Clinical trial NCT03960645
Conditions: HIV-1-infection
Sponsor: Gilead Sciences
Start date: 2019-06-28; Completion date: 2022-08-18
Enrollment: 62 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the steady state PK of bictegravir (BIC) and confirm the dose of BIC/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg fixed dose combination (FDC) in HIV-1 infected, virologically suppressed pregnant women in their second and third trimesters.

Detailed description:

Arms: arm 1: Pregnant women participants will receive fixed dose combination (FDC) tablet of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg for up to 38 weeks (from the second or third trimesters of pregnancy, depending on enrollment, through 12 weeks post-partum). arm 2: Neonates who will be born to women participants in the study will be followed from birth up to 8 weeks of age after obtaining consent from the parent or legal guardian. None of the neonates that participate in the study will be treated with the study drug.
Interventions: intervention 1: B/F/TAF
Intervention descriptions: intervention 1: 50/200/25 mg FDC tablet administered orally once daily without regard to food.

Protocol documents:
Prot_000.pdf: 


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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....................................................................13
1.
INTRODUCTION ..............................................................................................................................................16
1.1.
Background ............................................................................................................................................16
1.2.
B/F/TAF.................................................................................................................................................17
1.2.1.
General Information .............................................................................................................17
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................17
1.2.3.
Clinical Trials of Bictegravir and B/F/TAF .........................................................................18
1.3.
Rationale for This Study ........................................................................................................................25
1.4.
Rationale for Dose Selection..................................................................................................................26
1.5.
Risk/Benefit Assessment for the Study..................................................................................................27
1.6.
Compliance ............................................................................................................................................28
2.
OBJECTIVES.....................................................................................................................................................29
3.
STUDY DESIGN................................................................................................................................................30
3.1.
Endpoints ...............................................................................................................................................30
3.2.
Study Design..........................................................................................................................................30
3.3.
Study Treatments ...................................................................................................................................30
3.4.
Duration of Treatment............................................................................................................................30
4.
SUBJECT POPULATION..................................................................................................................................31
4.1.
Number of Participants and Subject Selection.......................................................................................31
4.2.
Inclusion Criteria....................................................................................................................................31
4.3.
Exclusion Criteria...................................................................................................................................32
4.4.
Enrollment Criteria for Neonates ...........................................................................................................34
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................35
5.1.
Enrollment..............................................................................................................................................35
5.2.
Description and Handling of B/F/TAF...................................................................................................35
5.2.1.
Formulation..........................................................................................................................35
5.2.2.
Packaging and Labeling .......................................................................................................35
5.2.3.
Storage and Handling...........................................................................................................35
5.3.
Dosage and Administration....................................................................................................................36
5.4.
Prior and Concomitant Medications.......................................................................................................36
5.5.
Accountability for B/F/TAF...................................................................................................................38
5.5.1.
Investigational Medicinal Product Return or Disposal.........................................................38
6.
STUDY PROCEDURES ....................................................................................................................................39
6.1.
Subject Enrollment.................................................................................................................................39
6.2.
Pretreatment Assessments......................................................................................................................39
6.2.1.
Screening Visit .....................................................................................................................39
6.3.
Subject Enrollment.................................................................................................................................41
6.4.
Day 1 Assessments.................................................................................................................................41
6.5.
Treatment Assessments..........................................................................................................................42


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6.5.1.
Maternal treatment assessments (Weeks 4-24 visits, Delivery Visit and 
Weeks 6 and 12 Post-partum visits).....................................................................................42
6.5.2.
Neonatal assessments ...........................................................................................................43
6.5.3.
Pharmacokinetic Evaluations ...............................................................................................44
6.6.
Post-treatment Assessments ...................................................................................................................45
6.7.
Early Study Drug Discontinuation Assessments....................................................................................45
6.7.1.
30-Day Follow-up Visit........................................................................................................46
6.8.
Criteria for Discontinuation of Study Treatment....................................................................................47
6.9.
End of Study...........................................................................................................................................48
6.10.
Post Study Care......................................................................................................................................48
6.11.
Virologic Failure....................................................................................................................................48
6.11.1.
Management of Virologic Rebound .....................................................................................48
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................51
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................51
7.1.1.
Adverse Events.....................................................................................................................51
7.1.2.
Serious Adverse Events........................................................................................................52
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................52
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................52
7.2.2.
Assessment of Severity ........................................................................................................53
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................53
7.4.
Gilead Reporting Requirements.............................................................................................................55
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................55
7.6.
Toxicity Management ............................................................................................................................56
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event..................................................56
7.6.2.
Grade 3 Laboratory Abnormality or Clinical Event.............................................................56
7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event.............................................................57
7.7.
Special Situations Reports......................................................................................................................57
7.7.1.
Definitions of Special Situations..........................................................................................57
7.7.2.
Instructions for Reporting Special Situations.......................................................................58
8.
STATISTICAL CONSIDERATIONS................................................................................................................60
8.1.
Analysis Objectives and Endpoints........................................................................................................60
8.1.1.
Analysis Objectives..............................................................................................................60
8.1.2.
Primary Endpoint .................................................................................................................60
8.1.3.
Secondary Endpoint .............................................................................................................61
8.1.4.
Other Endpoints of Interest ..................................................................................................61
8.2.
Analysis Conventions.............................................................................................................................61
8.2.1.
Analysis Sets ........................................................................................................................61
8.3.
Data Handling Conventions ...................................................................................................................62
8.4.
Demographic Data and Baseline Characteristics ...................................................................................62
8.5.
Efficacy Analysis ...................................................................................................................................62
8.6.
Safety Analysis.......................................................................................................................................63
8.6.1.
Extent of Exposure...............................................................................................................63
8.6.2.
Adverse Events.....................................................................................................................63
8.6.3.
Laboratory Evaluations ........................................................................................................64
8.6.4.
Other Safety Evaluations......................................................................................................64
8.7.
Pharmacokinetic Analysis......................................................................................................................64
8.8.
Sample Size............................................................................................................................................65
9.
RESPONSIBILITIES..........................................................................................................................................66
9.1.
Investigator Responsibilities ..................................................................................................................66


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9.1.1.
Good Clinical Practice..........................................................................................................66
9.1.2.
Financial Disclosure.............................................................................................................66
9.1.3.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................66
9.1.4.
Informed Consent.................................................................................................................66
9.1.5.
Confidentiality......................................................................................................................67
9.1.6.
Study Files and Retention of Records ..................................................................................67
9.1.7.
Case Report Forms...............................................................................................................69
9.1.8.
Investigational Medicinal Product Accountability and Return.............................................69
9.1.9.
Inspections............................................................................................................................69
9.1.10.
Protocol Compliance............................................................................................................69
9.2.
Sponsor Responsibilities ........................................................................................................................70
9.2.1.
Protocol Modifications.........................................................................................................70
9.2.2.
Study Report and Publications .............................................................................................70
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................71
9.3.1.
Payment Reporting...............................................................................................................71
9.3.2.
Access to Information for Monitoring..................................................................................71
9.3.3.
Access to Information for Auditing or Inspections ..............................................................71
9.3.4.
Study Discontinuation..........................................................................................................71
10.
REFERENCES ...................................................................................................................................................72
11.
APPENDICES ....................................................................................................................................................75
Appendix 1.
Investigator Signature Page....................................................................................................76
Appendix 2.
Maternal and Neonatal Study Procedures Tables...................................................................77
Appendix 3.
Management of Clinical and Laboratory Adverse Events......................................................80
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities...............81
Appendix 5.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC Guidelines) ...........................103
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential and 
Postpartum Contraceptive Requirements .............................................................................105
LIST OF IN-TEXT TABLES
Table 1-1.
Pooled Virologic Outcomes of Studies 1489 and 1490 at Week 48 in 
Treatment-Naïve Patientsa......................................................................................................21
Table 1-2.
Virologic Outcomes of Studies 1844 and 1878 at Week 48a..................................................23
Table 1-3.
GS-US-380-1961: Virologic Outcome at Week 48 Using the US FDA-Defined 
Snapshot Algorithm and HIV-1 RNA Cutoff at 50 copies/mL (Full Analysis Set) ...............25
Table 5-1.
Prior and Concomitant Medications.......................................................................................37
Table 8-1.
Statistical Comparisons for Pharmacokinetic Analyses .........................................................65
LIST OF IN-TEXT FIGURES
Figure 1-1.
GS-US-141-1219: Mean and 95% CIs of Change from Baseline in HIV-1 RNA 
(log10 copies/mL) (PP Analysis Set).......................................................................................19
Figure 6-1.
Virologic Rebound Schema....................................................................................................50


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1b, Open-label study to Evaluate the PK, Safety and Efficacy 
of B/F/TAF in HIV-1 infected, Virologically Suppressed, Pregnant 
Women in their Second and Third Trimesters
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
125589
Not applicable
Not available
Study Centers 
Planned:
Approximately 20 centers globally 
Objectives:
The primary objective of this study is as follows:

To evaluate the steady state pharmacokinetics (PK) of 
bictegravir (BIC) and confirm the dose of
BIC/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg 
fixed dose combination (FDC) in the second and third trimesters of 
pregnancy
The secondary objectives of this study are as follows: 

To evaluate the steady state PK of emtricitabine (FTC) and TAF in 
the second and third trimesters of pregnancy 

To evaluate maintenance of HIV-1 virologic suppression  in 
pregnant women receiving the B/F/TAF FDC during the second 
and/or third trimesters
The exploratory objectives of this study are as follows:

To assess frequency of HIV-1 transmission from pregnant women 
taking B/F/TAF during the second and third trimesters to the 
neonate

To evaluate the safety and tolerability of the B/F/TAF FDC in 
HIV-1 infected virologically suppressed pregnant women during 
the second and third trimesters through post-partum

To evaluate the safety of B/F/TAF in neonates with in utero 
exposure to B/F/TAF


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
To explore the PK of tenofovir diphosphate (TFV-DP) in PBMCs 
in pregnancy following administration of the B/F/TAF FDC

To explore the elimination of BIC and TAF in neonates from in 
utero exposure

To explore placental transfer of BIC and TAF
Study Design:
Phase 1b, open-label, multiple dose study in HIV-1 infected pregnant 
women in their second and/or third trimesters
Number of 
Participants
Planned:
Up to 35 participants total.
At least 25 participants will be enrolled to obtain at least 20 evaluable 
pairs of PK assessments between the second trimester and post-partum
and at least 20 evaluable pairs of PK assessment between the third 
trimester and post-partum. Replacement participants may be enrolled 
if originally enrolled participants do not complete all intensive PK 
visits as expected. 
Infants born to women participating in the study will be followed from 
birth to 4-8 weeks of age if consent is obtained from the parents/legal 
guardian. 
Target Population:
HIV-1 infected pregnant female participants who are virologically 
suppressed for ≥ 6 months prior to screening and are at least 12 weeks 
gestation but less than 31 weeks gestation at the time of the Screening 
Visit.
Infants born to women participating in the study will be followed from 
birth to 4-8 weeks of age if consent is obtained from the parents/legal 
guardian. 
Duration of 
Treatment:
Participants will be treated for up to approximately 38 weeks (from the 
second or third trimesters of pregnancy, depending on enrollment, 
through 12 weeks post-partum). Participants who complete the study 
through Week 12 post-partum visit will be required to return to the 
clinic 30 days after the Week 12 post-partum visit for a 30-Day 
Follow-Up Visit.
Diagnosis and Main 
Eligibility Criteria:
HIV-1 infected women with singleton pregnancy and meet the 
following criteria at screening: 

At least 12 weeks but not more than 31 weeks pregnant

Documented plasma HIV-1 RNA < 50 copies/mL on a stable 
regimen (or undetectable HIV-1 RNA level according to the local 
assay being used if the limit of detection is ≥ 50 copies/mL) for 
≥6 months preceding the Screening visit


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
The last two HIV-1 RNA measurements prior to screening must be 
< 50 copies/mL; however, unconfirmed virologic elevations of 
≥50 copies/mL; (transient detectable viremia, or “blip”) in the past 
are acceptable.

Estimated GFR (calculated by Cockcroft-Gault)  ≥ 90 mL/min

No documented or suspected resistance to FTC, TFV, or INSTIs 
including, but not limited to, the reverse transcriptase resistance 
mutations K65R or M184V/I

No chronic hepatitis B virus (HBV) infection

Agree not to breastfeed for the duration of the study

Normal ultrasound with no evidence of any fetal malformation or 
structural abnormality affecting either fetus or placenta

Normal maternal alfa-fetoprotein level
Study Procedures/
Frequency:
MATERNAL
Following completion of Screening and Day 1 visits, eligible 
participants will be required to return for study visits at Weeks 4, 8, 
12, 16, 20 and 24 dependent on time of enrollment (unless delivery 
has occurred by that time point). The day of delivery will be 
considered as the Delivery Visit for study purposes. 
Following delivery, participants will be required to return for study 
visits for Weeks 6 and 12 post-partum visits and a 30-Day Follow-up 
Visit.
For all eligible participants, blood samples will be collected at Day 1 
and all subsequent visits.
For all eligible participants, urine samples will be collected at Day 1, 
Weeks 12 and 24, and Weeks 6 and 12 post-partum visits. 
Assessments of adverse events and concomitant medications are 
performed at each visit.
Pharmacokinetic Assessments

Study Drug Administration for Intensive Pharmacokinetic 
On the days of intensive pharmacokinetic (iPK) sampling, study 
drug will be administered in the morning in the clinic. Following 
study drug administration participants will fast until after 
collection of the 2 hour PK sample. Additionally, participants will 
be restricted from water consumption 1 hour before and 1 hour 
after study drug administration (except for the 240 mL given with 
the study drug). 


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If a subject is unable to fast for the iPK visit, the visit may 
proceed. Participants should be consistent if they choose to fast or 
not fast during the iPK visits (i.e. if the participant fasts at the first 
iPK visit, then they should fast at all other iPK visits). Diary cards 
will be provided to all participants to record the time of study drug 
administration prior to the iPK visit.

PK Collection During Pregnancy:
Intensive PK visits will be completed after subject administers 
B/F/TAF for at least 3 weeks. 
For participants who enroll during the second trimester, serial 
blood samples for iPK evaluation will be collected at or between 
20 to 28 weeks of gestation, and during the third trimester, at or 
between 30 to 38 weeks of gestation.  
For participants who enroll during the third trimester, serial blood 
samples for iPK evaluation will be collected at or between 30 to 
38 weeks of gestation.  

PK Collection Post-partum:
Serial blood samples for iPK evaluation will be collected for all 
participants at Week 6 and Week 12 post-partum visits. 

Intensive PK Sample Collection Timepoints:
Blood samples will be collected at the following time points at the 
iPK visits: 
Pre-dose (≤ 5 minutes prior to dosing) 
0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose
A single anytime PK sample will be collected at the Early Study 
Drug Discontinuation (ESDD) Visit, if applicable

PBMC Collection: 
For participants enrolled at sites that can process PBMC samples, a 
trough PBMC sample will be collected 24 hours following the 
in-clinic dose administered at the iPK visits.  

Sparse PK Collection at the Delivery Visit: A single maternal 
blood sample and an umbilical cord blood sample after cord 
clamping will be collected soon after delivery.


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Safety Assessments 

Complete physical exam: Screening, Day 1, Week 4, Week 12,
Weeks 6 and 12 post-partum, and at the ESDD Visit, if applicable. 

Symptom-driven physical exam: Weeks 8, 16, 20 and 24, and 
30-Day Follow-up Visit

Vital signs (blood pressure, heart rate, respiration rate, and body 
temperature): Screening, Day 1 and all subsequent visits

Height: Screening

Weight: Screening, Day 1 and all subsequent visits

Estimated glomerular filtration rate according to the 
Cockcroft-Gault formula: Screening, Day 1, Weeks 12 and 24, and 
Weeks 6 and 12 post-partum visits

Clinical laboratory tests (hematology, chemistry, and urinalysis): 
Screening, Day 1, Weeks 12 and 24, Weeks 6 and 12 post-partum,
30-Day Follow-up Visit and at the ESDD visit, if applicable

Maternal alfa-fetoprotein level: Screening

Urine drug and alcohol assessments: Screening, Day 1

12-lead electrocardiogram (ECG): Screening

Hepatitis B virus, hepatitis C virus testing: Screening

HIV-1 RNA testing: Screening, Day 1 and all subsequent visits

CD4+ cell count: Screening, Day 1, and Week 12 post-partum
visit.
Assessments at the Delivery Visit
At the Delivery Visit, the date of delivery and outcome of the 
pregnancy will be recorded and a blood sample will be collected for 
HIV-1 RNA testing. Additionally, blood samples will be collected for 
PK assessments as described above. 
Assessment of adverse events (AEs) and concomitant medications will 
continue throughout the study. All clinical and clinically significant 
laboratory toxicities will be managed per protocol requirements. 
INFANTS
Infants will be enrolled and followed from birth to 4 to 8 weeks of age
if parent/legal guardian consent is provided.


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Sparse PK Collection:
Sparse PK blood samples will be collected, if possible, at the 
following time points: at or between 0 to < 2 hours, 2 to < 3 hours, 3 
to 8 hours, 18 to 28 hours, 36 to 72 hours, and 5 to 7 days after birth.
These time points may vary based on birth weight, additional 
instructions will be included in the Pharmacokinetic Sample 
Collection and Processing Instructions Manual.
Neonatal Assessments 

Complete physical exam: Physical examination at birth and once 
between 4 to 8 weeks of age

Vital signs (heart rate, respiration rate, and body temperature): at 
birth and once between 4 to 8 weeks of age

Apgar scoring: at 5 and 10 minutes after delivery, if recorded

Anthropometric measures: Head circumference, weight and length 
at birth and once between 4 to 8 weeks of age

Blood samples will be collected for PK assessments

HIV-1 RNA and safety assessments which includes CBC, LFTs 
(ALT, AST, total and direct bilirubin) may be completed using the 
sparse PK samples collected on the day of birth, if there is 
sufficient volume. If blood volume is insufficient, results from 
testing performed per standard of care will be obtained.

HIV-1 RNA and safety assessments may be completed once
between 4 to 8 weeks of age or results from testing performed per 
standard of care between 4 to 8 weeks of age will be obtained.
Test Product, Dose, 
and Mode of 
Administration:
FDC of bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 
25 mg (B/F/TAF 50/200/25 mg) administered orally, once daily 
without regard to food
Reference Therapy, 
Dose, and Mode of 
Administration:
None
Criteria for 
Evaluation:
Safety:
Adverse events and clinical laboratory tests to evaluate the safety and 
tolerability of the treatment regimen.
Efficacy:
The efficacy endpoint is:
Maternal HIV-1 RNA < 50 copies/mL at the time of delivery


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Pharmacokinetics:
Plasma concentrations of BIC, FTC and TAF will be determined and 
PK evaluated, as applicable. Protein binding of BIC from maternal 
intensive PK samples will be assessed at 24 hours post-dose. Protein 
binding of TAF from maternal intensive PK samples may be assessed 
at 3 hours post-dose. Plasma protein binding of BIC and TAF from 
maternal samples may also be evaluated at an additional time point 
corresponding to Tmax of the respective analyte. Plasma concentrations 
of other metabolites may be determined and PK explored. 
Intracellular concentrations of TFV-DP in PBMCs will be determined, 
as applicable.
The following plasma PK parameters will be calculated for BIC, FTC 
and TAF, as applicable: AUCtau, AUClast, Cmax, Ctau, Clast, Tmax, λz, 
CL/F, Vz/F, T½, and cord blood to maternal plasma concentration ratios,
as applicable. The PK of other analytes may be explored. 
Concentrations of TFV-DP in peripheral blood mononuclear cells
(PBMCs) will be analyzed and Ctau will be calculated, as applicable. 
Additionally, BIC and TAF T½ will be calculated in infants where 
possible.
Statistical Methods:
Pharmacokinetics:
Plasma concentrations and PK parameters will be listed and 
summarized using descriptive statistics by visit for maternal and 
infant, respectively. 
An analysis of variance (ANOVA) using a mixed-effects model with 
visit as a fixed effect and subject as a random effect will be fitted to 
the natural logarithmic transformation of maternal PK parameters 
(AUCtau, Cmax and Ctau, as applicable) for each analyte of interest. 
Two-sided 90% confidence intervals (CIs) will be calculated for the 
ratios of geometric least-squares means (GLSMs) between pregnancy 
(second or third trimester) and 12 weeks post-partum. 
The terminal half-life of BIC for infants, and the cord blood to 
maternal plasma concentrations ratio for BIC at delivery will be 
calculated and summarized.
Efficacy: 
The proportion of participants with plasma HIV-1 RNA 
< 50 copies/mL at the time of delivery will be summarized using the 
missing = excluded approach for imputing missing HIV-1 RNA 
values.
Efficacy data for infants will be listed and may be summarized by visit 
if applicable.


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Safety: 
The AE data will be listed by subject. Treatment-emergent AEs, 
serious adverse events (SAEs), and AEs leading to permanent study 
drug discontinuation will be summarized by system organ class, and 
preferred term using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA).
Listings of individual subject vital signs, 12-lead ECG parameters, and 
laboratory results will be provided. Laboratory results and change 
from baseline for vital signs and selected lab tests will be summarized 
at scheduled visits. The incidence of treatment-emergent laboratory 
abnormalities will be summarized.
Safety data for infants will be listed and may be summarized if 
applicable.
Sample Size:
With 20 evaluable participants, the study has at least 74% power to 
show that the lower bound of the 90% CI of the ratio for AUCtau of 
BIC during pregnancy relative to post-partum is > 50%, assuming a 
decrease of 40% in AUCtau of BIC during pregnancy relative to 
post-partum. It was assumed that a standard deviation (SD) of BIC 
AUCtau is no more than 0.34 on a natural logarithm scale, which is 
supported by a pooled PK analysis from 4 previous Gilead Phase 3 
studies. With 25% overage, a total sample size of at least 
25 participants will be required.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius 
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ANOVA
Analysis of Variance
ARV
Antiretroviral
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus time 
curve
BIC
bictegravir, B, GS-9883
B/F/TAF
bictegravir/emtricitabine/ tenofovir alafenamide, Biktarvy
BID
twice a day 
BUN
blood urea nitrogen
CBC
complete blood count
CHB
chronic hepatitis B
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
COBI, /C
Cobicistat
Ctau
the observed drug concentration at the end of the dosing interval
CPK
creatine phosphokinase
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CYP
cytochrome P450
DHHS
Department of Health and Human Services
DNA
deoxyribonucleic acid
DTG
dolutegravir, Tivicay
ECG
Electrocardiogram
eCRF
electronic case report form(s)
eGFR
estimated glomerular filtration rate
FAS
full analysis set
EVG
elvitegravir, E
E/C/F/TAF
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Genvoya
E/C/F/TDF
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, Stribild


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FAS
full analysis set
FDA
(United States) Food and Drug Administration
FDC
fixed dose combination
F/TAF 
emtricitabine/tenofovir alafenamide , Descovy
F/TDF
emtricitabine/tenofovir disoproxil fumarate, Truvada
FSH
follicle-stimulating hormone
FTC, F
emtricitabine, Emtriva
GCP
Good Clinical Practice (Guidelines)
GGT
gamma glutamyl transferase
GLSM
geometric least squares mean
GSI
Gilead Sciences, Inc.
GS-9883
bictegravir, B, BIC
GS-9883/F/TAF
GS-9883/emtricitabine/tenofovir alafenamide, B/F/TAF, Biktarvy
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HBeAb
hepatitis B e-antibody
HBeAg
hepatitis B e-antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high-density polyethylene
HCC
hepatocellular carcinoma
hERG
human Ether-à-go-go-Related Gene
HIV
human immunodeficiency virus
HIV Sx
HIV Symptoms  Distress Module
HIV
HIV Treatment Satisfaction Questionnaire
HIV-TSQs
HIV Treatment Satisfaction Questionnaire Status
HIV-TSQc
HIV Treatment Satisfaction Questionnaire Change
HLA
human leukocyte antigen
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug (Application)
INSTI
integrase strand-transfer inhibitors
IRB
institutional review board
IWRS
interactive web response system
KS
Kaposi’s sarcoma
LDH
lactate dehydrogenase


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LLN
lower limit of the normal range
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MH
Mantel-Haenszel
min
Minute
mmHg
millimeters mercury
nM
nanoMolar
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOEL
no observed effect level
OL
Open Label
NOAEL
no observed adverse effect level
NRTI
nucleoside/nucleotide reverse transcriptase inhibitor
PEP
post-exposure prophxylaxis
P-gp
P-glycoprotein
PI
protease inhibitor
PK
Pharmacokinetic
PT
preferred term 
PT
prothrombin time 
PTM
placebo-to-match
PVE
Pharmacovigilance and Epidemiology
QD
once daily 
RAL
Raltegravir
RNA
ribonucleic acid
SA
single agent
SAE
serious adverse event
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TAF
tenofovir alafenamide 
TAM
thymidine analogue mutation
TDF
tenofovir disoproxil fumarate, Viread
TFV-DP
tenofovir diphosphate (TFVpp)
tmax
the time (observed time point) of Cmax
TSH
thyroid stimulating hormone
UGT1A1
uridine 5'-diphospho-glucuronosyltransferase 
UGT
uridine glucuronosyltransferase
ULN
upper limit of the normal range
US
United States


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1.
INTRODUCTION
1.1.
Background
Human immunodeficiency virus-1 (HIV-1) infection is a life-threatening and serious disease that 
is of major public health interest around the world. There are approximately 2.4 million people in 
North America and Western and Central Europe living with HIV-1 and 37 million people 
worldwide {Joint United Nations Programme on HIV/AIDS (UNAIDS) 2016}. The infection, if 
left untreated or suboptimally treated, is characterized by deterioration in immune function, 
ultimately resulting in death. Therapeutic strategies for the treatment of HIV-1 disease have been 
significantly advanced by the availability of highly active antiretroviral therapy (HAART); the 
introduction of HAART was associated with a dramatic decrease in acquired immune deficiency 
syndrome (AIDS)-related morbidity and mortality {Mocroft 1998, Palella 1998, Sterne 2005}.
With the success of potent and well-tolerated antiretroviral therapy (ART) clinical attention has 
become more focused on the optimization of tolerability, long-term safety, and adherence of 
potent ART regimens {Costagliola 2014}.
For ART-naive HIV-infected patients, current treatment guidelines recommend that initial 
therapy for most people consist of 2 nucleos(t)ide reverse transcriptase inhibitors (N[t]RTI) and 
an integrase strand-transfer inhibitor (INSTI) {Panel on Antiretroviral Guidelines for Adults and 
Adolescents 2018}. 
Bictegravir (BIC) (previously referred to as GS-9883) is a potent inhibitor of HIV-1 integrase.  
Antiviral testing has shown that BIC is active against a broad panel of HIV-1 viral lab strains and 
clinical isolates. BIC is fully active in vitro against a panel of mutant viruses with resistance to 
NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). 
Some integrase mutant viruses that are resistant to the INSTIs raltegravir (RAL) and elvitegravir 
(EVG) remain largely sensitive to BIC in vitro, though there is limited clinical data in this 
population.
Gilead Sciences (Gilead) has coformulated BIC with the NRTI emtricitabine (FTC; F) and the 
NtRTI TAF into a fixed dose combination (FDC) tablet that is suitable for once daily use. This 
bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) FDC provides a potent, convenient, 
tolerable, and practical regimen for the long term treatment of patients with HIV infection. 
B/F/TAF (Biktarvy®) was approved for the treatment of adults with HIV-1 infection by the FDA 
and is recommended in DHHS (Department of Health and Human Services) treatment 
guidelines.


