/TAF over FTC/TDF will be established.
8.5.2.
Secondary Analyses
The proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 96, as defined by the FDA 
snapshot algorithm, will be analyzed using the same method as for the primary efficacy endpoint.
8.6.
Safety Analysis
All safety analyses will be performed using the safety analysis set.

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All safety data collected on or after the date that study regimen was first taken up to the date of 
last dose of study regimen plus 30 days will be summarized by treatment group according to the 
study regimen received.  Data for the pretreatment period and the period post the date of last 
dose of study regimen plus 30 days will be included in data listings.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to IMP data will be generated from the IMP administration data. 
Exposure data will be summarized by treatment group.
Duration of exposure to IMP will be expressed as the number of weeks between the first and last 
dose of the study regimen, inclusive, regardless of temporary interruptions in study regimen 
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 that begins on or after the date of first dose of 
IMP study regimen up to 30 days after the date of last dose of IMP study regimen or any AEs 
leading to study regimen discontinuation
Summaries (number and percentage of subjects) of treatment-emergent adverse events (by SOC 
and PT) will be provided by treatment group. Additional summaries will include summaries for 
adverse events by grade, Investigator’s assessment of relationship to IMP, and effect on IMP 
dosing.
On an ongoing basis adverse events will be reviewed for events that might meet the definition of 
Category C events that are indicative of an AIDS-Defining Diagnoses. The Gilead medical 
personnel will review the possible Category C events and approve the events that meet the 
definition. Those events that do meet the Category C definition of an AIDS-Defining Diagnosis 
will be listed.
A listing of Category C, AIDS-Defining Diagnosis, can be found in Appendix 6.
8.6.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled visits will be summarized.

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Graded laboratory abnormalities will be defined using the grading scheme defined in Grading of 
laboratory abnormalities provided in Appendix 4.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
one toxicity grade from baseline at any time post baseline up to and including the date of last 
dose of study regimen plus 30 days, will be summarized by treatment group. If baseline data are 
missing, then any graded abnormality (i.e. at least a Grade 1) will be considered treatment 
emergent. The maximum toxicity grade will be summarized by laboratory parameter.
Laboratory abnormalities that occur before the first dose of study regimen or after the subject has 
been discontinued from treatment plus 30 days will be included in a data listing.
8.6.4.
Bone Mineral Density
Percentage change from baseline in hip and spine BMD will be summarized.  The difference in 
percentage change at Week 48 from baseline between the two treatment arms will be tested using 
ANOVA model, including the third agent stratum (boosted protease inhibitors vs. other agents) 
as a fixed effect.
Missing post-baseline values for BMD will be imputed using last observation carried forward 
(LOCF).
8.6.5.
Other Safety Evaluations
Safety ECGs will be summarized for subjects in the Safety Analysis Set. Number and percent of 
subjects with abnormal safety ECG will be summarized by visit.
8.7.
Pharmacokinetic Analysis
The PK concentration data of individual analytes may be explored.
8.8.
Analysis of Evaluations of Bone Turnover, Renal Tubular Function, and 
Inflammation
The observed values and changes from baseline in these evaluations will be summarized by 
treatment group and visit using descriptive statistics, based on the safety analysis set. The 
difference in change from baseline in these evaluations between two treatment arms will be 
tested using van Elteren method, stratified by the third agents (boosted protease inhibitors vs. 
other agents).
The skewness of the data will be examined and a natural log transformation may be applied
especially for exploratory analysis. If any transformation is applied, the changes from baseline
will be reported in original units (ie, back transformation will be applied to the generated
statistics, eg: fold-change from baseline may be reported instead of change from baseline).

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8.9.
Sample Size
A total of 500 HIV-1 infected subjects, randomized in a 1:1 ratio to two arms (250 subjects per 
arm), achieves at least 90% power to detect a non-inferiority margin of 10% in Week 48 
response rate (HIV-1 RNA < 50 copies/mL as defined by the FDA snapshot algorithm) 
difference between the two groups. For sample size and power computation, it is assumed that 
both treatment arms have a response rate of 0.87, that a non-inferiority margin is 0.10, and that 
the significance level of the test is at a one-sided 0.025 level.
8.10.
Independent Data Monitoring Committee
An external multidisciplinary data monitoring committee (DMC) will review the progress of the 
study and perform interim reviews of safety data, and provide recommendation to Gilead 
whether the nature, frequency, and severity of adverse effects associated with study treatment 
warrant the early termination of the study in the best interests of the participants, whether the 
study should continue as planned, or the study should continue with modifications. The DMC 
may also provide recommendations as needed regarding study design, and the collection or 
analysis of data.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.
An analysis for the Week 12 IDMC meeting will be conducted after the first 250 subjects are
enrolled and complete Week 12, and subsequently when all enrolled subjects complete Week 24 
of the study. Gilead Sciences does not have a prior intent to ask the IDMC to review Weeks 48 
results and to consider early termination of the study even if there is early evidence of favorable 
efficacy.

