A Phase 2b Study to Evaluate the Efficacy, Safety and PK of a Combination of Bictegravir, Emtricitabine, and Tenofovir Alafenamide Fumarate for Treatment of HIV-1 Infection in Patients With Drug Susceptible-TB on a Rifampicin-based Regimen
Phase: PHASE2
Conditions: HIV/AIDS, Tuberculosis, Pulmonary
Sponsor: Centre for the AIDS Programme of Research in South Africa

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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Version 3.0, 04 July 2022 
 
CAPRISA 093 
 
INSTI’s FOR THE MANAGEMENT OF HIV-ASSOCIATED TB 
(INSIGHT STUDY): 
 
A phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a 
combination of Bictegravir, Emtricitabine, and Tenofovir Alafenamide Fumarate for 
treatment of HIV-1 infection in patients with drug-susceptible tuberculosis on a 
Rifampicin-based treatment regimen: 
 
 
A Phase 2b Open-label Randomised-Controlled Trial 
 
 
 
A research protocol prepared by: 
 
 
Centre for the AIDS Programme of Research in South Africa 
CAPRISA 
 
 
 
Funded by: 
THE NATIONAL INSTITUTES OF HEALTH AND THE SOUTH AFRICAN MEDICAL 
RESEARCH COUNCIL 
Grant # 1R01AI152142-01 
 
 
 
Principal Investigators/Project Coordinator* 
 
Dr Anushka Naidoo* 
Prof. Kelly E Dooley 
Principal Investigator (South Africa) 
Co-Principal Investigator (USA) 
CAPRISA- 2nd Floor 
John Hopkins University. 
Doris Duke Medical Research Institute 
School of Medicine 
Nelson R. Mandela School of Medicine 
600 N. Wolfe Street, Osler 527 
University of KwaZulu Natal 
Baltimore, MD 21287 
719 Umbilo Road 
 
Congella, 4013, Durban 
 
 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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TABLE OF CONTENTS 
 
ACRONYMS ............................................................................................................................. 10 
 
SCHEMA .................................................................................................................................. 12 
 
1. INTRODUCTION ................................................................................................................ 16 
1.1. Background and Rationale ................................................................................................ 16 
1.2. Benefit and Risk Assessment ........................................................................................... 18 
1.2.1. Risk Assessments ...................................................................................................... 18 
1.2.2. Benefit Assessment .................................................................................................... 21 
1.2.3. Overall Risk and Benefit Conclusion .......................................................................... 21 
 
2. STUDY AIM AND OBJECTIVES ........................................................................................ 21 
2.1. AIM ................................................................................................................................... 21 
2.2. Primary objective .............................................................................................................. 22 
2.3. Secondary objectives ........................................................................................................ 22 
2.4. Exploratory objectives ....................................................................................................... 22 
 
3. INVESTIGATIONAL PLAN ................................................................................................ 23 
3.1. Study Design and Setting ................................................................................................. 23 
3.2. Study Site and Population ................................................................................................. 23 
3.3. Study Endpoints ................................................................................................................ 23 
 
4. INCLUSION AND EXCLUSION CRITERIA ....................................................................... 24 
4.1. Inclusion criteria ................................................................................................................ 24 
4.2. Exclusion criteria (at the time of screening) ...................................................................... 25 
 
5. RANDOMIZATION PROCEDURES ................................................................................... 25 
 
6. STUDY TREATMENT ........................................................................................................ 25 
6.1. Regimens, Administration and Duration ............................................................................ 25 
6.2. Description of Study drug: ................................................................................................. 26 
6.3. Study product adverse effects information ........................................................................ 26 
6.4. Pharmacy: Product Supply, Distribution, Accountability and Storage ............................... 29 
6.5. Adherence to study products ............................................................................................ 29 
 
7. CLINICAL AND LABORATORY EVALUATIONS ............................................................. 30 
7.1. Schedule of Events (SoE) ................................................................................................. 30 
7.2. Timing of Evaluations ........................................................................................................ 31 
7.2.1. Screening Evaluations (Visit 1) ................................................................................... 32 
7.2.2. Baseline, Randomization and Enrollment (Visit 2)...................................................... 33 
7.2.3. Post Entry Evaluations: Follow-ups (Visits 3 to 9) ...................................................... 34 
7.2.4. Study Visit Window and Unscheduled Visits .............................................................. 36 
7.3. Evaluations during study ................................................................................................... 36 
7.3.1. HIV testing .................................................................................................................. 36 
7.3.2. Targeted Physical Exam/Clinical safety monitoring .................................................... 36 
7.3.3. Pregnancy Testing ..................................................................................................... 37 
7.3.4. Concomitant medication reviews will be conducted by the clinical staff. .................... 37 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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8. CLINICAL MANAGEMENT ISSUES .................................................................................. 37 
8.1. Clinical Management Issues at baseline and follow up during study conduct ................... 37 
8.2. Specific Clinical Management Scenarios .......................................................................... 37 
8.2.1. Withdrawal of study drug ............................................................................................ 37 
8.2.2. Virological suppression and definition of treatment failure ......................................... 37 
8.2.3. Reporting AE’s ........................................................................................................... 37 
8.2.4. TB treatment............................................................................................................... 38 
8.3. Guiding Principles of Toxicity Management ...................................................................... 38 
8.3.1. Grade 1 Adverse Events ............................................................................................ 38 
8.3.2. Grade 2 Adverse Events ............................................................................................ 38 
8.3.3. Grade 3 and 4 Adverse Events .................................................................................. 38 
8.4. Specific toxicity management ........................................................................................... 39 
8.5. Reporting Serious Adverse Events (SAEs) ....................................................................... 40 
8.6. Safety Monitoring .............................................................................................................. 40 
 
9. STATISTICAL CONSIDERATIONS ................................................................................... 41 
9.1. Sample size determination: ............................................................................................... 41 
9.2. Analysis including statistical methods: .............................................................................. 42 
9.3. Explanation on how the results of this study will be used ................................................. 43 
9.3.1. Publication of results: ................................................................................................. 43 
 
10. HUMAN PARTICIPANTS ................................................................................................... 43 
10.1. Patient Recruitment ....................................................................................................... 43 
10.2. Ethics ............................................................................................................................. 43 
10.3. Regulatory and ethical review ........................................................................................ 44 
10.4. Informed consent process ............................................................................................. 44 
10.5. Participant Confidentiality .............................................................................................. 44 
10.6. Good Clinical Practice ................................................................................................... 44 
 
11. DATA MANAGEMENT ....................................................................................................... 45 
11.1. Data Collection and Methods ......................................................................................... 45 
11.2. Information management (Database) and analysis software ......................................... 45 
11.3. Data Security, Protection/Confidentiality, Flow, Imported Data and Data coding........... 45 
11.4. Data Storage ................................................................................................................. 46 
11.5. Quality control (QC)/ Quality assurance (QA) ................................................................ 47 
 
12. BIOHAZARD CONTAINMENT ........................................................................................... 47 
 
13. BIBLIOGRAPHY AND REFERENCED CITED: ................................................................. 47 
 
APPENDICE 1: PARTICIPANT INFORMED CONSENT ......................................................... 50 
 
INSIGHT PATIENT INFORMED CONSENT ............................................................................ 50 
 
 
 
 
 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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SITES AND LABORATORIES PARTICIPATING IN THE STUDY: 
 
Clinical Research Site 
Contact person 
Contact Details 
The CAPRISA Springfield 
Clinical Research Site 
The King DinuZulu Hospital (KDH) 
MDR-TB Complex 
Corner of Dr R D Naidoo Drive and 
Viola Road 
Sydenham Durban 
GPS Coordinates: 30.987036 | - 
29.823575 
Durban 
4001 
South Africa 
Dr Kogieleum 
Naidoo 
(Project Director/Site 
Director) 
 
 
 
Dr Anushka 
Naidoo 
Tel: +27 31 260 4687/4574/4555 
Fax: +27 31 307 3936 
+27 31 260 4566 
E-mail: 
Kogie.Naidoo@caprisa.org 
 
 
E-mail: 
Anushka.naidoo@caprisa.org 
Laboratories 
Contact person 
Contact Details 
Storage/PBMC Laboratory 
CAPRISA Research Laboratory 
Doris Duke Medical Research 
Institute (2nd Floor) 
Nelson R Mandela School of 
Medicine 
University of KwaZulu Natal 
719 Umbilo Road, Congella 
Durban 
4013 
South Africa 
Ms Natasha 
Samsunder 
(Head of CAPRISA 
Laboratories) 
Tel: +27 31 260 4454 
Fax: +27 31 260 4566 
E-mail: 
Natasha.Samsunder@caprisa.org 
Safety Bloods 
Neuberg Global Laboratory 
11 Dan Pienaar Road 
Amanzimtoti 
Durban 
4013 
South Africa 
Ryan Pillay 
Tel: +27 31 9040510 
Fax: +27 31 9040553 
BARC Laboratory 
11 Napier Road,  
Richmond  
Johannesburg 
Gauteng 
South Africa  
 
Emmah Mtsweni 
Tel: +27-11-242-7343         
Cell: +27-72-325-4821 
Email:emmah.mtsweni@barcsa.co.za
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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PROTOCOL TEAM ROSTER 
 
Name 
Qualifications Role In The Project 
Contact Details 
Anushka Naidoo 
BPharm, 
MMedSc, PhD 
Principal Investigator/ 
Project Coordinator 
CAPRISA Offices 
Doris Duke Medical Research 
Institute (2nd Floor) 
Nelson R Mandela School of 
Medicine University of KwaZulu Natal 
719 Umbilo Road, Congella Durban, 
4013 
South Africa 
Tel: +27 31 655 0553 
Fax: +27 31 260 4566 
E-mail: 
anushka.naidoo@caprisa.org 
Kelly E. Dooley 
MD, PhD 
Co-Principal 
Investigator (US-
based) 
Johns Hopkins University School of 
Medicine 
600 N. Wolfe Street, Osler 527 
Baltimore, MD 21287 
Tel: (443) 287-0517 (office) Email: 
kdooley1@jhmi.edu 
Kogieleum Naidoo 
MBChB PhD 
Co-Principal 
Investigator /Project 
Director 
CAPRISA Offices 
Doris Duke Medical Research 
Institute (2nd Floor) 
Nelson R Mandela School of 
Medicine University of KwaZulu Natal 
719 Umbilo Road, Congella Durban, 
4013 
South Africa 
Tel: +27 31 260 4687 
Fax: +27 31 260 4566 
E-mail: Kogie.Naidoo@caprisa.org 
Nesri Padayatchi 
MBChB  
PhD 
Co-Investigator 
CAPRISA Offices 
Doris Duke Medical Research 
Institute (2nd Floor) 
Nelson R Mandela School of 
Medicine University of KwaZulu Natal 
719 Umbilo Road, Congella Durban, 
4013 
South Africa 
Tel:+27 31 260 4574 
Fax: +27 31 260 4566 
E-mail: 
Nesri.padayatchi@caprisa.org 
Nonhlanha Yende- 
Zuma 
MSc PhD 
(Biostatistician) 
Co-investigator/Study 
Statistician 
CAPRISA Offices 
Doris Duke Medical Research 
Institute (2nd Floor) 
Nelson R Mandela School of 
Medicine University of KwaZulu Natal 
719 Umbilo Road, Congella Durban, 
4013 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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South Africa 
Tel:+27 31 260 4392 
Fax: +27 31 260 4566 
E-mail: 
Nonhlanhla.yende@caprisa.org 
Dr Tilagavathy 
Chinappa 
Dr Gillian Dorse 
 
Dr Rubeshan 
Perumal 
Dr Victress Busi 
Ntsalaze 
MBBCh 
Sub-investigator/ Site 
Research Clinician 
The CAPRISA Springfield Clinical 
Research Site 
The King DinuZulu Hospital (KDH) 
MDR-TB Complex 
Corner of Dr R D Naidoo Drive and 
Viola Road 
Sydenham Durban 
GPS Coordinates: 30.987036 | - 
29.823575 
Durban 4001 
South Africa 
Email: 
surie.chinappa@caprisa.org 
gillian.dorse@caprisa.org 
Rubeshan.perumal@caprisa.org 
Busi.Ntsalaze@caprisa.org 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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CAPRISA 093 
 
A phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of 
Bictegravir, Emtricitabine, and Tenofovir Alafenamide Fumarate for treatment of HIV-1 infection 
in patients with drug-susceptible tuberculosis on a Rifampicin-based treatment regimen: 
 
 
 
INVESTIGATOR SIGNATURE FORM 
Version 3.0 
04 July 2022 
A research protocol prepared by: 
Centre for the AIDS Programme of Research in South Africa CAPRISA 
 
Funded by: 
THE NATIONAL INSTITUTES OF HEALTH AND THE SOUTH AFRICAN MEDICAL 
RESEARCH COUNCIL 
 
Grant # 1R01AI152142-01 
 
I, the Investigator of Record/Principal Investigator, agree to conduct this study in full 
accordance with the provisions of this protocol. I have read and understand the 
information in the Investigator's Brochure(s)/Package inserts, including the potential risks 
and side effects of the products under investigation, and will ensure that all associates, 
colleagues, and employees assisting in the conduct of the study are informed about the 
obligations incurred by their contribution to the study. 
 