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Virologically suppressed, HIV-infected patients may switch from their current regimen because 
of safety or tolerability concerns or for regimen simplification. All patient populations may 
benefit from once-daily FDC regimens as these have been shown to provide increased adherence 
and improved clinical and virologic outcomes {Aldir 2014, Sterrantino 2012}. Virologically 
suppressive ART has also contributed to a decline in HIV incidence in communities with high 
rates of virologic suppression, by reducing the transmissibility of infected individuals on 
treatment {Grabowski 2017, Kurth 2011}.
All pregnant women living with HIV infection should receive effective antiretroviral therapy 
with at least three drugs for their own health and for the prevention of perinatal transmission of 
HIV. Treatment options for pregnant women may be limited due to risk of toxicity 
(e.g., didanosine, stavudine, full-dose ritonavir) or risk of low drug exposure and risk of 
virologic failure (e.g., elvitegravir/cobicistat) or risk of teratogenicity.  Although highly effective 
and well tolerated treatment options are available for the treatment of HIV infection in adults, PK 
and safety data to inform the use of newer ARVs in pregnant women remains limited {Panel on 
Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission 
2018}.
1.2.
B/F/TAF
1.2.1.
General Information
Bictegravir, a potent inhibitor of HIV-1 integrase, is now approved for the treatment of HIV 
infection as a component of FDC of B/F/TAF. For further information on bictegavir, refer to the 
investigator’s brochure.
1.2.2.
Preclinical Pharmacology and Toxicology
A core battery of safety pharmacology studies have been conducted with bictegravir. These 
include assessments of cytotoxicity, off-target receptor and ion-channel binding, effects on 
human Ether-à-go-go-Related Gene (hERG) potassium current and papillary muscle action 
potential, and in vivo studies in rats and dogs that evaluated effects of bictegravir on all major 
organ systems. Please refer to the investigator’s brochure for details.  
1.2.2.1.
Pharmacology
Bictegravir is absorbed following oral administration with peak plasma concentrations occurring 
at 2-4 hours after administration. The multiple dose pharmacokinetics of BIC are dose 
proportional over the dose range of 25 to 100 mg. Relative to fasting conditions, administration 
with either a moderate fat (~600 kcal, 27% fat) or high fat meal (~800 kcal, 50% fat) resulted in 
an increase in BIC AUC (24%). This modest change is not considered clinically meaningful and 
BIC can be administered with or without food.


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Bictegravir is mainly metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT1A1) 
and CYP3A. Bictegravir does not inhibit major human CYP isoforms or UGT1A1 at 
concentrations up to 25 M. Consequently, bictegravir is unlikely to be a clinically relevant 
inhibitor of these enzymes, and is not expected to inhibit the metabolic clearance of drugs 
metabolized by these enzymes. Bictegravir only modestly inhibits renal transporter OCT2 
(IC50 = 0.42 M). As a result, bictegravir is not expected to significantly interfere with the key 
transporter responsible for creatinine tubular elimination at the clinically projected Cmax. 
Additionally, the risk that bictegravir will affect the OCT2-mediated excretion of 
co-administered drugs is considered to be low.
BIC is primarily eliminated by hepatic metabolism. Renal excretion of intact BIC is a minor 
pathway (~1% of dose). The plasma BIC half-life was 17.3 hours.
1.2.2.2.
Toxicology
The nonclinical safety profile of BIC has been well characterized in genetic toxicology, safety 
pharmacology (central nervous system [CNS], cardiovascular [CV], respiratory), 
carcinogenicity, repeat-dose toxicity, and developmental toxicity studies. Bictegravir is not 
genotoxic and did not have adverse effects on the CNS, CV, or respiratory systems. Bictegravir 
demonstrated no carcinogenic potential in 6-month transgenic mouse or 2-year rat 
carcinogenicity studies at exposures 15- or 31-fold higher, respectively, than the estimated 
clinical exposure of BIC when administered as B/F/TAF (50/200/25 mg), hereafter referred to as 
exposure margins. The no-observed-adverse-effects levels (NOAELs) in chronic 26-week rat and 
39-week monkey toxicity studies were at exposure margins of 18-/46-fold (males/females) and 
7.0-fold, respectively. Administration of BIC to cynomolgus monkeys at a high dose of 
1000 mg/kg/day for 39 weeks resulted in microscopic liver changes that persisted through the 
recovery phase; observed increased alanine aminotransferase (ALT) activities at 1000 mg/kg/day 
exhibited reversibility. In offspring from rat and rabbit dams treated with BIC during pregnancy, 
there were no toxicologically significant effects on developmental endpoints, and studies in 
animals administered BIC have shown no evidence of teratogenicity or an effect on reproductive 
function.
1.2.3.
Clinical Trials of Bictegravir and B/F/TAF
Please refer to the B/F/TAF investigator’s brochure for a list of clinical studies of BIC and 
B/F/TAF as well as further information about these studies.
1.2.3.1.
Phase 1 Safety and Pharmacokinetics
Study GS-US-141-1218 was a four part, first-in-human study.  Parts A and B were randomized, 
double-blind, placebo-controlled, single and multiple ascending dose studies of BIC in healthy 
male and female participants which helped establish the PK of BIC and evaluated the drug-drug 
interaction potential with F/TAF FDC. Please see the investigator’s brochure for additional 
details.




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1.2.3.3.
Summary of Phase 2 Study (GS-US-141-1475)
Study GS-US-141-1475 is an ongoing Phase 2, randomized, double-blind, multicenter, 
active-controlled study to assess the safety and efficacy of a regimen containing BIC+FTC/TAF 
versus dolutegravir (DTG)+FTC/TAF in HIV-infected, ART-naive adult participants.
Eligible participants were randomized in a 2:1 ratio to receive BIC 75 mg + FTC/TAF 
(200/25 mg) + placebo-to-match DTG 50 mg once daily or DTG 50 mg + FTC/TAF (200/25 mg) 
+ placebo-to-match BIC 75 mg once daily.
The primary efficacy endpoint was the proportion of participants with HIV-1 RNA 
50 copies/mL at Week 24 as determined by the United States (US) Food and Drug 
Administration (FDA)-defined snapshot algorithm. The percentages of participants with HIV-1 
RNA < 50 copies/mL at Week 24 was high in both groups, as follows: BIC+FTC/TAF 96.9%; 
DTG+FTC/TAF 93.9%; difference in percentages: 2.9%, 95% CI: −8.5% to 14.2%. Because the 
lower bound of the 95% CI for the difference in response rate 
(BIC+FTC/TAF - DTG+FTC/TAF) was greater than the prespecified −12% margin, 
BIC+FTC/TAF was determined to be noninferior to DTG+FTC/TAF.
HIV-1 RNA levels decreased rapidly in the first 4 weeks following initiation of study drug in 
both treatment groups. No resistance to any INSTIs, NRTIs, NNRTIs, or PIs was detected 
through Week 48 in the BIC+FTC/TAF group. Both BIC+FTC/TAF and DTG+FTC/TAF were 
generally well tolerated through 48 weeks of treatment with similar proportions of adverse 
events reported in each treatment group. Participants in both groups were switched to open-label 
B/F/TAF after all participants completed 48 weeks of blinded treatment. 
1.2.3.4.
Summary of Phase 3 Studies
Treatment-Naïve Patients
In Study 1489, patients were randomized in a 1:1 ratio to receive either fixed-dose combination 
B/F/TAF (50/200/25 mg) (N = 314) or ABC/DTG/3TC (600/50/300 mg) (N = 315) once daily. 
In Study 1490, patients were randomized in a 1:1 ratio to receive either fixed-dose combination 
B/F/TAF (50/200/25 mg) (N = 320) or DTG + FTC/TAF (50+200/25 mg) (N = 325) once daily.
In Studies 1489 and 1490, the mean age was 35 years (range 18-77), 89% were male, 58% were 
White, 33% were Black, and 3% were Asian. 24% percent of patients identified as 
Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.4 log10 copies/mL 
(range 1.3-6.6). The mean baseline CD4+ cell count was 460 cells/mm3 (range 0-1636) and 
11% had CD4+ cell counts less than 200 cells/mm3. 18% of patients had baseline viral loads 
greater than 100,000 copies/mL. In both studies, patients were stratified by baseline HIV-1 RNA 
(less than or equal to 100,000 copies/mL, greater than 100,000 copies/mL to less than or equal to 
400,000 copies/mL, or greater than 400,000 copies/mL), by CD4 count (less than 50 cells/μL, 
50-199 cells/μL, or greater than or equal to 200 cells/μL), and by region (US or ex-US).
Treatment outcomes of Studies 1489 and 1490 through Week 48 are presented in Table 1-1.


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Table 1-1.
Pooled Virologic Outcomes of Studies 1489 and 1490 at Week 48 in 
Treatment-Naïve Patientsa
B/F/TAF FDC 
(N = 634)b
ABC/DTG/3TC
(N = 315)c
DTG + 
FTC/TAF
(N = 325)d
HIV-1 RNA < 50 copies/mL
91%
93%
93%
Treatment Difference (95% CI) 
B/F/TAF FDC vs. Comparator
-
-2.1%
(-5.9% to 1.6%)
-1.9%
(-5.6% to 1.8%)
HIV-1 RNA ≥50 copies/mLe
3%
3%
1%
No Virologic Data at Week 48 Window
6%
4%
6%
Discontinued Study Drug Due to AE or Deathf
<1%
1%
1%
Discontinued Study Drug Due to Other Reasons and 
Last Available HIV-1 RNA < 50 copies/mLg
4%
3%
4%
Missing Data During Window but on Study Drug
2%
<1%
1%
a.
Week 48 window was between Day 295 and 378 (inclusive).
b.
Pooled from Study 1489 (N = 314) and Study 1490 (N = 320).
c.
Study 1489
d.
Study 1490
e.
Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of 
efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the 
time of discontinuation had a viral value of ≥ 50 copies/mL.
f.
Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this 
resulted in no virologic data on treatment during the specified window.
g.
Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent, 
loss to follow-up, etc.
B/F/TAF FDC was noninferior in achieving HIV-1 RNA < 50 copies/mL at Week 48 when 
compared to ABC/DTG/3TC and DTG+FTC/TAF, respectively. Treatment outcomes were 
similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Studies 1489 and 1490, the mean increase from baseline in CD4+ count at Week 48 was 207, 
229, and 201 cells/mm3 in the pooled B/F/TAF FDC, ABC/DTG/3TC, and DTG+FTC/TAF 
groups, respectively.
Bone Mineral Density:
In Study 1489, bone mineral density (BMD) change from baseline to Week 48 was assessed by 
dual-energy X-ray absorptiometry (DXA). In patients who had both baseline and Week 48 hip 
and lumbar spine BMD measurements (N = 257 and 267 in the B/F/TAF FDC group and 
N = 270 and 274 in the ABC/DTG/3TC group, for hip and lumbar spine, respectively), mean 
percentage changes in BMD were similar in the B/F/TAF FDC group compared to the 
ABC/DTG/3TC group for hip (−0.8% vs. −1.0%) and lumbar spine (−0.8% vs.−0.6%).


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Virologically Suppressed Patients
In Study 1844, the efficacy and safety of switching from a regimen of DTG + ABC/3TC or 
ABC/DTG/3TC to B/F/TAF FDC were evaluated in a randomized, double-blind study of 
virologically-suppressed (HIV-1 RNA < 50 copies/mL) HIV-1 infected adults (N = 563). 
Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline 
regimen for at least 3 months prior to study entry. Patients were randomized in a 1:1 ratio to 
either switch to B/F/TAF FDC at baseline (N = 282), or stay on their baseline antiretroviral 
regimen (N = 281). Patients had a mean age of 45 years (range 20-71), 89% were male, 
73% were White, and 22% were Black. 17% of patients identified as Hispanic/Latino. The mean 
baseline CD4+ cell count was 723 cells/mm3 (range 124-2444).
In Study 1878, the efficacy and safety of switching from either ABC/3TC or FTC/TDF 
(200/300 mg) plus ATV or DRV (boosted by either COBI or RTV) to B/F/TAF FDC were 
evaluated in a randomized, open-label study of virologically-suppressed HIV-1 infected adults 
(N = 577). Patients must have been stably suppressed on their baseline regimen for at least 
6 months and INSTI naïve prior to study entry. Patients were randomized in a 1:1 ratio to either 
switch to B/F/TAF FDC (N = 290), or stay on their baseline antiretroviral regimen (N = 287). 
Patients had a mean age of 46 years (range 20-79), 83% were male, 66% were White, and 
26% were Black. 19% of patients identified as Hispanic/Latino. The mean baseline CD4+ cell 
count was 663 cells/mm3 (range 62-2582). Patients were stratified by prior treatment regimen. At 
screening, 15% of patients were receiving ABC/3TC plus ATV or DRV (boosted by either COBI 
or RTV) and 85% of patients were receiving FTC/TDF plus ATV or DRV (boosted by either 
COBI or RTV).
Treatment outcomes of Studies 1844 and 1878 through Week 48 are presented in Table 1-2.


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Table 1-2.
Virologic Outcomes of Studies 1844 and 1878 at Week 48a
Study 1844
Study 1878
B/F/TAF 
FDC 
(N = 282)
ABC/DTG/3TC
(N = 281)
B/F/TAF 
FDC
(N = 
290)
Baseline ATV-
or DRV-based 
regimen
(N = 287)
HIV-1 RNA < 50 copies/mL
94%
95%
92%
89%
Treatment Difference (95% CI)
-1.4% (-5.5% to 2.6%)
3.2% (-1.6% to 8.2%)
HIV-1 RNA ≥ 50 copies/mLb
1%
<1%
2%
2%
Treatment Difference (95% CI)
0.7% (-1.0% to 2.8%)
0.0% (-2.5% to 2.5%)
No Virologic Data at Week 48 Window
5%
5%
6%
9%
Discontinued Study Drug Due to AE or Death 
and Last Available HIV-1 RNA < 50 copies/mL
2%
1%
1%
1%
Discontinued Study Drug Due to Other Reasons 
and Last Available HIV-1 RNA <50 copies/mLc
2%
3%
3%
7%
Missing Data During Window but on Study Drug
2%
1%
2%
2%
a.
Week 48 window was between Day 295 and 378 (inclusive).
b.
Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of 
efficacy; patients who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a 
viral value of ≥ 50 copies/mL.
c.
Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g., withdrew consent 
loss to follow-up, etc.
In Study 1844, at Week 48, switching to B/F/TAF FDC was noninferior to remaining on 
ABC/DTG/3TC. The percentages of patients with HIV-1 RNA ≥50 copies/mL and who 
maintained HIV-1 RNA < 50 copies/mL were similar between the B/F/TAF FDC and 
ABC/DTG/3TC groups. The mean change from baseline in CD4+ count at Week 48 was 
−31 cells/mm3 in patients who switched to B/F/TAF FDC and 4 cells/mm3 in patients who stayed 
on ABC/DTG/3TC.
In Study 1878, at Week 48, switching to B/F/ es of patients with HIV-1 RNA ≥50 copies/mL 
and who maintained HIV-1 RNA < 50 copies/mTAF FDC was noninferior to remaining on an 
ATV- or DRV-based regimen. The percentagL were similar between the B/F/TAF FDC and 
ATV- or DRV-based regimen groups. The mean change from baseline in CD4+ count at 
Week 48 was 25 cells/mm3 in patients who switched to B/F/TAF FDC and 0 cells/mm3 in 
patients who stayed on their baseline regimen.


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Bone Mineral Density:
In Study 1844, BMD change from baseline to Week 48 was assessed by DXA. In patients who 
had both baseline and Week 48 hip and lumbar spine BMD measurements (N = 229 and 233 in 
the B/F/TAF FDC group and N = 242 and 244 in the ABC/DTG/3TC group, for hip and lumbar 
spine, respectively), mean percentage increases in BMD were similar in the B/F/TAF FDC group 
compared to the ABC/DTG/3TC group for hip (0.2% vs. 0.3%) and lumbar spine 
(0.7% vs.0.4%).
Virologically Suppressed Female Patients
In study 1961, the efficacy and safety of switching to B/F/TAF from either a protease inhibitor or 
boosted elvitegravir-containing regimen (E/C/F/TAF or E/C/F/TDF) was evaluated in HIV-1 
infected, virologically suppressed women (N=470). Participants were randomized (1:1) to switch 
to B/F/TAF (234) or stay on baseline regimen (SBR, n=236 [E/C/F/TAF n=125; E/C/F/TDF 
n=98; ATV+RTV+FTC/TDF n=13]). Participant median age was 39 years 37% black, 28.3% 
white, 21.7% Asian and CD4 count was 686 cells/μl. In Study 1961 at Week 48, switching to 
B/F/TAF FDC was noninferior to SBR. The percentages of patients with HIV-1 RNA 
≥50 copies/mL and who maintained HIV-1 RNA < 50 copies/mL were similar between the 
B/F/TAF FDC and SBR groups. The median change from baseline in CD4+ count at Week 48 
was +32 cells/mm3 in patients who switched to B/F/TAF FDC and +23 cells/mm3 in patients in 
the SBR group.
Treatment outcomes of Study 1961 through Week 48 are presented in Table 1-3.


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Table 1-3.
GS-US-380-1961: Virologic Outcome at Week 48 Using the US 
FDA-Defined Snapshot Algorithm and HIV-1 RNA Cutoff at 
50 copies/mL (Full Analysis Set)
B/F/TAF vs SBR
B/F/TAF
(N=234)
SBR
(N=236)
p-value
Difference in 
Percentages
(95.001% CI)
HIV-1 RNA < 50 copies/mL
224 
(95.7%)
225 
(95.3%)
1.00
0.4% (-3.7% to 4.5%)
HIV-1 RNA >= 50 copies/mL
4 (1.7%)
4 (1.7%)
1.00
0.0% (-2.9% to 2.9%)
HIV-1 RNA >= 50 copies/mL in Week 48 Window
4 (1.7%)
4 (1.7%)
Discontinued Study Drug Due to Lack of Efficacy
0
0
Discontinued Study Drug Due to AE/Death and Last 
Available HIV-1 RNA >= 50 copies/mL
0
0
Discontinued Study Drug Due to Other Reasonsa
and Last Available HIV-1 RNA >= 50 copies/mL
0
0
No Virologic Data in Week 48 Window
6 (2.6%)
7 (3.0%)
Discontinued Study Drug Due to AE/Death and Last
Available HIV-1 RNA < 50 copies/mL
0
1 (0.4%)
Discontinued Study Drug Due to Other Reasonsa
and Last Available HIV-1 RNA < 50 copies/mL
3 (1.3%)
4 (1.7%)
Missing Data During Window but on Study Drug
3 (1.3%)
2 (0.8%)
The Week 48 window is between Days 295 and 378 (inclusive).
a
Other reasons include participants 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.
P-values for the superiority test comparing the percentages between treatment groups were from the Fisher exact test.
The difference in percentages between treatment groups and their 95.001% CIs were calculated based on an unconditional exact 
method using 2 inverted 1-sided tests.
1.3.
Rationale for This Study
All pregnant women living with HIV infection should receive effective antiretroviral therapy 
with at least three drugs for their own health and for the prevention of perinatal transmission of 
HIV.  Treatment options for pregnant women may be limited due to risk of toxicity 
(e.g., didanosine, stavudine, full-dose ritonavir) or risk of low drug exposure and risk of 
virologic failure (e.g., elvitegravir/cobicistat) or risk of teratogenicity.  Although highly effective 
and well tolerated treatment options are available for the treatment of HIV infection in adults, PK 
and safety data to inform the use of newer ARVs in pregnant women remain limited {Panel on 
Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission 
2018}.


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The PK of many drugs, including ARVs, has been shown to be altered during pregnancy 
{Prezista USPI, Reyataz USPI, Edurant USPI, Tivicay USPI}{Gilbert 2015}.These changes in 
drug exposures have been attributed to the physiologic changes that occur during pregnancy, 
which include changes in plasma volume, protein binding, glomerular filtration rate and altered 
activity of drug metabolizing enzymes and transporters {Costantine 2014, Isoherranen 2013, 
Loebstein 1997}.
Bictegravir is an INSTI that is currently approved in a FDC of B/F/TAF for use once daily for 
the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults {Biktarvy 
USPI}. Bictegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase 1A1 
(UGT1A1) and CYP3A4. Increased activities of CYP3A and UGT1A1 have been reported 
during pregnancy {Hebert 2008, Jeong 2009} and decreased exposures of other ARVs that are 
substrates of these enzymes (i.e, dolutegravir and raltegravir) have been observed (Mulligan 
2018, Watts 2014). As such, there may be a possibility for reduced BIC exposures during 
pregnancy. No clinically relevant changes in the PK of FTC or TAF were observed in previous 
studies in HIV-infected pregnant women {Colbers 2013, Stek 2012}. 
The primary objective of this study is to characterize the pharmacokinetics (PK) of BIC and 
confirm the dose of the B/F/TAF FDC in virologically suppressed, HIV-1 infected pregnant 
women. Thus, this study aims at comparing the PK of BIC, FTC and TAF in HIV-infected 
pregnant women in the second or third trimesters of pregnancy relative to post-partum. This 
study will also characterize placental transfer of BIC and TAF to understand drug distribution 
into the fetus and the elimination of BIC and TAF in neonates from in utero exposure. 
Pharmacokinetic and safety data from this study will guide dose selection of B/F/TAF in 
pregnancy.  
1.4.
Rationale for Dose Selection
B/F/TAF 50/200/25 mg is the approved dose for treatment of HIV-1 infection in adults (Biktarvy 
USPI). 
The B/F/TAF Phase 3 studies support that virologic suppression and safety are maintained with 
mean BIC exposures at ~50% to 200% of the mean in adults {Lutz 2018}. Briefly, no exposure-
safety relationship was observed for BIC in Phase 3, supporting the safety of increases in BIC 
exposures ~200% of the mean in adults. With respect to efficacy, the results of B/F/TAF Phase 3 
exposure-efficacy analyses showed uniformly high virologic response rates (≥98.0%) across 
BIC exposure quartiles, with similar virologic response rates in the highest quartile and the 
lowest quartile observed. In the Phase 3 studies, the mean protein adjusted inhibitory quotient 
(IQ; Ctau/paEC95 [162 ng/mL]) was 16.1.
An evaluation of individual participants’ BIC IQ values as a function of whether or not the 
primary efficacy endpoint was met (HIV-1 RNA < 50 copies/mL at Week 48) revealed that all 
27 participants who had IQ values at or below 50% of the Phase 3 mean IQ of 16.1 had 
HIV-1 RNA < 50 copies/mL at the Week 48 visit. Therefore, the lower boundary of the BIC 
therapeutic window is unknown and the 50% lower limit is conservative. Importantly, the subject 
with the lowest observed BIC exposure (IQ = 4.7) would maintain Ctau well above paEC95 even 


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if their exposure decreased by 50% (IQ = 2.4). As such, participants with a decrease in exposures 
of 50% of the Phase 3 mean are expected to maintain virologic suppression. 
The Phase 3 data support the safety of increases in BIC exposures ~200% of the mean in adults. 
No exposure-safety relationship was observed for BIC in Phase 3 and the highest observed 
individual BIC AUCtau in the Phase 3 studies was approximately 230% that of the mean Phase 3 
BIC AUCtau, indicating that all participants with exposures around 200% of the Phase 3 mean are 
expected to maintain safety.
Changes in BIC exposure during the second and third trimesters of pregnancy in this study are 
expected to be within the range of those observed for other INSTIs that are substrates of CYP3A 
and UGT1A1, dolutegravir and raltegravir {Mulligan 2018, Watts 2014}. Exposures of these 
agents decreased 20 to 50% during pregnancy compared to post-partum. As BIC exposures 
≥50% of the mean in adults are expected to maintain virologic suppression and no clinically 
relevant changes in FTC and TAF are expected, B/F/TAF is anticipated to be efficacious and 
well tolerated during pregnancy.
1.5.
Risk/Benefit Assessment for the Study
Maintenance of virologic suppression is of paramount importance to protect the health of 
pregnant women and to prevent vertical transmission to the infant.  In general, pregnant women 
are encouraged to continue their current ART regimen during pregnancy, assuming that it is 
effective and well-tolerated {Panel on Treatment of Pregnant Women with HIV Infection and 
Prevention of Perinatal Transmission 2018}.  However, newer, highly effective ARVs such as 
B/F/TAF may provide benefits by reducing pill burden and toxicity while maintaining highly 
efficacious therapy without risk of drug resistance.  Bictegravir did not show any risk for 
embryo-fetal toxicity in pre-clinical species. There is limited information on TAF in pregnancy, 
but TDF, a different tenofovir prodrug, is recommended in pregnancy.  Potential risks associated 
with all classes of ARVs include immune reconstitution syndrome, lipodystrophy, and lactic 
acidosis with steatosis. The risk of class effects is considered to be low. Potential risks of 
switching ARVs during pregnancy could be loss of virologic control, development of drug 
resistance to some of the medications in B/F/TAF or new side effects.  Potential benefits may 
include provision of a new ARV therapy to this patient population that may have fewer side 
effects than alternative therapies. Other potential benefits include provisions of fixed dose 
combination therapy, and the knowledge that patient participation will contribute to the body of 
knowledge of HIV therapies. In addition, INSTIs exhibit rapid reduction of HIV-1 viral load, 
thereby providing a benefit to pregnant women with untreated HIV-1 infection.
In summary, the risk/benefit for this study is acceptable due to the following considerations: 

No clinically relevant changes in the PK of FTC or TAF were observed in previous studies in 
HIV-infected pregnant women 

Changes in BIC exposure during the second and third trimesters of pregnancy are anticipated 
to remain within the safe and efficacious ranges observed during the Phase 3 trials


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
B/F/TAF has been proven to be safe, well tolerated and effective in the treatment of 
HIV-infected patients, including in 470 women in Study GS-US-380-1961

No treatment emergent resistance developed in any patient treated with B/F/TAF during the 
Phase 2 and Phase 3 studies
The benefit-risk assessment for this study is favorable at this time. 
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 steady state pharmacokinetics (PK) of bictegravir (BIC) and confirm the dose 
of BIC/emtricitabine/tenofovir alafenamide (B/F/TAF) 50/200/25 mg fixed dose combination 
(FDC) in the second and third trimesters of pregnancy 
The secondary objectives of this study are:

To evaluate the steady state PK of emtricitabine (FTC) and TAF in the second and third 
trimesters of pregnancy 

To evaluate maintenance of HIV-1 virologic suppression  in pregnant women receiving the 
B/F/TAF FDC during the second and/or third trimesters
The exploratory objectives of this study are as follows:

To assess frequency of HIV-1 transmission from pregnant women taking B/F/TAF during the 
second and third trimesters to the neonate

To evaluate the safety and tolerability of the B/F/TAF FDC in HIV-1 infected virologically 
suppressed pregnant women during the second and third trimesters through post-partum

To evaluate the safety of B/F/TAF in neonates with in utero exposure to B/F/TAF

To explore the PK of tenofovir diphosphate (TFV-DP) in PBMCs in pregnancy following 
administration of the B/F/TAF FDC

To explore the elimination of BIC and TAF in neonates from in utero exposure

To explore placental transfer of BIC and TAF


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3.
STUDY DESIGN
3.1.
Endpoints
The primary endpoint of this study is:

The PK parameter AUCtau of BIC during the second and/or third trimesters through 
post-partum
The secondary endpoints of this study are:

The PK parameter AUCtau for FTC and TAF, and PK parameters AUClast, Cmax, Ctau, Clast,
Tmax, T1/2, CL/F, Vz/F, and λz for BIC, FTC, and TAF, as applicable

The proportion of participants with plasma HIV-1 RNA < 50 copies/mL at the time of 
delivery by missing = excluded approach.
3.2.
Study Design
This protocol describes an open-label, multicenter, multiple-dose study to evaluate the PK, 
efficacy, safety and tolerability of B/F/TAF in virologically suppressed, HIV-1 infected pregnant 
women in their second and third trimesters. 
3.3.
Study Treatments
Participants who provide written consent and meet all eligibility criteria will receive FDC of 
bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg (B/F/TAF 50/200/25 mg) 
administered orally, once daily without regard to food.
3.4.
Duration of Treatment
Participants will be treated for up to approximately 38 weeks. Following completion of a 30-day 
screening period and a Day 1 visit, eligible participants will be required to return for study visits 
at Weeks 4, 8, 12, 16, 20 and 24 dependent on time of enrollment (unless delivery has occurred 
by that time point). The day of delivery will be considered as the Delivery Visit for study 
purposes.
The screening period also may be extended under special circumstances with the explicit 
approval of Gilead Sciences.
Following delivery, participants will be required to return for study visits for Weeks 6 and 12 
post-partum visits. Participants who complete the study through the Week 12 post-partum visit 
will be required to return to the clinic 30 days after completion of the study drug dosing for a 30-
Day Follow-Up Visit. 


