Clinical trial NCT03797014
Conditions: HIV-1-infection Hepatitis B
Keywords: HIV-1 Hepatitis B HIV-HBV coinfection Bictegravir B/F/TAF Tenofovir alafenamide Biktarvy
Sponsor: University of Maryland, Baltimore
Start date: 2019-04-30; Completion date: 2023-05-05
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate the efficacy and safety of fixed dose combination (FDC) bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in adults coinfected with both HIV-1 and hepatitis B. As this is a switch study, all eligible subjects enrolled will be switched from their current antiretroviral regimen to B/F/TAF will be followed on treatment for 48 weeks.

Detailed description:

Arms: arm 1: Treatment group (1-arm study)
Interventions: intervention 1: B/F/TAF
Intervention descriptions: intervention 1: Fixed dose combination B/F/TAF (50 mg/ 200 mg/ 25 mg/ tablet) administered orally once daily without regards to food.

Protocol documents:
Prot_SAP_000.pdf: 
Efficacy, Safety, and Tolerability of 
Bictegravir/Emtricitabine/Tenofovir Alafenamide in Adults 
with HIV-HBV Coinfection 
(BEST-HBV)  
 
Protocol Number: HP-00083844 
NCT # 03797014 
Principal Investigators:  
Joel V. Chua, MD 
Institute of Human Virology   
University of Maryland School of Medicine 
725 West Lombard Street,  
Baltimore, MD 21201  
Tel. (410) 706-5704 
Fax (410) 706-3243 
Co-Investigators:  
Helena Kwakwa, MD 
Philadelphia Department of Public Health 
Philadelphia, PA 
 
Funded by: Gilead Sciences Inc., Foster City, CA 
Protocol Version: 4.0 
March 16, 2021 
 
 
CONFIDENTIAL 
The information contained in this protocol is confidential and is intended for the use of the clinical 
investigators and their study staff.  The information in this document is the property of Institute of 
Human Virology, and may not be disclosed unless federal or state law or regulations require such 
disclosure.   This information may be disclosed only to those persons involved in the study who 
have a need to know, with the obligation not to further disseminate this information. 


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PROTOCOL SYNOPSIS 
Title: Efficacy, Safety, and Tolerability of Bictegravir/Emtricitabine/Tenofovir Alafenamide in 
Adults with HIV-HBV Coinfection. 
Short Title: BEST-HBV 
Disease: Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection. 
Primary Objective: 
 To evaluate the efficacy of fixed dosed combination (FDC) bictegravir/emtricitabine/ 
tenofovir alafenamide (B/F/TAF) in adult subjects coinfected with HIV-1 and HBV, as 
determined by HIV-1 RNA <50 copies/mL at Week 24 by US FDA Snapshot Algorithm and/or 
HBV DNA <29 IU/mL at Week 24 by missing = failure method. 
Secondary Objectives: 
 Evaluate the safety and tolerability of FDC B/F/TAF in HIV-HBV coinfected subjects. 
 Evaluate the efficacy of FDC B/F/TAF in adult subjects coinfected with HIV-1 and HBV, as 
determined by HIV-1 RNA <50 copies/mL at Week 48 by FDA Snapshot Algorithm. 
 Evaluate the efficacy of FDC B/F/TAF in adult subjects coinfected with HIV-1 and HBV, as 
determined by HBV DNA <29 IU/mL at Week 48 by missing = failure method. 
 Evaluate the efficacy of FDC B/F/TAF in adult subjects coinfected with HIV-1 and HBV, as 
determined by improvement in CD4 count, ALT normalization, HBeAg loss, HBsAg loss, and 
improvement in FibroScan test scores from baseline to Week 24 and Week 48. 
 
Primary Endpoints: 
 Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 24 by FDA Snapshot 
Algorithm. 
 Proportion of subjects with HBV DNA <29 IU/mL at Week 24 by missing = failure method. 
Secondary Endpoints: 
 Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 by FDA Snapshot 
Algorithm. 
 Proportion of subjects with HBV DNA <29 IU/mL at Week 48 by missing = failure method. 
 Assessment of the safety and tolerability of the FDC B/F/TAF in HIV-HBV coinfected subjects 
as measured by the proportion of subjects who discontinue study medications due to AE. 
 Change from baseline in CD4 cell count and percentage at Week 24 and at 48. 
 Proportion of subjects with normalized ALT at Week 24 and Week 48. 
 Proportion of subjects with HBV e antigen (HBeAg) loss and seroconversion to anti-HBe at 
Week 24 and Week 48. 


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 Proportion of subjects with HBV surface antigen (HBsAg) loss and seroconversion to anti-
HBs at Week 24 and Week 48. 
 Change from baseline in Fibroscan test score at Week 24 and Week 48. 
 
Study Design: 
This is a multicenter, open-label phase 4 study to evaluate the efficacy, safety, and tolerability 
of treatment with fixed dosed combination bictegravir/emtricitabine/tenofovir alafenamide in 
adults with HIV-1 and HBV coinfection who are currently on a stable antiretroviral regimen for 
at least 3 months.  Subjects who provide written informed consent and meet all eligibility 
criteria will receive FDC Bictegravir 50 mg/Emtricitabine 200 mg/tenofovir alafenamide 25 mg 
(B/F/TAF) administered orally, once daily, without regard to food.  Enrolled subjects will be 
followed up for 48 weeks. 
 
 
Target Population: Adults with HIV/HBV coinfection currently on stable antiretroviral regimen 
for at least 3 months. 
Phase of Development: Phase 4. 
Duration of Treatment: 48 weeks. 
Estimated sample size: 60 participants. 
Estimated number needed to screen to achieve sample size: 75. 
Estimated Accrual Period: 12 months. 
 
Inclusion Criteria: 
 Age 18 years or older at enrollment. 
 Documented HIV-1 infection and currently on a stable regimen for at least 3 months prior to 
enrollment. 
 No known history of resistance to tenofovir alafenamide (TAF), emtricitabine (FTC), or 
Bictegravir (BIC) except M184V and M184I.  Those with M184V or M184I mutations will be 
allowed to enroll in the study. 
 Documented chronic HBV infection, based on any of the following: 


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a. Positive HBsAg result or nucleic acid test for HBV DNA (including qualitative, 
quantitative, and genotype testing) or positive HBeAg on two occasions at least 6 
months apart (any combination of these tests performed 6 months apart is 
acceptable); or 
b. Negative immunoglobulin M (IgM) antibodies to HBV core antigen (anti-HBc IgM) 
AND a positive results on one of the following tests: HBsAg, HBeAg, or nucleic acid 
test for HBV DNA (including qualitative, quantitative, and genotype testing) prior to 
or at screening.  
 No current or prior regimen containing three active anti-HBV agents (drugs active against 
HBV includes lamivudine [3TC], adefovir [ADV], entecavir [ETV], emtricitabine [FTC], 
tenofovir disoproxil fumarate [TDF], and tenofovir alafenamide [TAF]). 
 Must have a primary care provider(s) for medical management. 
 Females 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 F) from screening and throughout the duration of the 
study.  Female subjects who utilize hormonal contraceptive as one of their birth control 
methods must have used the same method for at least 3 months prior to study drug dosing. 
 Male subjects must be willing to abstain from heterosexual intercourse or use a condom 
throughout the study period. 
 Stated willingness to comply with all study procedures and availability for the duration of 
the study. 
 Written informed consent must be obtained before any study procedure is performed. 
Exclusion Criteria: 
 Women who are pregnant or breastfeeding. 
 Any known allergies to any of the components of B/F/TAF. 
 Treatment with another investigational drug within three months of enrollment. 
 Abnormal hematological and biochemical parameters at screening, including: 
a. Absolute neutrophil count (ANC) < 750 cells/mm3. 
b. Platelets < 50,000/mm3. 
c. Hemoglobin < 8.5 g/dL. 
d. AST or ALT of > 5 times upper limit of normal (ULN). 
e. Estimated GFR < 30 mL/min/1.73 m2. 
f. Total bilirubin > 1.5 times ULN. 
 Previous or current history of malignancy, other than cutaneous Kaposi’s sarcoma, basal cell 
carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma.  Note: Those 
with a history of malignancy who are in remission for two or more years may be included in 
the study. 


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 An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior to 
screening. 
 Subjects experiencing decompensated cirrhosis (e.g. ascites, encephalopathy, or variceal 
bleeding). 
 Acute hepatitis in the 30 days prior to study entry. 
 Active tuberculosis infection. 
 Subjects receiving ongoing therapy with any  medications contraindicated for co-
administration with B/F/TAF FDC, including but not limited to the following medications in 
the table below: 
Drug Class 
Prohibited Agents# 
Antiarrhythmic Agent 
Dofetilide 
Anticonvulsants 
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbamazepine 
Antimycobacterials 
Rifampin, Rifapentine, rifabutin 
GI Motility Agents 
Cisapride 
Herbal/Natural Supplements 
St. John’s Wort, Echinacea 
Miscellaneous agents  
Mitotane 
# 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. 
 Current alcohol or substance use that in the opinion of the investigator may interfere with 
subject study compliance 
 Any other clinical conditions that in the opinion of the investigator would make the subject 
unsuitable for the study or unable to comply with the dosing requirements 
Sample Size Justification & Statistical Analysis: 
The primary analysis endpoint to evaluate treatment efficacy used to compute the sample size 
is the observed HIV-1 viral suppression rate.  A true suppression rate at Week 24 of at least 91% 
would be considered active in this patient population.  An exact binomial test with a 0.05 type I 
error rate will have 84% power to detect the difference between the null hypothesis proportion 
(number of suppressed/total number treated) of 0.773 (based on published results) and the 
research hypothesis proportion of 0.910 (our educated guess on the desired rate of success) 
when the sample size is 60.  
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................................. 9 
1 
INTRODUCTION ..................................................................................................................... 12 
1.1 
Background & Scientific Rationale ................................................................................. 12 
1.1.1 
Tenofovir alafenamide in HIV-HBV Coinfection ...................................................... 12 
1.1.2 
Bictegravir: New HIV-1 Integrase Strand Transfer Inhibitor ................................... 13 
1.2 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) ........................................ 14 
1.2.1 
Description .............................................................................................................. 14 
1.2.2 
Nonclinical Toxicology and Pharmacology ............................................................. 14 
1.2.3 
Clinical Pharmacology ............................................................................................. 15 
1.2.4 
Clinical Studies on Bictegravir/Emtricitabine/Tenofovir Alafenamide ................... 18 
1.3 
B/F/TAF in HIV-HBV Coinfection & Study Hypothesis .................................................... 18 
1.4 
Risk and Benefit Assessments ........................................................................................ 18 
1.4.1 
Risk of using B/F/TAF (BIKTARVY®) ......................................................................... 18 
1.4.2 
Risk of Fibroscan Test.............................................................................................. 20 
1.4.3 
Risk of Blood Draw .................................................................................................. 20 
1.4.4 
Risk of Electrocardiogram (ECG) ............................................................................. 21 
1.4.5 
Risk of Allergic Reactions ........................................................................................ 21 
1.4.6 
Risk of Loss of Confidentiality ................................................................................. 21 
1.4.7 
Unexpected Risk and Discomforts .......................................................................... 21 
1.4.8 
Potential Benefits .................................................................................................... 21 
2 
OBJECTIVES ............................................................................................................................ 22 
2.1 
Primary Objective ........................................................................................................... 22 
2.2 
Secondary Objectives ..................................................................................................... 22 
2.3 
Exploratory Objectives ................................................................................................... 22 
2.4 
Primary Endpoints .......................................................................................................... 22 
2.5 
Secondary Endpoints ...................................................................................................... 22 
2.6 
Exploratory Endpoints .................................................................................................... 23 
3 
INVESTIGATIONAL PLAN ........................................................................................................ 23 
3.1 
Summary of Study Design .............................................................................................. 23 
3.2 
Study Procedures ........................................................................................................... 24 
3.2.1 
Pretreatment Assessments ..................................................................................... 24 
3.2.2 
Day 1 Assessments .................................................................................................. 25 
3.2.3 
Treatment Assessments .......................................................................................... 26 
3.2.4 
Early Study Drug Discontinuation Assessments ..................................................... 27 
3.2.5 
Criteria for Discontinuation of Study Treatment .................................................... 28 
3.2.6 
End of Study ............................................................................................................ 28 
3.2.7 
Post Study Care ....................................................................................................... 28 


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3.2.8 
Virologic Failure ...................................................................................................... 29 
3.2.9 
Management of Virologic Rebound ........................................................................ 29 
4 
DISCUSSION OF DESIGN ......................................................................................................... 32 
5 
STUDY POPULATION .............................................................................................................. 33 
5.1 
Number of Subjects and Subject Selection .................................................................... 33 
5.2 
Inclusion Criteria ............................................................................................................ 33 
5.3 
Exclusion Criteria ............................................................................................................ 34 
6 
STUDY INTERVENTION ........................................................................................................... 35 
6.1 
Study Assignment ........................................................................................................... 35 
6.2 
Method of Assignment to Study Intervention ............................................................... 35 
6.3 
Study Drug, Materials, and Supplies .............................................................................. 35 
6.3.1 
Formulation, Packaging, and Labeling .................................................................... 35 
6.3.2 
Storage Handling and Preparation.......................................................................... 36 
6.3.3 
Final Disposition of Clinical Supplies ....................................................................... 36 
6.4 
Dosage Administration ................................................................................................... 37 
6.5 
Blinding ........................................................................................................................... 37 
6.6 
Concomitant Medications .............................................................................................. 37 
7 
ADVERSE EVENT AND TOXICITY MANAGEMENT ................................................................... 38 
7.1 
Adverse Events ............................................................................................................... 38 
7.1.1 
Definition of AE ....................................................................................................... 38 
7.1.2 
Reporting Procedures for All Adverse Events ......................................................... 39 
7.1.3 
Adverse Events Severity .......................................................................................... 40 
7.1.4 
Adverse Event Relationship to Study Drug ............................................................. 40 
7.1.5 
Adverse Event Expectedness .................................................................................. 40 
7.2 
Serious Adverse Events .................................................................................................. 41 
7.2.1 
Definition of SAE ..................................................................................................... 41 
7.2.2 
Reporting of SAE ..................................................................................................... 41 
7.3 
Laboratory Tests ............................................................................................................. 42 
7.4 
Reporting of Events to Participants ............................................................................... 42 
7.5 
Reporting of Pregnancy .................................................................................................. 42 
7.6 
Toxicity Management ..................................................................................................... 43 
7.6.1 
Grade 1 and 2 Laboratory Abnormality or Clinical Event ....................................... 43 
7.6.2 
Grade 3 Laboratory Abnormality or Clinical Event ................................................. 43 
7.6.3 
Grade 4 Laboratory Abnormality or Clinical Event ................................................. 43 
7.6.4 
On-Treatment ALT Flare and Exacerbation of Hepatitis B Management ............... 44 
7.6.5 
On-Treatment Hepatitis C Management ................................................................ 45 
7.6.6 
On-Treatment Hepatitis D Management ................................................................ 45 
8 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................... 46 
9 
STATISTICAL CONSIDERATIONS ............................................................................................. 47 
9.1 
General Consideration & Populations for Analyses ....................................................... 47 
9.2 
Sample Size Determination ............................................................................................ 47 


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9.2.1 
Analysis Objectives ................................................................................................. 47 
9.2.2 
Analysis of the Primary Efficacy Endpoints ............................................................. 48 
9.2.3 
Analysis of the Secondary Endpoints ...................................................................... 49 
9.2.4 
Safety Analyses ....................................................................................................... 49 
9.2.5 
Baseline Descriptive Statistics................................................................................. 50 
9.2.6 
Planned Interim Analyses ....................................................................................... 50 
9.2.7 
Subgroup Analyses .................................................................................................. 50 
9.2.8 
Exploratory Analyses ............................................................................................... 50 
10 
ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS .................................. 51 
10.1 
Informed Consent Process ............................................................................................. 51 
10.2 
Study Discontinuation and Closure ................................................................................ 51 
10.3 
Confidentiality and Privacy ............................................................................................ 52 
10.4 
Future Use of Stored Specimens and Data .................................................................... 53 
10.5 
Key Roles and Study Governance ................................................................................... 53 
10.6 
SAFETY OVERSIGHT ........................................................................................................ 53 
10.7 
Clinical Monitoring ......................................................................................................... 54 
10.8 
Data Handling and Record Keeping................................................................................ 54 
10.8.1 
Data Collection and Management Responsibilities ................................................ 54 
10.8.2 
Study Records Retention ........................................................................................ 54 
10.9 
Protocol Deviation .......................................................................................................... 55 
10.10 
Publication and Data Sharing Policy ............................................................................... 55 
10.11 
Conflict of Interest Policy ............................................................................................... 55 
11 
REFERENCES ....................................................................................................................... 56 
APPENDIX A.  SCHEDULE OF ACTIVITIES ....................................................................................... 59 
APPENDIX B.  PROTOCOL AMENDMENT HISTORY ........................................................................ 61 
APPENDIX C.  MANAGEMENT OF CLINICAL & LABORATORY AEs ................................................. 62 
APPENDIX D.  MANAGEMENT OF ON-TREATMENT ALT FLARES .................................................. 63 
APPENDIX E.  DEFINITION OF STAGE 3 OPPORTUNISTIC ILLNESS IN HIV ..................................... 64 
APPENDIX F.  DEFINITION OF CHILDBEARING POTENTIAL, CONTRACTIVE REQUIREMENTS & 
PREGNANCY PRECAUTIONS .......................................................................................................... 65 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
ABBREVIATIONS 
DEFINITIONS 
3TC 
Lamivudine 
ABC 
Abacavir 
ADV 
Adefovir 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Anti-HBc (or HBcAb) 
Hepatitis B core antibody 
Anti-HBe (or HBeAb) 
Hepatitis B e antibody 
Anti-HBs (or HBsAb) 
Hepatitis B surface antibody 
APR 
Antiretroviral Pregnancy Registry 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
B/F/TAF 
Bictegravir/emtricitabine/tenofovir alafenamide 
BP 
Blood pressure 
BIC 
Bictegravir 
BRCP 
Breast cancer resistance protein 
c 
Cobicistat (e.g., as component of EVG/c/FTC/TAF) 
CBC 
Complete blood count 
CFR 
Clinical Research Unit 
CI 
Confidence Interval 
Cmax 
Maximum concentration of a drug achieved after dosing 
CMP 
Comprehensive metabolic panel 
CRU 
Clinical Research Unit 
CYP 
Cytochrome P450 enzyme 
DAIDS 
Division of Acquired Immune Deficiency Syndrome 
DDI 
Drug-drug interaction 
DNA 
Deoxyribonucleic acid 
DOH 
Department of Health 
DTG 
Dolutegravir 
ECG 
Electrocardiogram 
EVG 
Elvitegravir 
FDA 
(US) Food and Drug Administration 
FDC 
Fixed dose combination 
FSH 
Follicle stimulating hormone 
FTC 
Emtricitabine 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBcrAg 
Hepatitis B core related antigen 


