Clinical trial NCT02616029
Conditions: HIV-1 Infection
Sponsor: Gilead Sciences
Start date: 2015-12-17; Completion date: 2019-07-11
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) after switching from a stable regimen consisting of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) plus a third antiretroviral (ARV) agent in participants harboring the archived nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V and/or M184I in human immunodeficiency virus (HIV) -1 reverse transcriptase.

This is a two part study. If the rate of virologic failure in Part 1 is deemed acceptable, once the internal data monitoring committee officially completes the interim review, the study will continue to Part 2.

Detailed description:

Arms: arm 1: Participants with M184V and/or M184I mutations in reverse transcriptase and without any other NRTI resistance mutation switched from their current human immunodeficiency virus (HIV) treatment regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF (150/150/200/10 mg) FDC tablet orally once daily for 48 weeks.

Allowed third agents include: lopinavir/ritonavir (LPV/r), atazanavir + ritonavir (ATV+RTV), atazanavir+cobicistat (ATV+COBI), darunavir + ritonavir (DRV+RTV), darunavir + cobicistat (DRV+COBI), fosamprenavir + ritonavir (FPV + RTV), saquinavir + ritonavir (SQV + RTV), atazanavir (ATV) (no booster) efavirenz (EFV), rilpivirine (RPV), nevirapine (NVP), etravirine (ETR), raltegravir (RAL) or dolutegravir (DTG). arm 2: Participants with M184V and/or M184I mutations in reverse transcriptase and with or without 1 or 2 TAMs switched from their current HIV treatment regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF (150/150/200/10 mg) FDC tablet orally once daily for 48 weeks.

Allowed third agents include: LPV/r, ATV+RTV, ATV+COBI, DRV+RTV, DRV+COBI, FPV + RTV, SQV + RTV, ATV (no booster) EFV, RPV, NVP, ETR, RAL or DTG.
Interventions: intervention 1: E/C/F/TAF
Intervention descriptions: intervention 1: 150/150/200/10 mg FDC tablets administered orally once daily

Protocol documents:
SAP_002.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3b Open-Label Pilot Study to Evaluate Switching to 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) Fixed Dose Combination (FDC) in 
Virologically-Suppressed HIV-1 Infected Adult Subjects 
Harboring the Archived Isolated NRTI Resistance Mutation 
M184V/M184I
Name of Test Drug:
E/C/F/TAF FDC
Study Number:
GS-US-292-1824
Protocol Version:
Amendment 1
Protocol Date:
19 August 2016
Analysis Type:
Final Analysis
Analysis Plan Version:
3.0
Analysis Plan Date:
31 January 2020
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF ABBREVIATIONS........................................................................................................................................6
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design............................................................................................................................................8
1.3.
Sample Size and Power............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Week 12 Internal Data Monitoring Committee Analysis.......................................................................11
2.2.
Interim Analysis.....................................................................................................................................11
2.3.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................13
3.2.
Strata and Covariates..............................................................................................................................13
3.3.
Subject Subgroup Grouping...................................................................................................................13
3.4.
Multiple Comparisons............................................................................................................................13
3.5.
Missing Data and Outliers......................................................................................................................13
3.5.1.
Missing Data ........................................................................................................................13
3.5.2.
Outliers.................................................................................................................................13
3.6.
Data Handling Conventions and Transformations .................................................................................14
3.7.
Analysis Visit Windows.........................................................................................................................14
3.7.1.
Definition of Study Day .......................................................................................................14
3.7.2.
Analysis Visit Windows.......................................................................................................15
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................17
4.
SUBJECT DISPOSITION ..................................................................................................................................19
4.1.
Subject Enrollment and Disposition.......................................................................................................19
4.1.1.
Subject Enrollment...............................................................................................................19
4.1.2.
Disposition of Subjects.........................................................................................................19
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................19
4.2.1.
Duration of Exposure to Study Drug....................................................................................19
4.2.2.
Adherence to Study Drug.....................................................................................................20
4.3.
Protocol Deviations................................................................................................................................21
5.
BASELINE DATA .............................................................................................................................................22
5.1.
Demographics ........................................................................................................................................22
5.2.
Baseline Disease Characteristics............................................................................................................22
5.3.
Medical History......................................................................................................................................23
6.
EFFICACY ANALYSES ...................................................................................................................................24
6.1.
Primary Efficacy Endpoint.....................................................................................................................24
6.1.1.
Definition of Primary Efficacy Endpoint .............................................................................24


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6.1.1.1.
Definition of Pure Virologic Response at Week 12........................................24
6.1.1.2.
Joint Distribution of Pure Virologic Failure and Study Drug 
Discontinuation...............................................................................................24
6.1.1.3.
Time to Pure Virologic Failure Analysis........................................................25
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint....................................................25
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint ............................................................25
6.1.4.
Secondary Analysis for the Primary Efficacy Endpoint.......................................................26
6.1.4.1.
Analysis of Pure Virologic Response at Week 12 ..........................................26
6.1.5.
Subgroup Analysis for the Primary Efficacy Endpoint ........................................................26
6.2.
Secondary Efficacy Endpoints ...............................................................................................................26
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................26
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................26
6.2.2.1.
Analysis of Pure Virologic Response at Weeks 24 and 48.............................26
6.2.2.2.
Time to Pure Virologic Failure Analysis........................................................26
6.2.2.3.
Analysis of proportion of subjects with HIV-1 RNA < 50 
copies/mL at Weeks 12, 24, and 48 as determined by the US 
FDA-defined snapshot algorithm....................................................................27
6.2.2.4.
Analysis of proportion of subjects with HIV-1 RNA < 20 
copies/mL at Weeks 12, 24, and 48 as determined by the US 
FDA-defined snapshot algorithm....................................................................28
6.2.2.5.
Analysis of Proportion of Subjects with HIV-1 RNA 
< 50 copies/mL (Missing = Excluded and Missing = Failure 
Approaches)....................................................................................................28
6.2.2.6.
Analysis of CD4+ cell count...........................................................................29
6.2.2.7.
Analysis of CD4% ..........................................................................................29
6.3.
Changes From Protocol-Specified Efficacy Analyses............................................................................29
7.
SAFETY ANALYSES........................................................................................................................................30
7.1.
Adverse Events and Deaths....................................................................................................................30
7.1.1.
Adverse Event Dictionary ....................................................................................................30
7.1.2.
Adverse Event Severity........................................................................................................30
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................30
7.1.4.
Relationship of AEs to Study Procedure..............................................................................30
7.1.5.
Serious Adverse Events........................................................................................................30
7.1.6.
Treatment-Emergent Adverse Events...................................................................................31
7.1.6.1.
Definition of Treatment-Emergent Adverse Events .......................................31
7.1.6.2.
Incomplete Dates ............................................................................................31
7.1.7.
Summaries of Adverse Events and Deaths...........................................................................31
7.1.8.
Additional Analysis of Adverse Events ...............................................................................33
7.1.8.1.
Stage 3 Opportunistic Illnesses in HIV...........................................................33
7.1.9.
Fracture Events.....................................................................................................................33
7.2.
Laboratory Evaluations ..........................................................................................................................33
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................33
7.2.1.1.
Metabolic Assessments...................................................................................34
7.2.1.2.
Calcium Corrected for Albumin .....................................................................34
7.2.2.
Graded Laboratory Values ...................................................................................................34
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................35
7.2.2.2.
Summaries of Laboratory Abnormalities........................................................35
7.2.3.
Liver-related Laboratory Evaluations...................................................................................35
7.3.
Renal Safety Analyses............................................................................................................................36
7.3.1.
Serum Creatinine..................................................................................................................36
7.3.2.
Estimated Glomerular Filtration Rate ..................................................................................36
7.3.2.1.
Estimated Glomerular Filtration Rate: Cockroft-Gault...................................36


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7.3.2.2.
Estimated Glomerular Filtration Rate: CKD-EPI (cystatin 
C) ....................................................................................................................36
7.3.3.
Proteinuria by Urinalysis (Dipstick).....................................................................................37
7.3.4.
Proteinuria by Quantitative Assessment...............................................................................37
7.4.
Vital Signs..............................................................................................................................................37
7.5.
Prior and Concomitant Medications.......................................................................................................38
7.5.1.
Nonstudy-Drug Antiretroviral Medications .........................................................................38
7.5.2.
Concomitant Non-Antiretroviral Medications......................................................................38
7.6.
Electrocardiogram Results .....................................................................................................................39
7.7.
Other Safety Measures ...........................................................................................................................39
7.8.
Subject Subgroup for Safety Endpoints .................................................................................................39
7.9.
Changes From Protocol-Specified Safety Analyses...............................................................................39
8.
PATIENT REPORT OUTCOMES.....................................................................................................................40
8.1.
Adherence – Visual Analogue Scale (VAS) Adherence Questionnaire.................................................40
8.1.1.
VAS Statistical Method........................................................................................................40
8.2.
SF-36 (Version 2) Health Survey...........................................................................................................40
8.2.1.
Scoring the SF-36.................................................................................................................40
8.2.2.
SF-36 Statistical Analysis Method .......................................................................................40
8.3.
HIV Treatment Satisfaction Questionnaire ............................................................................................41
8.3.1.
HIV Treatment Satisfaction Questionnaires Statistical Analysis Method............................42
8.4.
Functional Assessment of Chronic Illness Therapy – Fatigue ...............................................................42
8.4.1.
Scoring the Functional Assessment of Chronic Illness Therapy – Fatigue ..........................42
8.4.2.
Functional Assessment of Chronic Illness Therapy – Fatigue Analysis 
Method .................................................................................................................................45
8.5.
EQ-5D-3L ..............................................................................................................................................45
8.5.1.
Scoring the EQ-5D-3L Descriptive System .........................................................................45
8.5.2.
EQ-5D Single Summary Index.............................................................................................46
8.5.3.
Scoring the EQ VAS ............................................................................................................46
8.5.4.
EQ-5D Statistical Analysis Method .....................................................................................46
9.
REFERENCES ...................................................................................................................................................47
10.
SOFTWARE.......................................................................................................................................................48
11.
SAP REVISION..................................................................................................................................................49
12.
APPENDICES ....................................................................................................................................................50
Appendix 1.
Schedule of Assessents...........................................................................................................51
Appendix 2.
Flowchart of US FDA-Defined Snapshot Algorithm (for Switch Study Trial)......................54
Appendix 3.
UK TTO Value Set for EQ-5D-3L Questionnaire..................................................................55
Appendix 4.
Fracture Events.......................................................................................................................59
Appendix 5.
Programming Specification....................................................................................................62


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LIST OF IN-TEXT TABLES
Table 3-1.
Analysis Visit Windows for HIV-1 RNA and VAS...............................................................15
Table 3-2.
Analysis Visit Windows for CD4+ Cell Count, CD4%, Hematology, Chemistry, 
Urinalysis, Urine Chemistry Laboratory Tests, eGFRCG, Vital Signs and Weight.................16
Table 3-3.
Analysis Visit Windows for Fasting Glucose, Lipid Panels, EQ-5D, SF-36, and 
FACIT-F.................................................................................................................................16
Table 3-4.
Analysis Visit Windows for ECG ..........................................................................................16
Table 3-5.
Analysis Visit Windows for HIVTSQs (at Day 1 Only) and HIVTSQc ................................17
Table 8-1.
List of Items on the HIVTSQ .................................................................................................41
Table 8-2.
Items by Subscale and Scoring Algorithm for FACIT-F........................................................43
Table 8-3.
Computation of Aggregate Scores..........................................................................................45
Table 8-4.
Scores of EQ-5D-3L Descriptive System...............................................................................45
Table 8-5.
Response Category for Responder Analysis...........................................................................46


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LIST OF ABBREVIATIONS
3TC
lamivudine
ABC
abacavir
AE
adverse event
ALT
alanine aminotransferase
ARV
antiretroviral
AST
aspartate aminotransferase
BMI
body mass index
CI
confidence interval
CK
creatine kinase
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
ECG
electrocardiogram
ESDD
early study drug discontinuation
ET
early termination
FAS
Full Analysis Set
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
FDC
fixed dose combination
GFR
glomerular filtration rate
Gilead
Gilead Sciences
Hb
hemoglobin
HIVTSQ
HIV Treatment Satisfaction Questionnaire
HLGT
high level group term
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
ID
identification
iDMC
Internal Data Monitoring Committee 
INSTI
integrase strand transfer inhibitor
ITT
intent to treat
KM
Kaplan-Meier
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
NNRTI
non-nucleoside reverse transcriptase inhibitors
NRTI
nucleoside reverse transcriptase inhibitors
PI
protease inhibitor
PP
per protocol
PRO
patient reported outcomes


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PT
preferred term
PVF
pure virologic failure
PVR
pure virologic response
Q1, Q3
first quartile, third quartile
SAE
serious adverse events
SAP
statistical analysis plan
SD
standard deviation
SI (units)
international system of units
SOC
system organ class
TAM
thymidine analogue associated mutations
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
UACR
urine albumin to creatinine ratio
UPCR
urine protein to creatinine ratio
ULN
upper limit of normal
VAS
visual analogue scale
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-292-1824. This SAP is based on the study protocol (Amendment 1) dated 
19 August 2016 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 
(E/C/F/TAF) fixed dose combination (FDC) after switching from a stable regimen consisting 
of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or abacavir (ABC)/lamivudine
(3TC) plus a third antiretroviral agent in maintaining HIV-1 RNA < 50 copies/mL at 
Week 12 (using pure virologic response) in subjects harboring the archived 
nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V 
and/or M184I in HIV-1 reverse transcriptase
The secondary objectives of this study are as follows:

To determine the safety and tolerability of E/C/F/TAF FDC in subjects switching from 
2 NRTI plus third antiretroviral agent regimens

To evaluate the development of new resistance mutations in subjects who develop virologic 
failure after switching to E/C/F/TAF FDC

To determine the durability of efficacy at Weeks 24 and 48 in maintaining HIV-1 RNA 
< 50 copies/mL using pure virologic response (PVR)
1.2.
Study Design
This is an open-label, single arm, multicenter, two part study to evaluate the efficacy and safety 
of switching to E/C/F/TAF FDC in HIV-1 infected adult subjects who are virologically 
suppressed (HIV-1 RNA < 50 copies/mL) harboring an archived isolated M184V and/or M184I 
mutation and who have been on a stable regimen consisting of FTC/TDF or ABC/3TC plus a 
third antiretroviral agent for ≥ 6 consecutive months prior to screening. Eligible subjects will be 
assigned to E/C/F/TAF FDC.
Enrollment of subjects will proceed in 2 parts: Part 1 and Part 2. Each part will consist of 
subjects who have a documented presence of M184V and/or M184I mutations (mixtures are 
acceptable) in reverse transcriptase. 


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In Part 1, the subjects will have M184V and/or M184I (mixtures are acceptable) in reverse 
transcriptase WITHOUT any other NRTI resistance mutation (including thymidine 
analogue-associated mutations (TAMs) [TAMs are: M41L, D67N, K70R, L210W, T215Y/F, and 
K219Q/E/N/R], K65R, K70E, T69 insertion, and/or Q151M mutation complex [A62V, V75I, 
F77L, F116Y, Q151M]. If the rate of virologic failure in Part 1 is deemed acceptable, after the 
internal Data Monitoring Committee (iDMC) officially completes the interim review, the study 
will continue to Part 2 (with the expanded entry criteria). 
In Part 2, the subjects will have M184V and/or M184I (mixtures are acceptable) in reverse 
transcriptase WITH or WITHOUT 1 or 2 TAMs. Evidence of K65R, K70E, T69 insertion, 
and/or Q151M mutation complex in subjects in addition to the resistance mutations above will 
not be eligible for entry into the study.
The study will consist of a 42-day screening period (within 42 days before Day 1 visit), followed 
by a 48 week treatment period. After Day 1, subjects will return for study visits at Weeks 4, 8, 
12, 16, 24, 36 and 48. End of study is defined as completion of the 48 weeks of treatment and the 
30 Day Follow-Up visit.
Plasma HIV-1 RNA, assessment of adverse events (AEs) and concomitant medications are 
performed at screening, baseline, Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, and 
Week 48/Early Study Drug Discontinuation (ESDD) visit.
Laboratory analyses (CD4+ cell count, estimated glomerular filtration rate [eGFRCG], serum 
chemistry, hematology, urinalysis and urine chemistry, pregnancy testing [for females of 
childbearing potential]), and vital signs are performed at screening, baseline, Week 4, Week 8, 
Week, 12, Week 24, Week 36, and Week 48/ESDD visit. Metabolic assessments are performed 
at baseline, Week 24, and Week 48.
12-Lead electrocardiogram (ECG) (performed supine) is collected at screening and 
Week 48/ESDD only.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies (ie, HBV virus surface antigen 
[HBsAg], hepatitis B core antibody [HBcAb], and hepatitis C virus [HBCAb] serologies 
[reflex HCV RNA is performed in subjects with positive HCVAb serology]) are performed at 
screening only. Height is collected at screening only.
For further details of assessments taken at each visit, see Schedule of Assessments, Appendix 1.
1.3.
Sample Size and Power
The primary analysis will describe the point estimate and 95% confidence interval (CI) around 
the proportion of subjects with HIV-1 RNA < 50 copies/ mL for the primary endpoint. If the 
observed pure virologic response rate is 90%, then with 100 participants, the width of the 95% 
CI will be ± 5.9% (large sample size approximation and binomial distribution).


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After the Week 12 (iDMC review for Part 1, the actual pure virologic response rate in Part 1 was 
determined to be 100%. Based on this, it was reasonable to assume that the observed pure 
virologic response rate for the study will be 95% or higher, and the sample size of the study was 
reduced to 64 subjects. Under this assumption, with a sample size of 64 subjects, the width of the 
95% CI will be ± 5.3% or lower (large sample size approximation and binomial distribution).


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Week 12 Internal Data Monitoring Committee Analysis
An internal Data Monitoring Committee (iDMC) reviewed the progress of the study and 
performed interim reviews of safety and efficacy data in order to protect subject welfare.
The initial interim review was conducted after all subjects enrolled in Part 1 completed the 
Week 12 visit assessment or prematurely discontinued study drug.
The iDMC’s role and responsibilities, including the scope of analysis to be provided to the 
iDMC, were provided in a mutually agreed upon charter, which defined the iDMC membership, 
meeting logistics, and meeting frequency. 
2.2.
Interim Analysis
No formal interim efficacy analysis, with the possibility of early termination for efficacy or 
futility, is planned.
2.3.
Final Analysis
After all subjects (Part 1 and Part 2) have completed the study, outstanding data queries have 
been resolved or adjudicated as unresolvable, and the data have been cleaned and finalized, the 
final analysis of the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (SD) or standard error (SE), median, 
first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set unless 
otherwise specified, and sorted by subject identification (ID) number, visit date, and time
(if applicable). Data collected on log forms, such as AEs, will be presented in chronological 
order within subject. The part (e.g. Part 1 or Part 2) under which subjects were enrolled will be 
included in the listings.
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If a subject was not dosed with study drug, the date of enrollment will be 
used instead of the first dose date of study drug. For screen failures, age as calculated on the date 
that informed consent was signed will be used.
In general, permanent discontinuation of study drug refers to premature discontinuation of study 
drug or completeness of study drug.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing. A summary of the number and percentage of subjects in each analysis 
set will be provided overall and by Parts 1 and 2.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis set includes all subjects who enrolled into the study. This is the 
primary analysis set for by-subject listings.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) will include all the subjects who were enrolled and received at least 
one dose of study drug. For the FAS, all efficacy data will be included, unless specified 
otherwise.  The FAS is the primary analysis set for the efficacy analyses.
Subjects meeting the following criteria will be excluded from the FAS:

Subjects who took Stribild or Descovy as part of the baseline antiretroviral (ARV) regimen 
and thus violated the inclusion criterion.


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3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all enrolled subjects who took at least 1 dose of study drug. 
This is the primary analysis set for safety analyses.
3.2.
Strata and Covariates
There is no stratification for enrollment.
3.3.
Subject Subgroup Grouping
The subjects will be grouped by Part 1, Part 2 and overall.
3.4.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.5.
Missing Data and Outliers
3.5.1.
Missing Data
A missing data point for a given study visit may be due to any of the following reasons:

A visit occurred in the window but data were not collected or were unusable

A visit did not occur in the window

A subject permanently discontinued from the study before reaching the window.
In general, values for missing data will not be imputed, unless otherwise specified.
For missing last dosing date of study drug, imputation rules are described in Section 3.5.1 and 
the SAP Appendix 5. The handling of missing or incomplete dates for AE onset is described in 
Section 7.1.6.2, and for concomitant medications in Section 7.5.2 as well as the SAP 
Appendix 5.
3.5.2.
Outliers
Outliers will be identified during the data management and data analysis processes, but no 
sensitivity analyses will be done to evaluate the impact of outliers on efficacy or safety 
outcomes, unless specified otherwise. All data will be included in the analyses.


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3.6.
Data Handling Conventions and Transformations
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows except for urine creatinine:

A value that is 1 unit less than the limit of quantitation (LOQ) will be used for calculation of 
descriptive statistics if the datum is reported in the form of “< x” (x is considered as the limit 
of quantitation). For example, if the values are reported as < 20 and < 5.0, values of 19 
and 4.9 will be used for calculation of summary statistics, respectively. An exception to this 
rule is: for values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used 
for calculation of summary statistics.

A value that is 1 unit above the LOQ will be used for calculation of descriptive statistics if 
the datum is reported in the form of “> x” (x is considered as the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used for calculation of descriptive statistics if the data is reported in the 
form of “≤x” or “≥x” (x is considered as the LOQ).
For urine creatinine, value of “< 1” is handled as a missing value in its summary and the 
calculation of related ratios.
3.7.
Analysis Visit Windows
3.7.1.
Definition of Study Day
Study Day 1 is defined as the day when the first dose of study drug (ie, E/C/F/TAF) was taken, 
as recorded on the Study Drug Administration eCRF form.
Study Days are calculated relative to Study Day 1. For events that occurred on or after 
Study Day 1 date, study days are calculated as (visit date minus date of the first dose plus 1). 
For events that occurred prior to Study Day 1, study days are calculated as (visit date minus date 
of the first dose).
Last Dose Date is the latest nonmissing end date of study drug (E/C/F/TAF) recorded on the 
Study Drug Administration eCRF form with “Study Drug Permanently Withdrawn” box checked 
for subjects who prematurely discontinued study drug or who completed study drug according to 
Study Drug Completion eCRF.
If the date of last dose is missing (eg, only year of last dose is known or completely missing due 
to lost to follow-up) for subjects who prematurely discontinued study drug, or for subjects who 
completed study drug, the latest of nonmissing study drug start dates and end dates, the clinic 
visit dates, and the laboratory visit dates excluding the date of 30-day follow-up visit will be 
used to impute the last dose date. For other partial missing last dose date, please see SAP 
Appendix 5 for details.


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Last Study Date is the latest of nonmissing study drug start dates and end dates, the clinic visit 
dates, and the laboratory visit dates including the 30-day follow-up visit date for subjects who 
prematurely discontinued study or who completed study according to Study Completion eCRF.
Baseline Value for HIV-1 RNA, CD4+ cell count, CD4%, hematology, chemistry, urinalysis 
and urine chemistry laboratory tests, fasting glucose and lipid panels, eGFRCG, cystatin C testing, 
vital signs and weight, safety electrocardiogram (ECG), Visual Analogue Scale (VAS) 
Adherence Questionnaire, Medical Outcome Study Short Form-36 Questionnaire (SF-36), HIV 
Treatment Satisfaction Questionnaire (HIVTSQ) (Status at Day 1 only), Functional Assessment 
of Chronic Illness Therapy Fatigue (FACIT-F), and EQ-5D is defined as the last nonmissing 
value obtained on or prior to Study Day 1.
3.7.2.
Analysis Visit Windows
Subject visits might not occur on protocol-specified days. Therefore, for the purpose of analysis, 
observations will be assigned to analysis windows.
The analysis windows for HIV-1 RNA and VAS are provided in Table 3-1.
Table 3-1.
Analysis Visit Windows for HIV-1 RNA and VAS
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
71
98
Week 16
112
99
140
Week 24
168
141
210
Week 36
252
211
294
Week 48
336
295
378
The analysis windows for CD4+ cell count, CD4%, hematology, chemistry, urinalysis, urine 
chemistry laboratory tests, eGFRCG, vital signs and weight, are provided in Table 3-2.


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Table 3-2.
Analysis Visit Windows for CD4+ Cell Count, CD4%, Hematology, 
Chemistry, Urinalysis, Urine Chemistry Laboratory Tests, eGFRCG, 
Vital Signs and Weight
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
28
2
42
Week 8
56
43
70
Week 12
84
71
126
Week 24
168
127
210
Week 36
252
211
294
Week 48
336
295
378
The analysis windows for fasting glucose, lipid panels, EQ-5D, SF-36, and FACIT-F are 
provided in Table 3-3.
Table 3-3.
Analysis Visit Windows for Fasting Glucose, Lipid Panels, EQ-5D, 
SF-36, and FACIT-F
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 24
168
2
252
Week 48
336
253
420
Lipid panel includes total cholesterol, HDL, direct LDL and triglycerides.
The analysis windows for ECG are provided in Table 3-4.
Table 3-4.
Analysis Visit Windows for ECG
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 48
336
2
671


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The analysis windows for HIVTSQs (at Day 1 Only) and HIVTSQc are provided in Table 3-5.
Table 3-5.
Analysis Visit Windows for HIVTSQs (at Day 1 Only) and HIVTSQc
Nominal Visit
Nominal Day
Lower Limit
Upper Limit
Baseline
1
(none)
1
Week 4
28
2
98
Week 24
168
99
252
Week 48
336
253
420
3.7.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require one value per analysis window. When a single value is 
needed, the following rule(s) will be used:
If multiple nonmissing numeric observations exist in a window, records will be chosen as 
follows:

For baseline, the last available record on or prior to the date of the first dose of study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, average (geometric mean for HIV-1 RNA and arithmetic mean for others) will be 
computed for that day.

For postbaseline visits:
For key efficacy and safety data (ie, HIV-1 RNA level, CD4+ cell count, and CD4%), the 
latest record in the window will be selected.
For other numeric observations, the record closest to the nominal day for that visit will be 
selected. If there are 2 records equidistant from the nominal day, the latest will be 
selected.
If there is more than 1 record on the selected day, the average will be taken
(geometric mean for HIV-1 RNA and arithmetic mean for others).


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If multiple nonmissing categorical observations (eg, safety ECG results) exist in a window, 
records will be chosen as follows:

For baseline, the last available record on or prior to the date of the first dose of the study drug 
will be selected. If there are multiple records with the same time or no time recorded on the 
same day, the value with the lowest severity will be selected (eg, normal will be selected over 
abnormal for safety ECG findings).

For postbaseline visits, the most conservative value within the window will be selected 
(eg, abnormal will be selected over normal for safety ECG)


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
4.1.1.
Subject Enrollment
The number and percentage of subjects enrolled in each country and by each investigator within 
a country will be summarized for all subjects in the Safety Analysis Set by Parts 1 and 2. 
The enrollment related data will be listed.
4.1.2.
Disposition of Subjects
A summary of subject disposition will be provided overall and by Parts 1 and 2. This summary 
will present the number and/or percentage of subjects screened, screen failure subjects who were 
not enrollment, subjects who met all eligibility criteria and were not enrolled, subjects enrolled, 
subjects enrolled but not treated, subjects in the Safety Analysis Set, subjects in the FAS.
In addition, the number and percentage of subjects meeting the following criteria will be 
summarized:

Prematurely discontinued study drug (with summary of reasons for discontinuing treatment)

Prematurely discontinued from the study (with summary of reasons for discontinuing the 
study).
The denominator for the percentage of subjects in each category will be the number of subjects 
in the Safety Analysis Set.
A data listing of reasons for premature study drug discontinuation will be provided.
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Duration of exposure to study drug will be defined as (last dose date first dose date + 1), 
regardless of temporary interruptions in study drug administration, and will be expressed in 
weeks (recorded to 1 decimal place, eg, 4.5 weeks). 


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Duration of exposure to study drug will be summarized overall and by Parts 1 and 2 using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum). The number and 
percentage of subjects in the following categories will also be summarized: ≥ 4 weeks [28 days], 
≥ 8 weeks [56 days], ≥ 12 weeks [84 days], ≥ 16 weeks [112 days], ≥ 24 weeks [168 days], 
≥36 weeks [252 days], and ≥48 weeks [336 days]. These categories start with a cumulative 
count thus subjects who complete the study will be counted from the first category up.
Time to premature discontinuation of study drug will be analyzed using the Kaplan-Meier (KM) 
method for all subjects in the Safety Analysis Set and by Parts 1 and 2.
A KM plot of the estimates for time to premature discontinuation will be generated.
4.2.2.
Adherence to Study Drug
Study drug regimen adherence will be computed based on pill counts. The numbers of pills of 
study drug (E/C/F/TAF) dispensed and returned are captured on Study Drug Accountability 
eCRF.
Adherence (%) of study drug regimen for each study drug will be calculated as follows:
Adherence (%)  100 ×
	
    

	
    
= 100 ×
∑No. of pills taken at each dispensing period[/]
∑No. of pills prescribed at each dispensing period[2]
[1] Number of pills taken at a distinct dispensing period for a study drug is calculated as the 
minimum of (a) the daily number of pills prescribed for the study drug multiplied by the 
duration of treatment at the dispensing period of the same dispensing date, and (b) the number 
of pills taken for the study drug (number of pills dispensed minus the number of pills returned). 
Total number of pills taken is determined by summing the number of pills taken for each study 
drug contained in the study drug regimen from all evaluable dispensing periods. 
[2] Number of pills prescribed at a distinct dispensing period for a study drug is calculated as the 
daily number of pills prescribed for the study drug multiplied by the duration of treatment at 
the dispensing period of the same dispensing date. Total number of pills prescribed is determined 
by summing the number of pills prescribed for the study drug from all evaluable dispensing 
periods.
The duration of treatment at a dispensing period for a study drug is calculated as the minimum 
of (a) the last returned date of the same dispensing period for the study drug, (b) date of 
premature discontinuation of the study drug, and (c) next pill dispensing date of the study drug, 
minus dispensing date of the study drug. 