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4.
SUBJECT POPULATION
4.1.
Number of Participants and Subject Selection
Up to 35 participants who meet all eligibility criteria will be enrolled.
At least 25 participants will be enrolled to obtain at least 20 evaluable pairs of PK assessments 
between the second trimesters and post-partum and at least 20 evaluable pairs of PK assessment 
between the third trimesters and post-partum. Replacement participants may be enrolled if 
participants do not complete all intensive PK visits as expected.
Infants born to women participating in the study will be followed from birth to 4-8 weeks of age 
if consent is obtained from the parents/legal guardian.
4.2.
Inclusion Criteria
Participants 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) Female participants of age 18 to < 40 years with singleton pregnancy, at least 12 weeks but 
not more than 31 weeks pregnant at the time of screening
3) Agree not to breastfeed for the duration of the study
4) Currently on a stable antiretroviral regimen for ≥ 6 months preceding the screening visit
5) Documented plasma HIV-1 RNA levels of < 50 copies/mL for ≥ 6 months preceding the 
screening visit and have HIV-1 RNA < 50 copies/mL at the Screening Visit
a) In the preceding 6 months prior to screening, one episode of “blip” (HIV-1 RNA 
≥50 copies/mL 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) Have no documented or suspected resistance to FTC, TFV, or INSTIs including, but not 
limited to, the reverse transcriptase resistance mutations K65R or M184V/I.
a) Historic genotype reports will be collected if available


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7) Have a normal ultrasound, completed locally prior to the Day 1 visit, with no evidence of any 
fetal malformation or structural abnormality affecting either fetus or placenta
8) Normal maternal alfa-fetoprotein level at the Screening Visit
9) Estimated glomerular filtration rate (eGFR) 90 mL/min according to the Cockcroft-Gault 
(C-G) formula {Cockcroft 1976}:
(140 – age in years) (wt in kg) 0.85 CLcr (mL/min)
72 (serum creatinine in mg/dL)
(140 – age in years) (wt in kg) 0.85  CLcr (mL/sec)
72 (serum creatinine in umol/L) 0. 6786
10) Normal ECG (or if abnormal, determined by the investigator not to be clinically significant)
11) Hepatic transaminases (AST and ALT) 5 upper limit of normal (ULN)
12) Total bilirubin 1.5 mg/dL (26 umol/L), or normal direct bilirubin
13) Adequate hematologic function (absolute neutrophil count ≥750/mm3 (≥ 0.75 GI/L); 
platelets ≥50,000/mm3 (≥ 50 GI/L); hemoglobin ≥ 9.5 g/dL (≥95 g/L))
14) Serum amylase ≤ 5 × ULN (participants with serum amylase > 5 × ULN will remain eligible 
if serum lipase is ≤5 × ULN)
15) Participants of childbearing potential must agree to utilize protocol recommended highly 
effective contraceptive methods or be non-heterosexually active or practice sexual abstinence 
(as defined in Appendix 6) during the post-partum period of the study, and for 7 days 
following the last dose of study drug. 
4.3.
Exclusion Criteria
Participants who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Have chronic hepatitis B virus (HBV) as determined by either:
a) Positive HBV surface antigen (HBsAg) at the Screening Visit
b) Negative HBV surface antigen, negative HBV surface antibody, positive HBV core 
antibody and quantifiable HBV DNA (HBV DNA ≥ 20 IU/mL) at the Screening Visit
2) Have active hepatitis C virus (HCV) infection
a) Positive anti-HCV antibody and negative HCV polymerase chain reaction (PCR) results 
are acceptable


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3) An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to 
screening (refer to Appendix 5)
4) Participants experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, or variceal 
bleeding)
5) Have been treated with immunosuppressant therapies or chemotherapeutic agents within 
3 months of study screening, or expected to receive these agents or systemic steroids during 
the study (e.g, corticosteroids, immunoglobulins, and other immune- or cytokine-based 
therapies)
6) Malignancy within 5 years of screening other than cutaneous Kaposi’s sarcoma, completely 
resected non-melanoma skin cancer (basal cell carcinoma or non-invasive cutaneous 
squamous carcinoma), or completely resected carcinoma in-situ of the cervix (CIN 3) or anus 
(AIN 3). A prior malignancy treated with curative therapy and for which there has been no 
evidence of disease for at least five years prior to screening is allowed.
7) Current alcohol or substance use judged by the Investigator to potentially interfere with 
participant study compliance
8) Active, serious infections (other than HIV-1 infection) requiring antibiotic or antifungal 
therapy within 30 days prior to Day 1
9) Participation in any other clinical trial, including observational studies,  without prior 
approval from the sponsor is prohibited while participating in this trial
10) Any other clinical condition, including pregnancy complications such as gestational diabetes
or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable 
for the study or unable to comply with the dosing requirements
11) Active tuberculosis infection
12) Known hypersensitivity to B/F/TAF, their metabolites, or formulation excipient.
13) Participants receiving ongoing therapy with any of the following medications in the table 
below, including drugs not to be used with B/F/TAF
Drug Class
Agents Disallowed*
Antiarrhythmic Agent
Dofetilide
Anticonvulsants
phenobarbital, phenytoin, carbamazepine, oxcarbazepine
Antimycobacterials
rifampin, rifapentine, rifabutin
Antiretrovirals
Any antiretroviral drug that is not part of the study regimen
Herbal/Natural Supplements
St. John’s Wort
*
Administration of any of the above medications must be discontinued at least 30 days prior to the Day 1 visit and for the 
duration of the study.


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4.4.
Enrollment Criteria for Neonates
Neonates must meet the following inclusion criterion to be eligible for participation in this study.
1) Parent/legal guardian consent obtained for neonate participation. 
Neonates who meet any of the following exclusion criteria are not to be enrolled in this study:
1) If the mother has discontinued study drug > 24 hours prior to delivery
2) At birth, the neonate has a medical condition that, in the opinion of the Investigator  
precludes them from participating


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
Participants will be assigned a screening number at the time of consent. Day 1 visit cannot 
occur until the Investigator has confirmed the subject’s eligibility.
Once eligibility has been confirmed, each subject will be assigned a unique subject number using 
Interactive Web Response System (IWRS). Once a subject number has been assigned to a 
participant, 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 participant eligibility has been confirmed.
All eligible Participants will be provided B/F/TAF on Day 1 visit. The IWRS will assign study 
drug bottle numbers at each study visit. 
5.2.
Description and Handling of B/F/TAF
5.2.1.
Formulation
The B/F/TAF (50/200/25 mg) tablets are capsule-shaped, film-coated purplish-brown, debossed 
with "GSI" on one side of the tablet and "9883" on the other side of the tablet. Each tablet core 
contains 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. In 
addition to the active ingredients, the B/F/TAF tablets contain croscarmellose sodium, 
magnesium stearate, and microcrystalline cellulose. The tablet cores are film-coated with iron 
oxide red, iron oxide black, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
5.2.2.
Packaging and Labeling
B/F/TAF tablets are packaged in white, high density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, silica gel desiccant and polyester packing material.  Each bottle is enclosed 
with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner.
Study drug B/F/TAF to be distributed to centers in the US, Dominican Republic and Thailand 
shall be labeled to meet applicable requirements of the United States Food and Drug 
Administration (FDA), and/or other local regulations.
5.2.3.
Storage and Handling
Study drug (B/F/TAF) should be stored at controlled room temperature of 25°C (77°F); 
excursions are permitted between 15°C and 30°C (59°F and 86°F). Storage conditions are 
specified on the label. Until dispensed to the Participants, all bottles of study drug should be 
stored in a securely locked area, accessible only to authorized site personnel.


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To ensure the stability and proper identification, study drug should not be stored in a container 
other than the container in which it was supplied. Keep the bottle tightly closed to protect from 
moisture.
Consideration should be given to handling, preparation, and disposal through measures that 
minimize drug contact with the body. Appropriate precautions should be followed to avoid direct 
eye contact or exposure through inhalation when handling.
5.3.
Dosage and Administration  
B/F/TAF FDC tablets will be provided by Gilead Sciences. 
FDC of B/F/TAF containing bictegravir 50 mg / emtricitabine 200 mg / tenofovir alafenamide 
25 mg will be provided to all eligible Participants at Day 1. Study drug will be administered 
orally at approximately the same time each day without regard to food. 
5.4.
Prior and Concomitant Medications
The use of medications for the treatment of HIV-1 infection, other than B/F/TAF, is prohibited.
Medications listed in the following table and use of herbal/natural supplements are excluded or 
should be used with caution while participants are participating in the study.  This list should be 
utilized in jurisdictions in which B/F/TAF has NOT been approved.


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Table 5-1.
Prior and Concomitant Medications 
Drug Class
Agents Disallowed*
To Be Used With Caution
Medications or oral 
supplements containing 
polyvalent cations 
(e.g., Mg, Al, Ca, Fe): 
Calcium or iron 
supplements 
Cation-containing antacids 
or laxatives 
Buffered medications
Antacids containing Al/Mg or Calcium:
B/F/TAF can be taken under fasting conditions 
2 hours before antacids containing Al/Mg or 
calcium.
Routine administration of B/F/TAF 
simultaneously with, or 2 hours after, antacids 
containing Al/Mg or calcium is not 
recommended.
Supplements containing Calcium or Iron:
B/F/TAF and supplements containing calcium or 
iron can be taken together with food. Routine 
administration of B/F/TAF under fasting 
conditions simultaneously with, or 2 hours after, 
supplements containing calcium or iron is not 
recommended.
Antiarrhythmic Agent
dofetilide
Anticonvulsants
phenobarbital, phenytoin, 
carbamazepine, oxcarbazepine
Antimycobacterials
rifampin, rifapentine, rifabutin
Antiretrovirals
Any antiretroviral drug that is 
not part of the study regimen
Hypoglycemic agent
Metformin:
Refer to the prescribing information of 
metformin for assessing the benefit and risk of 
concomitant use of BIKTARVY and metformin.
Herbal/Natural 
Supplements
St. John’s Wort
*
Administration of any of the above medications must be discontinued at least 30 days prior to the Day 1 visit and for the 
duration of the study.
In jurisdictions in which B/F/TAF has been approved, consult the local prescribing 
information for B/F/TAF dose recommendations with concomitant medications.
Should participants have a need to initiate treatment with any excluded concomitant medication, 
the Gilead Medical Monitor must be consulted prior to initiation of the new medication. In 
instances where an excluded medication is initiated prior to discussion with the Sponsor, the 
Investigator must notify Gilead as soon as he/she is aware of the use of the excluded medication.


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5.5.
Accountability for B/F/TAF
The Investigator is responsible for ensuring adequate accountability of all used and unused IMP. 
This includes acknowledgement of receipt of each shipment of B/F/TAF (quantity and 
condition). All used and unused B/F/TAF bottles dispensed to Participants must be returned to 
the site.
B/F/TAF accountability records will be provided to each study site to:

Record the date received and quantity of IMP bottles

Record the date, subject number and the IMP lot number dispensed

Record the date, quantity of used and unused IMP returned, along with the initials of the 
person recording the information.
5.5.1.
Investigational Medicinal Product Return or Disposal
Return and disposal of B/F/TAF will be performed as outlined in Section 9.1.8.


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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. Additional information is 
provided in the study procedures manual.
The Investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
6.1.
Subject Enrollment 
It is the responsibility of the Investigator to ensure that participants are eligible for study prior to 
enrollment.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Participants will be screened within approximately 30 days before Day 1 to determine eligibility 
for participation in the study. The following will be performed and documented at screening:

Obtain written informed consent

Obtain medical history including history of HIV-1 disease-related events, and prior 
medications within 30 days of the screening visit

Complete physical examination (urogenital/anorectal exams will be performed at the 
discretion of the Investigator)

12-lead ECG performed supine

Height

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood samples for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, amylase (reflex lipase 
testing is performed in participants with total amylase > 1.5 × ULN), and TSH
Estimated glomerular filtration rate according to the Cockcroft-Gault formula
Hematology Profile: complete blood count (CBC) with differential and platelet count


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Maternal alfa-fetoprotein 
Plasma HIV-1 RNA 
Whole blood for HIV-1 genotype (if the sample is not collected at the screening visit, it 
may be collected at the Day 1 visit)
CD4+ cell count
Hepatitis B virus (HBV) blood panel: hepatitis B virus surface antigen (HBsAg), hepatitis 
B virus surface antibody (HBsAb) and hepatitis B virus core antibody (HBcAb)
The following will be conducted by the central laboratory if the following criteria are 
met:

If positive HBsAg, reflex testing for plasma HBV DNA, HBeAg (if negative, reflex 
HBeAb), and quantitative HBsAg

If positive HBcAb with negative HBsAg and negative HBsAb, reflex testing for 
plasma HBV DNA (if positive, reflex HBeAg). If HBeAg is performed and found to 
be negative, reflex HBeAb
Hepatitis C virus (HCVAb) serology. Participants who are HCVAb positive will have a 
HCV RNA test performed

Obtain urine samples for the following laboratory assessments:
Urinalysis
Drug and alcohol screening

Review concomitant medications

Record any SAEs and all AEs related to protocol mandated procedures occurring after 
signing of the consent form 
Participants meeting all of the inclusion criteria and none of the exclusion criteria will return to 
the clinic within approximately 30 days after screening for Day 1 Visit.
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any adverse events 
related to protocol-mandated procedures on the adverse events 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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6.3.
Subject Enrollment
Once eligibility has been confirmed and prior to or during the Day 1 visit, the Investigator or
designee will enroll the subject using the Interactive Web Response System (IWRS). Once a 
subject number has been assigned to a participant, 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.
6.4.
Day 1 Assessments 
The following evaluations are to be completed at the Day 1 Visit. The Investigator must have 
confirmed eligibility before proceeding with 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 measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood samples for the following laboratory analyses:
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, amylase (reflex lipase 
testing is performed in participants with total amylase > 1.5 × ULN), and TSH
Estimated glomerular filtration rate according to the Cockcroft-Gault formula
Hematology Profile: complete blood count (CBC) with differential and platelet count
Plasma HIV-1 RNA 
CD4+ cell count

Obtain urine samples for the following laboratory assessments:
Urinalysis
Drug and alcohol screening

Dispense FDC of B/F/TAF


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
Participants should be instructed to take FDC of B/F/TAF without regard to food (except as 
noted in Table 5-1). The participant should be counseled regarding the importance of 
adherence and taking their study medication at approximately the same time each day as 
directed by the Investigator

Provide a dosing diary to all participants for iPK sample collection
6.5.
Treatment Assessments
6.5.1.
Maternal treatment assessments (Weeks 4-24 visits, Delivery Visit and 
Weeks 6 and 12 Post-partum visits)
After completion of the Day 1 Visit, participants will return for Weeks 4, 8, 12, 16, 20 and 24 
visits dependent on time of enrollment and when delivery may occur. The day of delivery will be 
considered as the Delivery Visit for study purposes. After the delivery participants will return for 
Weeks 6 and 12 post-partum visits. 
Study visits are to be completed within ± 2 days of the protocol-specific visit date based on the 
Day 1 visit until delivery and within ± 2 days based on the date of delivery during the 
post-partum period of the study. 
The following assessments will be completed at all visits unless otherwise specified.

Review of AEs and changes in concomitant medications

Complete physical exam: 
Weeks 4 and 12
Weeks 6 and 12 post-partum

Symptom-driven physical exam: Weeks 8, 16, 20 and 24

Vital signs (blood pressure, heart rate, respiration rate, and body temperature) including 
weight

Obtain blood samples for the following laboratory analyses
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, amylase (reflex lipase 
testing is performed in participants with total amylase > 1.5 × ULN), and TSH (Weeks 12 
and 24, and Weeks 6 and 12 post-partum)
Estimated glomerular filtration rate according to the Cockcroft-Gault formula (Weeks 12 
and 24, and Weeks 6 and 12 post-partum)


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Hematology Profile: complete blood count (CBC) with differential and platelet count 
(Weeks 12 and 24, and Weeks 6 and 12 post-partum)
Plasma HIV-1 RNA
CD4+ cell count: Week 12 post-partum only
Intensive pharmacokinetic (iPK) evaluations will be completed as noted in Section 6.5.3.
Plasma storage samples for safety, virology or PK testing (except at Screening, Delivery 
Visit  and 30-Day Follow-up Visit)
For participants enrolled at sites that can process PBMC samples, a trough PBMC sample 
will be collected 24 hours following the in-clinic dose administered at the iPK visits.  

Obtain urine samples for the following laboratory assessments:
Urinalysis (Weeks 12 and 24, and Weeks 6 and 12 post-partum)
Urine pregnancy test (Week 6 and 12 post-partum): positive urine pregnancy tests will be 
confirmed with a serum test. If the test is positive, the subject will be discontinued

Document dispensation and accountability of FDC of B/F/TAF 
The following assessments will be completed at the Delivery Visit:

Date of delivery will be collected

Outcome of the pregnancy will be collected

Plasma sample for HIV-1 RNA will be obtained

Additionally Sparse PK samples will be collected per section 6.5.3
6.5.2.
Neonatal assessments 
Infants will be followed from birth to 4-8 weeks of age if enrolled. The following assessments 
will be completed at birth and once between 4 to 8 weeks of age unless otherwise specified:

Complete physical exam

Adverse Events

Vital signs ( heart rate, respiration rate, and body temperature)

Apgar scoring: at 5 and 10 minutes after delivery, if recorded


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
Anthropometric measures: Head circumference, weight and length

Blood samples will be collected for PK evaluation as noted in Section 6.5.3. 

HIV-1 RNA and safety assessments (CBC and LFT (ALT, AST, total and direct bilirubin) 
may be completed using the sparse PK samples collected on the day of birth, if there is 
sufficient volume. If blood volume is insufficient, results from testing performed per standard 
of care will be obtained.

HIV-1 RNA and safety assessments (CBC and LFT (ALT, AST, total and direct bilirubin) 
may be completed between 4 to 8 weeks of age or results from testing performed per 
standard of care between 4 to 8 weeks of age will be obtained. 
If the neonate is HIV-1 positive, additional genotypic assay may be completed if there is 
sufficient blood volume.
6.5.3.
Pharmacokinetic Evaluations
6.5.3.1.
Intensive Pharmacokinetic Evaluations

PK collection during pregnancy:
Intensive PK (iPK) visits will be completed after subject has been taking B/F/TAF for at 
least 3 weeks after Day 1 Visit (i.e after Day 21)
For participants who enroll during the second trimester, serial blood samples for iPK 
evaluation will be collected at or between 20 to 28 weeks of gestation, and during the 
third trimester, at or between 30 to 38 weeks of gestation.  
For participants who enroll during the third trimester, serial blood samples for iPK 
evaluation will be collected at or between 30 to 38 weeks of gestation.  

PK collection post-partum:
For all participants, serial blood samples for iPK evaluation will be collected at Weeks 6 
and 12 post-partum visits

Blood samples will be collected at the following time points at each iPK visit: 
Pre-dose (≤ 5 minutes prior to dosing), 
0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose
A single anytime PK sample will be collected at the ESDD visit, if applicable


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
On the days of iPK sampling, study drug will be administered in the morning in the clinic. 
Following study drug administration participants will fast until after collection of the 2-hour 
PK sample. Additionally, participants will be restricted from water consumption 1 hour 
before and 1 hour after study drug administration (except for the 240 mL given with the 
study drug). 

If a subject is unable to fast for the iPK visit, the visit may proceed, participants should be 
consistent if they choose to fast or not fast during the iPK visits (i.e. if the subject fasts at the 
first iPK visit, then they should fast at all other iPK visits). 

Subject dosing diary will be provided to all participants to record the time of study drug 
administration prior to the iPK visit. Completed dosing diaries will be collected from
participants on the day of the iPK Visit. If a dosing diary is not returned, the site may ask the 
subject for the time of the last dose and if it was taken with or without food. 
6.5.3.2.
Sparse PK Sample Collection at the Delivery Visit:

A single maternal blood sample and an umbilical cord blood sample after cord clamping will 
be collected soon after delivery.
6.5.3.3.
Sparse PK Sample Collection for the enrolled neonates:

Blood samples will be collected at the following time points, if possible: at or between 0 to < 
2 hours, 2 to < 3 hours, 3 to 8 hours, 18 to 28 hours, 36 to 72 hours, and 5 to 7 days after 
birth. These time points may vary based on birth weight, additional instructions will be 
included in the Pharmacokinetic Sample Collection and Processing Instructions Manual.
6.6.
Post-treatment Assessments
6.7.
Early Study Drug Discontinuation Assessments
If a subject discontinues their study drug administration prior to the Week 12 post-partum visit, 
the subject will be asked to return to the clinic within 72 hours of stopping study treatment for 
the Early Study Drug Discontinuation Visit. The subject will be asked to continue attending the 
scheduled study visits through the Week 12 post-partum visit. If this is not possible or acceptable 
to the subject or investigator, the subject may be withdrawn from the study. 
At the ESDD Visit, any evaluations showing abnormal results indicating that there is a possible 
or probable causal relationship with the study treatment, will be repeated until the abnormality is 
resolved (returns to the baseline value) or is otherwise explained. 
The following assessments will be completed at the ESDD Visit.

Review of AEs and changes in concomitant medications

Complete physical exam


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
Vital signs (blood pressure, heart rate, respiration rate, and body temperature) including 
weight

Obtain blood samples for the following laboratory analyses
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, amylase (reflex lipase 
testing is performed in participants with total amylase > 1.5 × ULN), and TSH 
Hematology Profile: complete blood count (CBC) with differential and platelet count 
Plasma HIV-1 RNA
Pharmacokinetic assessments as noted in Section 6.5.3

Obtain urine samples for the following laboratory assessments:
Urinalysis 
Urine pregnancy test (if the ESDD visit is after the delivery and if testing is clinically 
appropriate)
6.7.1.
30-Day Follow-up Visit
Participants who complete the study through their Week 12 post-partum Visit will be required to 
return to the clinic 30 days after their Week 12 post-partum Visit for a 30-Day Follow-Up Visit.
Participants who prematurely discontinue study treatment and refuse to continue in the study 
through the Week 12 post-partum Visit will be asked to return to the clinic 30 days after the 
completion of the Early Study Drugs Discontinuation Visit for the 30-Day Follow-up Visit.
Those participants who prematurely discontinue study treatment 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.


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For the purpose of scheduling a 30-Day Follow-Up Visit, a ± 6-day window may be used. 
The following evaluations are to be completed at the 30-Day Follow-Up Visit:

Review of AEs and changes in concomitant medications

Symptom-directed physical examination

Vital signs measurement (blood pressure, pulse, respiration rate, and temperature), including 
weight

Obtain blood samples for the following laboratory analyses
Chemistry profile: alkaline phosphatase, AST, ALT, GGT, total bilirubin, direct and 
indirect bilirubin, total protein, albumin, bicarbonate, BUN, calcium, chloride, creatinine, 
glucose, phosphorus, magnesium, potassium, sodium, uric acid, amylase (reflex lipase 
testing is performed in participants with total amylase > 1.5 × ULN), and TSH 
Hematology Profile: complete blood count (CBC) with differential and platelet count 
Plasma HIV-1 RNA

Obtain urine samples for the following laboratory assessments:
Urinalysis 
Urine pregnancy test (positive urine pregnancy tests will be confirmed with a serum test).
At the 30-Day Follow-Up Visit, any evaluations showing abnormal results believed to be a 
reasonable possibility of a causal relationship with study treatment will be repeated weekly (or as 
often as deemed prudent by the Investigator) until the abnormality is resolved, returns to baseline 
(Day 1) value, or is otherwise explained.  
6.8.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the Investigator, affect assessments of 
clinical status to a significant degree. 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


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
Subject request to discontinue for any reason

Subject noncompliance

Discontinuation of the study at the request of Gilead, a regulatory agency or an institutional 
review board or independent ethics committee (IRB/IEC)
6.9.
End of Study
The end of the study will be the last subject’s last observation (or visit).
6.10.
Post Study Care
After the subject has completed/terminated their participation in the study, long-term care for the 
participant will remain the responsibility of their primary treating physician.
6.11.
Virologic Failure
Virologic failure is defined as confirmed virologic rebound of HIV-1 RNA ≥50 copies/mL at 
2 consecutive visits.
6.11.1.
Management of Virologic Rebound
Participants who meet the criteria listed below will be considered to have virologic rebound 
(VR):

At any post Day 1 visit, a rebound in HIV-1 RNA ≥50 copies/mL
If the HIV-1 RNA is ≥ 50 and < 200 copies/mL, a reflex HIV-1 RNA repeat test will be 
conducted on available plasma samples. If the repeat result is < 50 copies/mL, no further action 
is required. If the repeat result is ≥ 50 copies/mL participants will be asked to return to the clinic 
for a scheduled or unscheduled blood draw (2 to 3 weeks after the date of the original test that 
resulted in HIV-1 RNA VR) for confirmation of VR. 
If virologic rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA is 
≥200 copies/mL, the plasma sample from the confirmation visit will be the primary sample used 
for HIV-1 genotypic and phenotypic testing.  If resistance to study treatment is detected subject 
may be discontinued at Investigator’s discretion or per local treatment guidelines.
If no resistance to study treatment is detected from the genotype or phenotype, the participant 
may remain on study treatment and HIV-1 RNA should be analyzed at a new visit (within 2 to 
3 weeks after date of test with HIV-1 RNA ≥50 copies/mL). Investigators should carefully
evaluate the benefits and risks of remaining on study treatment for each subject and document 
this assessment in the on-site medical record.


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6.11.1.1.
Participants with HIV-1 RNA ≥ 50 copies/mL at Study Drug Discontinuation
Participants with HIV-1 RNA ≥ 50 copies/mL at study drug discontinuation or last visit will be 
considered virologic failures and will be asked to return for an unscheduled visit within 2 to 
3 weeks for a retest.
Participants with HIV-1 RNA ≥ 200 copies/mL at study drug discontinuation or last visit will 
also have resistance testing conducted.