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HBeAg 
Hepatitis B e antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HDV 
Hepatitis D virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
hsCRP 
High sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IgM 
Immunoglobulin M 
IHV 
Institute of Human Virology 
INR 
International normalized ratio 
INSTI 
Integrase stand transfer inhibitor 
IRB 
Institutional Review Board 
IU 
International units 
MATE 
Multidrug and toxin extrusion transporter 
mL 
Milliliter 
N 
Number 
NCT 
National Clinical Trial 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
NRTI 
Nucleos(t)ide reverse transcriptase inhibitor 
OCT 
Organic cation transporter 
OHRP 
Office for Human Research Protection 
P 
Pulse rate 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
P-gp 
P-glycoprotein 
PI 
Principal Investigator 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PVE 
(Gilead Sciences) Pharmacovigilance and Epidemiology 
QA 
Quality assurance 
QC 
Quality control 
QD 
Once daily (i.e. quaque die) 
R 
Respiratory rate 
RAL 
Raltegravir 
RAV 
Resistance associated variant 
RBC 
Red blood cell (erythrocyte) count 


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RHD 
Recommended human dose 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SC 
Study coordinator 
SMC 
Safety Monitoring Committee 
T 
Temperature 
t1/2 
Half-life 
tmax 
Time after administration of a drug when the maximum 
plasma concentration is reached 
TAF 
Tenofovir alafenamide 
TDF 
Tenofovir disoproxil fumarate 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
U.S. 
United States 
VL 
Viral load 
WBC 
White blood cell count 
WOCP 
Woman of childbearing potential 
Wt 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 


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1 INTRODUCTION 
1.1 Background & Scientific Rationale 
Human immunodeficiency virus-1 (HIV-1) infection is a life-threatening and serious disease that 
is of global public health importance.  More than 37 million people worldwide are living with 
HIV-1 infection.  Of these HIV-1 infected populations, about 5-20% are also coinfected with the 
hepatitis B virus (HBV) (Singh K, et al. 2017).  In the United States (U.S.), about 10% of people 
with HIV are coinfected with HBV, and about 20% of all new HBV infections are among gay and 
bisexual men (CDC Fact Sheet 2017).  HIV-HBV coinfection has been associated with a higher 
risk of morbidity and mortality, especially with regard to accelerated liver disease progression 
leading to hepatic failure, need for liver transplantation, and death (Colin JF, et al. 1999; Thio CL 
2002).  In addition, HBV coinfection accelerates immunologic and clinical progression of HIV 
infection as well as increases the risk of hepatotoxicity when combination antiretroviral therapy 
(ART) are used (Sun HY et al. 2014).  Nevertheless, the availability of HBV-active ART regimens 
has significantly improved the outcome of the HIV-HBV coinfected population, leading to longer 
life expectancies and lower rates of morbidities.  
The University of Maryland Medical System has multiple clinical practices that care for patients 
living with HIV-1 and chronic HBV.  Close to four thousand patients infected with HIV-1 are 
under its care.    The estimated prevalence rate of HIV-HBV coinfection in these clinical 
practices are between 2-3%.  The HIV/HBV target population is predominantly Black or of 
African American heritage (89%) followed by White (9.6%), and close to 80% are males.  
Approximately 87% are already on tenofovir (either TDF or TAF) based regimen as part of their 
backbone NRTI.  In addition, majority of these coinfected patients are on integrase inhibitor 
(63.8%), though some are still on NNRTIs (14.5%) and others on various protease inhibitors 
(21.7%).  Of those on integrase inhibitors, two-thirds are on dolutegravir (65.9%), while the rest 
are on either elvitegravir (27.3%) or raltegravir (6.8%). 
1.1.1  Tenofovir alafenamide in HIV-HBV Coinfection 
Tenofovir, in the form of tenofovir disoproxil fumarate (TDF) has been one of the mainstay 
agents for the treatment of chronic HBV infection.  Tenofovir disoproxil fumarate has 
demonstrated potency and predictable high long-term efficacy resulting in sustained HBV viral 
suppression with favorable safety profile (EASL 2017).  The durability of tenofovir based therapy 
has been well documented with published data as long as 7-years showing 99.3% of patients 
(N=427) taking TDF maintaining viral suppression.  In this publication by Dr. Maria Buti and 
colleagues, 80% had ALT normalization, and close to 12% of HBeAg-positive chronic HBV 
subjects had HBsAg loss (Buti M et al. 2015).  Long-term therapy with TDF was also associated 


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with regression of fibrosis in up to 80% by year 5 (Marcellin P et al. 2013).  In addition, no 
resistance to TDF was detected in these multi-year studies (Buti M et al. 2015).   The lack of 
resistance-associated variants (RAV) developing during TDF therapy has be thought to be 
related to several possible factors including: (1) the high binding affinity of tenofovir to YMDD 
(the HBV reverse transcriptase target); (2) higher (30 times) dosage of the tenofovir (compared 
to other anti-HBV drugs such as adefovir); and (3) the constrained mutational space due to 
gene overlap in HBV genome (Van Hemert et al. 2014). 
Tenofovir alafenamide (TAF) is a phosphonated prodrug of tenofovir, developed by Gilead 
Sciences, due to its enhanced plasma stability compared to TDF.  This allows higher levels of the 
active intracellular form of tenofovir diphosphate to concentrate in target cells such as the 
hepatocytes and lymphoid cells, for the treatment of HBV and HIV-1, respectively (Mukurami E 
et al 2013; Birkus G et al. 2012).  As it is able to remain mostly intact in the plasma, TAF 
administration is associated with reduced systemic tenofovir exposure compared to TDF, 
resulting in corresponding reduction in renal or bone complications (Agarwal K et al. 2015).  
The efficacy of TAF against chronic HBV infection has been demonstrated in 2 phase III clinical 
trials.  Among HBe antigen negative chronic HBV patients, TAF was found to be non-inferior to 
TDF at 48 weeks with HBV DNA suppression (defined as <29 IU/mL) of 94% vs 93%, respectively 
(Buti M, et al. 2016).  Similarly, among patients with positive HBeAg at baseline, TAF was also 
found to be non-inferior to TDF with HBV suppression rates of 64% versus 67% (p-value not 
significant), respectively (Chan HLY, et al. 2016).  In these studies, TAF had a more favorable 
side effect profile with fewer declines in bone marrow density and smaller changes in renal 
safety parameters compared to TDF at 48 weeks.  Tenofovir alafenamide has been used as a 
component of elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (EVG/c/FTC/TAF) for 
adults with HIV-HBV coinfection in an open-label noncomparative switch study in Study 1249.  
In this study, at 48 weeks of EVG/c/FTC/TAF, 91.7% of the 72 subjects maintained or achieved 
virologic suppression (HIV-1 RNA <50 copies/mL and HBV DNA <29 IU/mL) (Gallant J et al. 
2016).  The seroconversion rate was 2.9% in HBsAg-positive subjects and in 3.9% of HBeAg-
positive subjects.  Those with abnormal ALT at baseline, 40% had ALT normalization.  TAF is a 
major component of the FDC B/F/TAF that is to be investigated in this study. 
1.1.2 Bictegravir: New HIV-1 Integrase Strand Transfer Inhibitor 
Bictegravir (BIC) is a recently approved integrase strand transfer inhibitor (INSTI) with a longer 
dissociation half-life from wild-type and G140S+Q148H mutant integrase-DNA complexes in 
vitro than other INSTIs, including dolutegravir (DTG), raltegravir (RAL), and elvitegravir (EVG) 
(White K, et al. 2017).  Therefore, BIC is predicted to have a higher genetic barrier to resistance 
than other integrase inhibitors.  Bictegravir has a more potent antiviral activity against 


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G140S/Q148H integrase variants in vitro than DTG (Hightower K, et al. 2011).  In addition, BIC 
has a better resistance profile compared to DTG, based upon in vitro data from patient-derived 
clinical isolates (While K, et al. 2016; Tsiang M, et al. 2016).  Bictegravir does not require 
boosting (unlike EVG) and therefore has less drug-drug interaction potential.  Bictegravir is 
currently available only in a fixed-dose combination (FDC) tablet, coformulated with 
Emtricitabine (FTC) and tenofovir alafenamide (TAF), administered as a one pill, once daily 
regimen, and is given with or without food. 
1.2 Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) 
1.2.1 Description 
Bictegravir/emtricitabine/tenofovir alafenamide is FDA-approved (approval date February 
2018) fixed dose combination drug regimen under the brand name BIKTARVY® (Gilead Sciences 
Inc.).  It is indicated as a complete regimen for the treatment of HIV-1 infection in adults who 
have no antiretroviral treatment history or to replace the current antiretroviral regimen in 
those who are virologically suppressed (i.e. HIV-1 RNA <50 copies/mL) on a stable antiretroviral 
regimen (Biktarvy 2018).  Bictegravir/emtricitabine/tenofovir alafenamide contains an HIV-1 
integrase strand transfer inhibitor, bictegravir, and two HIV-1 nucleos(t)ide analog reverse 
transcriptase inhibitors, tenofovir alafenamide (TAF) and emtricitabine (FTC).  Both TAF and FTC 
have activity against HBV infection.  B/F/TAF is a complete regimen that has the potential to 
offer HIV-HBV coinfected patients a simple, once daily regimen containing drug components 
that provides a high barrier to resistance against both HIV-1 and HBV.  B/F/TAF does not require 
boosting, and potentially offers an effective and safe alternative to other regimens, without 
need for human leukocyte antigen (HLA) testing or close monitoring of renal or bone toxicities.    
1.2.2 Nonclinical Toxicology and Pharmacology 
1.2.2.1 Studies of Carcinogenesis, Mutagenesis, and Impairment of Fertility 
Bictegravir was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 
100 mg/kg/day in males and 300 mg/kg/day in females.  BIC was not genotoxic in the reverse 
mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.  BIC did not 
affect fertility, reproductive performance or embryonic viability in male and female rats at 29 
times higher exposures (area under the curve [AUC]) than in humans at the recommended dose 
of 50 mg BIC in B/F/TAF (BIKTARVY®). (Biktarvy 2018) 
Emtricitabine, in long-term carcinogenicity studies, was found to have no drug-related increases 
in tumor incidence found in mice at doses up to 750 mg per kg per day (25 times the human 
systemic exposure at the recommended dose of 200 mg per day in B/F/TAF), or in rats at doses 
up to 600 mg per kg per day (30 times the human systemic exposure at the recommended dose 


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in B/F/TAF).  Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), 
mouse lymphoma or mouse micronucleus assays.   Emtricitabine did not affect fertility in male 
rats at approximately 140 times or in male and female mice at approximately 60 times higher 
exposures (AUC) than in humans given the recommended 200 mg daily dose in BIKTARVY. 
Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through 
sexual maturity at daily exposures (AUC) of approximately 60 times higher than human 
exposures at the recommended 200 mg daily dose in B/F/TAF (BIKTARVY®). (Biktarvy 2018) 
Since tenofovir alafenamide (TAF) is rapidly converted to tenofovir and a lower tenofovir 
exposure in rats and mice was observed after TAF administration compared to TDF 
administration, carcinogenicity studies were conducted only with TDF.  Long-term oral 
carcinogenicity studies of TDF in mice and rats were carried out at exposures up to 
approximately 10 times (mice) and four times (rats) those observed in humans at the 
recommended dose of TDF (300 mg) for HIV-1 infection.  The tenofovir exposure in these 
studies was approximately 151 times (mice) and 51 times (rat) those observed in humans after 
administration of the daily recommended dose of B/F/TAF (BIKTARVY®).  At the high dose in 
female mice, liver adenomas were increased at tenofovir exposures approximately 10 times 
(300 mg TDF) and 151 times (BIKTARVY®) the exposure observed in humans. In rats, the study 
was negative for carcinogenic findings.  Tenofovir alafenamide was not genotoxic in the reverse 
mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.  There were 
no effects on fertility, mating performance or early embryonic development when TAF was 
administered to male rats at a dose equivalent to 155 times (25 mg TAF) the human dose based 
on body surface area comparisons for 28 days prior to mating and to female rats for 14 days 
prior to mating through Day 7 of gestation. (Biktarvy 2018) 
1.2.2.2 Animal Toxicology and Pharmacology 
Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs 
with similar severity after three and nine month administration of TAF; reversibility was seen 
after a three-month recovery period.  No eye toxicity was observed in the dog at systemic 
exposures of seven (TAF) and 14 (tenofovir) times the exposure seen in humans with the 
recommended daily TAF dose in B/F/TAF (BIKTARVY®). (Biktarvy 2018) 
1.2.3 Clinical Pharmacology 
1.2.3.1 Mechanism of Action 
Bictegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer 
inhibitor; INSTI), and HIV-1 encoded enzyme that is required for viral replication.  Inhibition of 


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integrase prevents the integration of linear HIV-1 DNA into host genomic DNA, blocking the 
formation of the HIV-1 provirus and propagation of the virus. (Biktarvy 2018) 
Emtricitabine is a synthetic nucleoside analog of cytidine, and is phosphorylated by cellular 
enzymes to form emtricitabine 5’-triphosphate.  Emtricitabine 5’-triphosphate inhibits the 
activity of the HIV-1 reverse transcriptase by competing with the natural substrate 
deoxycytidine 5’-triphosphate and by being incorporated into nascent viral DNA which results in 
chain termination.  Emtricitabine 5’-triphosphate is a weak inhibitor of mammalian DNA 
polymerase α, β, Ɛ, and mitochondrial DNA polymerase γ. (Biktarvy 2018) 
Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine 
monophosphate analog).  Plasma exposure to TAF allows for permeation into cells and then 
TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A.  Tenofovir is 
subsequently phosphorylated by cellular kinases to the active metabolite tenofovir 
diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral 
DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir 
diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial 
DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture. (Biktarvy 
2018) 
Tenofovir alafenamide has clinical trial proven activity against HBV.  Tenofovir alafenamide as a 
lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the 
hepatic uptake transporters OATP1B1 and OATP1B3.  Tenofovir alafenamide is then converted 
to tenofovir through hydrolysis primarily by carboxylesterase 1 (CES1) in primary hepatocytes.  
Intracellular tenofovir is subsequently phosphorylated by cellular kinase to the 
pharmacologically active metabolite tenofovir diphosphate.  Tenofovir diphosphate inhibits 
HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which 
results in DNA chain termination.  Tenofovir diphosphate is a weak inhibitor of mammalian DNA 
polymerase that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to 
mitochondria in cell culture. (Vemlidy 2018) 
1.2.3.2 Pharmacodynamics 
Cardiac electrophysiology studies were conducted in a QT/QTc trial that enrolled 48 health 
volunteers.  In this study, BIC at doses 1.5 to 6 time recommended dose did not affect the 
QT/QTc interval and did not prolong the PR interval.  TAF at the recommended dose or at a 
dose 5 times the recommended dose did not affect the QT/QTc interval and did not prolong the 
PR interval.  The effect of FTC on the QT interval is not known. (Biktarvy 2018) 


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In studies with healthy subjects, the mean change from baseline in serum creatinine with 
administration of BIC 75 mg (1.5 times the approved recommended dosage) once daily with 
food for 14 days was 0.1 mg per dL on Days 7 and 14 compared to placebo.  BID did not have 
significant effect on the estimated creatinine clearance or on the actual glomerular filtration 
rate. (Biktarvy 2018) 
1.2.3.3 Pharmacokinetics 
The pharmacokinetic (PK) properties of B/F/TAF components are summarized in Table 1-1.  The 
multiple dose PK parameters of BIC, FTC, and TAF based on population pharmacokinetic 
analysis as well as a more complete PK description of the regimen and its components are 
found in the BIKTARVY U.S. package insert published by Gilead Sciences Inc.  It should be noted 
that the pharmacokinetics of B/F/ TAF have not been evaluated in subjects coinfected with 
HBV. 
Table 1-1: Pharmacokinetic Properties of BIC, FTC, and TAF 
 
BIC 
FTC 
TAF 
Absorption 
tmax (hours) 
Effect of high fat mean (relative to fasting) 
    AUC ratio 
    Cmax ratio 
 
2.0 - 4.0 
 
1.24 (1.16, 1.33) 
1.13 (1.06, 1.20) 
 
1.5 - 2.0 
 
0.96 (0.93, 0.99) 
0.86 (0.78, 0.93) 
 
0.5 - 2.0 
 
1.63 (1.43, 1.85) 
0.92 (0.73, 1.14) 
Distribution 
% bound to human plasma protein 
Blood-to-plasma ratio 
 
>99% 
0.64 
 
<4% 
0.6 
 
~80% 
1.0 
Elimination 
t1/2 (hours) 
 
17.3 (14.8, 20.7) 
 
10.4 (9.0 
 
0.51 (0.45, 0.62) 
Metabolism 
Metabolic pathway(s) 
 
CYP3A 
UGT1A1 
 
Not significantly 
metabolized 
 
Cathepsin A (PBMC) 
CES1 (hepatocytes) 
Excretion 
Major route of elimination 
 
 
% of dose excreted in urine 
% of dose excreted in feces 
 
Metabolism 
 
 
35% 
60.3% 
 
Glomerular filtration 
and active tubular 
secretion 
70% 
13.7% 
 
Metabolism 
 
 
<1% 
31.7% 
The half-life of tenofovir diphosphate, the active metabolite of TAF, is between 150-180 hours 
within the hepatocytes.  In vivo, TAF is hydrolyzed within cells to form tenofovir (major 
metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate.  In vitro 
studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and 
macrophages, and by carboxylesterase 1 (CES1) in hepatocytes. 