 
Principal Investigator 
 
Signature ____________________________                           ___________________________  
 
       Date of Signature (DD/MMM/YY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name  
Anushka Naidoo 
Title  
Dr 
Institution  
Address  
CAPRISA 
Doris Duke Medical Research Institute, 2nd Floor, Nelson R 
Mandela School of Medicine, University of KwaZulu Natal, 719 
Umbilo Road, Durban, 4001, South Africa 
Tel: +27 31 655 0550 
Fax: +27 31 260 4566 
Email: Anushka.naidoo@caprisa.org 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 8 of 50  
Version 3.0, 04 July 2022 
 
Co-Principal Investigator (US-based) 
 
 
Signature ____________________________                           ___________________________  
 
       Date of Signature (DD/MMM/YY) 
 
 
 
 
 
 
 
 
 
 
 
Co-Principal Investigator 
 
 
Signature ____________________________                           ___________________________  
 
        Date of Signature (DD/MMM/YY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Investigator 
 
 
Signature ____________________________                             ___________________________  
 
        Date of Signature (DD/MMM/YY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name  
Kelly Dooley 
Title  
Prof  
Institution  
Address  
Johns Hopkins University School of Medicine 
600 N. Wolfe Street, Osler 527, Baltimore, MD 21287 
Tel: (443) 287-0517 (office)  
Email: kdooley1@jhmi.edu 
Name  
Kogieleum Naidoo 
Title  
Prof  
Institution  
Address  
CAPRISA 
Doris Duke Medical Research Institute, 2nd Floor, Nelson R 
Mandela 
School of Medicine, University of KwaZulu Natal, 719 Umbilo 
Road, 
Durban, 4001, South Africa 
Tel: +27 31 260 4687 
Fax: +27 31 260 4566 
Email: Kogie.Naidoo@caprisa.org 
 
 
Name  
Nesri Padayatchi 
Title  
Prof  
Institution  
Address  
CAPRISA 
Doris Duke Medical Research Institute, 2nd Floor, Nelson R 
Mandela 
School of Medicine, University of KwaZulu Natal, 719 Umbilo 
Road, 
Durban, 4001, South Africa 
Tel: +27 31 260 4687 
Fax: +27 31 260 4566 
Email:  nesri.padayatchi@caprisa.org 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 9 of 50  
Version 3.0, 04 July 2022 
 
 
Co- Investigator 
 
 
Signature ____________________________                           ___________________________  
 
Date of Signature (DD/MMM/YY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name  
Nonhlanha Yende- Zuma  
Title  
Dr 
Institution  
Address  
CAPRISA 
Doris Duke Medical Research Institute, 2nd Floor, Nelson R 
Mandela 
School of Medicine, University of KwaZulu Natal, 719 Umbilo 
Road, 
Durban, 4001, South Africa 
Tel:+27 31 260 4392 
Fax: +27 31 260 4566 
E-mail: Nonhlanhla.yende@caprisa.org 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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ACRONYMS 
 
Acquired Immunodeficiency Syndrome 
AIDS 
Lamivudine 
3TC 
Adverse Events 
AE 
Antiretroviral Treatment 
ART 
Area under the concentration time curve 
AUC 
Bictegravir 
BIC 
Biktarvy 
BIC/TAF/FTC 
Below Limit of Quantification 
BLQ 
Centre for the AIDS Programme of Research in South Africa 
CAPRISA 
Maximum concentration 
Cmax 
Co - Principal Investigator 
Co - PI 
Case Report Forms 
CRF 
Trough concentration 
Ctrough 
Cytochrome P450 
CYP 
Division of Acquired Immunodeficiency Syndrome 
DAIDS 
Dried Blood Spot Test 
DBS 
Data Safety Monitoring Committee 
DSMC 
Dolutegravir 
DTG 
Estimated glomerular filtration rate 
eGFR 
Calibur Flow Cytometer 
FACS 
Food and Drug Administration 
FDA 
Emtricitabine 
FTC 
Good Clinical Practice 
GCP 
Hair Analysis Laboratories 
HAL 
Hepatitis B virus 
HBV 
Human Immunodeficiency Virus 
HIV 
Isoniazid, Rifampicin, Pyrazinamide, Ethambutol 
HRZE 
International Council for Harmonisation 
ICH 
Integrase Strand Transfer Inhibitor 
InSTI 
Immune Reconstitution Syndrome 
IRIS 
KwaZulu – Natal 
KZN 
Low and Middle-Income Countries 
LMIC 
Latent TB co-infection 
LTBI 
Mother to Child Transmission 
MTCT 
Non - Nucleoside Reverse Transcriptase Inhibitor 
NNRTI 
Peripheral Blood Mononuclear Cell 
PBMC 
Pharmacodynamics 
PD 
Post-Exposure Prophylaxis 
PEP 
p-glycoprotein 
p-gp 
Principal Investigators 
PI 
Pharmacokinetics 
PK 
High Performance Liquid Chromatography and Mass Spectrometry 
PLC/MS-MS 
People Living with HIV 
PLWHIV 
Pre-Exposure Prophylaxis 
PrEP 
South Africa 
SA 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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South African Department of Health 
SA DoH 
Serious Adverse Events 
SAE 
Standard Deviation 
SD 
Standard of Care 
SOC 
Schedule of Events 
SoE 
Standard Operating Procedure 
SOP 
Tenofovir Alafenamide 
TAF 
Tuberculosis 
TB 
Tenofovir Disoproxil Fumarate 
TDF 
Tenofovir Diphosphate 
TFV - DP 
TDF/3TC/DTG 
TLD 
University of Cape Town 
UCT 
UDP-glucuronosyltransferases 
UGT 
University of KwaZulu Natal 
UKZN 
World Health Organisation 
WHO 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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SCHEMA 
 
Rationale: This study is being conducted to assess the antiretroviral activity of a fixed-
drug, single tablet, combination of Bictegravir 50mg/ Emtricitabine 200mg/ Tenofovir 
alafenamide 25mg (Biktarvy®) dosed twice daily in HIV-1 infected, ART-naïve and ART 
non-naïve patients with TB co-infection receiving a rifampicin-based tuberculosis (TB) 
treatment regimen. This study will assess the activity of Bictegravir and dolutegravir-
containing ART regimens in patients with drug-susceptible TB through 48 weeks. 
 
Design: This is a phase 2b open-label non-comparative randomised-controlled trial among 
HIV positive, ART naïve and ART non-naive, adult patients (>18 years) with drug-sensitive 
TB who are receiving a rifampicin-based first-line TB regimen. The primary objective is to 
assess the efficacy, safety and pharmacokinetics (PK) of twice daily, co-formulated 
Bictegravir (BIC) 50mg/ Emtricitabine (FTC) 200mg/ Tenofovir alafenamide (TAF) 25mg in 
HIV-positive ART-naïve and ART non-naïve patients with TB who are receiving a 
rifampicin-based treatment regimen and to characterize viral suppression rates at week 24 
through to week 48 in the BIC/FTC/TAF arm. A concurrent control arm in which 
participants receive a dolutegravir-based regimen (standard of care, SOC) will also be 
enrolled 
 
Duration: 48 weeks 
 
Sample Size: ~120 participants 
 
Population: The study will include adults (18 years and over) who are HIV positive, ART-
naïve and ART non-naïve. Patients with drug-sensitive TB who are on a first-line 
rifampicin-based treatment will be included. 
 
Randomization: Patients will be randomized in a 2:1 ratio to the Intervention or 
Control arm of the study 
 
Intervention Arm/BIC Arm: Bictegravir-emtricitabine-tenofovir alafenamide 
(BIC/FTC/TAF 50mg- 200mg-25mg –Biktarvy® fixed-drug combination single tablet) dosed 
twice daily during TB treatment and for two weeks following completion of TB treatment, 
then once daily thereafter. 
 
Control Arm/DTG Arm: Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- 
fixed- drug combination single tablet) plus Dolutegravir 50mg evening dose during TB 
treatment and for two weeks after completion of TB treatment, then TLD once daily 
thereafter- as per Standard of Care (SOC) 
 
Objectives: 
 
Primary objective: To characterize viral suppression rates (proportion of patients with 
suppressed viral load) at week 24 in the BIC arm 
 
Secondary objectives: 
To characterize viral suppression rates at weeks 12, 24 and 48 in the standard of care 
treatment (SOC) arm (currently, TDF 300mg/3TC 300mg/DTG 50mg) and at weeks 12 
and 48 in the BIC/FTC/TAF arm. 
 
To compare the pharmacokinetics (PK) of BIC when given twice daily and co-
administered with Rifampicin during tuberculosis treatment vs when given alone after 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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discontinuation of Rifampicin 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 14 of 50  
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To assess the incidence of TB associated IRIS in each arm, through week 24. 
 
To characterize the tolerability of treatment in each arm by assessing frequency of 
clinician- initiated treatment interruptions or switches through week 48. 
 
To assess frequency of ART drug resistance mutations in participants with detectable viral 
load at study visit weeks 24 and 48. 
 
Study Endpoints: 
 
Primary endpoint: Viral suppression rate (HIV-1 RNA <50 copies/mL) at week 24 in the 
BIC arm (using the FDA snapshot algorithm) 
 
Secondary Endpoints: 
Viral suppression rates (HIV-1 RNA <50 copies/mL) at weeks 12, 24 and 48 in the DTG 
arm and at 12 and 48 weeks in the BIC arm 
 
PK of BIC when given twice daily and co-administered with Rifampicin vs. during TB 
treatment vs when given alone after TB treatment completion 
 
Incidence of TB associated IRIS through week 24, by Arm 
 
Grade 3 or higher AEs, SAEs; clinician-initiated treatment interruptions or switches 
through week 48 
 
Frequency of ART drug resistance mutations in participants with detectable viral load at 
weeks 24 and 48 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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Version 3.0, 04 July 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: INSIGHT study patient screening and randomization plan 
STEP 1: PATIENT POPULATION 
HIV positive ART naïve and ART non-naïve adult patients on a rifampicin-based TB 
treatment 
STEP 2: SCREENING 
HIV test to establish HIV status & confirm rifampicin-susceptible TB/on TB treatment 
STEP 3: RANDOMIZATION (2:1 ratio) 
Intervention Arm (BIC) 
BIC/FTC/TAF (BID)- 
during TB treatment  
OD - after TB treatment 
Control Arm (DTG) -SOC 
DTG/TDF/3TC (OD) am 
+ DTG 50mg OD pm- 
during TB  treatment 
STEP 4: SCHEDULE OF EVALUATIONS 
Participants will be followed up as outlined in the SOE up  
until week 48 and thereafter they will be transitioned into  
Standard of Care 
PK assessments will be done at pre-defined timepoints 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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1. INTRODUCTION 
 
1.1. Background and Rationale 
 
Currently, there are approximately 40 million people living with HIV (PLWHIV) worldwide, 
and about half of PLWHIV live in Eastern and Southern Africa.1 By the end of 2017, an 
estimated 21.7 million people were accessing antiretroviral treatment (ART) globally.1 South 
Africa has the largest HIV epidemic in the world with more than 7 million PLWHIV and the 
largest treatment programme with 4.4 million people on ART; > 25% live in KwaZulu-Natal. 
1 The World Health Organisation (WHO), currently recommends the Integrase Strand 
Transfer Inhibitor (InSTI), Dolutegravir (DTG) as the preferred back-bone of first-line ART 
regimens for the treatment of HIV-1 infection in adults, adolescents and children, 
particularly in Low and Middle-Income Countries (LMIC) regions such as Southern and 
Eastern Africa), where pre-treatment drug resistance to NNRTI reaches 10%.2,3 Second 
generation InSTI’s such as DTG and a newer drug, Bictegravir (BIC), have high antiviral 
potency, better safety and tolerability profiles than protease inhibitors (PI) and NNRTI’s, 
and are suitable for once daily administration with a high barrier to the development of HIV-
1 resistance.4-7 BIC may also demonstrate activity against some variants with reduced 
susceptibility to DTG. In large Phase 3 trials of BIC-emtricitabine-tenofovir alafenamide 
(BIC/FTC/TAF 50-200-25, now co- formulated as Biktarvy®), there was not a single episode 
of emergent resistance.4 In phase 3 trials, BIC/FTC/TAF and DTG (given with 
abacavir/lamivudine or FTC/TAF) displayed similar, high efficacy in establishing virologic 
suppression in treatment-naïve adults over 96 weeks of treatment.7,8 
 
Among PLWHIV, tuberculosis (TB) disease is the #1 cause of death. Of 10 million people 
incident cases of TB globally in 2017, 10% had HIV.9 In South Africa, 50-80% of PLWHIV 
have latent TB co-infection (LTBI).9 While ART reduces risk of progression from LTBI to TB 
disease, many patients only discover they have HIV at the time of pulmonary TB diagnosis. 
There is a morbidity and mortality benefit of treating HIV and TB concurrently, rather than 
starting ART after completion of TB treatment, especially for patients with low CD4 
counts.10 Current standard of care is to treat HIV and TB concurrently, rather than starting 
ART after completion of TB treatment, with ART started within 2-8 weeks after TB 
treatment initiation—this reduces risk of death as well as new opportunistic infections 
substantially.10,11 Co-treatment of HIV and TB, though, has its challenges. Rifampicin is a 
critical component of standard first-line TB drug regimens because of its unique sterilizing 
activity.11 No drug can adequately substitute for rifampicin in the TB drug regimen. 
However, rifampicin is a potent inducer of cytochrome P450 (CYP) enzymes, the UDP- 
glucuronosyltransferases (UGT), and drug transporters such as p-glycoprotein (p-gp) 
and therefore causes several significant drug-drug interactions.12 HIV-TB co-treatment 
options, thus, are limited by drug-drug interactions, availability of some TB or HIV drugs 
in local programs, and toxicity. 
 
ART scale-up in sub-Saharan Africa is progressing at a rapid pace. There are still areas for 
optimization, though, related to drug resistance and toxicity. Co-formulated InSTI’s such as 
BIC and DTG with reduced pill burden, fewer toxicities, reduced risk of virologic failure 
while preserving future treatment options, will ultimately maximize cost-effectiveness and 
clinical benefit in disease endemic resource-limited settings. Having different options for 
InSTI-based regimens that can be used together with standard rifampicin-based first-line 
treatment regimens (provided as fixed-dose combinations by TB programs) is extremely 
important, particularly in South Africa and KwaZulu Natal, the epicentre of the TB/HIV co-
epidemic. This allows HIV programs to use the same drugs to treat patients with and 
without TB. 
 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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Rationale for Biktarvy® and drug interaction between co-formulated BIC/TAF/FTC 
(Biktarvy®) and rifampicin-based TB drug-regimens in patients with TB: 
 
BIC is metabolized predominantly by CYP3A and UGT1A1. In a study involving HIV-
negative healthy volunteers, BIC trough (Ct) concentrations when given twice daily (as 
part of BIC/TAF/FTC) with rifampicin 600 mg once daily versus once daily alone, were 
reduced from 3070 mcg/mL to 608 mcg/mL (80% reduction), and AUC0-24 was reduced by 
approximately 60%.13 Trough concentrations of InSTI’s including BIC have been shown to 
be strongly associated with antiviral activity. The protein adjusted 95% effective trough 
concentration (pa EC95) of BIC is approximately 162ng/mL. In phase 3 efficacy studies of 
BIC once daily in HIV-1 infected individuals BIC trough concentrations were found to be 16 
times higher than the pa EC95. Despite the 80% reduction in BIC Ct with rifampicin co-
administration, average Ct remained 3.1-fold higher than the pa EC95, and all subjects in 
the healthy volunteer study, maintained Ct concentrations higher than the pa EC95. 
However, a modelling exercise using data from phase 3 trials suggested that in a larger 
population of patients, giving BIC twice daily with rifampicin may result in rare patients 
(about 3 in 1000) having trough concentrations lower than the pa EC95.13 For TAF, while 
the tenofovir disoproxil fumarate (TDF) formulation of tenofovir can be used without dose 
adjustment with TB drugs, there has been concern that TAF, a p-gp substrate, might not 
achieve target concentrations when given with rifampicin. TAF undergoes phosphorylation 
to form the active moiety tenofovir diphosphate (TFV-DP) within lymphoid cells, where it 
also exerts its activity.14,15 In a trial among healthy HIV-negative volunteers, TAF when 
dosed once daily alone compared to once daily with rifampicin 600mg, was shown to have 
decreased plasma TAF exposure by 47%, while intracellular TFV-DP was decreased by 
40%.16 However, intracellular TFV-DP concentrations were still over 4-fold higher on 
average than those achieved by standard dose TDF. These data support of the use of TAF 
when co-administered with rifampicin in patients with HIV and TB.16 In the same study, 
rifampicin did not affect FTC PK. 
 