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Figure 6-1.
Virologic Rebound Schema
a.
If the HIV-1 RNA is between 50 and 200 copies/mL, a reflex HIV-1 RNA repeat test will be conducted on available plasma 
samples. If the repeat result is < 50 copies/mL, then no further action is required. If the repeat result is ≥ 50 copies/mL then 
proceed to the scheduled or unscheduled visit 2 – 3 weeks later.
b.
If the retest result is < 50 copies/mL, then no further action is required. If the retest result is > 50 copies/mL this is protocol 
defined confirmed virologic failure and the Medical Monitor should be consulted. 
c.
If virologic rebound is confirmed and the last HIV-1 RNA is ≥ 200 copies/mL, the HIV-1 genotype and phenotype (reverse 
transcriptase, protease and integrase) will be analyzed. If the genotype and phenotype assay fails, Investigator reviews study 
treatment continuation/discontinuation options and discuss with the Medical Monitor prior to study treatment 
discontinuation.   
d.
If no new resistance to study treatment is detected, HIV-1 RNA will be repeated 2 – 3 weeks later. Investigator reviews 
study treatment continuation/discontinuation options and discuss with the Medical Monitor prior to study treatment 
discontinuation. The participant will remain in the study.
e.
A new ARV regimen may be configured, at the Investigator’s discretion and the participant will remain in the study.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg. hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7)

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.


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7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

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 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.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The Investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The Investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.


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It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity 
AE 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.
The distinction between the seriousness and the severity of an adverse event should be noted.
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For
example, a headache may be severe in intensity, but would not be classified as serious unless it
met one of the criteria for serious events.
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the
clinical severity in the context of the underlying conditions; this may or may not be in agreement
with the grading of the laboratory abnormality.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the electronic case report form (eCRF): all SAEs and adverse events 
related to protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study IMP must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.




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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the participant’s eCRF and the event description section of the SAE 
form
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy.
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory 
abnormality is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the 
laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the GSI Grading Scale for Severity of 
Adverse Events and Laboratory Abnormalities (refer to Appendix 4). For AEs 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.


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7.6.
Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in as outlined below:

Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Gilead Grading Scale for Severity of Adverse Events and Laboratory Abnormalities 
(refer to Appendix 4)

Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before study drug discontinuation, 
unless such a delay is not consistent with good medical practice.
Any questions regarding toxicity management should be directed to the Gilead Medical Monitor.
7.6.1.
Grades 1 and 2 Laboratory Abnormality or Clinical Event
Continue study drug at the discretion of the Investigator.
7.6.2.
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 will 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 Gilead 
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 will be permanently discontinued and the 
participant managed according to local practice. Recurrence of laboratory abnormalities 
considered unrelated to study drug may not require permanent discontinuation but requires 
discussion with the Gilead Medical Monitor.


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7.6.3.
Grade 4 Laboratory Abnormality or Clinical Event

For a Grade 4 clinical event or clinically significant Grade 4 laboratory abnormality 
confirmed by repeat testing that is considered related to study drug, study drug will be 
permanently discontinued and the participant managed according to local practice. The 
participant 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 (eg, Grade 4 CK after strenuous exercise, or triglyceride 
elevation that is nonfasting or that can be medically managed) or a clinical event considered 
unrelated to study drug.

Treatment-emergent toxicities will be noted by the investigator and brought to the attention 
of the Gilead medical monitor, who will have a discussion with the investigator and decide 
the appropriate course of action. Whether or not considered treatment-related, all participants
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or they are considered 
irreversible, or until there is a satisfactory explanation for the changes observed.

Any questions regarding toxicity management should be directed to the Gilead 
Medical Monitor.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints regardless of an associated AE, outcome of 
the pregnancy during the study, and pregnancy reports during the post-partum period of the 
study, an AE in an infant following exposure from breastfeeding, and an occupational exposure 
with an 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.




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7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead PVE within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
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:

To evaluate the steady state PK of BIC and confirm the dose of B/F/TAF 50/200/25 mg FDC 
in the second and third trimesters of pregnancy
The secondary objectives of this study are:

To evaluate the steady state PK of FTC and TAF in the second and third trimesters of 
pregnancy 

To evaluate maintenance of HIV-1 virologic suppression in pregnant women receiving the 
B/F/TAF FDC during the second and/or third trimesters
The exploratory objectives of this study are as follows:

To assess frequency of HIV-1 transmission from pregnant women taking B/F/TAF during the 
second and third trimesters to the neonate

To evaluate the safety and tolerability of the B/F/TAF FDC in HIV-1 infected virologically 
suppressed pregnant women during the second and third trimesters through post-partum

To evaluate the safety of B/F/TAF in neonates with in utero exposure to B/F/TAF

To explore the PK of TFV-DP in PBMCs in pregnancy following administration of the 
B/F/TAF FDC

To explore the elimination of BIC and TAF in neonates from in utero exposure

To explore placental transfer of BIC and TAF
8.1.2.
Primary Endpoint
The primary endpoint is the PK parameter AUCtau of BIC during the second and/or 
third trimesters through post-partum.


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8.1.3.
Secondary Endpoint
Secondary endpoints include:

The PK parameter AUCtau for FTC and TAF, and PK parameters AUClast, Cmax, Ctau, Clast,,
Tmax, T1/2, CL/F, Vz/F and λz for BIC, FTC and TAF, as applicable

The proportion of participants with plasma HIV-1 RNA < 50 copies/mL at the time of 
delivery by missing = excluded approach.
8.1.4.
Other Endpoints of Interest
Other endpoints of interest include the PK of PBMC-associated TFV-DP, cord blood to maternal 
plasma concentration ratio for BIC and TAF, as applicable and BIC and TAF T1/2 in infants, 
where possible. They also include the incidence of AEs and laboratory abnormality in infants.
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
All Enrolled
The All Enrolled analysis set includes all participants who are enrolled into the study. This is the 
primary analysis set for by-subject listings.
8.2.1.2.
Safety Analysis Set
The primary analysis set for safety analyses is defined as safety analysis set, which will include 
all participants who (1) enroll into the study and (2) have received at least 1 dose of study drug 
(ie, B/F/TAF). All the data collected up to 30 days after participants permanently discontinue 
their study drug will be included in the safety summaries, unless specified otherwise.
8.2.1.3.
Efficacy
The primary analysis set for efficacy analyses is defined as full analysis set (FAS), which will 
include all participants who (1) enroll into the study and (2) have received at least 1 dose of 
study drug (ie, B/F/TAF).
8.2.1.4.
Pharmacokinetics
Maternal: The primary analysis set for PK analyses is defined as the PK analysis set, which will 
include all participants who (1) enroll into the study, (2) have received at least 1 dose of study 
drug (ie, B/F/TAF), and (3) have at least 1 nonmissing PK concentration data for any analyte of 
interest reported by the PK lab.
Infant: The PK analysis set for infant will include all infants who (1) enroll into the study, 
(2) have at least 1 nonmissing PK concentration data for any analyte of interest reported by the 
PK lab.


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8.3.
Data Handling Conventions
HIV-1 RNA results of ‘No HIV-1 RNA detected’ and ‘< 20 cp/mL HIV-1 RNA Detected’ will 
be imputed as 19 copies/mL for analysis purpose. Logarithm (base 10) transformation will be 
applied to HIV-1 RNA values for efficacy analysis.
Natural logarithmic transformation of plasma concentration and PK parameters will be applied 
for PK analysis.
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed to the value of the lower or upper limit plus 
or minus 1 significant digit, respectively (eg, if the result of a continuous laboratory test is < 20, 
a value of 19 will be assigned).
Missing data can have an impact upon the interpretation of the trial data. In general, values for 
missing data will not be imputed. However, a missing pre-treatment laboratory result would be 
treated as normal (ie, no toxicity grade) for the laboratory abnormality summary.
All available data for participants that do not complete the study will be included in data listings.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized using standard descriptive 
methods including sample size, mean, SD, median, Q1, Q3, minimum, and maximum for 
continuous variables, and frequency and percentages for categorical variables.
Demographic summaries will include sex, race, ethnicity, and age.
Baseline data will include a summary of body weight, height, body mass index, eGFR, and 
HIV-1 infection.
8.5.
Efficacy Analysis
The primary efficacy endpoint is the proportion of participants with plasma HIV-1 RNA 
< 50 copies/mL at the time of delivery. It will be analyzed using the missing = excluded 
approach for imputing missing HIV-1 RNA values: all missing data will be excluded in the 
computation of the percentages (ie, missing data points will be excluded from both the numerator 
and denominator in the computation). The denominator for the percentages at a visit is the 
number of participants in the FAS with nonmissing HIV-1 RNA value at that visit.
The 95% CI of the proportion of participants with HIV-1 RNA < 50 copies/mL will be provided 
using the Clopper-Pearson Exact method. 
The efficacy data for infants may be summarized if applicable.


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8.6.
Safety Analysis
All safety analyses will be performed using the safety analysis set.
All safety data collected on or after the date that the study drug was first dispensed up to the date 
of last dose of the study drug plus 30 days will be summarized for participants in the safety 
analysis set. Data for the pretreatment will be included in data listings for all enrolled 
participants. 
8.6.1.
Extent of Exposure
A subject’s extent of exposure to study drug (ie, Gilead dispensed B/F/TAF) 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 the last dose of B/F/TAF, inclusive, regardless of temporary interruptions in study drug 
administration.
Dosing information for individual participants will be listed.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any adverse event with onset date on or after the study drug start 
date and no later than 30 days after the study drug stop date; or any adverse event leading to 
study drug discontinuation.
Summaries (number and percentage of participants) 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 
dosing.
On an ongoing basis, adverse events will be reviewed for events that might meet the definition of 
Stage 3 Opportunistic Illnesses in HIV are indicative of an AIDS-Defining Diagnoses. The 
Gilead medical personnel will review the possible Stage 3 events and approve the events that 
meet the definition. Those events that do meet the Stage 3 Opportunistic Illness definition of an 
AIDS-Defining Diagnosis will be listed.
A listing of Stage 3 Opportunistic Illnesses in HIV can be found in Appendix 5.


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8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Absolute values and changes from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the grading scheme in Appendix 4.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post baseline up to and including the date of last dose 
of study drug plus 30 days, will be summarized. If baseline data are missing, then any graded 
abnormality (ie, at least a Grade 1) will be considered treatment emergent. The maximum post 
baseline toxicity grade will be summarized by laboratory parameter.
Laboratory abnormalities that occur before the first dose of study drug or after the last dose of 
study drug plus 30 days will be included in a data listing.
8.6.4.
Other Safety Evaluations
Vital signs will be summarized as appropriate. Safety data for infants might be summarized if 
necessary.
8.7.
Pharmacokinetic Analysis
Maternal:
Plasma concentrations of BIC, FTC, and TAF will be summarized by nominal sampling time 
using descriptive statistics. Pharmacokinetic parameters (AUCtau, Cmax, Ctau, Tmax, and T½, 
as appropriate) will be listed and summarized for BIC, FTC, and TAF using descriptive statistics 
(eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, SD, median, Q1, 
Q3, minimum, and maximum). Plasma concentrations over time will be plotted in semi 
logarithmic and linear formats as mean SD, and median (Q1, Q3).
In addition, an ANOVA using a mixed-effects model with visit as a fixed effect and subject as a 
random effect will be fitted to the natural logarithmic transformation of PK parameters (AUCtau, 
Cmax and Ctau, as applicable) for each analyte of interest (ie, BIC, FTC, and TAF). Two-sided 
90% CIs will be calculated for the ratios of GLSMs between pregnancy (second and 
third trimesters) and post-partum (6 and 12 weeks after delivery, respectively).


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Table 8-1.
Statistical Comparisons for Pharmacokinetic Analyses
Analytes
PK Parameter
Comparison
No Effect Boundary
for Lower Bound of 
90% CI
Test
Reference
BIC
AUCtau
Cmax
Ctau
Second Trimester
12 Weeks post-partum
> 50%
BIC
AUCtau
Cmax
Ctau
Third Trimester
12 Weeks post-partum
> 50%
BIC
AUCtau
Cmax
Ctau
Second Trimester
6 Weeks post-partum
> 50%
BIC
AUCtau
Cmax
Ctau
Third Trimester
6 Weeks post-partum
> 50%
Infant:
Plasma concentration of BIC will be summarized by nominal sampling time using descriptive 
statistics. The terminal half-life of BIC will be calculated, where possible, and summarized.
The cord blood to maternal plasma concentrations ratio for BIC and TAF, as applicable, will be 
calculated, where possible, and summarized.
8.8.
Sample Size
With 20 evaluable participants, the study has at least 74% power to show that the lower bound of 
the 90% CI of the ratio for AUCtau of BIC during pregnancy relative to post-partum is > 50%, 
assuming a decrease of 40% in AUCtau of BIC during pregnancy relative to post-partum. It was 
assumed that a standard deviation (SD) of BIC AUCtau is no more than 0.34 on a natural 
logarithm scale, which is supported by a pooled PK analysis from 4 previous Gilead B/F/TAF 
Phase 3 studies. With 25% overage, a total sample size of at least 25 participants will be 
required.


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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 ICH E6(R2) Good 
Clinical Practices and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide 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.
9.1.3.
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 any modifications made to the protocol or any accompanying material to be provided to the 
subject after initial approval, with the exception of those necessary to reduce immediate risk to 
study participants.
9.1.4.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study, including the infants who may enroll, after adequate explanation of 
the aims, methods, objectives, and potential hazards of the study and before undertaking any 
study-related procedures. The investigator must use the most current IRB- or IEC-approved 
consent form for documenting written informed consent. Each informed consent will be 
appropriately signed and dated by the subject or the subject’s legally authorized representative 
and the person conducting the consent discussion, and also by an impartial witness if required by 
local requirements. The consent form will inform participants about pharmacogenomic testing 


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and sample retention, and their right to receive clinically relevant pharmacogenomic analysis 
results.
9.1.5.
Confidentiality
The investigator must assure that participants’ anonymity will be strictly maintained and that 
their identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to the Sponsor or laboratory. Laboratory specimens must be 
labeled in such a way as to protect subject identity while allowing the results to be recorded to 
the proper subject. Refer to specific laboratory instructions. NOTE: The investigator must keep a 
screening log showing codes, names, and addresses for all participants screened and for all 
participants 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’s brochure, this protocol, eCRF, the IMP, and any other study information, remain 
the sole and exclusive property of Gilead during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.6.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);


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


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9.1.7.
Case Report Forms
For each subject consented, an eCRF casebook will be completed by an authorized study staff 
member whose training for this function is completed in EDC. The eCRF casebook will only 
capture the data required per the protocol schedule of events and procedures. The 
Inclusion/Exclusion Criteria and Enrollment eCRFs should be completed only after all data 
related to eligibility have been received. Subsequent to data entry, a study monitor will perform 
source data verification within the EDC system. System-generated or manual queries will be 
issued to the investigative site staff as data discrepancies are identified by the monitor or internal 
Gilead staff, who routinely review the data for completeness, correctness, and consistency. The 
site coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and providing the 
reason for the update (e.g. data entry error). Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to any interim time points or database lock 
(as instructed by Gilead), the investigator will use his/her log in credentials to confirm that the 
forms have been reviewed, and that the entries accurately reflect the information in the source 
documents. At the conclusion of the trial, Gilead will provide the site with a read-only archive 
copy of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.6.
9.1.8.
Investigational Medicinal Product Accountability and Return
Where possible, IMP should be destroyed at the site. If the site has an appropriate SOP for drug 
destruction as determined by Gilead, the site may destroy used (empty or partially empty) and 
unused IMP supplies in accordance with that site’s approved SOP. A copy of the site’s approved 
SOP will be obtained for central files. If IMP is destroyed on site, the investigator must maintain 
accurate records for all IMP destroyed. Records must show the identification and quantity of 
each unit destroyed, the method of destruction, and the person who disposed of the IMP. Upon 
study completion, copies of the IMP accountability records must be filed at the site. Another 
copy will be returned to Gilead. 
If the site does not have an appropriate SOP for drug destruction, used and unused IMP supplies 
are to be sent to the designated disposal facility for eventual destruction. The study monitor will 
provide instructions for return.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs, or to regulatory authority or health authority 
inspectors.
9.1.10.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.


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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study participants, 
may be made only by Gilead. The investigator must submit all protocol modifications to the IRB
in accordance with local requirements and receive documented approval before modifications 
can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) may be prepared and provided to the regulatory agency. Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.5).
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.


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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.
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 participants’ interests.


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10.
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Isoherranen N, Thummel KE. Drug Metabolism and Transport During Pregnancy: How Does 
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Jeong S, Nguyen PD, Desta Z. Comprehensive in vitro analysis of voriconazole inhibition of 
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Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Aids Update 2016. Available 
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significance, challenges, and opportunities [Author Manuscript]. Current 
HIV/AIDS reports 2011;8 (1):62-72.


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Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical 
relevance. Clin Pharmacokinet 1997;33 (5).
Lutz J, Shao Y, Ling J, Custodio J, Martin H, Quirk E, et al. Bictegravir/Emtricitabine/Tenofovir 
Alafenamide Phase 3 Exposure-Response Analysis of Safety and Efficacy in the 
Treatment of HIV Infection [Poster 6]. 19th International Workshop on Clinical 
Pharmacology of Antiviral Therapy, May 22–24; 2018 May 22–24; Baltimore, 
Maryland. 
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of 
mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. 
Lancet 1998;352 (9142):1725-30.
Mulligan N, Best BM, Wang J, Capparelli EV, Stek A, Barr E, et al. Dolutegravir 
Pharmacokinetics in Pregnant and Postpartum Women Living with HIV. AIDS
2018;32 (6):729-37.
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining 
Morbidity and Mortality Among Patients With Advanced Human 
Immunodeficiency Virus Infection. N Eng J Med 1998;338 (13):853-60.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of 
Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of 
Health and Human Services. Available at 
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Last 
Updated : 27 March.  2018.
Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal 
Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant 
Women with HIV Infection and Interventions to Reduce Perinatal HIV 
Transmission in the United States. Available at: 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Last Updated: 7 
December.  2018.
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.
Stek A, Best B, Luo W, Capparelli E, Burchett S, Hu C, et al. Effect of pregnancy on 
emtricitabine pharmacokinetics. HIV Med 2012;13 (4):226-35.
Sterne J, Hernán M, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Long-term effectiveness 
of potent antiretroviral therapy in preventing AIDS and death: a prospective 
cohort study. Lancet 2005;366 (9483):378-84.


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Sterrantino G, Santoro L, Bartolozzi D, Trotta M, Zaccarelli M. Self-reported adherence supports 
patient preference for the single tablet regimen (STR) in the current cART era. 
Patient preference and adherence 2012;6:427-33.
Watts D, Stek A, Best B, Wang J, Capparelli E, Cressey T, et al. Raltegravir Pharmacokinetics 
during Pregnancy [Author Manuscript]. J Acquir Immune Defic Syndr. 2014;67 
(4):375-81.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Maternal and Neonatal Study Procedures Tables
Appendix 3.
Management of Clinical and Laboratory Adverse Events
Appendix 4.
GSI Grading Scale for Severity of Adverse Events and Laboratory Abnormalities
Appendix 5.
Definitions of Stage 3 Opportunistic Illnesses in HIV (CDC Guidelines)
Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing Potential and 
Postpartum Contraceptive Requirements




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Appendix 2.
Maternal and Neonatal Study Procedures Tables
Maternal Study Procedures Table
Study Procedure
Screening
Day 1
Visits before the delivery
Delivery 
Visitj
Post-partum Visit
30-Day 
Follow-up Visit
ESDD
Week 4
Weeks 8, 12, 16, 
20 & 24 
(dependent on 
time of 
enrollment)a
Week 6
Week 12
Written Informed 
Consent
X
Medical History
X
Complete Physical 
Examinationb
X
X
X
Xb
X
X
X
ECG
X
Symptom-directed 
Physical Examinationc
Xc
X
Vital Signs (including 
weight)
X
X
X
X
X
X
X
X
Height
X
Laboratory 
Assessmentsd
X
X
Xd
X
X
X
X
Maternal alfa-
fetoprotein level
X
Urine Pregnancy Teste
X
X
X
X
eGFRf
X
X
Xe
X
X
HIV-1 RNA
X
X
X
X
X
X
X
X
X


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Study Procedure
Screening
Day 1
Visits before the delivery
Delivery 
Visitj
Post-partum Visit
30-Day 
Follow-up Visit
ESDD
Week 4
Weeks 8, 12, 16, 
20 & 24 
(dependent on 
time of 
enrollment)a
Week 6
Week 12
Whole Blood Sample 
for HIV-1 Genotypingg
X
CD4+ cell count
X
X
X
HBV and HCV Testing
X
Ultrasoundh
X
Intensive PK Sample 
Collectioni, j
X
X
X
X
Sparse PK Sample 
Collectionk
X
Plasma Storage Sample
X
X
X
X
X
X
PBMC Sample 
Collectionl
X
X
X
X
Drug and Alcohol 
Screening
X
X
Adverse Event and 
Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Date of Delivery
X
Pregnancy outcome
X
B/F/TAF Dispensation
X
X
X
X
X
B/F/TAF 
Accountability
X
X
X
X
X


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a.
After completion of the Week 4 visit, participants will be required to come back for a study visit every 4 weeks (Weeks 8, 12, 16, 20, 24 dependent on time of enrollment and 
time of delivery). Study visits may be completed within ± 2 days of protocol-specified visit date. 
b.
A complete physical examination will be completed at Day 1, Week 4, Week 12 and Weeks 6 and 12 post-partum visits, and at the ESDD visit. 
c.
A symptom directed physical examination will be completed at Weeks 8, 16, 20 and 24 visits and at the 30-Day Follow-up Visit.
d.
Clinical laboratory assessments include hematology, chemistry and urinalysis which will be completed at Screening, Day 1, Weeks 12 and 24, Weeks 6 and 12 post-partum
visits, 30-Day Follow-up Visit and ESDD Visit. 
e.
Urine pregnancy testing will be completed at the ESDD if it is clinical appropriate and the subject is in the post-partum phase of the study.
f.
eGFR will be calculated at Screening, Day 1, Weeks 12 and 24, and Weeks 6 and 12 post-partum visits.
g.
Sample may be collected at Screening OR Day 1.
h.
Ultrasound should be completed prior to the Day 1 visit. An ultrasound completed prior to the screening visit is acceptable.
i.
Before delivery, Intensive PK sample collection will be completed after subject administers B/F/TAF for at-least 3 weeks. For participants enrolled during the second 
trimester, iPK sample collection will be completed at or between 20 to 28 weeks of gestation and at or between 30 to 38 weeks of gestation. For participants enrolled during 
the third trimester, iPK sample collection will be completed at or between 30 to 38 weeks of gestation.
j.
After delivery, iPK sample collection will be completed at Week 6 and Week 12 post-partum visits.
k.
A single maternal blood sample and an umbilical cord sample after cord clamping will be collected at the time of delivery (Delivery Visit).
l.
For participants enrolled at sites that can process PBMC samples, a trough PBMC sample will be collected 24 hours following the in-clinic dose administered at the iPK 
visits.
m.
The day of delivery will be considered as the Delivery Visit for study purposes.
Neonatal Study Procedures Table
Study Procedure
Delivery Visit
4-8 Weeks of age
Complete Physical Examination
X
X
Vital signs
X
X
Apgar scoren
X
Anthropometric measureso
X
X
HIV-1 RNA and Safety Assessmentsp
X
X
Sparse PK Sample Collectionq
X
n.
Apgar score will be collected if it is recorded at the time of birth per standard of care
o.
Head circumference, weight and length at birth and 4-8 weeks of age will be collected
p.
HIV-1 RNA and safety assessments which includes CBC, LFTs (ALT, AST, total and direct bilirubin) may be completed using the sparse PK samples collected on the day of 
birth, if there is sufficient volume. If blood volume is insufficient, results from testing performed per standard of care will be obtained. HIV-1 RNA and safety assessments 
will also be completed at 4-8 weeks of age if possible or results from testing performed per standard of care will be obtained. 
q.
Sparse PK blood samples will be collected at the following time points, if possible: at or between 0 to < 2 hours, 2 to < 3 hours, 3 to 8 hours, 18 to 28 hours, 36 to 72 hours, 
and 5 to 7 days after birth. These time points may vary based on birth weight, additional instructions will be included in the Pharmacokinetic Sample Collection and 
Processing Instructions Manual.


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Appendix 3.
Management of Clinical and Laboratory Adverse Events
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 


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


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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 participants.  Please follow the Gilead convention of 
grading any result within the lower limit of the normal range (LLN) and ULN a 0.