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1.2.4 Clinical Studies on Bictegravir/Emtricitabine/Tenofovir Alafenamide 
Bictegravir/Emtricitabine/tenofovir alafenamide (B/F/TAF) has been clinically shown to be 
highly effective in the treatment of HIV-1 infection based upon two phase 3 treatment-naïve 
trials, the Study 1489 and Study 1490.  In Study 1489 study (Gallant J, et al. 2017), N = 631, 
B/F/TAF demonstrated non-inferiority to DTG/ABC/3TC (VL ≤ 50 copies/mL at 48 weeks, 
B/F/TAF 92.4% vs. DTG/ABC/3TC 93.0%, p=0.78).  No treatment emergent resistance developed 
in either treatment arm.  This study excluded HIV-HBV coinfected patients.  In Study 1490 (Sax 
PE, et al. 2017), N = 742, B/F/TAF demonstrated non-inferiority to DTG + TAF/FTC (VL ≤ 50 
copies/mL at 48 weeks, BIC 89% vs DTG 93%, p=0.12).  There were no treatment emergent 
resistance in either arm.   In contrast to the previous study, HBV coinfection were allowed to be 
enrolled in Study 1490.  Nevertheless, of the 320 patients in the study who received B/F/TAF, 
only eight (2%) subjects were coinfected with HBV (Sax PE, et al. 2017).  
1.3 B/F/TAF in HIV-HBV Coinfection & Study Hypothesis 
Though the safety and efficacy of B/F/TAF has been well established in the treatment of HIV-1 
infection and TAF has been found to be as efficacious and durable as TDF in the treatment of 
HBV infection, there is limited data on the use of B/F/TAF in the HIV-HBV coinfected 
subpopulation.  The 2 phase III registration studies (Treatment-naïve Study 1490 and switch 
Study 1878) that allowed HIV/HBV coinfected subjects to be enrolled had a total of only 16 
coinfected subjects who received B/F/TAF (Gallant J, et al. 2017, Sax PE, et al. 2017).  In Study 
1490, all eight coinfected participants who received B/F/TAF had HIV-1 RNA ≤50 copies/mL and 
HBV DNA <29 IU/mL at Week 48 (Rockstroh JK et al. 2018).  Likewise, in Study 1878, all eight 
volunteers with HIV-HBV coinfection maintained suppression against both viruses (Rockstroh JK 
et al. 2018).  Thus, there is a need for additional data to further validate the use of B/F/TAF as a 
mainstay regimen in the treatment of HIV-HBV coinfected people.  This study will be conducted 
to obtain real-world data in a larger population to help address this need.  The main hypothesis 
of this study is that fixed-dose combination (FDC) B/F/TAF is safe and efficacious in the 
treatment of adults coinfected with HIV-1 and HBV virus. 
1.4 Risk and Benefit Assessments 
1.4.1 Risk of using B/F/TAF (BIKTARVY®) 
1.4.1.1 Adverse Events in Clinical Trials 
The most common adverse events reported in at least 5% of subjects in those who have taken 
B/F/TAF are diarrhea, nausea, and headache.  The proportion of subjects who discontinued 
treatment with B/F/TAF due to adverse events, regardless of severity was 1%.  The majority 
(87%) of adverse events associated with B/F/TAF were Grade 1.  Table 1-2 displays the 


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frequency of adverse events greater than or equal to 2% in the two treatment naïve registry 
studies (Study 1489 and study 1490), attributed to study drug by the investigator. (Biktarvy 
2018) 
Table 1-2: Adverse Reactions (All Grades) Reported in >2% of HIV Infected Adults with No 
Antiretroviral Treatment History Receiving B/F/TAF in Study 1489 or 1490 (Week 48 Analysis) 
Adverse Reactions 
Study 1489 
N=314 
Study 1490 
N=325 
Diarrhea 
6% 
3% 
Nausea 
5% 
3% 
Headache 
5% 
4% 
Fatigue 
3% 
2% 
Abnormal dreams 
3% 
<1% 
Dizziness 
2% 
2% 
Insomnia 
2% 
2% 
 
1.4.1.2 Pregnancy and Breastfeeding Risks 
The prevalence of birth defects per 100 live births among HIV-1 infected women with a first 
trimester exposure to any ART is 2.7 (95% confidence interval (CI): 2.4-3.1), i.e. 255 outcomes 
with defects of 9,336 live births according to the Antiretroviral Pregnancy Registry, January 
2018 interim report (AP Registry 2018).  This prevalence of defects was not significantly 
different from those with an initial exposure during the 2nd and 3rd trimester, nor was it 
different from non-HIV population based pregnancy registries (AP Registry 2018).  In the U.S. 
general population, the estimated background risk of major birth defects and miscarriage in 
clinically recognized pregnancies is 2–4% and 15–20%, respectively.  
A pregnancy exposure registry (The Antiretroviral Pregnancy Registry or APR) is being used to 
monitors pregnancy outcomes in women exposed to B/F/TAF during pregnancy.  Currently, 
there is insufficient human data on the use of B/F/TAF during pregnancy to inform of drug-
associated risk of birth defects and miscarriage.  Both BIC and TAF use in pregnant women have 
not been evaluated.  There is a limited number of women with use of FTC use during pregnancy 
reported in the APR with prevalence rates not different from general population (AP Registry 
2018).  (Biktarvy 2018) 
In animal studies, there is no evidence of adverse reproductive developmental outcomes 
observed with any of the components of B/F/TAF at exposure that were either not maternally 
toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human 


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dose (RHD).  During organogenesis, systemic exposures to BIC were approximately 36 (rats) and 
0.6 times (rabbits), to FTC were approximately 60 (mice) and 108 times (rabbits), and to TAF 
were approximately two (rats) and 78 times (rabbits) the exposure at the recommended human 
dose of B/F/TAF. (Biktarvy 2018) 
The Center for Disease Control and Prevention recommends that HIV-1 infected mothers in the 
U.S. not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.  
Nevertheless, it is not known whether B/F/TAF or any of its components are present in human 
breast milk, affects human milk production, or has effects on the breastfeeding infant. (Biktarvy 
2018) 
As the effects of B/F/TAF on an unborn baby or a nursing infant are not known, care must be 
taken to avoid pregnancy in female subjects or in female partners of male subjects during this 
study and following completion of study treatment (30 days after completion for women, 14 
days after completion for men).  Subjects will be excluded if they are pregnant, planning to 
become pregnant, or while breast-feeding. 
1.4.2 Risk of FibroScan® Test 
FibroScan® is a noninvasive diagnostic ultrasound based device used to measure liver scarring, 
or fibrosis, caused by various diseases including HBV.  It provides a non-surgical alternative to 
liver biopsy to assess liver damage.   
In preparation for this procedure, subjects will be advised not to eat or drink (excluding water) 
for at least 3 hours prior to procedure.  The FibroScan® test usually takes about 5-10 minutes.  
During the procedure, the subject will lie supine on his/her back with the right arm raised 
behind his/her head and the right abdominal area is exposed.  A trained study staff member 
will apply a water-based gel to the skin and place the non-invasive probe over the liver area. 
Fasting prior to procedure can result in hypoglycemia, lightheadedness or fainting.  During the 
procedure, there is a small but possible risk of localized allergic reaction and irritation related to 
the water-based lubricating gel as well as discomfort due to positioning while in supine 
position.    
1.4.3 Risk of Blood Draw 
Collecting blood samples from a vein may cause pain, bruising, lightheadedness, fainting, 
bleeding and rarely infection at the site of the needle stick. 


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1.4.4 Risk of Electrocardiogram (ECG) 
After an ECG, subjects may experience mild skin irritation, slight redness or itching where the 
recording patches were placed.  They may also need to have chest hair shaved for the 
procedure. 
1.4.5 Risk of Allergic Reactions 
Allergic reaction is always possible with a drug that the study participant has never been 
exposed to before.  Serious allergic reactions that can be life-threatening may occur.  Some 
things that happen during any allergic reaction to any type of medication are: rash, difficulty 
breathing, wheezing, sudden drop in blood pressure, swelling around the mouth, throat, or 
eyes, fast pulse, and/or sweating may occur.  Study participants will be monitored closely for 
any reactions. 
1.4.6 Risk of Loss of Confidentiality 
There is always a potential for the loss of confidentiality.  This risk will be minimized by keeping 
all study data stored and secured.  Electronic data will be password protected. Private 
information will only be given out as listed in the Health Insurance Portability and 
Accountability Act (HIPAA) form. 
1.4.7 Unexpected Risk and Discomforts 
There may be risks in this study that are not yet known, or that happens rarely when subjects 
take these study drugs.  Subjects will be told of any new information that could affect their 
safety during study participation. 
1.4.8 Potential Benefits 
All patients with HIV-1 infection should receive effective antiretroviral therapy.  Selection of 
drugs for HIV-1 patients coinfected with HBV should take into consideration the regimen’s anti-
HBV activity to prevent potentially life-threatening hepatitis flares.  B/F/TAF FDC regimen has 
the potential to offer HIV-HBV infected patients a simple, once daily regimen containing drug 
components that provides a high barrier to resistance against both HIV-1 and HBV.  B/F/TAF 
does not require a boosting agent, and offers an effective and safe alternative to other 
regimens, without need for HLA testing or close monitoring of renal or bone toxicities.   In 
addition, patient participation in this study will contribute to the body of knowledge about 
treatment for HIV-HBV coinfection. 


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2 OBJECTIVES 
2.1 Primary Objective 
 To evaluate the efficacy of fixed dosed combination (FDC) bictegravir/emtricitabine/ 
tenofovir alafenamide (B/F/TAF) in adult subjects coinfected with HIV-1 and HBV, as 
determined by HIV-1 RNA <50 copies/mL at Week 24 by US FDA Snapshot Algorithm and/or 
HBV DNA <29 IU/mL at Week 24 by missing = failure method. 
2.2  Secondary Objectives 
 Evaluate the safety and tolerability of FDC B/F/TAF in HIV-HBV coinfected subjects. 
 Evaluate the efficacy of FDC B/F/TAF in adult subjects coinfected with HIV-1 and HBV, as 
determined by HIV-1 RNA <50 copies/mL at Week 48 by FDA Snapshot Algorithm. 
 Evaluate the efficacy of FDC B/F/TAF in adult subjects coinfected with HIV-1 and HBV, as 
determined by HBV DNA <29 IU/mL at Week 48 by missing = failure method. 
 Evaluate the efficacy of FDC B/F/TAF in adult subjects coinfected with HIV-1 and HBV, as 
determined by improvement in CD4 count, ALT normalization, HBeAg loss, HBsAg loss, and 
improvement in Fibroscan test scores from baseline to Week 24 and Week 48. 
2.3  Exploratory Objectives 
 Evaluate changes in quantitative HBsAg levels during treatment with FDC B/F/TAF. 
 Evaluate any changes in immune activation markers (plasma hsCRP, IL-6, TNF-α, and D-
dimer and cellular HLA-DR+CD38+ CD4 and CD8 T lymphocytes) during treatment with FDC 
B/F/TAF. 
2.4 Primary Endpoints 
 Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 24 by FDA Snapshot 
Algorithm. 
 Proportion of subjects with HBV DNA <29 IU/mL at Week 24 by missing = failure method. 
2.5  Secondary Endpoints 
 Proportion of subjects with HIV-1 RNA <50 copies/mL at Week 48 by FDA Snapshot 
Algorithm. 
 Proportion of subjects with HBV DNA <29 IU/mL at Week 48 by missing = failure method. 
 Assessment of the safety and tolerability of the FDC B/F/TAF in HIV-HBV coinfected subjects 
as measured by the proportion of subjects who discontinue study medications due to AE. 
 Change from baseline in CD4 cell count and percentage at Week 24 and at 48. 


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 Proportion of subjects with normalized ALT at Week 24 and Week 48. 
 Proportion of subjects with HBV e antigen (HBeAg) loss and seroconversion to anti-HBe at 
Week 24 and Week 48. 
 Proportion of subjects with HBV surface antigen (HBsAg) loss and seroconversion to anti-
HBs at Week 24 and Week 48. 
 Change from baseline in Fibroscan test score at Week 24 and Week 48. 
2.6 Exploratory Endpoints 
 Change from baseline in quantitative HBsAg at Week 24 and Week 48. 
 Assessment of changes in immune activation markers (plasma hsCRP, IL-6, TNF-α, and D-
dimer and cellular HLA-DR+CD38+ CD4 and CD8 T lymphocytes) during treatment with FDC 
B/F/TAF. 
3 INVESTIGATIONAL PLAN 
3.1 Summary of Study Design 
This is a multicenter, open-label phase 4 study to evaluate the efficacy, safety, and tolerability 
of treatment with fixed dosed combination bictegravir/emtricitabine/tenofovir alafenamide in 
adults with HIV-1 and HBV coinfection who are currently on a stable antiretroviral regimen for 
at least 3 months.  Two sites are planned to participate: Institute of Human Virology (IHV), 
University of Maryland, Baltimore, MD and Philadelphia Department of Health (DOH) Clinic.  
Subjects who provide written informed consent and meet all eligibility criteria will receive fixed 
dose combination of Bictegravir 50 mg/Emtricitabine 200 mg/tenofovir alafenamide 25 mg 
(B/F/TAF) administered orally one pill once daily, without regard to food.  Study treatment 
duration for enrolled subjects will be 48 weeks.  Safety evaluations will consist of adverse 
event, physical examination (including vital signs), and clinical laboratory data.  Efficacy will be 
evaluated by HIV RNA and HBV DNA levels. 
Figure 3-1. Study Schema 
 


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24 
 
3.2 Study Procedures 
See also Schedule of Activities (Appendix A). 
3.2.1 Pretreatment Assessments 
3.2.1.1 Screening Assessments (Day -90 to Day -3)  
The following screening assessments must be done to determine subject eligibility.  Written 
consent will be obtained before conducting any study procedures. 
 Screen for inclusion/exclusion (see Section 5). 
 Medical History. 
 Complete physical examination, including weight, height, and vital signs (blood pressure, 
respiratory rate, heart rate, and temperature). 
 Collect concomitant medication information. 
 12-lead electrocardiogram (ECG). 
 Plasma HIV-1 RNA. 
 Plasma HBV DNA. 
 Quantitative HBsAg level. 
 CD4 cell count. 
 HBV profile [HBsAg, HBeAg, anti-HBs, anti-HBe, and anti-HBc both IgM and total]. 
 HCV serology. 
 HDV serology. 
 Complete blood count [hematocrit, hematocrit, erythrocyte count (RBC), white blood 
cell count (WBC), percentage and absolute WBC differential counts, platelet count]. 
 Comprehensive metabolic panel [glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, total carbon dioxide, calcium, total protein, albumin, total globulin, 
total bilirubin, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase]. 
 Coagulation tests [activated partial thromboplastin time (PTT), prothrombin time (PT), 
international normalized ratio (INR)]. 
 Urinalysis. 
 Serum pregnancy test for women of childbearing potential (defined as a woman who is 
physiologically capable of becoming pregnant). 
With the exception of the serum pregnancy test, outside clinical laboratory tests may be 
used for screening if it was done within 90 days of screening. 


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3.2.2 Day 1 Assessments 
Screening tests must be available before the subject is eligible for study participation.  Once 
screening is completed and the subject meets all eligibility criteria, the subject will obtain 
baseline evaluations.  Study drug administration may occur after completion of all baseline 
procedures. 
Before Study Drug Administration: 
 Review eligibility criteria (see Section 5) and confirm eligibility of subject. 
 Obtain interval medical history. 
 Conduct complete physical examination, including weight and vital signs [blood 
pressure (BP), respiratory rate (R), heart rate (HR), and temperature (T)]. 
 Collect concomitant medication information. 
 Plasma HIV-1 RNA 
 Plasma HBV DNA. 
 Quantitative HBsAg level. 
 CD4 cell count. 
 HIV-1 genotype/phenotype, if HIV-1 RNA is ≥500 copies/mL. 
 HBV genotype and resistance assay, if HBV DNA is ≥500 IU/mL. 
 Complete blood count. 
 Comprehensive metabolic panel. 
 Urine pregnancy test for women of childbearing potential. 
 FibroScan test (IHV only) – this test may be conducted within 30 days prior to or on 
the Day 1 Visit. 
 Blood for PAXgene DNA and RNA analysis. 
 Blood for storage of plasma, serum, and peripheral blood mononuclear cells (PBMC) 
for future research purposes. 
Study Drug Administration (and Post-Study Drug Assessments): 
 Administer first dose of B/F/TAF. 
 Dispense study drug supply (remainder of 60-day supply). 
 Reinforce study drug instruction: subjects are to take one (1) tablet of B/F/TAF once 
daily upon awakening with at least 8 oz. of plain water, and without regards to food. 
 Dispense Study Drug Diary. 
 Collect adverse event information. 
 Collect concomitant medication information. 
 Instruct subject to bring all study drugs and bottles to each future study visits. 


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3.2.3 Treatment Assessments 
3.2.3.1 Week 4 and 8 Visits (± 7 days) 
 Obtain interval medical history. 
 Conduct targeted physical examination (if needed), including weight and vital signs [BP, 
R, HR, T]. 
 Collect concomitant medication information. 
 Collect adverse event information. 
 Evaluate Patient Diary and number of used and unused tablets. 
 Plasma HIV-1 RNA. 
 Plasma HBV DNA. 
 Quantitative HBsAg level. 
 Complete blood count. 
 Comprehensive metabolic panel. 
 Urine pregnancy test for women of childbearing potential. 
 Blood for storage of plasma, serum, and PBMCs. 
 Dispense study drug supply (30-day supply for Week 4; 60-day supply for Week 8). 
 Reinforce study drug instruction: subjects are to take one (1) tablet of B/F/TAF once 
daily upon awakening with at least 8 oz. of plain water, and without regards to food. 
 Instruct subject to bring all study drugs and bottles to each future study visits. 
3.2.3.2 Week 12, 24, and 36 Visits (± 2 weeks for Week 12 and Week 36; ± 4 weeks for 
Week 24) 
 Obtain interval medical history. 
 Conduct targeted physical examination (if needed), including weight and vital signs [BP, 
R, HR, T]. 
 Collect concomitant medication information. 
 Collect adverse event information. 
 Evaluate Patient Diary and number of used and unused tablets. 
 Plasma HIV-1 RNA. 
 Plasma HBV DNA. 
 Quantitative HBsAg level. 
 CD4 cell count.  
 Complete blood count. 
 Comprehensive metabolic panel. 
 Urine pregnancy test for women of childbearing potential. 
 Blood for PAXgene RNA analysis. 
 Blood for storage of plasma, serum, and PBMCs. 