What is the clinical relevance, though, of the above-described drug interactions among 
patients taking combination HIV treatment (BIC/TAF/FTC twice daily) and receiving full 
first-line TB treatment (isoniazid, rifampicin, pyrazinamide, ethambutol, HRZE)? 
In the initial Phase 1B trial of BIC monotherapy in which the drug was given at doses of 5, 
25, 50, or 100 mg daily for 10 days to HIV treatment-naïve patients (mean baseline HIV 
viral load of 4.4 log), even the 5 mg dose was potent, reducing viral load substantially (1.5 
log in 10 days), without emergence of resistance after stopping the drug. 6 Subsequent 
Phase 2 and 3 trials of combination therapy evaluated the drug at 75 mg (Phase 2) or 50 
mg (Phase 3).17 At those doses, no PK-PD relationships could be seen, and no resistance 
emerged. Bictegravir is not available as a single 50mg tablet formulation. 
 
The PK of TAF and FTC when dosed twice daily with HRZE, and the safety and efficacy of 
these drugs as part of combination therapy in patients with HIV-associated TB is untested. 
FTC, though, is a well-tolerated drug, even at higher dosing levels (300 mg once daily 18or 
200 mg twice a day).19 Among patients with moderate renal impairment receiving the 
standard 200mg dose, increases in FTC exposure did not have an impact on safety.20 
Genvoya® (FDC containing elvitegravir, cobicistat, FTC, and TAF) full-strength tablets 
have been given to children as light as 25kg, resulting in high mg/kg doses and FTC and 
TAF exposures that were 75% and 71% higher than average in adults, yet participants 
tolerated the regimen well; there were no serious adverse events or adverse event-related 
discontinuations.21 In a study in HIV-infected adults with end- stage renal disease, 
standard-dose Genvoya® produced elevated drug concentrations, but the overall safety 
profile was not affected.22 Moreover, because FTC is renally eliminated and its exposures 
had previously been observed to be increased in adults with mild-to-moderate renal 
impairment, analysis of adverse events potentially associated with FTC (i.e., among those 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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listed in the prescribing information as having at least 10% incidence), was carried out 
separately in the study. The overall incidence of these prespecified events occurred in 
nearly half of study participants; however, those events considered related to study drug 
were reported for less than 
10%, all were grade 1 or 2 in severity, and none led to premature discontinuation of study 
drug.22 In the healthy volunteer study of BIC/TAF/FTC twice daily with rifampicin, FTC 
concentrations were, not surprisingly, doubled; no additional safety concerns were 
reported, although long term data will be needed.13 As seen previously, PK and safety 
results in healthy HIV-negative volunteers do not reliably predict PK, safety, and efficacy 
among patients with HIV-TB taking full treatment for both HIV and TB,23-26 so these 
studies must be conducted in careful and rigorous manner in the relevant study 
population 
 
This phase 2 open-label randomised controlled trial will compare the efficacy, safety and 
PK of a single combination pill of BIC, FTC and TAF dosed twice daily versus current 
standard of care treatment for HIV positive, ART-naïve and ART non-naïve, adult patients 
with TB co-infection on a rifampicin-based first-line TB treatment regimen, in Durban, 
South Africa. We hypothesize that this combination will be highly effective, given the 
potency of TAF (and anticipated higher intracellular concentrations of TFV-DP when it’s 
given twice daily, even with rifampicin), contribution of FTC (potentially higher when given 
twice daily), and high potency of BIC with theoretical reductions below the pa EC95 being 
rare and mitigated by twice daily dosing, making any potential time below this threshold 
short, as well as strong companion agents. 
 
1.2. Benefit and Risk Assessment 
 
Summaries of findings from both clinical and non-clinical studies conducted with Biktarvy® 
can be found in the most current version of the Investigator’s Brochure (IB) and the 
package insert/FDA Label. The following section outlines the risk assessment and 
mitigation strategy for the use of Biktarvy® as described in this protocol. 
The approved country product labels should be referenced for rifampicin and all other 
components of the TB treatment regimen and dolutegravir as well as the fixed-dose 
combination of Dolutegravir [Tenofovir/Lamivudine/Dolutegravir (TLD)] being used as 
standard of care in South Africa. 
 
1.2.1. Risk Assessments 
 
All medications have adverse event (AE) profiles that must be assessed prior to use, 
allowing for an appropriate risk/benefit assessment. Some considerations when using BIC 
are presented in Table 1, however a full description of risks are described in the approved 
package insert/FDA label and investigator brochure. 
All clinical and safety data [AE’s, Severe adverse events (SAE’s), treatment interruptions], 
HIV RNA viral load and CD4 cell counts, including immune reconstitution syndrome (IRIS) 
events will be collected and recorded on study case report forms (CRF’s). Events will be 
monitored using SAE reports and alerts for Grade 3 or 4 laboratory toxicities (according to 
the Division of Acquired Immune Deficiency Syndrome [DAIDS] toxicity grading for HIV-
infected patients as described in the protocol and study procedure manuals or SOPs. All 
AE and SAE reporting will be done in accordance with ICH-GCP and local guidelines as 
outlined in the study management plan. Serious/severe events will be managed 
appropriately including, but not limited to, investigational product (IP) being withdrawn, and 
will be followed to resolution by the study investigators. Severity of AEs will be assessed 
using the DAIDS (Division of Acquired Immune Deficiency Syndrome) Table for Grading the 
Severity of Adult Adverse Events, Version 2.1, July 2017. 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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There is some uncertainty regarding the safety and efficacy of twice daily Biktarvy® for the 
treatment of HIV-1 infection during rifampicin co-treatment in patients with TB. We will 
carefully monitor safety and efficacy outcomes in the study, and planned interim analyses 
to review safety, viral load, and PK data. 
Data Safety Monitoring Committee (DSMC) 
meetings will be held after the first 10 patients in the BIC arm have completed the 24-week 
visit and again after half the study population from both arms has reached 24 weeks on-
treatment. An interim analysis at week 24 when at least half of the trial participants have 
been enrolled will be conducted to review safety and efficacy in the two arms. There is 
evidence to suggest that twice daily Biktarvy® will be safe and effective during rifampicin 
co-treatment. Although preliminary data from healthy volunteer studies suggested that 
significant reductions in bictegravir concentrations during rifampicin- coadministration will 
occur, these concentrations remained above the paEC95 which is strongly associated with 
antiviral activity, in all patients. Furthermore despite >40% reductions in TAF and TFV-DP 
when TAF is given with rifampicin, intracellular concentrations of the active drug, TFV-DP, 
were still 4-fold higher on average than those achieved by standard dose TDF. As seen 
previously, PK and safety results in healthy HIV-negative volunteers do not reliably predict 
PK, safety, and efficacy among patients with HIV-TB taking full treatment for both HIV and 
TB,23-26  so these studies must be conducted in careful and rigorous manner in the relevant 
study population to provide accurate, clinically relevant information. 
The safety of FTC twice daily dosing needs to be monitored, however high exposures in 
several studies suggest that FTC twice daily may be safely administered. Should safety 
and efficacy data be unfavourable in the Biktarvy® arm the study will be stopped and 
patients will be switched to an appropriate SOC regimen. 
 
Table 1: Considerations when using Bictegravir 
 
Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
For full information refer to the Investigational Product (Biktarvy [BIC]) Package insert/FDA label and 
Investigator 
GI intolerance  
(nausea, diarrhea) 
Two randomized, double-blind, active-
controlled trails (Trial 1489 and 1490 
N=314 and N=320 respectively) 
identified the most common adverse 
reactions (all Grades) reported nausea, 
diarrhoea and headache in at least 5% 
of subjects in Biktarvy® group. 87% of 
adverse events were Grade 1 
Routine monitoring of these 
symptoms/and clinical and 
laboratory evaluations will be done 
Pregnancy/Neural 
Tube Defects 
There are insufficient human data on the 
use of Biktarvy® during pregnancy to 
inform a drug- associated risk of birth 
defects and miscarriage. 
In animal reproduction studies, no 
evidence of adverse developmental 
outcomes was observed with the 
components of Biktarvy® at exposures 
that were either not maternally toxic 
(rabbits) or greater than (rats and mice) 
those in humans at the recommended 
human dose (RHD) 
Bictegravir: Data from an observational 
study in Botswana showed that 
dolutegravir, another 
All participants will be excluded from 
the study if pregnant at screening 
phase 
Females of child-bearing potential must 
have a negative pregnancy test at 
screening and be willing to adhere to 
two effective methods of contraception 
(barrier and a non- barrier form of 
contraception during the study, starting 
at least 14 days prior to enrolment) if 
sexually active. Pregnancy testing will 
be done at all study visits 

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integrase inhibitor, was associated with 
increased risk of neural tube defects when 
administered at the time of conception 
and in early pregnancy. Data available to 
date from other sources including the 
APR, clinical trials, and post marketing 
data are insufficient to address this risk 
with BIC. 
Immune 
Reconstitution 
Syndrome 
This has been reported in 
patients with combination 
antiretroviral therapy During the 
initial phase of combination 
antiretroviral treatment, patients 
whose 
immune system responds may develop 
an inflammatory response to indolent or 
residual opportunistic infections [such as 
Mycobacterium avium infection, 
cytomegalovirus, Pneumocystis jirovecii 
pneumonia (PCP), or tuberculosis], 
which may 
necessitate further evaluation and 
treatment. 
Routine monitoring of these 
symptoms/and clinical and laboratory 
evaluations will be done. Steroids will 
be used, in accordance with standard 
of care to manage patients with 
clinical manifestations of IRIS. 
Potential drug 
interactions 
Because Biktarvy® is a complete 
regimen, coadministration with other 
antiretroviral medications for the 
treatment of HIV-1 infection, substrates 
of OCT2 and MATE1, a strong inducer of 
CYP3A, dofetilide, anticonvulsants and 
antimycobacterials is not recommended. 
Antacids (aluminium (Al) or magnesium 
(Mg) based) should be used with 
caution. 
Concomitant medications will be 
monitored and Biktarvy® will not be 
administered with other antiretroviral 
drugs or with drugs known to have 
significant interactions with the drug 
with the exception of rifampicin which 
is being studied in this protocol. 
Patients will be counseled to use 
Biktarvy at least 2 hours before 
antacids containing Al or Mg 
Renal Function 
Changes in Serum Creatinine: BIC has 
been shown to increase serum 
creatinine due to inhibition of tubular 
secretion of creatinine without affecting 
renal glomerular function 
Changes in Bilirubin: In Trials 1489 and 
1490, total bilirubin increases were 
observed in 12% of subjects 
administered Biktarvy® through Week 
48. 
Increases were primarily Grade 1 (1.0 to 
1.5 x ULN) (9%) and 
Grade 2 (1.5 to 2.5 x ULN) (3%). 
Routine monitoring of these 
symptoms/and clinical and laboratory 
evaluations will be done at each study 
visit 
Liver function 
Graded bilirubin increases in the 
ABC/DTG/3TC, and DTG + 
FTC/TAF groups, were 4% and 6%, 
respectively. Increases were primarily 
Grade 1 (3% ABC/DTG/3TC and 5% 
DTG + 
FTC/TAF) or Grade 2 (1% 
ABC/DTG/3TC and 1% DTG + 
FTC/TAF). 
 
Nervous system 
and 
Neuropsychiatric 
Headache, Abnormal dreams and 
insomnia reported. 
Suicidal ideation, suicide attempt, and 
Monitored as part of targeted physical 
exam and clinical monitoring 

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adverse events 
depression suicidal occurred in <1% of 
subjects administered BIKTARVY; all 
events were serious and primarily 
occurred in subjects with a pre-existing 
history of depression, prior 
suicide attempt or psychiatric illness 
 
1.2.2. Benefit Assessment 
 
Co-treatment of HIV and TB reduces morbidity and mortality in co-infected patients. 
Availability of treatment options of ART drug regimens and within drug classes is important, 
particularly in high HIV burden settings in LMIC countries. Currently Dolutegravir is the only 
first-line InSTI available for use in adult patients for ARV programs in South Africa. This 
study will be the first to generate new data that may support the use of a potent 
antiretroviral FDC, Biktarvy®, in HIV-1 infected adult patients with TB co-infection taking 
rifampicin-containing first-line treatment with HRZE. This will create a new and highly 
desirable treatment option for patients with HIV-associated TB in settings where this drug is 
already available. Importantly, demonstrating that Biktarvy® can be used in patients with TB 
will fill a critical gap and help support the case for its introduction into Africa, where ~70% 
of the global burden of HIV is concentrated and in particular in South Africa, which has one 
of the largest incidence of HIV and TB co-infection rates in the world. If co-formulated 
BIC/TAF/FTC given twice daily is safe and effective in patients with HIV-associated TB, this 
will be an important option for these patients. As it is easier for programs in LMIC to deliver 
similar formulations of drugs for different patient populations (rather than different drugs for 
patients with and without TB), this will also be a helpful missing piece for introduction of 
BIC/TAF/FTC, a highly- popular FDC in the US and Europe, to Africa. Given that 
BIC/TAF/FTC is potent, safe, available in a single-tablet FDC, and has activity even against 
some InSTI resistant strains, it is very important that it be available in African settings. 
Additionally, it will be helpful for TAF roll-out, a drug that has a better safety profile for bone 
and renal adverse events than TDF, which has been hindered, in part, by lack of data in 
HIV-TB co-infected patients. 
 