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia 
130 to <LLN mEq/L
125 to 130 mEq/L
121 to 125 mEq/L
121 mEq/L
130 to <LLN mmol/L
125 to 130 mmol/L
121 to 125 mmol/L
121 mmol/L
Hypernatremia 
>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/dL51681 
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


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CHEMISTRY
Grade 1
Grade 2
Grade 3
Grade 4
Hyperglycemia, Fasting
110 to 125 mg/dL
6.08 to 6.96 mmol/L
>125 to 250 mg/dL
>6.96 to 13.90 mmol/L
>250 to 500 mg/dL
>13.90 to 27.79 mmol/L
>500 mg/dL
>27.79 mmol/L
Hypocalcemia 
(corrected for albumin if 
appropriate*)
Adult and Pediatric
2 Years
7.8 <LLN mg/dL
1.94 to <LLN mmol/L
7.0 to 7.8 mg/dL
1.74 to 1.94 mmol/L
6.1 to 7.0 mg/dL
1.51 to 1.74 mmol/L
6.1 mg/dL
1.51 mmol/L
Pediatric ≥7 days -2 Years
7.8 to 8.4 mg/dL
1.94 to 2.10 mmol/L
7.0 to <7.8 mg/dL 
1.74 to <1.94 mmolL
6.1 to  <7.0 mg/dL
1.51 to < 1.74 mmolL
< 6.1 mg/dL
< 1.51 mmol/L
Infant, 7 Days
6.5 to 7.5 mg/dL
1.61 to 1.88  mmol/L
6.0 to 6.5 mg/dL
1.49 to < 1.61 mmol/L
5.5 to 6.0 mg/dL
1.36 to < 1.49 mmol/L 
5.5 mg/dL
< 1.36 mmol/L
Hypercalcemia (corrected 
for albumin if appropriate*)
Adult and Pediatric 
7 Days
>ULN to 11.5 mg/dL
11.5 to 12.5 mg/dL
12.5 to 13.5 mg/dL
13.5 mg/dL
>ULN to 2.88 mmol/L
2.88 to 3.13 mmol/L
3.13 to 3.38 mmol/L
3.38 mmol/L
Infant, 7 Days
11.5 to 12.4 mg/dL
2.86 to 3.10  mmol/L
12.4 to 12.9 mg/dL
> 3.10 to 3.23  mmol/L
12.9 to 13.5 mg/dL
> 3.23 to 3.38  mmol/L
13.5 mg/dL
> 3.38 mmol/L
Hypocalcemia (ionized)
3.0 mg/dL to LLN
2.5 to < 3.0 mg/dL
2.0 to 2.5 mg/dL
2.0 mg/dL
0.74 mmol/L to LLN
0.62 to 0.74 mmol/L
0.49 to 0.62 mmol/L
0.49 mmol/L
Hypercalcemia (ionized)
ULN to 6.0 mg/dL
6.0 to 6.5 mg/dL
6.5 to 7.0 mg/dL
7.0 mg/dL
ULN to 1.50 mmol/L
1.50 to 1.63 mmol/L
1.63 to 1.75 mmol/L
1.75 mmol/L
Hypomagnesemia
1.40 to  <LLN mg/dL
1.2 to <LLN mEq/L
1.04 to 1.40 mg/dL
0.9 to   1.2 mEq/L
0.67 to 1.04 mg/dL
0.6 to 0.9 mEq/L
0.67 mg/dL
0.6 mEq/L
0.58 to <LLN mmol/L
0.43 to 0.58 mmol/L
0.28 to 0.43 mmol/L
0.28 mmol/L


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


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


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


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


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


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


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


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


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


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


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


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


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


B/F/TAF
Protocol GS-US-380-5310
Final
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Original
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SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Acute Systemic Allergic 
Reaction 
Localized urticaria 
(wheals) with no medical 
intervention indicated
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
bronchospasm
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR laryngeal 
edema
Chills
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & 
functional activities
NA
Fatigue
Malaise
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities
Symptoms causing greater than 
minimal interference with usual 
social & functional activities
Symptoms causing inability to 
perform usual social & 
functional activities
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care 
functions
Fever (nonaxillary)
37.7C to 38.6C
99.8F to 101.5F
38.7C to 39.3C
101.6F to 102.8F
39.4C to 40.5C
102.9F to 104.9F
40.5C 
104.9F
Pain- Indicate Body Site
See also Injection Site 
Pain, Headache, 
Arthralgia, and Myalgia
Pain causing no or 
minimal interference with 
usual social & functional 
activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to 
perform usual social & 
functional activities
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other than ER 
visit) indicated
Unintentional Weight 
Loss
NA
5% to 9% loss in body weight from 
baseline
10% to 19% loss in body 
weight from baseline
20% loss in body weight 
from baseline OR  Aggressive 
intervention indicated 
[eg, tube feeding or total 
parenteral nutrition]


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


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Protocol GS-US-380-5310
Final
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Original
CONFIDENTIAL
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ENDOCRINE/METABOLIC
Grade 1
Grade 2
Grade 3
Grade 4
Lipodystrophy (eg, back 
of neck, breasts, 
abdomen)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious 
changes on casual visual 
inspection
NA
Diabetes Mellitus
NA
New onset without need to initiate 
medication OR Modification of 
current meds to regain glucose 
control
New onset with initiation of 
indicated med OR Diabetes 
uncontrolled despite treatment 
modification
Life-threatening consequences 
(eg, ketoacidosis, 
hyperosmolar non-ketotic 
coma) 
Gynecomastia
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA
Hyperthyroidism 
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid suppression therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, thyroid storm)
Hypothyroidism
Asymptomatic
Symptomatic causing greater than 
minimal interference with usual 
social & functional activities OR 
Thyroid replacement therapy 
indicated
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification 
Life-threatening consequences 
(eg, myxedema coma)
Lipoatrophy (eg, fat loss 
from the face, extremities, 
buttocks)
Detectable by study 
participant or caregiver 
(for young children and 
disabled adults)
Detectable on physical exam by 
health care provider
Disfiguring OR Obvious on 
casual visual inspection
NA


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


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


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


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Original
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Appendix 6.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential and Postpartum 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.
2) Post-partum Contraception Requirements for Female Participants
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Data from clinical pharmacokinetic interaction studies of B/F/TAF have demonstrated that there 
is no reduction in the clinical efficacy of hormonal contraception. Non-clinical toxicity studies of 
B/F/TAF have demonstrated no adverse effect on fertility or embryo-fetal development. 
However, there are currently no other clinical studies of B/F/TAF in pregnant women.  Please 
refer to the latest version of the investigator’s brochure for additional information.
b. Post-partum Contraception Requirements for Female Participants of Childbearing 
Potential
The inclusion of female Participants of childbearing potential requires using at least an 
acceptable effective contraceptive measure during the postpartum period until the end of study. 
The appropriate contraceptive measure and timing of initiation for women who are postpartum 
should be discussed with the healthcare provider managing the patient in the postpartum period. 
In the event of a delayed menstrual period after the resumption of menses in the postpartum 
period (over one month between menstruations), a pregnancy test must be performed to rule out 
pregnancy.  This is even true for women of childbearing potential with infrequent or irregular 
periods.  They must also agree to one of the following from postpartum until 7 days after the last 
dose of study drug.
Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual lifestyle.
Or


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Consistent and correct use of 1 of the following methods of birth control listed below. 

Intrauterine device (IUD) with a failure rate of <1% per year

Intrauterine hormone-releasing system (IUS) with a failure rate of <1% per year

Tubal sterilization

Essure micro-insert system (provided confirmation of success 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)

Barrier methods (one female barrier and one male barrier must be used in combination)
Female barriers: Diaphragm with spermicide or Cervical cap with spermicide
Male barriers: Male condom (with or without spermicide)

Hormonal methods
Oral contraceptives (either combined or progesterone only)
Injectable progesterone
Implants of levonorgestrel
Transdermal contraceptive patch
Contraceptive vaginal ring
Participants must also refrain from egg donation and in vitro fertilization during treatment and 
until at least 7 days after the last dose of study drug.
3) Unacceptable Birth Control Methods During the Post-partum Period
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.
4) Procedures to be Followed in the Event of Pregnancy During the Post-partum Period
Participants will be instructed to notify the investigator if they become pregnant during the 
post-partum period of the study, or if they become pregnant within 7 days of last study drug 
dose. Participants who become pregnant or who suspect that they are pregnant during the 
post-partum period must report the information to the investigator and discontinue study drug 
immediately. Instructions for reporting pregnancy and pregnancy outcomes that occur during the 
post-partum period of the study are outlined in Section 7.7.2.1.

SAP_001.pdf: 
B/ F/ T A F
G S- U S- 3 8 0- 5 3 1 0
Statistical A nal ysis Pla n – Fi nal A nal ysis
Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 1
1 5 N o v 2 0 2 2
S T A TI S TI C A L A N A L Y SI S P L A N
St u d y Title:
A P hase 1 b, O pe n-la bel st u d y t o E val uate t he P K, Safet y a n d 
Efficac y of B/ F/ T A F i n HI V- 1 i nfecte d, Vir ol o gicall y 
S u p presse d, Pre g na nt W o me n i n t heir Sec o n d a n d T hir d 
Tri mesters
St u d y P h ase:
1 b
N a me of Test Dr u g: 
Bicte gra vir/ E mtricita bi ne/ Te n ofi vir Alafe na mi de ( B/ F/ T A F; 
G S- 9 8 8 3/ F/ T A F)
St u d y N u m ber:
G S- U S- 3 8 0- 5 3 1 0
Pr ot oc ol Versi o n ( D ate): 
Ori gi nal ( 0 2 A pril 2 0 1 9)
A n al ysis T y pe:
Fi nal A nal ysis
A n al ysis Pl a n Versi o n: 
Versi o n 1. 0
A n al ysis Pl a n D ate: 
1 5 N o v 2 0 2 2
A n al ysis Pl a n A ut h or(s):
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N
 
 
P P D
P P D




B/ F/ T A F
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C O N FI D E N TI A L
Pa ge 3
1 5 N o v 2 0 2 2
4. 2. 2.   
A d here nce t o St u d y Dr u g Re gi me n....................................................................................... 2 5
4. 3.  
Pr ot oc ol De viati o ns................................................................................................................................. 2 6
4. 4.   
Assess me nt of C O VI D- 1 9 I m pact........................................................................................................... 2 7
4. 4. 1.  
St u d y Dr u g or St u d y Disc o nti n uati o n D ue t o C O VI D- 1 9..................................................... 2 7
4. 4. 2.  
Pr ot oc ol De viati o ns D ue t o C O VI D- 1 9 ................................................................................ 2 7
4. 4. 3.   
Misse d a n d Virt ual Visits D ue t o C O VI D- 1 9 ....................................................................... 2 7
4. 4. 4.   
A d verse E ve nts D ue t o C O VI D- 1 9....................................................................................... 2 7
5.  
B A S E LI N E C H A R A C T E RI S TI C S..................................................................................................................... 2 8
5. 1.   
De m o gra p hics a n d Baseli ne C haracteristics ........................................................................................... 2 8
5. 2.   
Ot her Baseli ne C haracteristics ................................................................................................................ 2 8
5. 3.   
Me dical Hist or y....................................................................................................................................... 2 9
6.  
E F FI C A C Y A N A L Y S E S..................................................................................................................................... 3 0
6. 1.  
Efficac y E n d p oi nts .................................................................................................................................. 3 0
6. 2.   
A nal ysis of t he Efficac y E n d p oi nts......................................................................................................... 3 0
6. 2. 1.   
A nal ysis of C D 4 + Cell C o u nt................................................................................................ 3 1
6. 2. 2.   
A nal ysis of C D 4 %................................................................................................................. 3 1
6. 3.  
C ha n ges Fr o m Pr ot oc ol- S pecifie d Efficac y A nal yses ............................................................................ 3 1
7.  
S A F E T Y A N A L Y S E S......................................................................................................................................... 3 2
7. 1.   
A d verse E ve nts a n d Deat hs..................................................................................................................... 3 2
7. 1. 1.   
A d verse E ve nt Dicti o nar y ..................................................................................................... 3 2
7. 1. 2.   
A d verse E ve nt Se verit y......................................................................................................... 3 2
7. 1. 3.  
Relati o ns hi p of A d verse E ve nts t o St u d y Dr u g..................................................................... 3 2
7. 1. 4.  
Relati o ns hi p of A d verse E ve nts t o St u d y Pr oce d ure............................................................. 3 2
7. 1. 5.  
Seri o us A d verse E ve nts......................................................................................................... 3 2
7. 1. 6.  
Treat me nt- E mer ge nt A d verse E ve nts.................................................................................... 3 3
7. 1. 6. 1.   
Defi niti o n of Treat me nt E mer ge nt A d verse E ve nts ........................................ 3 3
7. 1. 6. 2.  
I nc o m plete Dates............................................................................................. 3 3
7. 1. 7.  
S u m maries of A d verse E ve nts a n d Deat hs............................................................................ 3 3
7. 1. 7. 1.  
Treat me nt-e mer ge nt A d verse E ve nts f or a d ult partici pa nts............................ 3 4
7. 1. 7. 2.   
A d verse E ve nts f or ne o nate partici pa nts ......................................................... 3 5
7. 1. 8.   
A d diti o nal A nal ysis of A d verse E ve nts ................................................................................ 3 6
7. 1. 8. 1.   
A Sta ge 3 O p p ort u nistic Ill nesses i n HI V........................................................ 3 6
7. 2.  
La b orat or y E val uati o ns ........................................................................................................................... 3 6
7. 2. 1.  
S u m maries of N u meric La b orat or y Res ults.......................................................................... 3 7
7. 2. 2.   
Gra de d La b orat or y Val ues .................................................................................................... 3 7
7. 2. 2. 1.  
Treat me nt- E mer ge nt La b orat or y A b n or malities ............................................. 3 8
7. 2. 2. 2.  
S u m maries of La b orat or y A b n or malities ........................................................ 3 8
7. 2. 3.  
Li ver- Relate d La b orat or y E val uati o ns.................................................................................. 3 9
7. 2. 4.  
Re nal- Relate d La b orat or y E val uati o ns.................................................................................. 3 9
7. 2. 4. 1.  
Ser u m Creati ni ne a n d e G F R C G ........................................................................ 3 9
7. 3.  
B o d y Wei g ht, Hei g ht, B MI, a n d Vital Si g ns........................................................................................... 4 0
7. 4.  
Pri or a n d C o nc o mita nt Me dicati o ns........................................................................................................ 4 0
7. 4. 1.   
N o nst u d y Dr u g A ntiretr o viral Me dicati o ns........................................................................... 4 0
7. 4. 2.  
C o nc o mita nt N o n- A R V Me dicati o ns.................................................................................... 4 0
7. 5.  
Electr ocar di o gra m Res ults....................................................................................................................... 4 1
7. 6.   
Ot her Safet y Meas ures ............................................................................................................................ 4 1
7. 7.  
C ha n ges Fr o m Pr ot oc ol- S pecifie d Safet y A nal yses................................................................................ 4 1
8.  
P H A R M A C O KI N E TI C E V A L U A TI O N/ A N A L Y SI S........................................................................................ 4 2
8. 1.  
Esti mati o n of P har mac o ki netic Para meters............................................................................................. 4 2
8. 2.  
P har mac o ki netic Para meters ................................................................................................................... 4 2


B/ F/ T A F
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C O N FI D E N TI A L
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8. 3.  
Statistical A nal ysis Met h o ds ................................................................................................................... 4 3
8. 3. 1.   
Ge neral C o nsi derati o ns ......................................................................................................... 4 3
8. 3. 2.  
Statistical Met h o d ol o g y......................................................................................................... 4 5
8. 4.  
Se nsiti vit y A nal ysis................................................................................................................................. 4 7
9.  
R E F E R E N C E S..................................................................................................................................................... 4 8
1 0. 
S O F T W A R E......................................................................................................................................................... 4 9
1 1. 
S A P R E VI SI O N................................................................................................................................................... 5 0
A P P E N DI C E S .............................................................................................................................................................. 5 1
A p pe n di x 1.   
Mater nal a n d Ne o natal St u d y Pr oce d ures Ta bles.................................................................. 5 1
A p pe n di x 2.   
A d verse E ve nts of C O VI D- 1 9 a n d S us pecte d C O VI D- 1 9 I nfecti o n.................................... 5 4
A p pe n di x 3.   
Data C ollecti o n of C O VI D- 1 9 Data...................................................................................... 5 5
A p pe n di x 4.  
Pr o gra m mi n g S pecificati o n................................................................................................... 5 6
 


B/ F/ T A F
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LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A Q L
a b o ve q ua ntitati o n li mit
A R V
A ntiretr o viral
A S T
as partate a mi n otra nsferase
B E
bi oe q ui vale nce
B/ F/ T A F 
bicte gra vir/e mtricita bi ne/ te n of o vir alafe na mi de, Bi ktar v y ®
BI C
bicte gra vir, B, G S- 9 8 8 3
B L Q
bel o w t he li mit of q ua ntitati o n
B MI
b o d y mass i n de x
C F R
C o de of Fe deral Re g ulati o ns
CI
c o nfi de nce i nter val
C R F
case re p ort f or m
C S R
cli nical st u d y re p ort
C T C A E 
C o m m o n T o xicit y Criteria f or A d verse E ve nts
D M C
data m o nit ori n g c o m mittee
E C G
electr ocar di o gra m
E T
earl y ter mi nati o n
E V G
el vite gra vir, E
F A S
F ull a nal ysis set
F D C
fi xe d d ose c o m bi nati o n
F T C
e mtricita bi ne
Gilea d 
Gilea d Scie nces
G L S M 
ge o metric least-s q uares mea n
H b
he m o gl o bi n
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n ( of Tec h nical Re q uire me nts f or Re gistrati o n of 
P har mace uticals f or H u ma n Use)
L L O Q 
l o wer li mit of q ua ntitati o n
Me d D R A 
Me dical Dicti o nar y f or Re g ulat or y Acti vities
P K
p har mac o ki netic
P P
per pr ot oc ol
P T
preferre d ter m
Q 1, Q 3 
first q uartile, t hir d q uartile
S A P
statistical a nal ysis pla n
S D
sta n dar d de viati o n
SI 
I nter nati o nal S yste m of U nits ( S yste me I nter nati o nal d’ U nites)
S O C
s yste m or ga n class
T A F
te n of o vir alafe na mi de
T E A E 
treat me nt-e mer ge nt a d verse e ve nt


B/ F/ T A F
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C O N FI D E N TI A L
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T F Ls
ta bles, fi g ures, a n d listi n gs
T F V- D P 
te n of o vir di p h os p hate
U L O Q 
u p per li mit of q ua ntificati o n
U L N
u p per li mit of n or mal
V R
ve ntric ular rate
W H O
W orl d Healt h Or ga nizati o n


B/ F/ T A F
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P H A R M A C O KI N E TI C A B B R E VI A TI O N S
z
ter mi nal eli mi nati o n rate c o nsta nt, esti mate d b y li near re gressi o n of t he ter mi nal 
eli mi nati o n p hase of t he l o g plas ma/ser u m c o nce ntrati o n of dr u g vers us ti me c ur ve of t he 
dr u g
A U C
area u n der t he plas ma/ser u m c o nce ntrati o n vers us ti me c ur ve
% A U C
e x p
Perce nta ge of A U C e xtra p olate d bet wee n A U C last a n d A U Ci nf
A U C i nf
area u n der t he plas ma/ser u m c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o i nfi nit y
A U C last
area u n der t he plas ma/ser u m c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o t he last 
q ua ntifia ble c o nce ntrati o n
A U C ta u
area u n der t he plas ma/ser u m c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o ta u ( d osi n g 
i nter val)
C L ss/ F
a p pare nt cleara nce after a d mi nistrati o n of t he dr u g at stea d y state:
C L ss/ F = D ose/ A U C0-ta u, w here “ D ose” is t he d ose of t he dr u g
C last
last o bser ve d q ua ntifia ble plas ma/ser u m c o nce ntrati o n of t he dr u g
C ma x
ma xi m u m o bser ve d plas ma/ser u m c o nce ntrati o n of dr u g
t½
esti mate of t he a p pare nt ter mi nal half-life of t he dr u g i n plas ma/ser u m, calc ulate d b y 
di vi di n g t he nat ural l o g of 2 b y t he ter mi nal eli mi nati o n rate c o nsta nt ( z)
T last
ti me ( o bser ve d ti me p oi nt) of Clast
T ma x
ti me ( o bser ve d ti me p oi nt) of Cma x
V z/ F
A p pare nt v ol u me of distri b uti o n of t he dr u g




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1. 2.  
St u d y E n d p oi nts
T he pri mar y e n d p oi nt of t his st u d y is:

T he P K para meter A U C ta u of BI C d uri n g t he sec o n d a n d/ or t hir d tri mesters t hr o u g h 
p ost- part u m
T he sec o n dar y e n d p oi nts of t his st u d y are:

T he P K para meter A U C ta u f or F T C a n d T A F, a n d P K para meters A U Clast, Cma x , Cta u,  Clast, 
T ma x , T1/ 2, C L/ F, Vz/ F, a n d λz f or BI C, F T C, a n d T A F, as a p plica ble

T he pr o p orti o n of partici pa nts wit h plas ma HI V- 1 R N A < 5 0 c o pies/ m L at t he ti me of 
deli ver y b y missi n g = e xcl u de d a p pr oac h
1. 3.  
St u d y Desi g n
T his is a n o pe n-la bel, m ultice nter, m ulti ple- d ose st u d y t o e val uate t he P K, efficac y, safet y a n d 
t olera bilit y of B/ F/ T A F i n vir ol o gicall y s u p presse d, HI V- 1 i nfecte d pre g na nt w o me n i n t heir 
sec o n d a n d t hir d tri mesters.
At least 2 5 partici pa nts will be e nr olle d t o o btai n at least 2 0 e val ua ble pairs of P K assess me nts 
bet wee n t he sec o n d tri mester a n d p ost- part u m a n d at least 2 0 e val ua ble pairs of P K assess me nts 
bet wee n t he t hir d tri mester a n d p ost- part u m. Re place me nt partici pa nts ma y be e nr olle d if 
ori gi nall y e nr olle d partici pa nts d o n ot c o m plete all i nte nsi ve P K visits as e x pecte d.
I nfa nts b or n t o w o me n partici pati n g i n t he st u d y will be f oll o we d fr o m birt h t o 4- 8 wee ks of a ge 
if c o nse nt is o btai ne d fr o m t he pare nts/le gal g uar dia n.
Partici pa nts will be treate d wit h B/ F/ T A F f or u p t o a p pr o xi matel y 3 8 wee ks (fr o m t he sec o n d or 
t hir d tri mesters of pre g na nc y, de pe n di n g o n e nr oll me nt, t hr o u g h 1 2 wee ks p ost- part u m). 
Partici pa nts w h o c o m plete t he st u d y t hr o u g h t he Wee k 1 2 p ost- part u m visit will be re q uire d t o 
ret ur n t o t he cli nic 3 0 da ys after t he Wee k 1 2 p ost- part u m visit f or a 3 0- Da y F oll o w- U p Visit.
M A T E R N A L
F oll o wi n g c o m pleti o n of Scree ni n g a n d Da y 1 visits, eli gi ble partici pa nts will be re q uire d t o 
ret ur n f or st u d y visits at Wee ks 4, 8, 1 2, 1 6, 2 0 a n d 2 4 de pe n de nt o n ti me of e nr oll me nt ( u nless 
deli ver y has occ urre d b y t hat ti me p oi nt). T he da y of deli ver y will be c o nsi dere d as t he Deli ver y 
Visit f or st u d y p ur p oses.
F oll o wi n g deli ver y, partici pa nts will be re q uire d t o ret ur n f or st u d y visits f or Wee ks 6 a n d 1 2 
p ost- part u m visits a n d a 3 0- Da y F oll o w- u p Visit.
F or all eli gi ble partici pa nts, bl o o d sa m ples will be c ollecte d at Da y 1 a n d all s u bse q ue nt visits.
F or all eli gi ble partici pa nts, uri ne sa m ples will be c ollecte d at Da y 1, Wee ks 1 2 a n d 2 4, a n d 
Wee ks 6 a n d 1 2 p ost- part u m visits.








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2.  
T Y P E O F P L A N N E D A N A L Y SI S
2. 1.  
I nteri m A n al ysis
2. 1. 1 
Pl a n ne d I nteri m A n al ysis
N o i nteri m a nal ysis is pla n ne d.
2. 1. 2
 D at a M o nit ori n g C o m mittee A n al yses
T his st u d y d oes n ot ha ve a data m o nit ori n g c o m mittee ( D M C). T heref ore, n o a nal yses will be 
c o n d ucte d f or t he D M C.
2. 2.  
Fi n al A n al ysis
After all partici pa nts ha ve c o m plete d t he st u d y, o utsta n di n g data q ueries ha ve bee n res ol ve d or 
a dj u dicate d as u nres ol va ble, a n d t he data ha ve bee n clea ne d a n d fi nalize d, t he fi nal a nal ysis of 
t he data will be perf or me d. T he a nal ysis of t he pri mar y e n d p oi nt will be c o n d ucte d at t he ti me of 
t he fi nal a nal ysis.
2. 3.   
C h a n ges fr o m Pr ot oc ol- S pecifie d A n al ysis
N o c ha n ges fr o m pr ot oc ol-s pecifie d a nal yses are pla n ne d.


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3.   
G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y S E S
A nal ysis res ults will be prese nte d usi n g descri pti ve statistics. F or cate g orical varia bles, t he 
n u m ber a n d perce nta ge of partici pa nts i n eac h cate g or y will be prese nte d; f or c o nti n u o us 
varia bles, t he n u m ber of partici pa nts ( n), mea n, sta n dar d de viati o n ( S D) or sta n dar d err or ( S E), 
me dia n, first q uartile ( Q 1), t hir d q uartile ( Q 3), mi ni m u m, a n d ma xi m u m will be prese nte d.
B y-s u bject listi n gs will be prese nte d f or all partici pa nts i n t he All E nr olle d A nal ysis Set, a n d 
s orte d b y partici pa nt i de ntificati o n (I D) n u m ber i n asce n di n g or der, visit date, a n d ti me 
(if a p plica ble), u nless ot her wise s pecifie d. Data c ollecte d o n l o g f or ms, s uc h as A Es, will be 
prese nte d i n c hr o n ol o gical or der wit hi n partici pa nt. A ge, se x at birt h, race, a n d et h nicit y will be 
i ncl u de d i n t he listi n gs, as s pace per mits. 
I n ge neral, f or a d ult partici pa nts, a ge (i n years) o n t he date of t he first d ose of st u d y dr u g will be 
use d f or a nal yses a n d prese ntati o n i n listi n gs. If o nl y birt h year is c ollecte d o n t he e C R F, 
“ 0 1 Ja n uar y” will be use d f or t he u n k n o w n birt h da y a n d m o nt h f or t he p ur p ose of a ge 
calc ulati o n, si milarl y, if o nl y birt h year a n d m o nt h are c ollecte d o n t he e C R F, “ 0 1” will be use d 
f or t he u n k n o w n birt h da y f or t he p ur p ose of a ge calc ulati o n. A ge is set as 1 da y f or Ne o nate 
partici pa nts at e nr oll me nt.
I n ge neral, per ma ne nt disc o nti n uati o n of st u d y dr u g refers t o pre mat ure disc o nti n uati o n of st u d y 
dr u g or c o m pleti o n of st u d y dr u g.
3. 1.   
A n al ysis Sets
A nal ysis sets defi ne t he partici pa nts t o be i ncl u de d i n a n a nal ysis. A nal ysis sets a n d t heir 
defi niti o ns are pr o vi de d i n t his secti o n. T he a nal ysis set will be i de ntifie d a n d i ncl u de d as a 
s u btitle of eac h ta ble, fi g ure, a n d listi n g.
F or eac h a nal ysis set, t he n u m ber a n d perce nta ge of partici pa nts eli gi ble f or i ncl usi o n will be 
s u m marize d. A listi n g of reas o ns f or e xcl usi o n fr o m a nal ysis sets will be pr o vi de d b y partici pa nt.
3. 1. 1.   
All E nr olle d  A n al ysis Set
T he All E nr olle d A nal ysis Set i ncl u des all partici pa nts w h o e nr olle d i nt o t he st u d y. T his i ncl u des 
a d ult partici pa nts a n d i nfa nts b or n t o w o me n partici pati n g i n t he st u d y.




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3. 3.  
E x a mi n ati o n of P artici p a nt S u b gr o u ps
T here are n o pres pecifie d partici pa nt s u b gr o u pi n gs f or a nal yses.
3. 4.   
M ulti ple C o m p aris o ns
A dj ust me nts f or m ulti plicit y will n ot be ma de f or testi n g, beca use n o f or mal statistical testi n g 
will be perf or me d i n t his st u d y.
3. 5.   
Missi n g D at a a n d O utliers
3. 5. 1.   
Missi n g D at a
A missi n g dat u m f or a gi ve n st u d y a nal ysis wi n d o w ma y be d ue t o a n y of t he f oll o wi n g reas o ns:

A visit occ urri n g i n t he wi n d o w b ut data were n ot c ollecte d or were u n usa ble 

A visit n ot occ urri n g i n t he wi n d o w

A partici pa nt pre mat urel y disc o nti n ui n g fr o m t he st u d y bef ore reac hi n g t he wi n d o w
I n ge neral, val ues f or missi n g data will n ot be i m p ute d, u nless met h o ds f or ha n dli n g missi n g data 
are s pecifie d.
T he ha n dli n g of missi n g or i nc o m plete dates f or A E o nset is descri be d i n Secti o n 7. 1. 6. 2 , a n d f or 
c o nc o mita nt me dicati o ns i n Secti o n 7. 4. 2 .
3. 5. 2.   
O utliers
O utliers will be i de ntifie d d uri n g t he data ma na ge me nt a n d data a nal ysis pr ocess, b ut n o 
se nsiti vit y a nal yses will be d o ne, u nless s pecifie d ot her wise. All data will be i ncl u de d i n t he 
a nal yses. 
3. 6.   
D at a H a n dli n g C o n ve nti o ns a n d Tr a nsf or m ati o ns
T he f oll o wi n g c o n ve nti o ns will be use d f or t he i m p utati o n of date of birt h w he n it is partiall y 
missi n g or n ot c ollecte d:

If o nl y m o nt h a n d year of birt h is c ollecte d, t he n “ 1 5” will be i m p ute d as t he da y of birt h

If o nl y year of birt h is c ollecte d, t he n “ 0 1 J ul y” will be i m p ute d as t he da y a n d m o nt h of 
birt h

If year of birt h is missi n g, t he n date of birt h will n ot be i m p ute d. I n ge neral, a ge c ollecte d 
at Da y 1 (i n years) will be use d f or a nal yses a n d prese nte d i n listi n gs. 