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 Dispense study drug supply (90-day supply). 
 Reinforce study drug instruction: subjects are to take one (1) tablet of B/F/TAF once 
daily upon awakening with at least 8 oz. of plain water, and without regards to food. 
 Instruct subject to bring all study drugs and bottles to each future study visits. 
Additional Week 24 assessments: 
 HBV profile. 
 FibroScan test (IHV only).  This test may be done during the Week 24 visit, or within 2 
weeks (before or after) the scheduled Week 24 visit. 
3.2.3.3 Week 48 Visit (± 4 weeks): End-of-Study Assessments 
This describes the end-of-study assessments for all subjects including those who discontinue 
study prematurely.  
 Obtain interval medical history. 
 Conduct complete physical examination, including weight and vital signs [BP, R, HR, T]. 
 Collect concomitant medication information. 
 Collect adverse event information. 
 Evaluate Patient Diary and number of used and unused tablets. 
 Plasma HIV-1 RNA. 
 Plasma HBV DNA. 
 Quantitative HBsAg level. 
 CD4 cell count.  
 HIV-1 genotype/phenotype, if HIV-1 RNA is ≥500 copies/mL. 
 HBV genotype and resistance assay, if HBV DNA is ≥500 IU/mL. 
 HBV profile. 
 Complete blood count. 
 Comprehensive metabolic panel. 
 Coagulation tests. 
 Urine pregnancy test for women of childbearing potential. 
 FibroScan test (IHV only).  This test may be done during the Visit, or within 2 weeks 
(before or after) the scheduled Week 48 visit. 
 Blood for PAXgene RNA analysis. 
 Blood for storage of plasma, serum, and PBMCs. 
3.2.4 Early Study Drug Discontinuation Assessments 
If the subject discontinues study drug prior to the Week 48 Visit, the subject will be asked to 
return to the clinic within 72 hours of stopping study drugs for the Early Study Drug 


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Discontinuation Visit.  The subject will be asked to continue attending the scheduled study visits 
through Week 48, unless informed consent has been withdrawn. 
At the Early Study Drug Discontinuation Visit, any evaluation showing abnormal results 
indicating that there is a possible or probable causal relationship with the study drug, will be 
repeated weekly (or as often as deemed prudent by the Investigator) until the abnormality is 
resolved, returns to Day 1, or is otherwise explained, or subject has withdrawn consent. 
Assessments for the Early Study Drug Discontinuation Visit will follow assessments for Week 48 
Visit (see Section 3.1.3.3) except for FibroScan test.  A FibroScan test will be done if this Early 
Study Drug Discontinuation Visit is also an End-of-Study Visit.  Additional safety labs may be 
done at the discretion of the Investigator. 
3.2.5 Criteria for Discontinuation of Study Treatment 
Study medication may be discontinued in the following instances: 
 Intercurrent illness that would, in the judgment of the Investigator, affect assessments 
of clinical status to a significant 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. 
 Subject requests to discontinue for any reason. 
 Subject noncompliance. 
 Pregnancy during the study. 
 Development of active tuberculosis infection. 
 Discontinuation of the study at the request of Gilead, a regulatory agency, or an 
institutional review board (IRB). 
3.2.6 End of Study 
The end of study will be the last patient’s last observation (or visit). 
3.2.7 Post Study Care 
After a subject has completed or terminated their participation in the study, long-term care for 
the subject will remain the responsibility of their primary treating physician. 
 


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3.2.8 Virologic Failure 
HIV-1 virologic failure is defined as virologic rebound or having HIV-1 RNA ≥50 copies/mL at 
study drug discontinuation, Week 24, or Week 48.  
HBV virologic failure is defined as virologic rebound or having HBV DNA ≥29 IU/mL at study drug 
discontinuation, Week 24, or Week 48.  Development of tenofovir resistance plus use of an 
anti-HBV agent (e.g. entecavir) other than the study drug during the treatment period will also 
be considered a HBV virologic failure. 
3.2.9 Management of Virologic Rebound 
Subjects who meet the criteria listed below will be considered to have virologic rebound: 
HIV-1 Virologic Rebound: 
 At any visit, a rebound in HIV-1 RNA ≥50 copies/mL, which is subsequently confirmed at 
the following scheduled or unscheduled visit; OR 
 At any visit, a >1 log10 increase in HIV-1 RNA from nadir which is subsequently confirmed 
at the following scheduled or unscheduled visit. 
Following unconfirmed virologic rebound, subjects will be asked to return to the clinic for a 
scheduled or unscheduled blood draw (2 to 3 weeks after the date of the original test that 
resulted in HIV-1 RNA virologic rebound) for confirmation of virologic rebound.  If virologic 
rebound is confirmed at the scheduled or unscheduled visit and the HIV-1 RNA is ≥500 
copies/mL, the blood sample from the confirmation test will be the primary sample used for 
HIV-1 genotypic and phenotypic testing.  Subjects with documented non-adherence within 72 
hours of the visit may not be tested for resistance.  Resistance testing will be conducted on a 
case-by-case basis.  Any subject may be discontinued at Investigator’s discretion. 
If no resistance is detected, the subject may remain on study drug and a repeat HIV-1 RNA 
should be repeated (approximately 2 to 3 weeks after date of test with HIV-1 RNA ≥50 
copies/mL).  Investigator should carefully evaluate the benefits and risk of remaining on the 
study drug for each individual subject and document this assessment in the medical record. 
Subject who are noncompliant on an ongoing basis will be considered for discontinuation per 
the Investigator’s discretion. 
For subjects who are off study drug but remain on study, it will be the Investigator’s discretion 
to manage virologic rebound. 
Figure 6-1 illustrates the algorithm for the management of subjects who meet the criteria for 
HIV-1 virologic rebound. 


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Figure 6-1: Virologic Rebound Schema for HIV-1. 
 
 
 
HBV Virologic Rebound: 
 At any visit, after achieving HBV DNA <29 IU/mL, a rebound in HBV DNA ≥29 IU/mL, 
which is subsequently confirmed at the following scheduled or unscheduled visit; OR 
 At any visit, a >1 log10 increase in HBV DNA from nadir which is subsequently confirmed 
at the following scheduled or unscheduled visit. 
Following unconfirmed virologic rebound, subjects will be asked to return to the clinic for a 
scheduled or unscheduled blood draw (2 to 3 weeks after the date of the original test that 
resulted in HBV DNA virologic rebound) for confirmation of virologic rebound.  If virologic 
rebound is confirmed at the scheduled or unscheduled visit and the HBV DNA is ≥500 IU/mL, 
the blood sample from the confirmation test will be the primary sample used for HBV 
genotyping and drug resistance assay.  Subjects with documented non-adherence within 72 
hours of the visit may not be tested for resistance.  After a subject’s first postbaseline 
resistance test, additional testing will be conducted on a case-by-case basis.  Any subject may 
be discontinued at Investigator’s discretion. 
If no resistance is detected, the subject may remain on study drug and a repeat HBV DNA 
should be repeated (approximately 2 to 3 weeks after date of latest test with HBV DNA ≥29 


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IU/mL).  Investigator should carefully evaluate the benefits and risk of remaining on the study 
drug for each individual subject and document this assessment in the medical record. 
Subject who are noncompliant on an ongoing basis will be considered for discontinuation per 
the Investigator’s discretion. 
For subjects who are off study drug but remain on study, it will be the Investigator’s discretion 
to manage virologic rebound. 
Figure 6-2 illustrates the algorithm for the management of subjects who meet the criteria for 
HBV virologic rebound. 
 
*Addition of a “3rd” HBV agent in the setting of tenofovir resistance is considered a HBV virologic failure. 
 
 
 
 


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4 DISCUSSION OF DESIGN 
This is a multicenter, open-label phase 4 study to evaluate the efficacy, safety, and tolerability 
of treatment with fixed dosed combination B/F/TAF in adults with HIV-1 and HBV coinfection.  
This study design allows direct assessment of the safety and efficacy of B/F/TAF in this patient 
population. 
Dose: B/F/TAF is FDA-approved as a fixed dose combination one pill once daily taken orally 
without regards to food.  The approved regimen contains 50 mg of bictegravir, 200 mg of 
emtricitabine, and 25 mg of tenofovir alafenamide.  Efficacy of this FDC B/F/TAF for HIV-1 
infection has been established based on four double blind, randomized, active control 
multicenter studies (two treatment naïve and two switch studies) with 1206 subjects receiving 
B/F/TAF and combined virologic suppression rate of 91.8% at Week 48 by FDA Snapshot 
analysis.  In these studies, less than 1% discontinued B/F/TAF due to adverse events.  The 
selected dosing is therefore most appropriate for use in this study. 
Safety Endpoints: The safety assessments used in this trial are standard assessments for Phase 
4 studies evaluating the safety of repeated dosing. 
Efficacy Endpoints: Assessment of quantitative plasma HIV-1 RNA and HBV DNA is the standard 
procedure for determining effectiveness of HIV-1 and HBV therapies, respectively.  Both 
primary and secondary efficacy endpoints use both quantitative HIV-1 RNA and HBV DNA levels 
as main assessment measure.  Additional assessments in this trial (e.g. CD4 count, ALT changes, 
FibroScan test) are also standard measures in trials with HIV-HBV coinfection. 
Length of Assessment: The efficacy and safety assessments will be evaluated through end of 
study.  This period spans a total of 48 weeks for all subjects.  This duration of assessment is 
standard in studies involving HIV-HBV coinfection with primary and secondary endpoints 
marked at Week 24 and Week 48. 
Eligibility Criteria: This is a phase 4 switch study for subjects with HIV-HBV coinfection.  
Eligibility criteria has been designed to include subjects who in real life may or may not be 
virally suppressed but would benefit from use of B/F/TAF.  This will allow a broader applicability 
of the study results to a much wider HIV-HBV coinfection population.  In addition, recent 
studies have shown that high efficacy was observed among subjects with baseline M184V or 
M184I who switched to B/F/TAF with 98% of these subjects achieving HIV-1 RNA <50 copies/mL 
at their last study visit and with no treatment emergent resistance developing (Andreatta K et 
al 2019).  


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5 STUDY POPULATION 
The investigators participating in this study have expertise in the diagnosis and management of 
patients with HIV and HBV.  This study will be conducted in the Institute of Human Virology, 
University of Maryland, Baltimore, MD.  Investigators will diagnose subjects with HIV and HBV 
based on history, physical examination, and laboratory studies.   
Participation in this study is voluntary.  The nature of the study will be fully explained to each 
subject during the informed consent process.  The subjects will have the opportunity to ask 
questions.  An informed consent document will then be signed by the subject and the person 
performing the consent discussion, and retained by the investigator according to Good Clinical 
Practice (GCP).  The investigator will retain all documents according to GCP.  A copy of the 
signed informed consent document will be given to the subject. 
Eligibility for enrollment will be based on the results of screening utilizing the following 
inclusion and exclusion criteria.  
5.1 Number of Subjects and Subject Selection 
This study will enroll approximately 60 subjects who meet the eligibility criteria.  We estimate 
that up to 75 subjects will need to be screened to achieve this enrollment number. 
5.2 Inclusion Criteria 
Subjects may be included in the study only if they meet all of the following criteria: 
1. Age 18 years or older at enrollment. 
2. Documented HIV-1 infection and currently on a stable regimen for at least 3 months 
prior to enrollment. 
3. No known history of resistance to TAF, FTC, or BIC except M184V and M184I.  Those 
with M184V or M184I mutations will be allowed to enroll in the study. 
4. Documented chronic HBV infection, based on any of the following: 
a. Positive HBsAg result or nucleic acid test for HBV DNA (including qualitative, 
quantitative, and genotype testing) or positive HBeAg on two occasions at least 
6 months apart (any combination of these tests performed 6 months apart is 
acceptable); or 
b. Negative immunoglobulin M (IgM) antibodies to HBV core antigen (anti-HBc 
IgM) AND a positive results on one of the following tests: HBsAg, HBeAg, or 
nucleic acid test for HBV DNA (including qualitative, quantitative, and genotype 
testing) prior to or at screening.  


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5. No current or prior regimen containing three active anti-HBV agents (drugs active 
against HBV includes lamivudine [3TC], adefovir [ADV], entecavir [ETV], emtricitabine 
[FTC], tenofovir disoproxil fumarate [TDF], and tenofovir alafenamide [TAF]). 
6. Must have a primary care provider(s) for medical management. 
7. Females 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 F) from screening and throughout the duration of 
the study.  Female subjects who utilize hormonal contraceptive as one of their birth 
control methods must have used the same method for at least 3 months prior to study 
drug dosing. 
8.  Male subjects must be willing to abstain from heterosexual intercourse or use a 
condom throughout the study period. 
9. Stated willingness to comply with all study procedures and availability for the duration 
of the study. 
10. Written informed consent must be obtained before any study procedure is performed. 
5.3 Exclusion Criteria 
Subject meeting any of the following criteria will not be eligible to participate in the study: 
1. Females who are pregnant or breastfeeding. 
2. Any known allergies to any of the components of B/F/TAF. 
3. Treatment with another investigational drug within three months of enrollment. 
4. Abnormal hematological and biochemical parameters at screening, including: 
a. Absolute neutrophil count (ANC) < 750 cells/mm3. 
b. Platelets < 50,000/mm3. 
c. Hemoglobin < 8.5 g/dL. 
d. AST or ALT of > 5 times upper limit of normal (ULN). 
e. Estimated GFR < 30 mL/min/1.73 m2. 
f. Total bilirubin > 1.5 times ULN. 
5. Previous or current history of malignancy, other than cutaneous Kaposi’s sarcoma, 
basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma.  
Note: Those with a history of malignancy who are in remission for two or more years 
may be included in the study. 
6. An opportunistic illness indicative of stage 3 HIV diagnosed within the 30 days prior 
to screening. 
7. Subjects experiencing decompensated cirrhosis (e.g. ascites, encephalopathy, or 
variceal bleeding). 
8. Acute hepatitis in the 30 days prior to study entry. 


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9. Active tuberculosis infection. 
10. Subjects receiving ongoing therapy with any  medications contraindicated for co-
administration with B/F/TAF FDC, including but not limited to the following 
medications in the table below: 
Drug Class 
Prohibited Agents# 
Antiarrhythmic Agent 
Dofetilide 
Anticonvulsants 
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbamazepine 
Antimycobacterials 
Rifampin, Rifapentine, Rifabutin 
GI Motility Agents 
Cisapride 
Herbal/Natural Supplements 
St. John’s Wort, Echinacea 
Miscellaneous Agents  
Mitotane 
# 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. 
11. Current alcohol or substance use that in the opinion of the investigator may 
interfere with subject study compliance. 
12. Any other clinical conditions that in the opinion of the investigator would make the 
subject unsuitable for the study or unable to comply with the dosing requirements. 
6 STUDY INTERVENTION 
6.1 Study Assignment 
This is an open-label study and all eligible subjects will receive fixed dose combination 
bictegravir/emtricitabine/tenofovir alafenamide taken one pill once daily oral treatment. 
6.2 Method of Assignment to Study Intervention 
This is an open-label one-arm study. 
6.3 Study Drug, Materials, and Supplies 
6.3.1 Formulation, Packaging, and Labeling 
Bictegravir 50 mg/Emtricitabine 200 mg/Tenofovir alafenamide 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 


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cellulose. The tablet cores are film-coated with iron oxide red, iron oxide black, polyethylene 
glycol, polyvinyl alcohol, talc, and titanium dioxide. 
The 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. 
6.3.2 Storage Handling and Preparation 
Study drugs should be stored at room temperature of 25oC (77oF); excursions are permitted 
between 15oC and 30oC (59oF and 86oF).  Storage conditions are specified on the label.  Until 
dispensed to the subjects, all bottles of study drugs will be stored in a securely locked area, 
accessible only to authorized site personnel. 
To ensure the stability and proper identification, study drug(s) will not be stored in a container 
other than the container in which they were supplied. 
Bottles will be relabeled by the Investigational Pharmacist as prescribed to each study subject 
after consent is given and subjects are found to be eligible. 
Consideration should be given to handling, preparation, and disposal through measures that 
will minimize drug contact with the body.  Appropriate precautions should be followed to avoid 
direct eye contact or exposure through inhalation when handling. 
6.3.3 Final Disposition of Clinical Supplies 
At the end of the study, final study drug supply and accountability records will be reconciled as 
to drug shipped, drug consumed, and drug remaining.  Any discrepancies noted will be 
documented. 
Subject accountability for study drug will be ensured through subject interview (during visits), 
diaries, and study drug reconciliation at selected visits before dispensing drug supply for the 
next visit interval.  At certain clinic visits, subjects will be asked to return any unused study drug 
to the study site.  Final drug accountability reconciliation will be performed at the subject visit 
occurring at the end of therapy or at early discontinuation.  Unused study drug will be 
destroyed.  


