A Phase 3b Multi-center, Open Label, Single Arm, 52-week Study, Evaluating the Feasibility, Efficacy and Safety of Rapid Test and Treat Intervention in Newly Diagnosed HIV-1 Infected Adults Using a Fixed Dose Combination of Dolutegravir Plus Lamivudine (DOVATO) as a First Line Regimen
Phase: PHASE3
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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ViiV Healthcare group of companies
212355
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TITLE PAGE
Protocol Title: A Phase 3b multi-center, open label, single arm, 52-week pilot study, 
evaluating the feasibility, efficacy and safety of a rapid Test and Treat intervention in 
newly diagnosed HIV-1 infected adults using a fixed dose combination of dolutegravir 
plus lamivudine (DOVATO) as a first line regimen
Protocol Number: 212355/ 01
Compound Number:
GSK1349572+GR109714 (GSK3515864)
Study Phase: PHASE IIIB
Short Title: Rapid Test and Treat dolutegravir plus lamivudine study in newly diagnosed 
HIV-1 infected adults
US IND Sponsor Name and Legal Registered Address:
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is supporting ViiV 
Healthcare in the conduct of this study.  
PPD Inc is operationalizing this study with GlaxoSmithKline support.
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual.
Regulatory Agency Identifying Number(s): US IND: 127475/ EudraCT: 2018-000177-
72
Approval Date: 06-JUN-2019
Copyright 2019 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 1
06-Jun-2019
2019N398432_01
Original Protocol
25-MAR-2019
2019N398432_00
Amendment 01 06-June-2019
Overall Rationale for the Amendment:
A global protocol amendment was required to update the primary objective and endpoint 
based on FDA feedback.  Additional changes were incorporated as a result of feedback 
and discussion from the Investigator Meeting held in May 2019.  Administrative changes 
for clarity and corrections to minor errors in the previous version of the protocol were 
made.  Changes were made in the Protocol Summary sections to reflect text changes in 
other sections of the protocol, as appropriate.
 
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Section # and Name
Description of Change
Brief Rationale
Title Page
1.1 Synopsis
2.1 Study Rationale
4.2 Scientific Rationale 
for Study Design
Study Rationale was revised to more 
accurately state the goal for conducting 
this study 
Modified study rationale to better reflect the 
primary goal of the study which is to provide 
pilot data regarding the feasibility, efficacy and 
safety of using DTG + 3TC FDC in a test and 
treat model of care setting
1.1 Synopsis
3 Objectives and 
Endpoints
4.1 Overall Design
8.1.1 Primary Efficacy 
Endpoint
8.1.2 Secondary 
Efficacy Endpoints
9.5.1 Efficacy Analysis
9.5.2 Secondary 
Analysis
Primary Objective modified to match the 
study rationale
Primary Endpoint modified to reflect 
observed analysis at Week 24, per FDA 
feedback
Modified the primary objective to add to the 
evaluation of the “feasibility” of a Test and Treat 
Model of Care from evaluating the “efficacy and 
safety” of DTG + 3TC FDC in this setting
Modified primary endpoint to remove the 
analysis using a modified FDA Snapshot 
Algorithm to an observed analysis based on 
FDA feedback
Secondary endpoint modified to reflect 
an Observed analysis at Week 48, per 
FDA feedback
As in the primary endpoint the secondary 
endpoint was modified to remove the modified 
FDA Snapshot analysis 
1.1 Synopsis
1.2 Schema
1.3 Schedule of 
Activities (SoA)
2.1 Study Rationale 
2.3.1 Risk Assessment
3 Objectives and 
Endpoints
4.1 Overall Design
4.2 Scientific Rationale 
for the study
6.3 Measure to 
Minimize Bias
7.2.1 Screening/Day 1
Laboratory Safety 
Criteria
8 Study Assessments 
and Procedures
8.2.1 Physical 
Examinations
8.2.2 Vital Signs
9.3 First-line DTG + 
3TC Regimen 
Modification
10.2 Clinical 
Screening Visit and Day 1 Visit were 
merged into one visit and text changed to 
“...must be on the same day.”
Modifications were made for all activities 
and references to Screening and Day 1 
as separate visits, to reflect merging 
them into one visit.
Screening and Day 1 were combined to better 
reflect the test and treat model of care setting 
where participants are diagnosed and initiate 
HIV-1 treatment on the same day
 
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Section # and Name
Description of Change
Brief Rationale
Laboratory Tests
10.6.2 Study 
Intervention Restart 
after Stopping for Liver 
Criteria
1.3 SoA
1.3.1 SoA for ART 
Regimen Modification
2.3.1 Risk Assessment
5.1 Inclusion Criteria
7.4 Other Additional 
Intervention Criteria
8.3.5 Pregnancy
10.2 Clinical 
Laboratory Tests
10.5 Contraceptive 
Guidance
10.10 Abbreviations
Gender neutral terms have replaced the 
use of females or women. 
The gender-neutral terms include: 
participants, females at birth, sex at birth, 
current gender, participants of 
childbearing potential (POCBP).
Text regarding females or women of 
childbearing potential or reproductive potential 
have been modified to gender neutral language 
to make the study protocol more Trans inclusive
2.3.1 Risk Assessment
5.1 Inclusion Criteria
5.2 Exclusion Criteria
7.4 Other Additional 
Intervention Criteria
8.3.5 Pregnancy
9.5.2 Secondary 
Analysis
10.2 Clinical 
Laboratory Tests
10.5.3 Collection of 
Pregnancy Information
Pregnancy status at the Screening/Day 1 
visit has been modified to state that 
participants who are beyond the first 
trimester of a pregnancy are eligible to 
enrol in the study.
Pregnancy during the study has been 
modified to state that participants who 
become pregnant during the study and 
are detected in the first trimester should 
immediately discontinue DTG + 3TC FDC 
and be started on an alternate regimen 
that does not contain DTG.  If the 
pregnancy is after the first trimester, the 
participant can continue study treatment.  
The allowance of pregnant participants to 
remain on study intervention if the pregnancy is 
detected after the first trimester as this is more
consistent with the DOVATO label
1.1 Synopsis
4.1 Overall Design
9.6 Interim Analysis
The Week 12 interim analysis was been 
modified to state that this may be 
conducted.
Depending on the number of participants who 
require a change from first line regimen based 
on Screening/Day 1 labs, the Week 12 analysis 
may or may not be conducted. 
1.3 Schedule of 
Activities (SoA)
Modified the text in the comment field for 
HIV Diagnostic Test by adding that the 
HIV-1 diagnosis is new “and confirmed”
Restating the need for the confirmation of the 
HIV-1 diagnosis by 2 tests
Added collection of plasma samples at 
the Week 52 visit
Correction from original protocol 
 
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Section # and Name
Description of Change
Brief Rationale
Added collection of HBV 3TC Resistance 
and HBV DNA samples for participants 
with confirmed HBV infection from 
Screening/Day 1 labs at Weeks 1 and 
Week 4
Added the check marks to match the comment 
associated with the collection of these samples 
for participants with HBV infection
1.3 Schedule of 
Activities (SoA)
10.2 Clinical 
Laboratory 
Assessments
HLA B5701 testing as needed was added
Testing for HLA B5701 was added if an 
Investigator is considering using abacavir when 
modifying ART
1.3.1 SoA for ART 
Regimen Modification
4.1 Overall Design
10.2 Clinical 
Laboratory Tests
Modified the comments to clarify when 
HBV 3TC Resistance and HBV DNA 
samples should be collected for 
ART modification visits are not at the 
Week 1 or at the Week 4 study visit, or if 
an HBV infection is acquired after 
Screening/Day 1”
Clarification of sample collection
Modified the header note for clarification 
about what assessments need to be 
completed if either of the ART 
Modification Visits occurs at a scheduled 
study visit
Clarification of visit assessments 
5.2 Exclusion Criteria
Exclusion Criteria 2: Created to capture 
changes in pregnancy status at 
Screening/Day 1
Created to exclude participants from the study 
who are in their first trimester of pregnancy
Exclusion 3: Removed restrictions 
regarding known renal impairment and 
HBV infection status, and modified text 
for known HIV-1 resistance prior to Day 1
Removed restrictions as it is common for some 
sites to have this information as part of their 
usual clinical practice.  Additionally, if the HepB 
serologies indicated the participant was HBV 
negative, the original exclusion criteria would 
have unnecessarily excluded that person
Exclusion 4: Modified the study allowed 
CDC Class 3 stage diseases
Modified to include an exemption for cutaneous 
Kaposi’s sarcoma not requiring systemic 
therapy as treatment of this condition does not 
pose an added safety risk for patients who are 
initiating ART, including DTG + 3TC in 
treatment of HIV-1
Exclusion 5 was modified, and Exclusion 
6 was added to create separate criteria 
for known or suspected hepatic 
impairment from known or suspected 
hepatitis B.
As hepatic impairment and hepatitis B are 
unique conditions, these were separated into 2 
criteria 
1.1 Synopsis
1.3 Schedule of Events
2.1 Study Rationale
Added text to clarify that Screening/Day 1 
must be 14 days or less from the time of 
the “initial” HIV-1 infection diagnosis
Text added for clarification
 