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I n ge neral, a ge c ollecte d at Da y 1 (i n years) will be use d f or a nal yses a n d prese nte d i n listi n gs. If 
a ge at Da y 1 is n ot a vaila ble f or a partici pa nt, t he n a ge deri ve d base d o n date of birt h a n d t he 
Da y 1 visit date will be use d i nstea d. 
N o n- P K Data t hat are c o nti n u o us i n nat ure b ut are less t ha n t he l o wer li mit of q ua ntitati o n 
( L L O Q) or a b o ve t he u p per li mit of q ua ntificati o n ( U L O Q) will be i m p ute d as f oll o ws:

A val ue t hat is 1 u nit less t ha n t he L L O Q will be use d t o calc ulate descri pti ve statistics if 
t he dat u m is re p orte d i n t he f or m of “ x” ( w here x is c o nsi dere d t he L L O Q). F or 
e xa m ple, if t he val ues are re p orte d as < 5 0 a n d < 5. 0, val ues of 4 9 a n d 4. 9, res pecti vel y, 
will be use d t o calc ulate s u m mar y statistics. A n e xce pti o n t o t his r ule is a n y val ue re p orte d 
as < 1 or < 0. 1, etc. F or val ues re p orte d as < 1 or < 0. 1, a val ue of 0. 9 or 0. 0 9, res pecti vel y, 
will be use d t o calc ulate s u m mar y statistics.

A val ue t hat is 1 u nit a b o ve t he U L O Q will be use d t o calc ulate descri pti ve statistics if t he 
dat u m is re p orte d i n t he f or m of “ > x” ( w here x is c o nsi dere d t he U L O Q). Val ues wit h 
deci mal p oi nts will f oll o w t he sa me l o gic as t he b ullet p oi nt a b o ve.

T he li mit of q ua ntitati o ns will be use d t o calc ulate descri pti ve statistics if t he dat u m is 
re p orte d i n t he f or m of “ ≤ x” or “ ≥ x” ( w here x is c o nsi dere d t he li mit of q ua ntitati o ns, 
i.e., L L O Q a n d U L O Q).
If met h o ds base d o n t he ass u m pti o n t hat t he data are n or mall y distri b ute d are n ot a de q uate, 
a nal yses ma y be perf or me d o n tra nsf or me d data or n o n para metric a nal ysis met h o ds ma y be use d, 
as a p pr o priate.
Nat ural l o garit h mic tra nsf or mati o n will be use d f or plas ma c o nce ntrati o ns a n d a nal ysis of P K 
para meters. Plas ma c o nce ntrati o n val ues t hat are bel o w t he li mit of q ua ntitati o n ( B L Q) will be 
prese nte d as “ B L Q” i n t he c o nce ntrati o n data listi n g. F or a d ult partici pa nts, val ues t hat are 
“ B L Q” will be treate d as 0 at pre d ose ti me p oi nts, a n d o ne- half t he val ue of L L O Q at p ost d ose 
ti me p oi nts f or deter mi nati o n of s u m mar y a n d or der statistics. F or ne o nate partici pa nts, val ues 
t hat are B L Q will be treate d as o ne- half t he val ue of t he L L O Q f or deter mi nati o n of s u m mar y 
a n d or der statistics. P K c o nce ntrati o n res ult of “ A Q L” (i.e., a b o ve q ua ntitati o n li mit) will be 
i m p ute d as t he U L O Q + 1 f or a d ults a n d   
 t o c o m p ute t he s u m mar y a n d or der statistics. 
F or mater nal a n d u m bilical c or d plas ma P K c o nce ntrati o ns, val ues of “ B L Q” a n d “ A Q L” will be 
i m p ute d usi n g t he sa me r ule t o calc ulate t he s u m mar y a n d or der statistics o n t h ose a nal ytes, b ut 
t he c or d bl o o d t o mater nal plas ma c o nce ntrati o n rati o will n ot be i m p ute d if a n y val ue of c or d 
bl o o d or mater nal plas ma c o nce ntrati o n is “ B L Q” or “ A Q L”.
T he f oll o wi n g c o n ve nti o ns will be use d f or t he prese ntati o n of s u m mar y a n d or der statistics: 

If at least 1 partici pa nt has a c o nce ntrati o n val ue of “ B L Q” f or t he ti me p oi nt, t he 
mi ni m u m val ue will be dis pla ye d as “ B L Q”.

If m ore t ha n 2 5 % of t he partici pa nts ha ve a c o nce ntrati o n data val ue of “ B L Q” f or a gi ve n 
ti me p oi nt, t he mi ni m u m a n d Q 1 val ues will be dis pla ye d as “ B L Q”. 
C CI


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
If m ore t ha n 5 0 % of t he partici pa nts ha ve a c o nce ntrati o n data val ue of “ B L Q” f or a gi ve n 
ti me p oi nt, t he mi ni m u m, Q 1, a n d me dia n val ues will be dis pla ye d as “ B L Q”. 

If m ore t ha n 7 5 % of t he partici pa nts ha ve a c o nce ntrati o n data val ue of “ B L Q” f or a gi ve n 
ti me p oi nt, t he mi ni m u m, Q 1, me dia n, a n d Q 3 val ues will be dis pla ye d as “ B L Q”. 

If all partici pa nts ha ve c o nce ntrati o n data val ues of “ B L Q” f or a gi ve n ti me p oi nt, all or der 
statistics ( mi ni m u m, Q 1, me dia n, Q 3, a n d ma xi m u m) a n d s u m mar y statistics will be 
dis pla ye d as “ B L Q”.
P K para meters t hat are “ B L Q” will be i m p ute d as o ne- half L L O Q bef ore l o g tra nsf or mati o n or 
statistical m o del fitti n g. 
F or uri ne creati ni ne, a val ue of “ < 1” is ha n dle d as a missi n g val ue i n its s u m mar y a n d t he 
calc ulati o n of relate d rati os. 
L o garit h mic ( base 1 0) tra nsf or mati o ns will be a p plie d t o HI V- 1 R N A f or efficac y a nal yses. HI V-
1 R N A res ults of “ N o HI V- 1 R N A detecte d” a n d “ < 2 0 c p/ m L HI V- 1 R N A Detecte d” will be 
i m p ute d as 1 9 c o pies/ m L f or a nal ysis p ur p oses. 
3. 7.   
A n al ysis Visit Wi n d o ws a n d Visit Defi niti o ns
3. 7. 1.   
Defi niti o n of St u d y D a y
3. 7. 1. 1.   
Defi niti o n of St u d y Da y f or A d ults 
St u d y D a y 1  is defi ne d as t he da y w he n t he first d ose of t he st u d y dr u g (i.e., B/ F/ T A F) was 
ta ke n f or a d ults, as rec or de d o n t he St u d y Dr u g A d mi nistrati o n e C R F.
B aseli ne v al ue is defi ne d as t he last val ue o btai ne d o n or pri or t o St u d y Da y 1 f or all 
assess me nts e xce pt p har mac o ki netic a nal ysis.
St u d y D a ys are calc ulate d relati ve t o St u d y Da y 1. F or e ve nts t hat occ urre d o n or after t he St u d y 
Da y 1 date, st u d y da ys are calc ulate d as ( visit date mi n us St u d y Da y 1 pl us 1). F or e ve nts t hat 
occ urre d pri or t o St u d y Da y 1, st u d y da ys are calc ulate d as ( visit date mi n us St u d y Da y 1).
L ast D ose D ate is defi ne d as t he latest st u d y dr u g e n d dates rec or de d o n t he St u d y D ur g 
A d mi nistrati o n e C R F wit h “ Per ma ne ntl y Wit h dra w n” b o x c hec ke d f or partici pa nts w h o 
pre mat urel y disc o nti n ue d or c o m plete d st u d y dr u g acc or di n g t o t he St u d y Dr u g C o m pleti o n 
e C R F.
Pre d ose v al ue  f or P K a nal ysis, is defi ne d as t he last a vaila ble off-treat me nt val ue c ollecte d pri or 
t o t he first d ose of st u d y dr u g.




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T a ble 3- 1.  
Pre- p art u m A n al ysis Wi n d o ws f or HI V- 1 R N A a n d Vit al Si g ns
Visit I D
N o mi n al D a y 
L o wer Li mit 
U p per Li mit
Baseli ne
1
Wee k 4
2 8
2
4 2
Wee k 8
5 6
4 3
7 0
Wee k 1 2
8 4
7 1
9 8
Wee k 1 6
1 1 2
9 9
1 2 6
Wee k 2 0
1 4 0
1 2 7
1 5 4
Wee k 2 4
1 6 8
1 5 5
1 8 2
Wee k K
( K is e ver y 4 wee ks after pre vi o us visit 
bef ore deli ver y de pe n de nt o n ti me of 
e nr oll me nt)
K * 7
( K- 2) * 7 + 1
Mi n(( K + 2) * 7, deli ver y 
da y)
B aseli ne v al ue is defi ne d as t he last val ue o btai ne d o n or pri or t o St u d y Da y 1 f or all assess me nts. T he pre- part u m 
a nal ysis wi n d o w’s defi niti o n is base d o n St u d y Da ys.
T a ble 3- 2.  
P ost- p art u m A n al ysis Wi n d o ws f or HI V- 1 R N A a n d Vit al Si g ns
Visit I D
N o mi n al D a y 
L o wer Li mit 
U p per Li mit
Deli ver y
1
Wee k 6 p ost- part u m
4 2
2
6 3
Wee k 1 2 p ost- part u m
8 4
6 4
1 0 5
Wee k K p ost- part u m ( K is e ver y 6 
wee ks)
K * 7
( K- 3) * 7 + 1
( K + 3) * 7
V al ue at Deli ver y is defi ne d as t he val ue o btai ne d o n or t he date of deli ver y f or all assess me nts. T he p ost- part u m 
a nal ysis wi n d o w’s defi niti o n is base d o n p ost- part u m St u d y Da ys.
Vital Si g ns were n ot meas ure d at t he date of deli ver y.
T a ble 3- 3.  
P ost- p art u m A n al ysis Wi n d o ws f or C D 4 + cell c o u nt a n d C D 4 %
Visit I D
N o mi n al D a y 
L o wer Li mit 
U p per Li mit
Deli ver y
1
Wee k 1 2 p ost- part u m
8 4
2
1 0 5
Wee k K p ost- part u m ( K is e ver y 6 
wee ks)
K * 7
( K- 3) * 7 + 1
( K + 3) * 7
T he p ost- part u m a nal ysis wi n d o w’s defi niti o n is base d o n t he da y of deli ver y.
C D 4 cell c o u nts a n d perce nta ge were n ot meas ure d at t he date of deli ver y.




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3. 7. 3.  
Selecti o n of D at a i n t he E ve nt of M ulti ple Rec or ds i n a n A n al ysis Visit 
Wi n d o w 
T his secti o n o nl y a p plies t o a d ult partici pa nts a nal ysis, a n d n ot a p plica ble t o ne o nate partici pa nts 
a nal ysis.
De pe n di n g o n t he statistical a nal ysis met h o d, si n gle val ues ma y be re q uire d f or eac h a nal ysis 
wi n d o w. F or e xa m ple, c ha n ge fr o m baseli ne b y visit us uall y re q uires a si n gle val ue, w hereas a 
ti me-t o-e ve nt a nal ysis w o ul d n ot re q uire 1 val ue per a nal ysis wi n d o w. 
If m ulti ple vali d, n o n missi n g n u meric o bserf vati o ns e xist i n a n a nal ysis wi n d o w, rec or ds will be 
c h ose n base d o n t he f oll o wi n g r ules if a si n gle val ue is nee de d:

F or baseli ne, t he last n o n missi n g val ue o n or pri or t o t he first d osi n g date of st u d y dr u g 
will be selecte d, u nless s pecifie d differe ntl y. If t here are m ulti ple rec or ds wit h t he sa me 
ti me or n o ti me rec or de d o n t he sa me da y, t he baseli ne val ue will be t he a vera ge of t he 
meas ure me nts f or c o nti n u o us data, e xce pt f or HI V- 1 R N A (see bel o w), or t he 
meas ure me nt wit h t he l o west se verit y (e g, n or mal will be selecte d o ver a b n or mal f or 
safet y electr ocar di o gra m [ E C G] fi n di n gs) f or cate g orical data.

F or p ost baseli ne val ues:

F or C D 4 + cell c o u nt, C D 4 %, t he rec or d(s) c ollecte d o n t he latest da y i n t he wi n d o w will 
be selecte d f or a nal ysis.

F or ot her n u meric o bser vati o ns (e xce pt HI V- 1 R N A, C D 4 + cell c o u nt a n d C D 4 %), t he 
rec or d(s) c ollecte d o n t he da y cl osest t o t he n o mi nal da y f or t hat visit will be selecte d. If 
t here are 2 da ys e q ui dista nt fr o m t he n o mi nal da y, t he later da y will be selecte d.

F or a n y o bser vati o ns e xce pt HI V- 1 R N A, if t here are m ulti ple rec or ds o n t he selecte d 
da y, t he a vera ge will be ta ke n f or c o nti n u o us data a n d t he w orse se verit y will be ta ke n f or 
cate g orical data, u nless ot her wise s pecifie d.

F or baseli ne a n d p ost baseli ne HI V- 1 R N A, t he latest (c o nsi deri n g b ot h c ollecti o n date a n d 
ti me) rec or d(s) i n t he wi n d o w will be selecte d. If b ot h “ HI V R N A Ta q ma n 2. 0” a n d “ HI V 
R N A Re peat” (i.e., t he HI V- 1 R N A res ult o btai ne d fr o m a n a d diti o nal ali q u ot of t he 
ori gi nal sa m ple) are a vaila ble wit h t he sa me c ollecti o n ti me, t he res ults fr o m t he “ HI V 
R N A Re peat” will be selecte d f or a nal ysis p ur p oses; ot her wise, if t here are m ulti ple “ HI V 
R N A Ta q ma n 2. 0” rec or ds wit h t he sa me c ollecti o n ti me, t he ge o metric mea n will be 
ta ke n f or a nal ysis p ur p oses.
If m ulti ple vali d n o n missi n g cate g orical o bser vati o ns e xist i n a wi n d o w, rec or ds will be c h ose n 
as f oll o ws:

F or baseli ne, t he last a vaila ble rec or d o n or pri or t o t he first d ose date of st u d y dr u g will 
be selecte d. If t here are m ulti ple rec or ds wit h t he sa me ti me or n o ti me rec or de d o n t he 


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sa me da y, t he val ue wit h t he l o west se verit y will be selecte d (e g, n or mal will be selecte d 
o ver a b n or mal f or safet y E C G fi n di n gs).

F or p ost baseli ne visits, t he m ost c o nser vati ve val ue wit hi n t he wi n d o w will be selecte d 
(e g, a b n or mal will be selecte d o ver n or mal f or safet y E C G fi n di n gs).


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4.  
S U B J E C T DI S P O SI TI O N
4. 1.  
E nr oll me nt a n d Dis p ositi o n
4. 1. 1 E nr oll me nt 
Ke y st u d y dates (i.e., first partici pa nt scree ne d, first partici pa nt e nr olle d, last partici pa nt e nr olle d, 
last partici pa nt last visit f or t he pri mar y e n d p oi nt, a n d last partici pa nt last visit f or t he cli nical 
st u d y re p ort) will be pr o vi de d.
A s u m mar y of partici pa nt e nr oll me nt will be pr o vi de d b y a d ults,   
 a n d t otal partici pa nts 
f or eac h c o u ntr y a n d i n vesti gat or.
4. 1. 2. Dis p ositi o n 
S u m maries of partici pa nt dis p ositi o n will be pr o vi de d f or a d ult a n d ne o nate partici pa nts, 
res pecti vel y.
T hese s u m maries will prese nt t he n u m ber of partici pa nts i n eac h of t he cate g ories liste d bel o w:

Partici pa nts scree ne d (f or A d ults 
)

Scree n fail ure partici pa nts w h o were n ot e nr olle d (f or A d ults 
)

Partici pa nts met all eli gi bilit y criteria a n d n ot e nr olle d (f or A d ults 
)

Partici pa nts e nr olle d (f or A d ults 
)

Partici pa nts e nr olle d a n d ne ver treate d (f or A d ults o nl y)

Partici pa nts i n Safet y A nal ysis Set (f or A d ults 
)

Partici pa nts i n F ull A nal ysis Set (f or A d ults 
)

Partici pa nts w h o c o m plete d st u d y dr u g (f or A d ults o nl y)

Partici pa nts w h o pre mat urel y disc o nti n ue d st u d y dr u g wit h reas o ns (f or A d ults o nl y)

Partici pa nts w h o c o m plete d st u d y (f or A d ults o nl y)

Partici pa nts w h o pre mat urel y disc o nti n ue d fr o m st u d y wit h reas o ns (f or A d ults o nl y)
F or t he stat us of st u d y dr u g a n d st u d y c o m pleti o n a n d reas o ns f or pre mat ure disc o nti n uati o n, t he 
n u m ber a n d perce nta ge of partici pa nts i n eac h cate g or y will be pr o vi de d f or A d ult partici pa nts 
o nl y. T he de n o mi nat or f or t he perce nta ge calc ulati o n will be t he t otal n u m ber of partici pa nts i n 
t he Safet y A nal ysis Set. I n a d diti o n, a fl o wc hart will be pr o vi de d t o de pict t he dis p ositi o n.
C CI
C CI
C CI
C CI
C CI
C CI
C CI




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disc o nti n uati o n of t he st u d y dr u g, a n d (c) ne xt pill dis pe nsi n g date of t he st u d y dr u g, mi n us 
dis pe nsi n g date of t he st u d y dr u g.
T he ne xt pill dis pe nsi n g date is t he f oll o wi n g dis pe nsi n g date of t he st u d y dr u g re gar dless of t he 
b ottle ret ur n date. 
F or a rec or d w here t he n u m ber of pills ret ur ne d was missi n g ( wit h “ Yes” a ns were d f or 
“ Was B ottle ret ur ne d?” q uesti o n), it is ass u me d t he n u m ber of pills ret ur ne d was zer o. If t he 
n u m ber of pills dis pe nse d was missi n g or a n y st u d y dr u g b ottle was n ot ret ur ne d or t he b ottle 
ret ur n stat us was u n k n o w n, t he n all rec or ds i n t hat dis pe nsi n g peri o d f or t hat st u d y dr u g will be 
e xcl u de d fr o m b ot h de n o mi nat or a n d n u merat or calc ulati o n.
A d here nce will be calc ulate d usi n g all data fr o m t he e ntire d osi n g peri o d u p t o t he date of 
per ma ne nt disc o nti n uati o n of t he st u d y dr u g f or partici pa nts w h o pre mat urel y disc o nti n ue d st u d y 
dr u g or c o m plete d st u d y dr u g. 
Descri pti ve statistics f or a d here nce f or a st u d y dr u g re gi me n ( n, mea n, S D, me dia n, Q 1, Q 3, 
mi ni m u m, a n d ma xi m u m) al o n g wit h t he n u m ber a n d perce nta ge of partici pa nts bel o n gi n g t o 
a d here nce cate g ories (e g, < 8 0 %, ≥ 8 0 % t o < 9 0 %, ≥ 9 0 % t o < 9 5 %, ≥ 9 5 %) will be pr o vi de d f or 
partici pa nts w h o ret ur n at least 1 b ottle a n d ha ve calc ula ble a d here nce d uri n g t he st u d y i n t he 
Safet y A nal ysis Set f or a d ult partici pa nts. N o i nfere ntial statistics will be pr o vi de d.
A b y-s u bject listi n g will be pr o vi de d t o dis pla y st u d y dr u g a d mi nistrati o n data, i ncl u di n g pla n ne d 
ti me p oi nt, st u d y dr u g, d ose date a n d ti me, d ose a n d u nit of st u d y dr u g. T his o nl y a p plies t o a d ult 
partici pa nts. A b y-s u bject listi n g of st u d y dr u g acc o u nta bilit y will be pr o vi de d se paratel y b y 
partici pa nt I D n u m ber (i n asce n di n g or der) a n d visit (i n c hr o n ol o gical or der) f or a d ult 
partici pa nts.
4. 3.  
Pr ot oc ol De vi ati o ns
A b y-s u bject listi n g will be pr o vi de d f or t h ose partici pa nts w h o vi olate d at least 1 eli gi bilit y 
(i ncl usi o n or e xcl usi o n) criteri o n b ut g ot e nr olle d i n t he st u d y. T he listi n g will prese nt t he e ntr y 
criteri o n ( or criteria if m ore t ha n 1 vi olati o n) t hat partici pa nts di d n ot meet a n d relate d 
c o m me nts, if c ollecte d.
Pr ot oc ol de viati o ns occ urri n g after partici pa nts e ntere d t he st u d y are d oc u me nte d d uri n g r o uti ne 
m o nit ori n g. T he n u m ber a n d perce nta ge of partici pa nts wit h i m p orta nt pr ot oc ol de viati o ns b y 
de viati o n cate g or y (e g, eli gi bilit y criteria, i nf or me d c o nse nt) will be s u m marize d base d o n t he 
n u m ber of a d ult a n d ne o nate partici pa nts i n t he All E nr olle d A nal ysis Set, res pecti vel y .
A n y i m p orta nt de viati o ns i de ntifie d will be i ncl u de d i n a b y-s u bject listi n g, a n d e val uate d t o 
deter mi ne if it j ustifies e xcl u di n g t he partici pa nt fr o m a n y a nal ysis sets. If n o I P D e xists, a n 
e m pt y listi n g will be create d. 


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4. 4.   
Assess me nt of C O VI D- 1 9 I m p act
T his st u d y was o n g oi n g d uri n g t he n o vel c or o na vir us ( C O VI D- 1 9) pa n de mic w hic h has a n 
i m pact o n t he st u d y c o n d uct. S o me partici pa nts were u na ble t o atte n d o nsite visits d ue t o s helter 
i n place g ui deli nes, site cl os ures, or ot her reas o ns. T his secti o n descri bes h o w s pecial sit uati o ns 
d ue t o C O VI D- 1 9 will be ha n dle d i n t he a nal ysis.
4. 4. 1.  
St u d y Dr u g or St u d y Disc o nti n u ati o n D ue t o C O VI D- 1 9
A b y-s u bject listi n g of reas o ns f or pre mat ure st u d y dr u g or st u d y disc o nti n uati o n d ue t o C O VI D-
1 9 will be pr o vi de d if a p plica ble. T his o nl y a p plies t o a d ult partici pa nts. 
4. 4. 2.  
Pr ot oc ol De vi ati o ns D ue t o C O VI D- 1 9
A b y-s u bject listi n g will be pr o vi de d f or partici pa nts wit h i m p orta nt pr ot oc ol de viati o ns relate d 
t o C O VI D- 1 9 if a p plica ble. A se parate listi n g will be pr o vi de d f or partici pa nts wit h n o n-
i m p orta nt pr ot oc ol de viati o ns relate d t o C O VI D- 1 9 if a p plica ble.
4. 4. 3.   
Misse d a n d Virt u al Visits D ue t o C O VI D- 1 9
A b y-s u bject listi n g of partici pa nts wit h misse d or virt ual visits d ue t o C O VI D- 1 9 will be 
pr o vi de d b y partici pa nt I D n u m ber i n asce n di n g or der.
I nf or mati o n re gar di n g misse d or virt ual visits d ue t o C O VI D- 1 9 will be c ollecte d as free te xt i n 
t he C R F c o m me nt fiel ds. T he deter mi nati o n of misse d or virt ual visits d ue t o C O VI D- 1 9 will be 
d o ne usi n g Nat ural La n g ua ge Pr ocessi n g ( N L P) t o searc h t he C R F c o m me nt fiel ds.  A detaile d 
e x pla nati o n of t he al g orit h m is gi ve n i n A p pe n di x 2. A d verse E ve nts of C O VI D- 1 9 a n d 
S us pecte d C O VI D- 1 9 I nfecti o n .
4. 4. 4.   
A d verse E ve nts D ue t o C O VI D- 1 9
A Es of C O VI D- 1 9 will be i ncl u de d i n a nal yses of A Es if a p plica ble, w hic h will be deter mi ne d 
t hr o u g h C O VI D- 1 9 S M Q N arr o w  searc h. A b y-s u bject listi n g of A Es of C O VI D- 1 9 will be 
pr o vi de d if a p plica ble.


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5.  
B A S E LI N E C H A R A C T E RI S TI C S
5. 1.   
De m o gr a p hics a n d B aseli ne C h ar acteristics
Partici pa nt de m o gra p hic varia bles (i.e., a ge, se x, race, a n d et h nicit y) a n d baseli ne c haracteristics 
( b o d y wei g ht [i n k g], hei g ht [i n c m], b o d y mass i n de x [ B MI; i n k g/ m 2; f or a d ult partici pa nts 
o nl y]) will be s u m marize d o verall usi n g descri pti ve statistics f or c o nti n u o us varia bles a n d usi n g 
n u m ber a n d perce nta ge of partici pa nts f or cate g orical varia bles. T he s u m mar y of de m o gra p hic 
a n d baseli ne data will be pr o vi de d f or t he Safet y A nal ysis Set a n d Ne o nate Safet y A nal ysis Set, 
res pecti vel y.
A b y-s u bject de m o gra p hic listi n g, i ncl u di n g t he i nf or me d c o nse nt date, will be pr o vi de d b y 
partici pa nt I D n u m ber i n asce n di n g or der.
5. 2.   
Ot her B aseli ne C h ar acteristics
T he f oll o wi n g ot her baseli ne c haracteristics ( or baseli ne disease c haracteristics) will als o be 
i ncl u de d a n d s u m marize d usi n g descri pti ve statistics f or t he Safet y A nal ysis Set a n d Ne o nate 
Safet y A nal ysis Set, res pecti vel y.
F or a d ult partici pa nts a nal ysis: 

HI V- 1 R N A cate g ories (c o pies/ m L): (a) < 5 0, ( b) ≥ 5 0

C D 4 + cell c o u nt (/ μ L)

C D 4 + cell c o u nt cate g ories (/ μ L): (a) < 5 0, ( b) ≥ 5 0 t o < 2 0 0, (c) ≥ 2 0 0 t o < 3 5 0, 
( d) ≥ 3 5 0 t o < 5 0 0, a n d (e) ≥ 5 0 0 

C D 4 perce nta ge ( %)

M o de of i nfecti o n ( HI V ris k fact ors)

HI V disease stat us

e G F R C G  ( m L/ mi n)

E C G ( N or mal/ A b n or mal)
F or ne o nate partici pa nts a nal ysis:

HI V- 1 R N A cate g ories (c o pies/ m L): (a) < 5 0, ( b) ≥ 5 0

A p gar sc ore 


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
Hea d circ u mfere nce (c m)

A nt hr o p o metric meas ures
A p gar sc ore a n d A nt hr o p o metric meas ures will be s u m marize d as n u meric varia bles i n baseli ne 
disease c haracteristcs.
A b y-s u bject listi n g of ot her baseli ne c haracteristics will be pr o vi de d b y partici pa nt I D n u m ber i n 
asce n di n g or der.
5. 3.   
Me dic al Hist or y
Ge neral me dical hist or y data will be c ollecte d at scree ni n g f or a d ult partici pa nts o nl y. Ge neral 
me dical hist or y data will be c o de d usi n g t he c urre nt versi o n of Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A).
A s u m mar y of disease-s pecific me dical hist or y will be pr o vi de d f or t he Safet y A nal ysis Set f or 
a d ult partici pa nts. N o f or mal statistical testi n g is pla n ne d.
A b y-s u bject listi n g of me dical hist or y will be pr o vi de d f or all a d ult partici pa nts b y partici pa nt 
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
4 0 0 t o < 1 0 0 0 c o pies/ m L

≥ 1 0 0 0 c o pies/ m L
T he 9 5 % CI of t he pr o p orti o n of partici pa nts wit h HI V- 1 R N A < 5 0 c o pies/ m L will be pr o vi de d 
usi n g t he Cl o p per- Pears o n E xact met h o d.
6. 2. 1.   
A n al ysis of C D 4 + Cell C o u nt
All C D 4 + cell c o u nt (/ µ L) will be s u m marize d usi n g o bser ve d, o n-treat me nt data (i.e., data 
c ollecte d u p t o 1 da y after after per ma ne nt disc o nti n uati o n of st u d y dr u g) f or parici pa nts i n t he 
F ull A nal ysis Set f or a d ult partici pa nts.
T he C D 4 + cell c o u nt (/ µ L) a n d c ha n ges fr o m baseli ne will als o be s u m marize d b y visit f or a d ult 
partici pa nts usi n g descri pti ve statistics.
6. 2. 2.   
A n al ysis of C D 4 %
All C D 4 % will be s u m marize d usi n g o bser ve d, o n-treat me nt data (i.e., data c ollecte d u p t o 1 da y 
after per ma ne nt disc o nti n uati o n of st u d y dr u g) f or a d ult parici pa nts i n t he F ull A nal ysis Set.
T he C D 4 % a n d c ha n ge fr o m baseli ne will als o be s u m marize d b y visit f or a d ult partici pa nts 
usi n g descri pti ve statistics.
6. 3.   
C h a n ges Fr o m Pr ot oc ol- S pecifie d Effic ac y A n al yses
T he c ha n ge fr o m baseli ne i n C D 4 + cell c o u nt (/ µ L) a n d C D 4 % was a d de d as efficac y e n d p oi nts 
f or a nal ysis i n t his S A P.