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6.4 Dosage Administration 
Subjects will be instructed to take study drug (1 tablet of B/F/TAF) orally with at least 8 ounces 
of plain water once daily in the morning throughout the treatment period.  On Day 1, the first 
dose of the study medication will be administered in clinic after baseline labs have been drawn. 
Following initial dosing at Day 1, the study team will provide the subject the remainder of the 
30-day study supply to continue on the following day.  Subjects will receive additional 30-day 
supply on Week 4 and Week 8 visits, and 90-day supply on Week 12, 24, and 36 visits. 
The study team will be responsible for explaining the correct use of the study drug to the 
subject, verifying that the instructions are followed properly, maintaining accurate records of 
study drug dispensing, and collection of all used study drug, including empty drug packaging. 
Subjects will be instructed to contact the investigator as soon as possible if a complaint or 
problem with the study drug exists, so that the situation can be assessed in a timely manner. 
6.5 Blinding 
This is an open-label noncomparative study.  Both the subject and study personnel with direct 
contact with the subject will know the study treatment that is administered. 
6.6 Concomitant Medications 
Drug interaction studies have been conducted with B/F/TAF or its components.  A complete 
summary of the pharmacokinetic effects of other drugs on B/F/TAF or its components are 
found in the BIKTARVY® package Insert (Biktarvy 2018).   
Bictegravir is a substrate of CYP3A and UGT1A1.  BIC is also an inhibitor of the organic 
transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro, such 
that coadministration of BIC with drugs that are substrate of OCT2 and MATE1 (e.g. dofetilide) 
may increase their plasma concentration.  On the other hand, TAF is a substrate of P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP), thus, coadministration of drugs 
that inhibit these enzymes may increase the absorption and plasma concentration of TAF.  TAF 
is not an inhibitor of drug transporters P-gp, BCRP, renal transporter MATE1 or OCT2.  At 
clinically relevant concentrations, both BIC and TAF are not an inhibitor of hepatic transporters 
OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1, OAT3, or CYP (including CYP3A) or 
UGT1A1 enzymes.  A list of prohibited medications are listed in Table 6-1. 
 


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Table 6-1: List of Prohibited Medications  
Drug Class 
Prohibited Agents# 
Antiarrhythmic Agent 
Dofetilide 
Anticonvulsants 
Phenobarbital, Phenytoin, Carbamazepine, Oxcarbamazepine 
Antimycobacterials 
Rifampin, Rifapentine 
GI Motility Agents 
Cisapride 
Herbal/Natural Supplements 
St. John’s Wort, Echinacea 
Miscellaneous Agents  
Mitotane 
# 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. 
 
7 ADVERSE EVENT AND TOXICITY MANAGEMENT 
7.1 Adverse Events 
7.1.1 Definition of AE 
An adverse event (AE) will be defined as any new unfavorable or unintended sign, symptom, or 
disease, or change of an existing condition, which occurs during or after treatment, whether or 
not considered treatment-related.  If clinically significant laboratory value lead to or are 
associated with clinical symptom(s), the diagnosis should be reported as an AE.  The lack of 
drug effect is not any AE in clinical trials because the purpose of the clinical trial is to establish 
drug effect. 
An AE does not include the following: 
 Medical or surgical procedure such as surgery, endoscopy, tooth extraction, and 
transfusion.  The condition that led to the procedure may be an AE and must be reported. 
 Pre-existing disease, condition, or laboratory abnormalities present or detected before the 
screening visit that do not worsen. 
 Situations where an untoward medical occurrence has not occurred (e.g. hospitalization for 
elective surgery, social, and/or convenience admissions). 
 Overdose without clinical sequelae. 
 Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 


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an AE.  Such condition or abnormality is considered a pre-existing and should be 
documented on the medical history in the CRF. 
Prior to enrollment, study personnel will note the occurrence and nature of each subject’s 
medical condition(s) in the Medical History section of the CRF.  During the remainder of the 
study, study personnel will again note any change in the condition(s) and the occurrence and 
nature of any adverse events. 
If a subject experiences an AE after the Informed Consent document is signed (entry) but the 
subject is never assigned to treatment (enrollment), the event will only be reported if the 
investigator believes that the event may have been caused by a protocol procedure. 
Adverse event information will be collected from the time subject signs the informed consent 
and until the end of the subject’s study participation, i.e. Study Week 48 (end-of-study visit) or 
earlier if consent has been withdrawn.  All AEs occurring after the subject has entered the study 
(that is, after the Informed Consent document is signed) must be recorded in the CRF.  If the 
study drug is discontinued for a subject, study personnel must report and clearly document the 
circumstances and data leading to any such discontinuation, using designated CRFs.  For AEs, 
the subject should be followed until the event resolves or stabilizes, with frequency of follow-
up at the discretion of the investigator. 
In case the investigator notices an unanticipated benefit to the subject, study personnel should 
enter “unexpected benefit” with the actual event term (for example, the complete actual term 
would be “unexpected benefit – sleeping longer”). 
Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported for tracking purposes.  Data on fetal outcome and breastfeeding are collected for 
regulatory reporting and drug safety evaluation.  
7.1.2 Reporting Procedures for All Adverse Events 
The investigators are responsible for monitoring the safety of subjects who have entered this 
study and noting any event that seems unusual, even if this event may be considered an 
unanticipated benefit to the subject.  The investigator is responsible for appropriate medical 
care of subjects during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that causes the subject to discontinue the study.  The subject should be 
followed until the event is resolved or explained.  Frequency of follow-up will be left to 
discretion of the investigator. 


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7.1.3 Adverse Events Severity 
The Division of AIDS (DAIDS) Table for “Grading the Severity of Adult and Pediatric Adverse 
Events” corrected version 2.1 (July 2017) will be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant.  If the experience is not covered in 
the DAIDS criteria, the following guidelines should be used to grade severity: 
 Mild (grade 1): Mild symptoms causing no or minimal interference with usual social and 
functional activities with intervention not indicated.  
 Moderate (grade 2): Moderate symptoms causing greater than minimal interference with 
usual social and functional activities with intervention indicate.  
 Severe (grade 3): Severe symptoms causing inability to perform usual social and functional 
activities with intervention or hospitalization indicated.  
 Life-threatening (grade 4): Potentially life-threatening symptoms causing inability to 
perform basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death.  
The term “severe” is a measure of intensity and a severe AE is not necessarily serious. 
7.1.4 Adverse Event Relationship to Study Drug 
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
study drug therapy using clinical judgment and the following considerations: 
 Yes (reasonably related): There is reasonable possibility that the event may have been 
caused by the study drug. 
 No (not related): Evidence exist that the adverse event has an etiology other than the study 
drug.  For SAEs, an alternative causality must be provider (e.g., pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication).  
Ineffective treatment should not be considered as causally related in the context of adverse 
event reporting. 
7.1.5 Adverse Event Expectedness 
The investigator will be responsible for determining whether an adverse event is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study 
intervention. 


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7.2 Serious Adverse Events 
7.2.1 Definition of SAE 
A serious adverse event (SAE) is defined as an AE that suggests a significant hazard or side 
effects, regardless of the relationship to study drug.  An SAE includes, but may not be limited to, 
any event that: 
 Results in Death. 
 Is life threatening.  This definition implies that the subject, in the view of the investigator, is 
at immediate risk of death from the event.  It does not include an event that, had it 
occurred in a more serious form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Results in congenital anomaly or birth defect. 
Medical and scientific judgment will be exercised in deciding whether classification of an AE as 
serious is appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization, but may jeopardize the 
subject or require intervention to prevent one of the outcomes listed in the definition above.  
Examples of medically important events include intensive treatment in an emergency room or 
at home for allergic bronchospasms; development of drug dependency or drug abuse.  
Infections resulting from contaminated medicinal product will be considered a medically 
important event.  
7.2.2 Reporting of SAE 
All SAE will be reported to the IRB per institutional guidelines.  SAEs (regardless of relationship) 
must be reported to Gilead Pharmacovigilance and Epidemiology (PVE) Office within fifteen 
(15) calendar days of first becoming aware of the event.  In turn, the study sponsor will be 
responsible for reporting any unexpected fatal or life-threatening suspected adverse reactions 
to the Division of Antiviral Agents at the FDA no later than seven (7) calendar days after receipt 
of the information.  Safety reporting to the FDA will be done within the reporting requirement 
under 21 CFR 312.32. 
The Gilead PVE Office will be notified via fax or email of any potential safety issues or any 
protocol amendments or changes to the informed consent arising from a safety concern 
associated with any Gilead products within fifteen (15) days of first becoming aware of such 
event.  Except for periodic safety reports, copies of all reports submitted to government 
agencies that are related to the study, as well as any correspondence with any such authorities 
will be provided to Gilead Sciences. 


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Contact information:  
Gilead Sciences Inc., Pharmacovigilance and Epidemiology (PVE)  
333 Lakeside Drive, Foster City, CA 94404 
Fax: (650) 522-5477 
Tel: (650) 522-5114 
Email: Safety_FC@gilead.com 
 
7.3 Laboratory Tests 
Clinical laboratory tests will be performed at the time specified in the Study Schedule (see 
Section 12: Schedule of Activities).  All clinical laboratory assessments will be analyzed through 
a designated laboratory. 
The investigator must further evaluate laboratory values that fall outside a clinically accepted 
reference range or values that differ significantly from previous values.  Investigators must also 
document their review of each laboratory report by signing or initialing and dating each report. 
Clinically significant laboratory abnormalities will be reported as AEs. 
7.4 Reporting of Events to Participants 
Any adverse event or serious adverse event that affects the risk/benefit ratio to subjects will 
prompt a revision to the informed consent document.  All subjects will be notified of the 
additional risk and re-consented at their next visit, or earlier if the situation requires. 
7.5 Reporting of Pregnancy 
Pregnancy itself is not an adverse event.  However, complications of pregnancies are AEs and 
may be SAEs.  Pertinent obstetrical information of all pregnancies will be reported to the Gilead 
PVE via fax or email within fifteen (15) calendar days from site awareness of the pregnancy.  .  
The participant will be advised to notify her obstetrician of study agent exposure.   
Pregnancy outcome data (e.g., delivery outcome, spontaneous, or elective termination of the 
pregnancy, presence of absence of birth defects, congenital abnormalities, or other 
complications) will be reported to the Gilead PVE Office within fifteen (15) calendar days of the 
site awareness on a protocol-specified form.   


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7.6 Toxicity Management 
All clinical and clinically significant laboratory toxicities will be managed according to uniform 
guidelines detailed in Appendix C as outlined below. 
 Clinical events and clinically significant laboratory abnormalities will be graded according to 
the Division of AIDS (DAIDS) Table for “Grading the Severity of Adult and Pediatric 
Adverse Events” corrected version 2.1 (July 2017).   
 Grade 3 and 4 laboratory abnormalities that are found to be clinically significant should be 
confirmed by a repeat testing within 3 calendar days of awareness of the results and before 
study drug discontinuation, unless such a delay is not consistent with good medical practice. 
7.6.1 Grade 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 clinical AE or clinically significant laboratory abnormality that is considered 
unrelated to the study drug, the study drug may be continued. 
 For Grade 3 clinical AE or clinically significant laboratory abnormality that is considered to 
be related to study drug confirmed by repeat test, the study drug should be withheld until 
the toxicity returns to ≤ Grade 2.  
 When restarting study drug following resolution of the adverse event, the study drug should 
be restarted at full dose. 
 If a laboratory abnormality recurs to ≥ Grade 3 following rechallenge with study drug and is 
considered related to the study drug, then the study drug should be permanently 
discontinued and the subject managed according to local standard of care practice.  
Recurrence of laboratory abnormalities considered unrelated to study drug may not require 
permanent discontinuation and study drug may be continued according to the discretion of 
the Investigator. 
7.6.3 Grade 4 Laboratory Abnormality or Clinical Event 
 For Grade 4 clinical AE or clinically significant laboratory abnormality confirmed by repeat 
testing that is considered related to the study drug, the study drug should be permanently 
discontinued and subject managed according to local standard of care practice.  The subject 
should be followed as clinically indicated until the laboratory abnormality returns to 
baseline or is otherwise explained, whichever occurs first.  Clinically significant Grade 4 
laboratory abnormality that is not confirmed by repeat testing should be management 
according to the algorithm for the new toxicity grade. 


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 Study drug may be continued without dose interruption for a clinically non-significant Grade 
4 laboratory abnormality (e.g., Grade 4 triglyceride elevation that is nonfasting or that can 
be medically managed) or a clinical event considered unrelated to study drug. 
7.6.4 On-Treatment ALT Flare and Exacerbation of Hepatitis B Management 
On-treatment ALT flare is defined as: 
 Confirmed (within 3 days of awareness of initial laboratory results) serum ALT > 2 x Day 1 
value and >10 x ULN, with or without associated symptoms. 
7.6.4.1 Management of ALT Flare in Subjects Receiving Study Medications 
If laboratory results indicate elevation of ALT > 2 x Day 1 value and > 10 x ULN, the following is 
recommended: 
 Schedule the subject to return to the clinic as soon as possible (ideally within 3 days 
after initial laboratory results were drawn).  During the visit, a clinical assessment of the 
subject will be performed.  The assessment should include a physical examination and 
evaluation of the subject’s mental status.   
 If the ALT elevation is confirmed, check labs for plasma HBV DNA reflex to genotype and 
drug resistance testing, HBV serology, HDV, HAV IgM, and HCV. 
Recommend to check the following laboratory parameters: serum ALT and AST, total bilirubin, 
INR, and serum albumin.  Based on the results of the confirmatory tests, the following 
treatment modifications are recommended: 
If Normal or Stable Total Bilirubin or INR related to Day 1 Liver Function Test 
If ALT levels are elevated (i.e., >2 x Day 1 and >10 x ULN) with normal or stable total bilirubin 
and INR related to Day 1, the subject may remain on study medication and should be 
monitored weekly until ALT levels return to normal or Day 1 level.  During monitoring, if the ALT 
values remain persistently elevated, the Investigator has the discretion based on clinical 
judgment whether to withhold study drug or not. 
If Elevated Total Bilirubin or INR related to Day 1 Liver Function Test 
If ALT levels are elevated (i.e., >2 x Day 1 and >10 x ULN), with total bilirubin confirmed to be 2 
x Day 1 value, and INR level is 0.5 above Day 1, provided both are >ULN, the Investigator should 
consider discontinuing study medication (unless the safety of the patient is of immediate 
concern).  The subject should be monitored weekly as long as ALT, total bilirubin, and INR 
values remain elevated or above Day 1 values. 


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During monitoring, if the ALT values and the liver function tests remain persistently elevated, 
and no alternative cause other than the study drug has been found, the Investigator should 
discuss with a member of the Safety Monitoring Committee whether the study drug should be 
discontinued. 
7.6.4.2 Management of Exacerbation of Hepatitis B in Subjects who have Discontinued 
Study Medication 
If laboratory results indicate (1) an ALT elevation >2 x Day 1 and >10 x ULN alone OR associated 
with (2) abnormal laboratory parameters suggestive of worsening hepatic function (total 
bilirubin >2 x Day 1, INR >0.5 above Day 1, provided both are > ULN) and the subject is on no 
post-study therapy for HBV, the following is recommended: 
 Schedule the subject to return to the clinic as soon as possible (ideally no later than 3 
days after the initial laboratory values were drawn).  During the visit, perform a clinical 
assessment of the subject. 
 Check the following laboratory parameters: serum ALT and AST, bilirubin, INR, and 
albumin. 
 If the ALT elevation is confirmed, check labs for plasma HBV DNA reflex to genotype and 
drug resistance testing, HBV serology (HBsAg and HBsAb), HDV, HAV IgM, and HCV.  If 
serum HBV DNA is increasing, the Investigator should consider immediate initiation of 
approved HBV therapy. 
 The subject should be followed until laboratory parameters (ALT, total bilirubin, INR) 
return to normal or Day 1 up to a maximum of 6 months after the initial occurrence of 
the event. 
7.6.5 On-Treatment Hepatitis C Management 
If a subject tests positive for HCV RNA at screening or develops signs or symptoms of active 
hepatitis C, Sponsor recommends that local medical practice be followed at the discretion of 
the Investigator.  Study medications may be continued without dose interruption.  Should 
subject’s primary treating physician or the Investigator decide to initiate hepatitis C treatment, 
drug-drug interaction should be evaluated.  Subject should return to the clinic for scheduled or 
unscheduled follow up visit(s) according to local medical practice for laboratory evaluation. 
7.6.6 On-Treatment Hepatitis D Management 
If a subject tests positive for HDV at screening or develops signs or symptoms of active hepatitis 
D, Sponsor recommends that local medical practice be followed at the discretion of the 
Investigator. 


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8 QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the U.S. Code of Federal Regulations (CFR) applicable to 
clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR 
Part 812). 
The investigator agrees to be responsible for implementing and maintaining quality control and 
quality assurance systems to ensure that trials are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of GCP, and all 
applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical study. 
The investigator also agrees to conduct the study in an efficient and diligent manner and in 
conformance with this protocol; generally accepted standard of GCP; and all applicable federal, 
state, and local laws, rules and regulations relating to the conduct of the clinical study. 
The investigator must allow study-related monitoring, audits, and inspection by the IRB, 
sponsor (or designee), government regulatory agencies, and, if applicable, University 
compliance and quality assurance groups of all trial-related documents and procedures.   
The investigator shall prepare and maintain accurate study documentation in compliance with 
GCP standards and applicable federal, state, and local laws, rules and regulations.  
The IHV Clinical Research Unit (CRU) will perform internal quality management of study 
conduct, data and biological specimen collection, documentation and completion.  An 
individualized quality management plan will be developed. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be addressed. 
 


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9 STATISTICAL CONSIDERATIONS 
9.1 General Consideration & Populations for Analyses 
The primary analysis for efficacy analyses will employ intention-to-treat (ITT) population 
defined as the full analysis population, which will include all subjects who have received at least 
1 dose of the study drug.   
The secondary analysis for efficacy analyses will employ a per-protocol (PP) population, which 
will include all subjects who have received at least one dose of the study drug, and have not 
committed any major protocol violation, including the violation of key eligibility criteria.  In the 
Week 24 (or Week 48) per-protocol analysis, subjects meeting any of the following criteria will 
be excluded: 
a. Subjects who do not have on-treatment HIV-1 RNA and/or HBV DNA in the Week 24 (or 
Week 48) analysis window, except when missing data is due to discontinuation of study 
drug for lack of efficacy. 
b. Subjects who were removed from study due to nonadherence to study drug or due to 
protocol violation by the subject. 
9.2 Sample Size Determination 
This study is anticipated to screen up to 75 subjects to enroll approximately 60 subjects 
coinfected with HIV and HBV, who are currently on antiretroviral therapy.  The primary analysis 
endpoint to evaluate treatment efficacy used to compute the sample size is the observed HIV-1 
viral suppression rate.  A true suppression rate at Week 24 of at least 91% would be considered 
active in this patient population.  An exact binomial test with a 0.05 type I error rate will have 
84% power to detect the difference between the null hypothesis proportion (number of 
suppressed/total number treated) of 0.773 (based on published results) and the research 
hypothesis proportion of 0.910 (our educated guess on the desired rate of success) when the 
sample size is 60.  
 