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The next pill dispensing date is the following dispensing date of the study drug regardless of 
the bottle return date. 
For a record where the number of pills returned was missing (with “Yes” answered for “Was the 
Bottle returned?” question), it is assumed the number of pills returned was zero. If the number of 
pills dispensed was missing or any study drug bottle was not returned or the bottle return status 
was unknown for the same dispensing date, all records for the same dispensing date for that 
study drug will be excluded from both denominator and numerator calculation. 
Descriptive statistics for adherence to study drug regimen (n, mean, SD, median, Q1, Q3, 
minimum and maximum) along with the number and percentage of subjects belonging to 
adherence categories (eg, < 80%, ≥ 80% to < 90%, ≥ 90% to < 95%, ≥95%) will be provided 
overall and by Parts 1 and 2 for subjects who return at least 1 bottle and have calculable 
adherence during the study in the Safety Analysis Set. 
4.3.
Protocol Deviations 
A listing will be provided for all enrolled subjects who violated at least one inclusion or 
exclusion criterion. The listing will include the criteria not met.


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5.
BASELINE DATA
5.1.
Demographics
Subject demographic data (age, sex, race, and ethnicity) and baseline characteristics (body 
weight, height, body mass index [BMI]) will be summarized overall and by Parts 1 and 2 using 
descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and maximum) for continuous 
data and by the number and percent of subjects for categorical data. The summaries of 
demographic data and baseline characteristics will be provided using the Safety Analysis Set. 
Age is calculated as age in years at first dose of study drug.
5.2.
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized overall and by Parts 1 and 2:

HIV-1 RNA categories (copies/mL): (a) < 50, (b) ≥50

CD4+ cell count (/μL)

CD4+ cell count categories (/μL): (a) < 50, (b) ≥ 50 to < 200, (c) ≥ 200 to < 350, (d) ≥350 to 
< 500, and (e) ≥500

CD4 percentage (%)

HIV risk factors (mode of infection): (a) Heterosexual Sex; (b) Homosexual Sex; (c) IV Drug 
Use; (d) Transfusion; (e) Vertical Transmission; (f) Other; (g) Unknown

HIV disease status: (a) Asymptomatic; (b) Symptomatic HIV Infection; (c) AIDS; 
(d) Unknown

HBV Surface Antigen Status (Yes, No)

HCV Antibody Status (Yes, No)

Estimated GFR by CG (see Section 7.3.2.1)

Estimated GFR by CKD-EPI (see Section 7.3.2.2)

Proteinuria by urinalysis (dipstick)

Tobacco smoking history (Current/Former)

Genetic mother/father/ brother/sister with myocardial infarction/stroke before 50 years-old?

Currently using indinavir, lopinavir, or abacavir


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
Baseline alanine aminotransferase (ALT) (U/L)

Baseline aspartate aminotransferase (AST) (U/L)

Baseline platelet count (103/µL)
A by-subject listing of baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
General medical history data will be collected at screening and listed only. General medical 
history data will not be coded.


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6.
EFFICACY ANALYSES 
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects with HIV-1 RNA < 50 copies/mL at
Week 12 as defined by PVR.
6.1.1.1.
Definition of Pure Virologic Response at Week 12
The following criterion is considered for classifying subjects as a pure virologic responder at 
Week 12:

No confirmed rebound (ie, no instances of either HIV-1 RNA ≥ 50 copies/mL on 2 
consecutive visits or last available HIV-1 RNA ≥ 50 copies/mL followed by premature 
discontinuation of study) by the upper limit of the Week 12 analysis window. 
Note: For confirmation of virologic rebound, the first HIV-1 RNA datum must occur on or 
before the upper limit of the Week 12 analysis window. The confirming event (ie, the second of 
the 2 consecutive HIV-1 RNA values or premature study discontinuation) can occur after the 
upper limit of the Week 12 analysis window.
Subjects who meet the above criterion are PVRs at Week 12; otherwise subjects are pure 
virologic failures (PVFs) at Week 12.
6.1.1.2.
Joint Distribution of Pure Virologic Failure and Study Drug Discontinuation
PVF at Week 48 is defined similary as PVF at Week 12, except that the time point is at Week 48.  
For subjects with PVF at Week 48, event time is defined as the day of the first occurrence of 
confirmed HIV-1 RNA ≥50 copies/mL or the collection time of last available HIV-1 RNA 
≥50 copies/mL followed by premature discontinuation of study.
Drug discontinuation (DC) is defined as subjects who prematurely discontinued study drug on or 
prior to the upper limit of the Week 48 analysis window. The premature study drug 
discontinuation date is the last dose date defined in Section 3.7.1.
To better understand the relationship between study drug discontinuation and pure virologic 
failure by Week 48, subjects will be classified into the following 4 categories:

Success is defined as subjects who were pure virologic responders and did not discontinue 
study drug prematurely.

PVF alone is defined as subjects who were pure virologic failures but did not discontinue 
study drug prematurely.


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
DC alone is defined as subjects who were pure virologic responders but discontinued study 
drug prematurely.

PVF and DC is defined as subjects who were pure virologic failures and discontinued study 
drug prematurely.
For ‘DC alone’ and ‘PVF and DC’ categories, reasons for DC will be grouped into 
3 mutually exclusively categories: (1) DC due to drug, including discontinuation due to lack of 
efficacy, death, or AE; (2) DC due to choice, including discontinuation due to noncompliance, 
withdrew consent, protocol violation, or investigator’s discretion (3) DC due to administration, 
including lost to follow-up or pregnancy.  For each premature study drug discontinuation 
group under ‘PVF and DC’ category, outcomes will further be broken down into 
3 mutually exclusively categories based on the sequence when PVF and DC occurred: 
(1) PVF-DC is defined as subjects who met the criteria for PVF followed by DC; 
(2) PVF/DC is defined as subjects who met the criteria for PVF and DC at the same time; 
(3) DC-PVF is defined as subjects who had DC first and then met the criteria for PVF.
The pure virologic response analysis will be descriptive in nature using the FAS only. No 
inferential statistics will be provided.
6.1.1.3.
Time to Pure Virologic Failure Analysis
For subjects who do not experience a confirmed rebound (ie, HIV-1 RNA ≥50 copies/mL on 
2 consecutive visits or the last available HIV-1 RNA ≥50 copies/mL followed by premature 
discontinuation of study) by the data cut, subjects will be censored at the last HIV-1 RNA 
collection date. For subjects who experience confirmed rebound, the time to PVF will be defined 
as the earlier time of 2 consecutive HIV-1 RNA ≥50 copies/mL or the last available HIV-1 RNA 
≥ 50 copies/mL followed by premature discontinuation of study. 
Time to PVF will be analyzed using the Kaplan-Meier method by treatment group using the 
FAS. The log rank test will be performed to compare the difference in time to PVF between the 
2 treatment groups stratified by the prior treatment regimen (ie, STB, ATR, or
ATV/boosted+TVD). 
Lastly, subjects who failed according to snapshot algorithm, pure virologic failure analysis 
algorithms, or had premature study drug discontinuation by Week 48 will be listed. 
6.1.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
No formal statistical hypotheses are being tested.
6.1.3.
Primary Analysis of the Primary Efficacy Endpoint
The number and proportion of subjects with PVR and PVF at Week 12 will be summarized 
overall and by Parts 1 and 2. Two-sided 95% CIs will be constructed for the overall estimate of 
PVR and PVF using the normal approximation and the exact method. 


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6.1.4.
Secondary Analysis for the Primary Efficacy Endpoint
6.1.4.1.
Analysis of Pure Virologic Response at Week 12
Subjects who took Stribild or Descovy as part of the baseline ARV regiment were excluded from 
the FAS. A sensitivity analysis will be performed by including these subjects in the PVR 
analysis.
6.1.5.
Subgroup Analysis for the Primary Efficacy Endpoint
No subgroup analyses will be performed.
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints are:

HIV-1 RNA< 50 copies/mL at Weeks 24 and 48 using PVR (See Section 6.2.2.2)

HIV-1 RNA < 50 copies/mL at Weeks 12, 24 and 48 using the Food and Drug 
Administration (FDA) snapshot analysis (sensitivity analysis)

The proportion of subjects with HIV-1 RNA < 20 copies/mL at Weeks 12, 24, and 48 as 
determined by the US FDA-defined snapshot algorithm. 

The proportion of subjects with HIV-1 RNA 50 copies/mL at Weeks 12, 24, and 48 as 
defined by 2 different missing data imputation methods.

The change from baseline in CD4+ cell count at Weeks 12, 24, and 48

The change from baseline in CD4% at Weeks 12, 24, and 48
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
6.2.2.1.
Analysis of Pure Virologic Response at Weeks 24 and 48
The number and proportion of subjects with PVR at Weeks 24 and 48 will be summarized 
overall and by Parts 1 and 2. Two-sided 95% CIs will be constructed for the overall estimate of 
PVR using the normal approximation and the exact method.
6.2.2.2.
Time to Pure Virologic Failure Analysis
For subjects who do not experience a confirmed rebound (ie, HIV-1 RNA ≥50 copies/mL on 
2 consecutive visits or the last available HIV-1 RNA ≥50 copies/mL followed by premature 
discontinuation of study), subjects will be censored at the last HIV-1 RNA collection date. For 
subjects who experience confirmed rebound, the time to PVF will be defined as the earlier time 
of 2 consecutive HIV-1 RNA ≥50 copies/mL or the last available HIV-1 RNA ≥50 copies/mL 
followed by premature discontinuation of study. 
Time to PVF will be analyzed using the KM method by Part 1 and Part 2 using the FAS.


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Lastly, subjects who failed according to snapshot algorithm, pure virologic failure analysis 
algorithms, or had premature study drug discontinuation by Week 48 will be listed. 
6.2.2.3.
Analysis of proportion of subjects with HIV-1 RNA < 50 copies/mL at Weeks 12, 
24, and 48 as determined by the US FDA-defined snapshot algorithm
The analysis windows for Weeks 12, 24, and 48 are defined in Table 3-1. All HIV-1 RNA data 
collected on-treatment (eg, data collected up to 1 day after the last dose date of study drug) will 
be used in the US FDA-defined snapshot algorithm. Virologic outcome will be defined as the 
following categories:

HIV-1 RNA < 50 copies/mL: this includes subjects who have the last available on-treatment 
HIV-1 RNA < 50 copies/mL in the analysis window

HIV-1 RNA ≥50 copies/mL: this includes subjects: 
a.
Who have the last available on-treatment HIV-1 RNA ≥ 50 copies/mL in the analysis 
window, or 
b. Who do not have on-treatment HIV-1 RNA data in the analysis window and 
1) Who discontinue study drug prior to or in the analysis window due to lack of efficacy 
(note: Lack of efficacy is defined as having the check-box for Lack of efficacy 
marked on the Study Drug Completion eCRF), or 
2) Who discontinue study drug prior to or in the analysis window due to AE or death
and have the last available on-treatment HIV-1 RNA ≥50 copies/mL
3) Who discontinue study drug prior to or in the analysis window due to reasons other 
than AE, death, or lack of efficacy and have the last available on-treatment HIV-1 
RNA ≥ 50 copies/mL 

No Virologic Data (in the Window): this includes subjects who do not have on-treatment 
HIV-1 RNA data in the analysis window because of the following: 
1) Discontinuation of study drug prior to or in the analysis window due to AE or death 
and the last available on-treatment HIV-1 RNA < 50 copies/mL, or
2) Discontinuation of study drug prior to or in the analysis window due to reasons other 
than AE, death, or lack of efficacy and the last available on-treatment HIV-1 
RNA < 50 copies/mL, or 
3) Missing data during the window but on study drug.
Virologic outcomes for the US FDA-defined snapshot algorithm will also be listed.


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Note: For switch study populations, the US FDA-defined snapshot algorithm classifies subjects 
who discontinue study drug due to AE or death and have the last available on-treatment HIV-1 
RNA value ≥ 50 copies/mL as HIV-1 RNA value ≥50 copies/mL. For a treatment naïve study 
population, the US FDA-defined snapshot algorithm classifies these subjects as having No 
Virologic Data in the analysis window.
The number and percentage of subjects achieving HIV-1 RNA < 50 copies/mL, HIV-1 RNA 
≥50 copies/mL, and reasons for no virologic data at Weeks 12, 24, and 48 will be summarized 
overall and by Parts 1 and 2. Two-sided 95% CIs will be constructed for overall estimates using 
the exact method.
6.2.2.4.
Analysis of proportion of subjects with HIV-1 RNA < 20 copies/mL at Weeks 12, 
24, and 48 as determined by the US FDA-defined snapshot algorithm
The number and percentage of subjects achieving HIV-1 RNA < 20 copies/mL, HIV-1 RNA 
≥20 copies/mL, and reasons for no virologic data at Weeks 12, 24, and 48 will be summarized 
overall and by Parts 1 and 2. Two-sided 95% CIs will be constructed for the overall estimate of 
the proportion of subjects with HIV-1 RNA < 20 copies/mL using the exact method.
6.2.2.5.
Analysis of Proportion of Subjects with HIV-1 RNA < 50 copies/mL
(Missing
Excluded and Missing  Failure Approaches)
The proportion of subjects with HIV-1 RNA < 50 copies/mL will also be analyzed using the 
following 2 methods for imputing missing HIV-1 RNA values, where the proportions will be 
expressed as percentages in all tables, listings, and figures:

Missing  Failure (M  F)
In this approach, all missing data will be treated as HIV-1 RNA ≥50 copies/mL. The 
denominator for percentages at a visit is based on the number of subjects in the FAS.

Missing  Excluded (M  E)
In this approach, all missing data will be excluded in the computation of the proportions
(ie, missing data points will be excluded from both the numerator and denominator). The 
denominator for percentages at a visit is based on the number of subjects in the FAS with 
non-missing HIV-1 RNA value at that visit.
For both M  F and M
E analyses, the number and percentage of subjects with HIV-1 RNA in 
the following categories will be summarized:

< 50 copies/mL

< 20 copies/mL
< 20 copies/mL Not Detectable
< 20 copies/mL Detectable


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
20 to < 50 copies/mL 

≥ 50 copies/mL 

Missing (only applicable for M  F analysis)
The proportion of subjects with HIV-1 RNA < 50 copies/mL as defined by the 2 different
missing data imputation methods will be summarized for each visit. Two-sided 95% CIs will be 
constructed using the exact method.
For M  F analysis, results will be summarized and plotted for visits up to and including 
Week 12. For M  E analysis, results will be summarized for each visit.
6.2.2.6.
Analysis of CD4+ cell count
Analysis of CD4+ cell count will be based on on-treatment data (ie, data collected up to 1 day 
after the last dose date of study drug) using observed data (ie, missing will be excluded) for 
subjects in the FAS. 
The change from baseline in CD4+ cell count at Weeks 12, 24, and 48 will be summarized 
overall and by Parts 1 and 2 using descriptive statistics. The change from baseline in CD4+ cell 
count will be similarly summarized at the visits other than Weeks 12, 24, and 48. 
6.2.2.7.
Analysis of CD4%
Analysis of CD4% will be based on on-treatment data (ie, up to 1 day after the last dose date of 
study drug) using observed data (ie, missing will be excluded) for subjects in the FAS. 
The change from baseline in CD4% at Weeks 12, 24, and 48 will be summarized overall and by 
Parts 1 and 2 using descriptive statistics. The change from baseline in CD4% will be similarly 
summarized at the visits other than Weeks 12, 24, and 48.
6.3.
Changes From Protocol-Specified Efficacy Analyses
For the primary efficacy endpoint, PVR at Week 12, the protocol specifies that 95% CIs will be 
generated using the normal approximation method, but in the SAP, both the normal 
approximation and the exact methods are specified.


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7.
SAFETY ANALYSES
Safety data will be summarized for the subjects in the Safety Analysis Set. All safety data 
collected on or after the date of the first dose of study drug up to the last dose date of study drug 
plus 30 days for subjects who have permanently discontinued study drug, or all available data for 
subjects who are ongoing will be summarized overall and by Parts 1 and 2, unless specified 
otherwise. All safety data will be included in data listings.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, 
latest version). 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.
7.1.2.
Adverse Event Severity
AEs are graded by the investigator as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) or 
Grade 4 (life threatening) according to toxicity criteria specified in the Study 
Protocol Appendix 4. The severity grade of events for which the investigator did not record 
severity will be categorized as “missing” for tabular summaries and data listings, and will be 
considered the least severe for the purposes of sorting for data presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator answers “Related” to the question “Related to 
Study Treatment?” in the CRF. Events for which the investigator did not record relationship to 
study drug will be considered related to study drug. Data listings will show relationship as 
missing.
7.1.4.
Relationship of AEs to Study Procedure
Adverse events for which “Yes” is marked for question “Related to Study Procedures?” in the 
eCRF will be identified and included in the AE listing.
7.1.5.
Serious Adverse Events
Serious adverse events (SAEs) are those identified as serious in the clinical database. The 
clinical database will be reconciled with the SAE database from the Pharmacovigilance and 
Epidemiology (PVE) Department before database finalization.


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7.1.6.
Treatment-Emergent Adverse Events 
7.1.6.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AE with onset date on or after the study drug start date and no later than 30 days after 
permanent discontinuation of study drug, or

Any AE leading to premature discontinuation of study drug. 
7.1.6.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The month and year of the AE onset date is the same as or after the month and year (or year) 
of the first dosing date of study drug, and

The month and year of the AE onset date is the same as or before the month and year 
(or year) of the date corresponding to 30 days after the date of the last dose of study drug
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
7.1.7.
Summaries of Adverse Events and Deaths
A brief summary of AEs will show overall and by Parts 1 and 2, the number and percentage of 
subjects who had:

Any TEAE

Any Grade 2, 3 or 4 TEAE

Any Grade 3 or 4 TEAE

Any study-drug-related TEAE

Any Grade 2, 3 or 4 study-drug-related TEAE

Any Grade 3 or 4 study-drug-related TEAE


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
Any serious TEAE

Any serious study-drug-related TEAE

Any TEAE leading to premature study drug discontinuation

Treatment-emergent death
Treatment-emergent death refers to death occurring between the first dose date and the last dose 
date plus 30 days (inclusive).
Summaries (number and percentage of subjects) of AEs (by SOC, and PT) will be provided 
overall and by Parts 1 and 2 using the Safety Analysis Set as follows:

All TEAEs

All Grade 2, 3, or 4 TEAEs

Grade 3 or 4 TEAEs

All study-drug-related TEAEs

All Grade 2, 3, or 4 study-drug-related TEAEs

All Grade 3 or 4 study-drug-related TEAEs

All serious TEAEs

All study-drug-related serious TEAEs

All TEAEs that caused premature discontinuation from study drug
Multiple events will be counted only once per subject in each summary. For data presentation, 
SOC will be ordered alphabetically, and then by PT sorted by decreasing total frequency. For 
summaries by severity grade, the most severe event will be selected.
In addition to the by-treatment summaries, data listings will be provided for the following:

All AEs

Grade 3 and 4 AEs

SAEs

Adverse events leading to premature discontinuation of study drug

Deaths report


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7.1.8.
Additional Analysis of Adverse Events
7.1.8.1.
Stage 3 Opportunistic Illnesses in HIV
On an ongoing basis, AEs will be reviewed for events that might meet the definition of Stage 3 
opportunistic illnesses in HIV that are indicative of an AIDS-Defining Diagnoses 
(see Protocol Appendix 6). The Gilead medical monitor will review the possible Stage 3 
opportunistic illnesses and approve the events that meet the definition. Events that meet the 
Stage 3 opportunistic illness definition of an AIDS-Defining Diagnosis will be listed.
7.1.9.
Fracture Events
The preferred terms included in analysis for fracture events are defined based on the 
Standardized MedDRA Query (SMQ) of osteoporosis/osteopenia of fractures and HLGT of 
fractures from MedDRA. The lists of PTs selected by clinical review from all the PT terms under 
SMQ of osteoporosis/osteopenia fractures and HLGT of fractures are presented in Appendix 4. 
Fracture events will be listed only.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days 
for subjects who have permanently discontinued study drug. The analysis will be based on values 
reported in conventional units. When values are below the LOQ, they will be listed as such, and 
the closest imputed value will be used for the purpose of calculating summary statistics as 
specified in Section 3.6.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, and urinalysis separately. Values falling 
outside of the relevant reference range and/or having a severity grade of 1 or higher on the 
Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities will be 
flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum and maximum) 
will be provided overall and by Parts 1 and 2 for each laboratory test specified in the study 
protocol as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window


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In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.
Overall median (Q1, Q3) change from baseline in selected safety endpoints including the fasting 
lipid panel parameters and fasting glucose over time will be plotted.
7.2.1.1.
Metabolic Assessments 
For the metabolic assessments (including total cholesterol, low density lipoprotein [LDL], high 
density lipoprotein [HDL], total cholesterol to HDL ratio, triglycerides, and glucose), only those 
measurements under fasting status will be summarized overall and by Parts 1 and 2. 
In addition, the number and percentage of subjects who took lipid modifying medications at the 
study entry and initiated the medications during the study will be provided, respectively. A lipid 
modifying medication is defined as a medication with drug class  “LIPID MODIFYING 
AGENTS” and CMDECOD containing the wording of “STATIN”.
A sensitivity analysis of fasting lipid tests (including total cholesterol, LDL, HDL, triglycerides, 
and total cholesterol to HDL ratio) will be performed by excluding subjects who took lipid 
modifying medications at study entry or initiated the medications during the study: baseline, 
Week 48. Only subjects with both baseline and Week 48 values will be included in the analysis.
7.2.1.2.
Calcium Corrected for Albumin
Calcium corrected for albumin will be calculated and summarized overall and by Parts 1 and 2. 
The following formula will be used when both serum calcium and albumin results for a given 
blood draw are available and serum albumin value is < 4.0 g/dL. 
Calcium corrected for albumin (mg/dL)  serum calcium (mg/dL) + 0.8 x (4.0 albumin (g/dL)). 
Toxicity grading for calcium will be applied based on the corrected values. 
7.2.2.
Graded Laboratory Values
The criteria specified in the study protocol will be used to grade laboratory results as Grade 0, 
mild (Grade 1), moderate (Grade 2), severe (Grade 3) or potentially life threatening (Grade 4). 
Grade 0 includes all values that do not meet criteria for an abnormality of at least Grade 1. Some 
laboratory tests have criteria for both increased and decreased levels; analyses for each direction 
(i.e., increased, decreased) will be presented separately.
For triglycerides, LDL, and cholesterol, the protocol specified toxicity grade scale is for fasting 
test values, so nonfasting lipid results (or lipid results without known fasting status) will not be 
graded or summarized by toxicity grades. 
If there is any laboratory toxicity grading scale overlapping with normal reference ranges 
(eg, Grade 1 scale overlaps with normal reference ranges), laboratory values within normal range 
will be grade 0, except lipid tests.


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7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are 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 drug plus 30 days for subjects who permanently discontinued study drug. If the relevant 
baseline laboratory data are missing, then any abnormality of at least Grade 1 will be considered 
treatment emergent.
For serum glucose, fasting glucose and nonfasting glucose are graded based on different grading 
criteria as specified in the protocol. Treatment-emergent laboratory abnormalities will be 
summarized for fasting glucose. Since nonfasting glucose was not assessed at baseline, the 
maximum postbaseline grade instead of treatment-emergent laboratory abnormalities will be 
summarized.
7.2.2.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) of laboratory abnormalities will
be provided overall and by Parts 1 and 2 (subjects categorized according to most severe 
abnormality grade):

Treatment-emergent laboratory abnormalities

Treatment-emergent Grade 3 and 4 laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
non-missing post-baseline values. A listing of all graded laboratory abnormalities and all Grade 3 
or Grade 4 laboratory abnormalities will be provided.
7.2.3.
Liver-related Laboratory Evaluations
The number and percentage of subjects will be summarized overall and by Parts 1 and 2 for the 
following liver-related laboratory tests and categories: 

AST: (a) > 3 x Upper limit of normal (ULN), (b) > 5 x ULN, (c) > 10 x ULN, 
(d) > 20 x ULN 

ALT: (a) > 3 x ULN, (b) > 5 x ULN, (c) > 10 x ULN, (d) > 20 x ULN 

AST or ALT: (a) > 3 x ULN, (b) > 5 x ULN, (c) > 10 x ULN, (d) > 20 x ULN 

Total bilirubin: (a) > 1 x ULN, (b) > 2 x ULN 

Alkaline phosphatase (ALP) > 1.5 x ULN 

AST or ALT > 3 x ULN and total bilirubin: (a) > 1.5 x ULN, (b) > 2 x ULN 

AST or ALT > 3 x ULN and total bilirubin > 2 x ULN and ALP < 2 x ULN 


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The summary will include data from all the postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, 
and the composite endpoint of AST or ALT, total bilirubin, and ALP, subjects will be counted 
once when the criteria are met at the same postbaseline visit date. The denominator is the number 
of subjects in the Safety Analysis Set with nonmissing postbaseline value of the tests in 
evaluation at the same postbaseline visit date. 
Subjects with AST or ALT > 3 x ULN will also be listed.
7.3.
Renal Safety Analyses
7.3.1.
Serum Creatinine
The baseline, postbaseline and change from baseline in serum creatinine at each visit will be 
summarized overall and by Parts 1 and 2 for each visit using descriptive statistics.
The median (Q1, Q3) of change from baseline in observed serum creatinine over time will be 
plotted.
7.3.2.
Estimated Glomerular Filtration Rate
7.3.2.1.
Estimated Glomerular Filtration Rate: Cockroft-Gault
The Cockroft-Gault formula will be used to calculate eGFRCG:
eGFRCG (mL/min)  [(140 age (years)) × weight (kg) × (0.85 if female)] / (SCr 
(mg/dL) × 72),
where weight is total body mass in kilograms, and SCr is serum creatinine.
Summary of baseline, post-baseline, and change from baseline in eGFRCG will also be provided
overall and by Parts 1 and 2.
Median (Q1, Q3) change from baseline in eGFRCG over time will be plotted.
7.3.2.2.
Estimated Glomerular Filtration Rate: CKD-EPI (cystatin C)
The CKD-EPI (cystatin C) formula will be used to calculate eGFRCKD EPI:
eGFRCKD EPI (mL/min/1.73 m2)  133 × min(Scys/0.8, 1) 0.499 × max(Scys/0.8, 1) 1.328 × 
0.996Age [× 0.932 if female],
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of Scys/κ or 
1, and max (Scys/0.8,1) indicates the maximum of Scys/κ or 1.
Only baseline values will be summarized. See Section 5.2 for details.


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7.3.3.
Proteinuria by Urinalysis (Dipstick)
The proteinuria by urinalysis (dipstick) toxicity grade (Grade 0 to Grade 3) at Weeks 12, 24, 
and 48 will be summarized by baseline proteinuria toxicity grade and treatment. In addition, the 
last on-treatment proteinuria toxicity grade will also be summarized by baseline proteinuria 
toxicity grade and overall and by Parts 1 and 2. On-treatment values include data collected after 
the last dose date up to the last dose date plus 1 day for subjects who permanently discontinued 
study drug. 
7.3.4.
Proteinuria by Quantitative Assessment
The baseline, postbaseline, changes from baseline, and percentage change from baseline in urine 
protein to creatinine ratio (UPCR) and urine albumin to creatinine ratio (UACR) will be 
summarized overall and by Parts 1 and 2 for each visit using descriptive statistics.
The number and percentage of subjects with UPCR ≤ 200 mg/g versus > 200 mg/g will be 
summarized by baseline category at Weeks 12, 24, and 48, and based on the last on-treatment 
value (up to 1 day after the last dose date of study drug {KDIGO Guideline Development Staff 
2013}). 
The number and percentage of subjects with UACR < 30 mg/g versus ≥30 mg/g will be 
summarized by baseline category at Weeks 12, 24, and 48, and the last on-treatment value 
(after first dose date up to 1 day after the last dose date of study drug {KDIGO Guideline 
Development Staff 2013}). 
Median (Q1, Q3) percentage change from baseline in UPCR and UACR over time will be 
plotted.
7.4.
Vital Signs
Descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) will be provided 
overall and by Parts 1 and 2 for each visit and vital sign as follows:

Baseline values

Values at each postbaseline analysis window

Change from baseline to each postbaseline analysis window 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.7.3.
A listing of weight, BMI, height, and vital signs will be provided. 