Our proposed study is important to undertake as it will improve the chances of access to 
a potent ART co-formulation in Africa, where it is most needed. 
 
1.2.3. Overall Risk and Benefit Conclusion 
 
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with Biktarvy® (using twice daily dosing) 
may be justified by the anticipated benefits that may be afforded to HIV-1/TB co-infected 
ART-naïve and ART non-naïve adults if this regimen is shown to be safe and effective. 
There are no data to support the safety and efficacy of Biktarvy® twice daily for the 
treatment of HIV-1 infection in patients with TB on rifampicin co-treatment and it is unlikely 
that this highly potent, safe, drug with a high resistance profile, that may provide effective 
future ART treatment options, will be made available in Africa if it cannot be used in 
patients with tuberculosis. 
 
2. STUDY AIM AND OBJECTIVES 
 
2.1. AIM 
 
To assess the efficacy, safety and pharmacokinetics of twice daily, co-formulated BIC 
50mg/FTC 200mg/TAF 25mg in HIV positive, ART naïve and ART non-naïve patients 
with drug susceptible tuberculosis who are receiving a rifampicin-based regimen in 

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South Africa. A concurrent, non- comparative control arm of participants receiving 
current standard of care HIV treatment will be enrolled. 
 
2.2. Primary objective 
 
To characterize viral suppression rates (proportion of patients with HIV VL<50) at week 
24 in the BIC/FTC/TAF arm. 
 
2.3. Secondary objectives 
 
To characterize viral suppression rates (proportion of patients with HIV VL<50) at 
weeks 12, 24 and 48 in the standard of care treatment (SOC) arm (currently, TDF 
300mg/3TC 300mg/DTG 50mg) and at weeks 12 and 48 in the BIC/FTC/TAF arm. 
 
To compare the pharmacokinetics (PK) of BIC when given twice daily and co-
administered with Rifampicin during tuberculosis treatment vs when given alone after 
discontinuation of Rifampicin. 
 
To assess the incidence of TB associated IRIS in each arm, through week 24. 
 
To characterize the tolerability of treatment in each arm by assessing frequency of 
clinician- initiated treatment interruptions or switches through week 48. 
 
To assess frequency of ART drug resistance mutations in participants with detectable viral 
load at study visit weeks 24 and 48. 
 
2.4. Exploratory objectives 
 
To determine the effects of pharmacogenetics (genetic variability in drug metabolising 
enzymes or drug transporters including but not limited to UGT1A, p-glycoprotein) on 
BIC/FTC/TAF PK. 
 
To compare the pharmacokinetics (PK) of TAF, intracellular TFV-DP, FTC and DTG when 
given twice daily and co-administered with Rifampicin during tuberculosis treatment vs 
when given alone after discontinuation of Rifampicin. 
 
To determine the PK of TB drugs. 
 
To describe the PK in hair of BIC, FTC, TAF during and after co-treatment with 
Rifampicin.  
 
To describe maternal and fetal outcomes among women who become pregnant on 
study. 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
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3. INVESTIGATIONAL PLAN 
 
3.1. Study Design and Setting 
 
This is a phase 2b open-label randomized-controlled clinical trial evaluating Biktarvy® 
for treatment of HIV positive, ART-naïve and ART non-naïve patients with TB co-
infection on a rifampicin first-line TB treatment regimen. The study will enrol 
approximately 120 participants. 
Patients will be randomized to receive one of the two ART treatment regimens as listed below 
in a 2:1 ratio. 
 
“Study drugs” refer to the drugs listed in the Intervention/BIC arm in Table 2 and drugs 
used in the Control/DTG arm of the study are considered standard of care (SOC). 
 
Table 2: Study Regimens 
 
Arm 
During TB treatment (and for 2 
weeks after rifampicin is stopped) 
After TB treatment 
(through week 48) 
Intervention Arm/BIC 
Arm ~80 participants 
BIC/FTC/TAF (twice daily)- 
BIC/FTC/TAF (once daily)- 
Control Arm/DTG 
Arm (SOC) 
~40 participants 
DTG/TDF/3TC (once daily) 
+ DTG 50mg once daily 
(evening/pm dose) 
DTG/TDF/3TC (once daily) 
BIC – Bictegravir 50mg; DTG – Dolutegravir 50mg; FTC – Emtricitabine 300mg; TDF – Tenofovir 300mg; TAF – 
Tenofovir Alafenamide 25mg; 3TC – Lamivudine 300mg 
BIC/FTC/TAF fixed-drug combination -Biktarvy® and TDF/3TC/DTG fixed drug combination- TLD 
 
 
The study will enrol and follow up participants for 48 weeks and ART therapy will be 
provided over 48 weeks for the Intervention Arm, and the Control Arm in accordance with 
randomization. 
 
3.2. Study Site and Population 
 
The study will be conducted primarily at the Centre for the AIDS Programme of Research 
in South Africa (CAPRISA) Springfield Clinical Research Site in Durban, Kwa-Zulu Natal. 
This research clinic is located at a district hospital that provides HIV and TB testing and 
treatment services. This site initiates approximately 30-50 newly diagnosed HIV infected 
patients on ART each month. In addition, the TB clinic at the district hospital initiates ~30-
40 patients on TB treatment per month. CAPRISA works closely with surrounding primary 
health care clinics and the local TB program and receives referrals from those programs 
within the eThekwini district (Durban).The eThekwini district registered 19106 HIV-1 
positive TB patients in 2017/2018, and 15767 TB-HIV co-infected patients on ART (with a 
83% co-infection rate).27 Individuals that are interested in study participation and are willing 
to provide informed consent will be screened for study eligibility. 
 
3.3. Study Endpoints 
 
Primary Endpoint: 
• Proportion of patients with suppressed viral load (HIV-1 RNA <50 copies/mL) at 
week 24 in the BIC arm (as per FDA snapshot algorithm) 
 
 

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Secondary Endpoints: 
 
• Viral suppression rates (HIV-1 RNA <50 copies/mL) at weeks 12, 24 and 48 in the DTG 
arm and at 12 and 48 weeks in the BIC arm 
 
• PK of BIC when given twice daily and co-administered with Rifampicin vs. during TB 
treatment vs when given alone after TB treatment completion 
 
• Incidence of TB associated IRIS through week 24, by Arm 
 
• Grade 3 or higher AEs, SAEs; clinician-initiated treatment interruptions or switches 
through week 48. 
 
• Frequency of ART drug resistance mutations in participants with detectable viral load at 
weeks 24 and 48. 
 
Exploratory endpoints: 
 
• PK of FTC, TAF, and intracellular TFV-DP when given twice daily and co-administered 
with Rifampicin vs. during TB treatment vs when given alone after TB treatment 
completion 
 
• PK of TB drugs 
 
• Effects of pharmacogenetics of drug metabolising enzymes or drug transporters (e.g. 
UGT1A1, CYP3A, p-gp) on BIC/FTC/TAF/DTG PK 
 
• Association between hair PK and virologic suppression 
 
4. INCLUSION AND EXCLUSION CRITERIA 
 
4.1. Inclusion criteria 
 
• Adults ≥ 18 years of age with Karnofsky score ≥ 70 
• Confirmed rifampicin-susceptible tuberculosis and/or 
• On first-line rifampicin-based tuberculosis treatment (not > 8 weeks at the 
time of enrolment) 
• Documented HIV-1 infection, ART-naïve OR ART non-naïve (patients to have no 
exposure to ART medication at least ≥ 3 months at the time of enrollment) 
• Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 
• Alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN) 
• Total bilirubin ≤2.5 times ULN 
• Creatinine ≤2 times ULN 
• Hemoglobin ≥ 7.0 g/dL (6.5 g/dL for females) 
• Platelet count ≥ 50,000/mm3 
• Absolute Neutrophil Count (ANC) ≥650/mm3 
• Able and willing to provide written informed consent 
• Female patients agree to use both a barrier and a non-barrier form of 
contraception during the study, starting at least 14 days prior to enrolment 
 
 

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4.2. Exclusion criteria (at the time of screening) 
 
• Pregnancy or breastfeeding (or planned pregnancy within 12 months of study entry) 
• Prior use of antiretroviral drugs for pre-exposure prophylaxis (PrEP) or post-
exposure prophylaxis (PEP) < 3 months at the time of enrolment  
• Hepatitis B surface antigen positive OR Hepatitis B virus (HBV) infection OR 
active systemic infections (other than HIV-1 infection) requiring systemic 
antibiotic or antifungal therapy current or within 30 days prior to baseline that 
could, in the opinion of the investigator, interfere with study procedures or 
assessment of study outcomes 
• Participants with a CD4+ cell count of < 50 cells/ μl 
• Any verified Grade 4 laboratory abnormality, with the exception of, Grade 4 
triglycerides. A single repeat test is allowed during the Screening period to verify a 
result 
• Patients on metformin (> 500mg, 12hourly) 
• Patients with an uncontrolled psychiatric co-morbidity. Patients who, in the 
investigator’s judgment, pose a significant suicidality risk. Recent history of 
suicidal behavior and/or suicidal ideation may be considered as evidence of 
serious suicide risk 
• Other condition or circumstance deemed by clinician/investigators to be 
detrimental to patient safety or study conduct 
• Unwilling to be part of the main pharmacokinetic (PK) study and have PK blood draws 
done (NB there is a semi-intensive PK substudy which is optional) 
 
NOTE: All potential participants will undergo screening evaluations to determine eligibility. 
The Principal investigator (or designate) will assess eligibility and ensure that the 
participant meets all of the inclusion criteria. Participants may be deemed ineligible at the 
discretion of the principal investigator or designate based on safety or other criteria 
 
5. RANDOMIZATION PROCEDURES 
 
A sufficient number of patients will be screened and those deemed eligible will be 
randomized in a 2:1 ratio to Intervention/BIC arm or to a non-comparative Control/DTG 
arm. Participants will be randomized according to a predetermined random order by the 
study statistician. The computer- generated randomisation list will be generated by a 
statistician, where random permutation blocks of different sizes will be used. Either opaque 
sealed envelopes or electronic randomisation system will be used for study arm allocation. 
The envelopes will be stored in a locked cupboard and opened in sequential order by study 
team members authorized to perform randomization procedures by the Principal 
Investigator. In the case of electronic randomization, the password protected randomisation 
list will be sent to the data manager so that it can be uploaded into the database. The study 
will be open label. 
 
6. STUDY TREATMENT 
 
6.1. Regimens, Administration and Duration 
 
Participants will be randomized in a 2:1 ratio as outlined above to either the Intervention 
(BIC) Arm or Control (DTG) Arm as described below. 
 

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The Intervention Arm ART regimen is a fixed-drug combination of a single tablet co-
formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir 
alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during 
rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter 
the BIC/FTC/TAF single tablet co-formulation will be taken once daily.  
Treatment should be initiated as soon as possible after randomization. 
 
 
6.2. Description of Study drug: 
 
Biktarvy® is a fixed dose combination, single tablet containing bictegravir (BIC), 
emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. 
BIC is an integrase strand transfer inhibitor (INSTI). FTC, a synthetic nucleoside analog of 
cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an 
HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate 
(nucleotide) analog of adenosine 5′- monophosphate. Each tablet contains 50 mg of BIC 
(equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF 
(equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive 
ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. 
 
Standard of Care (SOC) ART regimens for the non-comparative Control arm will be 
provided in accordance with the current National South African ART Treatment guidelines 
and will be accessed through the South African Department of Health (DoH) government 
facilities and pharmaceutical services to the study clinic for provision to participants during 
the study. The standard ART regimen consists of a triple drug, single pill, fixed-dose 
combination, comprising Tenofovir 300mg, Lamivudine 300mg and Dolutegravir 50mg 
(TDF/3TC/DTG)/ (TLD), and is the current SOC first-line ART regimen recommended in 
the South African National ART Treatment guidelines. The recommended dosing for 
patients on TB treatment who are receiving rifampicin is DTG 50mg twice daily and 
TDF/3TC once daily (i.e. TLD once daily and a single DTG 50mg tablet in the evening). 
Patients will receive study treatment until two weeks after completing TB treatment, after 
which dosing will be transitioned to once daily. 
 
Standard-first line anti-TB drug treatment consisting of Isoniazid, Rifampicin, 
Pyrazinamide and Ethambutol (HRZE) will be provided in accordance with the current 
National South African TB Treatment guidelines in both arms of the study. Participants in 
our study will receive the current standard of care TB drug treatment that will be accessed 
by the study, through the South African Department of Health (DoH) governmental clinics 
and/or hospitals, for provision to participants. 
 
6.3. Study product adverse effects information 
 
Table 2 outlines possible adverse effects and drug interactions. However, this list is not all 
inclusive and each adverse effect must be examined in conjunction with the full clinical 
picture. At each clinic visit patients will be asked about adverse events that have occurred 
since their previous visit and a physical examination will be performed. 
Refer to the current investigator brochure/package insert for a full list of adverse events 
and drug interactions. 
 