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Section # and Name
Description of Change
Brief Rationale
4.1 Overall Design
4.2 Scientific Rationale 
for Study Design
Title Page
1.1 Synopsis
4.3 Justification of 
Dose
Use of DTG + 3TC FDC has been edited 
to DOVATO, where appropriate
Added to indicate that DOVATO is approved in 
the U.S.
2.3 Benefit/Risk 
Assessment
10.3.4 Recording and 
Follow-Up of AE and 
SAE
10.4.1.6 Rash
11 References
Addition of the Tivicay, Epivir and/or 
DOVATO Package inserts as references 
where appropriate.
Reference information
2.3.1 Risk Assessment
10.7 Prohibited 
Medications
Removed pilsicainide as a theoretical 
serious drug interaction
Pilsicainide was removed as this drug is not 
available in the U.S.
Throughout the 
Protocol
Revised all instances of DTG + 3TC to 
DTG + 3TC FDC when referring to study 
medication
Consistency and for clarity of when the FDC is 
applicable or the individual agents are 
applicable
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY........................................................................................11
1.1.
Synopsis.....................................................................................................11
1.2.
Schema ......................................................................................................15
1.3.
Schedule of Activities (SoA)........................................................................16
1.3.1.
SoA for ART Regimen Modifications............................................24
2.
INTRODUCTION....................................................................................................26
2.1.
Study Rationale ..........................................................................................26
2.2.
Background ................................................................................................26
2.3.
Benefit/Risk Assessment ............................................................................28
2.3.1.
Risk Assessment .........................................................................29
2.3.2.
Benefit Assessment.....................................................................33
2.3.3.
Overall Benefit: Risk Conclusion..................................................33
3.
OBJECTIVES AND ENDPOINTS...........................................................................33
4.
STUDY DESIGN ....................................................................................................35
4.1.
Overall Design ............................................................................................35
4.2.
Scientific Rationale for Study Design ..........................................................37
4.3.
Justification for Dose ..................................................................................38
4.4.
End of Study Definition ...............................................................................38
5.
STUDY POPULATION...........................................................................................39
5.1.
Inclusion Criteria.........................................................................................39
5.2.
Exclusion Criteria........................................................................................42
5.3.
Lifestyle Considerations..............................................................................43
5.4.
Screen Failures...........................................................................................43
6.
STUDY INTERVENTION........................................................................................43
6.1.
Study Intervention Administered .................................................................44
6.2.
Preparation/Handling/Storage/Accountability..............................................45
6.3.
Measures to Minimize Bias: Study Intervention and Blinding ......................45
6.4.
Study Intervention Compliance ...................................................................45
6.5.
Dose Modification .......................................................................................46
6.6.
Concomitant Therapy..................................................................................46
6.6.1.
Permitted Medications and Non-Drug Therapies..........................46
6.7.
Treatment after the End of the Study ..........................................................47
7.
STUDY INTERVENTION DISCONTINUATION CRITERIA ....................................47
7.1.
Discontinuation of Study Intervention..........................................................47
7.2.
Additional Intervention Criteria....................................................................47
7.2.1.
Baseline Laboratory Safety Criteria:.............................................47
7.2.2.
Baseline Resistance Mutation Criteria: ........................................48
7.3.
Virologic Failure Criteria..............................................................................48
7.3.1.
Confirmatory testing of virologic non-response: ...........................49
7.3.2.
Management of Virologic Non-Response.....................................49
7.4.
Other Additional Intervention Criteria: .........................................................50
 
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7.5.
Liver Chemistry Stopping Criteria ...............................................................51
7.5.1.
Temporary Discontinuation ..........................................................51
7.5.2.
Study Intervention Restart ...........................................................51
7.6.
Participant Discontinuation/Withdrawal from the Study ...............................52
7.7.
Lost to Follow Up........................................................................................53
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................53
8.1.
Efficacy Assessments.................................................................................56
8.1.1.
Primary Efficacy Endpoint............................................................57
8.1.2.
Secondary Efficacy Endpoints .....................................................57
8.2.
Safety Assessments ...................................................................................57
8.2.1.
Physical Examinations.................................................................57
8.2.2.
Vital Signs....................................................................................57
8.2.3.
Clinical Safety Laboratory Assessments ......................................58
8.2.4.
Suicidal Ideation and Behaviour Risk Monitoring .........................58
8.3.
Adverse Events and Serious Adverse Events.............................................59
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................59
8.3.2.
Method of Detecting AEs and SAEs.............................................60
8.3.3.
Follow-up of AEs and SAEs.........................................................60
8.3.4.
Regulatory Reporting Requirements for SAEs .............................60
8.3.5.
Pregnancy ...................................................................................61
8.3.6.
Cardiovascular and Death Events................................................61
8.3.7.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................62
8.4.
Treatment of Overdose...............................................................................62
8.5.
Pharmacokinetics .......................................................................................63
8.6.
Pharmacodynamics ....................................................................................63
8.7.
Genetics .....................................................................................................63
8.8.
Biomarkers .................................................................................................63
8.9.
Health Economics and Outcome Research.................................................63
8.10.
HIV-1 Polymerase Viral Genotyping and Phenotyping ................................63
8.10.1.
HIV-1 Exploratory Analysis ..........................................................64
9.
STATISTICAL CONSIDERATIONS........................................................................64
9.1.
Statistical Hypotheses.................................................................................64
9.2.
Sample Size ...............................................................................................64
9.2.1.
Sample Size Considerations........................................................64
9.2.2.
Sample Size Sensitivity................................................................65
9.3.
First-line DTG + 3TC FDC Regimen Modification .......................................66
9.4.
Data Analysis Considerations .....................................................................66
9.4.1.
Analysis Populations....................................................................66
9.5.
Key Elements of the Analysis Plan..............................................................66
9.5.1.
Efficacy Analysis..........................................................................66
9.5.2.
Secondary Analyses ....................................................................67
9.5.3.
Safety Analyses...........................................................................68
9.5.3.1.
Viral Genotyping/Phenotyping Analyses.....................69
9.5.4.
Other Analyses ............................................................................69
9.6.
Interim Analyses .........................................................................................69
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................71
 
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10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................71
10.1.1.
Regulatory and Ethical Considerations ........................................71
10.1.2.
Financial Disclosure.....................................................................71
10.1.3.
Informed Consent Process ..........................................................72
10.1.4.
Data Protection............................................................................72
10.1.5.
Publication Policy.........................................................................72
10.1.6.
Dissemination of Clinical Study Data ...........................................73
10.1.7.
Data Quality Assurance ...............................................................73
10.1.8.
Source Documents ......................................................................74
10.1.9.
Study and Site Closure ................................................................74
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................75
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................77
10.3.1.
Definition of AE............................................................................77
10.3.2.
Definition of SAE..........................................................................78
10.3.3.
Definition of Cardiovascular Events .............................................79
10.3.4.
Recording and Follow-Up of AE and SAE....................................79
10.3.5.
Reporting of SAE and other events to ViiV/GSK/PPD..................81
10.4.
Appendix 4: Toxicity Management ..............................................................83
10.4.1.
Specific Toxicities/Adverse Event Management...........................84
10.4.1.1.
Liver Chemistry Stopping and Follow-up 
Criteria........................................................................85
10.4.1.2.
Restarting Study Intervention .....................................85
10.4.1.3.
Decline in Renal Function...........................................85
10.4.1.4.
Proteinuria..................................................................85
10.4.1.5.
Allergic reaction..........................................................86
10.4.1.6.
Rash...........................................................................86
10.4.1.7.
Hypertriglyceridemia/Hypercholesterolemia................87
10.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................88
10.5.1.
Definitions:...................................................................................88
10.5.2.
Contraception Guidance: .............................................................88
10.5.3.
Collection of Pregnancy Information: ...........................................90
10.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge Guidelines....................91
10.6.1.
Liver Chemistry Stopping Criteria:  Required Actions and 
Follow up Assessments ...............................................................91
10.6.2.
Study Intervention Restart after Stopping for Liver Criteria ..........94
10.7.
Appendix 7: Prohibited Medications............................................................99
10.8.
Appendix 8:  Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events Version 2.1, March 2017...................101
10.9.
Appendix 9:  CDC Classification for HIV-1 Infection (2014).......................131
10.10. Appendix 10: Abbreviations and Trademarks............................................133
10.11. Appendix 11: Protocol Amendment History...............................................136
11. REFERENCES.....................................................................................................137
 