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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, “Protection of Human Subject”, and 21 CFR, part 56, “Institutional Review Board”.
The Investigator and all applicable Sub-Investigators will comply with 21 CFR, Part 54, 
“Financial Disclosure by Investigators”, providing documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under study. This 
documentation must be provided prior to the Investigator’s (and any Sub-Investigator’s) 
participation in the study. The Investigator and Sub-Investigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.

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

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

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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in 
the audit trail of the system.  Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g. data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy 
of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate standard operating procedure (SOP) for drug destruction as determined by 
Gilead QA, the site may destroy used (empty or partially empty) and unused IMP supplies in 
accordance with that site’s approved SOP. A copy of the site’s approved SOP will be obtained 
for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs [or] IECs, or to regulatory authority or health 
authority inspectors.

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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB [or] 
IEC in accordance with local requirements and receive documented IRB [or] IEC approval 
before modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency. Gilead will 
ensure that the report meets the standards set out in the ICH Guideline for Structure and Content 
of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, e.g. attendance at Investigator's Meetings.  If required under the applicable statutory 
and regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 

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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.
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
13
Robbins BL, Greenhaw JJ, Connelly MC, Fridland A. Metabolic pathways for 
activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human 
lymphoid cells. Antimicrob Agents Chemother 1995;39 (10):2304-8.
2202
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16:31-41.
13585
Schneider E, Whitmore S, Glynn KM, Dominguez K, Mitsch A, McKenna MT. 
Revised surveillance case definitions for HIV infection among adults, 
adolescents, and children aged <18 months and for HIV infection and AIDS 
among children aged 18 months to <13 years--United States, 2008. MMWR 
Recomm Rep 2008;57 (RR-10):1-12.
16658
Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, 
et al. Comparison of changes in bone density and turnover with abacavir-
lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results 
from the ASSERT study. Clin Infect Dis 2010;51 (8):963-72.
21057
DeJesus E, Rockstroh J, Henry K, Molina J-M, Gathe J, Ramanathan S, et al. Co-
formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil 
fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and 
tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a 
randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012;379:2429-
38.
25124
Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. 
Efficacy and safety of tenofovir DF vs stavudine in combination therapy in 
antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292 (2):191-
201.
25126
McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, et al. Bone 
mineral density and fractures in antiretroviral-naive persons randomized to 
receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along 
with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a 
substudy of ACTG A5202. J Infect Dis 2011;203 (12):1791-801.
25149
Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 
2000. Lancet 2003;362 (9387):847-52.
26885
Gilead Sciences Inc. VIREAD® (tenofovir disoproxil fumarate) tablets, for oral 
use VIREAD® (tenofovir disoproxil fumarate) powder, for oral use. U.S. 
Prescribing Information.  Foster City, CA. Revised October 2013:

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27071
Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: 
UNAIDS report on the global AIDS epidemic.  2013.
27621
Williams I, Churchill D, Anderson J, Boffito M, Bower M, Cairns G, et al. British 
HIV Association guidelines for the treatment of HIV-1-positive adults with 
antiretroviral therapy 2012 (Updated November 2013. All changed text is cast in 
yellow highlight.). HIV Med 2014;15 Suppl 1:1-85.
29705
Costagliola D. Demographics of HIV and aging. Curr Opin HIV AIDS 2014;9 
(4):294-301.
32519
Department of Health and Human Services (DHHS). Guidelines for the Use of 
Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Developed by 
the HHS 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. 
Revised 13 November 2014.