 
 
 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 27 of 50  
Version 3.0, 04 July 2022 
 
 
 
 
Table 3: Possible adverse effects and drug interactions. 
For full list of all adverse events, drug interactions and special precautions refer to the drug 
package insert/FDA label or investigator brochure 
 
Study Drug 
Adverse effects 
Drug interactions 
Comments 
Biktarvy® 
(BIC/FTC/TAF) 
Severe acute 
exacerbations of hepatitis 
B, immune reconstitution 
syndrome, new onset or 
worsening renal 
impairment, lactic 
acidosis/severe 
hepatomegaly with 
steatosis 
Diarrhea, nausea, 
headache, fatigue, 
abnormal dreams, 
dizziness, insomnia 
Dofetilide due to the potential for 
increased dofetilide plasma 
concentrations and associated serious 
and/or life – threatening events 
Herbal products (St John Wort, Other) 
may decrease the effect of BIC and 
TAF 
Biktarvy® is a 
combination regimen, 
coadministration with 
other antiretroviral 
medications for the 
treatment of HIV-1 
infection is not 
recommended. 
Dolutegravir 
Insomnia, headache, 
Dizziness 
Potential for weight gain 
Neural tube defects 
Allergic reaction which 
may cause a rash. You 
may develop a rash with 
any of the following signs 
or symptoms: 
Fever 
General ill feeling Extreme 
tiredness Muscle or joint 
aches Blisters or sores in 
your mouth 
Blisters or peeling skin 
Redness or swelling of 
your eyes 
Swelling of your mouth, 
face, lips, or tongue 
Trouble breathing 
Liver problems – drug 
Induced Liver Injury 
Nausea or vomiting Loss 
of appetite 
Pain, aching, or 
tenderness on your right 
side below your ribs 
Changes in liver test 
results, more common in 
people with hepatitis B or 
C. 
Drugs that are metabolic inducers may 
decrease the plasma concentrations of 
dolutegravir. 
Dolutegravir is reduced with non- 
nucleoside reverse transcriptase 
inhibitor: Etravirine and 
Non-nucleoside reverse transcriptase 
inhibitor: Efavirenz, Non-nucleoside 
reverse transcriptase inhibitor: 
Nevirapine, Protease inhibitors: 
Fosamprenavir/ritonavir 
Rifampicin 
Oral calcium or iron supplements, 
including multivitamins containing 
calcium or iron 
Yellowing of your skin or 
whites of your eyes 
(jaundice) 
Dark or tea- colored 
urine or pale- colored 
bowel movements 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 28 of 50  
Version 3.0, 04 July 2022 
Increase in fat around the 
waist and stomach area 
-Increase in fat on the back 
of the neck Thinning of the 
face, legs, and arms 
Breast enlargement 
Tenofovir 
Diarrhoea, nausea, fatigue, 
headache, dizziness, 
depression, insomnia, 
abnormal dreams, and 
rash 
Severe Acute 
Exacerbations of Hepatitis 
B 
New Onset or Worsening 
Renal Impairment 
Lactic Acidosis/Severe 
Hepatomegaly with 
Steatosis 
Bone Effects of Tenofovir 
DF 
Immune Reconstitution 
Syndrome 
When tenofovir DF was  administered 
with didanosine the Cmax and AUC of 
didanosine increased significantly. 
Higher didanosine concentrations could 
potentiate didanosine- associated 
adverse reactions, including 
pancreatitis, and neuropathy. 
Suppression of CD4+ cell counts has 
been observed in patients receiving 
tenofovir DF with didanosine 400 mg 
daily. 
Tenofovir decreases the AUC and 
Cmin of atazanavir Lopinavir/ritonavir, 
atazanavir coadministered with 
ritonavir, and darunavir coadministered 
with ritonavir have been shown to 
increase tenofovir concentrations 
 
Lamivudine 
Headache Feeling tired 
Dizziness 
Numbness, tingling, and 
pain in the hands or feet 
Depression 
Trouble sleeping Rash 
Upset stomach, vomiting, 
nausea, loose or watery 
stools 
Pancreatitis (inflammation 
of the pancreas), which 
may cause death. 
If you develop pancreatitis, 
you may have one or more 
of the following: stomach 
pain, nausea, and 
vomiting. Abnormal 
pancreatic and liver 
function blood tests 
Methadone: An increased methadone 
dose may be required in a small 
number of patients. 
-Coadministration of single doses of 
lamivudine and sorbitol resulted in a 
sorbitol dose-dependent reduction in 
lamivudine exposures. When possible, 
avoid use of sorbitol- containing 
medicines with lamivudine-containing 
medicines 
 
Rifampicin 
Gastro-intestinal: nausea, 
anorexia, mild abdominal 
pain, diarrhoea. Cutaneous 
reactions: mild flushing 
and pruritus. Hepatitis 
especially if alcoholic or 
history of liver disease. 
Efavirenz, nevirapine, protease 
inhibitors. Rifampicin is an enzyme 
inducer and increases metabolism of 
oral anticoagulants (warfarin), oral 
diabetic drugs, digoxin, phenobarbitone 
and other anti- epileptics and several 
other drugs and drug classes. 
Colours urine, sweat and 
tears orange-pink. 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 29 of 50  
Version 3.0, 04 July 2022 
 
 
6.4. Pharmacy: Product Supply, Distribution, Accountability and Storage 
 
All ART treatment, with the exception of the fixed dose combination BIC/FTC/TAF 
(Biktarvy®) will be procured from the SA Department of Health or municipal facilities 
and/or pharmaceutical wholesalers, where necessary. Biktarvy® will be procured from 
Gilead Sciences in patient ready pack-sizes for the duration of the study. 
The study pharmacy will maintain accountability records of all investigational drugs and 
study products dispensed. In addition, records of manufacturer, batch number and expiry 
information will be maintained by the study pharmacist. Unused study product will be re-
issued to the participant at the discretion of the study pharmacist and in accordance with 
the stipulated dosing schedule. 
Dispensing of study product will be done either directly to the study patient or to 
authorized study staff if the patient is unable to present in person to the study pharmacy. 
Study product will be stored between 15- 25C (< 30C) or in accordance with manufacturer 
instructions and temperature records will be maintained at the study pharmacy. Unused or 
never dispensed study drug (IP) may be returned to Gilead Sciences if required, by the 
sponsor, or may be destroyed on site. Destruction of unused and never dispensed study 
product will be managed in accordance with in-country regulations and the study pharmacy 
standard operating procedure (SOP) for study product destruction, after study PI and 
Gilead sciences Inc, approval. 
 
6.5. Adherence to study products 
 
Adherence monitoring will be done using pharmacy pill count and medication refill 
information as well as participant self-report. Adherence to study product will be assessed 
at the study pharmacy at each study visit. This will be achieved by pill count reconciliation 
and will be documented on a case report form (CRF). Patient self-reported reasons for 
non-adherence will be assessed and adherence counseling will be provided, if needed, 
based on pill count and self-report. 
 
6.5.1 
Adherence measured by an Electronic Dose Monitoring (EDM) device 
 
In addition to pill counts and patient self-report we will utilize an EDM device to measure 
adherence of the patients ART medication. EDM devices are an important tool to measure 
and support adherence. If a pill is missed, recognized through failure to open the pillbox, a 
SMS will be sent to the patient reminding him/her of the missed dose. In patients who 
have missed 3 or more doses of their ART medication based on the EDM which will 
submit real-time short message system (sms) to the study staff, the participants may be 
called in to the study clinic for enhanced adherence counselling and a single pre-dose PK 
sample may be taken to determine drug exposure. 
 
 
 
 
 
 
 
 
 
 
Serious: flu-like syndrome 
and shock 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 30 of 50  
Version 3.0, 04 July 2022 
 
 
 
 
7. CLINICAL AND LABORATORY EVALUATIONS 
 
7.1. Schedule of Events (SoE) 
 
 
Table 4: Study Table of Evaluations  
 
Schedule of 
Evaluations: 
Description 
Screening
Randomization 
and 
Enrolment* 
Follow-up 
End 
of 
study 
Trial Visit 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 8 
Visit 9 
Day/week 
Screening D0 
Enrolment 
D28/ 
Week 
4 
Week 
8 
Week 
12 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Informed consent 
X 
 
 
 
 
 
 
 
 
Age verification 
X 
 
 
 
 
 
 
 
 
HIV confirmatory test 
X 
 
 
 
 
 
 
 
 
Urine pregnancy 
test in females 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (incl. 
height and weight) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Physical 
exam/Clinical safety 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Verification of eligibility 
 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Safety bloods (Hb, 
Urea, Creatinine, e-
GFR, ALT, AST, 
Bilirubin, Amylase, 
platelets FBC and 
other as clinically 
indicated) # 
X 
X# 
X 
X 
X 
X 
X 
X 
X 
HEP B surface antigen 
X 
 
 
X 
 
X 
 
 
X 
Drug-susceptible TB 
diagnosis and/or 
confirmation of 
previous results 
(GeneXpert - 
including Rif resistance) 
X 
 
 
 
 
 
 
 
 
Sputum Smear testing* 
X 
 
 
X 
 
X 
 
 
 
Sputum Culture* 
(genotypic/ phenotypic 
testing for RIF/INH 
resistance at month 
6 only if positive) 
 
 
 
X 
 
X 
 
 
 
CD4+ cell count 
X 
 
 
 
 
X 
 
 
X 
HIV-RNA viral load ** 
X 
 
X 
X 
X 
X 
 
X 
X 
ART administration 
 
X 
X 
X 
X 
X 
X 
X 
X 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 31 of 50  
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TB treatment (duration 
may 
vary) 
X 
X 
X 
X 
X 
 
 
 
 
AEs/SAEs assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
TB associated IRIS 
Assessment 
 
 
X 
X 
X 
 
 
 
 
Concomitant medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK blood draws*** 
 
 
X 
X 
X 
X 
X 
 
X 
Dry blood spots for PK 
analysis*** 
 
 
X 
X 
X 
X 
X 
 
X 
Pharmacogenetic 
sample 
storage (buffy coat) 
 
X 
 
 
 
 
 
 
 
PBMC Cell Storage 
 
X 
 
 
 
X 
 
 
X 
Hair sample## 
 
 
X 
X 
X 
X 
X 
 
 
Stored plasma sample 
for HIV- 1 genotyping$ 
 
X 
 
 
 
X$ 
 
 
X$ 
Electronic Dose 
Monitoring ® 
 
X 
X 
X 
X 
X 
X 
X 
X 
* TB tests in accordance with SOC and as indicated 
 
# Safety bloods will be repeated at enrolment unless this visit (Enrolment) is within 72 hours of 
screening, and/or if deemed necessary by clinician/investigator 
Screening evaluations to determine eligibility must be completed <14 days prior to randomization. 
 
** if viral load detectable any time after week 24 or at week 24 or 48 participants may be 
counselled and a VL retest may be done 2-4 weeks later 
 
*** sampling timepoints and required visits for PK sampling and DBS are specified in protocol section 
7.2.3 per arm. Sampling timepoints are also specified for semi-intensive PK sub-study in section 
7.2.3. ALL other timepoints marked are considered optional/not required 
6.5.1 Single pre-dose sampling will be done where required in patients with poor adherence 
(more than 3 missed doses) based on an EDM   
 
 
## hair samples are optional 
 
$ samples will be stored for genotyping in patients with detectable HIV-RNA viral load at week 24 and 
48, but may be stored at visits after week 24 if VL detectable after retest at 2-4 weeks 
We will conduct resistance testing in real-time for all drugs in the regimen including integrase 
inhibitor in patients with suboptimal viral responses. If at week 12 and after, if viral load 
increases by a log or greater compared to the most recent visit, and after counseling/retest, if there is 
no improvement of viral load on retest, then resistance testing for integrase and other ARV drug 
resistance will be done as indicated. 
In patients who are ARV non-naïve may have real time resistance done at baseline if required and at the 
discretion of the study PI and/or study clinician 
 
® Provision of EDM devices to study participants are optional  
 
The study SoE will be followed except when procedures are clinically indicated or not in accordance 
with clinical judgement. 
 
7.2. Timing of Evaluations 
 
Refer to Table 4 above for a summary of the evaluations. 
 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 32 of 50  
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7.2.1. Screening Evaluations (Visit 1) 
 
Informed Consent 
After identifying potential participants for the study, written screening informed 
consent will be obtained from these participants. 
Age verification 
Age verification will be done using the participant SA identification document or other 
relevant official document to verify the date of birth and age (>18 years) 
 
HIV and TB Testing 
 
HIV confirmatory testing will be carried out using a licensed rapid HIV test. HIV positive 
results will be confirmed by a second licensed rapid HIV test. Discordant results may be 
confirmed by ELISA. A sputum sample will be obtained for sputum smear testing, 
GeneXpert analysis and to confirm TB infection and rifampicin (RIF) resistance, where 
required (if these tests have not already been done or results are not available from the 
local TB program). All TB tests will be done in accordance with SOC and TB treatment 
guidelines. IF participants have been initiated onto TB treatment prior to screening then the 
duration of TB treatment and baseline TB test screening results will be documented to 
ensure not > 8 weeks of rifampicin-based TB treatment has been taken and baseline 
confirmation of TB infection (clinical or microbiological) and rifampicin-sensitive TB on 
GeneXpert will be documented, where applicable. 
 
Clinical and Laboratory Evaluations 
 
Patients will have all vital signs (including height and weight) measured, a targeted clinical 
exam or clinical safety monitoring will be done. Safety blood will be drawn for Haemoglobin 
(Hb), Urea, Creatinine, calculation of Estimated glomerular filtration rate (e-GFR), Aspartate 
transaminases (AST), Alanine aminotransferase (ALT), total bilirubin, amylase, platelets 
and full blood count. 
Hepatitis B surface antigen testing will be done. Any other testing will be done as 
clinically indicated. A pregnancy test (using urine sample) is required at every visit 
if patient is a woman/female of child-bearing potential. 
 
Baseline CD4 count and Viral Load Testing 
CD4 cell-counts and HIV-RNA viral load testing will be done. 
 
TB Treatment 
If a participant has already initiated on rifampicin-based TB treatment the duration of 
treatment will be determined and documented to ensure not > than 8 weeks of rifampicin 
treatment has been completed. TB treatment will be provided and continued in the study 
as per SOC. 
 
Concomitant Medication Review 
Concomitant medication (ConMed) will be reviewed and documented on a ConMed CRF 
or other source document by the study clinician or designated clinical staff. 
 
Screening evaluations to determine eligibility must be completed <14 days prior to 
randomization. 
 
 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 33 of 50  
Version 3.0, 04 July 2022 
Screening Failures: 
 
In addition to data being collected on participants who enrol into the study, demographic, 
clinical, and laboratory data on screening failures will be captured in a Screening Failure 
Results form and entered into the study database. A participant is considered as a screen 
failure if the participants conditions change upon providing an informed consent, or the 
outcome of the any baseline tests and assessments fail to meet one or more of the entry 
criteria or as per investigator discretion. 
Participants who has failed screening procedures may be rescreened for entry into the 
study, at the discretion of the clinician or investigators. 
 
7.2.2. Baseline, Randomization and Enrollment (Visit 2) 
 
Randomization. 
 
Informed Consent 
Once the participants meet all the conditions of the inclusion criteria, the informed consent 
form will be reviewed at enrolment. 
 
Verification of Eligibility and Randomisation 
Eligibility criteria will be assessed by a study clinician and documented prior to 
randomization. On- study entry evaluations will occur after randomization. If the patient 
meets the enrolment criteria and verification of eligibility, the site must then randomize each 
new patient according to Randomization Procedures outlined in the protocol. Baseline 
evaluations (according to SoE, Table 3) will be completed at the screening and enrolment 
visits (unless otherwise stated by the Study PI or study clinician) and patients should start 
on assigned study therapy as soon as possible after randomization. 
 