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Phase IIIb multi-center, open label, single arm, 52-week pilot study, 
evaluating the feasibility, efficacy and safety of a rapid test and treat intervention in 
newly diagnosed HIV-1 infected adults using a fixed dose combination of dolutegravir 
plus lamivudine (DOVATO) as a first line regimen
Short Title: Rapid Test and Treat with dolutegravir plus lamivudine in newly diagnosed 
HIV-1 infected adults
Rationale:
Study 212355 is a pilot study being conducted to provide the first evaluation of the 
feasibility, effectiveness and safety of using a fixed dose combination (FDC) of 
Dolutegravir (DTG) plus Lamivudine (3TC) as a first line regimen of a rapid Test and 
Treat model of care over 48 weeks.  Participants with a new and confirmed diagnosis of 
HIV-1 infection will initiate DTG + 3TC FDC immediately (or, for those participants 
referred from another site, within 14 days of initial diagnosis at the external clinic/testing 
center) at the Screening/Day 1 Visit, prior to safety laboratory tests and HIV-1 resistance
mutation laboratory results being available for review.  The Screening/Day 1 Visit is 
considered Baseline.  
This study aims to evaluate the feasibility, efficacy and safety of using DTG + 3TC FDC 
as a first regimen in a rapid Test and Treat care setting in the U.S, where the prevalence 
of both transmitted M184V/I and co-infection with Hepatitis B virus is low.
Objectives and Endpoints:
Objective
Endpoint
Primary

To evaluate the feasibility and 
efficacy of a rapid Test and Treat 
model of care in participants with a 
new diagnosis of HIV-1 initiating 
treatment with DTG + 3TC FDC 
immediately (or, for those 
participants referred from another 
site, within 14 days of initial 
diagnosis at the external 
clinic/testing center).

Percentage of all participants who 
have plasma HIV-1 RNA <50 c/mL 
at Week 24, regardless of ART 
regimen (observed analysis)
Secondary

To demonstrate the antiviral activity 
of DTG + 3TC FDC over 48 weeks

Proportion of participants:
who have plasma HIV-1 RNA <50 
 
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Objective
Endpoint
c/mL at Week 48, regardless of 
ART regimen (observed analysis)
with plasma HIV-1 RNA <50 
c/mL at Week 24 and 48 using the 
FDA Snapshot algorithm 

Time to suppression of HIV-1 RNA 
<50 c/mL

To evaluate the barriers (e.g., HIV-1 
resistance mutation results) to 
initiate and maintain DTG + 3TC 
FDC treatment in a Test and Treat 
Model of Care

Proportion of participants who 
change first line regimen of DTG + 
3TC FDC due to Baseline labs or 
HIV-1 resistance mutation results

To assess viral HIV-1 resistance 
mutation in participants meeting 
confirmed virologic failure criteria

Incidence of treatment-emergent 
genotypic and phenotypic resistance 
to DTG and/or 3TC, or any other 
ART if treatment is modified, in 
participants meeting confirmed 
virologic failure criteria

To evaluate the safety and 
tolerability of a rapid test and treat 
model of care using DTG + 3TC 
FDC as first line regimen 

Incidence and severity of adverse 
events and laboratory abnormalities

Proportion of participants who 
discontinue treatment due to AEs 
and drug-related AEs over 48 weeks 
of treatment

To evaluate the immune effects of a 
rapid test and treat model of care 
using DTG + 3TC FDC as first line 
regimen

Change from Baseline in CD4+ cell 
counts and CD4+/CD8+ ratio at 
Weeks 24 and 48

Incidence of disease progression 
(stage 3 HIV-associated conditions, 
AIDS, and death) through Week 48

To evaluate retention in care

Proportion of participants 
o who completed their Week 24 and 
Week 48 Visit;
o who complete their Week 24 and 
Week 48 Visit and have a HIV-1 
RNA <200 c/mL
Exploratory

To evaluate the effect of participant
demographics and Baseline 

Proportion of participants with 
plasma HIV-1 RNA <50 c/mL at 
 
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Objective
Endpoint
characteristics on the feasibility and
efficacy of a test and treat model of 
care using DTG + 3TC FDC as first 
line regimen
Weeks 24 and 48 by participant
subgroup(s) by Observed Analysis

To asses change in treatment 
symptom index for participants 
under a rapid test and treat model of 
care using DTG + 3TC FDC as a 
first line regimen 

Change from Baseline in overall 
symptom bother score from the HIV 
Symptom Distress Module at Weeks 
4, 8, 12, 24, 36, and 48 

To assess change in specific 
symptoms for participants treated 
with DTG + 3TC FDC

Change from Baseline in 20 item-
specific symptoms from the HIV 
Symptom Distress Module at Weeks 
4, 8, 12, 24, 36, and 48

To assess adherence to study 
treatment

Adherence will be assessed by 
participant recall on number of doses 
missed over the 7 days prior to the 
Visit
Overall Design:
This is a Phase IIIb multi-center, open label, single arm, 52-week pilot study, evaluating 
the feasibility, efficacy and safety of once daily dolutegravir plus lamivudine fixed dose 
combination (FDC) regimen in a rapid test and treat intervention in newly diagnosed 
HIV-1 infected adults.
The study will enrol participants in the U.S. with a new and confirmed diagnosis of HIV1 
infection and are willing to initiate anti-retroviral therapy (ART) immediately (or, for 
those participants referred from another site, within 14 days of initial diagnosis at the 
external clinic/testing center).  
Study 212355 will include a Screening/Day 1 Visit, and visits at Weeks 1, 4, 8, 12, 24, 
36, 48, 52 and a potential Follow-up Visit.
The Screening/Day 1 Visit must be the same day.  Labs will be drawn prior to initiating 
study treatment on Day 1. The Screening/Day 1 Visit is considered Baseline.  
Investigators will review safety labs as they become available and schedule a visit with 
the participant to review (Week 1 Visit).  HIV-1 resistance mutation results will be 
reviewed as they are made available (Week 4 Visit).  
When all participants complete their Week 12 Visit, an Interim Analysis may be 
conducted to review the proportion of participants requiring a modification in treatment.  
The primary endpoint is the proportion of all participants with plasma HIV-1 RNA 
<50 c/mL at Week 24, regardless of ART regimen, using an observed analysis).
 
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The Week 48 analysis will take place after the last participant has completed the Week 52
Visit.  Participants who require a virologic retest at Week 48, must have HIV-1 RNA 
level re-assessed by a second measurement performed 2-4 weeks later, which will be 
captured under the Week 52 Visit.  All participants who remain in the study at Week 48 
will complete the Week 52 Visit where study intervention stop date will be captured and 
collect and follow-up on AEs and SAEs.
An in-clinic Follow-Up Visit will be conducted 4 weeks after the last dose of study 
medication for participants with ongoing SAEs and non-serious AEs of special interest, 
regardless of attributability.  The investigator, in consultation with the medical monitor, 
should follow-up with the participant until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up.
Disclosure Statement: This is a single group, open-label, treatment study with 1 arm.
Number of Participants:
The study will recruit approximately 120 individuals.  It is expected around 150 
individuals to be screened to meet this number of enrolled individuals.  If less than 120 
individuals have been enrolled after 150 individuals have been screened, screening will 
continue until enrolment of approximately 120 individuals is met. 
Intervention Groups and Duration:
A participant’s total time in the study will be approximately 13 months and includes a 
maximum of 14 days from the time of the initial HIV-1 diagnosis to the Screening/Day 1 
Visit and initiation of study drug, a 52-week treatment period and a 4-week follow-up 
phase.
Study intervention, 50 mg DTG + 300 mg 3TC will be provided to all participants as a
fixed dose combination (FDC) as first line therapy.  DTG + 3TC FDC will be taken 
orally, once daily, with or without food.
Participants meeting safety criteria and HIV-1 resistance mutation criteria (e.g., M184I, 
M184V, K65R) based on the Screening/Day 1 laboratory data will modify their current 
DTG + 3TC FDC treatment and will remain in the study.  Criterion for the management 
of virologic non-response criteria are prespecified for study visits at and after Week 8.  
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1.2.
Schema
Figure 1
Study Schematic
The study will enrol participants with a new and confirmed diagnosis of HIV-1 infection 
and are willing to initiate anti-retroviral therapy (ART) immediately (or, for those 
participants referred from another site, within 14 days of initial diagnosis at the external 
clinic/testing center).  If participants HIV-1 resistance mutation results are known prior to 
Day 1, they will be excluded. 
The Screening Visit and Day 1 Visit must be the same day.  Labs will be drawn prior to 
study treatment on Day 1. Investigators will review safety labs as they become available
and schedule a visit with the participant to review (Week 1 Visit).  HIV-1 resistance 
mutation results will be reviewed as they are made available (Week 4 Visit).  
When all participants complete their Week 12 Visit, an Interim Analysis may be 
conducted to review the proportion of participants requiring a modification in treatment
for any reason (e.g., Screening/Day 1 HIV-1 resistance mutation, Screening/Day 1
abnormal laboratory results, etc).  
The primary endpoint is the proportion of participants with plasma HIV-1 RNA 
<50 c/mL at Week 24, regardless of ART Regimen (Observed Analysis).
Additional visits will be at Weeks 8, 36, 48, 52 and a potential Follow-up Visit.  
 