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7.5.
Prior and Concomitant Medications
7.5.1.
Nonstudy-Drug Antiretroviral Medications
Nonstudy drug ARV medications used prior to, during, or after the study (if collected), will be 
coded using the Gilead-modified World Health Organisation (WHO) Drug Dictionary. The 
WHO preferred name and drug code will be attached to the clinical database. All nonstudy-drug 
ARV medications will be listed. No inferential statistics will be provided. 
Nonstudy-drug ARV medication with an end date one day before the first dose date of study 
drug will be considered as nonstudy-drug ARV medication received immediately prior to the 
first dose date of study drug (or pre-switch ARV used).
Nonstudy-drug ARV medication received immediately prior to the first dose date of study drug 
will be summarized by ARV drug class and generic name for subjects in the Safety Analysis Set. 
Multiple drug use (by drug class or generic name) will be counted only once per subject. Drug 
classes were presented alphabetically and generic names within each drug class were presented 
by descending order of the total frequency. No inferential statistics will be provided.
7.5.2.
Concomitant Non-Antiretroviral Medications
Concomitant non-ARV medications (ie, medications other than study drug that are taken while 
receiving study drug) will be coded using the WHO Drug Dictionary. The WHO preferred name 
and drug code will be attached to the clinical database. Use of concomitant medications from 
Study Day 1 up to the date of last dose of study drug will be summarized (number and 
percentage of subjects) overall and by Parts 1 and 2 by preferred name. Multiple drug use 
(by preferred name) will be counted once only per subject. The summary will be sorted 
alphabetically by decreasing total frequency within a class. 
If the start or stop date of non-ARV medications is incomplete, the month and year (or year alone 
if month is not recorded) of start or stop date will be used to determine whether the non-ARV 
medications are concomitant or not as follows. The medication is concomitant if the month and 
year of start or stop (or year of the start or stop) of the medication do not meeting any of 
following criteria:

The month and year of start of the medication is after the date of the last dose of study drug

The month and year of stop of the medication is before the date of the first dose of study drug 
If the start and stop date of non-ARV medications are not missing, the start date is not after last 
dose date and the stop date is not before first dose date, or the non-ARV medications are marked 
as ongoing and start date is on or before last dose date, the non-ARV medications are 
concomitant. 


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Summaries of concomitant non-ARV medications will be provided for the Safety Analysis Set. 
Subjects with any concomitant non-ARV medications will be listed. No inferential statistics will 
be provided. 
7.6.
Electrocardiogram Results
The number and percentage of subjects in the Safety Analysis Set with an investigator’s ECG 
assessment of normal, abnormal but not clinically significant, or abnormal and clinically 
significant will be summarized overall and by Parts 1 and 2 and by baseline ECG result for each 
visit. No inferential statistics will be provided. 
A listing of safety ECG results will be provided including treatment, assessment date and time, 
and ECG results.
7.7.
Other Safety Measures
A data listing will be provided for subjects experiencing pregnancy during the study.
7.8.
Subject Subgroup for Safety Endpoints
Not applicable.
7.9.
Changes From Protocol-Specified Safety Analyses
No change from protocol-specified safety analyses is planned.


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8.
PATIENT REPORT OUTCOMES
The Patient reported outcomes (PROs) include: (1) Visual Analogue Scale (VAS) adherence 
questionnaires; (2) Short Form-36 Version 2 Health Survey (SF-36); (3) HIVTSQs Status 
version (at Day 1 only)/HIVTSQc
Change version (post-Day 1); (4) FACIT-F; (5) EQ-5D. 
Unless otherwise stated, multiple responses and out of range responses will be set to missing and 
missing responses will not be imputed. The Safety Analysis Set will be used in all analyses. No 
inferential statistics will be provided. All reported data will be listed.
8.1.
Adherence – Visual Analogue Scale (VAS) Adherence Questionnaire
The VAS adherence questionnaire is a 3-item, self-reported questionnaire that assesses the 
degree to which ARV medication was taken in the past 30 days.
For the VAS, the subject is asked to describe their adherence to their ARV regimen by using a 
linear scale (0% 100%) to indicate what percent of medications was taken in the last 30 days 
(0%  taken none of prescribed anti-HIV medication, and 100%  taken all doses of prescribed 
anti-HIV medication). Two additional questions ask how many days the subject has missed 
medications in the last 30 days and how many days the subject has missed medications in the last 
4 days.
8.1.1.
VAS Statistical Method
The VAS (%) absolute value and its change from baseline at each visit will be summarized 
overall and by Parts 1 and 2 using descriptive statistics. Number of days with missed doses in the 
past 30 days and past 4 days will be summarized categorically (eg, < 2, 2 to < 4, 4 to < 6, ≥6 for 
the past 30 days; 0 and > 0 for the past 4 days) at each visit.
8.2.
SF-36 (Version 2) Health Survey
The SF-36 Version 2 is a 36-item, self-reported, generic, comprehensive, and widely used 
questionnaire that is designed to measure health-related quality of life in the general population, 
as well as in subject groups with diverse chronic diseases including HIV/AIDS. Responses from 
the 36 items are used to construct 8 health domains including physical functioning, social 
functioning, general health, vitality, bodily pain, mental health, role capacity-physical, and role 
capacity-emotional. Furthermore, 2 summary scores, the Physical Component Summary (PCS)
score and Mental Component Summary (MCS) score, aggregate information from the 8 SF-36 
domains in a way that captures 80% to 85% of the variance in the 8 domains.
8.2.1.
Scoring the SF-36
The 8 domains and 2 component summary scores of the SF-36 will be calculated according to 
“How to Score Version 2 of the SF-36 Health Survey (Chapters 6 and 7)” {Maruish 2011}
published by QualityMetric Inc {using 2009 population norms}. Scores for each of the 8 domain 
including PCS and MCS range from 0 to 100 with higher score indicating a better functioning.
8.2.2.
SF-36 Statistical Analysis Method 
Scores for each domain, PCS, and MCS will be summarized overall and by Parts 1 and 2 for 
each visit using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and maximum).


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A by-subject listing for the scores for each domain, PCS, and MCS will be provided by subject 
ID number and visits in chronological order.
8.3.
HIV Treatment Satisfaction Questionnaire
At baseline, a treatment satisfaction scale total will be calculated as the sum of the responses to 
the 10 question items on the HIVTSQs form (range from 0 to 60). At postbaseline visits, a 
treatment satisfaction scale total in change will be calculated as the sum of the responses to the 
10 question items on the HIVTSQc form (range from -30 to 30).
Additionally, two subscale scores, one for general satisfaction/clinical and another for 
lifestyle/ease will be computed. Each subscale ranges from 0 to 30 on the HIVTSQs form and 
from -15 to 15 on the HIVTSQc form.
Table 8-1 lists the questions, possible responses for both the status and change questionnaires, as 
well as the subscale each question belongs to.
Table 8-1.
List of Items on the HIVTSQ
Question
Response Options for 
Status Form
Response Options for Change 
Form
Subscale
How satisfied are you with 
your current treatment?
Very satisfied 6 to 0 very 
dissatisfied
Much more satisfied now 
3 to
3 much less satisfied now
General 
Satisfaction/Clinical
How well controlled do you 
feel your HIV has been 
recently?
Very well controlled 6 to 0 very 
poorly controlled
Much better controlled now 3 to 
3 much worse controlled now
General 
Satisfaction/Clinical
How satisfied are you with 
any side effects of your 
present treatment?
Very satisfied 6 to 0 very 
dissatisfied
Much more satisfied now 
3 to
3 much less satisfied now
General 
Satisfaction/Clinical
How satisfied are you with 
the demands made by your 
current treatment?
Very satisfied 6 to 0 very 
dissatisfied
Much more satisfied now 
3 to
3 much less satisfied now
Lifestyle/Ease
How convenient have you 
been finding your treatment 
to be recently?
Very convenient 6 to 0 very 
inconvenient
Much more convenient now 3 to 
3 much less convenient now
Lifestyle/Ease
How flexible have you been 
finding your treatment to be 
recently?
Very flexible 6 to 0 very 
inflexible
Much more flexible now 3 to
3 
much less flexible now
Lifestyle/Ease
How satisfied are you with 
your understanding of your 
HIV?
Very satisfied 6 to 0 very 
dissatisfied
Much more satisfied now 
3 to
3 much less satisfied now
Lifestyle/Ease
How satisfied are you with 
the extent to which the 
treatment fits in with your 
lifestyle?
Very satisfied 6 to 0 very 
dissatisfied
Much more satisfied now 
3 to
3 much less satisfied now
Lifestyle/Ease
Would you recommend your 
present treatment to 
someone else with HIV?
Yes I would definitely 
recommend the treatment 6 to 0 
No I would definitely not 
recommend the treatment
Much more likely to 
recommend the treatment now 3 
to 3 much less likely to 
recommend the treatment now
General 
Satisfaction/Clinical
How satisfied would you be 
to continue with your 
present form of treatment?
Very satisfied 6 to 0 very 
dissatisfied
Much more satisfied now 
3 to
3 much less satisfied now
General 
Satisfaction/Clinical


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8.3.1.
HIV Treatment Satisfaction Questionnaires Statistical Analysis Method
The HIVTSQs scale and subscale totals at baseline, and the HIVTSQc scale and subscale totals 
at each visit will be summarized using descriptive statistics. 
For each subscale, if more than 1 question is missing, then the subscale total or subscale total in
change will be set to missing. Otherwise, the missing response will be imputed by taking the 
average of the non-missing responses from the other questions in that subscale.
For the scale total or scale total in change, if more than 5 questions are missing, then the value 
will be set to missing. Otherwise, the missing response(s) will be imputed by taking the average 
of the nonmissing responses from the other questions.
If two responses are provided for a single question, and the scores are next to each other, then the 
midpoint will be used. If two responses are provided for a single question, and the scores are not 
immediately next to each other, then the response will be considered missing.
8.4.
Functional Assessment of Chronic Illness Therapy – Fatigue 
The Functional Assessment of Chronic Illness Therapy (FACIT) was adopted from the 
Functional Assessment of Cancer Therapy in 1997 as an instrument to measure the health related 
quality of life (HRQOL) of patients with chronic illnesses. FACIT-F contains 13 additional items 
not in the initial FACIT questionnaire under the heading “Additional Concerns” that comprise 
the fatigue subscale.
The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Version 4.0 is a
40 item, self-reported questionnaire which measures the HRQOL of patients with chronic 
illnesses over a one-week time interval. Each item takes a range of 0 4, corresponding to 
(0) Not at all; (1) A little bit; (2) Somewhat; (3) Quite a bit; (4) Very much. Forty individual 
items generate 5 subscales: (1) Physical Well-Being (PWB); (2) Social/Family Well-Being 
(SWB); (3) Emotional Well-Being (EWB); (4) Functional Well-Being (FWB); and (5) Fatigue 
Subscale (FS). 
8.4.1.
Scoring the Functional Assessment of Chronic Illness Therapy – Fatigue
Full details of the scoring of the FACIT-F are available in the initial publication. A brief 
overview appears below. Instructions for scoring each subscale are presented in the table below. 
If “Reverse item?” is “Yes”, then the response should be reversed by substracting the response 
from “4” (ie, New response  4 original response).
Missing values will not be imputed. Prorating subscale scores is acceptable as long as more than 
50% of items were answered (a minimum of 4 out of 7 items, 4 of 6 items, and 7 out of 
13 items). This is done by multiplying the sum of the subscale by the number of items in the 
subscale, then dividing by the number of items actually answered.


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Table 8-2.
Items by Subscale and Scoring Algorithm for FACIT-F
Subscale
Item Code
Reverse item?
Scoring Algorithm
PWB
GP1
Yes
Sum individual item score 
Multiply by 7 
Divide by the number of answered items 
(Score range: 0 28)
GP2
Yes
GP3
Yes
GP4
Yes
GP5
Yes
GP6
Yes
GP7
Yes
SWB
GS1
No
Sum individual item score --> 
Multiply by 7 ---> 
Divide by the number of answered items 
(Score range: 0 28)
GS2
No
GS3
No
GS4
No
GS5
No
GS6
No
GS7
No
EWB
GE1
Yes
Sum individual item score 
Multiply by 7 
Divide by the number of answered items 
(Score range: 0 24)
GE2
No
GE3
Yes
GE4
Yes
GE5
Yes
GE6
Yes
FWB
GF1
No
Sum individual item score 
Multiply by 7 
Divide by the number of answered items 
(Score range: 0 28)
GF2
No
GF3
No
GF4
No
GF5
No
GF6
No
GF7
No


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Subscale
Item Code
Reverse item?
Scoring Algorithm
FS
HI7
Yes
Sum individual item score 
Multiply by 13 
Divide by the number of answered items
(Score range: 0 52)
HI12
Yes
An1
Yes
An2
Yes
An3
Yes
An4
Yes
An5
No
An7
No
An8
Yes
An12
Yes
An14
Yes
An15
Yes
An16
Yes
PWB  Physical Well Being; SWB  Social/Family Well Being; EWB  Emotional Well Being; FWB  Functional Well Being; 
and FS  Fatigue Subscale.


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Three aggregate scores can be computed as shown in Table 8-3, subject to the requirements 
listed: 
Table 8-3.
Computation of Aggregate Scores
Aggregate Score
Formula
Requirement
FACIT-F Trial 
Outcome Index (TOI)
PWB+FWB+FS
PWB, FWB, FS all nonmissing
FACT-G total score
PWB + SWB + EWB + FWB
At least 80% nonmissing (ie, 22 out of 27)
FACIT-F total score
PWB + SWB + EWB + FWB + FS
At least 80% nonmissing (ie, 33 out of 40)
FACIT F  Functional Assessment of Chronic Illness Therapy Fatigue; PWB  Physical Well Being; SWB  Social/Family 
Well Being; EWB  Emotional Well Being; FWB  Functional Well Being; and FS  Fatigue Subscale.
8.4.2.
Functional Assessment of Chronic Illness Therapy – Fatigue Analysis 
Method
Scores for each subscale and aggregate score will be summarized overall and by Parts 1 and 2 for 
each visit using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and maximum). 
A by-subject listing for the scores for each subscale and aggregate score will be provided by 
subject ID number and visits in chronological order.
8.5.
EQ-5D-3L
The EQ-5D-3L consists of the EQ-5D descriptive system and the EQ visual analogue scale 
(EQ VAS). The EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 
no problems, some problems, extreme problems. The EQ VAS records the respondent’s self-rated 
health on a vertical, visual analogue scale from 0 (“Worst imaginable health state”) to 100
(“Best imaginable health state”). This information can be used as a quantitative measure of 
health outcomes as judged by the individual respondents {Rabin 2011}. 
8.5.1.
Scoring the EQ-5D-3L Descriptive System
The scores of EQ-5D-3L descriptive system are described in Table 8-4.
Table 8-4.
Scores of EQ-5D-3L Descriptive System
Original Response Category
Score
No problems
1
Some problems
2
Extreme problems
3
Note: Missing values is to be coded as 9. Ambiguous values (eg, 2 boxes are ticked for a single dimension) should be treated as 
missing values.


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8.5.2.
EQ-5D Single Summary Index
EQ-5D health states, defined by the EQ-5D descriptive system, will be converted into a 
single summary index using the UK time trade-off (TTO) value set (Appendix 3). For example, 
the health state is 11111 if the response to each of the 5 dimensions of the EQ-5D system is 1. 
Since there are 3 possible responses (ie, 1, 2 and 3) to each of the 5 dimensions of the EQ-5D 
system, there are 35  243 health states in total. 
For the UK TTO value set, the index is calculated for each of the health states (see Appendix 3
for details). Missing responses for EQ-5D-3L Questionnaire will not be imputed. If any one of 
the 5 dimensions is missing, the index will be missing.
8.5.3.
Scoring the EQ VAS
For EQ VAS, the value is scored from 0 (“Worst imaginable health state”) to 
100 (“Best imaginable health state”). Missing values is to be coded as “999”. Ambiguous values 
(eg. the line crosses the VAS twice) should be treated as missing values.
8.5.4.
EQ-5D Statistical Analysis Method
For the 5 descriptive scores, the number and percentage of subjects with a response of 
“No problems”, “Some problems” and “Extreme problems” will be summarized overall and by 
Parts 1 and 2 for each visit. No inferential statistics will be provided.
For the index score and VAS score, change from baseline will be summarized overall and by 
Parts 1 and 2 for each visit. No inferential statistics will be provided.
In addition, responder analysis will be performed based on the index score to determine the 
proportion of patients with health worsening or improvement by visit. Worsening or 
improvement in health (see Table 8-5), as measured by the proportion of patients experiencing a 
decrease or an increase of ≥ 0.07, which is the minimally important difference (MID) {Walters 
2005}, in the index score. No inferential statistics will be provided.
Table 8-5.
Response Category for Responder Analysis
Response Category
Change from Baseline in Index Score
Worsening
≤ -0.07
No change
> -0.07 and < 0.07
Improvement
≥ 0.07


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9.
REFERENCES
KDIGO Guideline Development Staff. KDIGO 2012 Clinical Practice Guideline for the 
Evaluation and Management of Chronic Kidney Disease. Kidney international. 
Supplement 2013;3 (1):v-150.
Maruish ME. User's manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality Metric 
Incorporated.; 2011. 
Rabin R, Oemar M, Oppe M. EQ-5D-3L User Guide: Basic information on how to use the EQ-
5D-3L instrument Version 4.0.  EuroQol Group, 2011:
U. S. Department of Health and Human Services, Food and Drug Administration (FDA), Center 
for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 
Infection: Developing Antiretroviral Drugs for Treatment. Guidance for Industry. 
Silver Spring, MD.  November, 2015.
Walters SJ, Brazier JE. Comparison of the minimally important difference for two health state 
utility measures: EQ-5D and SF-6D. Qual Life Res 2005;14 (6):1523-32.


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10.
SOFTWARE
SAS® Software Version 9.1. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version 7.0. Statistical Solutions, Cork, Ireland.


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11.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision
06 November, 2019
List of 
abbreviations
List of abbreviations updated.
To update the list of 
abbreviations.
06 November, 2019
Section 1.2
Added K60R to list of resistance 
criteria for Part 1 subjects. 
To be align with the protocol.
31 January, 2020
Section 5.2
Removed the summary of 
baseline medical history: 
diabetes, hypertension, 
cardiovascular disease, and 
hyperlipidemia.
Data not present in the SDTM 
data.
06 November, 2019
Section 7.1.7
Removed HLT from AE 
summaries
Removed HLT due to small 
sample sizes.
06 November, 2019
Appendix 3
Added Appendix 3.
To provide more details on UK 
TTO Value Set for EQ-5D-3L 
Questionnaire.
06 November, 2019
Appendix 4
Added Appendix 4.
To provide more details on 
baseline medical history: 
diabetes, hypertension, 
cardiovascular disease, and 
hyperlipidemia.
31 January, 2020
Appendix 4
Removed Appendix 4.
Data not present in the SDTM 
data.
06 November, 2019
Appendix 7
Added Item 41).
To provide more programming 
details on “currently using 
abacavir, indinavir or 
lopinavir”.


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12.
APPENDICES
Appendix 1.
Schedule of Assessents
Appendix 2.
Flowchart of US FDA-Defined Snapshot Algorithm (for Switch Study Trial)
Appendix 3.
UK TTO Value Set for EQ-5D-3L Questionnaire
Appendix 4.
Fracture Events
Appendix 5.
Programming Specification


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Appendix 1.
Schedule of Assessents
Study Procedure
Screening
Day 1b
End of Week
c
30 Day 
Follow-up
ESDD
d
4
8
12
16
t
24
36
48
Informed Consent
X
Medical History
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Complete Physical 
Exame
X
X
X
X
X
Symptom Directed 
Physical Examf
X
X
X
X
X
12 Lead ECG 
(Performed Supine)
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
Height
X
Urinalysis and Urine 
Chemistry
X
X
X
X
X
X
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
X
Urine Pregnancy Testg
X
X
X
X
X
X
X
X
Serum Pregnancy Testg
X
Chemistry Profileh
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsi
X
X
X
Estimated GFRj
X
X
X
X
X
X
X
X
X
Hematology Profilek
X
X
X
X
X
X
X
X
X
X
Plasma HIV 1 RNAl
X
X
X
X
X
X
X
X
X
X
X


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Study Procedure
Screening
Day 1b
End of Week
c
30 Day 
Follow-up
ESDD
d
4
8
12
16
t
24
36
48
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
HBV and HCV 
Serologiesm
X
Plasma Sample Storagen
X
X
X
X
X
X
X
X
X
Whole Blood Samplep
X
HIV 1 
Genotype/Phenotypeq
X
X
Cystatin C Testingu
X
Questionnaires: VAS, 
HIVTSQs, HIVTSQc, 
EQ 5D, SF 36, and 
FACIT Fr
X
X
X
X
X
X
X
X
X
Enrollment
X
Study Drug Dispensation 
and Accountability
X
X
X
X
X
X
X
Xs
Xs
a
Evaluations to be completed within 42 days prior to the 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. E/C/F/TAF FDC
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 16, ± 6 days of the protocol 
specified date through Week 36, and all other study visits except Week 48. Week 48 visit window is ± 6 weeks of the protocol specified visit date, and this clinical visit
window coincides with the Week 48 statistical analysis window for HIV 1 RNA.
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through
Week 48 visit even if the subject discontinues study drug.
e
Complete physical examination every 48 weeks (urogenital/anorectal exams will be performed at the discretion of the Investigator)
f
Symptom directed physical examination as needed.
g
Females of childbearing potential only. Positive urine pregnancy tests will be confirmed with a serum test.
h
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium. At visits in which metabolic assessments are to be performed, analyses of glucose will be done as part of the fasting metabolic assessments
and not as part of the chemistry profile.
PPD
I 
I 


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i
Metabolic Assessments: Fasting 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.
j
Estimated GFR according to the Cockcroft Gault formula for creatinine clearance 
k
CBC with differential and platelet count
l
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 Day 1 results). HIV 1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic failure with HIV 1 RNA value ≥ 50 copies/mL. 
Subjects should be managed according to Figure 6 1 of the protocol, Management of Virologic Failure.
m
Hepatitis B virus surface antigen serology (HBsAg) and Hepatitis C virus (HBVAb) serology (reflex HCV RNA is performed in subjects with positive HCVAb serology)
n
Plasma sample storage for safety and virology testing
p
Whole blood sample collected at Screening Visit for proviral genotype analysis of archived resistance
q
HIV 1 genotype/phenotype resistance testing only conducted for subjects with unconfirmed virologic rebound with HIV 1 RNA value ≥ 50 copies/mL at the Week 48 and
r
ESDD visit. Subjects should be managed according to Figure 6 1 of the protocol, Management of Virologic Failure. HIV 1 genotype/phenotype sample collection to occur if 
subjects
s
HIV 1 RNA lab values meet the criteria described in this section.
EQ 5D, SF 36, and FACIT F will be administered at Day 1, Weeks 24 and 48. VAS will be administered on Day 1, Weeks 4, 8, 12, 16, 24, 36, 48 and ESDD. HIVTSQs will 
be administered on Day 1. HIVTSQc will be administered at Weeks 4, 24, 48 and ESDD.
t
Drug accountability only; study drug will not be dispensed at this visit.
u
At Week 16, subject will have only the following assessments completed: Review of AEs and changes in concomitant medications, blood sample collection for plasma
v
HIV 1 RNA and plasma sample storage. Study drug dispensation and accountability will be documented.
w
Estimated GFR according to CKD EPI formula for cystatin clearance will be used for Nephrotoxicity Management per Section 7.5.4 of the protocol.
PPDI 


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Appendix 2.
Flowchart of US FDA-Defined Snapshot Algorithm (for Switch Study 
Trial)
The following flowchart for US FDA-defined snapshot algorithm is based on the US FDA 
Guidance on Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for 
treatment {U. S. Department of Health and Human Services 2015}
Is there at least I un-
treatment* HlV-J RNA data 
Yes____ collected in the Snapshot 
u 
Is the last available 011-treannent* 
HIV-I RNA in the Snapshot 
window < 50 copies/mL? 
Yes 
HJV-lRl\A < 
50 copks/ml,. 
HCV-1 Rl A~ 
50 copies/mL 
window? 
w 
Is study drug prematurely 
discontinued on or piior to the 
upper limit of the Snapshot 
window'? 
I 
Yes • 
ls discontinuation of the study 
drug due to Lack of Efficacy'! 
No 
I 
No 
ls discontinuation of the study 
drug due to AE/Dcath? 
Yes 
ls the last available on-
Is the last available 011-
treatment* HIV-I RNA < treatment* HIV-1 RNA < 
50 copieshnL 
50 copies/mL 
o Virologic Data: 
Discontinued Study 
Drug Due to Other 
Reason and Last IDV-1 
~A < 50 copics/mL 
o Virologic Data: 
Discontinued Study 
Drug Due to AE/Death 
and Last KIV-1 R 'A< 
50 copics/m L 
No 
No Virologic Data: 
Missing Oat~ during 
Window but on Study 
Drug 
* On-Treatment HIV-I RNA data include all .HIV- I RNA data for subjects who are on-going and .HIV-I RNA data up to I 
day after the last dose date of study drug for subjects who prematurely discontinue or complete study drug. 


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Appendix 3.
UK TTO Value Set for EQ-5D-3L Questionnaire
For the UK TTO value set, the index is calculated for each of the health states based on the 
following equation:
Index  1 0.081 0.069 MO2 0.314 MO3 0.104 SC2 0.214 SC3 0.036 UA2 
0.094 UA3 0.123 PD2 0.386 PD3 0.071 AD2 0.236 AD3 0.269 N3

-0.081 is a constant term for any dysfunctional state.

MO2 is a dummy variable for level 2 of Mobility. 

MO3 is a dummy variable for level 3 of Mobility.

SC2 is a dummy variable for level 2 of Self Care. 

SC3 is a dummy variable for level 3 of Self Care.

UA2 is a dummy variable for level 2 of Usual Activities.

UA3 is a dummy variable for level 3 of Usual Activities.

PD2 is a dummy variable for level 2 of Pain/Discomfort.

PD3 is a dummy variable for level 3 of Pain/Discomfort. 

AD2 is a dummy variable for level 2 of Anxiety/Depression.

AD3 is a dummy variable for level 3 of Anxiety/Depression.

N3 is a dummy variable that represents level 3 occurs within at least one dimension.
The index score is missing if any one of the 5 dimensions is missing.


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UK TTO
Health State
Index Value
Health State
Index Value
Health State
Index Value
11111
1.000
12233
-0.112
21132
0.124
11112
0.848
12311
0.452
21133
-0.041
11113
0.414
12312
0.381
21211
0.814
11121
0.796
12313
0.216
21212
0.743
11122
0.725
12321
0.329
21213
0.309
11123
0.291
12322
0.258
21221
0.691
11131
0.264
12323
0.093
21222
0.620
11132
0.193
12331
0.066
21223
0.186
11133
0.028
12332
-0.005
21231
0.159
11211
0.883
12333
-0.170
21232
0.088
11212
0.812
13111
0.436
21233
-0.077
11213
0.378
13112
0.365
21311
0.487
11221
0.760
13113
0.200
21312
0.416
11222
0.689
13121
0.313
21313
0.251
11223
0.255
13122
0.242
21321
0.364
11231
0.228
13123
0.077
21322
0.293
11232
0.157
13131
0.050
21323
0.128
11233
-0.008
13132
-0.021
21331
0.101
11311
0.556
13133
-0.186
21332
0.030
11312
0.485
13211
0.400
21333
-0.135
11313
0.320
13212
0.329
22111
0.746
11321
0.433
13213
0.164
22112
0.675
11322
0.362
13221
0.277
22113
0.241
11323
0.197
13222
0.206
22121
0.623
11331
0.170
13223
0.041
22122
0.552
11332
0.099
13231
0.014
22123
0.118
11333
-0.066
13232
-0.057
22131
0.091
12111
0.815
13233
-0.222
22132
0.020
12112
0.744
13311
0.342
22133
-0.145
12113
0.310
13312
0.271
22211
0.710
12121
0.692
13313
0.106
22212
0.639
12122
0.621
13321
0.219
22213
0.205


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UK TTO
Health State
Index Value
Health State
Index Value
Health State
Index Value
12123
0.187
13322
0.148
22221
0.587
12131
0.160
13323
-0.017
22222
0.516
12132
0.089
13331
-0.044
22223
0.082
12133
-0.076
13332
-0.115
22231
0.055
12211
0.779
13333
-0.280
22232
-0.016
12212
0.708
21111
0.850
22233
-0.181
12213
0.274
21112
0.779
22311
0.383
12221
0.656
21113
0.345
22312
0.312
12222
0.585
21121
0.727
22313
0.147
12223
0.151
21122
0.656
22321
0.260
12231
0.124
21123
0.222
22322
0.189
12232
0.053
21131
0.195
22323
0.024
UK TTO
Health State
Index Value
Health State
Index Value
Health State
Index Value
22331
-0.003
31223
-0.059
33122
-0.072
22332
-0.074
31231
-0.086
33123
-0.237
22333
-0.239
31232
-0.157
33131
-0.264
23111
0.367
31233
-0.322
33132
-0.335
23112
0.296
31311
0.242
33133
-0.500
23113
0.131
31312
0.171
33211
0.086
23121
0.244
31313
0.006
33212
0.015
23122
0.173
31321
0.119
33213
-0.150
23123
0.008
31322
0.048
33221
-0.037
23131
-0.019
31323
-0.117
33222
-0.108
23132
-0.090
31331
-0.144
33223
-0.273
23133
-0.255
31332
-0.215
33231
-0.300
23211
0.331
31333
-0.380
33232
-0.371
23212
0.260
32111
0.232
33233
-0.536
23213
0.095
32112
0.161
33311
0.028
23221
0.208
32113
-0.004
33312
-0.043


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UK TTO
Health State
Index Value
Health State
Index Value
Health State
Index Value
23222
0.137
32121
0.109
33313
-0.208
23223
-0.028
32122
0.038
33321
-0.095
23231
-0.055
32123
-0.127
33322
-0.166
23232
-0.126
32131
-0.154
33323
-0.331
23233
-0.291
32132
-0.225
33331
-0.358
23311
0.273
32133
-0.390
33332
-0.429
23312
0.202
32211
0.196
33333
-0.594
23313
0.037
32212
0.125
23321
0.150
32213
-0.040
23322
0.079
32221
0.073
23323
-0.086
32222
0.002
23331
-0.113
32223
-0.163
23332
-0.184
32231
-0.190
23333
-0.349
32232
-0.261
31111
0.336
32233
-0.426
31112
0.265
32311
0.138
31113
0.100
32312
0.067
31121
0.213
32313
-0.098
31122
0.142
32321
0.015
31123
-0.023
32322
-0.056
31131
-0.050
32323
-0.221
31132
-0.121
32331
-0.248
31133
-0.286
32332
-0.319
31211
0.300
32333
-0.484
31212
0.229
33111
0.122
31213
0.064
33112
0.051
31221
0.177
33113
-0.114
31222
0.106
33121
-0.001


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Appendix 4.
Fracture Events
The selected PTs from the SMQ of osteoporosis/osteopenia and HLGT of fractures based on 
clinical review are listed as follows.
Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Acetabulum fracture
Ankle fracture
Atypical femur fracture
Atypical fracture
Avulsion fracture
Bone fissure
Bone fragmentation
Cervical vertebral fracture
Chance fracture
Clavicle fracture
Closed fracture manipulation
Comminuted fracture
Complicated fracture
Compression fracture
Craniofacial fracture
Epiphyseal fracture
External fixation of fracture
Facial bones fracture
Femoral neck fracture
Femur fracture
Fibula fracture
Flail chest
Foot fracture
Forearm fracture
Fracture
Fracture displacement
Fracture of clavicle due to birth trauma
Fracture treatment
Fractured coccyx


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Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Fractured ischium
Fractured sacrum
Fractured skull depressed
Greenstick fracture
Hand fracture
Hip fracture
Humerus fracture
Ilium fracture
Impacted fracture
Internal fixation of fracture
Jaw fracture
Limb fracture
Lisfranc fracture
Lower limb fracture
Lumbar vertebral fracture
Multiple fractures
Open fracture
Open reduction of fracture
Open reduction of spinal fracture
Osteochondral fracture
Osteoporotic fracture
Patella fracture
Pathological fracture
Pelvic fracture
Periprosthetic fracture
Pubis fracture
Radius fracture
Rib fracture
Sacroiliac fracture
Scapula fracture
Scapulothoracic dissociation
Skull fracture
Skull fractured base


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Selected PTs Based on SMQ of Osteoporosis/Osteopenia and HLGT of Fractures
Spinal compression fracture
Spinal fracture
Sternal fracture
Stress fracture
Tartrate-resistant acid phosphatase decreased
Thoracic vertebral fracture
Tibia fracture
Torus fracture
Traumatic fracture
Ulna fracture
Upper limb fracture
Vertebroplasty
Wrist fracture
Vertebral body replacement
Note: AEs are coded by MedDRA 22.0.