Clinical and Laboratory Evaluations 
Patients will have all vital signs (including weight) measured, a targeted clinical exam or 
clinical safety monitoring will be done. Safety blood will be drawn for Hb, Urea, creatinine, 
(e-GFR calculated), AST, ALT, total bilirubin, amylase, platelets and FBC and any other 
safety testing as clinically indicated unless within 72 hours of safety bloods done at 
screening visit. 
 
A pregnancy test (using urine sample) is required at every visit if patient is a 
woman/female of child-bearing potential. 
 
Culture for genotypic/phenotypic testing for RIF/Isoniazid INH resistance testing will be 
done as per standard of care for TB treatment. 
 
ART Administration and TB Treatment 
ART treatment will be administered in accordance with the study arm to which the 
participant is randomized. The Intervention Arm ART will consist of BIC/FTC/TAF as a 
fixed dose single tablet, coformulation (Biktarvy®). Control arm participants will receive a 
DTG-based regimen in accordance with standard of care. 
All TB treatment will be in accordance with standard of care and South African National TB 
treatment guidelines. All participants must be on a rifampicin-based TB treatment regimen 
(i.e have rifampicin-sensitive tuberculosis). If a participant has already initiated on 
rifampicin-based TB treatment the duration of treatment will be determined and any further 
changes to regarding TB treatment since screening will be documented to ensure not > 
than 8 weeks of rifampicin treatment has been completed. 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 34 of 50  
Version 3.0, 04 July 2022 
Concomitant Medication Review 
Concomitant medication (ConMed) will be reviewed and any changes from 
screening will be documented on a ConMed CRF and new concomitant medication 
will be recorded. 
 
HIV-1 Genotyping 
Plasma samples will be stored for later HIV-1 genotyping in patients meeting criteria for 
virologic failure at visits at Week 24 or later (virologic failure defined as viral load > 400 
copies/mL on repeat VL testing 2-4 weeks after that visit, following adherence counselling). 
Real-time resistance testing may be done at any time in the study, due to sub-optimal 
viral responses based on clinical judgment after discussion with investigators. We will 
conduct resistance testing in real-time for all drugs in the regimen including integrase 
inhibitor in patients with suboptimal viral responses. If at week 12 and after, if viral load 
increases by a log or greater compared to the most recent visit, and after 
counseling/retest, if there is no improvement of viral load on retest, then resistance 
testing for integrase and other ARV drug resistance will be done. 
 
Pharmacogenetic testing 
Buffy coat samples will be stored for future pharmacogenetic testing in patients who 
agree on informed consent for storage of these samples. 
 
7.2.3. Post Entry Evaluations: Follow-ups (Visits 3 to 9) 
 
Clinical and Laboratory Evaluations 
 
Patients will have all vital signs (including weight) measured, a targeted clinical exam or 
clinical safety monitoring will be done. Safety blood will be drawn for Hb, Urea, creatinine, 
(e-GFR calculated), AST, ALT, total bilirubin, amylase, platelets and FBC and any other 
safety testing as clinically indicated at all follow up visits. Hep B surface antigen testing 
will be done at visit 4, 6 and 9. A pregnancy test (urine) is required at every visit if 
patient is a woman of child-bearing potential. 
 
TB Testing 
Sputum smear testing may be done at visit 4, and 6 or as indicated as per standard of 
care in the National TB treatment guideline. Sputum for Culture will be done in accordance 
with SOC and TB treatment guidelines at visit 4, 6. Genotypic/phenotypic testing for 
RIF/INH resistance may be done at visit 6 if culture positive. 
 
CD4 count and Viral Load Testing 
 
CD4 cell-counts (at visit 6 and 9) and HIV-RNA viral load testing (at visit 3, 4, 5, 6, 8 
and 9) will be done. 
If viral load is detectable any time after week 24, or at week 24 or 48, participants 
may be counselled and a retest done 2-4 weeks later. 
 
 
ART Administration and TB Treatment 
 
ART treatment based on arm allocation will be provided at each visit until week 48 (unless 
discontinuations or disruption to treatment due to safety or other issues occur). TB 
treatment will be provided in accordance with standard of care until completed. 
 
Adverse events (AEs) and Serious adverse events (SAEs) assessment 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 35 of 50  
Version 3.0, 04 July 2022 
All participants will be assessed for any Aes and SAEs at every visit and these will be 
documented and reported accordingly. 
 
TB associated (Immune Reconstitution Syndrome) IRIS assessment 
 
A TB associated IRIS assessment will be done at visit 3, 4 and 5. Monitoring and 
assessment for and management of IRIS will be done at specified visits and as clinically 
indicated as well as in accordance with time of TB treatment initiation. 
 
Concomitant Medication Review 
Concomitant medication (ConMed) will be reviewed and any further changes from 
screening and enrolment will be documented on a ConMed CRF at all follow up study 
visits as per SOE. 
 
Pharmacokinetic (PK) Study 
 
PK assessments will be performed in the study. The pharmacokinetic sub-study aims to 
assess the PK of BIC, FTC, TAF, and intracellular TFV-DP and DTG when given twice 
daily and co- administered with Rifampicin vs. during TB treatment vs when given alone 
after TB treatment completion. All participants who consent to participation in this sub-
study will be included. The time of last dose of all ART and TB drugs and time of dose 
taken in clinic (observed dose) will be recorded for all PK visits. PK sampling may be 
delayed/deferred if the participant missed the last dose/s of drug or if rifampicin has been 
temporarily withheld for any reason during TB treatment. 
 
PK sampling: 
 
PK samples (~ 4 ml plasma and DBS) will be collected on all participants in the BIC 
arm using sparse sampling techniques as follows: 
 
Visits 3 and 5 
 
Pre-dose (within 10-14 hours post previous dose during twice daily dosing), 
At 1 to 4 hours post-dose in the study clinic 
 
After the completion of TB treatment (discontinuation of rifampicin) at Visit 7 or after (if 
extended TB treatment duration) 
at pre-dose (20-28hr post previous dose for once daily 
dosing) At 1 to 4 hours post-dose in the study clinic 
 
Additional pre-dose PK samples (~4ml plasma and DBS) in both the BIC and DTG 
arm of the study will be collected at Visits 4, 6, and 9 (to correlate with VL results, 
where applicable). 
 
Pre-dose (i.e. within 20-28h of previous dose during once daily dosing after TB 
treatment completion; within 10-14h post previous dose during twice daily dosing) 
 
Semi-Intensive PK sampling study in a subset of patients in the BIC arm ONLY 
 
Semi-intensive PK sampling (~ 4 ml plasma and DBS) on a subset of 
approximately 30-40 patients in the BIC arm will be conducted as follows: 
 
at Pre-dose 0, 1, 2, 4, 6 and 8-12 hours, post-dose at Visit 3 and 5 [during twice daily 
dosing on rifampicin] 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 36 of 50  
Version 3.0, 04 July 2022 
at pre-dose 0, 1, 2, 4, 6-8 and 24-25 hours, at Visit 7 or after [once daily dosing after 
rifampicin stopped]. 
 
This proposed PK study in a subset of patients will be used to help stabilize the PK model 
so that we can fully characterize the PK profile of study drugs with and without co-
administered TB treatment. Sparse data on the full group from the sparse sampling done 
on all patients will help characterize magnitude of and sources of variability. The 
preference will be for these participants to be enrolled early in the trial so that these PK 
data can contribute to interim analyses, if needed. 
 
Hair sampling. 
Optional hair samples will be collected at Visit 3, 4, 5, 6 and 7. 
 
Peripheral Blood Mononuclear Cell (PBMC) Cell Storage 
 
PBMC samples may be taken for storage and future testing. 
 
HIV-1 Genotyping 
 
Plasma samples will be stored for later HIV-1 genotyping in patients at visit 6 and 9 (or 
any timepoint after visit 6) in patients meeting criteria for virologic failure at visits at 
Week 24 or later (virologic failure defined as viral load > 400 copies/mL on repeat VL 
testing 2-4 weeks after that visit, following adherence counselling). 
Real-time resistance may be done at any time in the study, due to sub-optimal viral 
responses based on clinical judgment after discussion with investigators. We will conduct 
resistance testing in real-time for all drugs in the regimen including integrase inhibitor in 
patients with suboptimal viral responses. If at week 12 and after, if viral load increases by a 
log or greater compared to the most recent visit, and after counseling/retest, if there is no 
improvement of viral load on retest, then resistance testing for integrase and other ARV 
drug resistance will be done as indicated. 
 
7.2.4. Study Visit Window and Unscheduled Visits 
 
The window period for all scheduled monthly study visits (visit 3, 4, 5) is ±7 days and ± 14 
days for visit , 6 7, 8 and 9. Any visit for which a patient attends outside of the specified 
visit window but not in addition to those required as per the ‘schedule of evaluations’ 
should be considered as an early/late visit. The assessments which are undertaken as part 
of an early/late visit should reflect those for the visit which will be or has been missed. Any 
additional assessments should be undertaken as clinically indicated. 
 
 
7.3. Evaluations during study 
 
7.3.1. HIV testing will be done using approved rapid tests (initial and confirmatory). TB 
evaluations will be done to confirm drug-susceptible TB and document rifampicin-
based TB treatment regimens, where required. 
 
7.3.2. Targeted Physical Exam/Clinical safety monitoring 
 
A targeted physical examination and clinical safety monitoring will be performed at every 
study visit after baseline (in accordance with the SoE) and on subsequent clinically required 
visits. This will include neuropsychiatric evaluations. 
 

PI: Dr A Naidoo 
Site: CAPRISA   
Study No: CAP 093 
Page 37 of 50  
Version 3.0, 04 July 2022 
7.3.3. Pregnancy Testing 
For women of reproductive potential: The pregnancy test using a urine-test performed at 
all visits study according to SoE must be negative. 
 
7.3.4. Concomitant medication reviews will be conducted by the clinical staff. 
 
 
8. CLINICAL MANAGEMENT ISSUES 
 
8.1. Clinical Management Issues at baseline and follow up during study conduct 
Patients who meet study eligibility criteria at screening and are enrolled into the study will 
be followed for 48 weeks. All other safety and clinical will be done in accordance with the 
Schedule of Evaluations (SoE) and in line with current South African Department of 
Health Adult ART Guidelines and the TB treatment guidelines in co-infected patients. 
 
The INSIGHT study will use the Division of AIDS Table for Grading the Severity of Adult 
and Paediatric Adverse Events (DAIDS AE Grading Table) Version 2.1, July 2017 to 
assess and grade adverse events or baseline abnormalities. 
 
8.2. Specific Clinical Management Scenarios 
 
8.2.1. Withdrawal of study drug 
 
A clinician/investigator may withdraw one or all drugs in the study treatment in the event of 
a serious or life-threatening adverse event that is possibly or probably related to study 
drug, if this is deemed to be in the patients’ best interest. This will be discussed with the 
study PI or designee before the decision is made, unless in an emergency situation. All 
safety issues need to be followed up until resolution to < Grade 2 (DAIDS Table for 
Grading Adult and Paediatric Toxicity Events) 
 
8.2.2. Virological suppression and definition of treatment failure 
 
HIV-1 RNA (viral load) testing will be done and monitored during follow-up to ensure 
adequate viral suppression from baseline. If patients rebound after achieving <50 copies 
per/ml then adherence counselling will be done. Any patient with a detectable HIV viral load 
(≥ 50 copies/mL) at Weeks 24 or 48 will undergo counselling and adherence support and 
have a recheck in 2-4 weeks. If suppressed at recheck, that will count as a success. A 
treatment failure will be defined as a participant with a viral load >400 copies/mL at week 24 
or 48 or as defined by the FDA snapshot algorithm. Patients with confirmed virological 
failure will be switched to an appropriate second-line regimen in accordance with standard 
of care and the National ART Treatment guideline and followed up in the study until 
transition to standard of care within a DoH or other healthcare facility. 
 
Real-time resistance testing may be done at any time in the study, due to sub-optimal 
viral responses based on clinical judgment after discussion with investigators. We will 
conduct resistance testing in real-time for all drugs in the regimen including integrase 
inhibitor in patients with suboptimal viral responses. If at week 12 and after, if viral load 
increases by a log or greater compared to the most recent visit, and after 
counseling/retest, if there is no improvement of viral load on retest, then resistance 
testing for integrase and other ARV drug resistance will be done. 
 
8.2.3. Reporting AE’s 
 

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The most common adverse effects known to be associated with the study drugs are 
included in the current version of the Investigator brochure and package insert/FDA label 
for Biktarvy. Some of these are summarized in the protocol (see Table 2 above). The 
investigators are responsible for reporting all Grade 3 and Grade 4 adverse events that are 
observed or reported during the study, regardless of whether they are thought to be related 
to the study drugs as recorded in patients chart notes. All Adverse Events including SAEs 
will be reported in accordance with ICH and SA GCP guidelines. 
 
8.2.4. TB treatment 
 
If participants who are randomized and enrolled into the study are later determined to be 
resistant to any of the drugs in the TB regimen then treatment for TB will be adjusted in 
accordance with standard of care- for resistance (e.g. isoniazid -monoresistance) or if 
rifampicin mono-resistance or multi-drug resistance is confirmed then the participant will be 
treated in accordance with national TB treatment guideline. If the patient is in the standard of 
care (SOC) arm on dolutegravir-based ART, then the participant will be continued on 
dolutegravir and the dose adjusted in accordance with SOC for patients who on rifampicin-
based/non-rifampicin-based TB treatment. If the patient is in the intervention arm on Biktarvy 
the participant will either be continued on Bictegravir once daily (if not on rifampicin) or 
switched to appropriate SOC ART (based on investigator discretion) and continued to be 
followed up in the study in accordance with intention to treat analysis. 
 
8.3. Guiding Principles of Toxicity Management 
 
For adverse events, that is in the investigator’s judgment may be due to study drugs, the 
following general approach to management should be applied however clinical judgement 
and investigator decision may be overriding:  General management principles 
 
8.3.1. Grade 1 Adverse Events  
 
In general, for grade 1 events the patient will be followed carefully and the study 
drugs will be continued. 
 
8.3.2. Grade 2 Adverse Events  
 
For grade 2 events the patient will be followed more closely, with additional laboratory 
and/or clinic visits as necessary; drugs should be continued unless in the view of the 
clinician/investigator this would be unsafe. 
 