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1.3.
Schedule of Activities (SoA)
Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
a.
The Screening/Day 1 Visit is to assess the participant’s appropriateness for the study, confirm the participant has a new diagnosis of HIV-1 infection and is willing to initiate ART on 
the same day. For those participants referred from another site, Screening/Day 1 must be 14 days or less from the initial diagnosis at the external clinic/testing center.
b.
If the participant meets all study inclusion and exclusion criteria, participant will start study treatment (DTG + 3TC FDC) at the end of Screening/Day 1 Visit after all other 
assessments have been completed. 
c.
Participants will attend a Week 1 Visit after notification from the sites once the Screening/Day 1 laboratory results become available.  Investigators should review the safety labs and 
assess whether any additional interventions are required (see Section 7.2 Discontinuation and Additional Intervention Criteria).
d.
Participants will attend a Week 4 Visit after notification from the sites once the HIV-1 Resistance mutation results become available.  Investigators should review the resistance data 
and assess whether additional interventions are required (see Section 7.2 Discontinuation and Additional Intervention Criteria).
e.
At Week 8, if the decrease HIV-1 RNA is less than 2.0 log10 c/mL, a retest should be scheduled 2-4 weeks later, unless plasma HIV-1 RNA is <200 c/mL.
f.
At Week 12, participants will require a virologic retest if HIV-1 RNA 1000 c/mL.
g.
At Week 24 and Week 48 participants will require a virologic retest if HIV-1 RNA 50 c/mL.  At Week 36, participants will require a virologic retest if HIV-1 RNA 200 c/mL.
h.
Participants who require a virologic retest at Week 48, must have HIV-1 RNA level re-assessed by a second measurement performed 2-4 weeks later, which will be captured under 
the Week 52 Visit.
i.
An in-clinic Follow-up Visit will be conducted 4 weeks after the last dose of study medication only for participants with the following conditions at the last on-study visit: All ongoing 
SAEs and non-serious AEs of special interest (as defined in Section 2.3.1), regardless of attributability.  However, the investigator, in consultation with the medical monitor, should 
follow-up with the participant until the event is resolved, stabilized, otherwise explained, or the participant is lost to follow-up.
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
Clinical and Other Assessments
Informed consent
X
Inclusion and 
exclusion criteria
X
Inclusion/exclusion criteria will be fully assessed at the Screening/Day 1
Visit. 
Demography
X
Sex at birth and current gender by subject will be collected.
Medical history 
(includes active 
substance usage)
X
Full medical history will be conducted prior to initiating study intervention 
and include assessments of cardiovascular, metabolic (e.g., Type I or II 
diabetes mellitus), psychiatric (e.g., depression), renal (e.g., 
nephrolithiasis, nephropathy, renal failure), hepatobiliary disorders (e.g., 
history of jaundice, icterus, ascites) and bone disorders.
Current Medical 
Conditions
X
Symptom Directed 
Physical Exam
X
Limited physical examination to include blood pressure (recorded in 
eCRF) for Framingham score assessment. 
Physical exams should be conducted as part of normal routine clinical care 
but will not be collected systematically in the eCRF.  Abnormalities noted 
during any exam must be recorded in the eCRF (e.g. in the current medical 
conditions or AE logs).
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
Cardiovascular risk 
assessment 
X
At Diagnosis Visit, assessment for cardiovascular risk will include height, 
weight, blood pressure, smoking status and history, pertinent medical 
conditions (e.g., hypertension, diabetes mellitus), and family history of 
premature cardiovascular disease. Body mass index (BMI) will be 
calculated within the eCRF. 
Vital signs
X
X
X
X
X
X
X
X
X
X
Blood pressure to be measured after resting in a semi-supine position for at 
least 5 minutes.
Body Weight
X
X
X
X
X
X
X
X
X
X
BMI will be calculated within the eCRF.  
The same scale should be used at each study visit.
Prior PEP/PREP 
Therapy
X
Participants who received HIV post-exposure prophylaxis (PEP) or pre-
exposure prophylaxis (PrEP) in the past are allowed as long as the last 
PEP/PrEP dose was >6 months from HIV diagnosis or there is documented 
HIV sero-negativity at least 2 months after the last prophylactic dose and 
before the date of HIV diagnosis.
HIV risk factors and 
mode of 
transmission
X
CDC Classification 
for HIV-1 Infection
X
Review the Baseline laboratory results as they become available and 
record in the eCRF (see Section 10.9).
HIV associated 
conditions
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
Suicidality 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Investigator must assess participant suicidality using their usual clinical 
practice.
HIV Symptom 
Distress Module
X
X
X
X
X
X
X
X
Questionnaire/Surveys are recommended to be administered at the 
beginning of the visit before any other assessments are conducted.  See 
Section 8.9 for additional information on how this questionnaire should be 
completed.
Laboratory assessments
HIV Diagnostic Test
X*
*Participants must have a new and confirmed diagnosis of HIV-1 infection 
based on the criterion outlined in Section 5.1 (Inclusion Criteria).
HIV Diagnostic test results should be stored in the participant source 
documents. 
Quantitative plasma 
HIV-1 RNA
X
X
X
X
X
X
X
X
X
X
See Section 7.3 Virologic Failure Criteria for more information on how to 
manage suspected and confirmed viral failures. 
If a subject requires a regimen modification (e.g., based on Baseline labs, a 
Confirmed Virologic Failure, or an AE), see SoA ART Regimen 
Modification Section 1.3.1.
Whole Blood
X
X
X
X*
*Collect sample only if Withdrawal Visit is replacing the Week 24 or 
Week 48 Visit.
Lymphocyte subset
X
X
X
X
X
X
X
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
Plasma for HIV 
genotyping
X
An additional plasma for HIV genotyping will be included at the time of 
regimen change in case of Baseline HIV-1 resistance mutations (see 
Section 1.3.1).
Plasma for storage
X
X
X
X
X
X
X
X
X
X
Plasma samples for storage will be collected at each visit, including 
unscheduled visits (e.g. for HIV-1 RNA levels and immunological 
parameters).  Additionally, these samples will be used when needed such 
as when samples are lost or arrive at the laboratory unevaluable or as a 
priority need for genotypic and/or phenotypic analyses when participants 
meet Confirmed Virologic Failure criteria.
Clinical Chemistry
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Lipid Panel
X
X
X
HBsAg, anti-HBc, 
anti-HBs, and HBV 
DNA
X
HBV DNA testing will be performed for participants with positive anti-
HBc and negative HBsAg and negative anti-HBs.  
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
HBV 3TC 
Resistance and HBV 
DNA (only for 
participants with 
chronic HBV 
infection)
X
X*
X*
*Testing for HBV 3TC resistance will be performed using samples from 
Week 1 or Week 4 (depending on when ART modification occurs) as well 
as Baseline samples.  For these participants, HBV DNA will also be 
obtained at the Week 1 and/or Week 4 visit.
HCV antibody
X
Rapid plasma reagin 
(RPR)
X
Urinalysis 
X
X
X
X
X
X
X
A morning specimen is preferred.  Reflex microscopic.
Pregnancy test 
(POCBP only)
S/U
S
S
S
S
S
S
S
S
S
Pregnancy testing will be conducted (participants of childbearing potential 
only) on serum (S) samples.  At Screening/Day 1 Visit (before start of 
study treatment), a urine (U) test must be used to confirm pregnancy status 
prior to administration of study treatment.
Remind participants of childbearing potential at each study visit of the 
need to avoid pregnancy and to adhere to the study’s contraception 
requirements.
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
FSH
X
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in females at birth
not using hormonal contraception or hormonal replacement therapy 
(HRT).  
HLA B5701*
*Testing for HLA B5701 may be required before adding or modifying 
ART therapy and should be discussed with the Medical Monitor. Please 
schedule this test using the Unscheduled Q2 requisition.
Study treatment
IWRS
X
X
X
X
Screening/Day 1 is the day the participant initiates study treatment.
At Week 36, an extra bottle of study intervention should be provided so 
that all participants will have treatment until Week 52 in case a virologic 
retest is required.
Dispense 
DTG + 3TC FDC 
study treatment 
X
X
X
X
Participants must return their pill container.  Site should remind 
participants of the importance of adherence.
ART may be modified as described in Section 7.  Required ART 
modification assessments are outlined in Section 1.3.1.
Treatment 
Adherence
X
X
X
X
X
X
X
X
X
7-day participant recall.  All study treatment stop and start dates must be 
recorded.
 