9.2.1 Analysis Objectives 
The primary objective of this study is to evaluate the efficacy of FDC B/F/TAF in adults 
coinfected with both HIV-1 and HBV, after switching from their current antiretroviral regimen, 
as determined by HIV-1 RNA <50 copies/mL and/or HBV DNA <29 IU/mL at Week 24.   
The secondary objectives of the study include evaluation of HIV-1 and HBV viral suppression at 
Week 48 as well as safety and tolerability at Week 24 and Week 48. 


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9.2.2  Analysis of the Primary Efficacy Endpoints 
The primary endpoints are: 
 The proportion of subjects with HIV-1 RNA <50 copies/mL at Week 24 as defined by the US 
FDA Snapshot Algorithm. 
 The proportion of subjects with plasma HBV DNA <29 IU/mL at Week 24 using the missing = 
failure method. 
9.2.2.1 US FDA Snapshot Algorithm for HIV-1 Efficacy Analyses 
The analysis window at Week 24 is defined as from Study Day 140 to Day 196.  All HIV-1 RNA 
data collected on-treatment will be used in the snapshot algorithm.  HIV-1 Virologic outcome 
will be defined as the following categories: 
 HIV-1 Virologic Success: this includes subject who have the last available HIV-1 RNA < 50 
copies/mL in the Week 24 analysis window while on study treatment. 
 HIV-1 Virologic Failure: this includes subjects who 
a. Have the last available HIV-1 RNA ≥ 50 copies/mL in the Week 24 analysis window 
while on study treatment, or 
b. Do not have on-treatment HIV-1 RNA data in the Week 24 analysis window and  
1) Discontinue study drug prior to or in the Week 24 analysis window due to 
lack of efficacy, or 
2) Discontinue study drug prior to or in the Week 24 analysis window due to 
reasons other than adverse events (AE), death, or lack of efficacy and have 
the last available HIV-1 RNA up to 1 day after the premature discontinuation 
of the study drug ≥ 50 copies/mL. 
 No HIV-1 Virologic Data in the Week 24 analysis window: this includes subjects who do not 
have on-treatment HIV-1 RNA data in the Week 24 analysis window because of the 
following: 
a. Discontinuation of the study drug prior to or in the Week 24 analysis window due to 
AE or death (regardless of whether the last available HIV-1 RNA up to 1 day after the 
premature discontinuation of the study drug < 50 copies/mL or not), or 
b. Discontinuation of the study drug prior to or in the Week 24 analysis window due to 
reasons other than AE, death, or lack of efficacy (e.g., withdrew consent and loss to 
follow-up) and the last available HIV-1 RNA up to 1 day after the premature 
discontinuation of the study drug is < 50 copies/mL, or 
c. Missing data during the window but remains on study drug. 
 


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9.2.2.2 Missing = Failure Method for HBV Efficacy Analyses 
Similarly, the analysis window at Week 24 for HBV DNA outcomes is defined as from Study Day 
140 to Day 196.  For HBV DNA analysis, this study will use the missing = failure method.  HBV 
virologic outcome will be defined as follows: 
 HBV Virologic Success: this includes subject who have the last available HBV DNA <29 IU/mL 
in the Week 24 analysis window while on study treatment. 
 HBV Virologic Failure: this includes subjects who 
a. Have the last available HBV DNA ≥ 29 IU/mL in the Week 24 analysis window while 
on study treatment, or 
b. Do not have on-treatment HBV DNA data in the Week 24 analysis window regardless 
of reason (e.g. discontinued study drug due to AE, death or lack of efficacy; missed 
Week 24 visit; withdrew consent for any reason). 
9.2.3 Analysis of the Secondary Endpoints 
The secondary endpoints include: 
 The proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 as defined by the US 
FDA Snapshot Algorithm. 
 The proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 48 using the missing = 
failure method. 
 Change from baseline in CD4 cell count and percentage at Week 24 and at 48. 
 Proportion of subjects with normalized ALT at Week 24 and Week 48. 
 Proportion of subjects with HBV e antigen (HBeAg) loss and seroconversion to anti-HBe at 
Week 24 and Week 48. 
 Proportion of subjects with HBV surface antigen (HBsAg) loss and seroconversion to anti-
HBs at Week 24 and Week 48. 
 Change from baseline in Fibroscan test score at Week 24 and Week 48. 
9.2.4 Safety Analyses 
All safety analysis will be performed using the intention-to-treat population.  All safety data 
collected on or after the date, that the study drug was first administered up to the end of the 
subject’s study participation will be summarized for the subject in the safety analysis. 
The primary safety endpoint is the proportion of subjects who discontinues study drug due to 
an adverse event. 
There is no formal stopping rule for this trial.  The toxicity data will be monitored closely 
through the therapy.  Addressing the safety of FDC B/F/TAF, a maximum width 95% confidence 


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interval (CI) for any adverse event, grade 3 or higher toxicity will be about 28%.  For 50 patients 
on the study, if the true unknown probability of a rare toxicity is 0.05 (5%), the probability of 
observing one or more toxicities is 0.92 (92%), and for 3% true toxicity rate, it is 78%.  
9.2.5 Baseline Descriptive Statistics 
Demographics and other baseline characteristics will be summarized by treatment group. 
9.2.6 Planned Interim Analyses 
No interim analyses are planned for this study. 
9.2.7 Subgroup Analyses 
For subgroup analyses, the analysis of the efficacy endpoints will be performed and stratified 
based on age group, sex, race, baseline CD4 count, HBV DNA viral load, baseline HBeAg status, 
and baseline HBsAg level.  
9.2.8 Exploratory Analyses 
Exploratory analyses will include assessment of changes in quantitative HBsAg and immune 
activation markers during study drug treatment.  Immune markers includes plasma hsCRP, IL-6, 
TNF-α, and D-dimer and cellular HLA-DR+CD38+ CD4 and CD8 T lymphocytes.  The exploratory 
analyses will determine group difference in the exploratory endpoints from baseline (Day 1) to 
Week 24 and Week 48 time points using a paired t-test.  All inferential tests will be indicated 
statistical significance with a P-value of less than 0.05 (two-sided). 
 
 
 
 
 
 


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10 ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
10.1 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to participate in 
the study and continues throughout the individual’s study participation.  The informed consent 
form will be IRB-approved and the participant will be asked to read and review the document.  
The investigator is responsible for presenting the risks and benefits of study participation to the 
subject in simple terms using the informed consent document.  The investigator will ensure that 
written informed consent is obtained from each subject or legally authorized representative by 
obtaining the appropriate signatures and dates on the informed consent document before the 
performance of protocol evaluations or procedures.   
Participants must be informed that participation is voluntary and that they may withdraw from 
the study at any time, without prejudice. Copies of the informed consent documents will be 
given to the participants for their records. The informed consent process will be conducted and 
documented in the source document (including the date), and the screening form signed, 
before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
Additionally, employees or students will be made aware that employment status or academic 
standing will not be affected by your participation or non-participation in this study.  Students 
or employees will not be consented by anyone in a supervisory role. 
As the majority of the patient populations from which the study participants are drawn are 
literate, written informed consent will typically be provided during the informed consent 
process.  However, oral consent will be obtained for illiterate participants as consistent with 
UMB IRB Policy without separate IRB approval for each specific use.  At Continuing Reviews, the 
UMB IRB will be informed of the number of illiterate participants who provided consent 
verbally.  A non-study team witness will be present for the oral consenting process. 
10.2 Study Discontinuation and Closure 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause.  
The suspending or terminating party will provide written notification, documenting the reason 
for study suspension or termination, to the study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor, and regulatory authorities in a timely manner.  If the 
study is prematurely terminated or suspended, the Investigator will promptly inform study 


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participants, the IRB, and sponsor, and he will provide the reason(s) for the termination or 
suspension.  Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, DSMB, IRB and/or Food and Drug Administration (FDA) as 
appropriate. 
10.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 


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Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be entered into the electronic database for future analysis.  This will not include 
the participant’s contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry 
and study management systems used by the IHV research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived at the 
IHV. 
10.4 Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored at University of Maryland, Institute of 
Human Virology.  With the participant’s approval within the consent and as approved by local 
IRB, de-identified biological samples may be shared with Gilead Sciences, Inc. with the goal of 
sharing of data.  These samples could be used to research immune response to HBV, its 
complications and other conditions for which individuals with HBV are at increased risk, and to 
improve treatment.  Gilead Sciences, Inc. will also be provided with a code-link that will allow 
linking the biological specimens with the phenotypic data from each participant, maintaining 
the blinding of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have optional biological specimens for future research stored, in which case they will be 
destroyed.   
When the study is completed, access to study data and/or samples will be provided by Dr. Joel 
Chua. 
10.5 Key Roles and Study Governance 
Principal Investigator 
Joel Chua, MD; Assistant Professor 
University of Maryland,  Institute of Human Virology 
725 W. Lombard Street 
410-706-5704 
JChua@ihv.umaryland.edu 
 
10.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a Safety Monitoring Committee (SMC) composed 
of individuals with the appropriate expertise, including experience with the treatment and/or 
care of those with HIV-1 and HBV.  At least two members of the SMC will be independent from 


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the study conduct and free of conflict of interest, or measures should be in place to minimize 
perceived conflict of interest.  The SMC will meet at least semiannually to assess safety and 
efficacy data.  The SMC will provide its input to the study sponsor and Principal Investigator. 
10.7 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial complies with the currently approved protocol/amendment(s), with ICH 
GCP, and with applicable regulatory requirement(s).  
Monitoring will begin as the first two subjects screen for the clinical trial.  This will entail a 
clinical research nurse providing 100% verification of screening consent and data verification of 
the first 2 subjects.  An independent SMC member will be available for consultation as needed 
for any medical concerns.  
Once subjects begin enrollment, consent and eligibility verification will continue at 100%, with 
15% targeted subject data review.   
10.8 Data Handling and Record Keeping 
10.8.1 Data Collection and Management Responsibilities 
All research data and results will be recorded using data collection forms.  Source documents 
will support the data collected and will include, but not limited to; clinical findings and 
observations, laboratory and test data, hospital medical records, physician or office charts, 
physician or nursing notes, recorded data from automated instruments, x-rays, etc.  Research 
data will be entered into a secure electronic database.  This electronic database tracks all data 
corrections made by authorized users, providing audit trails for monitoring or query. 
10.8.2 Study Records Retention 
The investigator is responsible for retaining all essential documents listed in the ICH GCP 
Guideline.  All essential documentation for all study subjects are to be maintained by the 
investigators in a secure storage facility for a minimum of 5 years.  The FDA requires study 
records to be retained for up to 2 years after marketing approval or disapproval (21 CFR 
312.62), or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational agent for a specific indication.  These records are also to be 
maintained in compliance with IRB, state, and federal medical records retention requirements, 
whichever is longest.  All stored records are to be kept confidential to the extent required by 
federal, state, and local law. 


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10.9 Protocol Deviation 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP guidelines. 
The noncompliance may be either on the part of the participant, the Investigator, or the study 
staff.  When a protocol deviation by the Investigator or his study staff occurs, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
 5.1 Quality Assurance and Quality Control, section 5.1.1  
 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the Investigator to use continuous vigilance to identify and report 
deviations that constitute Reportable New Information within 5 working days of identification 
of the protocol deviation or as prescribed by local IRB requirements.  The Investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. 
10.10 Publication and Data Sharing Policy 
This trial is registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov.  In addition, every attempt will be made to publish results in 
peer-reviewed journals.   
10.11 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed accordingly.  Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial.   
 
 
 
 
 


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participants with pre-existing M184V/I who switched to bictegravir/emtricitabine/tenofovir 
alafenamide. In: 17th European AIDS Conference. November 6-9, 2019, Basel, Switzerland.  
Abstract PE13/21. 
Antiretroviral Pregnancy Registry Steering Committee. (2018) Antiretroviral pregnancy registry 
interim report for January 1989 through 31 January 2018. Available from URL: 
www.APRegistry.com. 
Agarwal K, Fung SK, Nguyen TT, et al. (2015) Twenty-eight day safety, antiviral activity, and 
pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. J 
Hepatol. 62(3):533-540. 
Biktarvy [U.S. package insert]. Gilead Sciences Inc. Foster City CA. Revised: 2/2018. 
Birkus G, Bam RA, Frey CR, et al. (2012) Intracellular activation pathways for GS7340 and the 
effect of antiviral protease inhibitors. In: 19th Conference on Retroviruses and Opportunistic 
Infections. Mar 5-8, 2012, Seattle, WA. Abstract 577. 
Buti M, Gane E, Seto WK, et al. (2016) Tenofovir alafenamide versus tenofovir disoproxil 
fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: 
a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 
1(3):196-206. 
Buti M, Tsai N, Petersen J, et al. (2015) Severe-year efficacy and safety of treatment with 
tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci. 60(5):1457-
1464. 
Center for Disease Control and Prevention.  (2017) CDC fact sheet: HIV and Viral hepatitis. 
https://www.cdc.gov/hiv/pdf/library/factsheets/hiv-viral-hepatitis.pdf. Accessed 04 Dec 2018. 
Chan HLY, Fung S, Seto WK, et al. (2016) Tenofovir alafenamide versus tenofovir disoproxil 
fumarate for the treatment of HBeAg positive chronic hepatitis B virus infection: a randomised, 
double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 1(3):185–195. 
Colin JF, Cazals-Hatem D, Loriot M a, et al. (1999) Influence of human immunodeficiency virus 
infection on chronic hepatitis B in homosexual men. Hepatology. 29:1306-1310. 


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57 
 
European Association for the Study of the Liver (EASL). (2017) EASL 2017 clinical practice 
guidelines on the management of hepatitis B virus infection. J Hepatol. 67:370-398. 
Gallant J, Brunetta J, Crofoot G, et al. (2016) Brief report: Efficacy and safety of switching to a 
single-tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in HIV-1/ 
hepatitis B-coinfected adults. J Acquir Immune Defic Syndr. 73(3):294-298. 
Gallant J, Lazzarin A, Mills A, et al. (2017) Bictegravir, emtricitabine, and tenofovir alafenamide 
versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-
380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. 
Lancet. 390:2063-2072. 
Hightower KE, Wang R, Deanda F, et al. (2011) Dolutegravir (S/GSK1349572) exhibits 
significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase 
inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother. 55(10):4552-
4559. 
Marcellin P, Gane E, Afdhal N, et al. (2013) Regression of cirrhosis during treatment with 
tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. 
Lancet. 381(9865):468-475. 
Murakami E, Babusis D, Wang T, et al. (2013) Efficient hepatic delivery of tenofovir by prodrug 
tenofovir alafenamide in nonclinical studies supports low-dose treatment of hepatitis B virus. 
HepDart 2013. Dec 8-13, 2013, Hawaii, Hawaii. Abstract 104. 
Rockstroh JK, Sax PE, Daar ES, et al. (2018) High HBV and HIV suppression with treatment of 
HIV/HBV coinfection in B/F/TAF studies. CROI (Boston, MA) Abstract 618, 2018 March 4-7. 
Session number P-K06. 
Sax PE, Pozniak A, Montes ML, et al. (2017) Coformulated bictegravir, emtricitabine, and 
tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for 
initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, 
phase 3, non-inferiority trial. Lancet. 390:2073-2082. 
Singh KP, Crane M, Audsley J, et al. (2017) HIV-hepatitis B virus coinfection: epidemiology, 
pathogenesis, and treatment.  AIDS 31:2035-2052. 


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Sun HY, Sheng WH, Tsai MS, et al. (2014) Hepatitis B virus coinfection in human 
immunodeficiency virus-infected patients: a review. World J Gastroenterol. 20(40):14598-
14614. 
Thio CL. (2002) HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter 
Cohort Study (MACS). Lancet. 360(9349):1921-1926. 
Tsiang M, Jones GS, Goldsmith J, et al. (2016) Antiviral activity of Bictegravir (GS-9883), a novel 
potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile.  
Antimiccrob Agents Chemother. 60(12): 7086-7097. 
Van Hemert FJ, Berkhout B, Zaaijer HL. (2014) Differential binding of tenofovir and adefovir to 
reverse transcriptase of hepatitis B virus. PLoS One. 9(9): e106324. 
Vemlidy [U.S. package insert]. (2018) Gilead Sciences Inc. Foster City CA.  
While KL, Cihlar T, Miller MD. (2016) Potent activity of Bictegravir (BIC; GS-9883), a novel 
unboosted HIV-1 integrase strand transfer inhibitor (INSTI), against patient isolates with INSTI-
resistance. 14th European Workshop on HIV and Hepatitis (Rome, Italy), Abstract O-01, 2016 
May 25-27. 
White KL, Niedziela-Majka A, Novikov N, et al. (2017) Bictegravir dissociation half-life from HIV-
1 G140S+Q148H integrase/DNA complexes. CROI (Seattle WA) Abstract 497, 2017 February 13-
16. Session number P-J3. 
Zheng L., Rosenkranz SL, Taiwo B., et al. (2013) The Design of Single-Arm Clinical Trials of 
Combination Antiretroviral Regimens for Treatment-Naïve HIV-Infected Patients. AIDS Res Hum 
Retroviruses. 29(4):652-657. 
 