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7.  
S A F E T Y A N A L Y S E S
Safet y data will be s u m marize d f or t he a d ult partici pa nts i n t he Safet y A nal ysis Set, as well as 
ne o nate partici pa nts i n t he Ne o nate Safet y A nal ysis Set, res pecti vel y. T his secti o n a p plies t o 
b ot h a d ult a n d ne o nate partici pa nts u nless ot her wise s pecifie d. H o we ver, treat me nt e mer ge nt 
defi niti o ns i n t his secti o n o nl y a p plies t o a d ult partici pa nts.
F or a d ult partici pa nts, all safet y data c ollecte d u p t o 3 0 da ys after per ma ne nt disc o nti n uati o n of 
st u d y dr u g will be s u m marize d, u nless s pecifie d ot her wise. F or ne o nate partici pa nts, all A Es, 
deat hs, la b a b n or malities will be i ncl u de d a n d s u m marize d.
All safet y data will be i ncl u de d i n data listi n gs.
7. 1.   
A d verse E ve nts a n d De at hs
7. 1. 1.   
A d verse E ve nt Dicti o n ar y
Cli nical a n d la b orat or y a d verse e ve nts ( A Es) will be c o de d usi n g t he c urre nt versi o n of t he 
Me d D R A. S yste m or ga n class ( S O C), hi g h-le vel gr o u p ter m ( H L G T), hi g h-le vel ter m ( H L T), 
preferre d ter m ( P T), a n d l o wer-le vel ter m ( L L T) will be pr o vi de d i n t he A E dataset.
7. 1. 2.   
A d verse E ve nt Se verit y
A d verse e ve nts are gra de d b y t he i n vesti gat or as Gra de 1, 2, 3, or 4  acc or di n g t o t o xicit y criteria 
s pecifie d i n t he pr ot oc ol. T he se verit y gra de of e ve nts f or w hic h t he i n vesti gat or di d n ot rec or d 
se verit y will be cate g orize d as “ missi n g” f or ta b ular s u m maries a n d data listi n gs. 
7. 1. 3.   
Rel ati o ns hi p of A d verse E ve nts t o St u d y Dr u g
St u d y dr u g relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Relate d” o n t he A E case 
re p ort f or m ( C R F) t o t he q uesti o n of “ Relate d t o St u d y Treat me nt.” Relate d ness will al wa ys 
defa ult t o t he i n vesti gat or’s c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he 
i n vesti gat or di d n ot rec or d relati o ns hi p t o st u d y dr u g will be c o nsi dere d relate d t o st u d y dr u g f or 
s u m mar y p ur p oses. H o we ver, b y-s u bject data listi n gs will s h o w t he relati o ns hi p as missi n g fr o m 
t hat ca pt ure d o n t he C R F.
7. 1. 4.   
Rel ati o ns hi p of A d verse E ve nts t o St u d y Pr oce d ure
St u d y pr oce d ure relate d A Es are t h ose f or w hic h t he i n vesti gat or selecte d “ Yes” o n t he A E C R F 
t o t he q uesti o n of “ Relate d t o St u d y Pr oce d ures.” Relate d ness will al wa ys defa ult t o t he 
i n vesti gat or’s c h oice, n ot t hat of t he me dical m o nit or. E ve nts f or w hic h t he i n vesti gat or di d n ot 
rec or d relati o ns hi ps t o st u d y pr oce d ure will be c o nsi dere d relate d t o st u d y pr oce d ure. H o we ver, 
b y-s u bject data listi n gs will s h o w t he relati o ns hi p as missi n g fr o m t hat ca pt ure d o n t he C R F.
7. 1. 5.  
Seri o us A d verse E ve nts




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7. 1. 7. 1.  
Treat me nt-e mer ge nt A d verse E ve nts f or a d ult partici pa nts
A brief, hi g h-le vel s u m mar y of t he n u m ber a n d perce nta ge of a d ult partici pa nts w h o e x perie nce d 
at least 1 T E A E i n t he cate g ories descri bes bel o w will be pr o vi de d. All deat hs o bser ve d i n t he 
st u d y will als o be i ncl u de d i n t his s u m mar y.
T he n u m ber a n d perce nta ge of partici pa nt w h o e x perie nce d at least 1 T E A E will be pr o vi de d a n d 
s u m marize d b y S O C, H L T a n d P T:

T E A Es
F or t he A E cate g ories descri be bel o w, s u m maries will be pr o vi de d b y S O C a n d P T:

T E A Es wit h Gra de 3 or hi g her

T E A Es wit h Gra de 2 or hi g her

T E treat me nt-relate d A Es 

T E treat me nt-relate d A Es wit h Gra de 3 or hi g her

T E treat me nt-relate d A Es wit h Gra de 2 or hi g her

T E S A Es

T E treat me nt-relate d S A Es

T E A Es lea di n g t o pre mat ure disc o nti n uati o n fr o m st u d y dr u g 

T E A Es lea di n g t o pre mat ure disc o nti n uati o n fr o m st u d y (if a p plica ble)

T E A Es lea di n g t o deat h (i.e., o utc o me of deat h, if a p plica ble)

All deat hs

Treat me nt-e mer ge nt deat hs
A brief, hi g h-le vel s u m mar y of A Es descri be d a b o ve will be pr o vi de d b y t he n u m ber a n d 
perce nta ge of partici pa nts w h o e x perie nce d t he a b o ve A Es. Treat me nt-e mer ge nt deat hs o bser ve d 
i n t he st u d y will be als o i ncl u de d i n t his s u m mar y.
Treat me nt-e mer ge nt deat h refers t o deat hs t hat occ urre d bet wee n t he first d ose date a n d t he last 
d ose date pl us 3 0 da ys (i ncl usi ve).
M ulti ple e ve nts will be c o u nte d o nl y o nce per partici pa nt i n eac h s u m mar y. A d verse e ve nts will 
be s u m marize d a n d liste d first i n al p ha betic or der of S O C (a n d H L T wit hi n eac h S O C if 
a p plica ble), a n d t he n b y P T i n desce n di n g or der of t otal fre q ue nc y wit hi n eac h S O C. F or 


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s u m maries b y se verit y gra de, t he m ost se vere gra de will be use d f or t h ose A Es t hat occ urre d 
m ore t ha n o nce i n a n i n di vi d ual partici pa nt d uri n g t he st u d y. 
I n a d diti o n t o t he a b o ve s u m mar y ta bles, all T E A Es, T E S A Es, T E treat me nt-relate d A Es, a n d 
T E treat me nt-relate d S A Es will be s u m marize d b y P T o nl y, i n desce n di n g or der of t otal 
fre q ue nc y.
I n a d diti o n, data listi n gs will be pr o vi de d f or a d ults f or t he f oll o wi n gs:

All A Es, i n dicati n g w het her t he e ve nt is treat me nt e mer ge nt

All S A Es

All deat hs 

All A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y dr u g (t his o nl y a p plies t o a d ult 
partici pa nts)

All A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y
7. 1. 7. 2.   
A d verse E ve nts f or ne o nate partici pa nts
A brief, hi g h-le vel s u m mar y of t he n u m ber a n d perce nta ge of ne o nate partici pa nts w h o 
e x perie nce d at least 1 A E i n t he cate g ories descri bes bel o w will be pr o vi de d. All deat hs o bser ve d 
i n t he st u d y will als o be i ncl u de d i n t his s u m mar y.
T he n u m ber a n d perce nta ge of partici pa nt w h o e x perie nce d at lease 1 A E will be pr o vi de d a n d 
s u m marize d b y S O C, H L T a n d P T:

A Es
F or t he A E cate g ories descri be bel o w, s u m maries will be pr o vi de d b y S O C a n d P T:

A Es wit h Gra de 3 or hi g her

A Es wit h Gra de 2 or hi g her

S A Es

A Es lea di n g t o pre mat ure disc o nti n uati o n fr o m st u d y (if a p plica ble)

A Es lea di n g t o deat h (i.e., o utc o me of deat h, if a p plica ble)

All Deat h


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M ulti ple e ve nts will be c o u nte d o nl y o nce per partici pa nt i n eac h s u m mar y. A d verse e ve nts will 
be s u m marize d a n d liste d first i n al p ha betic or der of S O C (a n d H L T wit hi n eac h S O C if 
a p plica ble), a n d t he n b y P T i n desce n di n g or der of t otal fre q ue nc y wit hi n eac h S O C. F or 
s u m maries b y se verit y gra de, t he m ost se vere gra de will be use d f or t h ose A Es t hat occ urre d 
m ore t ha n o nce i n a n i n di vi d ual partici pa nt d uri n g t he st u d y. 
I n a d diti o n t o t he a b o ve s u m mar y ta bles, all A Es a n d S A Es will be s u m marize d b y P T o nl y, i n 
desce n di n g or der of t otal fre q ue nc y.
I n a d diti o n, data listi n gs will be pr o vi de d f or a d ults f or t he f oll o wi n g:

All A Es

All S A Es

All Deat hs 

All A Es lea di n g t o pre mat ure disc o nti n uati o n of st u d y treat me nt or st u d y.
7. 1. 8.   
A d diti o n al A n al ysis of A d verse E ve nts
7. 1. 8. 1.   
A Sta ge 3 O p p ort u nistic Ill nesses i n HI V
O n a n o n g oi n g basis, A Es will be re vie we d f or e ve nts t hat mi g ht meet t he defi niti o n of sta ge 3 
o p p ort u nistic ill nesses i n HI V t hat are i n dicati ve of a n AI D S- defi ni n g dia g n oses (see Pr ot oc ol 
A p pe n di x 5). T he Gilea d me dical m o nit or will re vie w t he p ossi ble sta ge 3 o p p ort u nistic ill nesses 
a n d a p pr o ve t he e ve nts t hat meet t he defi niti o n. E ve nts t hat meet t he sta ge 3 o p p ort u nistic ill ness 
defi niti o n of a n AI D S- Defi ni n g Dia g n osis will be liste d.
7. 2.  
L a b or at or y E v al u ati o ns
La b orat or y data c ollecte d d uri n g t he st u d y will be a nal yze d a n d s u m marize d usi n g b ot h 
q ua ntitati ve a n d q ualitati ve met h o ds. S u m maries of la b orat or y data will be pr o vi de d f or t he 
Safet y A nal ysis Set a n d Ne o nate Safet y A nal ysis Set. T he a nal ysis will be base d o n val ues 
re p orte d i n c o n ve nti o nal u nits. W he n val ues are bel o w t he L O Q, t he y will be liste d as s uc h, a n d 
t he cl osest i m p ute d val ue will be use d f or t he p ur p ose of calc ulati n g s u m mar y statistics as 
s pecifie d i n Secti o n 3. 7 . 
A b y-s u bject listi n g f or la b orat or y test res ults will be pr o vi de d b y partici pa nt I D n u m ber a n d 
visit i n c hr o n ol o gical or der f or he mat ol o g y, c he mistr y, a n d uri nal ysis (as a p plica ble) se paratel y. 
Val ues falli n g o utsi de of t he refere nce ra n ge a n d/ or ha vi n g a se verit y gra de of 1 or hi g her o n t he 
Gilea d Gra di n g Scale f or Se verit y of A d verse E ve nts a n d La b orat or y A b n or malities will be 
fla g ge d i n t he data listi n gs, as a p pr o priate. 


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7. 2. 1.  
S u m m aries of N u meric L a b or at or y Res ults
F or A d ult partici pa nts a nal ysis, s u m maries will i ncl u de data c ollecte d u p t he t he last d ose of 
st u d y dr u g pl us 3 0 da ys f or partici pa nts w h o ha ve per ma ne ntl y disc o nti n ue d st u d y dr u g.
Descri pti ve statistics will be pr o vi de d f or eac h la b orat or y test s pecifie d i n t he st u d y pr ot oc ol as 
f oll o ws:

Baseli ne val ues 

Val ues at eac h p ost baseli ne a nal ysis wi n d o w

C ha n ge fr o m baseli ne at eac h p ost baseli ne a nal ysis wi n d o w
A baseli ne la b orat or y val ue will be defi ne d as t he last n o n missi n g val ue o btai ne d o n or pri or t o 
t he date of first d ose of st u d y dr u g f or A d ult partici pa nts. 
C ha n ge fr o m baseli ne t o a p ost baseli ne visit will be defi ne d as t he p ost baseli ne val ue mi n us t he 
baseli ne val ue. T he mea n, me dia n, Q 1, Q 3, mi ni m u m, a n d ma xi m u m val ues will be dis pla ye d t o 
t he re p orte d n u m ber of di gits; S D val ues will be dis pla ye d t o t he re p orte d n u m ber of di gits pl us 
1.
I n t he case of m ulti ple val ues i n a n a nal ysis wi n d o w, data will be selecte d f or a nal ysis as 
descri be d i n Secti o n 3. 7 .
F or Ne o nate partici pa nts a nal ysis, la b orat or y res ults will be base d o n n o mi nal visits a n d c ha n ge 
fr o m baseli ne d oes n ot a p pl y t o Ne o nate a nal ysis, i.e. o nl y baseli ne val ues a n d val ues at wee k 4-
8 visit will be prese nte d. La n g ua ges a b o ut c ha n ge fr o m baseli ne d o n ot a p pl y t o ne o nate 
partici pa nts a nal ysis.
7. 2. 2.   
Gr a de d L a b or at or y V al ues
T he Gilea d Gra di n g Scale f or Se verit y of A d verse E ve nts a n d La b orat or y A b n or malities will be 
use d f or assi g ni n g t o xicit y gra des ( 0 t o 4) t o la b orat or y res ults f or a nal ysis. Gra de 0 i ncl u des all 
val ues t hat d o n ot meet t he criteria f or a n a b n or malit y of at least Gra de 1. F or la b orat or y tests 
wit h criteria f or b ot h i ncrease d a n d decrease d le vels, a nal yses f or eac h directi o n (i.e., i ncrease d, 
decrease d) will be prese nte d se paratel y. 
If t here is a n y la b orat or y t o xicit y gra di n g scale o verla p pi n g wit h t he n or mal refere nce ra n ges 
(e g, Gra de 1 scale o verla ps wit h n or mal refere nce ra n ges), la b orat or y val ues t hat are wit hi n t he 
n or mal ra n ge will be Gra de 0, e xce pt f or li pi d tests. 




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7. 2. 3.  
Li ver- Rel ate d L a b or at or y E v al u ati o ns
Li ver relate d la b orat or y e val uati o ns o nl y a p plies t o a nal ysis o n a d ult partici pa nts.
Li ver-relate d a b n or malities after i nitial st u d y dr u g d osi n g will be e xa mi ne d a n d s u m marize d 
usi n g t he n u m ber a n d perce nta ge of partici pa nts w h o were re p orte d t o ha ve t he f oll o wi n g 
la b orat or y test val ues f or p ost baseli ne meas ure me nts:

As partate a mi n otra nsferase ( A S T): (a) > 3 ti mes of t he u p per li mit of refere nce ra n ge 
( U L N), ( b) > 5 × U L N, (c) > 1 0 × U L N, ( d) > 2 0 × U L N

Ala ni ne a mi n otra nsferase ( A L T): (a) > 3 × U L N, ( b) > 5 × U L N, (c) > 1 0 × U L N, 
( d) > 2 0 × U L N

A S T or A L T: (a) > 3 × U L N, ( b) > 5 × U L N, (c) > 1 0 × U L N, ( d) > 2 0 × U L N

T otal bilir u bi n: (a) > 1 × U L N, ( b) > 2 × U L N

Al kali ne p h os p hatase ( A L P) > 1. 5 × U L N

A S T or A L T > 3 × U L N a n d t otal bilir u bi n: (a) > 1. 5 × U L N, ( b) > 2 × U L N

A S T or A L T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N a n d A L P < 2 × U L N
T he s u m mar y will i ncl u de data fr o m all p ost baseli ne visits u p t o 3 0 da ys after t he last d ose of 
st u d y dr u g f or a d ults. F or i n di vi d ual la b orat or y tests, partici pa nts will be c o u nte d o nce base d o n 
t he m ost se vere p ost baseli ne val ue. F or b ot h t he c o m p osite e n d p oi nt of A S T or A L T a n d t otal 
bilir u bi n, a n d t he c o m p osite e n d p oi nt of A S T or A L T, t otal bilir u bi n, a n d A L P, partici pa nts will 
be c o u nte d o nce w he n t he criteria are met at t he sa me p ost baseli ne visit date. T he de n o mi nat or is 
t he n u m ber of a d ult partici pa nts i n t he Safet y A nal ysis Set as a p plica ble wit h n o n missi n g 
p ost baseli ne val ue of t he tests i n e val uati o n at t he sa me p ost baseli ne visit date. Partici pa nts wit h 
A S T or A L T > 3 × U L N will als o be liste d.
I n a d diti o n, baseli ne, p ost baseli ne, a n d c ha n ge fr o m baseli ne i n A S T, A L T, A L P, a n d t otal 
bilir u bi n will be s u m marize d b y visit usi n g descri pti ve statistics. 
7. 2. 4.   
Re n al- Rel ate d L a b or at or y E v al u ati o ns
Re nal relate d la b orat or y e val uati o ns o nl y a p plies t o a nal ysis o n a d ult partici pa nts.
7. 2. 4. 1.  
Ser u m Creati ni ne a n d e G F R C G
Baseli ne, p ost baseli ne, a n d c ha n ge fr o m baseli ne i n ser u m creati ni ne a n d e G F R C G  will be 
s u m marize d b y visit usi n g descri pti ve statistics. 




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w het her t he n o n- A R Vs are c o nc o mita nt or n ot. T he me dicati o n is c o nc o mita nt if t he m o nt h a n d 
year of t he start or st o p ( or year of t he start or st o p, if m o nt h is n ot rec or de d) of t he me dicati o n 
d oes n ot meet eit her of t he f oll o wi n g criteria:

T he m o nt h a n d year of start of t he me dicati o n is after t he date of t he last d ose of st u d y 
dr u g

T he m o nt h a n d year of st o p of t he me dicati o n is bef ore t he date of t he first d ose of st u d y 
dr u g
If t he start a n d st o p date of n o n- A R V me dicati o ns are c o m plete, t he start date is n ot after last d ose 
date a n d t he st o p date is n ot bef ore first d ose date, or t he n o n- A R V me dicati o ns are mar ke d as 
o n g oi n g a n d start date is o n or bef ore last d ose date, t he n o n- A R V me dicati o ns are c o nc o mita nt.
S u m maries of n o n- A R V c o nc o mita nt me dicati o ns will be pr o vi de d f or t he safet y a nal ysis set. 
Partici pa nts wit h a n y n o n- A R V c o nc o mita nt me dicati o ns will be liste d. N o i nfere ntial statistics 
will be pr o vi de d.
7. 5.  
Electr oc ar di o gr a m Res ults
A b y-s u bject listi n g f or a d ult partici pa nts f or E C G assess me nt res ults will be pr o vi de d b y 
partici pa nt I D n u m ber a n d ti me p oi nt i n c hr o n ol o gical or der.
7. 6.   
Ot her S afet y Me as ures
N o a d diti o nal safet y meas ures are s pecifie d i n t he pr ot oc ol.
7. 7.   
C h a n ges Fr o m Pr ot oc ol- S pecifie d S afet y A n al yses
T here are n o de viati o ns fr o m t he pr ot oc ol-s pecifie d safet y a nal yses.


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8.  
P H A R M A C O KI N E TI C E V A L U A TI O N/ A N A L Y SI S
8. 1.  
Esti m ati o n of P h ar m ac o ki netic P ar a meters
P har mac o ki netic ( P K) para meters will be esti mate d usi n g P h oe ni x Wi n N o nli n ®  s oft ware usi n g 
sta n dar d n o nc o m part me ntal met h o ds. T he li near u p/l o g d o w n r ule will be use d i n c o nj u ncti o n 
wit h t he a p pr o priate n o nc o m part me ntal m o del, wit h i n p ut val ues f or d ose le vel, d osi n g ti me, P K 
c o nce ntrati o n, a n d c orres p o n di n g real-ti me val ues, base d o n dr u g d osi n g ti mes w he ne ver 
p ossi ble.
All pre d ose sa m ple ti mes bef ore ti me-zer o will be c o n verte d t o zer o.
F or area u n der t he c ur ve ( A U C), sa m ples bel o w t he li mit of q ua ntitati o n ( B L Q) of t he 
bi oa nal ytical assa ys occ urri n g pri or t o t he ac hie ve me nt of t he first q ua ntifia ble c o nce ntrati o n will 
be assi g ne d a c o nce ntrati o n val ue of zer o t o pre ve nt o veresti mati o n of t he i nitial A U C. Sa m ples 
t hat are B L Q at all ot her ti me p oi nts will be treate d as missi n g data i n Wi n N o nli n. T he n o mi nal 
ti me p oi nt f or a ke y e ve nt (e g, uri ne c ollecti o n) or d osi n g i nter val (τ) ma y be use d t o per mit 
direct calc ulati o n of A U C o ver s pecific ti me i nter vals. T he a p pr o priate ness of t his a p pr oac h will 
be assesse d b y t he P K scie ntist o n a pr ofile- b y- pr ofile basis.
P har mac o ki netic para meters s uc h as Vz/ F a n d t 1/ 2 are de pe n de nt o n a n acc urate esti mati o n of t he 
ter mi nal eli mi nati o n p hase of dr u g. T he a p pr o priate ness of calc ulati n g t hese para meters will be 
e val uate d u p o n i ns pecti o n of P K data o n a pr ofile- b y- pr ofile basis b y t he P K scie ntist. F or 
i nsta nce, t he m o del esti mates of Vz/ F a n d t1/ 2 ma y be f o u n d n ot acc urate e n o u g h f or s o me 
partici pa nts (i.e., a dj uste d R-s q uare d < 0. 8). I n t his case, t he Vz/ F a n d t 1/ 2 f or t h ose partici pa nts 
will n ot be use d t o c o m p ute t he s u m mar y statistics. 
A listi n g of i n di vi d ual partici pa nt data f or t he deter mi nati o n of plas ma half-life a n d 
c orres p o n di n g c orrelati o n c oefficie nt will be pr o vi de d f or eac h a nal yte, i ncl u di n g i nte nsi ve P K 
sa m pli n g da y, n u m ber of data p oi nts i n re gressi o n, start ti me, e n d ti me, a n d c orrelati o n 
c oefficie nt.
8. 2.  
P h ar m ac o ki netic P ar a meters
P har mac o ki netic para meters will be ge nerate d f or all a d ult partici pa nts f or w h o m para meters ca n 
be deri ve d as a p plica ble. 
 (see Ta ble 8- 1 ).
T a ble 8- 1.  
St u d y Tre at me nts a n d Ass oci ate d A n al ytes
A n al ysis p o p ul ati o n
Tre at me nt
A n al yte(s)
A d ults
B/ F/ T A F
BI C, T A F, F T C, T F V- D P 
C CI
C CI


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Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 3
1 5 N o v 2 0 2 2
U n b o u n d plas ma BI C a n d T A F c o nce ntrati o ns a n d P K para meters will be a nal yze d usi n g 
descri pti ve statistics as a p plica ble. 
T he a nal ytes a n d para meters prese nte d i n Ta ble 8- 2  will be use d t o e val uate t he P K o bjecti ves of 
t he st u d y f or a d ult partici pa nts. N o para meters will be calc ulate d f or T F V- D P, d ue t o o ne 
ti me p oi nt sa m pli n g per i nte nsi ve P K visit 
 
. T he P K para meters t o be esti mate d i n t his st u d y are liste d a n d 
defi ne d i n t he P har mac o ki netic A b bre viati o ns secti o n.
T a ble 8- 2.  
P h ar m ac o ki netic P ar a meters f or E ac h A n al yte
A n al ysis 
p o p ul ati o n 
A n al ytes
S a m ple M atri x
P ar a meters
A d ults
BI C
P L A S M A
A U C ta u, U n b o u n d A U Cta u, Cta u, 
U n b o u n d C ta u, Cma x , U n b o u n d Cma x , 
A U C last, Clast, Tma x , Tlast, C Lss/ F, Vz/ F, 
t1/ 2
A d ults
T A F
P L A S M A
A U C ta u, U n b o u n d A U Cta u, Cma x , 
U n b o u n d C ma x , A U Clast, Clast, Tma x , 
T last, C Lss/ F, Vz/ F, t1/ 2
A d ults
F T C
P L A S M A
A U C ta u, Cta u, Cma x , A U Clast, Clast, Tma x , 
T last, C Lss/ F, Vz/ F, t1/ 2
Ne o nate 
BI C
P L A S M A
t1/ 2 (if a p plica ble)
Ne o nate 
T A F
P L A S M A
t1/ 2 (if a p plica ble)
8. 3.  
St atistic al A n al ysis Met h o ds
8. 3. 1.   
Ge ner al C o nsi der ati o ns
I n di vi d ual partici pa nt c o nce ntrati o n data a n d i n di vi d ual partici pa nt P K para meters f or BI C, T A F, 
F T C, a n d T F V- D P will be liste d a n d s u m marize d usi n g descri pti ve statistics b y visit da y, as 
a p plica ble. S u m mar y statistics ( n u m bers of partici pa nts, mea n, S D, c oefficie nt of variati o n 
[ % C V], me dia n, mi ni m u m, ma xi m u m, Q 1, a n d Q 3) will be prese nte d f or b ot h i n di vi d ual 
partici pa nt c o nce ntrati o n data b y ti me p oi nt a n d visit da y, a n d i n di vi d ual partici pa nt P K 
para meters b y visit da y. M ore o ver, t he ge o metric mea n, 9 5 % c o nfi de nce i nter val ( CI), a n d t he 
mea n a n d S D of t he nat ural l o g-tra nsf or me d val ues will be prese nte d f or i n di vi d ual partici pa nt 
P K para meter data. 
Pr otei n bi n di n g i nf or mati o n f or BI C a n d T A F will be liste d a n d s u m mar y statistics ( n u m bers of 
partici pa nts, mea n, S D, c oefficie nt of variati o n [ % C V], me dia n, mi ni m u m, ma xi m u m, Q 1, a n d 
Q 3) will be prese nte d f or pr otei n b o u n d a n d u n b o u n d fracti o n ( %) b y visit f or eac h a nal yte, 
res pecti vel y. Pr otei n bi n di n g data will be use d t o calc ulate u n b o u n d plas ma c o nce ntrati o ns a n d 
u n b o u n d P K para meters f or BI C a n d T A F. 
C CI