 
 
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Procedures
Screening / Day 1 
(Baseline) a, b
Intervention Period Weeks
Withdrawal
Follow-up i
Comments
1 c
4 d
8 e
12 f
24 g
36
48g, h
52 h
Adverse Event (AE) 
review
X
==============X=============
X
X
X
Only AEs related to study related events will be collected between 
obtaining informed consent and initiation of study treatment on 
Screening/Day 1.  After Day 1, all AEs and SAEs will be collected 
through the Follow-up Visit.  See additional information in the SAE 
Review on Follow-up assessments.
Serious Adverse 
Event (SAE) review
X
============X===============
X
X
X
Only SAEs related to study participation or to a concomitantly 
administered ViiV Healthcare/GSK product will be collected between 
obtaining informed consent and administration of study drug at the 
Screening/Day 1 Visit.
Only Participants with ongoing SAEs and non-serious AEs of special 
interest (as defined in Section 2.3.1), regardless of attributability, will 
attend a Follow-up Visit approximately four weeks after their last dose of 
study treatment.  Assessments at the Follow-up Visit should reflect any 
ongoing complaints (e.g. blood draws to follow a laboratory abnormality).  
The investigator, in consultation with the medical monitor, should follow-
up with the participant until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up
Prior and 
Concomitant 
medication review
X
============X===============
X
X
X
Prior medications over the last 4 weeks will be collected at the 
Screening/Day 1 Visit.
 
 
 
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1.3.1.
SoA for ART Regimen Modifications
Procedures
ART 
Regimen 
Modification
a
Post-ART 
Regimen 
Modification b
Note: If the ART Regimen Modification Visit or the Post-ART Regimen 
Modification Visit occurs at a scheduled visit (Section 1.3), assessments should be 
completed at the scheduled visit and only the additional assessments in this table 
should be completed.
a.
The ART Regimen Modification visit is used when modifying a participants ART regimen (e.g., based on Baseline labs, a Confirmed Virologic Failure, or 
an AE) between scheduled visits.  
b.
Four weeks after the ART modification, the participant must return for the Post ART regimen Modification Visit; participants will resume the regular study 
visit schedule after this visit.  
Clinical and Other Assessments
Vital signs
X
X
Blood pressure to be measured after resting in a semi-supine position for at least 
5 minutes.
Body Weight
X
X
BMI will be calculated within the eCRF.  
The same scale should be used at each study visit.
Suicidality Assessment
X
X
Investigator must assess participant suicidality using their usual clinical standards.
HIV associated conditions
X
X
HIV Symptom Distress 
Module
X
X
Questionnaire/Surveys are recommended to be administered at the beginning of the 
visit before any other assessments are conducted.  See Section 8.9 for additional 
information on how this questionnaire should be completed.
Laboratory assessments
Quantitative plasma HIV-1 
RNA
X*
X
*If the ART modification is based on Baseline laboratory results, a HIV-1 RNA 
sample is not required at the ART Regimen Modification Visit.  If the ART 
Modification Visit is not aligned with a regular study visit and an HIV-1 RNA 
assessment in the last 4 weeks is not available, a HIV-1 RNA sample should be 
collected at this visit.
Whole Blood
X
Lymphocyte subset
X
 
 
 
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Procedures
ART 
Regimen 
Modification
a
Post-ART 
Regimen 
Modification b
Note: If the ART Regimen Modification Visit or the Post-ART Regimen 
Modification Visit occurs at a scheduled visit (Section 1.3), assessments should be 
completed at the scheduled visit and only the additional assessments in this table 
should be completed.
Plasma for storage
X
X
Plasma samples for storage will be collected (e.g. for HIV-1 RNA levels and 
immunological parameters). These samples will be used when needed such as when 
samples are lost or arrive at the laboratory unevaluable or as a priority need for 
genotypic and/or phenotypic analyses when participants meet Confirmed Virologic 
Failure criteria.
Clinical Chemistry
X
Hematology
X
HBV 3TC Resistance and 
HBV DNA (only for 
participants with chronic HBV 
infection)
X*
* A sample should be taken for HBV 3TC resistance and HBV DNA if the ART 
modification visit is not at the Week 1 or at the Week 4 study visit, or if a chronic
HBV infection is acquired during the study after Baseline.
Urinalysis 
X
A morning specimen is preferred.  Reflex microscopic.
Pregnancy test (POCBP only)
S
S
Pregnancy testing will be conducted (participants of childbearing potential only) on 
serum (S) samples.
Remind participants of childbearing potential at each study visit of the need to avoid 
pregnancy and to adhere to the study’s contraception requirements.
Study treatment
Treatment Adherence
X
X
7-day participant recall.  All study treatment stop and start dates must be recorded.
Adverse Event (AE) review
X
X
Serious Adverse Event (SAE) 
review
X
X
Concomitant medication 
review
X
X
 
 
 
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2.
INTRODUCTION
Early initiation of antiretroviral therapy (ART) reduces morbidity and mortality for 
individuals infected with HIV. Supressing viral replication with ART also reduces the 
potential for transmission of HIV. Because of this, ART is recommended for all persons 
with HIV viremia regardless of CD4 count.  Delays between diagnosis and treatment 
results in many individuals not engaging in their care.  Thus, rapid ART initiation (Test 
and Treat) at the time of HIV-1 diagnosis is imperative for increasing the proportion of 
individuals starting ART earlier and achieving and maintaining viral suppression DHHS, 
2018].
The goal of rapid Test and Treat is for adults with newly diagnosed HIV-1 infection to be 
offered and start ART, as well as counselling as soon as possible [Saag, 2018; WHO, 
2017].  The International AIDS Society (IAS) Guideline [Saag, 2018] and the World 
Health Organization (WHO) [WHO, 2017] recommend a rapid start of ART.  The rapid 
start strategy has been tested in multiple randomized controlled, pilot clinical studies 
[Bacon, 2018; Rosen, 2016; Koenig, 2017]. Recent studies have demonstrated the 
efficacy of immediate ART at entry into care. Same day ART improves the rate of viral 
suppression, reduces the time to viral suppression, improves retention in care, and reduce 
the risk of transmission.  The percentage of naïve patients initiating therapy the same day 
as diagnosis has increased almost 50% since 2015 to 19% in 2017.  However, for a 
variety of reasons, not all ART regimens are suitable for use in a rapid test& treat setting.
2.1.
Study Rationale
Study 212355 is a 52-week pilot study that will evaluate the feasibility, efficacy and 
safety of using a fixed dose combination (FDC) of Dolutegravir (DTG) plus Lamivudine 
(3TC) as a first line regimen in a Test and Treat model of care.  Participants with a new 
diagnosis of HIV-1 infection will initiate DTG + 3TC FDC within 14 days of the initial 
diagnosis at the Screening/Day 1 Visit, prior to safety laboratory results, Hepatitis B 
serologies, and HIV-1 drug resistance genotype results being available for review.
There are possible barriers to DTG + 3TC FDC use in a rapid Test and Treat model of 
care due to concerns over the potential initiation of therapy in participants with 
transmitted M184V, M184I or K65R mutation or HBV-HIV co infection. This study 
aims to evaluate the feasibility, efficacy and safety of using DTG + 3TC FDC as a first 
regimen in a rapid Test and Treat care setting in the U.S, where the prevalence of both 
transmitted M184V/I and co-infection with HBV is low.
2.2.
Background
FDCs and once-daily single tablet regimen have greatly simplified the treatment of 
people living with HIV and may be of greater importance in people with lifestyles or care 
commitments that may impair adherence to dosing schedules, including some women and 
those in underserved populations.  In a study by Paterson et. al. [Paterson, 2000], a linear 
relationship between levels of adherence and viral load suppression was observed. 
Adherence to therapy is essential to achieve viral suppression and prevent emergence of 
resistance mutations. Among regimens of comparable efficacy, physicians and people 
 