 
 
 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
59 
 
APPENDIX A.  SCHEDULE OF ACTIVITIES 
Study Procedures 
Screening   
(D-90 to -3) 
Day 1 
Study Week 
4 
8 
12 
24 
36 
48g 
 Administrative Procedures 
Informed Consent 
X 
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
X 
X 
  
  
  
  
  
  
Complete Medical History 
X 
  
  
  
  
  
  
  
Interval Medical History 
  
X 
X 
 X 
 X  
X  
X 
X  
Administer 1st Dose of Study Drug 
  
X 
  
  
  
  
  
  
Study Drug and Diary Dispensation 
  
X 
X 
X 
X 
X 
X 
  
Study Drug Accountability 
  
  
X 
X 
X 
X 
X 
X 
 Clinical Procedures/Assessments 
Complete Physical Exam 
X 
X 
  
  
  
  
  
X 
Targeted Physical Exam, if needed 
  
  
X 
X 
X 
X 
X 
  
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event   
  
X 
X 
X 
X 
X 
X 
X 
Height 
X 
  
  
  
  
  
  
  
Vital Signs (T, P, R, BP) and Wt 
X 
 X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
  
  
  
  
  
  
  
  Clinical Laboratory Tests 
Plasma HIV-1 RNA 
Xa 
X 
X 
X 
X 
X 
X 
X 
Plasma HBV DNA 
Xa 
X 
X 
X 
X 
X 
X 
X 
Quantitative HBsAg level 
Xa 
X 
X 
X 
X 
X 
X 
X 
CD4 Cell Count 
Xa 
X 
  
  
X 
X 
X 
X 
HBsAg/HBcAb/HBsAb/HBeAg/HBeAb 
Xa 
  
  
  
  
X 
  
X 
HIV-1 Genotype/Phenotypeb 
  
X 
  
  
  
  
  
X 
HBV Resistance Assayc 
  
X 
  
  
  
  
  
X 
HBV Genotypec 
  
X 
  
  
  
  
  
  
HCV serology 
Xa 
  
  
  
  
  
  
  
HDV serology 
Xa 
  
  
  
  
  
  
  
CBC 
Xa 
X 
X 
X 
X 
X 
X 
X 
CMP 
Xa 
X 
X 
X 
X 
X 
X 
X 
Coagulation Tests (PT/PTT) 
Xa 
  
  
  
  
  
  
X 
Fibroscan (IHV only) 
  
Xe 
  
  
  
Xf 
  
Xf 
Urinalysis 
Xa 
  
  
  
  
  
  
  
Urine pregnancy test (if WOCPd) 
  
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test (if WOCPd) 
X 
  
  
  
  
  
  
  
 Research Laboratory Tests 
PAXgene RNA Assay 
  
X 
  
  
X 
X 
X 
X 
PAXgene DNA Assay 
  
X 
  
  
  
  
  
  
PBMC Storage 
  
X 
X 
X 
X 
X 
X 
X 
Plasma Storage  
  
X 
X 
X 
X 
X 
X 
X 
Serum Storage 
  
X 
X 
X 
X 
X 
X 
X 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
60 
 
Legend: 
a May use outside labs if within 90 days. 
b If HIV-1 RNA is ≥500 copies/mL 
c If HBV DNA is ≥500 IU/mL 
d Woman of childbearing potential 
e Fibroscan at Baseline (Day 1) may be conducted within 30 days prior to Day 1 Visit. 
f Fibroscan at Week 24 and Week 48, may be conducted 2 weeks before or after the Study Visit. 
g Week 48 (End of Study) Visit procedures will be used for Early Termination/Subject Withdrawal Visits. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
61 
 
APPENDIX B.  PROTOCOL AMENDMENT HISTORY 
Version 
(version date) 
Affected Sections 
Description of Changes 
Brief Rationale 
1.1 
 
3.2.2. Day 1 
Assessments 
Dispense study drug supply 
from 30-days to up to 60-days 
Allow extra study drug 
to be dispense to 
subjects on Day 1 to 
avoid having them ran 
out before next study 
visit window.  
 
2.0 
 
5.3 Exclusion 
Criteria 
Clarification on history of 
malignancy as an exclusion 
Allow subjects with 
history of malignancy 
that is in remission to 
be included in this 
phase 4 study. 
 
3.0 
 
5.2 Inclusion 
Criteria and Figure 
3-1 in Study 
Schema. Rationale 
in Section 4. 
Discussion of 
Design  
 
Eligibility to allow those with 
M18V mutation and those 
who are currently not HIV 
suppressed to enter the 
study. 
 
 
Allows subjects with 
M184V and M184I 
mutation or having HIV 
viral load not 
suppressed to be 
included in the study as 
these does not affect 
response to B/F/TAF.  
Rationale added to 
Section 4. Discussion of 
Design 
 
4.0 
 
 
3.1 Study Design, 
and 3.2 Study 
Procedures  
Change from single center to 
multicenter study. Fibroscan 
will only be done in the IHV. 
Allow addition of a 
second site (Philadelphia 
DOH clinic). Only IHV 
site has FibroScan to 
conduct this procedure. 
 
 
 
 
 
 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
62 
 
APPENDIX C.  MANAGEMENT OF CLINICAL & LABORATORY AEs 
 
 
 
 
 
 
 
 
 
 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
63 
 
APPENDIX D.  MANAGEMENT OF ON-TREATMENT ALT FLARES 
 
 
 
 
 
 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
64 
 
APPENDIX E.  DEFINITION OF STAGE 3 OPPORTUNISTIC ILLNESS IN HIV 
Based on CDC Guidelines, Stage 3 HIV/AIDS opportunistic infections are as follows: 
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 
23. Salmonella septicemia, recurrent 
24. Toxoplasmosis of brain 
25. Wasting syndrome attributed to HIV infection 
 
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
65 
 
APPENDIX F.  DEFINITION OF CHILDBEARING POTENTIAL, CONTRACTIVE 
REQUIREMENTS & PREGNANCY PRECAUTIONS 
Definition of Childbearing Potential 
For the purpose 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. 
Contraception Requirement for Female Subjects 
a. Study Drug Effect on Pregnancy and Hormonal Contraception 
The effect of B/F/TAF in pregnancy is currently not known.  Relevant non-clinical reproductive 
studies for human pregnancy do not indicate a strong suspicion of human teratogenicity or fetal 
toxicity.   Data from clinical pharmacokinetic interaction studies of B/F/TAF have demonstrated 
that there is no reduction in the clinical efficacy of hormonal contraception or that the effect on 
hormonal contraception is insignificant.  Please refer to the latest BIKTARVY U.S. package insert 
for more information. 
b. Study Drug Effect on Pregnancy and Hormonal Contraception 
To be included in the study, women of childbearing potential requires the use of highly 
effective contraceptive measures.  They must have a negative serum pregnancy test at 
Screening and negative urine pregnancy test on the Day 1 visit prior to enrollment.  At the 
minimum, a pregnancy test will be performed at the end of relevant systemic exposure.  In the 
event of a delayed menstrual period (over one month between menstruations), a pregnancy 
test must be performed to rule out pregnancy.  This will apply even to women of childbearing 
potential with infrequent or irregular periods.   
 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
66 
 
Female subject must agree to at least one of the following from Screening until end of study: 
 Complete abstinence from intercourse of reproductive potential.  Abstinence is an 
acceptable method of contraception only when it is in line with the subject’s preferred 
and usual lifestyle. 
OR 
 Consistent and correct use of 1 of the following methods of birth control: 
− 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) 
OR 
  Consistent and correct use of hormonal method and one barrier method 
− Barrier methods: 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 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 
 
Contraceptive Requirements for Male Subjects 
Relevant systemic concentrations of the study drug may in theory be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with 
female partners of childbearing potential must abstain from heterosexual intercourse or use 
condoms during treatment and until end of study. 


BEST-HBV Protocol Version 4.0: March 16, 2021 
 
67 
 
Procedures to Follow in the Event of Pregnancy 
Subjects will be instructed to notify the study team if they become pregnant at any time during 
the study.  Subject who become pregnant or who is suspected to be pregnant must report the 
information to the Investigator and after a thorough assessment, the study drug may be 
discontinued based on clinical judgment.  Subjects whose partner has become pregnant or 
suspects she is pregnant during the study must report the information to the Investigator. 

ICF_001.pdf: 
Page 1 of 12
RESEARCH CONSENT FORM 
Protocol Title:  Efficacy, Safety, and Tolerability of Bictegravir/Emtricitabine/Tenofovir 
Alafenamide in Adults with HIV-HBV Coinfection.
Study No.: HP-00083844
Principal Investigator: Joel Chua, MD 410-706-5704
Sponsor: Institute of Human Virology
You are being invited to take part in a research study. This Consent Form tells you all about the study.  The study 
staff will talk to you about this information.  Please read the information carefully and talk about it with anyone you 
want.  If you have questions at any time, please ask the study staff or study doctor who will answer your questions.
Before you agree to participate in this study, you need to know the risks and benefits so that you can make an 
informed decision.  This process is known as “informed consent”.   Once you have read the information and know 
about the study, you will be asked to sign this form before joining the study. You will get a copy to keep with you.
Your decision to participate in this study is voluntary.  This means that you are free to decide to join this study or 
not join this study.  You are also free to leave the study at any time.  If you choose not to join this study, there will 
be no impact on your regular medical care.
PURPOSE OF STUDY
This is a study for adults who are infected with both HIV and hepatitis B virus.  The purpose of this research is to 
determine how safe and how effective a medication called BIKTARVY® is on patients that have both HIV and 
hepatitis B infection.  BIKTARVY® is a fixed-dose combination drug containing Bictegravir, Emtricitabine, and 
Tenofovir Alafenamide, and is approved by the Food and Drug Administration (FDA) for the treatment of HIV 
infection.  Tenofovir Alafenamide, which is a component of BIKTARVY®, is FDA-approved for the treatment of 
hepatitis B infection.  BIKTARVY® has not been well studied in patients with both HIV and hepatitis B.
CONCISE SUMMARY:
This is a research study to find out if a drug called BIKTARVY® is safe and effective for the treatment of 
patients with both HIV and hepatitis B virus.  Participation in this research study is voluntary. All eligible 
participants will take BIKTARVY® one pill once daily for the duration of this 48-week treatment study.  
During each of the 8 study visit, your blood will be tested for both HIV and hepatitis B levels.  There are risk to 
taking this study drug that are described in detail in this document.  The most common side effects include 
diarrhea, nausea, and headaches.
If you are interested in learning more about this study, please continue reading below.
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 2 of 12
The long-term goal of our research is to find a highly effective, convenient (one pill once daily), and safe 
medication for the treatment of patient with both HIV and hepatitis B infection.  BIKTARVY® is a one pill once 
daily drug that can be taken without regards to food, and has a high barrier of resistance against both HIV and 
hepatitis B – that is to say, these viruses have a hard time developing resistance against BIKTARVY®.  
We believe that by patients switching to BIKTARVY®, both their HIV and hepatitis B will remain well controlled 
throughout the study.   If you are interested and found to be eligible, you will be asked to switch your current HIV 
drugs to BIKTARVY® for the duration of the study, which is 48 weeks.  The manufacturer, Gilead Sciences, Inc., 
will provide the study drug and funding for this study led by Dr. Joel Chua.
PROCEDURES
This multicenter study is conducted in the Clinical Research Unit of the Institute of Human Virology (IHV) and 
Newlands Health Clinic (Philadelphia PA).  We estimate that we will need to screen 75 people for this study in 
order for 60 people to complete the study treatment.  If you decide to participate in the study and found to be 
eligible for the study treatment, you will be asked to stop taking your current HIV medications, and in its place, you 
will start taking BIKTARVY one pill once daily for 48 weeks.  
If you participate in this study, you will be in the study for about 15 months (1-3 months for screening and 12 
months taking the study treatment.  There will be about eight scheduled study visits, most lasting for 30 minutes to 
2 hours.  Approximately 150 teaspoons of blood will be drawn over the course of the study and is approximately 
the amount of blood drawn during a standard blood donation.  Please refer to the attached detailed study schedules.
If you are a woman of childbearing potential, you will have blood collected for a pregnancy test during the 
screening visit.  The pregnancy test must be negative for you to enroll in the study.  A urine pregnancy test will be 
performed during each study drug treatment.  You will need to stop taking study drugs if you are found to be 
pregnant.  If you think you are pregnant, you must notify study personnel immediately.
Screening Visit
During the screening visit, the study doctor or nurse practitioner will take a complete medical history and perform a 
physical exam.  Study staff will perform some tests or procedures to see if you meet the requirements for being in 
the study.  An electrocardiogram (ECG) will be done to look at your heart rhythm.  Blood tests will be done to find 
out about your health, and we will collect approximately 11 teaspoons of blood.  We will also ask you questions 
about your health.  If you meet the requirements, you will have up to 90 days from this Screening Visit to start the 
study drug treatment.  This screening visit lasts approximately 2 hours.
Day 1 (Start of BIKTARVY)
If you meet all the requirements to participate in the study, and if you agree to do so, you will return to start the 
study.  A study doctor or nurse practitioner will take a medical history and perform a physical exam on you.  We 
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 3 of 12
will check your starting HIV and hepatitis B levels, CD4 cell count, complete blood count, chemistries, and 
research labs.  You will be told to stop your current HIV medications and start taking BIKTARVY® once daily with 
a cup of water every morning for the duration of the study.  You will take the first dose of BIKTARVY® (one 
tablet) with a cup of plain water, while being observed by a study staff.  You will be sent home with the remainder 
of the 60-day supply of BIKTARVY®.  You will also be provided a Patient Diary to take home and where you will 
record the date and time when you take your study drugs.  This visit will last approximately 2 hours.  We will 
collect approximately 25 teaspoons of blood during this Day 1 visit.
For IHV site only: You will also undergo a FibroScan test (a non-invasive ultrasound-based device that measures 
liver stiffness and therefore able to tell the level of scarring from hepatitis B) prior to your first BIKTARVY® dose.  
This test can be done either on your Day 1 visit or as early as 30 days prior to your Day 1 visit.  During the 
Fibroscan test a trained study staff member will apply a water-based gel to the skin and place the non-invasive 
probe over the liver area.  In preparation for this procedure, you will be advised not to eat or drink (including water) 
for at least 3 hours prior to procedure.  This procedure will last approximately 5-10 minutes.
Week 4 and 8
A study nurse will assess you for any side effects and check your current medications.  Blood will be collected to 
test for HIV and hepatitis B levels, CD4 cell count, complete blood count, chemistries, and research labs.  You will 
return with your Patient Diary and remaining study drugs and bottle.  You will be sent home with 30-day and 60-
day supply of study drug for Week 4 and Week 8, respectively.  Approximately 15 teaspoons of blood will be 
collected for these visits.  These visits will take about 30-60 minutes.
Week 12, 24, and 36
A study nurse will assess you for any side effects and check your current medications.  Blood will be collected to 
test for HIV and hepatitis B levels, CD4 cell count, complete blood count, chemistries, and research labs.  You will 
return with your Patient Diary and remaining study drugs and bottles.  You will be sent home with 90-day supply of 
study drug.  Approximately 18 teaspoons (23 teaspoons for Week 24) of blood will be collected for these visits.  
These visits will take about 30-60 minutes.
For IHV site only: In addition, on Week 24, you also undergo a FibroScan test (same as to the one described on 
Day 1 visit).  This test may be done during the Week 24 visit, or within 2 weeks (before or after) of Week 24 visit.  
This procedure will last approximately 5-10 minutes. 
If your HIV and/or hepatitis B levels rebound during study drug treatment, we will ask you to the clinic for a blood 
draw to recheck the virus levels to confirm if this is a true rebound or not.  Blood may also be taken to test for 
genotype and resistance tests.
Week 48 (End-of-Study Visit)
This is the end of study visit.  You will be asked to return all bottles and pills.  You will also be asked to bring and 
return your Patient Diary, which will be kept in your study records.  A study nurse will assess you for any side 
effects and check your current medications.  If needed, a study doctor or nurse practitioner may perform a physical 
examination.  Blood will be collected to test for HIV and hepatitis B levels, CD4 cell count, complete blood count, 
chemistries, clotting labs, and research labs. You will return with your Patient Diary and remaining study drugs and 
bottles.  Approximately 25 teaspoons of blood will be collected during this visit.  This visit will take about 60 
minutes.
For IHV site only: You also undergo a FibroScan test (same as to the one described on Day 1 visit).  This test may 
be done during the Week 48 visit, or within 2 weeks (before or after) of Week 48 visit.  This procedure will last 
approximately 5-10 minutes.  
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 4 of 12
Your long-term HIV and Hepatitis B care after this end of study visit will remain the responsibility of your primary 
treating doctor.  Your doctor may decide to continue you on BIKTARVY® or switch you to a different regimen 
after completion of the study.
RESEARCH STORAGE SAMPLES
To help with this research, we will be collecting blood samples (research storage labs) for use in current and future 
laboratory research.  These samples will be stored by the University of Maryland, Institute of Human Virology 
researchers indefinitely and may be used in future research to learn more about HIV, hepatitis B, and their 
interaction with the immune system.  All samples will be stored with coded numbers.  No identifying information 
will be sent to Gilead Sciences, Inc. for further HIV and hepatitis B research including drug development.  You 
would not receive payment for any new drug discoveries.  If samples are tested for genetic markers, the results will 
not be labeled with your name.  We will not be using the samples to generate a cell line for genetic testing.  
Samples and data will be stored without your name, but will be coded with a special study number that does not 
identify you.  Only study staff will have access to the code-breaker that links your name and code.  Samples will be 
kept in secure facilities with limited access.  No results of this future laboratory research will be provided to you. If 
you withdraw from this study, the stored samples will not be removed from storage unless you specifically request 
that they be destroyed.
WHAT ARE MY RESPONSIBILITIES IF I TAKE PART IN THIS RESEARCH?
If you decide to take part in this study, you will be responsible to:

Take all study drugs as directed by your study staff and doctor.

Follow all instructions given to you.  If you are unsure about what you are supposed to do, ask your study 
team.

Come to all your scheduled study visits and procedures.  Let your study team know as soon as possible if 
you are not able to attend a study visit so he/she can work with you to make other arrangements.

Inform the study team of all information regarding your health and medications.

Consult with the study doctor before starting any new medications or herbal/natural supplements. 

Take and store your study drug as instructed, and return the unused study drug and/or empty bottles to the 
study doctor’s office as instructed. 