 
8.3.3. Grade 3 and 4 Adverse Events 
 
Any grade 3 or 4 event should be carefully assessed. The research clinician should rule out 
other possible causes of the symptoms before discontinuing study medication. When 
possible, concomitant medications should be with-held first at the discretion of the research 
clinician/and or after discussion with investigators, if causality is suspected. If after careful 
assessment and in the clinician’s judgment the event is due to study drug(s), the causative 
study drug(s) may be withheld, after discussion with investigators unless in an emergency 
situation. The patient should be permanently discontinued from study medications if it is in 
their best interests to do so. Further HIV treatment will be directed by the clinician in 
consultation with the investigator. The patient will continue to be followed according to the 
protocol. Other adverse events of any grade not thought to be due to the study drugs, 
should be managed at the discretion of the research clinician; study treatment should be 

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continued, if possible. 
 
8.4. Specific toxicity management 
 
Liver toxicity: 
 
Liver chemistry threshold stopping criteria have been designed to assure subject 
safety and to evaluate liver event etiology during administration of IP and the Follow-up 
period. 
If ALT >2 × ULN, liver chemistries should be monitored weekly for 2 weeks, then every 2 
weeks thereafter until normalized. 
While receiving IP co-administered with TB treatment, both will be stopped if any of the 
following liver chemistry criteria are met: 
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin; bilirubin fractionation 
required) NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable 
and a subject meets the criterion of total bilirubin 2 × ULN, then the event meets liver 
stopping criteria; 
ALT 3 × ULN with symptoms or worsening of acute hepatitis or hypersensitivity such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia, OR 
ALT ≥5 × ULN; regardless of symptoms 
After completion of TB treatment, while receiving IP, ART will be stopped if any of the 
following liver chemistry criteria are met: 
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin; bilirubin fractionation 
required) NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable 
and a subject meets the criterion of total bilirubin 2 × ULN, then the event meets liver 
stopping criteria; 
ALT 3 × ULN (if baseline ALT is <ULN) with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia, OR 
ALT 3 × baseline ALT with symptoms or worsening of acute hepatitis or hypersensitivity 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia; ALT  5 × ULN and <8 × ULN (after TB treatment is complete) that persists 
2 weeks (with bilirubin <2 × ULN and no signs or symptoms of acute hepatitis or 
hypersensitivity); ALT 5 × ULN but <8 × ULN (after TB treatment is complete) and cannot 
be monitored weekly for >2 weeks; and subjects who develop ALT 5 × ULN should be 
followed weekly until resolution or stabilization (ALT <5 × ULN on 2 consecutive 
evaluations); 
ALT > 8 × ULN; regardless of symptoms. 
If liver stopping criteria are met, the study team, in collaboration with investigators where 
will determine next steps, which may include a liver-sparing TB regimen, relevant 
laboratory tests to look for alternative causes, or other measures. 
 
Renal Toxicity, Immune Reconstitution Inflammatory Syndrome (IRIS) events and 
Neuropsychiatric adverse events will be graded according to the Division of AIDS Table 
for Grading the Severity of Adult and Paediatric Adverse Events (DAIDS AE Grading 
Table) Version 2.1, July 2017 and will be managed in accordance with local guidelines 
and recommendations for Biktarvy based on investigator brochure. Additional specific 
clinical management criteria will be outlined in the study specific manual or clinical SOPS. 

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8.5. Reporting Serious Adverse Events (SAEs) 
 
The following Serious Adverse Event will be reportable to the database and regulatory 
authorities: AE’s that: 
 
 
• Results in death 
• Is immediately life threatening at the time of  occurrence  
• Results in persistent or significant disability or incapacity  
• Requires in-patient hospitalization or prolongs hospitalization  
• Results in a congenital anomaly or birth defect 
• Is deemed an “important medical event” by the Investigator (may not be 
immediately life threatening or result in death or hospitalization but may 
jeopardize the patient e.g. convulsions. 
• This will include any adverse event that is unexpected, but related to the study 
product, eg cardiac failure 
 
8.6. Safety Monitoring  
 
Procedures for assessing safety 
At each clinic visit patients will be asked about changes (adverse events) that have 
occurred since their previous visit. Physical assessments will be performed at baseline 
and on subsequent scheduled visits or as clinically indicated. 
Safety laboratory investigations will be performed at screening and in accordance 
with the schedule of evaluations, as well as determined by the study clinician 
based on the safety evaluations. 
 
Screening tests and scheduled subsequent visits will include: Liver function, renal 
function, full blood count: At screening, baseline and study visit until week 48 of follow 
up. 
Pregnancy test: At screening, baseline and every month thereafter as per 
the SoE. Monitoring for TB associated IRIS events, as per SOE and SOC 
Neuropsychiatric adverse events, symptoms of depression and suicidal ideation 
 
Any adverse events detected will be graded according to a modified version of the toxicity 
criteria produced by the Division of AIDS and coded using Medra Coding or similar. 
Serious adverse events will be reported to SAPHRA and the UKZN Biomedical Research 
Ethics Committee. (BREC) according to their specific requirements. 
 
Discontinuation of study treatment: 
The investigator may discontinue a patient from study drug or treatment/s in the event of a 
severe or serious adverse event, or at any time he/she thinks it is in the patient’s best 
interest. If there is a medical reason for withdrawing study treatment, the patient will 
remain under the supervision of the investigator until satisfactory health has returned 
irrespectively of the reason for discontinuation. The frequency of patient review will be 
determined by the clinical need to ensure optimal care. 
 
Withdrawal from the study 
Participation in the study is strictly voluntary. A participant has the right to withdraw from the 
study at any time for any reason. Patients who withdraw their consent will not have to 
undergo any follow up procedures. The study investigator may withdraw participants from 
the study if it is in the participants best interest to do so or if participant unable or unwilling 

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to adhere to study visits or procedures. 
 
Data Safety Monitoring and Review: 
 
Participant safety will be closely monitored both internally by the protocol safety review team 
(PSRT) and externally by a data safety and monitoring committee (DSMC) 
 
The PSRT will provide clinical safety oversight on study. The PSRT will consist of Study 
investigators and an independent external clinician (Infectious Diseases Specialist/Physician). 
The membership, scope of responsibility, role and modus operandi of the PSRT will be detailed 
in the terms of reference as part of the study management plan. 
This study will be reviewed by a data safety monitoring committee (DSMC). The DSMC will 
be comprised by a statistician, and at least two experts in TB or HIV clinical trials 
(infectious disease specialist and/or clinical pharmacologist preferable), all independent of 
the study team. The study DSMC will conduct an interim review of safety, PK, and viral 
load data after the first 10 participants have completed the 24-week visit in the BIC arm. An 
interim analysis at week 24 when at least half of the trial participants have been enrolled 
will be conducted to review safety and efficacy in the two arms. These data will be 
reviewed by the DSMC and recommendations will be made to the study team. We will 
conduct PK analysis during the study once the first 10 participants in the BIC arm have 
reached/completed their week 12 visit. This will allow for PK data to be available to be 
included for the DSMC interim review of safety, viral load and clinical outcomes after the 
first 10 participants complete the week 24 visit, as outlined above. The study team will also 
review PK data as soon as these are received and will share these with the DSMC in 
advance of the planned interim analysis if there are any concerns. We will conduct 
resistance testing in real-time for all drugs in the regimen including integrase inhibitor in 
patients with suboptimal viral responses. If at week 12 and after, if viral load increases by a 
log or greater compared to the most recent visit, and after counseling/retest, if there is no 
improvement of viral load on retest, then resistance testing for integrase and other ARV 
drug resistance will be done i.e. if viral loads are declining and then stop declining (even 
with adherence counseling and retest ~2 weeks later), after 12 weeks on treatment, then 
real time resistance testing will be done and appropriate steps taken should resistance be 
detected. Resistance testing data will be shared with the DSMC. 
A full DSMC review will be scheduled at least annually after opening to accrual or on a 
frequency determined by the DSMC. For each full review, summaries provided to the 
DSMC will be described in an open report that is also available to study investigators and 
provides data from both arms combined and a closed report in which data will be broken 
down by treatment arm (available only to the statistician and the DSMC and/or DAIDS 
medical officer, where applicable). Participants’ baseline demographic and medical history 
will be summarized. Review of study conduct will address site accrual, premature study 
discontinuations and their reasons (administrative or loss to follow-up), tracking of potential 
losses to follow-up, data completeness. The SMC will also review participants’ safety data, 
frequency and causes of death, as well as incidence of virologic failure. 
In addition, internal reviews of patient charts, SAE reports and regulatory submissions will 
be conducted by the CAPRISA quality assurance (QA) team in accordance with stipulated 
timelines. External monitoring may be conducted by an independent monitor designated by 
the study investigators to conduct study compliance or quality assessments and or DAIDS 
medical officer or committee where applicable. 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1. Sample size determination: 
 
The study is not designed to compare primary and secondary outcomes between the two 

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study arms. Rather, the sample size is based on precision for estimating the response rate 
in the BIC arm, following similar design in the REFLATE28 and INSPIRING24 trials. 
Assuming an 85% response rate for BIC/FTC/TAF at week 24,7,8,17 a sample size of 66-80 
subjects in the BIC arm would have >85% power to detect a response rate of greater than 
70%. The sample size has been chosen to provide an adequate number of subjects for 
assessing the antiretroviral activity of BIC/FTC/TAF.  
 
A non-comparative control group of 30-40 patients will be enrolled in the DTG arm to 
provide safety and efficacy parameters for standard-of-care treatment in the local setting, to 
contextualize the BIC arm results and to serve as a baseline comparator group for safety 
and efficacy parameters. 
 
9.2. Analysis including statistical methods: 
 
Analysis of the primary endpoint will be conducted on all participants who are randomly 
assigned and receive at least one dose of the study drug, regardless of attendance of post- 
enrolment study visits (modified intent to treat population) who have drug-sensitive TB and 
were on rifampicin-based TB treatment. The primary endpoint of viral suppression at 24 
weeks will be assessed after all enrolled participants have either completed 24 weeks of 
study follow-up or have prematurely discontinued the study drug or were deemed lost to 
follow-up. Any patient with a detectable HIV viral load (>50 copies/mL) at Weeks 24 or 48 
will undergo counselling and adherence support and have a recheck in 2-4 weeks. If 
suppressed at recheck, that will count as a success. The primary efficacy endpoint is the 
proportion of patients with a viral load (HIV-1 RNA) of <50 copies per ml at week 24 in the 
BIC/FTC/TAF arm using the FDA snapshot algorithm. 
 
Secondary endpoints or outcomes will be reported for both arms. 
Secondary endpoints are proportion of patients with a viral load (HIV-1 RNA) of <50 
copies per ml at week 12 and 48 in the BIC/FTC/TAF arm and at week 12, 24 and 48 in 
the SOC arm. The proportion of participants with viral suppression at week 12 and week 
48 will be reported (both mITT and per protocol analyses). Safety data will be summarized 
for all patients. To assess tolerability and safety, we will report proportions of participants 
who will experience grade 3 or 4 AEs, SAEs as well as the proportion with treatment 
interruptions or switches. Depending on the number of incident TB-IRIS cases, the 
incidence rate or the proportion will be reported. 
 
Pharmacokinetic Analysis Plan: 
 
PK assessments will be performed in the BIC arm in participants provided informed 
consent. PK samples in the control arm may be stored for later analysis. 
 
PK parameters (Ct, Cmax, AUC) will be computed for all subjects who undergo semi-
intensive sampling. Analytes to be measured include BIC, TAF, intracellular TFV-DP 
and DTG. PK parameters will be estimated by application of a nonlinear model using 
standard noncompartmental methods (WinNonlin® software). Descriptive statistics 
(n, mean, standard deviation (SD), coefficient of variation [%CV], minimum, median, 
maximum, Q1, Q3, geometric mean, and its 95% CI) will be calculated. Geometric 
mean ratios for Ct, Cmax, AUC will be generated, comparing these parameters during 
TB treatment vs. without concurrent TB treatment. For concentration values below 
limit of quantification (BLQ), the number of subjects with values of BLQ will be 
presented and treated as missing data. Using data from both the semi-intensive PK 
sub-study and the sparse sampling in the overall study population, a population PK 
model (Non-Linear Mixed Effects Models) will also be developed, both to describe 
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trough concentrations. 
 
Optional: Hair samples may be collected as part of the study, and if budget allows, 
exposures of BIC, TAF and FTC and DTG will be measured. This may help to distinguish 
issues of adherence vs. low PK due to drug interaction and to determine associations 
between drug levels in hair and viral suppression. 
 
9.3. Explanation on how the results of this study will be used 
 
Clinical trial data of the safety, efficacy and tolerability of BIC and TAF in HIV endemic 
African settings, particularly in the context of HIV and TB co-infection, which accounts 
for approximately 50-80% of prevalent cases, is unavailable. 
This study will generate new data that may support the use of a potent antiretroviral FDC, 
Biktarvy®, in HIV-1 infected adult patients with TB co-infection taking rifampicin-containing 
first-line treatment. If the outcome of the study is favourable, there may be potential to have 
a new and highly desirable treatment option for patients with HIV-associated TB in settings 
where this drug is already available. Importantly, demonstrating that Biktarvy® can be used 
in patients with TB will fill a critical gap and help support the case for its introduction into 
Africa, where ~70% of the global 
burden of HIV is concentrated and in particular in South Africa, which has one of the 
largest incidence of HIV and TB co-infection rates in the world. 
 
9.3.1. Publication of results: Study results will be published in a peer-reviewed 
journal/s and disseminated at appropriate national or international conferences. 
 
10. HUMAN PARTICIPANTS 
 
10.1. 
Patient Recruitment 
 
Patients will be recruited from the King Dinuzulu, District Hospital where the CAPRISA 
Springfield Clinical Research site is located in Durban, KZN, well as from surrounding SA 
DoH and municipal clinics or facilities. Recruiters will be stationed within the HIV/TB 
facilities and potential patients can be approached through several mechanisms: 
 
HCT services – HIV testing and counselling is routinely offered at the SA DoH and 
municipal facilities which provides an ideal opportunity to conduct pre-screening. 
Each Health Care Facility has an in-house National Health Laboratory Service. All HIV-
infected, new patients with a positive smear and GeneXpert Rifampicin sensitive can be 
identified at the laboratory and followed-up by a CAPRISA recruiter based at the facility. 
Clinic referrals - Clinicians or Professional Nurses at selected DoH and/ municipal 
facilities will be informed on the study protocol and can refer patients for enrolment. 
 