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living with HIV-1 who receive ART rate total pill burden, dosing frequency, and safety 
concerns among the greatest obstacles to achieving adherence. Drug resistant virus 
eventually emerges in most people who struggle with consistent adherence. To achieve 
successful long-term treatment, the prevention of drug resistance has become the most 
significant challenge.
DTG is a potent dual cation binding INSTI, exhibiting rapid reduction in viral load, best 
in class efficacy, and a high barrier to resistance.  These properties and its safety profile 
make it an optimal core agent for 2-drug regimens. In addition, due to its mechanism of 
metabolism, DTG lacks many of the frequent DDIs associated with other medications 
commonly taken by people living with HIV.  To date, the efficacy, pharmacokinetics 
(PK), safety and drug interaction potential of DTG has been evaluated in an extensive 
program of Phase I to IIIB clinical trials [TIVICAY Package Insert, 2018; DTG IB, 
2018].
3TC is a potent cytidine nucleoside analogue without major side effects and has a well 
proven safety profile.  Available since 1995 as a single agent (EPIVIR) [EPIVIR Package 
Insert, 2018], it is also available as part of three FDC products (zidovudine (ZDV)/3TC, 
COMBIVIR, abacavir (ABC)/3TC, EPZICOM/KIVEXA, ABC/3TC/DTG, TRIUMEQ).  
3TC monotherapy is known to select for resistance due to a single point mutation that 
reduces antiviral activity.  However, it is predicted that 3TC, when combined with DTG 
with its high barrier to resistance and ability to confer a very rapid decline in HIV-1 
RNA, may be less likely to select for resistance consistent with clinical studies combining 
DTG, 3TC and ABC [Walmsley, 2013; Walmsley, 2015; Cahn, 2018].  
A pilot study (PADDLE) evaluated the anti-viral efficacy, safety and tolerability of a 2-
drug regimen with DTG 50 mg and 3TC 300 mg, both dosed once daily [Cahn, 2017].  
Twenty treatment naïve participants were enrolled, with a median baseline viral load of 
24,128 c/mL.  A rapid decline in viral load was observed, with a median viral load decay 
from baseline to Week 12 of 2.74 logs.  At Week 48, 90% (18 of 20) reached a viral load 
of <50 c/mL.  Four subjects were enrolled with baseline HIV-RNA 100,000 c/mL; all 
achieved HIV-RNA <400 c/mL at Week 3, and <50 c/mL at Week 8.  No major 
tolerability issues were observed.
The AIDS Clinical Trial Group (ACTG) Study A5353 evaluated DTG + 3TC in 120 
treatment-naïve HIV-1 infected participants, including with HIV-1 RNA 1000 c/mL and 
<500,000 c/mL [Taiwo, 2018].  The median viral load was 4.61 log10 at baseline; 37 of 
the 120 participants had viral load 100,000 c/mL. Virologic efficacy (<50 c/mL) at 
Week 24 was 108/120 (90%), with comparable results in the >100,000 c/mL (89%) and 
the 100,000 (90%) strata’s.  One participant discontinued the study at Week 18 due to 
non-compliance with study treatment and met confirmed virologic failure criteria at 
Week 24 (off ART) with the M184V plus the mixture R263R/K mutations detected (no 
mutation seen at baseline).  Two participants experienced Grade 3 possible/probable 
treatment-related AEs; no participants discontinued study treatment due to AEs.
DTG + 3TC FDC provides a novel, well-tolerated two-drug first-line regimen for HIV 
infected treatment- naïve patients that, by having one less anti-retroviral (ARV) in the 
regimen may potentially limit the cumulative risk of drug-related toxicities.  GEMINI 1 
 
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and GEMINI 2 showed that in adult HIV 1 infected ART-naïve participants with a 
Screening HIV-1 RNA of 500,000 copies/mL (c/mL) and with no drug-resistance 
mutations, DTG + 3TC was non-inferior to DTG + TDF/FTC at Week 48 [Cahn, 2019].  
The proportion of participants with plasma HIV-1 RNA <50 c/mL was similar in each
treatment group.  At least 90% of participants in each treatment group had plasma HIV-1 
RNA <50 c/mL using the Snapshot algorithm.  DTG + 3TC was effective across a 
diverse spectrum of ART-naïve participants, including those with high Baseline HIV-1 
RNA (>100,000 c/mL).  Over 48 weeks, the pooled safety data was consistent with the 
known safety profile for the individual products.  There was a small number of AEs 
leading to withdrawal of study drug; few were considered drug-related.  Clinical 
laboratory assessments demonstrated there were no newly identified laboratory signals of 
concern.  DTG + 3TC was associated with lower impact on renal and bone biomarkers 
compared with DTG + TDF/FTC FDC.
One of the potential risks of a two-drug regimen, such as DTG + 3TC FDC, is the 
increase in virologic failure associated with the emergence of HIV-1 resistance
mutations.  DTG, with its higher barrier to resistance, may reduce treatment-emergent 
resistance in participants taking a two-drug regimen.  The overall efficacy data from the 
pivotal Phase III studies of DTG in ART-naïve participants are extensive, with no 
resistance mutations being identified through 144 weeks of treatment (SINGLE, 
ING114467) [Walmsley, 2015].  The absence of treatment-emergent mutations to DTG 
or background agents in ART-naïve individuals, rapid virologic response demonstrated 
for DTG-based regimens, and the in vitro potency and well-tolerated safety profile of 
both DTG and 3TC all provide a strong rationale for the development of a DTG + 3TC 
single tablet regimen as a treatment option for people living with HIV.  In the Gemini 
studies, there was no emergent INSTI or NRTI resistance observed for participants 
meeting confirmed virologic withdrawal criterion in either the DTG + 3TC or 
DTG + TDF/FTC treatment arms [Cahn, 2019].
2.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of DTG, 3TC or DTG + 3TC FDC may be found in 
the most recent version of the Investigator’s Brochure (IB) and any IB supplements and 
the product labels [TIVICAY Package Insert, 2018; EPIVIR Package Insert, 2018; 
DOVATO Package Insert, 2019].
The following section outlines the risk assessment and mitigation strategy for DTG and 
3TC in this protocol. 
 
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2.3.1.
Risk Assessment
The following table outlines the risk assessment and mitigation strategy for this protocol.  Additionally, all participants will be closely 
monitored over the first 12 weeks of study intervention (Weeks 1, 4, 8 and 12 Visits), with visits every 12 weeks thereafter.
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Study Intervention [DTG, 3TC]
Refer to DTG IBs and country product labels for additional information
DTG: Hypersensitivity 
reaction (HSR) and rash
DTG: HSR has been observed uncommonly with DTG.  Rash was commonly 
reported in DTG Phase IIb/III clinical trials; episodes were generally mild to 
moderate in intensity; no episodes of severe rash, such as Stevens-Johnson 
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and erythema multiforme 
were reported. 
Specific/detailed toxicity management guidance is provided for HSR 
and rash (Section 10.4.1.6).
The participant informed consent form (ICF) includes information on 
this risk and the actions participants should take in the event of a 
HSR or associated signs and symptoms.
DTG: Drug induced liver 
injury (DILI) and other 
clinically significant liver 
chemistry elevations 
3TC: Use in HBV co-infected 
participants and emergence 
of HBV variants resistant to 
DTG: Non-clinical data suggested a possible, albeit low, risk for hepatobiliary 
toxicity with DTG.  Drug-related hepatitis is considered an uncommon risk for 
ART containing DTG regardless of dose or treatment population.  For 
participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-
infection, improvements in immunosuppression as a result of HIV virologic and 
immunologic responses to DTG- containing ART, along with inadequate 
therapy for HBV co-infected participants, likely contributed to significant 
elevations in liver chemistries.  A review of post-marketing data found that the 
number of cases reporting particularly severe liver dysfunction was found to be 
very low in the context of exposure to DTG and DTG/ABC/3TC. The reported 
cases of severe liver dysfunction (including acute hepatic failure) are complex 
with potential confounding factors but in a very small number of cases, drug-
induced liver injury is likely and the role of DTG containing regimens cannot be 
ruled out particularly in those involving DTG with ABC/3TC or DTG/ABC/3TC.
3TC:  Current treatment guidelines [DHHS, 2018; EACS, 2017] do not 
recommend monotherapy with 3TC for participants with HBV infection, which 
is what participants randomised to DTG + 3TC FDC, would effectively be 
receiving.  Emergence of HBV variants associated with resistance to 3TC has 
been reported in HIV-1-infected participants who have received 3TC-
containing antiretroviral regimens in the presence of concurrent infection with 
Participants will be tested for chronic hepatitis B at Baseline
(Screening/Day 1).
Participants with chronic hepatitis B infection as shown by either of 
the following should either have Tenofovir added to their regimen or 
switch to a Tenofovir containing regimen.