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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations
Appendix 6.
Definitions of HIV-1 Related Disease (CDC Guidelines)

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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b, Randomized, Double-Blind, Switch Study to Evaluate FffAF in HIV-1 Infected 
Subjects who are Virologically Suppressed on Regimens containing ABC/3TC 
GS-US-311-1717 Original Protocol: 11 March 2015 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Moupal Das, MD, MPH (Pnnted) 
Medical Monitor 
B/1 I ) O!f)l5 
PPD 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and l agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 89 
II March 2015 

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Appendix 2.
Study Procedures Table
Study Procedure
Screena
Day 1b
End of Weekc
Post-
Week 96 d
Unblinding 
Visit v
30 Day 
Follow-up e
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
ESDD f
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
X
X
Complete Physical 
Exam
X
X
X
X
X
X
X g
X
X
Symptom-Directed 
Physical Examh
X
X
X
X
X
X
X
X
12-Lead ECG 
(performed supine)
X
X
X
Xz
X
X
Vital Signs and 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xy
X
Height
X
Urinalysis and 
Urine Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xaa
X
Urine Storage 
Sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Pregnancy 
Testi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Study Procedure
Screena
Day 1b
End of Weekc
Post-
Week 96 d
Unblinding 
Visit v
30 Day 
Follow-up e
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
ESDD f
Serum Pregnancy 
Testi
X
Chemistry Profilej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Metabolic 
Assessmentsk
X
X
X
X
X
Xr
X
Estimated GFRw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
Profilel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 
RNAx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma Sample 
Storagem
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Storage 
Samplem
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Whole Blood 
Storage Samplebb
X
Whole Blood 
Sample for PBMCs
Xdd
HBV Serology
X

F/TAF
Protocol GS-US-311-1717
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 92
11 March 2015
Study Procedure
Screena
Day 1b
End of Weekc
Post-
Week 96 d
Unblinding 
Visit v
30 Day 
Follow-up e
4
8
12
24
36
48
60
72
84
96
Every 
12 Weeks
ESDD f
HCVAb Serologyn
X
HIV-1 
Genotype/Phenotypeo
Xo
Single PK Samplep
X
X
X
X
Post-dose PK 
Sampleq
X
X
Platelet substudy 
blood sample
Xee
Xee
Xee
Xee
DXA Scan (spine 
& hip)s
X
X
X
X
X
X s
X
X
Evaluations of 
bone turnover,
renal tubular 
function, 
inflammation and 
platelet functiont
X
X
X
X
X
X
X
Xt
Randomization
X
Study Drug 
Dispensation and 
Accountability
X
X
X
X
X
X
X
X
X
X
X
X
Xcc
Xu
a
Evaluations to be completed within 30 days prior to Day 1 Visit.
b
Subjects will be dispensed study drug on the Day 1 Visit; initiation of treatment with the study drug must take place within 24 hours after the Day 1 visit. F/TAF, ABC/3TC, 
placebo-to-match F/TAF and placebo-to-match ABC/3TC will be provided by the Sponsor. 
c
All study visits are to be scheduled relative to the Day 1 Visit date. Visit windows are 2 days of the protocol specified date through Week 12, 6 days of the protocol 
specified date through Week 36, and all other study visits except Week 48 and Week 96. Weeks 48 and 96 visit windows are 6 weeks of the protocol specified date.