10.2. 
Ethics 
 
Study Impact and Justification: 
Our study will fill key knowledge gaps, on the use of InSTI’s for the treatment of HIV-1 
infection in the context of patients with tuberculosis co-infection on a rifampicin -based 
treatment regimen. The study will have high impact given that firstly, South Africa and 
KwaZulu Natal in particular are in the epicentre of the TB-HIV co-epidemic with >70% co-
infection rates among TB patients. 
Secondly, there are no data to support the safety and efficacy of Biktarvy® twice daily for 
the treatment of HIV-1 infection in patients with TB on rifampicin co-treatment and it is 
unlikely that this highly potent, safe, drug with a high resistance profile, that may provide 
effective future ART treatment options, will be made available in Africa if it cannot be used 

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in patients with drug- susceptible tuberculosis. Additionally, it will be helpful for TAF roll-out, 
a drug that has a better safety profile for bone and renal adverse events than TDF, which 
has been hindered, in part, by lack of data in HIV-TB co-infected patients 
 
 
10.3. 
Regulatory and ethical review 
The study will be conducted under the oversight of the University of KwaZulu-Natal, Nelson 
R Mandela School of Medicine Biomedical Research Ethics Committee (BREC) and the 
South African Health Products Regulatory Authority (SAPHRA). The study protocol will be 
submitted to the ethics committee and regulatory entities by the Principal Investigator and 
reviewed and approved by the ethics committee prior to study initiation. The investigator 
will provide progress reports and all other information required by the ethics 
committee/regulatory institutions to conduct its reviews. On approval of the study we will 
register the study with SANCTR (South African National Clinical Trials Register). We will 
also seek approval for the study from the SA DoH and/or other relevant stakeholders 
 
10.4. 
Informed consent process 
Written informed consent will be obtained from each study participant prior to screening 
and enrolment. Written informed consent will also be obtained for long-term specimen 
storage and possible future analyses. However, consent for specimen storage is not a 
pre-condition for study participation. Participants will be provided with a copy of their 
informed consent forms if they wish to receive them. 
 
Study informed consent forms will describe the purpose of the study, the procedures 
to be followed, and the risks and benefits of participation. The informed consent 
forms will also be translated into isiZulu and the accuracy of the translation will be 
verified through independent back-translation. 
 
The study consent process will include an assessment of each potential participant’s 
understanding of the study and the risks and benefits of study participation, which are 
essential for an informed decision. Participants who are not able to demonstrate adequate 
understanding of key concepts will not be enrolled in the study. 
 
10.5. 
Participant Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the 
site will be identified by coded number only to maintain participant confidentiality. All 
records will be kept locked. All computer entry and networking programs will be done 
with coded numbers only. 
Clinical information will not be released without written permission of the participant, 
except as necessary for monitoring by the ethics committee or the sponsor’s designee. 
CAPRISA External monitors will also review clinical information. QA officers and Head of 
QA will not be on delegation of Authority Log as these staff serve as internal and/or 
external monitors. 
 
10.6. 
Good Clinical Practice 
The study will be carried out according to ICH-GCP and South African Good Clinical 
Practice Guidelines (SA GCP). The Principal Investigator and/or designee will ensure that 
the study staff are conducting the trial in accordance with current SA GCP and ICH-GCP 
guidelines, ensure appropriate human subjects training for all study staff and safety of all 
trial participants. The study protocol and patient informed consents and all future revisions 
of these latter documents, will be reviewed and approved by the UKZN Biomedical 
Research Ethics Committee (UKZN BREC) and South African Health Product Regulatory 
Authority (SAPHRA)) prior to implementation. Quality control officers will perform daily 

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quality checks on patient data and a Data manager will oversee the maintenance and 
completeness of the patient data. 
 
All Serious Adverse Events (SAE’s) will be reported to UKZN BREC and SAPHRA 
within 7 business days of site awareness. The Data Safety Monitoring Committee 
(DSMC) will meet at designated timepoints to analyse and discuss safety data and 
make recommendations for the continuation of the trial and participant care. 
 
 
11. DATA MANAGEMENT 
 
The entry, storage and cleaning of study data will be conducted under the 
oversight of the CAPRISA Data Management core. 
 
11.1. 
Data Collection and Methods 
 
Data will be collected on one-ply case report forms (CRFs) or E-CRFs which will be 
developed by the study team. All site study staff will be trained in the correct completion of 
CRFs. If data entered on the CRFs are taken from an external source (e.g., laboratory 
reports, patient records), the source documents will be maintained in the participant’s 
medical chart or study file at the site and will be available for review. When CRFs undergo 
changes, appropriate authorization is obtained from the study team and all the changes are 
clearly documented. Each revision of the CRF will contain a clearly identified version 
number. Case Report Forms (CRFs) will be provided for each patient. At screening 
participants will be issued a Screening Identification number (SID) by the site, where 
applicable. At enrolment participants will be identified by a patient identification number 
(PID) provided by the CAPRISA Data Management Center. This PID is used on all CRFs 
to identify the participant for the duration of the study. 
Data will be collected at all study visits. Patients will be required to attend at the clinic for a 
screening visit and if found to be eligible, informed consent will be administered and the 
patient will be enrolled into the study. Post enrollment visits will be done in accordance with 
the SoE and where clinically indicated. 
 
11.2. 
Information management (Database) and analysis software 
 
The INSIGHT study will be using the DFdiscover clinical trial database system, 2018 V 
5,1,4, which is compliant with FDA 21 CFR Part 11 regulations and the software is ISO 
9001:2015 certified. DFexplore is a desktop/ laptop software application that forms part of 
the DFdiscover clinical trial management system, which supports data collection by paper, 
scanned document and fax. All methods can be used in the same study. which is used to 
enter, review and modify subject data, and to submit it over the internet to a DFdiscover 
server, also known as Electronic Data Capture or EDC. DFcollect is a mobile software 
application that forms part of the DFdiscover clinical trial management system, by using a 
compatible mobile device. Statistical Analysis Software (SAS) is used for analysis 
purposes. 
 
 
 
11.3. 
Data Security, Protection/Confidentiality, Flow, Imported Data and Data coding 
 
Database security: 
CRFs will be scanned to the DFdiscover server via encrypted communication, and makes 
use of electronic signatures, consisting of usernames and passwords. Permission levels 
are assigned based on study data collection and review requirements. Study data is stored 

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on the CAPRISA server housed at the CAPRISA head office at DDMRI (Doris Duke 
Medical Research Institute) and will be backed up at regular intervals, with backups stored 
in a secure location with restricted access. 
 
Data Protection/Confidentiality 
Participants will be assigned a unique identifier. Any participant record or data set will 
contain the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred externally. The participant will be informed that 
his/her study-related data will be used in accordance with local data protection law. The 
level of data disclosure will also be explained to the participant. The participant will be 
informed that his/her study records may be examined by monitors or other authorized 
personnel appointed by the PI/sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
 
Data flow: 
For paper-based studies: 
CRFs will be scanned into DFexplore which uses optical character recognition (OCR) to 
read the check boxes and numerical fields on the CRFs and store them in the study 
database. Any fields not recognized by the OCR system will be entered manually by the 
Data Encoders. A Data encoder will validate all data by cross-checking the scanned 
version to what is recorded through OCR, into the database. A second data encoder will 
validate the same set of data for verification. Data encoders will create queries, should any 
data be invalid or illegal. All queries arising during validation of the data will be recorded in 
quality control (QC) reports and sent to the sites on a regular basis. Any queries resulting 
in a change to the database will be documented and attached to the original CRF. 
 
Imported data: 
Any data that will be imported into a study database will include an encryption component 
in order to ascertain the reliability of the data. Files will be stored on the CAPRISA 
Sharepoint server. 
 
Data coding: 
This study will make use of MedDRA coding for all Adverse Events. This function will be 
performed by the study clinician or designee. MedDRA is a clinically-validated international 
medical terminology used by regulatory authorities and the regulated biopharmaceutical 
industry. 
Instructions concerning the recording of study data on CRFs will be provided by the 
CAPRISA Data Management core. Completed CRFs must be checked by the 
designated on-site Quality Control officer and upon approval, must be submitted into the 
data management system. 
CAPRISA Data encoders and Data Managers located at the CAPRISA offices verify and 
validate the patient data. Quality control reports are produced, and approved data then 
added to the study database according to CAPRISA data management (SOPs) Study 
Operating Procedures. 
 
It is the responsibility of the CAPRISA data management core to assure the quality of 
computerized data for the study. Study staff will be trained in source documentation 
requirements and in proper forms completion techniques. 
 
11.4. 
Data Storage 
Original and electronic copies of study CRFs and related documents will be stored 
securely both during and after study completion. During the study, the original completed 
forms for each participant will be kept on-site at the CAPRISA Springfield Research 

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site/other CAPRISA site/offices. The forms will be stored in an access secured, double-
locked, fire and waterproof room. Upon completion of the study, and finalization of the 
database for analysis, the original forms will be bound and kept off-site (separate site) for 
long-term storage, where applicable. 
Docufile or other relevant storage or archiving facilities, designated by CAPRISA will be 
used to archive large amounts of documents. Database files will be password-protected, 
and access to the files will be limited to authorized study staff members only. Quality 
control and validation checks will be performed and data cleaning steps will be 
undertaken prior to finalizing the study database for analysis. Analyses will be 
conducted by study statisticians. 
 
11.5. 
Quality control (QC)/ Quality assurance (QA) 
 
A quality check of the study forms will be conducted before the forms are entered 
scanned or faxed. The QC procedures will specify the following types of checks: 
• There are no illegible handwritten items, spelling errors, etc. 
• Responses are clearly within designated spaces. 
• All fields are completed with participant data or reason for no data is noted 
in or near the field. 
• The participant's PID is recorded on all pages of the forms. 
• The CAPRISA laboratory manager will also be responsible for checking that all the 
laboratories involved in the study are complying with QA procedures. The CAPRISA 
pharmacist will check that all drug related documentation meets Good Clinical Practice 
(GCP) requirements for drug accountability. 
• QC and QA of data will be undertaken according to the relevant SOPs and 
Study specific procedures manual, where applicable. 
 
 
12. BIOHAZARD CONTAINMENT 
As the transmission of HIV and other pathogens can occur through contact with 
contaminated needles, blood, blood products, and other secretions, appropriate blood and 
secretion precautions will be employed by all personnel in the drawing of blood and 
collection of other specimens and shipping and handling of all specimens for this study, as 
currently recommended by the Centers for Disease Control and Prevention and the 
National Institutes of Health. 
 
All dangerous materials, including diagnostic specimens and infectious substances, must 
be transported using packaging mandated by CFR 42 Part 72. Please refer to instructions 
detailed in the International Air Transport Association (IATA) Dangerous Goods 
Regulations. 
 
 
 
 
 
13. BIBLIOGRAPHY AND REFERENCED CITED: 
 
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2. WHO. POLICY BRIEF: Updated Recommendations on First-Line And Second-Line 
Antiretroviral Regimens And Post-Exposure Prophylaxis And Recommendations On 

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Early Infant Diagnosis Of HIV. Available from 
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Emtricitabine- Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 
Weeks. Antimicrob Agents Chemother 2019;63. 
5. Deeks ED. Bictegravir/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 
Infection. Drugs 2018;78:1817-28. 
6. Gallant JE, Thompson M, DeJesus E, et al. Antiviral Activity, Safety, and 
Pharmacokinetics of Bictegravir as 10-Day Monotherapy in HIV-1-Infected Adults. 
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7. Stellbrink H-J, Arribas JR, Stephens JL, et al. Co-formulated bictegravir, emtricitabine, 
and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir 
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9. WHO. Global tuberculosis report 2018 Available from 
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drugs during tuberculosis therapy. N Engl J Med 2010;362:697-706. 
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Switzerland: World Health Organisation; 2010. 
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drug interactions: experimental and model-based approaches to drug-drug interaction 
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13. Joseph M. Custodio SKW, Sean Collins, Amanda Vu, Deqing Xiao, Hal Martin, Erin 
Quirk, Brian P. Kearney, Anita Mathias. Pharmacokinetics of bictegravir administered 
administered twice daily in combination with rifampin. In: Program and abstracts of the 
2018 Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; 
Boston. Abstract 34. 2018. 
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product characteristics. 2018. http://www.ema.europa.eu/. Accessed 03 June 
2019.2018. 
15. Sciences. G. Biktarvy® (bictegravir, emtricitabine, and tenofovir alafenamide): US 
prescribing information. 2018. https://www.accessdata.fda.gov/. Accessed 03 Jun 
20192018. 
16. Maddalena Cerrone OA, Megan Neary, Mark A. Marzinke, Teresa Parsons, Andrew 
Owen, Gary Maartens, Anton Pozniak, Charles W. Flexner, Marta Boffito. Rifampin 
effect on tenofovir alafenamide (TAF) plasma/ intracellular pharmacokinetics. 25th 
CROI. Boston. 4–7 March 2018. Oral abstract 28LB. 2018. 
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tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, 
for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, 

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multicentre, phase 3, non- inferiority trial. Lancet 2017;390:2073-82. 
18. Gish RG, Leung NWY, Wright TL, et al. Dose range study of pharmacokinetics, safety, 
and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus 
infection. Antimicrob Agents Chemother 2002;46:1734-40. 
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21. Natukunda E, Gaur AH, Kosalaraksa P, et al. Safety, efficacy, and pharmacokinetics 
of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in 
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22. Eron JJ, Jr., Lelievre JD, Kalayjian R, et al. Safety of elvitegravir, cobicistat, 
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disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b 
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23. Brooks KM, George JM, Pau AK, et al. Cytokine-Mediated Systemic Adverse 
Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-
Weekly Isoniazid and Rifapentine. Clin Infect Dis 2018;67:193-201. 
24. Dooley KE, Kaplan R, Mwelase N, et al. Dolutegravir-Based Antiretroviral Therapy 
for Patients Co-Infected with Tuberculosis and Hiv: A Multicenter, Noncomparative, 
Open-Label, Randomized Trial. Clin Infect Dis 2019. 
25. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the 
HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with 
rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic 
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27. KwaZulu Natal Department of Health 
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Report No.: 
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Infect Dis 2014;14:459-67. 

PI: Dr A Naidoo 
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Study No: CAP 093 
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APPENDICE 1: EXAMPLE OF PARTICIPANT INFORMED CONSENT 
 
INSIGHT PATIENT INFORMED CONSENT 
 
STUDY INFORMED CONSENT FORM 
 
 
***The Study Informed Consent has been appended as a 
separate attachment