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Appendix 5.
Programming Specification
General Conventions
1) The standard mock tables 
(http://gnet/biometrics/stat/doc/Standard%20TFL_Final%20GNET%202009%2005%2015.d
oc) are default outputs developed based on standard CRF and standard SAP template.
Changes to the CRFs or SAP may warrant changes to these outputs. 
2) Italicized text in the mocks indicates that the entry is either optional or can be replaced by a 
more suitable term depending on the content.
3) Whenever possible, do not reference footnote by symbol within the body of the table and 
table title unless it greatly improves the clarity.
4) Titles should not exceed 128 characters (including the word “table,” the table number, 
punctuation, and spaces). If a title must exceed 128 characters, key descriptive information 
should be presented in the first 128 characters.
5) For completeness, please always include all the possible categories on standard CRF, 
including those with zero counts.
6) Treatment groups will be ordered as Gilead product in the first and then the rest of active 
control groups in alphabetical order, and placebo in the last column. Within each treatment, 
dose level will be in ascending order. Separate column for total or subtotal are allowed if 
space permits depending on study design, eg, a subtotal column could combine dose levels 
within the same treatment.
7) The ordering of these mock tables is the default ordering in the TFLs, ie, enrollment, 
disposition, demographic, baseline data, efficacy, drug exposure, and safety. 
8) Number TFLs consecutively and do not use decimal numbering for unique items.
9) A maximum of three titles and seven footnotes is allowed. Additional lines document the 
date of date extraction, source of SAS program, output files, and date-time of outputs 
generated.
10) The precision in reporting numerical values should be as follows: 
a) Raw measurements will be reported the same as the data captured electronically or on the 
CRFs.
b) Standard deviation and stand error will be reported to one more significant decimal place 
than the raw measurement.
c) Mean, median, minimum, Q1, Q3, maximum, 95% CIs will be reported to the same 
number of decimal places of the raw measurements. 
d) Exceptions may be considered; for example if more than 4 significant digits are provided 
for the measurement. 


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11) The number of decimal places in reporting p-values should be as follows:
a) values less than 0.001 <0.001
b) values 0.001 to less than 0.10 round to 3 decimal places
c) values 0.10 and greater round to 2 decimal places
12) For lab summaries, tests will be grouped as Chemistry, Hematology, and Metabolic 
Assessments. Disease related biomarkers, eg, bone biomarkers, will be grouped separately. 
Summaries will be sorted alphabetically by test within group.
13) Study day: if visit date ≥first dose date, study day  visit date first dose date +1. 
If visit date < first dose date, study day  visit date first dose date.
Other Definitions
14) AGE calculated as follows:
a) AGE (years) is calculated from the number of days between the date of birth (DOB) and 
Day 1 (first dose date),
b) Use the SAS INTCK function to determine the number of “1st-of-month days” 
(eg, January 1st, February 1st, March 1st) between DOB and Day 1 (inclusive),
c) Divide the result in (b) by 12,
d) AGE  the integer of the result in (c),
e) If the DOB and Day 1 have the month in common and the birthday is later in the month 
than the date of Study Day 1, subtract one from the AGE result above.
For subjects enrolled and never dosed with study drug, age will be calculated from the date 
of enrollment.
15) All screened subjects refer to all subjects who are screened (ie, with nonmissing screening 
date) and have a screening number. For summarization, same subject is counted only once. 
DOB and other demographic information such as sex, race, and ethnicity, country and initials 
will be used for identifying unique screened subjects.
16) Screen failure subjects are the subjects who are screened and answered “No” for any 
inclusion criteria or “Yes” for any exclusion criteria regardless of which version of protocol 
the subject was consent to.
17) Subjects in the enrolled analysis set are defined as subjects enrolled into the study. 
IXRSENRL is the source to determine whether the subject is enrolled (ie, subject with 
nonmissing RGMNDTN in the IXRSENRL dataset) and confirmed by the eCRF ENROLL 
dataset (ie, ENROLLYN  “Yes” in ENROLL dataset).


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18) In disposition table, the reasons for premature discontinuation are displayed in the order as 
they appear on the eCRF.
19) Body mass index (BMI)
Calculated from height in meters (eg, height in cm/100) and weight in kilograms as:
BMI will be calculated only at baseline. Baseline height and weight will be used for the 
BMI
 (weight [kg])/ (height [meters]2) calculation (height will be obtained from Vital Signs 
eCRF at screening visit, weight will be obtained from Vital Signs eCRF at baseline visit, if 
it’s missing, weight at screening visit from Vital Signs eCRF will be used).
20) Please note, “Not Permitted” or missing categories will be excluded for p value generation 
for categorical data analysis (eg, CMH test or Fisher exact test).
21) HIV Taqman Calculations
If a HIV-1 RNA test value is reported as “< 20 cp/mL HIV-1 RNA Detected” or 
“No HIV-1 RNA detected”, a numeric value of 19 will be used for summary purpose.
22) For safety ECGs at postbaseline visits, the most conservative (worst) value within the 
window will be selected, eg, abnormal will be selected over normal for safety ECG or 
clinical significant abnormal will be selected over not clinical significant abnormal if there 
are multiple abnormal findings.
23) Last Dose Date and Last Study Date
a) Last Dose Date (ie, TRTEDTC or TRTEDT in ADSL)

For subjects with a partial last dosing date (ie, month and year of last dose are 
known), use the max (the dispensing dates of study drug bottles, study drug start dates 
and end dates, imputed last dose date [day imputed as 15]) as the final imputed last 
dose date. (However if dispensing date’s month is after last dose date’s month, data 
query is needed.)

If subject died and the death date is complete (ie, not partial date) and before the 
imputed last dose date, the complete death date should be used as the imputed last 
dose date.

If the date of last dose is missing (eg, only year of last dose is known or completely 
missing due to lost to follow-up), use the maximum of study drug start dates and end 
dates, clinic visit dates (i.e., visit dates from vital sign and ECG forms), and 
laboratory visit dates excluding the 30-day follow-up visit to impute the last dose 
date.


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b) Last Study Date is the maximum of nonmissing study drug start dates and end dates, 
clinic visit dates (i.e., visit dates from vital sign and ECG forms) and laboratory visit 
dates, including the 30-day follow-up visit date for subjects who prematurely 
discontinued study or who completed study according to study completion eCRF. Please 
note, if study drug start date or end date is partially missing, the imputed date (day 
imputed as 15) will be used. If subject died and the death date is complete (ie, not partial 
date) and before the imputed last study date, the complete death date should be used as the 
imputed last study date.
24) Toxicity Grades:
a) For toxicity grade summary, we will include all postbaseline graded results up to 30 days 
after last dose of study drug, not just those at summarized visits.
b) For hematuria grading, if the laboratory reports urine blood using the plus system 
(+1, +2, etc) and also provides quantitative results on reflex (ie, urine RBC), summarize 
only the grade of the urine RBC results, but list both grades of urine blood and urine 
RBC.
c) For glucose grading, as specified in SAP Section 7.2.2.1, the treatment-emergent flag 
cannot be determined for nonfasting glucose (including glucose results without a known 
fasting status). As a result, these records will be excluded from the “Maximum 
Treatment-emergent Toxicity Grade” summary in the “Treatment-emergent Laboratory 
Abnormalities” or “Treatment-emergent Grade 3 or 4 Laboratory Abnormalities” 
summary tables. In addition, fasting glucose and nonfasting glucose will be listed as two 
separate laboratory tests in the “Laboratory Abnormalities” and “Grade 3 or 4 Laboratory 
Abnormalities” listings. Only a maximum postbaseline toxicity flag will be displayed and 
the treatment-emergent flag will not be displayed for nonfasting glucose as the 
treatment-emergent flag cannot be determined for nonfasting glucose.
25) “On-treatment” HIV-1 RNA data in the SAP refer to the data up to 1 day after the date of 
premature discontinuation of study drug (eg, last dose date).
26) Primary and Efficacy analyses:
a) Listing for snapshot algorithm outcome:
In addition to flagging the values of HIV-1 RNA < 50 or ≥ 50 for snapshot algorithm 
virologic outcomes, flag the last available HIV-1 RNA value for the following categories:
i)
HIV-1 RNA >  50 copies/mL - Discontinued Study Drug Due to AE or Death and 
Last Available HIV-1 RNA >  50 copies/mL
ii) HIV-1 RNA >  50 copies/mL - Discontinued Study Drug Due to Other reason* and 
Last Available HIV-1 RNA >  50 copies/mL
iii) No virologic Data
Discontinued Study Drug Due to AE or Death and Last Available 
HIV-1 RNA < 50 copies/mL


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iv) No virologic Data Discontinued Study Drug Due to Other reason* and Last 
Available HIV-1 RNA < 50 copies/mL
Note: * Other reasons include subjects who discontinued study drug due to investigator’s 
discretion, subject decision, lost to follow-up, noncompliance with study drug, 
protocol violation, pregnancy, and study terminated by sponsor.
b) For patients discontinued study drugs, if the last HIV-1 RNA (< 50 copies/mL) was on 
the same day as the start date of a new non-study ARV, the subjects was not a failure for 
the Snapshot outcome.
c) For a subject who completed the study drug with Week 48 HIV-1 RNA missing, snapshot 
outcome for such subject would be "Missing data during the windows but on study drug".
27) TEAE
Events with Missing Onset Day and/or Month
The event is treatment emergent if the following 3 criteria are met:

The month and year (or year) of onset date is the same as or after the month and year 
(or year) of the first dose of study drug, and

The month and year (or year) of the onset date is the same as or before the month and 
year (or year) of 30th day after the date of the last dose of study drug, and

End date is as follows: 
The (complete) end date is on or after the first dose date, or
The month and year (or year) of end date is the same or after the month and year 
(or year) of the first dose of study drug, or
End date is completely missing
Events with Completely Missing Onset Date
An AE with a completely missing onset date is defined as TEAE if end date is as follows:

The (complete) end date is on or after the first dose date, or

The month and year (or year) of end date is the same or after the month and year (or year) 
of the first dose of study drug, or

End date is completely missing


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28) Urine Protein Correction
a) The calibrator material used in the quantitative assay for the measurement of urine 
protein (UP) was changed globally in Covance on May 27, 2016. All samples reported 
prior to May 27, 2016 (ie, RPTDTM < ‘May 27, 2016’) were tested by the calibrator 
material manufactured by Roche Diagnostics, while the samples reported on or after 
May 27, 2016 were tested by the calibrator material manufactured by Quantimetrix. 
Covance had 3 regional lab centers to run the samples. Each regional lab center 
conducted its own alternate (quantitative) method comparison, all of these comparison 
demonstrate that calibrator materials manufactured by the Roche and Quantimetrix yield 
comparable results as noted in the table below:
Regional Lab Center
Accession 
Numbersa
Regular Regression 
for UP Correctionb 
Correlation 
Coef.
Bias
Indianapolis Auto Chemistry
Start with 65
Y = 1.028 X – 3.70
0.9982
-2.34 (-4.91%)
Geneva Auto Chemistry
Start with 62 or 63 
Y = 0.981 X – 1.44
0.9993
-2.42 (-4.74%)
Singapore Auto Chemistry
Start with 64 or 66
Y = 0.980 X – 1.62
0.9996
-2.73 (-5.08%)
BML in China 
Start with 67 or 68
NA
NA
NA
a
Accession numbers specified which regional lab center tested the sample. For example, samples with accession number 
started with 65 were tested in Indianapolis Auto Chemistry Center. 
b
X and Y are the UP results using calibrator materials manufactured by Roche Diagnostics and Quantimetrix, respectively. 
b) In order to combine the UP results obtained from the 2 different assay methods for 
summary/comparison purpose, we will convert the UP results analyzed using the 
calibrator from Roche (ie, results reported prior to May 27, 2016) to Quantimetrix results 
by using the regression equation listed in above table. 
Original UP based 
on Reported Date
Original UP 
Categories
Accession 
Number
AVALC of Corrected UP 
(‘UP’ stands for Original UP)
UP reported 
on/after May 27, 
2016
ALL
ALL
AVALC of UP
UP reported before 
May 27, 2016
UP < 4.0
ALL
‘< 4.0’
UP ≥ 4.0
Start with 65
1.028 × UP - 3.70; if 1.028 × UP - 3.70 ≥ 4.0 
‘< 4.0’; if 1.028 × UP - 3.70 < 4.0
Start with 62 or 63
0.981 × UP – 1.44; if 0.981 × UP – 1.44 ≥ 4.0 
‘< 4.0’; if 0.981 × UP – 1.44 < 4.0
Start with 64 or 66
0.980 × UP – 1.62; if 0.980 × UP – 1.62 ≥ 4.0 
‘< 4.0’; if 0.980 × UP – 1.62 < 4.0


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c) The corrected UP results will be used for the following analysis and referred as “UP” in 
following text. If AVALC of the corrected UP is “< 4.0”, the AVAL of the corrected UP 
will be imputed as 3.9 mg/dL.
29) Unit conversion for some renal biomarkers derived from related tests with conventional units

Urine RPB (μg/L) to creatinine (mg/dL) ratio: 1 (μg/L) / (mg/dL)  100 × μg/g

Urine Beta-2-microglobulin (mg/L) to creatinine (mg/dL) ratio: 1 (mg/L) / (mg/dL)  
105 μg/g 

Urine Protein (mg/dL) to creatinine (mg/dL) ratio: 1 (mg/dL) / (mg/dL)  1000 × mg/g

Urine Albumin (mg/dL) to creatinine (mg/dL) ratio: 1 (mg/dL) / (mg/dL)  1000 × mg/g
30) Calculation of ratios
To calculate laboratory ratios (eg, urine RPB to creatinine ratio), lab value of each test in the 
ratio needs to be from the same accession number; if any test value used for the ratio 
calculation from the same accession number is missing , the ratio is not calculable 
(ie, missing). For urine creatinine, a value of “< 1” is handled as a missing value in the 
calculation of related ratios. For urine protein, a value of “< 4.0” is handled as a missing 
value in the calculation of UPCR.
31) Combined category of UP and UPCR
a) First merge UP and UPCR based on the subject identifier and accession number.
b) At each visit, based on UP to select which pair of records should be used for the analysis. 
That is, once a UP record is selected for that visit, the UPCR with the same accession 
number (if calculated) will be selected. Please note, UPCR is missing when UP 
< 4.0 mg/dL.
c) Subject will be classified as “UPCR ≤200 mg/g” if UP < 4.0 mg/dL or UPCR 
≤200 mg/g; Subject will be classified as “UPCR > 200 mg/g” if UPCR > 200 mg/g; 
Otherwise, subject will be classified as “Missing”.
32) Prior ARV
Non-study drug ARVs collected in prior ARV form with start date and stop date completely 
missing are considered “not concomitant”.
33) Lipid modifying medication analyses:

Lipid modifying medication is defined to be the concomitant medication with any 
concomitant medication class  “LIPID MODIFYING AGENTS” and CMDECOD 
contains wording of “STATIN” in the ADCM dataset.


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
Subjects who took lipid modifying medications at study entry refer to the subjects who 
use of the lipid modifying agents at study day 1 (ie, the first dose date). More 
specifically, subjects with “Lipid Modifying Agent Use at Study Entry” include those 
subjects in Safety Analysis Set with: 1) any selected CM record with the start date 
≤the first dose date, and 2) the end date of the selected CM record is ongoing or the end 
date of the selected CM record ≥ the first dose date.

Subjects who initiated lipid modifying medications during the study include the subjects 
in the Safety Analysis Set who didn’t take lipid modifying medications at study entry and 
met the following criteria: 1) for subjects who permanently discontinued study drug with 
any selected CM record started after the first dose date and on and prior to the last dose 
date; 2) for subjects who are still on study drug with any selected CM records started 
after the first dose date.

For lipid modifying medications with the start date completely unknown, we assume the 
start date is on or before the first dose date, lipid modifying medication was considered as 
being taken at study entry if the end date is not prior to the first dose date (ie, the end date 
is on or after the first dose date, completely unknown, or ongoing). 

Lipid modifying medications with the start date prior to the first dose date and the end 
date completely unknown were considered as being taken at study entry.
34) Age for laboratory test reference range will be based on the age at the sample collection date.
35) For figures, if at a visit where n (sample size) for any treatment group <  5, data for that 
treatment group will not be displayed at the visit in figure, but all data will be included in the 
corresponding table summary.
36) For the PRO data, data up to 30 day after the last dose date for subjects who permanently 
discontinued of study drug will be summarized.
37) For PRO data, unless otherwise stated, multiple responses and out of range responses will be 
set to missing and missing responses will not be imputed.
Out of range value is determined based on the following table for within-range response 
values:
SF-36v2 Health Survey:
Question
Response
Min
Max
1, 2, 4a to 4d, 5a to 5c, 6, 8, 9a to 9i, 10, 11a to 11d
1
5
3a to 3j
1
3
7
1
6


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VAS adherence questionnaire:
Questions
Response
Min
Max
1
0
100
2
0
30
3
0
4
38) Computing EQ-5D index values with SAS using the UK TTO value set
The variables for the 5 dimensions of the EQ-5D descriptive system should be named 
'mobility', 'selfcare', 'activity', 'pain', and 'anxiety'. The variable 'UK_TTO' contains the 
values of the EQ-5D index.
You can copy and paste the syntax below directly into the SAS syntax window.
******************************************************************
*
SAS syntax code for the computation of index  *
*
values with the UK MVH A1 TTO value set  *
******************************************************************;
data Euroqol.Uk_data;
set Euroqol.EQ5D_states;
UK_TTO = 1;
if (mobility = 2) then UK_TTO = UK_TTO 
0.069;
if (mobility = 3) then UK_TTO = UK_TTO 
0.314;
if (selfcare = 2) then UK_TTO = UK_TTO 
0.104;
if (selfcare = 3) then UK_TTO = UK_TTO 
0.214;
if (activity = 2) then UK_TTO = UK_TTO 
0.036;
if (activity = 3) then UK_TTO = UK_TTO 
0.094;
if (pain = 2) then UK_TTO = UK_TTO 
0.123;
if (pain = 3) then UK_TTO = UK_TTO 
0.386;
if (anxiety = 2) then UK_TTO = UK_TTO 
0.071;
if (anxiety = 3) then UK_TTO = UK_TTO 
0.236;
if (mobility ne 1) or (activity ne 1) or (selfcare ne 1) or (pain ne 1) or 
(anxiety ne 1) then UK_TTO = UK_TTO 
0.081;
if (mobility = 3) or (selfcare = 3) or (activity = 3) or (pain = 3) or 
(anxiety = 3) then UK_TTO = UK_TTO 
0.269;
if (mobility = .) or (selfcare = .) or (activity = .) or (pain = .) or 
(anxiety = .) then UK_TTO = . ;
output;
run;


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39) Smoking status at baseline
Smoking status at baseline (ie, never smoker, former smoker, and current smoker) will be 
summarized as part of the baseline disease characteristics. How to classify a subject as never, 
former, or current smoker at baseline is specified as follows: 
a) First, select only records with Type of Substance Use
 “Cigarettes” or “Cigars”. Records 
with Type of Substance Use
 “Other” (including chew tobacco, e-cigarettes, etc) will not 
be considered as smoking.
b) Second, for each selected substance use record, flag whether it is “Prior”, “Present”, or 
“Post” relative to the first dose date according to the Algorithm below. 
c) Finally, (1) the subject will be flagged as “Never smoker”, if the subject has no record 
with Type of Substance Use
 “Cigarettes” or “Cigars” or all selected records have a flag 
of “Post”; (2) the subject will be flagged as a “Former” smoker, if any selected records 
has a flag of “Prior” and no record of “Present”; (3) Otherwise, the subject will be 
flagged as a “Current” smoker, if any selected records has a flag of “Present”. 
Selected Substance Use Records
Prior
No
No
Yes
Yes
Yes
No
No
Yes
Present
No
No
No
No
Yes
Yes
Yes
Yes
Post
No
Yes
No
Yes
No
No
Yes
Yes
Smoking Status 
Never
Never
Former
Former
Current
Current
Current
Current
Algorithm to flag whether a selected record is “Prior”, “Present”, or “Post” relative to 
the first dose date:
d) the start and stop dates of the selected record are not completely missing (ie, at least year 
is known) or the start date is not missing and record is ongoing. The completed start or 
stop dates will be used to compare with the first dose date whenever possible. Otherwise, 
the month and year (or year alone if month is not recorded) of the start or stop dates will 
be used to compare with the first dose date when the start or stop date of the selected 
record is incomplete. 
i)
The record is flagged as “Prior”, if the stop date is before (<) the first dose date; 
ii) The record is flagged as “Present”, if the start date is on or before (≤) the first dose 
date and the stop date is on or after (≥) the first dose date, or the selected record is 
marked as ongoing and the start date is on or before (≤) the first dose date; 
iii) The record is flagged as “Post”, if the start date is after the first dose date;


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e) the start date of the selected record is completely missing. We assume that the start date 
is before the first dose date, the stop date (or the month and/or year of the stop date, if 
stop date is incomplete) will be used to determine whether the selected record is “Prior” 
or “Present” as follows.
i)
The record is flagged as “Prior”, if the stop date is before (<) the first dose date or the 
stop date is completed missing and the record is not marked as ongoing. 
ii) The record is flagged as “Present”, if the stop date is on or after (≥) the first dose date 
or the selected record is marked as ongoing.
f)
the start date of the selected record is before (<) the first dose date, but the stop date is 
completely missing and the record is not marked as ongoing. We assume that the end date 
is before the first dose date, the record is flagged as “Prior”.
g) the start date of the selected record is on or after the first dose date, but the stop date is 
completely missing and the record is not marked as ongoing. This is a data issue, should 
be queried first. However, this record is flagged as “Present” if the start date is on the 
first dose; this record is flagged as “Post” if the start date is after the first dose.
40) LDL: Conversions between 2nd and 3rd generations
LDL was analyzed by 2 different assays in the study: 2nd generation (including RCT2394, 
RCT2312, and RCT2811) and 3rd generation (RCT3870). Samples collected at earlier visits 
were analyzed using LDL 2nd generation assay. Samples collected at later visits were 
analyzed using LDL 3rd generation assay. The conversion formulas are as follow:
2nd Gen (mmol/L)  (3rd Gen - 0.0626)/0.882
3rd Gen (mmol/L)  (0.882 x 2nd Gen) + 0.0626
For this analysis, since LDL samples were analyzed by 2nd generation assay at Baseline, we 
only requested conversion from 3rd generation to 2nd generation.
For the analysis of change from baseline in fasting direct LDL: the sample analyzed by LDL 
3rd generation assay will be converted to 2nd generation as a new record with test codes of 
LIP.LDL.00.02 in raw data. During ADaM stage, a derived parameter code (FLDL2) for 
“Fasting LDL Cholesterol 2ND GEN Combined” will be generated to pool the records from 
both original (including test codes RCT2394, RCT2312, and RCT2811) and converted 
(LIP.LDL.00.02) 2nd generation results to calculate the change from baseline in fasting 
direct LDL.
For the analysis of toxicity grade for fasting direct LDL: toxicity grade will be based on the 
Gilead grading results (ie, toxgrg) from original values before conversion. In another words, 
during ADaM stage, a derived parameter code (FLDLTOX) for “Fasting LDL Cholesterol 
for Toxicity” will be generated to pool the records from 2nd generation (including RCT2394, 
RCT2312, and RCT2811) and 3rd generation (ie, RCT3870) to derive treatment-emergent 
toxicity grades, maximum postbaseline toxicity grades, etc.


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41) A subject is currently taking abacavir if the ingredient in the ARV form (variable INGRED) 
contains the substring “ABC” at baseline.  Similarly, a subject is considered currently taking 
indinavir or lopinavir if the abbreviation contains the substring “IDV” or “LPV”.

Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 3b Open-Label Pilot Study to Evaluate Switching to 
Elvitegravir/Cobicistat/Emtricitabine/T enofovir Alafenamide 
(E/C/F/TAF) Fixed Dose Combination (FDC) in 
Virologically-Suppressed HIV-1 Infected Adult Subjects 
Harboring the Archived Isolated NRTI Resistance Mutation 
M184V/M184I 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
111,007 
2015-002710-74 
Clinical Trials.gov Identifier: 
NCT02616029 
Indication: 
Protocol ID: 
Gilead Clinical Program 
Manager: 
Gilead Medical Monitor: 
Gilead Study Director: 
Protocol Version/Date: 
HIV-1 Infection 
GS-US-292-1824 
Name: 
Telephone: 
Fax: 
Name: 
Telephone: 
Mobile: 
Name: 
Telephone: 
Mobile: 
Original: 
Amendment 1: 
PPD 
PPD 
PPD 
29 July2015 
19 August 2016 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiicularly 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 Boai·d or Independent Ethics Committee. The infonnation is only to be used 
by you in connection with authorized clinical studies of the investigational drng described in the 
protocol. You will not disclose any of the info1mation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessaiy to obtain info1med consent from those 
persons to whom the drng may be administered. 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................15
1.1.
Background ............................................................................................................................................15
1.2.
Tenofovir Alafenamide (TAF, GS-7340)...............................................................................................17
1.2.1.
General Information .............................................................................................................17
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................17
1.2.3.
Clinical Trials of E/C/F/TAF ...............................................................................................19
1.3.
Information About Comparator Regimens.............................................................................................21
1.4.
Rationale for this Study..........................................................................................................................21
1.5.
Risk/Benefit Assessment for the Study..................................................................................................21
1.6.
Compliance ............................................................................................................................................21
2.
OBJECTIVES.....................................................................................................................................................22
3.
STUDY DESIGN................................................................................................................................................23
3.1.
Study Design..........................................................................................................................................23
3.2.
Study Treatments ...................................................................................................................................24
3.3.
Duration of Treatment............................................................................................................................24
3.4.
End of Study...........................................................................................................................................24
3.5.
Post Study Care......................................................................................................................................24
3.6.
Source Data............................................................................................................................................25
3.7.
Samples for Optional Exploratory Assessments ....................................................................................25
4.
SUBJECT POPULATION..................................................................................................................................26
4.1.
Number of Subjects and Subject Selection ............................................................................................26
4.2.
Inclusion Criteria....................................................................................................................................26
4.3.
Exclusion Criteria...................................................................................................................................28
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................30
5.1.
Enrollment..............................................................................................................................................30
5.2.
Description and Handling of E/C/F/TAF FDC ......................................................................................30
5.2.1.
Formulation..........................................................................................................................30
5.2.2.
Packaging and Labeling .......................................................................................................30
5.2.3.
Storage and Handling...........................................................................................................31
5.3.
Dosage and Administration of E/C/F/TAF FDC....................................................................................31
5.4.
Prior and Concomitant Medications.......................................................................................................31
5.5.
Accountability of Study Drug ................................................................................................................36
5.5.1.
Study Drug Return or Disposal ............................................................................................36
6.
STUDY PROCEDURES ....................................................................................................................................37
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................37
6.2.
Pretreatment Assessments......................................................................................................................37
6.2.1.
Screening Visit .....................................................................................................................37
6.2.2.
Day 1 Visit ...........................................................................................................................39
6.3.
Treatment Assessments..........................................................................................................................40


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6.3.1.
Treatment Visits (Weeks 4 – 48)..........................................................................................40
6.4.
Post-treatment Assessments ...................................................................................................................43
6.4.1.
Early Study Drug Discontinuation (ESDD) Visit.................................................................43
6.4.2.
30-Day Follow-up Visit........................................................................................................44
6.5.
Assessments for Premature Discontinuation from Study.......................................................................45
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................45
6.7.
Other Evaluations...................................................................................................................................46
6.7.1.
Blood and Urine Storage......................................................................................................46
6.8.
Virologic Failure....................................................................................................................................46
6.8.1.
Management of Virologic Failure ........................................................................................46
6.8.2.
Resistance Analysis at Subjects Last Visit...........................................................................47
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................49
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................49
7.1.1.
Adverse Events.....................................................................................................................49
7.1.2.
Serious Adverse Events........................................................................................................49
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................50
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................50
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................50
7.2.2.
Assessment of Severity ........................................................................................................51
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................51
7.4.
Gilead Reporting Requirements.............................................................................................................53
7.5.
Toxicity Management ............................................................................................................................53
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................54
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................54
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................54
7.5.4.
Management of Potential Nephrotoxicity.............................................................................54
7.6.
Special Situations Reports......................................................................................................................55
7.6.1.
Definitions of Special Situations..........................................................................................55
7.6.2.
Instructions for Reporting Special Situations.......................................................................56
8.
STATISTICAL CONSIDERATIONS................................................................................................................58
8.1.
Analysis Objectives and Endpoints........................................................................................................58
8.1.1.
Analysis Objectives..............................................................................................................58
8.1.2.
Primary Endpoint .................................................................................................................58
8.1.3.
Secondary Endpoint .............................................................................................................58
8.2.
Analysis Conventions.............................................................................................................................59
8.2.1.
Analysis Sets ........................................................................................................................59
8.3.
Demographic Data and Baseline Characteristics ...................................................................................59
8.4.
Efficacy Analysis ...................................................................................................................................59
8.4.1.
Primary Analysis..................................................................................................................59
8.4.2.
Secondary Analyses .............................................................................................................60
8.5.
Safety Analysis.......................................................................................................................................60
8.5.1.
Extent of Exposure...............................................................................................................60
8.5.2.
Adverse Events.....................................................................................................................60
8.5.3.
Laboratory Evaluations ........................................................................................................61
8.5.4.
Other Safety Evaluations......................................................................................................61
8.6.
Sample Size............................................................................................................................................61
8.7.
Data Monitoring Committee ..................................................................................................................61
9.
RESPONSIBILITIES..........................................................................................................................................62
9.1.
Investigator Responsibilities ..................................................................................................................62


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9.1.1.
Good Clinical Practice..........................................................................................................62
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................62
9.1.3.
Informed Consent.................................................................................................................63
9.1.4.
Confidentiality......................................................................................................................63
9.1.5.
Study Files and Retention of Records ..................................................................................63
9.1.6.
Case Report Forms...............................................................................................................65
9.1.7.
Inspections............................................................................................................................65
9.1.8.
Protocol Compliance............................................................................................................65
9.2.
Sponsor Responsibilities ........................................................................................................................65
9.2.1.
Protocol Modifications.........................................................................................................65
9.2.2.
Study Report and Publications .............................................................................................65
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................66
9.3.1.
Payment Reporting...............................................................................................................66
9.3.2.
Access to Information for Monitoring..................................................................................66
9.3.3.
Access to Information for Auditing or Inspections ..............................................................66
9.3.4.
Study Discontinuation..........................................................................................................67
10.
REFERENCES ...................................................................................................................................................68
11.
APPENDICES ....................................................................................................................................................71
Appendix 1.
Investigator Signature Page....................................................................................................72
Appendix 2.
Study Procedures Table..........................................................................................................73
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................75
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............76
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................98
Appendix 6.
AIDS-Defining Conditions (CDC Guidelines) {Selik et al 2014}.......................................101
LIST OF IN-TEXT TABLES
Table 3-1.
Part 1 and Part 2 Resistance Criteria ......................................................................................23
Table 4-1.
Allowable Third Antiretroviral Agents of Pre-Existing Regimen..........................................28
Table 4-2.
Disallowed Agents .................................................................................................................29
Table 5-1.
Prior and Concomitant Medications.......................................................................................32
LIST OF IN-TEXT FIGURES
Figure 3-1.
Study Schema.........................................................................................................................24
Figure 6-1.
Management of Virologic Failure ..........................................................................................48


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 3b Open-Label Pilot Study to Evaluate Switching to 
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide 
(E/C/F/TAF) Fixed Dose Combination (FDC) in 
Virologically-Suppressed HIV-1 Infected Adult Subjects Harboring 
the Archived Isolated NRTI Resistance Mutation M184V/M184I
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
111,007
2015-002710-74
TBD
Study Centers Planned:
Approximately 38 centers in Europe and North America
Objectives:
The primary objective of this study is as follows:
To evaluate the efficacy of E/C/F/TAF fixed dose combination 
(FDC) after switching from a stable regimen consisting of
FTC/TDF or ABC/3TC plus a third antiretroviral agent in 
maintaining HIV-1 RNA < 50 copies/mL at Week 12 (using pure 
virologic response) in subjects harboring the archived NRTI 
resistance mutation M184V and/or M184I in HIV-1 reverse 
transcriptase
The secondary objectives of this study are as follows:
To determine the safety and tolerability of E/C/F/TAF FDC in 
subjects switching from 2 NRTI plus third antiretroviral agent 
regimens
To evaluate the development of new resistance mutations in 
subjects who develop virologic failure after switching to 
E/C/F/TAF FDC
To determine the durability of efficacy at Weeks 24 and 48 in 
maintaining HIV-1 RNA < 50 copies/mL using 
pure virologic response (PVR)


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Study Design:
Open-label, single arm, multicenter study to evaluate the efficacy 
and safety of switching to E/C/F/TAF FDC in HIV-1 infected adult 
subjects with HIV-1 RNA < 50 copies/mL harboring an archived 
isolated M184V and/or M184I mutation associated with NRTI 
resistance and who have been on a stable regimen consisting of 
FTC/TDF or ABC/3TC plus a third antiretroviral agent with HIV-1 
RNA below the detection limit for ≥ 6 months at screening. 
Subjects will have no evidence of previous virologic failure on a 
PI/r or INSTI-based regimen (with or without resistance to either 
class of ARV). Subjects may have evidence of a prior virologic 
failure on an NNRTI plus 2 NRTI-based regimen. Prior treatment 
changes due to tolerability will be allowed as long as virologic 
failure was not the reason for treatment change and the subject 
remained continuously suppressed.
Part 1
In Part 1, the enrollment criteria will allow 50 subjects to enter the 
study if they have M184V and/or M184I in HIV-1 reverse 
transcriptase WITHOUT any other NRTI resistance mutation 
(including thymidine analogue-associated mutations (TAMs) 
[M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R], 
K65R, K70E, T69 insertion and Q151M mutation complex 
[A62V, V75I, F77L, F116Y, Q151M]).
After these subjects in Part 1 have undergone their Week 12 visit, 
an interim efficacy review will be done by an internal Data 
Monitoring Committee (Internal DMC) that is independent of the 
study team and the study conduct activities, to ensure the rate of 
virologic failure is not unacceptably high. A pure virologic 
response (PVR) of < 80% would be considered unacceptable; 
safety monitoring will be designed to assure that the true value of 
PVR is above 80%.
Part 2
If the rate of virologic failure in Part 1 is deemed acceptable, once 
the internal DMC officially completes the interim review, entry 
criteria will be expanded and the study will continue to Part 2.
In Part 2, the enrollment criteria will be expanded to allow 
50 additional subjects to enter the study if they have M184V and/or 
M184I in HIV-1 reverse transcriptase WITH or WITHOUT
1 or 2 TAMs that include M41L, D67N, K70R, L210W, T215Y/F,
and K219Q/E/N/R (not including the K65R, K70E, T69 insertion, 
and/or Q151M mutation complex [A62V, V75I, F77L, F116Y, 
Q151M]).


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Safety Monitoring of Virologic Failures
All HIV-1 RNA values will be reviewed on an ongoing basis. 
Any post-Day 1 HIV-1 RNA ≥50 copies/mL will be repeated 
within 2-4 weeks. Subjects with confirmed HIV-1 RNA 
≥50 copies/mL will be managed in discussion with the Medical 
Monitor in accordance with guidelines developed for the 
E/C/F/TAF phase 3 program.
Number of Subjects 
Planned:
Approximately 100 subjects will be enrolled into the study.
Target Population:
HIV-1 infected adults (≥ 18 years) with HIV-1 RNA < 50 copies/mL 
on a stable regimen containing FTC/TDF or ABC/3TC plus an 
(allowed) third antiretroviral agent (refer to Table 4-1) for 
≥6 consecutive months prior to screening and documented 
presence of NRTI resistance mutation M184V and/or M184I in 
HIV-1 reverse transcriptase.
Duration of Treatment:
A 42 day screening period followed by 48 weeks of treatment and a 
30 Day Follow-Up visit after completion of study drug. 
Subjects that develop virologic failure will be followed for the 
duration of the study or longer to document virologic suppression 
on a revised regimen.
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:

Documented plasma HIV-1 RNA levels < 50 copies/mL for 
≥6 months preceding and at the screening visit (measured at 
least twice using the same assay). One unconfirmed virologic 
elevation or “blip” of ≥ 50 copies/mL after previously reaching 
viral suppression is acceptable.

Currently receiving an antiretroviral (ARV) regimen consisting 
of FTC/TDF or ABC/3TC plus a third antiretroviral agent for 
≥6 consecutive months preceding the Screening visit. Refer to 
Table 4-1 for allowed third agents.

No previous use of any approved or experimental integrase 
strand transfer inhibitor (INSTI) (for any length of time) if the 
current regimen contains a PI/r.


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All subjects must have a historical genotype report showing 
M184V and/or M184I (mixtures are acceptable) in HIV-1 reverse 
transcriptase WITHOUT (Part 1) and WITH or WITHOUT (Part 2)
1 or 2 TAMs. Subjects must not have any primary INSTI or 
primary PI resistance mutations. Additional NRTI resistance 
mutations not defined below are allowed, and NNRTI mutations are 
allowed (see Table 3-1).
Subjects identified as having the indicated resistance mutation profile 
from a historical genotype will then be tested for archived resistance 
by proviral genotype analysis (from whole blood) at screening visit. 
Proviral DNA tested must not have additional exclusion resistance 
mutations (defined in Table 3-1 for Part 1 or Part 2); if identified,
subjects will be excluded from entry into the study.
Part 1 Resistance Criteria (first 50 subjects): 
M184V and/or M184I (mixtures are acceptable) in reverse 
transcriptase WITHOUT any other NRTI resistance 
mutation (including TAMs [ M41L, D67N, K70R, L210W, 
T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion
and Q151M mutation complex [A62V, V75I, F77L, F116Y, 
Q151M]).
Part 2 Resistance Criteria (second 50 subjects; 
after the interim efficacy review): M184V and/or M184I 
(mixtures are acceptable) in reverse transcriptase WITH or 
WITHOUT 1 or 2 TAMs [M41L, D67N, K70R, L210W, 
T215Y/F, and K219Q/E/N/R]. Evidence of K65R, K70E,
T69 insertion and/or Q151M mutation complex [A62V, 
V75I, F77L, F116Y, Q151M] in addition to the resistance 
mutations above will not be eligible for entry into the study.
Must not have integrase or protease inhibitor (PI) mutations present 
on historical genotype. Non-Nucleoside Reverse Transcriptase 
Inhibitor (NNRTI) mutations are allowed.
Estimated glomerular filtration rate ≥30 mL/min according to the 
Cockcroft-Gault formula for creatinine clearance
Study Procedures/
Frequency:
Following Screening, eligible subjects will be required to return for 
study visits at Day 1, Weeks 4, 8, 12, 16, 24, 36 and 48. After the 
Week 48 visit, subjects will stop study drug and complete a 30-Day 
Follow-up visit to complete their participation in the study.
Laboratory analyses (hematology, chemistry, and urinalysis), 
HIV-1 RNA, CD4+ cell count, and complete or symptom directed 
physical examinations will be performed at Screening, Day 1 and 
specific subsequent study visits. 


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Amendment #1
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A whole blood sample will be collected at the Screening visit for 
proviral genotype analysis for archived resistance in subjects that 
possess an eligible historical genotype report. Subjects that develop 
virologic failure will have HIV-1 plasma genotype/phenotype of 
reverse transcriptase, protease and integrase.
Test Product, Dose, and 
Mode of Administration:
All subjects will receive elvitegravir 150 mg / cobicistat 150 mg /
emtricitabine 200 mg / tenofovir alafenamide 10 mg (E/C/F/TAF) 
FDC, administered orally, once daily, with food
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for Evaluation:
Efficacy of switch from the current regimen to E/C/F/TAF FDC 
will be evaluated using HIV-1 RNA values; safety will be assessed 
with adverse events and clinical laboratory tests.
Safety:
Safety of E/C/F/TAF FDC will be reviewed at Weeks 12, 24 and 48 
by assessing clinical laboratory tests and adverse events during the 
study.
Health Related 
Questionnaires:
Health related questionnaires will be administered, including the 
EQ-5D, Medical Outcome Study Short Form-36 (SF-36), 
Visual Analogue Scale (VAS), HIV Treatment Satisfaction 
Questionnaire (HIV-TSQ) and Functional Assessment of 
Chronic Illness Therapy – Fatigue (FACIT-F).
Efficacy:
Primary Endpoint:

HIV-1 RNA < 50 copies/mL at Week 12 using pure virologic 
response (PVR)
Secondary Endpoints:

Emergence of new mutations in HIV-1 reverse transcriptase and 
integrase (attempted on any post Day 1 sample with 
HIV-1 RNA ≥50 copies/mL)

HIV-1 RNA< 50 copies/mL at Weeks 24 and 48 using PVR

HIV-1 RNA < 50 copies/mL at Weeks 12, 24 and 48 using the 
FDA snapshot analysis (sensitivity analysis)

CD4+ cell count change from Day 1 at Weeks 12, 24 and 48


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Statistical Methods:
The primary endpoint of pure virologic response (PVR) with 
HIV-1 RNA < 50 copies/mL at Week 12 will be computed.
The following criteria are considered for classifying subjects as a 
pure virologic responder at Week 12:

Subject remains on study treatment

No confirmed virologic rebound as defined by:
HIV-1 RNA ≥ 50 copies/mL on 2 consecutive visits
HIV-1 RNA ≥ 50 copies/mL during study followed by 
premature discontinuation
Note: For confirmation of viral rebound, the first HIV-1 RNA 
must occur on or before the upper limit of the Week 12 analysis 
window, the confirming event (i.e., the second of the 
consecutive HIV-1 RNAs or premature study discontinuation) 
can occur after the upper limit of the Week 12 analysis window.
Subjects who meet the above criteria are pure virologic responders 
at Week 12; otherwise subjects are pure virologic failures (PVF) 
at Week 12.
Similar definition would hold for PVR at Weeks 24 and 48.
Sensitivity analyses of virologic failure will use the FDA snapshot 
analysis (and other sensitivity analyses such as missing equal 
failure) at Weeks 12, 24 and 48.
An interim efficacy analysis will be conducted when the first 
50 subjects complete 12 weeks of treatment. Based on the analysis 
of the primary efficacy variable (HIV-1 RNA < 50 copies/mL) 
using pure virologic response, study conduct may be altered based 
on the recommendations of the internal monitoring committee.
Descriptive statistics will summarize baseline characteristics, 
efficacy, and safety endpoints.
The primary analysis will describe the point estimate and 
95% confidence interval around the proportion of subjects with 
HIV-1 RNA < 50 copies/mL for the primary endpoint. If the 
observed pure virologic response rate is 90%, then with 
100 participants, the width of the 95% CI will be ± 5.9% 
(large sample size approximation and binomial distribution).
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
AhR
aryl hydrocarbon receptor
AK
adenylate kinase
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
DMC
data monitoring committee


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DNA
deoxyribonucleic acid
DRV
darunavir
DSPH
Drug Safety and Public Health
DTG
dolutegravir
ECG
electrocardiogram
EDC
electronic data capture
ETR
Etravirine
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
EFV
efavirenz
ETR
etravirine
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
FPV
Fosamprenavir
FDC
fixed dose combination
FSH
follicle-stimulating hormone
FTC
emtricitabine
F/TAF
emtricitabine/tenofovir alafenamide
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate
GCP
Good Clinical Practice (Guidelines)
GFR
glomerular filtration rate
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 antibody serology
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HIV-TSQs
HIV Treatment Satisfaction Questionnaire Status
HIV-TSQc
HIV Treatment Satisfaction Questionnaire Change


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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
IEC
Independent Ethics Committee
IND
Investigational New Drug (Application)
INSTI
integrase strand transfer inhibitor
IMP
Investigational Medicinal Product
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IWRS
interactive web response system
KS
Kaposi’s sarcoma
LAM
Lactational amenorrhea method
LDH
lactate dehydrogenase
LLN
lower limit of the normal range
LLT
low-level term
LLOQ
lower limit of quantification
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
PAH
pulmonary arterial hypertension
PI
protease inhibitor
PK
pharmacokinetic
PT
preferred term
PVR
pure virologic response
PXR
pregnane-X-receptor


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QA
Quality Assurance
QD
once daily
RAL
raltegravir
RBC
Red blood cells
RNA
ribonucleic acid
RPV
rilpivirine
RTV, /r
ritonavir
SA
single agent
SADR
serious adverse drug reaction
SAE
serious adverse event
SOC
system organ class
SOP
standard operating procedure
SQV
Saquinavir
SSRI
selective serotonin reuptake inhibitors
STB
Stribild®, EVG/COBI/FTC/TDF (E/C/F/TDF) STR
STR
single tablet regimen
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide (GS-7340)
TAF fumarate
tenofovir alafenamide fumarate (GS-7340-03)
TAM
thymidine analogue-associated mutation
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
VAS
visual analog scale
VR
virologic rebound
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 that is of major public health interest 
around the world. There are 35 million people worldwide and approximately 1.1 million people 
in the US living with HIV-1. Within Western and Central Europe, it is estimated that there are 
over 900,000 individuals living with HIV and 131,000 new infections in 2012.
The infection, if left untreated or suboptimally treated, is characterized by deterioration in 
immune function, the subsequent occurrence of opportunistic infections and malignancies, 
ultimately resulting in death. Therapeutic strategies for the treatment of HIV-1 disease have been 
significantly advanced by the availability of highly active antiretroviral therapy (HAART); 
the introduction of HAART was associated with a dramatic decrease in acquired immune 
deficiency syndrome (AIDS)-related morbidity and mortality.
The primary goals of ARV therapy for HIV-1 infection are to reduce HIV-associated morbidity 
and prolong the duration and quality of life, restore and preserve immunologic function, 
maximally and durably suppress plasma HIV viral load, and prevent HIV transmission. 
The DHHS guidelines list emtricitabine/tenofovir DF (FTC/TDF) as a preferred nucleos(t)ide 
reverse transcriptase inhibitor NRTI/NtRTI backbone in combination with either 
cobicistat-boosted elvitegravir [EVG/COBI] administered as EVG/COBI/FTC/TDF, raltegravir, 
dolutegravir or darunavir/ritonavir as an initial ARV regimen Although HAART has 
dramatically improved the prognosis of patients infected with HIV-1, eradication of the virus is 
not possible with currently available therapies. Long-term viral suppression and prevention of 
drug resistance are goals of successful therapy. In regimens of comparable efficacy, the total pill 
burden, dosing frequency, and concerns about safety and side effects are generally the most 
significant obstacles to achieving high adherence.
Tenofovir disoproxil fumarate (TDF) is a preferred NRTI among recommended regimens for 
treatment-naïve HIV-positive patients, but is associated with nephrotoxicity and reduced bone 
mineral density{Panel on Antiretroviral Guidelines for Adults and Adolescents 2016}. 
Lifelong antiretroviral treatment and the increasing comorbidities being recognized and treated 
in HIV-positive patients creates an urgent need to improve the safety profile of regimens that 
most effectively suppress HIV replication. Tenofovir alafenamide (TAF) is a novel oral prodrug 
of tenofovir (TFV), a nucleotide analog that inhibits HIV-1 reverse transcription; TAF was 
recently added as a preferred NRTI combination by the DHHS panel {Panel on Antiretroviral 
Guidelines for Adults and Adolescents 2016}. Gilead has coformulated TAF with the integrase 
strand transfer inhibitor elvitegravir (EVG), cobicistat (COBI), and emtricitabine (FTC) into a 
fixed dose combination (FDC). Compared to TDF, the use of TAF in the E/C/F/TAF FDC is 
provides enhanced lymphatic delivery of tenofovir, resulting in higher intracellular levels of the 
active phosphorylated moiety tenofovir-diphosphate, and lower systemic circulating levels of 
tenofovir. These features are translated into more F/TAF effective suppression of viral 
replication, and an improved tolerability and safety profile, especially with respect to renal and 
bone safety.


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The prevalence of M184V resistance mutation in reverse transcriptase (RT) region in 
HIV-1-infected pretreated patients is high {Miller et al 2004}, {Riddler et al 2008}, {Blanco et 
al 2014}, {Poon et al 2011}, {Haubrich et al 2007b}. In addition, patients with virologic failure 
to the first NNRT-based regimen will develop the M184V mutation in up to 60% of cases 
{Riddler et al 2008}, {Marconi et al 2008}, {Saini et al 2012}, {Miller et al 2012}. 
This mutation confers resistance to both FTC and 3TC, but not to tenofovir. However FTC may 
provide some benefit on viruses harboring M184V through the reduced viral fitness associated 
with this mutation {Wei et al 2002}, {Wei et al 2003}, {Deval et al 2004}. The M184V mutation 
also sensitizes the viral strain to TFV; viral hypersensitivity has been associated with better 
virologic response to regimens that contain the hypersensitive drug {Haubrich et al 2002}, 
{Whitcomb et al 2002}, {Shulman et al 2001}, {Haubrich 2004}, {Haubrich et al 2007a}.
The presence of HIV drug resistance mutations prior to treatment (i.e., transmitted drug resistance)
may affect virologic outcome if the mutation reduces susceptibility to a drug in the regimen.
Reduced outcome with transmitted resistance has been best demonstrated for the NNRTI and 
INSTI based regimens {Gibson et al 2014}, {Nicot et al 2015}, {Callegaro et al 2014}, {Li et al 
2013a}, {Li et al 2013b}. However, some mutations, even in the same drug class, may not 
preclude viral suppression. In an integrated resistance analysis from the phase 3 E/C/F/TDF 
treatment naïve studies, Kulkarni reported that 25% (89/353) had a baseline mutation, with 
9% of subjects having an NRTI mutation (including TAMs), 2% having PI mutations and 
17% having an NNRTI mutation {Kulkarni et al 2014}. Subjects with preexisting drug resistance 
mutations achieved Week 144 HIV-1 RNA < 50 copies/mL at rates similar to those without 
mutation (76% versus 78%, respectively).
To date, switch options in patients harboring isolated NRTI M184V/I mutation are limited. 
PI/r + FTC/TDF is currently the preferred choice. Continuing a PIr-based regimen raises the 
problem of long-term tolerability and cardiovascular risk in an aging population. 
Furthermore existing antiretroviral therapies used in this population have a high pill burden. 
Patients harboring M184V/I resistance mutation cannot benefit from a switch to TDF-based 
FDCs (EFV/FTC/TDF, RPV/FTC/TDF or EVG/COBI/FTC/TDF) because such patients were 
excluded from switch studies with these FDCs. Switching from a PI/r to an NNRTI-based
regimen, which theoretically has a lower barrier to resistance, has been successful with 
RPV/TDF/FTC in the SPIRIT study {Palella et al 2014}. Of 23 subjects with baseline NNRTI 
resistance (K103N), 22/24 (92%) maintained viral suppression at the last follow-up visit. 
Thus, there is precedent to switching from a PI/r regimen to a regimen without a PI with 
continued excellent control of viral suppression.
In addition, 4 subjects randomized to receive E/C/F/TDF in the Strategy-PI and Strategy-NNRTI 
protocols that had M184V mutations at baseline (mutations that were prohibited by protocol 
entry criteria and discovered during treatment) achieved viral suppression:

Subject 1: M184V, discontinued at Week 4 by medical monitor, HIV RNA < 50 copies/mL

Subject 2: M41L+L210W+T215Y, discontinued at Week 12 by the medical monitor,
HIV RNA < 50 copies/mL


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
Subject 3: M184V, discontinued at Week 24, HIV RNA < 50 copies/mL

Subject 4: M184V, stayed on study to Week 96, HIV RNA < 50 copies/mL
TAF is a novel prodrug of tenofovir with a unique metabolism that provides enhanced lymphoid 
cells delivery of tenofovir, resulting in a 4 fold increase in intracellular TFV-DP in PBMCs. 
Potentially, these higher intracellular levels of TFV-DP delivered by TAF may allow this agent 
to overcome resistance mutations that might decrease TDF potency. In vitro, TAF activity is 
observed to be better than TDF against NRTI resistant viruses (K65R, multiple TAMs 
and/or M184V) {Margot et al 2013}. In patients with limited treatment options because of an 
isolated M184V, E/C/F/TAF could be an option for simplification and could offer an alternative 
for those who cannot tolerate PI/r or who are at high cardiovascular risk.
1.2.
Tenofovir Alafenamide (TAF, GS-7340)
1.2.1.
General Information
Tenofovir alafenamide (GS-7340, TAF, or L-Alanine, 
N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]/phenoxyphosphinyl]-, 
1-methylethyl ester) is a 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 several 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.
For further information, refer to the current Investigator’s Brochure for E/C/F/TAF.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
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)
{Robbins et al 1995} and nucleotide diphosphate kinase, which are highly active and ubiquitous. 
AK exists as multiple isozymes (AK1 to AK4), with the phosphorylation of TFV mediated most 
efficiently by AK2.


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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.
1.2.2.2.
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 post-dosing 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.
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.
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 


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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.
1.2.3.
Clinical Trials of E/C/F/TAF
Clinical trials using tenofovir alafenamide, coformulated into the E/C/F/TAF STR include:

Study GS-US-292-0101 was a Phase 1 study of 40 subjects evaluating the relative 
bioavailability of two different formulations of E/C/F/TAF STR, each with TAF dose of 
25 mg or 40 mg, versus E/C/F/TDF STR or TAF 25 mg alone. Exposures of EVG, COBI, 
and FTC were comparable between E/C/F/TAF vs E/C/F/TDF regardless of formulation 
(monolayer or bi-layer). In contrast, TAF exposures were ~2.2-fold higher (and corresponding 
tenofovir exposures ~3-fold higher) when administered as E/C/F/TAF (25 mg) vs TAF SA 
25 mg for both formulations of the E/C/F/TAF, likely mediated by inhibition of 
Pgp-mediated intestinal secretion of TAF by COBI.

Study GS-US-292-0103 was a completed Phase 1 healthy volunteer study, which evaluated 
the PK and relative bioavailability of the E/C/F/TAF STR relative to the individual 
components at TAF doses of 10 (STR) or 25 mg SA. Results indicate that when dosed as the 
E/C/F/TAF 10 mg STR, TAF and TFV exposures were comparable to those observed with 
TAF 25 mg dosed alone. Exposures of EVG, COBI, and FTC were also comparable between 
the STR and individually dosed formulations.

Study GS-US-292-0102 is a Phase 2 ongoing, randomized, active-controlled study, 
comparing E/C/F/TAF (10 mg) versus Stribild® (STB, E/C/F/TDF) in treatment-naïve, 
HIV-1 infected subjects. At Week 48, the E/C/F/TAF demonstrated potent antiviral efficacy 
(HIV-1 RNA < 50 copies/mL) similar to STB (88.4% [99/112] vs 87.9% [51/58] using the 
snapshot algorithm); in the E/C/F/TAF group, no patient had emergent resistance to 1 or 
more components of the E/C/F/TAF. Importantly, E/C/F/TAF demonstrated a potential 
benefit over E/C/F/TDF in terms of renal and bone safety: smaller median decreases in 
eGFR (mL/min) (at Week 48, E/C/F/TAF -5.5 vs E/C/F/TDF -10.0 [P < 0.001) and smaller 
median percentage decreases in BMD (at Week 48, spine E/C/F/TAF -1.00 vs 
E/C/F/TDF -3.37 [P < 0.001], hip -0.62 vs -2.39 [P < 0.001]).

Studies GS-US-292-0104 and GS-US-292-0111 are two Phase 3, controlled, double-blind 
studies evaluating treatment-naive HIV-infected patients. These patients were recruited with 
an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centers in 
16 countries. Patients were randomly assigned (1:1) to receive E/C/F/TAF or E/C/F/TDF 
with matching placebo. Randomization was done by a computer-generated allocation 
sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region 
(USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were 
masked to treatment group. All participants who received one dose of study drug were 
included in the primary intention-to-treat efficacy and safety analyses. The main outcomes 


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were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at 
Week 48 as defined by the US Food and Drug Administration (FDA) snapshot algorithm 
(pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 
48 weeks. There were 1733 patients who received treatment (866 given E/C/F/TAF 
and 867 given E/C/F/TDF). E/C/F/TAF was non-inferior to E/C/F/TDF, with 
800 (92%) of 866 patients in the TAF group and 784 (90%) of 867 patients in the TDF group 
having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2.0%, 
95% CI -0.7 to 4.7). Patients given E/C/F/TAF had significantly smaller mean serum 
creatinine increases than those given E/C/F/TDF (0.08 vs 0.12 mg/dL; p < 0.0001), 
significantly less proteinuria (median % change -3 vs 20; p < 0.0001), and a significantly 
smaller decrease in bone mineral density at spine (mean % change -1.30 vs -2.86; p < 0.0001)
and hip (-0.66 vs -2.95; p < 0.0001) at 48 weeks. Interpretation through 48 weeks, more than 
90% of patients given E/C/F/TAF or E/C/F/TDF had virologic success. Renal and bone 
effects were significantly reduced in patients given E/C/F/TAF.