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Protocol GS-US-311-1717
Final
Gilead Sciences, Inc.
Original
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d
Study visits are to be completed within 6 days of the protocol-specified visit date unless otherwise specified.
e
Only required for those subjects who do not wish to continue to participate after the Unblinding Visit, all subjects in countries such as the UK , or those subjects who 
permanently discontinue study drug and do not continue in the study through at least one subsequent visit after the Early Study Drug Discontinuation Visit. For the purpose of 
scheduling a 30-Day Follow-Up Visit, a 6 days window may be used.
f
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through 
Unblinding visit even if the subject discontinues study drug.
g
Complete physical examination every 48 weeks (urogenital/anorectal exams will be performed at the discretion of the Investigator).
h
Symptom-directed physical examination as needed.
i
Females of childbearing potential only. Positive urine pregnancy tests will be confirmed with a serum test.
j
Chemistry profile: alkaline phosphatase, AST, ALT,  total bilirubin, direct and indirect bilirubin, total protein, albumin,  CPK, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, phosphorus, magnesium, potassium, sodium, uric acid, and amylase (reflex lipase testing is performed in subjects with total amylase 1.5 ULN) At Day 
1, Weeks 24, 48, 72, 96, and every 24 weeks post week 96, analyses of glucose will be done as part of the fasting metabolic assessments and not as part of the chemistry 
profile. 
k
Metabolic Assessments: Fasting glucose and lipid panel (total cholesterol, HDL, direct LDL, triglycerides). If the subject has not fasted prior to the visit, the visit may 
proceed, but the subject must return within 72 hours in a fasted state to draw blood for the metabolic assessments.
l
CBC with differential and platelet count.
m
Plasma storage samples for virology, safety, and/or pharmacokinetic analysis. Serum storage samples for possible additional clinical testing. 
n
If the antibody test result is positive, HCV RNA test will be performed to confirm HCV viremia
o
HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic failure with HIV-1 RNA value ≥ 400 copies/mL. Subjects should be 
managed according to the Virologic Failure Schema (Section 6.9). HIV-1 genotype/phenotype sample collection to occur if subjects HIV-1 RNA lab values meet the criteria 
described in this section.
p
At Weeks 8, 12, 24 and 36, subjects will have a single PK sample collected as part of their safety laboratory blood draws anytime pre-or post-dose.
q
At the Weeks 4 and 48 visits only, PK sample will be collected 15 minutes to 4 hours post-dose, following observed in-clinic dose. 
r
Metabolic assessments post week 96 will be performed every 24 weeks. 
s
DXA scan to be performed in all eligible subjects except for those in Germany, prior to study drug administration at Day 1 Visit. DXA scan also to be performed at visits
every 24 weeks up to Wk 96 and every 24 weeks Post-Wk 96 (can be performed ≤ 10 days before study visits), at Unblinding Visit and the ESDD visit (if the last scan was 
acquired > 12 weeks from the date of the ESDD Visit).
t
Blood for selected evaluations of bone turnover, including C-type collagen sequence (CTX) and procollagen type 1 N-terminal propeptide (P1NP),  inflammation including 
cystatin-C, IL-6, hs-CRP, d-dimer, sCD14, and sCD163, and platelet function including soluble glycoprotein VI (sGPVI), P-selectin, and soluble CD40 ligand will be 
collected. Urine for selected evaluations of renal tubular function, including retinol binding protein, and beta-2-microglobulin, will be collected.  Required for ESDD visit if 
last test was > 12 weeks from ESDD visit. Samples for bone turnover and renal tubular function will be collected fasted. If the subject has not fasted prior to the visit, the visit 
may proceed, but the subject must return within 72 hours in a fasted state to draw blood for these evaluations and provide a urine sample for these evaluations. 
u
Drug accountability only; study drug will not be dispensed at this visit.
v
At the Unblinding Visit, subjects (except in certain countries such as UK) will be given the option to receive open-label F/TAF FDC and attend study visits every 12 weeks 
until it becomes commercially available, or until Gilead Sciences terminates the study in that country.
w
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance 
x
If the HIV-1 RNA value is ≥ 50 copies/mL a retest should be collected at a scheduled or unscheduled visit, 2-4 weeks after the date of the original test (except for screening 
and baseline results).
y
Weight only

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Protocol GS-US-311-1717
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Gilead Sciences, Inc.
Original
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z
12-lead ECG performed supine every 48 weeks post week 96
aa
Urinalysis only
bb
Sample collected at Day 1 visit is for virology assessments.
cc
F/TAF will be provided to all subjects who would like to receive open-label F/TAF (except in certain countries such as UK). Study drug will not be provided to subjects who 
wish to discontinue participation at this visit.
dd
Single whole blood sample collection (Week 4 only): PBMC sample processing will be performed by the central laboratory; TFV-DP concentrations in PBMCs will be 
determined.
ee
Sample only collected for platelet substudy subjects at selected sites.