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Pa ge 4 4
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I n di vi d ual c o nce ntrati o n data listi n gs a n d s u m maries will i ncl u de all partici pa nts wit h 
c o nce ntrati o n data. T he sa m ple size f or eac h ti me p oi nt will be base d o n t he n u m ber of 
partici pa nts wit h n o n missi n g c o nce ntrati o n data at t hat ti me p oi nt. T he n u m ber of partici pa nts 
wit h c o nce ntrati o n B L Q will be prese nte d f or eac h ti me p oi nt. Ha n dli n g of B L Q data is s pecifie d 
i n Secti o n 3. 6 .
I n di vi d ual P K para meter data listi n gs a n d s u m maries will i ncl u de all partici pa nts f or w h o m P K 
para meter(s) ca n be deri ve d. T he sa m ple size f or eac h P K para meter will be base d o n t he n u m ber 
of partici pa nts wit h n o n missi n g data f or t hat P K para meter.
C o m parisi o ns bet wee n i n di vi d ual P K para meters bet wee n pre g na nc y a n d p ost part u m will be 
liste d a n d s u m marize d usi n g descri pti ve statistics.
T he f oll o wi n g ta bles will be pr o vi de d f or eac h a nal yte b y visit as a p plica ble:

I n di vi d ual partici pa nt plas ma a n d P B M C c o nce ntrati o n data a n d s u m mar y statistics

I n di vi d ual partici pa nt P K para meters a n d s u m mar y statistics

I n di vi d ual partici pa nt b o u n d a n d u n b o u n d fracti o ns of BI C or T A F a n d s u m mar y statistics 

I n di vi d ual partici pa nt c or d bl o o d t o mater nal bl o o d plas ma c o nce ntrati o n rati os a n d 
s u m mar y statistics ( BI C or T A F o nl y)
T he f oll o wi n g fi g ures will be pr o vi de d f or eac h a nal yte i ncl u di n g u n b o u n d plas ma BI C a n d 
u n b o u n d plas ma T A F b y visit da y as a p plica ble:

I n di vi d ual partici pa nt c o nce ntrati o n data vers us ti me ( o n li near a n d se mil o garit h mic 
scales)

Mea n ( ± S D) c o nce ntrati o n data vers us ti me ( o n li near a n d se mil o garit h mic scales)

Me dia n ( Q 1, Q 3) c o nce ntrati o n data vers us ti me ( o n li near a n d se mil o garit h mic scales)

S pa g hetti pl ots of P K para meters vers us ti me o n li near scale

B o x pl ots of P K para meters vers ue ti me o n li near scale
I n di vi d ual, mea n, a n d me dia n p ost d ose c o nce ntrati o n val ues t hat are ≤ L L O Q will n ot be 
dis pla ye d i n t he fi g ures a n d re mai ni n g p oi nts c o n necte d.
T he f oll o wi n g listi n gs will be pr o vi de d:

Plas ma a n d P B M C (if a p plica ble) P K sa m pli n g details b y partici pa nt, i ncl u di n g 
pr oce d ures, differe nces i n sc he d ule d a n d act ual dra w ti mes, a n d sa m ple a ge


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Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 5
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
I n di vi d ual data o n deter mi nati o n of plas ma half-life a n d c orres p o n di n g re gressi o n 
c orrelati o n c oefficie nt f or eac h a nal yte.
Plas ma c o nce ntrati o ns a n d P K para meters will be liste d a n d s u m marize d usi n g descri pti ve 
statistics b y visit f or mater nal a n d ne o nate P K a nal ysis sets, res pecti vel y. 
8. 3. 2.  
St atistic al Met h o d ol o g y
A d ults:
T he statistical c o m paris o ns of t he nat ural l o g-tra nsf or me d P K para meters f or eac h a nal yte of 
i nterest will be perf or me d. T he statistical m o deli n g will be base d o n t he P K A nal ysis Set f or t he 
a nal yte u n der e val uati o n. F or eac h a nal yte, all partici pa nts wit h a vaila ble data f or t he P K 
para meter u n der e val uati o n will be i ncl u de d i n t he m o deli n g. 
C o m paris o ns of i nterest are s h o w n i n Ta ble 8- 3 . 


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T a ble 8- 3.  
St atistic al C o m p aris o ns f or P h ar m ac o ki netic A n al yses
C o m p aris o n
A n al ytes
P K P ar a meter
Test 
Refere nce
N o Effect 
B o u n d ar y f or 
L o wer B o u n d 
of 9 0 % CI
Sec o n d 
Tri mester
Wee k 6 p ost-
part u m
> 5 0 %
Sec o n d 
Tri mester
Wee k 1 2 p ost-
part u m
> 5 0 %
T hir d 
Tri mester
Wee k 6 p ost-
part u m
> 5 0 %
BI C 
A U C ta u
C ma x
C ta u
U n b o u n d A U C ta u 
U n b o u n d C ma x 
U n b o u n d C ta u 
T hir d 
Tri mester
Wee k 1 2 p ost-
part u m
> 5 0 %
Sec o n d 
Tri mester
Wee k 6 p ost-
part u m
> 5 0 %
Sec o n d 
Tri mester
Wee k 1 2 p ost-
part u m
> 5 0 %
T hir d 
Tri mester
Wee k 6 p ost-
part u m
> 5 0 %
T A F
A U C ta u
C ma x
U n b o u n d A U C ta u 
U n b o u n d C ma x 
T hir d 
Tri mester
Wee k 1 2 p ost-
part u m
> 5 0 %
Sec o n d 
Tri mester
Wee k 6 p ost-
part u m
> 5 0 %
Sec o n d 
Tri mester
Wee k 1 2 p ost-
part u m
> 5 0 %
T hir d 
Tri mester
Wee k 6 p ost-
part u m
> 5 0 %
F T C
A U C ta u
C ma x
C ta u
T hir d 
Tri mester
Wee k 1 2 p ost-
part u m
> 5 0 %
F or eac h a nal yte a n d eac h P K para meter, a para metric ( n or mal t he or y) mi xe d-effects A N O V A 
m o del will be fitte d t o t he nat ural l o g-tra nsf or me d val ues of t he P K para meter u n der e val uati o n 
usi n g S A S ®  P R O C MI X E D.
T he statistical m o del will i ncl u de visit as a fi xe d effect a n d partici pa nt as a ra n d o m effect. T he 
f oll o wi n g sa m ple S A S P R O C MI X E D c o de will pr o vi de t he treat me nt c o m paris o n a nal ysis f or 
BI C a nal yte a n d para meter ‘ A U Cta u’, a n d t he 9 0 % CI calc ulati o ns f or nat ural l o g-tra nsf or me d 
P K para meters.
p r o c  m i x e d ;
w h e r e  a n a l y t e = ‘ B I C ’  a n d  p a r a m = ‘ A U C t a u ’ ;
c l a s s  s u b j i d  v i s i t ;
m o d e l  l n e s t  =  v i s i t /  d d f m = k r ;  


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C O N FI D E N TI A L
Pa ge 4 7
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r a n d o m  s u b j i d ;
l s m e a n s  v i s i t  /  d i f f  c l  a l p h a  =  0 . 1 ;
o d s  o u t p u t  E s t i m a t e s  =  L S _ D i f f s  L S M e a n s  =  L S _ M e a n s  C o v P a r m s  =  M S E ;
r u n ;
T he E S TI M A T E state me nt will be use d t o pr o d uce t he p oi nt esti mate a n d t he c orres p o n di n g 
9 0 % CI of t he differe nce i n P K para meters of i nterest o n a l o garit h mic scale. T he 
test-t o-refere nce rati o a n d ass ociate d 9 0 % CI will be calc ulate d b y ta ki n g t he e x p o ne nti o n of t he 
p oi nt esti mate a n d t he c orres p o n di n g l o wer a n d u p per li mits, w hic h is c o nsiste nt wit h t he 
t w o 1-si de d tests a p pr oac h { U. S. De part me nt of Healt h a n d H u ma n Ser vices 2 0 1 5 }.
I n di vi d ual partici pa nt esti mates of p har mc o ki netic para meters a n d c o m paris o ns wit h f ol d 
c ha n ges ( defi ne d as t he rati o bet wee n t he t w o q ua ntities at 2 visits) will be liste d a n d 
s u m marize d b y visits usi n g descri pti ve statistics.
Ne o n ate:
Plas ma c o nce ntrati o n of BI C a n d T A F will be s u m marize d b y n o mi nal sa m pli n g ti me usi n g 
descri pti ve statistics. T he P K para meters s uc h as ter mi nal half-life of BI C a n d T A F will be 
calc ulate d a n d s u m marize d if p ossi ble.
T he c or d bl o o d t o mater nal bl o o d plas ma c o nce ntrati o ns rati o f or BI C a n d T A F will be 
calc ulate d a n d s u m marize d. If “ B L Q” is prese nt, n o rati o nee d t o be ge nerate d f or t hat rec or d.  
8. 4.  
Se nsiti vit y A n al ysis
Se nsiti vit y a nal ysis ma y be c o n d ucte d f or t he ke y P K a nal yses if t he P K scie ntist i de ntifies P K 
data as q uesti o na ble. T he se nsiti vit y a nal ysis will e xcl u de s pecific data fr o m a nal yses, if 
a p pr o priate. If a se nsiti vit y a nal ysis is dee me d necessar y, a listi n g of t he P K para meter(s) data 
bei n g e xcl u de d, wit h ass ociate d reas o n(s) pr o vi de d b y t he P K scie ntist, will be ge nerate d.


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Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 4 8
1 5 N o v 2 0 2 2
9.   
R E F E R E N C E S
U. S. De part me nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n ( F D A), Ce nter 
f or Dr u g E val uati o n a n d Researc h ( C D E R). H u ma n I m m u n o deficie nc y Vir us- 1 I nfecti o n:  
De vel o pi n g A ntiretr o viral Dr u gs f or Treat me nt. G ui da nce f or I n d ustr y. Sil ver S pri n g, M D. 
N o ve m ber, 2 0 1 5.


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C O N FI D E N TI A L
Pa ge 4 9
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1 0.  
S O F T W A R E
S A S ®  S oft ware Versi o n 9. 4. ( S A S I nstit ute I nc., Car y, N C, U S A) is use d f or all pr o gra m mi n g of 
ta bles, listi n gs, a n d fi g ures.
n Q uer y A d vis or ® Versi o n 8. 5. 1 ( Statistical S ol uti o ns, C or k, Irela n d.) is use d f or sa m ple size a n d 
p o wer calc ulati o n.
P h oe ni x Wi n N o nli n ®  8. 3 ( P harsi g ht C or p orati o n, Pri ncet o n, NJ, U S A) is use d f or 
p har mac o ki netic/ p har mac o d y na mic ( P K/ P D) a nal yses.


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C O N FI D E N TI A L
Pa ge 5 0
1 5 N o v 2 0 2 2
1 1.  
S A P R E VI SI O N
Re visi o n D ate
( D D M M M Y Y Y Y) 
Secti o n 
S u m m ar y of Re visi o n
Re as o n f or Re visi o n


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A P P E N DI C E S
A p pe n di x 1. 
M ater n al a n d Ne o n at al St u d y Pr oce d ures T a bles
M ater n al St u d y Pr oce d ures T a ble 
Visits bef ore t he deli ver y
Deli ver y 
Visit j
P ost- p art u m Visit
St u d y Pr oce d ure 
Scree ni n g 
D a y 1 
Wee k 4
Wee ks 8, 1 2, 1 6, 
2 0 & 2 4 
( de pe n de nt o n 
ti me of 
e nr oll me nt) a
Wee k 6 
Wee k 1 2
3 0- D a y 
F oll o w- u p Visit 
E S D D
Writte n I nf or me d 
C o nse nt
X
Me dical Hist or y
X
C o m plete P h ysical 
E xa mi nati o n b
X 
X 
X
X b
X
X
X
E C G
X
S y m pt o m- directe d 
P h ysical E xa mi nati o n c
X c
X
Vital Si g ns (i ncl u di n g 
wei g ht)
X 
X 
X
X
X
X
X
X
Hei g ht
X
La b orat or y 
Assess me nts d
X 
X
X d
X
X
X
X
Mater nal alfa-
fet o pr otei n le vel
X
Uri ne Pre g na nc y Test e
X
X
X
X


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Versi o n 1. 0
C O N FI D E N TI A L
Pa ge 5 2
1 5 N o v 2 0 2 2
Visits bef ore t he deli ver y
Deli ver y 
Visit j
P ost- p art u m Visit
St u d y Pr oce d ure 
Scree ni n g 
D a y 1 
Wee k 4
Wee ks 8, 1 2, 1 6, 
2 0 & 2 4 
( de pe n de nt o n 
ti me of 
e nr oll ment) a
Wee k 6 
Wee k 1 2
3 0- D a y 
F oll o w- u p Visit 
E S D D
e G F Rf
X 
X
Xe
X
X
HI V- 1 R N A
X 
X 
X
X
X
X
X
X
X
W h ole Bl o o d Sa m ple 
f or HI V- 1 Ge n ot y pi n g g
X
C D 4 + cell c o u nt
X 
X
X
H B V a n d H C V Testi n g 
X
Ultras o u n d h
X
I nte nsi ve P K Sa m ple 
C ollecti o ni, j
X
X
X
X
S parse P K Sa m ple 
C ollecti o n k
X
Plas ma St ora ge Sa m ple
X 
X
X
X
X
X
Dr u g a n d Alc o h ol 
Scree ni n g
X 
X
A d verse E ve nt a n d 
C o nc o mita nt 
Me dicati o n Re vie w
X 
X 
X
X
X
X
X
X
X
Date of Deli ver y
X
Pre g na nc y o utc o me
X
B/ F/ T A F Dis pe nsati o n
X 
X
X
X
X
B/ F/ T A F 
Acc o u nta bilit y
X
X
X
X
X
C CI




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C O N FI D E N TI A L
Pa ge 5 4
1 5 N o v 2 0 2 2
A p pe n di x 2. 
A d verse E ve nts of C O VI D- 1 9 a n d S us pecte d C O VI D- 1 9 I nfecti o n
A n a d verse e ve nt rec or d will be fla g ge d as a d verse e ve nts f or C O VI D- 1 9 a n d S us pecte d C O VI D- 1 9 i nfecti o n if its Me d D R A P T is 
i ncl u de d i n t he pre-s pecifie d P T list, w hic h i ncl u des all P Ts fr o m t he narr o w searc h of t he f oll o wi n g C O VI D- 1 9 S M Qs u n der 
Me d D R A v 2 5. 0 pr o vi de d b y Gilea d G L P S (searc h na me: C O VI D- 1 9 ( S M Q) – Narr o w ) a n d re vie we d b y Gilea d me dical m o nit ors.
S M Q S o urce
A Es f or C O VI D- 1 9 a n d S us pecte d C O VI D- 1 9 i nfecti o n
C O VI D- 1 9 ( S M Q) ( N arr o w Sc o pe)


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C O N FI D E N TI A L
Pa ge 5 5
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A p pe n di x 3. 
D at a C ollecti o n of C O VI D- 1 9 D at a
T his a p pe n di x descri bes t he cli nical trial site c ollecti o n of C O VI D- 1 9 data pertai ni n g t o misse d/ virt ual visits a n d t he data pr ocessi n g 
al g orit h m t hat will be use d t o deter mi ne w hic h visits are missi n g a n d w hic h visits are virt ual.
Data C ollecti o n
A C O VI D- 1 9 s u p ple me nt t o t he e C R F C o m pleti o n G ui deli nes ( C C G) was pr o vi de d b y Cli nical Data Ma na ge me nt t o i nstr uct cli nical 
trial sites wit h data e ntr y e x pectati o ns pertai ni n g t o sce nari os relate d t o t he C O VI D- 1 9 pa n de mic.  If a visit was misse d, sites were 
i nstr ucte d t o e nter “ Visit misse d d ue t o C O VI D- 1 9” a n d if a n i n- pers o n visit was c o n d ucte d virt uall y, sites were i nstr ucte d t o e nter 
“ Virt ual visit d ue t o C O VI D- 1 9”.
Deter mi nati o n of Misse d a n d Virt ual Visits
Nat ural La n g ua ge Pr ocessi n g ( N L P) will be use d t o searc h t he C R F c o m me nt fiel ds t o i de ntif y i nsta nces of “ C O VI D- 1 9”, “ Virt ual”, 
or s y n o n y ms (see Ta ble X- 1 ).  T he searc h ter ms will be mai ntai ne d i n a gl o bal l o o k u p ta ble a n d ca n be m o difie d t o t u ne t he N L P 
m o del. A n y c o m me nts wit h C O VI D- 1 9 searc h ter ms, “ Misse d visit” or “ Virt ual visit” will be assi g ne d as f oll o ws:
i.  
If C O VI D- 1 9 ter ms are i de ntifie d t hr o u g h N L P a n d t he visit date is missi n g, t he n res ult is ” Misse d Visit”
ii.  
If C O VI D- 1 9 a n d Virt ual ter ms are i de ntifie d t hr o u g h N L P f or a visit, t he n res ult is “ Virt ual Visit”. W he n t here are 
m ulti ple rec or ds f or t he sa me partici pa nt a n d t he sa me visit, if o ne rec or d c o ul d be cate g orize d as “ Virt ual Visit”, all 
rec or ds ass ociate d wit h t his partici pa nt a n d t his visit will be cate g orize d as “ Virt ual Visit”
iii.   
Ot her wise res ult is missi n g


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T a ble X- 1.  
E x a m ples of Se arc hi n g Ter ms f or “ C O VI D- 1 9 ” a n d “ Virt u al ” Use d t o I de ntif y Misse d a n d Virt u al Visits
Se arc h Ter ms f or “ C O VI D- 1 9 ”
Se arc h Ter ms f or “ Virt u al ”
C O VI D 1 9
C O R O N A
C O R O N A VI R U S
P A N D E MI C
O U T B R E A K
C RI SI S
L O C K D O W N
Q U A R A N TI N E
S H E L T E R
VI R T U A L
T E L E M E D
T E L E H E A L T H
T E L E P H O N E
R E M O T E
T E L E M E DI CI N E 
T E L E C O N S U L T A TI O N
T E L E P H O NI C A L L Y
P H O N E
H O M E VI SI T
Z O O M
S K Y P E
A p pe n di x 4.
Pr o gr a m mi n g S pecific ati o n
1)
B o d y mass i n de x ( B MI) 
B MI will be calc ulate d o nl y at baseli ne as f oll o ws f or a d ults:
• 
B MI = ( wei g ht [ k g]) / ( hei g ht [ meters] ^ 2)
Baseli ne hei g ht a n d wei g ht will be use d f or t his calc ulati o n. B MI will n ot be p o p ulate d f or ne o nate partici pa nts.
2)
Calci u m C orrecte d f or Al b u mi n
Calci u m c orrecte d f or al b u mi n will be calc ulate d a n d s u m marize d f or t he st u d y. T he f oll o wi n g
f or m ula will be use d w he n b ot h ser u m calci u m a n d al b u mi n res ults f or a gi ve n bl o o d dra w n are
a vaila ble a n d ser u m al b u mi n val ue is < 4. 0 g/ d L.


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• 
Calci u m c orrecte d f or al b u mi n ( m g/ d L) = ser u m calci u m ( m g/ d L) + 0. 8 × ( 4. 0 – al b u mi n ( g/ d L)). 
T o xicit y gra di n g f or calci u m will be a p plie d base d o n t he c orrecte d val ues.
3)
Esti mate d G F R
T he f oll o wi n g f or m ula will be use d t o calc ulate t he esti mate d gl o mer ular filtrati o n (e G F R) rate acc or di n g t o t he C oc kcr oft Ga ult 
f or m ula (e G F RC G ):
• 
e G F R( C G) ( m L/ mi n) = [( 1 4 0 – a ge ( yrs)) × wei g ht [ k g]) × ( 0. 8 5 if fe male)] / ( S Cr ( m g/ d L) × 7 2),
w here wei g ht is t otal b o d y mass i n kil o gra ms, a n d S Cr is ser u m creati ni ne.
4)
Gra de d La b orat or y A b n or malities S u m mar y
T he f oll o wi n g la bels will be use d f or treat me nt-e mer ge nt la b orat or y a b n or malities a n d treat me nt-e mer ge nt Gra de 3 or 4 la b orat or y 
a b n or malities s u m mar y ta bles a n d listi n gs:


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B atter y
L a b Test L a bel
Use d i n l-l a bt o x Listi n g 
T o xicit y Directi o n
L a b Test L a bel
Use d i n t-l a bt o x T a ble
He m o gl o bi n
Decrease
He m o gl o bi n ( Decrease d)
Ne utr o p hils
Decrease
Ne utr o p hils ( Decrease d)
Platelets
Decrease
Platelets ( Decrease d)
He mat ol o g y
W B C
Decrease
W B C ( Decrease d)
Al b u mi n 
Decrease
Al b u mi n ( Decrease d)
Al kali ne P h os p hatase
I ncrease
Al kali ne P h os p hatase (I ncrease d)
A L T
I ncrease
A L T (I ncrease d)
A m ylase
I ncrease
A m ylase (I ncrease d)
A S T
I ncrease
A S T (I ncrease d)
Bicar b o nate
Decrease
Bicar b o nate ( Decrease d)
C orrecte d Calci u m
I ncrease
C orrecte d Calci u m ( H y percalce mia)
C orrecte d Calci u m
Decrease
C orrecte d Calci u m ( H y p ocalce mia)
Creati ne Ki nase ( C K)
I ncrease
Creati ne Ki nase (I ncrease d)
Creati ni ne
I ncrease
Creati ni ne (I ncrease d)
G G T
I ncrease
G G T (I ncrease d)
Li pase
I ncrease
Li pase (I ncrease d)
Ma g nesi u m
Decrease
Ma g nesi u m ( H y p o ma g nese mia)
P h os p hate
Decrease
P h os p hate ( H y p o p h os p hate mia)
Ser u m Gl uc ose ( Fasti n g)
I ncrease
Ser u m Gl uc ose ( Fasti n g, H y per gl yce mia)
Ser u m Gl uc ose ( Fasti n g) 
Decrease
Ser u m Gl uc ose ( Fasti n g, H y p o gl yce mia)
Ser u m Gl uc ose ( N o nfasti n g)
I ncrease
Ser u m Gl uc ose ( N o nfasti n g, H y per gl yce mia)
Ser u m Gl uc ose ( N o nfasti n g)
Decrease
Ser u m Gl uc ose ( N o nfasti n g, H y p o gl yce mia)
Ser u m P otassi u m
I ncrease
Ser u m P otassi u m ( H y per kale mia)
Ser u m P otassi u m
Decrease
Ser u m P otassi u m ( H y p o kale mia)
Ser u m S o di u m
I ncrease
Ser u m S o di u m ( H y per natre mia)
Ser u m S o di u m
Decrease
Ser u m S o di u m ( H y p o natre mia)
T otal Bilir u bi n
I ncrease
T otal Bilir u bi n ( H y per bilir u bi ne mia)
C he mistr y
T otal C h olester ol ( Fasti n g)
I ncrease
T otal C h olester ol ( Fasti n g, H y perc h olester ole mia)


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B atter y
L a b Test L a bel
Use d i n l-l a bt o x Listi n g 
T o xicit y Directi o n
L a b Test L a bel
Use d i n t-l a bt o x T a ble
Tri gl yceri des ( Fasti n g) 
I ncrease
Tri gl yceri des ( Fasti n g, I ncrease d)
L D L ( Fasti n g)
I ncrease
L D L ( Fasti n g, I ncrease d)
Urea Nitr o ge n ( B U N)
I ncrease
Urea Nitr o ge n (I ncrease d)
Uric Aci d
I ncrease
Uric Aci d ( H y per urice mia)
Uric Aci d
Decrease
Uric Aci d ( H y p o urice mia)
Uri ne Bl o o d
I ncrease
Uri ne R B C ( He mat uria, Q ua ntitati ve or Di pstic k) *
Uri ne Gl uc ose
I ncrease
Uri ne Gl uc ose ( Gl yc os uria)
Uri ne Pr otei n
I ncrease
Uri ne Pr otei n ( Pr otei n uria)
Uri nal ysis
Uri ne R B C ( Q ua ntitati ve)
I ncrease
Uri ne R B C ( He mat uria, Q ua ntitati ve or Di pstic k) *
*  
B ot h uri ne R B C base d o n micr osc o pic e xa mi nati o n, la bele d as He mat uria ( Q ua ntitati ve), a n d uri ne bl o o d base d o n a di pstic k, la bele d as He mat uria 
( Di pstic k), are assesse d r o uti nel y a n d assi g ne d a t o xicit y gra de i n t his st u d y. Uri ne R B C base d o n micr osc o pic e xa mi nati o n will be prese nte d i n la b orat or y 
t o xicit y s u m mar y ta bles a n d listi n gs w hile uri ne bl o o d base d o n a di pstic k will be prese nte d i n t he listi n gs o nl y.
5)
U n b o u n d plas ma BI C a n d T A F c o nce ntrati o n
U n b o u n d plas ma BI C a n d T A F c o nce ntrati o n ( n g/ m L) will be c o m p ute d usi n g plas ma BI C a n d T A F c o nce ntrati o n ( n g/ m L) a n d t he 
pr otei n u n b o u n d fracti o n:
• 
U n b o u n d plas ma BI C or T A F c o nce ntrati o n ( n g/ m L) = plas ma c o nce ntrati o n of BI C or T A F ( n g/ m L) × pr otei n u n b o u n d fracti o n.
6)
U nit c o n versi o n f or T F V- D P i n 
T he m olec ular wei g ht f or T F V- D P is 4 4 7. 1 7 g/ m ol ( htt ps:// p u bc he m. nc bi. nl m. ni h. g o v/c o m p o u n d/te n of o vir- di p h os p hate).
Gi ve n t he   
s peci me n is set t o a c o nta nt val ue of 5 0 0 0 milli o n cells/ m L i n t he test, 
C CI
C CI


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• 
1 n g/ milli o n cells T F V- D P fr o m t he   
 sa m ple is e q ui vale nt t o 
0. 0 0 1 µ g / milli o n c ells ×  5 0 0 0 milli o n c ells / m L 
4 4 7. 1 7 g / m ol
=
5 0 0 0 µ m ol / L 
4 4 7. 1 7 
=  
1 1. 1 8 1 4 µ m ol/ L.
C CI
C CI


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S A P- Fi n al- G S- U S- 3 8 0- 5 3 1 0- v 1. 0
E L E C T R O NI C SI G N A T U R E S
Si g n e d b y
M e a ni n g of Si g n at ur e 
S er v er D at e
( d d- M M M-
y y y y h h: m m: s s)
Bi o st ati sti c s e Si g n e d 
1 6- N o v- 2 0 2 2
0 5: 0 1: 3 6
Pr oj e ct T e a m
L e a d er e Si g n e d
1 6- N o v- 2 0 2 2
1 6: 3 1: 4 6
Cli ni c al P h ar m a c ol o g y
e Si g n e d
1 6- N o v- 2 0 2 2
1 8: 3 4: 1 6
P P D
P P D
P P D