Study GS-US-292-0109 is a phase 3 study designed to evaluate the safety, efficacy, 
and tolerability of switching to E/C/F/TAF in HIV-infected patients who are virologically 
suppressed on regimens containing TDF. Patients meeting the inclusion criteria of a plasma 
HIV-1 RNA less than 50 copies per mL for ≥ 96 weeks on stable TDF-based regimen with 
estimated creatinine clearance > 50 mL/min were randomly assigned (2:1) to switch to 
E/C/F/TAF (n = 959) or maintain their TDF-based regimen (n = 477). The regimens at 
baseline were E/C/F/TDF (n = 459), EFV/FTC/TDF (n = 376), and RTV-boosted 
ATV + FTC/TDF (n = 601). The main outcomes were the proportion of patients with plasma 
HIV-1 RNA less than 50 copies per mL at Week 48 as defined by the US Food and Drug 
Administration (FDA) snapshot algorithm (pre-specified noninferiority margin of 12%) 
and pre-specified renal and bone endpoints at 48 weeks. In this study of 1436 virologically 
suppressed patients, switching to E/C/F/TAF was non-inferior and statistically superior to 
continuing TDF-based regimen, with 97% of E/C/F/TAF patients and 93% of patients 
maintaining an TDF-based regimen having plasma HIV-1 RNA less than 50 copies per mL at 
Week 48 (adjusted difference 4.1%, 95% CI: 1.6 to 6.7). Patients switching to E/C/F/TAF 
had significant improvements in serum creatinine (p < 0.001) and eGFR (p < 0.001) 
than those maintaining TDF-based regimen. There were no Grade 2-4 serum creatinine 
increases in patients that switched to E/C/F/TAF. The difference in bone mineral density 
changes from baseline to 48 weeks significantly favored the patients switching to E/C/F/TAF 
with increases observed compared maintaining an TDF-based regimens where there 
were decreases in mean % change in BMD (spine: -0.28 vs +1.79; p < 0.001 and 
hip: -0.26 vs +1.37; p < 0.001). There were fewer discontinuations due to adverse events in 
the patients switching to E/C/F/TAF compared to continuing TDF-based regimen 
(0.9% vs 2.5%).

GS-US-292-0112, a Phase 3 open-label safety study of E/C/F/TAF in HIV-1 positive patients 
with mild to moderate renal impairment; Week 48 results demonstrated that patients who 
switched to E/C/F/TAF had no change in eGFR, and had significant improvements in 
measures of renal function including proteinuria, albuminuria, retinol binding protein and 
beta-2-microglobulin. These subjects also had improvements in measures of bone mineral 


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density. Importantly, because FTC was given without dose adjustment to patients with 
eGFR 30-50 mL/min, these patients had comparable safety profile to patients with 
eGFR 50-69 mL/min, with no increased rate of potential FTC related drug reactions, 
supporting the safety of FTC at higher exposures. In addition, 92% of study participants 
maintained virologic suppression (HIV-1 RNA < 50 copies/ml) at Week 48 after switching to 
E/C/F/TAF.
1.3.
Information About Comparator Regimens
There are no comparator regimens in this study; all subjects will be switched to E/C/F/TAF.
1.4.
Rationale for this Study
The aim of this pilot study is to validate the ability of E/C/F/TAF to maintain virological 
suppression in patients harboring M184V and/or M184I isolated mutations to NRTIs when 
switching from a TDF- or ABC-based regimen.
1.5.
Risk/Benefit Assessment for the Study
Potential risks of a patient’s study involvement include switching to a new unfamiliar regimen 
with potential loss of virologic control due to underlying HIV-1 drug resistance, the inconvenience
of more frequent clinical study visits and laboratory blood draws, and the associated pain and 
discomfort of phlebotomy. Risk will be mitigated by careful monitoring for virologic failures in 
real time during the conduct of the study and review by an internal data monitoring committee. 
Potential benefits may include the patient receiving a new antiretroviral regimen that is more 
convenient leading to improved adherence, potentially fewer adverse events than the current 
regimen, gaining access to E/C/F/TAF when it is not widely available or currently covered by the 
payer/healthcare system, and the knowledge that patient participation will be contributing 
towards a body of science.
1.6.
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 E/C/F/TAF fixed dose combination (FDC) after switching from a 
stable regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent in 
maintaining HIV-1 RNA < 50 copies/mL at Week 12 (using pure virologic response) 
in subjects harboring the archived NRTI resistance mutation M184V and/or M184I in 
HIV-1 reverse transcriptase
The secondary objectives of this study are:

To determine the safety and tolerability of E/C/F/TAF FDC in subjects switching from 
2 NRTI plus third antiretroviral agent regimens

To evaluate the development of new resistance mutations in subjects who develop virologic 
failure after switching to E/C/F/TAF FDC

To determine the durability of efficacy at Weeks 24 and 48 in maintaining 
HIV-1 RNA < 50 copies/mL using pure virologic response (PVR)


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3.
STUDY DESIGN
3.1.
Study Design
This protocol describes an open-label, single arm, multicenter, two part study to evaluate the 
efficacy and safety of switching to E/C/F/TAF FDC in HIV-1 infected adult subjects who are 
virologically suppressed (HIV-1 RNA < 50 copies/mL) harboring an archived isolated 
M184V and/or M184I mutation and who have been on a stable regimen consisting of FTC/TDF 
or ABC/3TC plus a third antiretroviral agent for ≥ 6 consecutive months prior to screening.
Both Part 1 and Part 2 will consist of subjects who have a documented presence of 
M184V and/or M184I mutations (mixtures are acceptable) in reverse transcriptase.
In Part 1, the first 50 subjects will have M184V and/or M184I (mixtures are acceptable) 
in reverse transcriptase WITHOUT any other NRTI resistance mutation (including thymidine 
analogue-associated mutations (TAMs) [M41L, D67N, K70R, L210W, T215Y/F, 
and K219Q/E/N/R], K65R, K70E, T69 insertion, and/or Q151M mutation complex [A62V, V75I,
F77L, F116Y, Q151M]. See Table 3-1.
If the rate of virologic failure in Part 1 is deemed acceptable, once the internal DMC officially 
completes the interim review the study will continue to Part 2 (with the expanded entry criteria).
In Part 2, the second 50 subjects will have M184V and/or M184I (mixtures are acceptable) 
in reverse transcriptase WITH or WITHOUT 1 or 2 thymidine analog-associated mutations.
Evidence of K65R, K70E,T69 insertion, and/or Q151M mutation complex in subjects in addition 
to the resistance mutations above will not be eligible for entry into the study. See Table 3-1.
Table 3-1.
Part 1 and Part 2 Resistance Criteria
Part 1
Part 2
Inclusion Resistance Mutations
TAMs
0 from:
0, 1, or 2 from:
M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R
Exclusion Resistance Mutations
NRTI-R
Any from:
K65R, K70E,T69 insertion, Q151M mutation complex
[A62V, V75I, F77L, F116Y, Q151M]
Primary PI-R
Any
Primary INSTI-R
Any
Additional Allowed Resistance Mutations
NRTI-R
Any not defined above
NNRTI-R
Any
TAM = thymidine analogue-associated mutation; NRTI = nucleos(t)ide reverse transcriptase inhibitor; PI = protease inhibitor; 
INSTI = integrase strand transfer inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; -R = resistance


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Figure 3-1. 
Study Schema 
Screening 
::;42 days 
Prior to 
Baseline 
Day 1 
Week 12 
(Prima1y Endpoint) 
I 
48 Weeks of Treatment on E/C/F/TAF 
(n = approximately 1 oot 
Week48 
30-Day 
Follow-upb,c 
a 
Following the Day 1 visit, subjects will retum for study visits at Weeks 4, 8, 12, 16, 24 36 and 48. 
b 
After 48 weeks, subjects will stop study drug and complete a 30-Day Follow-up visit to end their participation in the study. 
c 
Subjects who discontinue study drug administration before their Week 48 visit, \..,i.11 complete and ESDD visit. 
TI1ese subjects may remain on the study off study chug up to the Week 48 visit. Upon completion ofWe-ek 48 visit, 
subjects may be required to retum to the clinic for a 30-Day Follow-up visit to complete their participation in the study. 
3.2. 
Study Treatments 
Subjects who provide written consent and meet all eligibility criteria will switch from their 
cunent regimen consisting ofFTC/TDF or ABC/3TC plus a third antiretroviral agent to 
E/C/F/TAF FDC on Day 1. 
Allowed third agents include LPV/r, ATV+RTV, ATV+COBI, DRV+RTV, DRV+COBI, 
FPV + RTV, SQV + RTV, ATV(no booster) EFV, RPV, NVP, ETR, RAL or DTG. See 
Table 4-1. 
3.3. 
Duration of Treatment 
The study will consist of a 42-day screening period (within 42 days before Day 1 visit), 
followed by a 48 week treatment period. After Day 1, subjects will return for study visits at 
Weeks 4, 8, 12, 16, 24, 36 and 48. 
After Week 48, subjects will stop study drug and complete a 30-Day Follow-up visit. 
3.4. 
End of Study 
End of study is defined as completion of the 48 weeks of treatment and the 30 Day Follow-Up 
visit. 
3.5. 
Post Study Care 
After a subject has completed/te1minated their paiiicipation in the study, long-te1m cai·e for the 
subject will remain the responsibility of their primaiy treating physician. 
CONFIDENTIAL 
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EICIFITAF 
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3.6. 
Source Data 
Gilead will provide source document worksheets for all study visits. 
3.7. 
Samples for Optional Exploratory Assessments 
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Amendment # 1 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 100 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) Documented historical genotype report showing M184V and/or M184I (mixtures are 
acceptable) in reverse transcriptase. Subjects must not have any primary INSTI or primary PI 
resistance mutations present on historical genotype; NNRTI mutations are allowed.
Proviral DNA test must not have additional exclusion resistance mutations against PIs, 
NRTIs and INSTIs. See Table 3-1.

Part 1 (first 50 subjects): Historical genotype report must show M184V and/or M184I 
in reverse transcriptase WITHOUT any other NRTI resistance mutation 
(including thymidine analogue-associated mutations (TAMs) [ M41L, D67N, K70R, 
L210W, T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion and Q151M mutation 
complex [A62V, V75I, F77L, F116Y, Q151M]). See Table 3-1.

Part 2 (after the interim efficacy review – 50 subjects): Historical genotype report 
must show M184V and/or M184I in reverse transcriptase WITH or WITHOUT one or 
two thymidine analogue-associated mutations (TAMs) [M41L, D67N, K70R, L210W, 
T215Y/F, and K219Q/E/N/R]. Evidence of K65R, K70E, T69 insertion and/or
Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M] will not be eligible.
See Table 3-1.
4) Currently receiving an antiretroviral regimen consisting of FTC/TDF or ABC/3TC in 
combination with one third antiretroviral agent for ≥6 consecutive months preceding the
Screening Visit. Refer to Table 4-1 for allowed third agents of the pre-existing regimen


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5) Documented plasma HIV-1 RNA levels < 50 copies/mL for ≥ 6 months preceding the
screening visit (measured at least twice using the same assay).
a) In the preceding 6 months prior to screening, one episode of “blip” (HIV-1 RNA 
> 50 and < 400 copies/mL) is acceptable, only if HIV-1 RNA is < 50 copies/mL 
immediately before and after the “blip.”
b) 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).
6) Plasma HIV-1 RNA levels < 50 copies/mL at Screening Visit
7) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
8) Estimated glomerular filtration rate ≥ 30 mL/min according to the Cockcroft-Gault formula 
for creatinine clearance (eGFRCG) {Cockcroft et al 1976}:
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)
9) Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
10) Total bilirubin ≤ 1.5 mg/dL, and normal direct bilirubin (subjects with documented 
Gilbert’s syndrome or with atazanavir-associated hyperbilirubinemia may have total bilirubin 
up to 5 × ULN as long as direct bilirubin is normal)
11) Adequate hematologic function (absolute neutrophil count ≥1,000/mm3; 
platelets ≥50,000/mm3; hemoglobin ≥ 8.5 g/dL)
12) A female subject is eligible to enter the study if it is confirmed that she is:
a) Not pregnant confirmed by a negative serum pregnancy test, which is required for female 
subjects (unless permanently sterile or greater than two years post-menopausal)
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) Female subjects who have stopped menstruating for ≥ 12 months but do not have 
documentation of ovarian hormonal failure must have a serum follicle stimulating 
hormone (FSH) level at screening within the post-menopausal range based on the 
Central Laboratory Reference range.


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d) Of childbearing potential and agrees to utilize the protocol specified method of 
contraception or be non-heterosexually active or practice sexual abstinence from 
screening throughout the duration of study treatment and for 30 days following 
discontinuation of study drugs (as defined in Appendix 5)
e) 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 use the protocol specified method(s) of contraception during 
heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from 
screening 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 Third Antiretroviral Agents of Pre-Existing Regimen
Antiretroviral Class
Agents
Boosted PI
LPV/ra, ATV+RTVa, ATV+COBIa (or ATV/COBIa FDC), 
DRV+RTVa, DRV+COBIa (or DRV/COBIa FDC)
FPV+RTV, SQV+RTV, ATV(no booster)
NNRTI
EFV, RPV, NVP, ETR
INSTI
RAL, DTG
a
Change of pharmacoenhancer between RTV and COBI in itself, including change from PI+RTV to PI/COBI, is not 
considered as change of regimen.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
14) Subjects will have no evidence of previous virologic failure on a PI/r or INSTI-based 
regimen (with or without resistance to either class of ART). Subjects may have evidence of 
prior virologic failure on only an NNRTI plus 2 NRTI-based regimen.
15) Subjects on a current PI/r-based regimen will have no evidence of previous use of any 
approved or experimental integrase strand transfer inhibitor (INSTI) (for any length of time).
16) 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)
17) Hepatitis C infection that would require therapy during the study
18) Hepatitis B surface antigen (HBsAg) positive
19) Subjects with clinical evidence of decompensated cirrhosis (e.g., ascites, encephalopathy, 
variceal bleeding, etc.)
20) Females who are breastfeeding


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21) Positive serum pregnancy test
22) Have an implanted defibrillator or pacemaker
23) Current alcohol or substance use judged by the Investigator to potentially interfere with 
subject study compliance
24) 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 and must not be anticipated to 
require systemic therapy during the study
25) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or 
antifungal therapy within 30 days prior to Day 1
26) 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
27) Participation in any other clinical trial (including observational trials) without prior approval 
from the sponsor is prohibited while participating in this trial
28) Subjects receiving ongoing therapy with any of the medications in Table 4-2 and those listed 
in Section 5.4, including drugs not to be used with EVG, COBI, FTC or TAF (For EVG, 
COBI, and FTC refer to the individual agents Prescribing Information; for TAF refer to the 
E/C/F/TAF FDC Investigator’s Brochure); or subjects with any known allergies to the 
excipients of E/C/F/TAF FDC tablets.
Table 4-2.
Disallowed Agents
Drug Class
Agents Disalloweda
Alpha Adrenergic Receptor Antagonists
Alfuzosin
Calcium Channel Blockers
Bepridil
Anticonvulsants
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbazepine
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, Rifabutin
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
Inhaled Beta Agonist
Salmeterol
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Neuroleptics
Pimozide
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Sedatives/Hypnotics
Orally administered Midazolam, Triazolam
a
Administration of any of the above medications must be discontinued at least 30 days prior to the Day 1 visit and for the 
duration of the study.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
This is an open-label, single arm study. All subjects will receive open-label E/C/F/TAF.
Subjects will be assigned a screening number at the time of consent. Investigators must consult 
with the Medical Monitor and receive written approval prior to re-screening subjects.
Prior to enrollment to Day 1, the historical genotype report and proviral DNA resistance 
test result must be reviewed and approved by Gilead and subject eligibility confirmed.
Once eligibility has been confirmed by Gilead, each subject will be assigned a unique subject 
number using an Interactive Web Response System (IWRS). Once a subject number has been 
assigned, it will not be reassigned to any other subject. The subject number assignment may be 
performed up to 3 days prior to the in-clinic Day 1 visit provided that all screening procedures 
have been completed and subject eligibility has been confirmed.
Eligibility and all Day 1 visit tests and procedures must be completed prior to the 
administration of the first dose of study drug.
The IWRS will assign open-label study drug bottle numbers at each study visit. Study drug will 
be dispensed to the subjects in an open-label fashion. Initiation of treatment with the study drug 
must take place within 24 hours after the Day 1 visit.
5.2.
Description and Handling of E/C/F/TAF FDC
5.2.1.
Formulation
E/C/F/TAF FDC tablets are capsule-shaped, film-coated green tablets and are debossed with 
“GSI” on one side of the tablet and “510” on the other side of the tablet. E/C/F/TAF tablets 
contain 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 10 mg of TAF (as 11.2 mg of 
TAF fumarate). The E/C/F/TAF tablet core contains silicon dioxide, croscarmellose sodium, 
hydroxypropylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, 
and sodium lauryl sulfate as inactive ingredients and are film-coated with indigo carmine 
aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
yellow iron oxide.
5.2.2.
Packaging and Labeling
E/C/F/TAF FDC tablets are packaged in white, high density polyethylene (HDPE) bottles. 
Each bottle contains 30 tablets, silica gel desiccant and polyester material. Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed, aluminum-faced liner.
Study drug(s) to be distributed to centers in participating countries shall be labeled to meet 
applicable requirements of the EU Guideline to Good Manufacturing Practice −Annex 13 
(Investigational Medicinal Products), and/or other local regulations.


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5.2.3.
Storage and Handling
E/C/F/TAF tablets should be stored at controlled room temperature of 25 °C (77 °F); excursions
are permitted between 15 °C and 30 °C (59 °F and 86 °F). Storage conditions are specified on 
the label. Until dispensed to the subjects, all bottles of study drugs should be stored in a securely
locked area, accessible only to authorized site personnel.
To ensure the stability and proper identification, study drug should not be stored in a container
other than the container in which they were supplied.
Consideration should be given to handling, preparation, and disposal through measures that
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration of E/C/F/TAF FDC
E/C/F/TAF FDC tablets will be provided by Gilead Sciences.
E/C/F/TAF FDC tablets containing 150 mg of EVG, 150 mg of COBI, 200 mg of FTC, and 
10 mg of TAF will be provided to all eligible subjects at Day 1. Study drug will be administered 
orally at approximately the same time each day with food.
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).
5.4.
Prior and Concomitant Medications

Subjects receiving hormonal contraceptives should consider additional methods of 
contraception as concentrations of ethinyl estradiol may decrease and progestin level may 
increase on co-administration with study drug.

The use of medications for the treatment of HIV, other than study drug, is prohibited.

Subjects receiving concomitant medications that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious adverse 
events should consider alternative concomitant medications.

During the study, subjects may not receive any of the following concomitant medications:
Competitors of renal excretion (e.g., probenecid; high-dose non-steroidal 
anti-inflammatory drugs)
Known nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, 
cidofovir, foscarnet, cisplatin and pentamidine)

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. Any concomitant 
medication requiring adjustment or discontinuation due to renal impairment or a change in 
renal function on study should be managed per that drug’s prescribing information.


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Table 5-1.
Prior and Concomitant Medications
Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Acid Reducing Agents
Antacids
Concentration of study drug may decrease with 
antacids. Subjects may not take antacids 
(e.g., Tums, Mylanta); the ulcer medication 
sucralfate (Carafate); or vitamin or mineral 
supplements that contain calcium, iron or zinc for a 
minimum of 2 hours before and 2 hours after any 
dose of study drug.
Alpha Adrenergic Receptor 
Antagonists
Alfuzosin
Analgesics
Tramadol, Propoxyphene:
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.
Antiarrhythmics
Amiodarone, Flecainide Quinidine, Propafenone, 
Systemic Lidocaine, Mexiletine, Disopyramide:
Concentrations may increase with study drug(s) 
resulting in a potential for cardiac arrhythmias; 
clinical and ECG monitoring is recommended.
Calcium Channel Blockers
Bepridil
Felodipine, Nifedipine, Nicardipine, Verapamil, 
Diltiazem, Amlodipine:
Concentrations may increase with study drug(s). 
Clinical and ECG monitoring of subjects 
is recommended
Digoxin
Digoxin:
Concomitant use may result in increased levels; 
use with caution and with appropriate monitoring 
of serum digoxin levels. Digoxin therapy should 
be initiated at the lower dose, and the dose should 
be titrated to clinical response.
Antibacterials
Clarithromycin and Telithromycin: 
Concentrations may be altered with study drug(s); 
consider an alternative.
Anticoagulants
Warfarin:
Concentrations may increase or decrease with 
study drug(s); appropriate INR 
(International Normalized Ratio) monitoring 
is recommended.
Anticonvulsants
Phenobarbital, Phenytoin, 
Carbamazepine, 
Oxcarbazepine
Ethosuximide, Divalproex, Lamotrigine:
Concentrations may increase with study drug(s); 
clinical monitoring is recommended.


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs):
A dose reduction may be required for most drugs 
of this class with the exception of sertraline.
Tricyclics:
Concentrations may increase or decrease with 
study drug(s). Concentration monitoring is 
recommended to ensure adequate 
clinical response.
Trazodone:
Concomitant use with CYP3A inhibitors results 
in increased concentrations and adverse events; 
dose reduction should be considered.
Antifungals
Ketoconazole and Itraconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Daily dose of 
ketoconazole and itraconazole should be 
restricted to 200 mg. Subjects receiving 
ketoconazole or itraconazole should be monitored 
for adequate clinical response.
Voriconazole:
Concomitant use with study drug may result in an 
increase in concentrations. Clinical monitoring 
may be needed.
Antigout
Colchicine:
Concentrations may increase with study drug(s). 
Dose reductions of colchicine may be required. 
Should not be coadministered in patients with 
renal or hepatic impairment.
Treatment of Gout Flare:
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg
(half tablet) 1 hour later. Treatment course may 
be repeated no earlier than 3 days.
Prophylaxis of Gout Flares:
If the original regimen was 0.6 mg twice a day, 
the regimen should be adjusted to 0.3 mg once 
a day. If the original regimen was 0.6 mg once 
a day, the regimen should be adjusted to 0.3 mg
once every other day.
Treatment of Familial Mediterranean Fever:
Maximum daily dose of 0.6 mg
(may be given as 0.3 mg twice a day).


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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Antihistamines
Astemizole, Terfenadine
Antimycobacterials
Rifampin, Rifapentine, 
Rifabutin
β-Blockers
Metoprolol, Timolol:
Clinical and ECG monitoring of subjects is 
recommended. A dose decrease may be needed.
Corticosteroids: Inhaled/Nasal
Concomitant use of inhaled fluticasone and study 
drug(s) may increase plasma concentrations of 
fluticasone. Use is not recommended unless the 
potential benefit to the subject outweighs the risks 
of corticosteroid side effects. Alternatives should 
be considered, particularly for long-term use.
Corticosteroids: Systemic
Systemic dexamethasone, a CYP3A inducer, 
may significantly decrease elvitegravir and 
cobicistat plasma concentrations, which may 
result in loss of therapeutic effect and 
development of resistance. Alternative 
corticosteroids should be considered.
Use of Prednisone as a steroid burst (≤1 week
of use) should be monitored appropriately.
Endothelin Receptor Antagonists
Bosentan:
Coadministration may lead to decreased 
elvitegravir exposures and loss of therapeutic 
effect and development of resistance. 
Alternative endothelin receptor antagonists may 
be considered.
Ergot Derivatives
Ergotamine, Ergonovine
Dihydroergotamine
Methylergonovine
Ergometrine
GI Motility Agents
Cisapride
Herbal/Natural Supplements
St. John’s Wort, Echinacea
HMG-CoA Reductase Inhibitors
Simvastatin, Lovastatin
Atorvastatin:
Concentrations may increase with study drug(s). 
Start with the lowest dose; gradual increase in 
dose may be tailored to clinical response. Careful 
monitoring for signs and symptoms of muscle 
weakness or myopathy, including rhabdomyolysis.
Immunosuppressants
Cyclosporine, Rapamycin, Sirolimus, Tacrolimus: 
Concentrations may increase with study drug(s). 
Therapeutic monitoring should be considered.
Inhaled Beta Agonist
Salmeterol
Neuroleptics
Pimozide
Perphenazine, Risperidone, Thioridazine:
A dose decrease may be needed.


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Amendment #1
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Drug Class
Agents Disallowed
Use Discouraged and To Be Used With Caution
Opiates
Methadone:
Methadone exposures are unaffected upon 
coadministration with elvitegravir and cobicistat. 
No dose adjustment of methadone is required 
upon coadministration with study drug(s).
Meperidine (Pethidine):
Dosage increase and long-term use are not 
recommended due to increased levels of 
metabolite normeperidine, which has analgesic 
and CNS stimulant (e.g., seizures) activities.
Buprenorphine:
Concentrations of buprenorphine and 
norbuprenorphine are modestly increased and 
concentrations of naloxone are modestly decreased 
when coadministered with elvitegravir and 
cobicistat, with no effect on opioid 
pharmacodynimcs. The concentration changes are 
not considered clinically relevant and no dose 
adjustment of buprenorphine/naloxone is required 
upon coadministration with study drug(s).
Phosphodiesterase-5 Inhibitors
Sildenafil (for PAH)
Pulmonary Arterial Hypertension:
Tadalafil:
Caution should be exercised, including 
consideration of dose reduction, when 
coadministered for treatment of pulmonary 
arterial hypertension.
Erectile Dysfunction:
Sildenafil, Vardenafil, Tadalafil:
It is recommended that a single dose of Sildenafil 
no more than 25 mg in 48 hours, Vardenafil no 
more than 2.5 mg in 72 hours, or Tadalafil no 
more than 10 mg in 72 hours be coadministered.
Sedatives/Hypnotics
Orally administered 
Midazolam, Triazolam
Buspirone, Clorazepate, Diazepam, Estazolam, 
Flurazepam, Zolpidem:
A dose decrease may be needed for these drugs. 
Clinical monitoring is recommended.

Should subjects have a need to initiate treatment with any disallowed concomitant 
medication, the Gilead Sciences Medical Monitor must be consulted prior to initiation of the 
new medication. In instances where an excluded medication is initiated prior to discussion 
with the Sponsor, the Investigator must notify Gilead Sciences as soon as he/she is aware of 
the use of the disallowed medication.


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Amendment #1
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5.5.
Accountability of Study Drug
The Investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. Accountability records (Study Drug Inventory Log) will be provided to each study site in 
order to:

Record the date received and the quantity of study drug bottles.

Record the date, subject number, subject initials, the study drug bottle number dispensed.

Record the date, quantity of used and unused study drug returned by the subject, along with 
the initials of the person recording the information.
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 of the dates and quantities of all study drugs received, dispensed, and returned. 
Subjects should be instructed to return all unused study drug to the site at their study visits.
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 Study Drug 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 dispensed to individual subjects. The requirements
of all applicable drug dispensing laws will apply to all doses of study drugs dispensed by the 
Investigator (or designee).
The study drug inventory log must be available for inspection by the study monitor. 
Study medication supplies, including partially used or empty bottles, must be accounted for by 
the study monitor prior to destruction or return.
5.5.1.
Study Drug Return or Disposal
The study monitor will provide instructions for return. If return is not possible, the study monitor 
will evaluate each study center’s study drug disposal procedures and provide appropriate 
instruction for destruction of unused study drug. If the site has an appropriate standard operating 
procedure (SOP) for drug destruction as determined by Gilead Quality Assurance (QA), the site 
may destroy used (empty or partially empty) and unused study drug bottles in accordance with 
that site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files.
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug destroyed. Records must show the identification and quantity of each unit destroyed, the 
method of destruction, and the person who disposed of the study drug. Upon study completion, 
copies of the study drug accountability records must be filed at the site. Another copy will be 
returned to Gilead. The study monitor will review study drug bottles and associated records at 
periodic intervals.


E/C/F/TAF
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Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
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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 electronic Case Report Forms (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 the subject is eligible prior to enrollment.
Subjects who provide written consent and meet all eligibility criteria will receive 
elvitegravir 150 mg / cobicistat 150 mg / emtricitabine 200 mg / tenofovir alafenamide 10 mg
(E/C/F/TAF), on Day 1. Please refer to Section 5.1 for details about enrollment and treatment 
assignment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 42 days before enrollment (Day 1) to determine eligibility for 
participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history, including history of HIV-1 disease-related events, cigarette smoking
(current or previous smoker), diabetes, family cardiovascular history and prior medications 
within 30 days of the Screening Visit

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature)

Height and weight

12-lead ECG performed supine

Urine collection for the following laboratory analyses:
Urinalysis and Urine chemistry


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Amendment #1
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
Blood sample collection for the following laboratory analyses:
Serum pregnancy test (females of childbearing potential only). If the test is positive, 
the subject will not be enrolled.
FSH test is required for female subjects (age > 54 years) who have stopped menstruating 
for > 12 months but do not have documentation of ovarian hormonal failure.
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium
Estimated glomerular filtration rate according to the Cockcroft-Gault formula
(eGFRCG){Cockcroft et al 1976}:
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)
Hematology profile: complete blood count (CBC) with differential and platelet count
CD4+ cell count
Plasma HIV-1 RNA
Hepatitis B virus surface antigen serology (HBsAg)
Hepatitis C virus (HCVAb) serology (reflex HCV RNA is performed in subjects with 
positive HCVAb serology)
Whole blood sample collection for proviral genotype analysis of archived resistance

Review of concomitant medications

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 42 days after screening for the Day 1 assessments.
From the time of obtaining informed consent through the first administration of study drug, 
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.