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Protocol GS-US-311-1717
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
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Appendix 3.
Management of Clinical and Laboratory Adverse Events
Grade 1
Grade 4
Grade 3
Grade 2
May continue 
dosing at the 
discretion of the 
investigator
Repeat lab to 
confirm toxicity 
grade
Repeat lab to 
confirm toxicity 
grade
If confirmed and possibly and/or probably related to 
investigational medicinal products:
1.
Withhold investigational medicinal products until Grade 2
2.
Restart all investigational medicinal products at full dose
If confirmed and unrelated to 
investigational medicinal products, 
dosing may continue at the 
discretion of the investigator
If confirmed and 
possibly or probably 
related to 
investigational 
medicinal products,
discontinue 
investigational 
medicinal products
dosing permanently 
and follow at periodic 
intervals at least 
weekly until a return 
to baseline or is 
otherwise explained
If Grade 3 or 4 recurrence that is confirmed and possibly or 
probably related to investigational medicinal products, 
discontinue all investigational medicinal products dosing 
permanently
If Grade 3 or 4 recurrence that is considered unrelated to 
investigational medicinal products, continue all investigational 
medicinal products at the same dose at the discretion of the 
investigator

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Protocol GS-US-311-1717
Final
Gilead Sciences, Inc.
Original
CONFIDENTIAL
Page 96
11 March 2015
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Version: 18June2012
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL 
85 to 100 g/L
7.5 to 8.5 g/dL 
75 to 85 g/L
6.5 to 7.5 g/dL 
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days 
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L

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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Neutrophil Count 
(ANC)
Adult and Pediatric, 7 Days
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Infant, 2 – 7 Days
1250 to 1500/mm3
1.25 to 1.50 GI/L
1000 to 1250/mm3
1.00 to < 1.25 GI/L
750 to 1000/mm3
0.75 to < 1.00 GI/L
750/mm3
< 0.75 GI/L
Infant, 1 Day
4000 to 5000/mm3
4.00 to 5.00 GI/L
3000 to 4000/mm3
3.00 to < 4.00 GI/L
1500 to 3000/mm3
1.50 to < 3.00 GI/L
1500/mm3
< 1.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets 
100,000 to < 125,000/mm3
100 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

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Protocol GS-US-311-1717
Final
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Original
CONFIDENTIAL
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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
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% 

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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 
146  to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
146  to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia 
3.0 to 3.4 mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Hyperkalemia 
5.6 to 6.0 mEq/L
6.0 to 6.5 mEq/L
6.5 to 7.0 mEq/L
7.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mmol/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
40 to 55 mg/dL
30 to 40 mg/dL
30 mg/dL
3.03 to 3.58 mmol/L
2.20 to 3.03 mmol/L
1.64 to 2.20 mmol/L
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting 
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
7 Days
7.8 to 8.4  mg/dL
7.0 to 7.8 mg/dL
6.1 to 7.0 mg/dL
6.1 mg/dL
1.94 to 2.10 mmol/L
1.74 to 1.94 mmol/L
1.51 to 1.74 mmol/L
1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L

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Final
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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
1.5 to 2.0 mg/dL
1.0 to 1.5 mg/dL
1.0 mg/dL
0.63  to LLN mmol/L
0.47 to 0.63 mmol/L
0.31 to 0.47 mmol/L
0.31 mmol/L
Pediatric 1 Year–14 Years 
3.0 to 3.5 mg/dL
0.96 to 1.12 mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to 4.5 mg/dL
1.12 to 1.46 mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L

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Final
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Original
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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperbilirubinemia 
Adult and Pediatric 
> 14 Days
1.0 to 1.5 ULN 
1.5 to 2.5 ULN
2.5 to 5.0 ULN 
5.0 ULN 
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN 
2.50 to 5.00 ULN 
5.00 to 10.00 ULN 
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL 
10.0 to 12.0 mg/dL 
12.0 to 15.0 mg/dL 
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
1.5 mg/dL to LLN
1.0 to 1.5 mg/dL
0.5 to 1.0 mg/dL
0.5 mg/dL
87 μmol/L to LLN
57 to 87 μmol/L
27 to 57 μmol/L
27 μmol/L
Creatinine 
1.50 to 2.00 mg/dL
2.00 to 3.00 mg/dL
3.00 to 6.00 mg/dL 
6.00 mg/dL
133 to 177 μmol/L
177 to 265 μmol/L
265 to 530 μmol/L
530 μmol/L
Bicarbonate
16.0 mEq/L to LLN 
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
750 to 1200 mg/dL
1200 mg/dL
5.64–8.47 mmol/L
8.47–13.55 mmol/L
13.55 mmol/L

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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
LDL
(Fasting)
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to  4.92 mmol/L
>4.92 mmol/L
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

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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
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA

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

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

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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, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec 
Asymptomatic, QTc interval 
0.465 to 0.479 sec 
Asymptomatic, QTc interval 
0.480 sec 
Life-threatening 
consequences, e.g., Torsade de 
pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(e.g., anticoagulation, lysis 
filter, invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g.,
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g.,
pulmonary embolism, life-
threatening thrombus) 
Vasovagal Episode (associated 
with a procedure of any kind)
Present without loss of 
consciousness 
Present with transient loss of 
consciousness
NA 
NA
Ventricular Dysfunction 
(congestive heart failure, 
CHF)
NA
Asymptomatic diagnostic 
finding AND intervention 
indicated
New onset with symptoms 
OR Worsening symptomatic 
CHF
Life-threatening CHF

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

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

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

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GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without medical 
intervention indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention indicated
Life-threatening reduction in 
oral intake
Mucositis/Stomatitis 
(clinical exam)
See also Proctitis, 
Dysphagia-Odynophagia
Erythema of the mucosa
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes 
or ulcerations OR Mucosal 
bleeding with minor trauma
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding 
OR Life-threatening 
consequences (e.g., aspiration, 
choking)
Nausea 
Transient (24 hours) or 
intermittent nausea with no 
or minimal interference with 
oral intake
Persistent nausea resulting in 
decreased oral intake for 24–48 
hours
Persistent nausea resulting in 
minimal oral intake for 48 
hours OR Aggressive 
rehydration indicated (e.g.,
IV fluids)
Life-threatening consequences 
(e.g., hypotensive shock)
Pancreatitis
NA
Symptomatic AND 
Hospitalization not indicated 
(other than ER visit)
Symptomatic AND 
Hospitalization indicated 
(other than ER visit)
Life-threatening consequences 
(e.g., sepsis, circulatory 
failure, hemorrhage)
Proctitis (functional-
symptomatic)
Also see Mucositis/ 
Stomatitis for Clinical 
Exam
Rectal discomfort AND No 
intervention indicated
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social/ 
functional activities OR 
Operative intervention 
indicated 
Life-threatening consequences 
(e.g., perforation)
Vomiting
Transient or intermittent 
vomiting with no or 
minimal interference with 
oral intake
Frequent episodes of vomiting 
with no or mild dehydration
Persistent vomiting resulting 
in orthostatic hypotension OR 
Aggressive rehydration 
indicated
Life-threatening consequences 
(e.g., hypotensive shock)

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

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

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

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

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

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

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

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GENITOURINARY
Grade 1
Grade 2
Grade 3
Grade 4
Intermenstrual Bleeding 
(IMB)
Spotting observed by participant 
OR Minimal blood observed 
during clinical or colposcopic 
exam
Intermenstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle
Intermenstrual bleeding greater 
in duration or amount than usual 
menstrual cycle
Hemorrhage with life-
threatening hypotension OR 
Operative intervention 
indicated
Urinary Tract 
obstruction (e.g., stone)
NA
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction
Signs or symptoms of urinary 
tract obstruction with 
hydronephrosis or renal 
dysfunction
Obstruction causing life-
threatening consequences
INFECTION
Grade 1
Grade 2
Grade 3
Grade 4
Infection (any other 
than HIV infection)
Localized, no systemic 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 (e.g., septic 
shock)

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing
Potential, and Contraceptive Recommendations
1.
Pregnancy and Contraception Requirements for Males and Females of 
Childbearing Potential
The risks of treatment with the study drug during pregnancy have not been evaluated. Pregnancy 
must be excluded before the start of treatment with study drug and prevented thereafter by 
reliable contraceptive methods. Pregnancy tests will be performed regularly throughout this
study (Refer to Appendix 2). If females are using hormonal agents for contraception, the safety 
and/or efficacy may be affected by possible drug-drug interaction. However, if females are using 
hormonal agents for contraception, the hormonal agent may be continued and a non-hormonal 
method (or methods) must be used concurrently.  If females utilize hormonal agents as one of 
their contraceptive methods, it is required that the same hormonal method be used for at least 3 
months before study dosing. 
Please refer to the latest version of the Investigator’s Brochure for additional information.
Additional pregnancy precaution requirements may be indicated based on third agent selection 
(refer to the relevant local label) and should be implemented at the discretion of the investigator.
2.
Definition of Female of Childbearing Potential
For the purposes of this study, a female subject of childbearing potential is a non-menopausal 
female who has not had a hysterectomy, bilateral oophorectomy, or medically documented 
ovarian failure.
A female subject may be considered menopausal in either of the following conditions:

Surgical menopause: Appropriate medical documentation of prior complete bilateral 
oophorectomy (i.e., surgical removal of the ovaries and occurring at the age at which the 
procedure was performed)

If age > 54 years and with cessation for ≥12 months of previously occurring menses due to 
ovarian failure.