Positive for HBsAg; 

Negative for HBsAg and HBsAb, and positive for HBcAb and 
HBV DNA.
For participants with chronic HBV infection, testing for HBV 3TC 
resistance will be performed using samples from Week 1 and Week 
4 (depending on when ART modification occurs) as well as Baseline 
samples.  HBV DNA will also be obtained at the Week 1 or 
Week 4 visit.
Liver chemistries will be monitored. Specific/detailed liver stopping 
criteria and toxicity management guidance is provided for suspected 
DILI or other clinically significant liver chemistry elevations 
(Section 10.6).
 
 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Study Intervention [DTG, 3TC]
Refer to DTG IBs and country product labels for additional information
HBV.  Additionally, discontinuation of 3TC in HBV co-infected participants can 
result in severe exacerbations of hepatitis B.
DTG: Psychiatric disorders
DTG: Psychiatric disorders including suicidal ideation and behaviours are 
common in people living with HIV. Events of suicidal ideation, attempt, 
behaviour and completion were observed in clinical studies of DTG, primarily 
in participants with a pre-existing history of depression or other psychiatric 
illness. The psychiatric profile for DTG (including suicidality, depression, 
bipolar and hypomania, anxiety and abnormal dreams) was similar to RAL- or 
favourable compared with EFV- based regimens. 
Participants who in the investigator’s judgment, pose a significant 
suicidality risk, are excluded from participating.  Because of the 
elevated risk in the HIV- infected population, treatment emergent 
assessment of suicidality will be monitored during this study.  See 
Section 8.2.4 for additional information. 
Investigators must assess participant suicidality using their usual 
clinical practice at every study visit.
Investigators are advised to consider mental health consultation or 
referral for participants who experience signs of suicidal ideation or 
behaviour.
The participant informed consent form includes information on this 
risk of depression and suicidal ideation and behaviours.
DTG and 3TC: Increased 
rates of virologic failure/ 
Observed Resistance
DTG: Week 96 and Week 144 analyses for the Phase III/IIIb clinical studies 
supported the efficacy findings from earlier analyses and demonstrated robust 
maintenance of viral suppression with no finding of HIV-1 resistance in 
treatment-naïve participants. 
3TC:  M184V, M184I and K65R (associated with resistance on TDF treatment 
failure) single mutations that confer resistance to 3TC.  
Subjects with evidence of primary viral resistance based on the 
presence of M184I, M184V or K65R or any DTG primary resistance 
associated mutation will have their antiretroviral regimen modified 
based on the results of Baseline resistance genotype as they 
become available (Week 4 Visit) (see Section 7.2.2). 
Subjects will have HIV-1 RNA measured at each study visit. 
Subjects who meet the Confirmed Virologic Failure criteria will have 
a resistance genotype/phenotype performed, and their regimens 
may be modified based on the results of the resistance test.
DTG: Theoretical serious 
drug interaction with 
dofetilide 
Co-administration of DTG may increase dofetilide plasma concentration via 
inhibition of organic cation transporter (OCT-2), resulting in potentially life-
threatening toxicity. 
The co-administration of DTG with dofetilide is prohibited in the 
study (Section 10.7).
DTG and 3TC: Renal 
function
DTG: Mild elevations of creatinine have been observed with DTG which are 
related to a likely benign effect on creatinine secretion with inhibition of OCT-2.  
DTG has been shown to have no significant effect on glomerular filtration rate 
Due to requirements for dose reduction of 3TC in participants with 
renal dysfunction, participants with a creatinine clearance (CrCL) 
<30 mL/min/1.73 m2 will have DTG + 3TC FDC discontinued and 
 
 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Study Intervention [DTG, 3TC]
Refer to DTG IBs and country product labels for additional information
(GFR) or effective renal plasma flow.
3TC: 3TC is eliminated by renal excretion and exposures increase in 
participants with renal dysfunction.  3TC is not recommended to treat 
participants with a creatinine clearance <50 mL/min.
modify to a new ART regimen.
Creatinine Clearance (CrCl) will be calculated in all participants and 
renal function (creatinine clearance and serum phosphate) will be 
monitored at all study visits.
DTG: Neural tube defects
In one ongoing birth outcome surveillance study in Botswana, early results 
from an unplanned interim analysis show that 4/426 (0.9%) of cis women who 
were taking DTG when they became pregnant had babies with neural tube 
defects compared to a background rate of 0.1%.
1.
A participant who is female at birth is eligible to participate if not 
pregnant, if pregnant and past the first trimester , or of 
childbearing potential and agrees to follow one of the options 
listed in the Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Participants of Childbearing Potential 
(Section 10.5.2) for at least 2 weeks after the last dose of study 
medication.
2. Participants of childbearing potential who plan to become 
pregnant during the study are excluded;
3. Participants who become pregnant and are in the first trimester 
should immediately discontinue DTG + 3TC FDC and an 
alternate ART regimen that does not contain DTG should be 
started, unless no suitable alternative is available, in 
consultation with the Medical Monitor.  If the pregnancy is post 
first trimester, the participant can continue study treatment.  
Any participant who becomes pregnant during the study can 
remain in the study, including those who needed to modify the 
ART Regimen.
4. Participants who desire to be pregnant while in the study, or 
who state they no longer are willing to comply with the 
approved pregnancy avoidance methods, will have DTG + 3TC
FDC discontinued and switched to a new ART regimen.
5. Participants of childbearing potential are reminded re: 
pregnancy avoidance and adherence to contraception 
requirements at every study visit.
 
 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Study Intervention [DTG, 3TC]
Refer to DTG IBs and country product labels for additional information
6. Pregnancy status is monitored at every study visit.
a.
Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3 or 4 laboratory toxicities (per Division of Acquired Immune 
Deficiency Syndrome [DAIDS] toxicity gradings for HIV-infected participants). Serious/severe events will be managed appropriately including, but not limited to, withdrawal of 
study drug, and will be followed to resolution as per Sponsor’s standard medical monitoring practices.  
b.
Clinical Safety Data will be routinely reviewed in GlaxoSmithKline (GSK) /ViiV Safety Review Team meetings. This will include in-stream review of data from this clinical trial on a 
routine basis, review of aggregate data on a protocol and program basis when available, and review of competitor data from the literature.
 
 
 
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2.3.2.
Benefit Assessment
Individually, DTG and 3TC are conveniently dosed once daily without regard to meals, 
without need for a PK booster, and with limited safety implications resulting from 
theoretical or actual DDIs compared to other ART agents (including EFV and those 
requiring a PK booster).  In addition, the high barrier to HIV-1 resistance mutation 
observed with DTG should help protect against the development of resistance to both 
components of the DTG + 3TC FDC regimen.  Individually, DTG and 3TC in 
combination with other ARVs have demonstrated durable virologic and immunologic 
response. 
In general, ART immediately after diagnosis may increase participants’ engagement to 
care and increase adherence to ART. Study participants also may benefit from the 
medical tests and procedures performed as part of this study.
2.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in 
this study, the potential risks identified in association with DTG + 3TC FDC are justified 
by the anticipated benefits that may be afforded to study participants who rapidly initiate
this 2-drug regimen.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the feasibility and efficacy 
of a rapid Test and Treat model of care 
in participants with a new diagnosis of 
HIV-1 initiating treatment with DTG + 
3TC FDC immediately (or, for those 
participants referred from another site, 
within 14 days of initial diagnosis at 
the external clinic/testing center)

Percentage of all participants who have  
plasma HIV-1 RNA <50 c/mL at 
Week 24, regardless of ART regimen
(observed analysis)
Secondary

To demonstrate the antiviral activity of 
DTG + 3TC FDC over 48 weeks

Proportion of all participants:

who have plasma HIV-1 RNA <50 
c/mL at Week 48, regardless of ART 
regimen (observed analysis)

with plasma HIV-1 RNA <50 c/mL 
at Week 24 and 48 using the FDA 
Snapshot algorithm 

Time to suppression of HIV-1 RNA 
 
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Objectives
Endpoints
<50 c/mL

To evaluate the barriers (e.g., HIV-1 
resistance mutation results) to initiate 
and maintain DTG + 3TC FDC 
treatment in a Test and Treat Model of 
Care

Proportion of participants who change 
first line regimen of DTG + 3TC FDC 
due to Baseline laboratory results or 
HIV-1 resistance mutation results.  