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Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
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6.2.2.
Day 1 Visit
Eligible historical genotype report and subsequent proviral genotype test result for 
archived resistance must both be reviewed and approved by Gilead to confirm subject 
eligibility. Once subject’s full eligibility is confirmed, 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.

Review of AEs and changes in concomitant medications

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

Vital signs (blood pressure, pulse, respiration rate, and temperature), including weight

Urine collection for the following laboratory procedures:
Urinalysis and urine chemistry
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.
Urine sample storage for possible additional clinical testing

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium
Cystatin C testing
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.
Estimated GFR, according to the Cockcroft-Gault formula for creatinine clearance
Hematology profile: CBC with differential and platelet count
Plasma HIV-1 RNA


EICIFITAF 
Protocol GS-US-292-1824 
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-
CD4+ cell count 
-
Plasma sample storage for safety and virology testing 
Final 
Amendment # 1 
• 
Questionnaires: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire. 
-
Visual Analog Scale (VAS) 
-
HIV Treatment Satisfaction Questionnaire Status (HIV-TSQs) 
-
EQ-5D 
-
Medical Outcome Study Sho1i Foim-36 (SF-36) 
-
Functional Assessment of Chronic Illness Therapy - Fatigue (F ACIT-F) 
• 
Study diu g dispensation. Study diug will be dispensed in an open-label fashion. 
Subjects must initiate dosing of study diug within 24 hours after the Day 1 visit. 
• 
Subjects should be instructed to take E/C/F/TAF FDC tablets once daily with food at the 
same time each day. Subjects should also be counseled regarding the impo1iance of 
adherence and taking their study medications at approximately the same time each day. 
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, 16, 24, 36 and 48 
unless othe1wise 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 through Week 16 and completed 
within ± 6 days of the protocol-specified visit date through Week 36, unless othe1w ise specified. 
The visit window at Week 48 will be ± 6 weeks of the protocol-specified visit date, which 
coincides with the Week 48 statistical analysis window for HIV-1 RNA. For the purposes of 
scheduling the Week 48 visit, a ± 6 day window of the protocol-specified visit date should be 
used. 
Regularly scheduled evaluations will be made on all subjects whether or not they continue to 
receive study diug. 
CONFIDENTIAL 
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Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
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Note: At the Week 16 visit, the only assessments to be completed are:

Review of AEs and changes in concomitant medications

Blood sample collection for the following laboratory analyses:
Plasma HIV-1 RNA
Plasma sample storage for safety and virology testing

Document study drug dispensation and accountability for all study drug dispensed.

Questionnaire: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire.
Visual Analog Scale (VAS)
For all other visits, please complete the following:

Review of AEs and changes in concomitant medications

Complete physical examination (Weeks 24 and 48) (urogenital/anorectal exams will be 
performed at the discretion of the Investigator)

Symptom-directed physical examination as needed (Weeks 4, 8, 12 and 36)

12-lead ECG performed supine (Week 48 only)

Vital signs (blood pressure, pulse, respiration rate, and temperature), including weight

Urine collection for the following laboratory procedures:
Urinalysis and urine chemistry
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.
Urine sample storage for possible additional clinical testing

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium. 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.


EICIFITAF 
Protocol GS-US-292-1824 
Gilead Sciences, Inc. 
Final 
Amendment # 1 
-
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). 
-
Estimated GFR, according to the Cockcroft-Gault fonnula for creatinine clearance 
-
Hematology profile: CBC with differential and platelet count 
-
Plasma HIV-I RNA 
-
CD4+ cell count 
-
Plasma sample storage for safety and virology testing 
• 
Subjects who meet the criteria for virologic rebound should be managed according to 
Management ofVirologic Failure (Section 6.8). 
• 
HIV-I geno/phenotype resistance testing for subjects with unconfomed virologic rebound 
with HIV-I RNA value~ 50 copies/mL (Week 48 only) 
• 
Questionnaires: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire. 
-
Visual Analog Scale (VAS) (Weeks 4, 8, 12, 24, 36 and 48) 
-
HIV Treatment Satisfaction Questionnaire Change (HIV-TSQc) (Weeks 4, 24, and 48) 
-
EQ-5D (Weeks 24 and 48) 
-
SF-36 (Weeks 24 and 48) 
-
FACIT-F (Weeks 24 and 48) 
• 
Document study chug dispensation (Weeks 4, 8, 12, 24, and 36) and accountability for all 
study chug dispensed. 
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EICIFITAF 
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6.4. 
6.4.1. 
Post-treatment Assessments 
Early Study Drug Discontinuation (ESDD) Visit 
Final 
Amendment # 1 
If a subject discontinues study drng prior to the Week 48 visit, the subject will be asked to return 
to the clinic within 72 hours of stopping study diug for the ESDD visit. The subject will be asked 
to continue attending the scheduled study visits through Week 48. 
At the ESDD Visit, any evaluations showing abnormal results indicating that there is a 
possible or probable causal relationship with the study drug. will be repeated weekly 
(or as often as deemed prudent by the Investigator) until the abnormality is resolved, 
returns to baseline, or is otherwise explained. 
The following evaluations are to be completed at the Early Study Drng Discontinuation Visit: 
• 
Review of AEs and changes in concomitant medications 
• 
Complete physical examination (urogenital/anorectal exams will be perfo1med at the 
discretion of the Investigator) 
• 
12-lead ECG perfo1med supine 
• 
Vital signs (blood pressure, pulse, respiration rate, and temperature), including weight 
• 
Urine collection for the following laborato1y procedures: 
-
Urinalysis and urine chemistiy 
-
Urine pregnancy test (females of childbearing potential only); positive urine pregnancy 
tests will be confnmed with a sernm test. 
-
Urine sample storage for possible additional clinical testing 
• 
Blood sample collection for the following laborato1y analyses: 
-
Cheinistiy profile: alkaline phosphatase, AST, ALT, total bilirnbin, direct and indirect 
bilirnbin, total protein, albuinin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium 
-
Estimated GFR, according to the Cockcroft-Gault fonnula for creatinine clearance 
-
Hematology profile: CBC with differential and platelet count 
-
Plasma HIV-1 RNA 
-
CD4+ cell count 
-
Plasma sample storage for safety and virology testing 
CONFIDENTIAL 
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Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 44
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
Questionnaire: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire.
Visual Analog Scale (VAS)
HIV-TSQc

HIV-1 genotype/phenotype resistance testing for subjects with unconfirmed virologic 
rebound with HIV-1 RNA value ≥ 50 copies/mL

Questionnaire: Subject is to read questionnaire by her/himself and write/mark answers 
directly onto questionnaire.
HIV Treatment Satisfaction Questionnaire Change (HIV-TSQc)

Study drug accountability
6.4.2.
30-Day Follow-up Visit
Subjects who complete the study through the Week 48 visit 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 and refuse to continue study visits through 
Week 48 will be asked to return to the clinic after the completion of the ESDD visit for a 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:

Review of AEs and changes in concomitant medications

Symptom-directed physical examination as needed

Vital signs (blood pressure, pulse, respiration rate, and temperature), including weight

Urine collection for the following laboratory procedures:
Urinalysis and urine chemistry

Blood sample collection for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect 
bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium


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Amendment #1
CONFIDENTIAL
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Hematology profile: CBC with differential and platelet count
Plasma HIV-1 RNA
CD4+ cell count
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.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study (see Section 6.6, Criteria for Discontinuation of 
Study Treatment) and continue to perform the required study-related follow-up and procedures. 
If this is not possible or acceptable to the subject or Investigator, the subject may be withdrawn 
from the study.
6.6.
Criteria for Discontinuation of Study Treatment
Study drug may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Lack of efficacy (virologic 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)


EICIFITAF 
Protocol GS-US-292-1824 
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6.7. 
6.7.1. 
6.8. 
Other Evaluations 
Blood and Urine Storage 
Virologic Failure 
Final 
Amendment # 1 
Subjects who experience virologic rebound (VR), as defined below, will be considered to have 
virologic failure. 
Subjects will be considered to have virologic rebound if they have two consecutive confmned 
HIV-1 RNA test results of~ 50 copies/mL at a scheduled or unscheduled visit. 
6.8.1. 
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 confinnation 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 
intercmrent illnesses) 
• 
Investigators should discuss the management of all subjects with confmned virologic failure 
with the Medical Monitor. 
• If virologic failure is confnmed at the scheduled or unscheduled visit and HIV-1 RNA is 
50 copies/mL, the blood samples from the confnmation visit will be used for HIV-1 
genotype/phenotype testing. 
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Amendment #1
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
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 HIV-1 RNA ≥ 50 copies/mL). Investigators should carefully evaluate the benefits and 
risks of remaining on study drug for each individual subject and document this assessment in 
the onsite medical record. Investigators who opt to discontinue study drugs for an individual 
subject must discuss with the Medical Monitor prior to study drug discontinuation.
Please refer to Figure 6-1 for the management of subjects who meet the criteria for 
virologic failure.
6.8.2.
Resistance Analysis at Subjects Last Visit
Subjects with HIV-1 RNA < 50 copies/mL could experience unconfirmed blips of HIV-1 RNA 
≥50 copies/mL at their last study visit. Such subjects will be analyzed for resistance if the 
unconfirmed rebound happens at Week 48 or at the last visit while taking study drug
(or within 72 hours of discontinuation of study drug).


EICIFITAF 
Protocol GS-US-292-1824 
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Gilead Sciences, Inc. 
Amendment #1 
Figure 6-1. 
Management ofVirologic Failure 
Screening 
Treatment Period 
30-Day Follow-up 
Day l 
Unconfirmed 
virologic 
rebound: remain 
on study drug• 
At any visit, a rebound in HIV-I RNA to l!:: 50 copies/mL 
Return for scheduled/unscheduled lllV-I 
RNA and potential genotype/phenotype 
(2-4 week5 later) 
Confmned virologic 
reboundb 
Remain on study 
IDV-I genotype/phenotype' 
If no reverse transc1-iptase, p1·otease, 
01· integ1·ase resistance detected, 
continue on study drug or current 
regimen. Repeat HIV-I Ri"'JA' 
If reverse transcriptase, p.-otease, or 
integrase 1·esistance detected, 
discontinue study d.-ug 01· current 
regimen and construe.I a new 
ARV regimen• 
a 
If virologic rebound is not confirmed, the subject will remain on the study drug. 
b 
If virologic rebound is confumed, and the HIV-1 RNA is 2:: 50 copies/ml,, the HIV-1 genotype and phenotype 
(reverse transcriptase, protease and integrase resistance) will be analyzed. 
c 
Based on the results of the genotype/phenotype assays, the subject will remain or discontinue study drug. 
If genotyping/phenotyping assay fails, a new ARV regin1en may be configmed at the discretion of the Investigator in 
consultation with the Medical Monitor. 
d 
If no resistance detected, HIV-1 RNA will be repeated (2-4 weeks later). Investigator reviews study drug 
continuation/discontinuation options and discusses with Medical Monitor prior to discontinuation. 
e 
A new ARV regimen will be configtu·ed, at the Investigator's discretion, and the subject will remain in the study. 
CONFIDENTIAL 
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Amendment #1
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19 August 2016
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization


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
Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (e.g., clinical chemistry, hematology, and urinalysis) 
that require medical or surgical intervention or lead to study drug interruption, modification, 
or discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (e.g., anemia), not the 
laboratory result (i.e., decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, 
please refer to Appendix 3.
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 study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study drug. 
For SAEs, an alternative causality must be provided (e.g., pre-existing condition, underlying 
disease, intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the study drug.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures (e.g., venipuncture).
7.2.2.
Assessment of Severity
Severity 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 drug, the following types of events should 
be reported on the eCRF:

All SAEs and adverse events related to protocol-mandated procedures
Adverse Events
Following initiation of study drug, collect all AEs, regardless of cause or relationship, until 
4 weeks after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead 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 within 30-days of the last dose of study drug, 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 study drug, 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 guidelines.

At the time of study start, SAEs will be reported using an electronic SAE (eSAE) system. 
Gilead will notify sites in writing and provide training and account information prior to 
implementing an eSAE system.
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, i.e., 
the eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours as described below.

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.

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.

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 only 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.


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• 
Any medications necessaiy for ti·eatment of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
fo1m. 
Serious Adverse Event Paper Repo1iing Process 
• 
All SAEs will be recorded on the serious adverse event report fo1m and submitted by faxing 
or emailing the repo1i fo1m within 24 hours of the investigator's knowledge of the event to 
the attention of Gilead DSPH or to the designated CRO. 
Gilead Sciences DSPH 
Fax: 
E-mail: 
7.4. 
Gilead Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulato1y agencies repo1is of SAEs, serious adverse drng 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 
regulato1y agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in cmTent regulations. 
Assessment of expectedness for SAEs will be dete1mined by Gilead using reference safety 
info1mation specified in the investigator's brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR repo1is associated 
with any study drng. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulato1y agencies, and in accordance with the local 
institutional policy. 
7.5. 
Toxicity Management 
All clinical and clinically significant laborato1y toxicities will be managed according to unifo1m 
guidelines detailed in Appendix 3, as outlined below: 
• 
Clinical events and clinically significant laborato1y abnonnalities will be graded according to 
the GSI Grading Scale for Severity of Adverse Events and Laborato1y Abno1malities 
(Appendix 4). 
• 
Grade 3 and 4 clinically significant laborato1y abno1malities should be confinned by repeat 
testing within 3 calendai· days of receipt of results and before study drng discontinuation, 
unless such a delay is not consistent with good medical practice. 
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
Any questions regarding toxicity management should be directed to the 
Gilead Medical Monitor.
7.5.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event

Continue study drug at the discretion of the Investigator.
7.5.2.
Grade 3 Laboratory Abnormality or Clinical Event

For Grade 3 clinically significant laboratory abnormality or clinical event, study drug may be 
continued if the event is considered to be unrelated to study drug.

For a Grade 3 clinical event, or clinically significant laboratory abnormality confirmed by 
repeat testing, that is considered to be related to study drug, study drug should be withheld 
until the toxicity returns to ≤Grade 2. When restarting study drug following resolution of the 
adverse event, the study drug should be restarted at full dose upon discussion with the 
Medical Monitor.

If a laboratory abnormality recurs to ≥Grade 3 following rechallenge with study drug and is 
considered related to study drug, then study drug should be permanently discontinued and the 
subject managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to study drug may not require permanent discontinuation but requires 
discussion with the Medical Monitor.
7.5.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to study drug, study drug 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.

Study drug may be continued without dose interruption for a clinically non-significant 
Grade 4 laboratory abnormality (e.g., Grade 4 CK after strenuous exercise, or triglyceride 
elevation that is nonfasting or that can be medically managed) or a clinical event considered 
unrelated to study drug requires discussion with the Medical Monitor.
7.5.4.
Management of Potential Nephrotoxicity
Estimated glomerular filtration rate, according to the Cockcroft-Gault (eGFRCG) formula for
creatinine clearance, will be followed post-baseline during the study. All subjects with estimated 
eGFRCG < 30 mL/min must have serum creatinine measured again within 3 calendar days of 
receipt of results. At the time of this repeat serum creatinine assessment, Cystatin C will also be 
measured and the eGFR by CKD-EPI (cystatin C) will be calculated and compared with the 


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baseline measurement. Any subjects who have an estimated eGFRCG < 30 mL/min that also 
experience > 20% reduction in eGFR by CKD-EPI (cystatin C) from baseline or who have other 
clinical and/or laboratory evidence of acute renal failure will be discussed with the 
Medical Monitor and may discontinue from study drugs. For subjects with eGFRCG < 30 mL/min 
who are not discontinued based on toxicity management procedures above and considered to 
have stable renal function per Principal Investigator and Medical Monitor, it is not mandatory to 
repeat eGFR assessments within 3 days.
CKD-EPI (cystatin C) formula adjusted for age and sex:
eGFR (mL/min/1.73m2) = 133 × min(Scys/0.8, 1)−0.499 × max(Scys/0.8, 1) −1.328 × 0.996Age
[× 0.932 if female]
where Scys is serum cystatin C (mg/L), min (Scys/0.8,1) indicates the minimum of Scys/κ or 1, 
and max (Scys/0.8,1) indicates the maximum of Scys/κ or 1. All subjects with a change from 
baseline serum creatinine of ≥0.4 mg/dL must have serum creatinine repeated, with a concurrent 
urinalysis and urine chemistry, within two weeks of receipt of results. If a subject has a 
confirmed change from baseline serum creatinine of ≥0.4 mg/dL, the Medical Monitor should be 
notified and a consultation with a nephrologist should be obtained.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, occupational exposure with an AE, AEs in 
infants that occur while breastfeeding,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 study drug
given per administration or cumulatively which is above the maximum recommended dose as 
per protocol or in the product labelling (as it applies to the daily dose of the subject in question).
In cases of a discrepancy in drug accountability, overdose will be established only when it is 
clear that the subject has taken the excess dose(s). Overdose cannot be established when the 
subject cannot account for the discrepancy except in cases in which the investigator has reason to 
suspect that the subject has taken the additional dose(s).


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Product complaint associated with an adverse event is defined as complaints arising from 
potential deviations in the manufacture, packaging, or distribution of the medicinal product
associated with an adverse event, which is any untoward medical occurrence in a study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the study drug.
Occupational exposure with an AE is defined as exposure to a medicinal product as a result of 
one’s professional or non-professional occupation.
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study drug and throughout the study, including the post study drug follow-up period, 
to 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 (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.3. 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:
 and Fax: 
.
Pregnancies of female partners of male study subjects are not collected for E/C/F/TAF protocols.
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
PPD
PPD


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


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is as follows:

To evaluate the efficacy of E/C/F/TAF fixed dose combination (FDC) after switching from a 
stable regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent in 
maintaining HIV-1 RNA < 50 copies/mL at Week 12 (using pure virologic response) 
in subjects harboring the archived NRTI resistance mutation M184V and/or M184I in 
HIV-1 reverse transcriptase
The secondary objectives of this study are as follows:

To determine the safety and tolerability of E/C/F/TAF FDC in subjects switching from 
2 NRTI plus third antiretroviral agent regimens

To evaluate the development of new resistance mutations in subjects who develop virologic 
failure after switching to E/C/F/TAF FDC

To determine the durability of efficacy at Weeks 24 and 48 in maintaining 
HIV-1 RNA < 50 copies/mL using pure virologic response (PVR)
8.1.2.
Primary Endpoint
The primary endpoint is the proportion of subjects with HIV-1 RNA <50 copies/mL at Week 12 
as defined by pure virologic response.
8.1.3.
Secondary Endpoint
The secondary endpoints are the proportion of subjects with:

Emergence of new mutations in HIV-1 reverse transcriptase and integrase (attempted on any 
post Day 1 sample with HIV-1 RNA ≥50 copies/mL)

HIV-1 RNA< 50 copies/mL at Weeks 24 and 48 using PVR

HIV-1 RNA < 50 copies/mL at Weeks 12, 24 and 48 using the FDA snapshot analysis 
(sensitivity analysis)

CD4+ cell count change from Day 1 at Weeks 12, 24 and 48


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8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Efficacy
8.2.1.1.1.
Full Analysis Set (FAS)
The Full Analysis Set will include all the subjects who were randomized and received at least
one dose of study drug. The FAS will exclude subjects with major protocol violations 
(e.g., not having the correct historical mutation at study entry). The FAS analysis set is the 
primary analysis set for the efficacy analyses.
8.2.1.2.
Safety
The primary analysis set for safety analyses is defined as all subjects that received at least one 
dose of study drug.
All data collected during treatment will be included in the safety summaries.
8.3.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods.
Demographic summaries will include sex, race/ethnicity and age.
Baseline data will include a summary of body weight, height, body mass index, risk factors for 
HIV-1 infection.
8.4.
Efficacy Analysis
8.4.1.
Primary Analysis
The primary endpoint of pure virologic response (PVR) with HIV-1 RNA < 50 copies/mL at 
Week 12 will be computed.
The following criteria are considered for classifying subjects as a pure virologic responder at 
Week 12:

Subject remains on study treatment

No confirmed rebound as defined by:
HIV-1 RNA ≥ 50 copies/mL on 2 consecutive visits;
HIV RNA ≥ 50 copies/mL during study followed by premature discontinuation of study
Note: For confirmation of viral rebound, the first HIV-1 RNA must occur on or before the 
upper limit of the Week 12 analysis window, the confirming event (i.e., the second of the 
consecutive HIV-1 RNAs or premature study discontinuation) can occur after the upper limit 
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Subjects who meet the above criteria are pure virologic responders at Week 12; otherwise 
subjects are pure virologic failures (PVF) at Week 12. The 95% CI will be computed using 
normal approximation to the binomial proportions of PVR
8.4.2.
Secondary Analyses
A similar definition to the primary endpoint will be used for computing PVR at Weeks 24 and 48.
Sensitivity analyses of virologic failure using the FDA snapshot algorithm at Weeks 12, 24 and 48
(and other sensitivity analyses such as missing equal failure) will also be conducted.
8.5.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose of study drug plus 30 days will be summarized. Data for the pretreatment will be 
included in data listings.
8.5.1.
Extent of Exposure
A subject’s extent of exposure to study drug will be generated from the study drug 
administration data. Exposure data will be summarized.
Duration of exposure to study drug will be expressed as the number of weeks between the first 
and last dose of the study drug, inclusive, regardless of temporary interruptions in study drug 
administration, and summarized. Dosing information for individual subjects will be listed.
8.5.2.
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.
Treatment-emergent adverse events are adverse events that meet one of the following criteria:

Adverse events with onset dates on or after the first dose date of study drug, and no later than 
30 days after permanent discontinuation of study drug, or

Adverse events that result in permanent study drug discontinuation.
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC and PT) will be provided. Additional summaries will include summaries for adverse 
events by grade, Investigator’s assessment of relationship to study drug, and effect on study drug 
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8.5.3.
Laboratory Evaluations
Selected laboratory data will be summarized using only observed data. Absolute values and 
changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (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 the date of last dose of study 
drug plus 30 days, will be summarized. 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 drug or after the subject has
been discontinued from treatment plus 30 days will be included in a data listing.
8.5.4.
Other Safety Evaluations
Weight will be summarized by visit.
Safety ECGs will be listed and summarized for subjects in the Safety Analysis Set. The number 
and percent of subjects with abnormal safety ECG will be summarized by visit.
8.6.
Sample Size
The primary analysis will describe the point estimate and 95% confidence interval around the 
proportion of subjects with HIV-1 RNA < 50 copies/ mL for the primary endpoint. If the 
observed pure virologic response rate is 90%, then with 100 participants, the width of the 
95% CI will be ± 5.9% (large sample size approximation and binomial distribution).
8.7.
Data Monitoring Committee
An internal data monitoring committee (Internal DMC), independent of the study team, will 
review the progress of the study and perform interim reviews of safety, efficacy data and provide 
recommendation to Gilead whether the efficacy and the nature, frequency, and severity of 
adverse effects associated with study drug 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 committee will convene after the first 50 subjects enrolled 
complete Week 12 of the study. Based on the analysis of the primary efficacy variable 
(HIV-1 RNA < 50 copies/mL) using pure virologic response, study conduct may be altered based 
on the recommendations of the internal monitoring committee.
The Internal DMC’s specific activities will be defined by a mutually agreed charter, which will 
define the Internal DMC’s membership, conduct and meeting schedule.


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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 Subjects", and 21 CFR, Part 56, "Institutional Review 
Boards".
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54,
"Financial Disclosure by Clinical 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 subinvestigator’s)
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.


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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/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 a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The 
investigator must keep a screening log showing codes, names, and addresses for all subjects 
screened and for all subjects enrolled in the trial. Subject data will be processed in accordance 
with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the study drug, 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.


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


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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. The eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central monitoring 
of safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will be 
stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
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.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IECs, or to regulatory authority or health authority 
inspectors.
9.1.8.
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(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases.


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


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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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Amendment #1
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10.
REFERENCES
Blanco JL, Montaner JS, Marconi VC, Santoro MM, Campos-Loza AE, Shafer RW, et al. Lower 
prevalence of drug resistance mutations at first-line virological failure to first-line 
therapy with atripla vs. tenofovir + emtricitabine/lamivudine + efavirenz 
administered on a multiple tablet therapy. AIDS 2014;28 (17):2531-9.
Callegaro A, Di Filippo E, Astuti N, Ortega PA, Rizzi M, Farina C, et al. Early clinical response 
and presence of viral resistant minority variants: a proof of concept study 
[Abstract P227]. Presented at: HIV Drug Therapy Glasgow Congress 2014; 2014 
November 2-6; Glasgow, United Kingdom. J Int AIDS Soc 2014;17 (Suppl 
3):19759.
Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection 
and expanded surveillance case definition for AIDS among adolescents and 
adults. MMWR 1992;41 (RR-17):1-19.
Centers for Disease Control and Prevention. 1994 Revised Classification System for Human 
Immunodeficiency Virus Infection in Children Less Than 13 Years of Age. 
MMWR 1994;43 (RR-12):1-28.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
Deval J, White KL, Miller MD, Parkin NT, Courcambeck J, Halfon P, et al. Mechanistic basis 
for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing 
both K65R and M184V mutations. J Biol Chem 2004;279 (1):509-16.
Gibson RM, Weber J, Winner D, Miller MD, Quinones-Mateu ME. Contribution of human 
immunodeficiency virus type 1 minority variants to reduced drug susceptibility in 
patients on an integrase strand transfer inhibitor-based therapy. PLoS ONE 
2014;9 (8):e104512.
Haubrich RH. Resistance and replication capacity assays: clinical utility and interpretation. Top 
HIV Med 2004;12 (2):52-6.
Haubrich RH, Jiang H, Swanstrom R, Bates M, Katzenstein D, Petch L, et al. Non-nucleoside 
phenotypic hypersusceptibility cut-point determination from ACTG 359. HIV 
Clin Trials 2007a;8 (2):63-7.
Haubrich RH, Kemper CA, Hellmann NS, Keiser PH, Witt MD, Forthal DN, et al. The clinical 
relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a 
prospective cohort analysis. AIDS 2002;16 (15):F33-F40.


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Amendment #1
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Haubrich RH, Riddler SA, DiRienzo AG, Peeples L, Klingman KL, Garren KW, et al. Drug 
resistance at virological failure in a randomized, Phase III trial of NRTI-, PI- and 
NNRTI-sparing regimens for initial treatment of HIV-1 infection (ACTG 5142) 
[Abstract 57]. Presented at: XVI International HIV Drug Resistance Workshop: 
Basic Principles & Clinical Implications; 2007 June 12-16; St. Michael, 
Barbados. Antivir Ther 2007b;12 (Suppl 1):S66.
Kulkarni R, Abram ME, McColl DJ, Barnes T, Fordyce MW, Szwarcberg J, et al. Week 144 
Resistance Analysis of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF 
Versus Atazanavir+Ritonavir+Emtricitabine/Tenofovir DF in Antiretroviral-
Naive Patients. HIV Clin Trials 2014;15 (5):218-30.
Li JZ, Kuritzkes DR. Clinical implications of HIV-1 minority variants. Clin Infect Dis 2013a;56 
(11):1667-74.
Li JZ, Paredes R, Ribaudo HJ, Kozal MJ, Svarovskaia ES, Johnson JA, et al. Impact of minority 
nonnucleoside reverse transcriptase inhibitor resistance mutations on resistance 
genotype after virologic failure. J Infect Dis 2013b;207 (6):893-7.
Marconi VC, Sunpath H, Lu Z, Gordon M, Koranteng-Apeagyei K, Hampton J, et al. Prevalence 
of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy 
regimen in KwaZulu Natal, South Africa. Clin Infect Dis 2008;46 (10):1589-97.
Margot N, Liu Y, Babusis D, Miller MD, Callebaut C. Antiviral Activity of 
TenofovirAlafenamide (TAF) Against Major NRTI-Resistant Viruses: 
Improvement Over TDF/TFV Is Driven By Higher TFV-DP Loading in Target 
Cells [Abstract 23]. Presented at: International Workshop on HIV & Hepatitis 
Virus Drug Resistance and Curative Strategies; 2013 June 4-8; Toronto, Canada. 
Antivir Ther 2013;18 (Suppl 1):A31.
Miller MD, Haddad M, Su C, Gibbs C, McColl DJ, Guyer B. Trends in HIV-1 reverse 
transcriptase resistance-associated mutations and antiretroviral prescription data 
from 2003-2010. Antivir Ther 2012;17 (6):993-9.
Miller MD, Margot N, Lu B, Zhong L, Chen S-S, Cheng A, et al. Genotypic and phenotypic 
predictors of the magnitude of response to tenofovir disoproxil fumarate treatment 
in antiretroviral-experienced patients. J Infect Dis 2004;189 (5):837-46.
Nicot F, Saune K, Raymond S, Jeanne N, Carcenac R, Lefebvre C, et al. Minority resistant HIV-
1 variants and the response to first-line NNRTI therapy. J Clin Virol 2015;62:20-
4.
Palella FJ, Fisher M, Tebas P, Gazzard B, Ruane P, Lunzen JV, et al. Simplification to 
rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted 
protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-
suppressed participants. AIDS 2014;28 (3):335-44.