Women ≤54 years of age and with the absence of normal menses will be considered to be of 
childbearing potential.
3.
Contraceptive Requirements
Male subjects and female subjects of childbearing potential who engage in intercourse must 
agree to utilize protocol specified methods of contraception from the Screening/enrollment visit 
(for females) or first dose visit (for males) and for 30 days following the last dose of study drug. 
Female study subjects who are not heterosexually active must provide periodic confirmation of 
continued abstinence from heterosexual intercourse and regular pregnancy testing while taking 
study medication. The Investigator will counsel subjects on the protocol specified method(s) for 

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avoiding pregnancy in case the subject chooses to engage in heterosexual intercourse.  These 
methods are recommended due to the low failure rate (i.e., less than 1% per year).
Protocol specified contraceptive methods are as follows: (1) a combination of one hormonal 
method and one barrier method; (2) use of an intrauterine device (IUD) or tubal sterilization (See
Appendix Table 1 below) or (3) complete abstinence from intercourse. Periodic abstinence from 
intercourse (for example: calendar, ovulation, symptothermal, post-ovulation methods) is not 
permitted.
Acceptable hormonal methods include injectable progesterone, progesterone implants, 
combination oral contraceptives, transdermal contraceptive patch, and vaginal ring. Acceptable 
barrier methods include diaphragm, cervical cap, and the male condom. Female subjects must 
use either a hormonal method or a barrier method if the partner has a vasectomy. If a subject has
undergone tubal sterilization or has had a Copper T 380A IUD or LNg 20 IUD inserted, no other 
contraception is needed; 
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and the 
contraception methods described below must be used. Female subjects who utilize hormonal 
contraceptives as one of their birth control methods must have used the same method for at least
3 months before study dosing.
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test at Day 1 prior to receiving the first dose of study 
drug.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Methods to Use by Themselves
Combination Methods
Hormone Methods
(choose one and use with a barrier
method)
Barrier Methods
(choose one and use with a hormone 
method)
Intrauterine Devices (IUDs)

Copper T 380A IUD

LNg 20 IUD
Tubal Sterilization
Estrogen and Progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm
   OR
Cervical cap

Male condom (without 
spermicide)
Partner’s vasectomy must be used with a hormone or barrier method.
The Investigator will counsel all subjects on the most effective method(s) for avoiding pregnancy 
during the study.

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Male subjects must agree to use condoms during heterosexual intercourse and avoid sperm 
donation while enrolled in the study and for at least 30 days after administration of the last dose 
of study medication.
Use of condoms (except for lambskin) has been proven to decrease the risk of transmission of 
HIV and other sexually transmitted diseases. The use of spermicide is not recommended if the 
subject or subject’s partner is infected with HIV.
4.
Procedures to be Followed in the Event of Pregnancy
Female subjects will be instructed to notify the Investigator if they become pregnant at any time 
during the study, or if they become pregnant within 30 days of last study drug dose. Subjects 
who become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and seek the investigator’s advice regarding action required with 
the study drug immediately.
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.5.2.

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Appendix 6.
Definitions of HIV-1 Related Disease (CDC Guidelines)
Category B: Symptomatic Conditions in HIV-Infected Subjects

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Constitutional symptoms, such as fever (38.5C) or diarrhea lasting 1 month

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least two distinct episodes or more than 
one Dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

Peripheral neuropathy
Category C: AIDS-Defining Diagnoses

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (1 month duration)

Cytomegalovirus disease (other than liver, spleen or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related

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
Herpes simplex: chronic ulcer(s) (1 month duration); or bronchitis, pneumonitis or 
esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (1 month duration)

Kaposi’s sarcoma

Lymphoma, Burkitt’s (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Myobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis, pulmonary or extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome attributed to HIV infection
CDC surveillance case definitions for HIV infection and AIDS - 2008 {13585}