Do not share your study drugs with anyone.  You are the only person allowed to take the study drugs.

Keep the study drugs out of the reach of children and persons of limited ability to read or understand.

If you see a doctor or health care provider outside the research study, tell that doctor or health care provider 
that you are in an investigational research study, as certain medications could interact with the study drugs.

Fill out your Patient Diary (study drug dosing card) completely and honestly, and bring your Patient Diary 
with you to each study visit as instructed by the study team.

Tell the study staff if you wish to stop taking part in the study.

While on the study, avoid getting pregnant or prevent your partner from getting pregnant. Effective 
contraception methods includes the following: 

Complete abstinence (avoiding heterosexual contact)

Hormonal contraception (pills, implant or injected) 

Vasectomy

Hysterectomy (removal of uterus)

Tubal ligation/occlusion (“tubes tied”)

Tell the study staff immediately if you are pregnant or suspect to be pregnant.
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 5 of 12
POTENTIAL RISK AND DISCOMFORTS
Potential Risk with BIKTARVY®
The most common adverse events reported in at least 5% of patient who have taken BIKTARVY® are diarrhea, 
nausea, and headache.  The proportion of subjects who discontinued treatment with BIKTARVY® due to adverse 
events, regardless of severity was 1%.  The majority (87%) of adverse events associated with BIKTARVY® were 
mild.  
The most common side effects (occurring in more than 5% of people) reported were:
-
Diarrhea (3% to 6%)
-
Nausea (3% to 5%)
-
Headache (4% to 5%) 
Severe worsening of hepatitis B have been reported in patients who are coinfected with both HIV and hepatitis B 
and have discontinued their medication, and this may occur with discontinuation of BIKTARVY®.  It is therefore 
important that you inform study staff is you wish to be taken off BIKTARVY® in order that a safe plan for 
monitoring and appropriate anti-hepatitis B therapy may be started.
Risk of Viral Resistance
Treatment with drugs that directly inhibit the HIV and/or hepatitis B can lead to development of HIV and/or 
hepatitis B virus that is resistant to that drug and other drugs with the same type of action. These resistance 
mutations (changes in the virus) have been observed in the body as late as 4 to 5 years after treatment has ended. 
Some resistance mutations may reduce the chance of treatment success with future drugs with the same type of 
action or with different types of action.  It is possible that if you are treated with the drugs in this study and 
treatment does not work, you will develop resistance mutations that would make future treatment less successful.
Risk of FibroScan Test (will be done for IHV site only)
FibroScan is a noninvasive diagnostic ultrasound-based device used to measure liver scarring, or fibrosis, caused by 
various diseases including hepatitis B.  It provides a non-surgical alternative to liver biopsy to assess liver damage.  
In preparation for this procedure, subjects will be advised not to eat or drink (including water) for at least 3 hours 
prior to procedure.  The FibroScan test usually takes about 5-10 minutes.  During the procedure, the subject will lie 
on his/her back with the right arm raised behind his/her head and the right abdominal area is exposed.  A trained 
study staff member will apply a water-based gel to the skin and place the non-invasive probe over the liver area.
Fasting prior to procedure can result in hypoglycemia, lightheadedness or fainting.  During the procedure, there is a 
small but possible risk of localized allergic reaction and irritation related to the lubricating gel as well as discomfort 
due to positioning while in lying position.   
Risk of Blood Draws
Collecting a blood sample from a vein may cause pain, bruising, lightheadedness, fainting, and very rarely, 
infection at the site of the needle stick.
Risk of Electrocardiogram (ECG)
After you have an ECG, you may have mild irritation, slight redness, and itching on your skin where the recording 
patches are placed. You may have your chest shaved for this procedure.
Risk of Allergic Reaction
Allergic reaction is always possible with a drug you have not taken.  Serious allergic reactions that can be life-
threatening may occur.  Some things that happen during any allergic reaction to any type of medication are: rash, 
difficulty breathing, wheezing when you breathe, sudden drop in blood pressure, swelling around the mouth, throat, 
or eyes, fast pulse, and/or sweating.
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 6 of 12
Risk of Loss of Confidentiality and Privacy
There is always a potential for the loss of confidentiality and breach in privacy. This risk will be minimized by 
keeping all study data stored and secured behind locked doors. Electronic data will be password protected.  Study 
visits and procedures will be performed in private exam rooms.  Private information will only be given out as listed 
in the HIPAA form that you will separately review and sign, and only if necessary.
Unknown/Unexpected Risks and Discomforts
There may be risks in this study that are not yet known or happen rarely when subjects take these study drugs. You 
will be told of any new information that might cause you to change your mind about continuing to take part in this 
study.  As with any new drug, extra care has to be taken to monitor the side effects that are not always obvious.  If 
you feel any side effects or unusual symptoms, please notify your study doctor as soon as possible at the phone 
number listed in this form.
Pregnancy and Breast-Feeding
Because the effects of BIKTARVY® on an unborn baby or a nursing infant are not known, care must be taken to 
avoid pregnancy in female subjects or in female partners of male subjects during this study and following 
completion of study treatment (30 days after completion for women, 14 days after completion for men).
If you are a woman who is pregnant, intend to become pregnant, or is currently breastfeeding an infant, you cannot 
be in this study.  If you are a male whose partner is pregnant or who can get pregnant, you may participate in the 
study as long as you use condoms or abstain from sexual contact during the duration of the study.  You must protect 
yourself or your partner from becoming pregnant before, during, and after the study.  Women, and men with female 
partners capable of becoming pregnant, must use effective methods of birth control.  Your study doctor will need to 
document what type(s) of birth control you are using.
POTENTIAL BENEFITS
You may or may not benefit by taking part in this study.  There is no guarantee that you will receive direct benefit 
from your participation in this study.  All patients with HIV infection should receive effective treatment.  Selection 
of drugs for HIV-infected patients who are also infected with hepatitis B should take into consideration the 
regimen’s activity against hepatitis B to prevent potentially life-threatening hepatitis B flares.  Fixed dose 
combination BIKTARVY® has the potential to offer HIV-hepatitis B infected patients a simple, once daily regimen 
containing drug components that provides a high barrier to resistance against both HIV and Hepatitis B.  
BIKTARVY® does not require a boosting agent (less chance for drug-drug interaction), and may potentially offers 
an effective and safe alternative to other regimens, without need for HLA testing or close monitoring of renal or 
bone toxicities.   In addition, patient participation in this study will contribute to the body of knowledge about 
treatment for HIV-Hepatitis B dual infection.
ALTERNATIVES TO PARTICIPATION
You may choose not to take part in this study.  If you choose not to take part, your healthcare at the University of 
Maryland, Baltimore, will not be affected.  The study doctor can recommend other treatments. Alternative 
treatments may include approved standard of care, other research studies, palliative care, or no treatment.  If you 
have questions about alternate treatments and their potential benefits and risks, ask the study doctor for additional 
information.  You do not need to participate in this study to be treated for your HIV and hepatitis B dual infection.  
Additionally, if you are an employee or student, your employment status or academic standing at the University 
will not be affected by your participation or non-participation in this study.
COSTS TO PARTICIPANTS
Study procedures like study visits with the doctor and staff, and blood tests, will be done for free.  The Sponsor will 
supply the study medications.  Though you and/or your insurance may be financially responsible for paying for 
standard of care items and services received during this study.  The Participant is financially responsible for paying 
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 7 of 12
any insurance co-pay and/or deductible, if applicable. The Participant will not be responsible for the costs of 
services that are required only because the Participant is enrolled in the research study. 
PAYMENT TO PARTICIPANTS
Study participants will receive $50 cash for each completed visit, and an additional $25 for each FibroScan test you 
undergo (FibroScan tests are done at Day 1, Week 24, and Week 48 visits).  The total compensation will be up to 
$475 over the course of the study.  Payment will be made at each study visit.   
CONFIDENTIALITY AND ACCESS TO RECORDS
Efforts will be made to limit access to your personal information, including research study and medical records, to 
people who have a need to review this information. We cannot promise complete secrecy. Most of the information 
collected will contain a code in the place of your name, including visit records, lab test results and assessments.  
Organizations that may inspect and copy your information include the Institutional Review Board (IRB), other 
representatives of this organization, the Food and Drug Administration (“FDA”), the sponsor and or the sponsor’s 
authorized representative. The monitors, auditors, the IRB, and the Food and Drug Administration will be granted 
direct access to your medical records for verification of the research procedures and date. By signing this document 
you are authorizing this access.
The data from the study may be published. However, you will not be identified by name. People designated from 
the institutions where the study is being conducted and people from the sponsor will be allowed to inspect sections 
of your medical and research records related to the study. Everyone using study information will work to keep your 
personal information confidential. Your personal information will not be given out unless required by law.  Any 
newly documented HIV or hepatitis test results from this study will be reported as required under state law.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This 
web site will not include information that can identify you. At most, the web site will include a summary of the 
results. You can search this web site at any time.
RIGHT TO WITHDRAW
Your participation in this study is voluntary. You do not have to take part in this research. You are free to withdraw 
your consent at any time. Refusal to take part or to stop taking part in the study will involve no penalty or loss of 
benefits to which you are otherwise entitled. If you decide to stop taking part, or if you have questions, concerns, or 
complaints, or if you need to report a medical injury related to the research, please contact the investigator, Dr. Joel 
Chua at 410-706-5704.
If you withdraw from this study, data already collected may not be removed from the study database.  You will be 
asked whether the investigator can collect data from your routine medical care.  If you agree, this data will be 
handled the same as research data. 
CAN I BE REMOVED FROM THE RESEARCH?
The person in charge of the research study or the sponsor can remove you from the research study without your 
approval. Possible reasons for removal include need for failure to follow instructions of the research staff, or if the 
person in charge decides that, the research study is no longer in your best interest.  The sponsor can also end the 
research study early. The study doctor will tell you about this and you will have the chance to ask questions if this 
were to happen.
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 8 of 12
UNIVERSITY STATEMENT CONCERNING RESEARCH RISKS 
The University of Maryland, Baltimore (UMB) is committed to providing participants in its research the rights due 
them under State and federal law. You give up none of your legal rights by signing this consent form or by 
participating in the research project. This research has been reviewed and approved by the Institutional Review Board 
(IRB).  Please call the Institutional Review Board (IRB) if you have questions about your rights as a research subject.
Participating in research may result in an injury, as explained above. If you suffer any study-related injury, you may 
seek medical care from any healthcare provider.  UMB and/or one of its affiliated institutions or health care groups 
may help you obtain medical treatment for the specific injury and provide referrals to other health care facilities if 
you request this.  The costs of medical care for a study related injury would be billed to your medical insurance 
carrier.  If you incur uninsured medical costs, they will be your responsibility.
By signing this Consent Form, you are not giving up any legal rights.  If this research project is conducted in a 
negligent manner and you are injured as a direct result, you may be able to recover the costs of care and other 
damages from the individuals or organizations responsible for your injury.
If you have questions, concerns, complaints, or believe you have been harmed through participation in this research 
study as a result of researcher negligence, you can contact members of the IRB or the Human Research Protections 
Office (HRPO) to ask questions, discuss problems or concerns, obtain information, or offer input about your rights 
as a research participant. The contact information for the IRB and the HRPO is:
University of Maryland Baltimore
Human Research Protections Office 
620 W. Lexington Street, Second Floor
Baltimore, MD 21201
410-706-5037
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 9 of 12
Signing this consent form indicates that you have read this consent form (or have had it read to you), that your 
questions have been answered to your satisfaction, and that you voluntarily agree to participate in this research study. 
You will receive a copy of this signed consent form.
If you agree to participate in this study, please sign your name below.
___________________________________
Participant’s Signature 
Date:_______________________________
___________________________________
Participant’s Name (PRINTED)
___________________________________
Investigator or Designee Obtaining Consent 
Printed Name and Signature 
Date:______________________________
___________________________________
Witness
Date:______________________________
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 
10 of 12
SCHEDULE OF EVENTS
Study Week
Study Procedures
Screening     
(D-90 to -3)
Day 1
4
8
12
24
36
48f
 Administrative Procedures
Informed Consent
X
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria
X
X
 
 
 
 
 
 
Complete Medical History
X
 
 
 
 
 
 
 
Interval Medical History
 
X
X
 X
 X 
X 
X
X 
Administer 1st Dose of Study Drug
 
X
 
 
 
 
 
 
Receive Study Drug Supply
 
X
X
X
X
X
X
 
Check Patient Diary and Number of 
used and unused study drug
 
 
X
X
X
X
X
X
 Clinical Procedures/Assessments
Complete Physical Exam
X
X
 
 
 
 
 
X
Targeted Physical Exam, if needed
 
 
X
X
X
X
X
 
Concomitant medication
X
X
X
X
X
X
X
X
Adverse event  
 
X
X
X
X
X
X
X
Height
X
 
 
 
 
 
 
 
Vital Signs
X
 X
X
X
X
X
X
X
FibroScan Teste
 
Xe
 
 
 
Xe
 
Xe
Electrocardiogram (ECG)
X
 
 
 
 
 
 
 
  Clinical Laboratory Tests
HIV Viral Load
Xa
X
X
X
X
X
X
X
Hepatitis B Viral Load & HBsAg level
Xa
X
X
X
X
X
X
X
CD4 Cell Count
Xa
X
 
 
X
X
X
X
Hepatitis B serologies
Xa
 
 
 
 
X
 
X
HIV Genotype and Resistance Testsb
 
Xb
 
 
 
 
 
Xb
Hepatitis B Genotype and Resistance 
Testsc 
 
Xc
 
 
 
 
 
Xc
Hepatitis C and D testing
Xa
 
 
 
 
 
 
 
Complete Blood Count
Xa
X
X
X
X
X
X
X
Blood Chemistries
Xa
X
X
X
X
X
X
X
Clotting Factor Tests
Xa
 
 
 
 
 
 
X
Urinalysis
Xa
 
 
 
 
 
 
 
Urine Pregnancy Testd
 
X
X
X
X
X
X
X
Blood Pregnancy Testd 
X
 
 
 
 
 
 
 
 Research Laboratory Tests
Research labs and storage
 
X
X
X
X
X
X
X
Blood Volume (in teaspoons)
11
25
15
15
18
23
18
25
 LEGEND:
 
 
 
 
 
 
 
 
a Screening labs - ok to use available labs from clinic if < 90 days old.
 
 
 
 
b If HIV-1 RNA is >500 copies/mL.
 
 
 
 
 
 
 
 
c If HBV DNA is >500 IU/mL.
 
 
 
 
 
 
 
 
d For Women of Childbearing Potential.
 
 
 
 
 
 
 
e Baseline (Day 1) FibroScan test may be conducted within 30 days prior to Day 1 Visit. 
  FibroScan on Week 24 and Week 48 can be done on day of visit OR 2 weeks before or after the visit.
 
 
 
f  Week 48 Study Visit procedures will be used for Early Termination/Study Withdrawal Visits 
 
 
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 
11 of 12
Health Insurance Portability and Accountability Act (HIPAA)
AUTHORIZATION TO OBTAIN, USE AND DISCLOSE
PROTECTED HEALTH INFORMATION FOR RESEARCH
Name of Study Volunteer:  __________________________________________________________
Date of Birth:  ________________         Medical Record Number: _________________________
NAME OF THIS RESEARCH STUDY:  Efficacy, Safety, and Tolerability of Bictegravir/Emtricitabine/ 
Tenofovir Alafenamide in Adults with HIV-HBV Coinfection (BEST-HBV).
UMB IRB APPROVAL NUMBER: 
HP-00083844
RESEARCHER’S NAME: 
Joel Chua, MD
RESEARCHER’S CONTACT INFORMATION:         Institute of Human Virology
University of Maryland School of Medicine (UMSOM)
725 West Lombard Street
410-706-5704
This research study will use health information that identifies you/your child. If you/your child 
agree to participate, this researcher will use just the health information listed below.
THE SPECIFIC HEALTH INFORMATION TO BE USED OR SHARED:

Clinical laboratory tests

Physician or Provider notes

Research tests
Federal laws require this researcher to protect the privacy of this health information. He/she will share it 
only with the people and groups described here.
PEOPLE AND ORGANIZATIONS WHO WILL USE OR SHARE THIS INFORMATION:

Dr. Joel Chua and his research team.

The sponsor of the study, or its agents, such as data repositories or contract research 
organizations, and the Food and Drug Administration (FDA)
THIS AUTHORIZATION WILL NOT EXPIRE.   HOWEVER, YOU CAN REVOKE IT AT ANY TIME.
To revoke this Authorization, send a letter to this researcher stating your decision. He/she will stop 
collecting health information about you. This researcher might not allow you to continue in this study. 
He/she can use or share health information already gathered. 
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022


Informed Consent BEST-HBV V4.0 16 March 2021                                                                                              Page 
12 of 12
ADDITIONAL INFORMATION:

You can refuse to sign this form. If you do not sign it, you cannot participate in this study. This 
will not affect the care you receive at:
o
University Physicians, Inc. (UPI)
o
University of Maryland Medical System (UMMS)
It will not cause any loss of benefits to which you/your child are otherwise entitled.

Sometimes, government agencies such as the Food and Drug Administration or the Department of 
Social Services request copies of health information. The law may require this researcher, the 
UMSOM, UPI, or UMMS to give it to them.

This researcher will take reasonable steps to protect your health information. However, federal 
protection laws may not apply to people or groups outside the UMSOM, UMB, UPI, or UMMS.   

Except for certain special cases, you have the right to a copy of your health information created 
during this research study.  You may have to wait until the study ends. Ask this research how to 
get a copy of this information from him/her.
My signature indicates that I authorize the use and sharing of my protected health information for the 
purposes described above. I also permit my doctors and other health care providers to share my protected 
health information with this researcher for the purposes described above. 
Signature:  ____________________________________Date: _______________________
Name (printed) ______________________________________
Privacy Questions? Call the UMSOM Privacy Official (410-706-0337) with questions about your/your child’s rights 
and protections under privacy rules.
Other Questions? Call the researcher named on this form with any other questions.
HP-00083844 UM IRB Approval Date 3/31/2021
Do Not Sign this Form after this Date 1/6/2022