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Amendment #1
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Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. Available at 
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL. Accessed 15 
August.  2016.
Poon AF, Aldous JL, Mathews WC, Kitahata M, Kahn JS, Saag MS, et al. Transmitted drug 
resistance in the CFAR network of integrated clinical systems cohort: prevalence 
and effects on pre-therapy CD4 and viral load. PLoS ONE 2011;6 (6):e21189.
Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, et al. Class-
sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008;358 
(20):2095-106.
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.
Saini S, Bhalla P, Gautam H, Baveja UK, Pasha ST, Dewan R. Resistance-associated mutations 
in HIV-1 among patients failing first-line antiretroviral therapy. J Int Assoc 
Physicians AIDS Care (Chic) 2012;11 (3):203-9.
Selik RM, Mokotoff ED, Branson B, Owen SM, Whitmore S, Hall HI. Morbidity and Mortality 
Weekly Report (MMWR). Revised Surveillance Case Definition for HIV 
Infection - United States 2014. Centers for Disease Control and Prevention,  2014.
Shulman N, Zolopa AR, Passaro D, Shafer RW, Huang W, Katzenstein D, et al. Phenotypic 
hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-
experienced HIV-infected patients: impact on virological response to efavirenz-
based therapy. AIDS 2001;15 (9):1125-32.
Wei X, Liang C, Gotte M, Wainberg MA. The M184V mutation in HIV-1 reverse transcriptase 
reduces the restoration of wild-type replication by attenuated viruses. AIDS 
2002;16 (18):2391-8.
Wei X, Liang C, Gotte M, Wainberg MA. Negative effect of the M184V mutation in HIV-1 
reverse transcriptase on initiation of viral DNA synthesis. Virology 2003;311 
(1):202-12.
Whitcomb JM, Huang W, Limoli K, Paxinos E, Wring T, Skowron G, et al. Hypersusceptibility 
to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic 
and genotypic correlates. AIDS 2002;16 (15):F41-F7.


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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 Requirements
Appendix 6.
AIDS-Defining Conditions (CDC Guidelines) {Selik et al 2014}


PJC/FffAF 
Protocol GS-US-292-1824 
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Gilead Sciences, Inc. 
Amendment #1 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3b Open-Label Pilot Study to Evaluate Switching to 
Elvitegravir/Cobicistat/Emtricitabine/f enofovir Alafenamide (E/C/F /T AF) 
Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-] Infected Adult Subjects 
Harboring the Archived Isolated NRTI Resistance Mutation Ml 84V/M184I 
GS-US-292-1824, Amendment 1, 19 August 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
PD 
Medical Monitor 
Signature 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 72 
19 August 20 L6 


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Appendix 2.
Study Procedures Table
Study Procedure
Screeninga
Day 1b
End of Weekc
30 Day 
Follow-up
ESDDd
4
8
12
16t
24
36
48
Informed Consent
X
Medical History
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Complete Physical Exame
X
X
X
X
X
Symptom-Directed Physical Examf
X
X
X
X
X
12-Lead ECG (Performed Supine)
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
Height
X
Urinalysis and Urine Chemistry
X
X
X
X
X
X
X
X
X
X
Urine Storage Sample
X
X
X
X
X
X
X
X
Urine Pregnancy Testg
X
X
X
X
X
X
X
X
Serum Pregnancy Testg
X
Chemistry Profileh
X
X
X
X
X
X
X
X
X
X
Metabolic Assessmentsi
X
X
X
Estimated GFRj
X
X
X
X
X
X
X
X
X
Hematology Profilek
X
X
X
X
X
X
X
X
X
X
Plasma HIV-1 RNAl
X
X
X
X
X
X
X
X
X
X
X
CD4+ Cell Count
X
X
X
X
X
X
X
X
X
X
HBV and HCV Serologiesm
X
Plasma Sample Storagen
X
X
X
X
X
X
X
X
X
Whole Blood Samplep
X
HIV-1 Genotype/Phenotypeq
X
X
Cystatin C Testingu
X
CCI


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Study Procedure
Screeninga
Day 1b
End of Weekc
30 Day 
Follow-up
ESDDd
4
8
12
16t
24
36
48
Questionnaires: VAS, HIVTSQs, HIVTSQc, EQ-5D, 
SF-36, and FACIT-Fr
X
X
X
X
X
X
X
X
X
Enrollment
X
Study Drug Dispensation and Accountability
X
X
X
X
X
X
X
Xs
Xs
a
Evaluations to be completed within 42 days prior to the 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. E/C/F/TAF FDC
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 16, ± 6 days of the protocol 
specified date through Week 36, and all other study visits except Week 48. Week 48 visit window is ± 6 weeks of the protocol specified visit date, and this clinical visit 
window coincides with the Week 48 statistical analysis window for HIV-1 RNA.
d
Early Study Drug Discontinuation visit to occur within 72 hours of last dose of study drug. Subjects will be asked to continue attending the scheduled study visits through 
Week 48 visit even if the subject discontinues study drug.
e
Complete physical examination every 48 weeks (urogenital/anorectal exams will be performed at the discretion of the Investigator)
f
Symptom-directed physical examination as needed.
g
Females of childbearing potential only. Positive urine pregnancy tests will be confirmed with a serum test.
h
Chemistry profile: alkaline phosphatase, AST, ALT, total bilirubin, direct and indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, potassium and sodium. At visits in which metabolic assessments are to be performed, analyses of glucose will be done as part of the fasting metabolic assessments 
and not as part of the chemistry profile.
i
Metabolic Assessments: Fasting 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.
j
Estimated GFR according to the Cockcroft-Gault formula for creatinine clearance
k
CBC with differential and platelet count
l
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 Day 1 results). HIV-1 genotype/phenotype resistance testing only conducted for subjects with confirmed virologic failure with HIV-1 RNA value ≥ 50 copies/mL. 
Subjects should be managed according to Figure 6-1, Management of Virologic Failure.
m
Hepatitis B virus surface antigen serology (HBsAg) and Hepatitis C virus (HBVAb) serology (reflex HCV RNA is performed in subjects with positive HCVAb serology)
n
Plasma sample storage for safety and virology testing
o
p
Whole blood sample collected at Screening Visit for proviral genotype analysis of archived resistance
q
HIV-1 genotype/phenotype resistance testing only conducted for subjects with unconfirmed virologic rebound with HIV-1 RNA value ≥ 50 copies/mL at the Week 48 and 
ESDD visit. Subjects should be managed according to Figure 6-1, Management of Virologic Failure. HIV-1 genotype/phenotype sample collection to occur if subjects 
HIV-1 RNA lab values meet the criteria described in this section.
r
EQ-5D, SF-36, and FACIT-F will be administered at Day 1, Weeks 24 and 48. VAS will be administered on Day 1, Weeks 4, 8, 12, 16, 24, 36, 48 and ESDD. HIVTSQs will 
be administered on Day 1. HIVTSQc will be administered at Weeks 4, 24, 48 and ESDD.
s
Drug accountability only; study drug will not be dispensed at this visit.
t
At Week 16, subject will have only the following assessments completed: Review of AEs and changes in concomitant medications, blood sample collection for plasma 
HIV-1 RNA and plasma sample storage. Study drug dispensation and accountability will be documented.
u
Estimated GFR according to CKD-EPI formula for cystatin clearance will be used for Nephrotoxicity Management per Section 7.5.4.
CCI


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Amendment #1 
Appendix 3. 
Management of Clinical and Laboratory Adverse Events 
Grnde 1 
Grade 2 
Grnde 3 
Grade 4 
1, 
1, 
1 • 
1 • 
May continue dosing at 
If c.onfi.t-med and 
the discretion of the 
Repeat lab to confirm 
Repeat lab to confinn 
r--+ 
possibly or probably 
Investigator 
toxicity grade 
toxicity g..ade 
1·elated to study drug, 
discontinue study 
drug dosing 
permanently and 
" 
" 
,, 
follow at pel'iodic 
If confirmed and possibly and/or pl'Obably related to study drug: 
If confirmed and um·elated to study 
intervals at least 
weekly until a retur·n 
1. Withhold study drug until 
Grade 2 
drug, dosing may continue at the 
to baseline or is 
2. 
Resta11 study drug at full dose 
discretion of the investigator 
otherwise explained 
" 
If Grade 3 or 4 1·ecun·ence that is confirmed and possibly 01· 
If Grade 3 or 4 recunence that is considered unrelated to study 
probably 1·elated to study drug, discontinue all study drug 
drug, continue all study drug at the same dose at the discretion 
dosing pei·manently 
of the Investigat01· 
CONFIDENTIAL 
Page 75 
19 August 2016 


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 76
19 August 2016
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Antiviral Toxicity Grading Scale Version: 01 April 2015
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
HIV POSITIVE
Adult and Pediatric 57 Days
8.5 to 10.0 g/dL
85 to 100 g/L
7.5 to 8.5 g/dL
75 to 85 g/L
6.5 to 7.5 g/dL
65 to 75 g/L
6.5 g/dL
65 g/L
HIV NEGATIVE
Adult and Pediatric 57 Days
10.0 to 10.9 g/dL
100 to 109 g/L
OR
Any decrease from Baseline
2.5 to 3.5 g/dL
25 to 35 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
OR
Any decrease from Baseline
3.5 to 4.5 g/dL
35 to 45 g/L
7.0 to 9.0 g/dL
70 to 90 g/L
OR
Any decrease from Baseline
4.5 g/dL
45 g/L
7.0 g/dL
70 g/L
Infant, 36–56 Days
(HIV POSITIVE OR
NEGATIVE)
8.5 to 9.4 g/dL
85 to 94 g/L
7.0 to 8.5 g/dL
70 to 85 g/L
6.0 to 7.0 g/dL
60 to < 70 g/L
6.0 g/dL
< 60 g/L
Infant, 22–35 Days
(HIV POSITIVE OR
NEGATIVE)
9.5 to 10.5 g/dL
95 to 105 g/L
8.0 to 9.5 g/dL
80 to 95 g/L
7.0 to 8.0 g/dL
70 to 80 g/L
7.0 g/dL
70 g/L
Infant, 1–21 Days
(HIV POSITIVE OR
NEGATIVE)
12.0 to 13.0 g/dL
120 to 130 g/L
10.0 to 12.0 g/dL
100 to 120 g/L
9.0 to 10.0 g/dL
90 to 100 g/L
9.0 g/dL
90 g/L
Absolute Neutrophil Count
(ANC)
Adult and Pediatric,
≥ 7 Months#
1000 to 1300/mm3
750 to 1000/mm3
500 to 750/mm3
500/mm3
1.00 to 1.30 GI/L
0.75 to 1.00 GI/L
0.50 to 0.75 GI/L
0.50 GI/L
Absolute CD4+ Count
HIV NEGATIVE ONLY
Adult and Pediatric 
> 13 Years
300 to 400/mm3
300 to 400/μL
200 to 300/mm3
200 to 300/μL
100 to 200/mm3
100 to 200/μL
100/mm3
100/μL


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 77
19 August 2016
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count
HIV NEGATIVE ONLY
Adult and Pediatric 
13 Years
600 to 650/mm3
0.60 to 0.65 GI/L
500 to 600/mm3
0.50 to 0.60 GI/L
350 to 500/mm3
0.35 to 0.50 GI/L
350/mm3
0.35 GI/L
Platelets
100,000 to < 125,000/mm3
100 to 125 GI/L
50,000 to 100,000/mm3
50 to 100 GI/L
25,000 to 50,000/mm3
25 to 50 GI/L
25,000/mm3
25 GI/L
WBCs
2000/mm3 to 2500/mm3
1,500 to 2,000/mm3
1000 to 1,500/mm3
1000/mm3
2.00 GI/L to 2.50 GI/L
1.50 to 2.00 GI/L
1.00 to 1.50 GI/L
1.00 GI/L
Hypofibrinogenemia
100 to 200 mg/dL
75 to 100 mg/dL
50 to 75 mg/dL
50 mg/dL
1.00 to 2.00 g/L
0.75 to 1.00 g/L
0.50 to 0.75 g/L
0.50 g/L
Hyperfibrinogenemia
ULN to 600 mg/dL
600 mg/dL
—
—
ULN to 6.0 g/L
6.0 g/L
—
—
Fibrin Split Product
20 to 40 μg/mL
40 to 50 μg/mL
50 to 60 μg/mL
60 μg/mL
20 to 40 mg/L
40 to 50 mg/L
50 to 60 mg/L
60 mg/L
Prothrombin Time (PT)
1.00 to 1.25 ULN
1.25 to 1.50 ULN
1.50 to 3.00 ULN
3.00 ULN
International Normalized Ratio 
of prothrombin time (INR)
1.1 to 1.5 x ULN
>1.5 to 2.0 x ULN
>2.0 to 3.0 x ULN
>3.0 x ULN
Activated Partial
Thromboplastin Time (APTT)
1.00 to 1.66 ULN
1.66 to 2.33 ULN
2.33 to 3.00 ULN
3.00 ULN
Methemoglobin
5.0 to 10.0%
10.0 to 15.0%
15.0 to 20.0%
20.0%
#
An overlap between the Grade 1 scale and the Lab’s normal range for absolute neutrophils may result for pediatric subjects. Please follow the Gilead convention of grading 
any result within the LLN and ULN a 0.


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 78
19 August 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia
>ULN to 150 mEq/L
150 to 154 mEq/L
154 to 159 mEq/L
159 mEq/L
>ULN to 150 mmol/L
150 to 154 mmol/L
154 to 159 mmol/L
159 mmol/L
Hypokalemia
Adult and Pediatric
1 Year
3.0 to <LLN mEq/L
2.5 to 3.0 mEq/L
2.0 to 2.5 mEq/L
2.0 mEq/L
3.0 to <LLN mmol/L
2.5 to 3.0 mmol/L
2.0 to 2.5 mmol/L
2.0 mmol/L
Infant <1 Year
3.0 to 3.4 mEq/L
3.0 to 3.4 mmol/L
2.5 to 3.0 mEq/L
2.5 to <3.0 mmolL
2.0 to 2.5 mEq/L
2.0 to <2.5 mmolL
2.0 mEq/L
<2.0 mmolL
Hyperkalemia
Adult and Pediatric
1 Year
5.6 to 6.0 mEq/L
5.6 to 6.0 mmol/L
6.0 to 6.5 mEq/L
6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Infant <1 Year
>ULN to 6.0 mEq/L
>ULN to 6.0 mmol/L
> 6.0 to 6.5 mEq/L
> 6.0 to 6.5 mmol/L
6.5 to 7.0 mEq/L
6.5 to 7.0 mmol/L
7.0 mEq/L
7.0 mmol/L
Hypoglycemia
Adult and Pediatric
1 Month
55 to 64 mg/dL
3.03 to 3.58 mmol/L
40 to 55 mg/dL
2.20 to 3.03 mmol/L
30 to 40 mg/dL
1.64 to 2.20 mmol/L
30 mg/dL
1.64 mmol/L
Infant, 1 Month
50 to 54 mg/dL
2.8 to 3.0 mmol/L
40 to 50 mg/dL
2.2 to 2.8 mmol/L
30 to 40 mg/dL
1.7 to 2.2 mmol/L
30 mg/dL
1.7 mmol/L
Hyperglycemia, Nonfasting
116 to 160 mg/dL
160 to 250 mg/dL
250 to 500 mg/dL
500 mg/dL
6.42 to 8.91 mmol/L
8.91 to 13.90 mmol/L
13.90 to 27.79 mmol/L
27.79 mmol/L
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 79
19 August 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypocalcemia
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL
1.74 to <1.94 mmolL
6.1 to <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88 mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected for 
albumin if appropriate*)
Adult and Pediatric 7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10 mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23 mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38 mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to 1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 80
19 August 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hypophosphatemia
Adult and Pediatric
14 Years
2.0 to < LLN mg/dL
0.63 to LLN mmol/L
1.5 to 2.0 mg/dL
0.47 to 0.63 mmol/L
1.0 to 1.5 mg/dL
0.31 to 0.47 mmol/L
1.0 mg/dL
0.31 mmol/L
Pediatric 1 Year–14 Years
3.0 to <LLN mg/dL
0.96 to <LLN mmol/L
2.5 to 3.0 mg/dL
0.80 to < 0.96 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Pediatric 1 Year
3.5 to <LLN mg/dL
1.12 to <LLN mmol/L
2.5 to 3.5 mg/dL
0.80 to < 1.12 mmol/L
1.5 to 2.5 mg/dL
0.47 to < 0.80 mmol/L
1.5 mg/dL
< 0.47 mmol/L
Hyperbilirubinemia
Adult and Pediatric > 14 Days
1.0 to 1.5 ULN
1.5 to 2.5 ULN
2.5 to 5.0 ULN
5.0 ULN
Infant, 14 Days
(non-hemolytic)
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 to 30.0 mg/dL
> 428 to 513 μmol/L
30.0 mg/dL
> 513 μmol/L
Infant, 14 Days
(hemolytic)
NA
NA
20.0 to 25.0 mg/dL
342 to 428 μmol/L
25.0 mg/dL
> 428 μmol/L
Blood Urea Nitrogen
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Hyperuricemia
>ULN to 10.0 mg/dL
10.0 to 12.0 mg/dL
12.0 to 15.0 mg/dL
15.0 mg/dL
>ULN to 597 μmol/L
597 to 716 μmol/L
716 to 895 μmol/L
895 μmol/L
Hypouricemia
Adult and Pediatric
≥1 year
Infant < 1 Year
1.5 mg/dL to LLN
87 μmol/L to LLN
1.0 to 1.5 mg/dL
57 to 87 μmol/L
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
N/A
1.0 mg/dl to <LLN-
57 μmol to <LLN
0.5 to 1.0 mg/dL
27 to 57 μmol/L
0.5 mg/dL
27 μmol/L
Creatinine**
1.50 to 2.00 mg/dL
133 to 177 μmol/L
2.00 to 3.00 mg/dL
177 to 265 μmol/L
3.00 to 6.00 mg/dL
265 to 530 μmol/L
6.00 mg/dL
530 μmol/L


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 81
19 August 2016
CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Bicarbonate
Adult and Pediatric
≥ 4 Years
16.0 mEq/L to LLN
11.0 to 16.0 mEq/L
8.0 to 11.0 mEq/L
8.0 mEq/L
16.0 mmol/L to LLN
11.0 to 16.0 mmol/L
8.0 to 11.0 mmol/L
8.0 mmol/L
Pediatric < 4 Years
NA
11.0 mEq/Lto <LLN
8.0 to 11.0 mEq/L
8.0 mEq/L
11.0 mmol/L to <LLN
8.0 to 11.0 mmol/L
8.0 mmol/L
Triglycerides
(Fasting)
NA
500 to 750 mg/dL
5.64–8.47 mmol/L
750 to 1200 mg/dL
8.47–13.55 mmol/L
1200 mg/dL
13.55 mmol/L
LDL (Fasting)
Adult
130 to 160 mg/dL
>160 to 190 mg/dL
> 190 mg/dL
NA
3.35 to 4.15 mmol/L
>4.15 to 4.92 mmol/L
>4.92 mmol/L
LDL (Fasting)
Pediatric >2 to <18 years
110 to 130 mg/dL
>130 to 190 mg/dL
> 190 mg/dL
NA
2.84 to 3.37 mmol/L
>3.37 to 4.92 mmol/L
>4.92 mmol/L
Hypercholesterolemia
(Fasting)
200 to 239 mg/dL
239 to 300 mg/dL
300 mg/dL
NA
5.16 to 6.19 mmol/L
6.19 to 7.77 mmol/L
7.77 mmol/L
Pediatric 18 Years
170 to 199 mg/dL
4.39 to 5.15 mmol/L
199 to 300 mg/dL
5.15 to 7.77 mmol/L
300 mg/dL
7.77 mmol/L
NA
Creatine Kinase
3.0 to 6.0 ULN
6.0 to 10.0 ULN
10.0 to 20.0 ULN
20.0 ULN
*
Calcium should be corrected for albumin if albumin is < 4.0 g/dL.
**
An overlap between the Grade 1 scale and the Lab’s normal range for creatinine may result for Male subjects > 70 yrs. Please follow the Gilead convention of grading any 
result within the LLN and ULN a 0.


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 82
19 August 2016
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
AST (SGOT)
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
ALT (SGPT)
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
GGT
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Alkaline Phosphatase
1.25 to 2.50 ULN
2.50 to 5.00 ULN
5.00 to 10.00 ULN
10.00 ULN
Total Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Pancreatic Amylase
1.0 to 1.5 ULN
1.5 to 2.0 ULN
2.0 to 5.0 ULN
5.0 ULN
Lipase
1.0 to 1.5 ULN
1.5 to 3.0 ULN
3.0 to 5.0 ULN
5.0 ULN
Albumin
Pediatrics <16 years
≥ 16 years
-
2.0 to LLN g/dL
20 to LLN g/L
2.0 g/dL
20 g/L
NA
3.0 g/dL to LLN
30 g/L to LLN
2.0 to 3.0 g/dL
20 to 30 g/L
2.0 g/dL
20 g/L
NA


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 83
19 August 2016
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.


E/C/F/TAF
Protocol GS-US-292-1824
Final
Gilead Sciences, Inc.
Amendment #1
CONFIDENTIAL
Page 84
19 August 2016
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Arrhythmia (general)
(By ECG or physical exam)
Asymptomatic AND 
No intervention indicated
Asymptomatic AND 
Non-urgent medical 
intervention indicated
Symptomatic, 
non-life-threatening AND 
Non-urgent medical
intervention indicated
Life-threatening arrhythmia 
OR Urgent intervention 
indicated
Cardiac-ischemia/Infarction
NA
NA
Symptomatic ischemia 
(stable angina) OR Testing 
consistent with ischemia
Unstable angina OR Acute 
myocardial infarction
Hemorrhage
(significant acute blood loss)
NA
Symptomatic AND No 
transfusion indicated
Symptomatic AND 
Transfusion of 2 units 
packed RBCs (for children 
10 cc/kg) indicated
Life-threatening hypotension 
OR Transfusion of 2 units 
packed RBCs indicated
(for children 10 cc/kg) 
indicated
Hypertension (with repeat 
testing at same visit)
140–159 mmHg systolic
OR
90–99 mmHg diastolic
159–179 mmHg systolic
OR
99–109 mmHg diastolic
179 mmHg systolic
OR
109 mmHg diastolic
Life-threatening 
consequences
(e.g., malignant 
hypertension) OR 
Hospitalization (other than 
ER visit) indicated
Pediatric 17 Years 
(with repeat testing at same 
visit)
NA
91st–94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic)
≥95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic)
Life-threatening 
consequences
(e.g., malignant 
hypertension) OR 
Hospitalization indicated 
(other than emergency room 
visit)
Hypotension
NA
Symptomatic, corrected with 
oral fluid replacement
Symptomatic, IV fluids 
indicated
Shock requiring use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure


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CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Pericardial Effusion
Asymptomatic, small 
effusion requiring no 
intervention
Asymptomatic, moderate or 
larger effusion requiring no 
intervention
Effusion with 
non-life-threatening 
physiologic consequences 
OR Effusion with nonurgent 
intervention indicated
Life-threatening 
consequences 
(e.g., tamponade) OR Urgent 
intervention indicated
Prolonged PR Interval
PR interval
0.21 to 0.25 sec
PR interval
0.25 sec
Type II 2nd degree AV block 
OR Ventricular pause 
3.0 sec
Complete AV block
Pediatric 16 Years
1st degree AV block
(PR > normal for age and 
rate)
Type I 2nd degree AV block
Type II 2nd degree AV block
Complete AV block
Prolonged QTc
Asymptomatic, QTc interval 
0.45 to 0.47 sec OR Increase 
interval 0.03 sec above 
baseline
Asymptomatic, QTc interval 
0.48 to 0.49 sec OR Increase 
in interval 0.03 to 0.05 sec 
above baseline
Asymptomatic, QTc interval 
0.50 sec OR Increase in 
interval 0.06 sec above 
baseline
Life-threatening 
consequences, eg, Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Pediatric 16 Years
Asymptomatic, QTc interval 
0.450 to 0.464 sec
Asymptomatic, QTc interval 
0.465 to 0.479 sec
Asymptomatic, QTc interval 
0.480 sec
Life-threatening 
consequences, eg, Torsade 
de pointes or other associated 
serious ventricular 
dysrhythmia
Thrombosis/Embolism
NA
Deep vein thrombosis AND 
No intervention indicated 
(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 [eg, tube feeding or 
total parenteral nutrition]
Ascites
Asymptomatic
Symptomatic AND 
Intervention indicated (e.g., 
diuretics or therapeutic 
paracentesis)
Symptomatic despite 
intervention
Life-threatening 
consequences
Cholecystitis
NA
Symptomatic AND Medical 
intervention indicated
Radiologic, endoscopic, or 
operative intervention 
indicated
Life-threatening 
consequences
(e.g., sepsis or perforation)
Constipation
NA
Persistent constipation 
requiring regular use of 
dietary modifications, 
laxatives, or enemas
Obstipation with manual 
evacuation indicated
Life-threatening 
consequences 
(e.g., obstruction)
Diarrhea
Adult and Pediatric 1 Year
Transient or intermittent 
episodes of unformed stools 
OR Increase of 3 stools 
over baseline/24 hr
Persistent episodes of 
unformed to watery stools 
OR Increase of 4–6 stools 
over baseline per 24 hrs.
Bloody diarrhea OR Increase 
of 7 stools per 24-hour 
period OR IV fluid 
replacement indicated
Life-threatening 
consequences 
(e.g., hypotensive shock)
Pediatric 1 Year
Liquid stools (more 
unformed than usual) but 
usual number of stools
Liquid stools with increased 
number of stools OR Mild 
dehydration
Liquid stools with moderate 
dehydration
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR Hypotensive 
shock
Dysphagia-Odynophagia
Symptomatic but able to eat 
usual diet
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated
Life-threatening reduction in 
oral intake


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


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


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


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INJECTION SITE REACTION
Grade 1
Grade 2
Grade 3
Grade 4
Injection Site Pain
(pain without touching)
Or Tenderness
(pain when area is touched)
Pain/tenderness causing no 
or minimal limitation of use 
of limb
Pain/tenderness limiting use 
of limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities
Pain/tenderness causing 
inability to perform usual 
social & functional activities
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other than 
ER visit) indicated for 
management of 
pain/tenderness
Injection Site Reaction 
(Localized), 15 Years
Erythema OR Induration
of 5 5 cm to 9 9 cm 
(or 2581 cm2)
Erythema OR Induration OR 
Edema 9 cm any diameter 
(or 81 cm2)
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage
Necrosis (involving dermis 
and deeper tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR 
Edema > 2.5 cm diameter 
but < 50% surface area of the 
extremity segment
(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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Amendment #1
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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)
Basic Self-care Functions: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
Usual Social & Functional Activities: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.


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Amendment #1
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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a) Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. 
In addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b) Definition of Male Fertility
For the purposes of this study, a male born subject is considered of fertile after the initiation of
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a) Study Drug Effects on Pregnancy and Hormonal Contraception
The data of study drugs on pregnant women is limited or not available. There is no suspicion of 
human teratogenicity based on class effects or genotoxic potential. Relevant non clinical 
reproductive toxicity studies for human pregnancy do not indicate a strong suspicion of human 
teratogenicity/fetotoxicity. Data from clinical pharmacokinetic interaction studies of study drug 
have demonstrated that there is no reduction in the clinical efficacy of hormonal contraception or 
that the effect on hormonal contraception is insignificant. Please refer to the latest version of the 
investigator’s brochure for additional information.
b) Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures. They must also not rely on hormone-containing contraceptives as a form 
of birth control during the study. They must have a negative serum pregnancy test at Screening 
prior to study enrollment. A serum pregnancy test will be performed at all study visits and the 
end of relevant system exposure. In the event of a delayed menstrual period (over one month
between menstruations), a serum pregnancy test must be performed to rule out pregnancy. 
This is even true for women of childbearing potential with infrequent or irregular periods. 
Female subjects must agree to one of the following from Screening until 30 days following the 
end of relevant systemic exposure.


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
Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below:
Intrauterine device (IUD) with a failure rate of < 1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Or

Consistent and correct use of one hormonal method and one barrier method:
Barrier methods
o
Diaphragm with spermicide
o
Cervical cap with spermicide
o
Male condom (with or without spermicide)
Hormonal methods (the hormonal contraceptive should contain at least 30 mcg of 
ethinyl estradiol)
o
Intrauterine hormone-releasing system (IUS) with a failure rate of < 1% per year
o
Oral contraceptives (either combined or progesterone only)
o
Injectable progesterone
o
Implants of levonorgestrel
o
Transdermal contraceptive patch
o
Contraceptive vaginal ring
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.


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Amendment #1
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3) Contraception Requirements for Male Subjects
During the study, male subjects with female partners of childbearing potential should use 
condoms when engaging in intercourse of reproductive potential.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Instructions for 
reporting pregnancy, and pregnancy outcome are outlined in Section 7.6.2.1.


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Amendment #1
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Appendix 6.
AIDS-Defining Conditions (CDC Guidelines) {Selik et al 2014}

Bacterial infections, multiple or recurrent*

Candidiasis of bronchi, trachea, or lungs

Candidiasis of esophagus

Cervical cancer, invasive†

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (> 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age > 1 month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy attributed to HIV§

Herpes simplex: chronic ulcers (> 1 month's duration) or bronchitis, pneumonitis, or 
esophagitis (onset at age > 1 month)

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (> 1 month's duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary, of brain

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or extrapulmonary

Mycobacterium, other species or unidentified species, disseminated or extrapulmonary

Pneumocystis jirovecii (previously known as "Pneumocystis carinii") pneumonia

Pneumonia, recurrent†


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
Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain, onset at age > 1 month

Wasting syndrome attributed to HIV§
*
Only among children aged < 6 years
†
Only among adults, adolescents, and children aged ≥6 years
§
Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy 
and HIV wasting syndrome, are described in the following references {Centers for Disease Control and 
Prevention 1994}, {Centers for Disease Control and Prevention 1992}.