To assess viral resistance in 
participants meeting confirmed 
virologic failure criteria

Incidence of treatment-emergent 
genotypic and phenotypic resistance to 
DTG and/or 3TC, or any other ART if 
treatment is modified, in participants 
meeting confirmed virologic failure 
criteria

To evaluate the safety and tolerability 
of a rapid test and treat model of care 
using DTG + 3TC FDC as first line 
regimen 

Incidence and severity of adverse 
events (AEs) and laboratory 
abnormalities

Proportion of participants who 
discontinue treatment due to AEs and 
drug-related AEs over 48 weeks of 
treatment

To evaluate the immune effects of a 
rapid test and treat model of care using 
DTG + 3TC FDC as first line regimen

Change from Baseline in CD4+ cell 
counts and CD4+/CD8+ ratio at 
Weeks 24 and 48

Incidence of disease progression 
(stage 3 HIV-associated conditions, 
AIDS, and death) through Week 48

To evaluate retention in care 

Proportion of participants 
o who completed their Week 24 and 
Week 48 Visit;
o who complete their Week 24 and 
Week 48 Visit and have a HIV-1 RNA
<200 c/mL
Exploratory

To evaluate the effect of participant
demographics and Screening/Day 1
characteristics on the feasibility and
efficacy of a test and treat model of 
care using DTG + 3TC FDC as first 
line regimen

Proportion of participants with plasma 
HIV-1 RNA <50 c/mL by at Weeks 24 
and 48 by participant subgroup(s) by 
Observed Analysis

To asses change in treatment symptom 

Change from Baseline in overall 
 
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Objectives
Endpoints
index for participants under a rapid test 
and treat model of care using DTG + 
3TC FDC as a first line regimen 
symptom bother score from the HIV 
Symptom Distress Module at Weeks 4, 
8, 12, 24, 36, and 48 

To assess change in specific symptoms 
for participants treated with 
DTG + 3TC FDC

Change from Baseline in 20 item-
specific symptoms from the HIV 
Symptom Distress Module at Weeks 4, 
8, 12, 24, 36, and 48

To assess adherence to study treatment

Adherence will be assessed by 
participant recall on number of doses 
missed over the 7 days prior to the 
visit
4.
STUDY DESIGN
4.1.
Overall Design
Study 212355 is a Phase IIIb, multicentre, 52-week, open label, single arm, pilot study in 
adults with a new diagnosis of HIV-1, who are willing to start study treatment 
(DTG + 3TC FDC) immediately.  Eligible participants will be enrolled and started on 
DTG + 3TC FDC, without waiting for Screening/Day 1 laboratory results. The 
Screening/Day 1 Visit is considered Baseline.
The study will be conducted in the U.S., with approximately 120 participants with a new 
HIV-1 diagnosis who are willing to start DTG + 3TC FDC within 14 days of diagnosis.  
A participant’s total time in the study will be approximately 13 months and includes a 
maximum of 14 days between the initial diagnosis of HIV-1 infection and initiation of 
study drug at the Screening/Day 1 Visit, a 52-week treatment period and a 4-week 
follow-up phase if required.
This study will comprise:

The Screening/Day 1 Visit is the date the site assesses the participant’s 
appropriateness for the study and consents for and initiates study treatment.  
Diagnosis may have occurred at an external clinic/testing center prior to participant 
visiting the site.

Participants are considered HIV-1 infected when they have positive results from 
2 different HIV Rapid tests (different assay or manufacturer), or they are positive 
with an FDA-approved antigen/antibody combination immunoassay (4th
generation assay) or an FDA approved HIV antibody immunoassay that detects 
HIV-1 and HIV-2 antibodies (3rd generation assay) confirmed by an FDA-
approved antibody immunoassay that differentiates HIV-1 antibodies from 
HIV-2 antibodies or an HIV western blot or an HIV-1 RNA.
 
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
For participants who are referred to the study site with a single positive 
Rapid HIV test, a second and different Rapid HIV test (different assay or 
manufacturer) should be conducted. If the second Rapid HIV test is 
nonreactive, the participant is presumed to be HIV-negative. If both tests are 
reactive, the participant is confirmed HIV-infected.

Screening/Day 1 labs should be taken prior to the administration of study 
treatment.

Investigator should review the Baseline laboratory findings as they become available 
and schedule a study visit (Week 1), see Section 7.2 for additional information.  If  
results for HBV surface antigen (HBsAg) or HBV core antibody (anti-HBc) and 
HBV DNA are not available, this review should be completed at the Week 4 Visit 
when the HIV-1 resistance mutation results are available. 
Note: For participants with chronic HBV infection, testing for HBV 3TC resistance 
will be performed using samples from Week 1 or Week 4 (depending on when ART 
modification occurs) as well as Baseline samples.  In these participants, HBV DNA 
will also be obtained at the Week 1 or Week 4 visit.

A visit should be scheduled when the central laboratory data from Baseline genotype
for HIV-1 drug resistance mutations are available (Week 4 Visit) and additional 
intervention should be performed if required (see Section 7.2.2 for more details).  If 
the HBV surface antigen (HBsAg) or HBV core antibody (anti-HBc) and HBV DNA 
data were not available at the time of the Week 1 Visit, these results should be 
reviewed at Week 4.  The investigator should also review the tolerance to 
DTG + 3TC FDC, AEs, assess adherence to study treatment and enforce the 
importance of adherence.  

Virologic non-response criteria for Week 8, Week 12, and on or after Week 24 are 
defined in Section 7.3.

Additional study visits are scheduled at Weeks 12, 24, 36, 48, 52, and a potential 
Follow-up Visit.  At Week 36, study participants will be provided DTG + 3TC FDC 
to ensure that they have enough study intervention until Week 52.  
When the Investigator is modifying a participants ART regimen between scheduled 
visits, the study assessments shown in the SoA in Section 1.3.1 should be followed.  
During the ART Regimen Modification Visit, the date of the modification and the new 
ART regimen will be captured.  Four weeks after the ART modification (Post ART 
Regimen Modification Visit), the participant must return for another visit to determine 
adherence, safety of and virologic response to the new regimen.  The participants will 
resume regular study visit schedule after this visit. If the ART Regimen Modification 
Visit or the Post-ART Regimen Modification Visit occurs at a scheduled visit (Section 
1.3), assessments should be completed at the scheduled visit and only the additional 
assessments at the ART Modification visit should be completed.
When all participants complete the Week 12 Visit, an interim analysis may be conducted 
to review the proportion of participants that required a modification in ART regimen.  
 
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Additional details of the potential Interim Analysis at Week 12 can be found in Statistical 
Considerations Section 9.6.
The primary analysis at Week 24 will take place after the last participant has had their 
Week 24 viral load assessed, including any retests.  
All participants who remain in the study will complete the Week 52 Visit (which can 
occur anytime within 2-4 week of the Week 48 Visit), where study intervention stop date 
will be captured, and collect and follow-up on AEs and SAEs.  Participants who require a 
virologic retest must have HIV-1 RNA level re-assessed by a second measurement 
performed 2-4 weeks later, which will be captured under the Week 52 Visit.  
4.2.
Scientific Rationale for Study Design
Individuals who receive a diagnosis of HIV-1 infection should be started on ART as soon 
as possible after diagnosis.  Recently diagnosed individuals are often referred to HIV care 
providers for evaluation, follow-up and management, resulting in a delay between 
initiation and time ART is prescribed.  This delay between diagnosis and treatment 
results in many individuals not engaging in their care.  Thus, rapid ART initiation (Test 
and Treat), ideally on the same day of HIV-1 diagnosis may increase the proportion of 
individuals who start ART earlier and achieve and maintain viral suppression [DHHS,
2018; Saag, 2018].
When ARTs are started before HIV-1 resistance mutation results are available, the DHHS 
Guidelines recommend either DRV/r or DRV/c plus Tenofovir/FTC or DTG plus 
Tenofovir/FTC DHHS, 2018].  No specific type of tenofovir is favoured.  They do not 
recommend NNRTIs or the use of ABC.  Transmitted mutations conferring NNRTI 
resistance are more likely than mutations associated with PI or INSTI resistance. HLA-
B*5701 results may not be available rapidly.  Transmitted resistance to DRV and DTG is 
rare, and these drugs have high barriers to resistance.  First generation INSTIs are not 
recommended because of lower barriers to resistance.  BIC/TAF/FTC is not 
recommended because of lack of data.  
The IAS Guidelines also recommend a rapid ART initiation for all HIV infected 
individuals willing to start ART [Saag, 2018]. Current IAS guidelines recommend DTG 
plus TAF (or tenofovir disoproxil fumarate [TDF]), emtricitabine (or lamivudine)) or 
bictegravir/TAF/emtricitabine or boosted darunavir TAF (or TDF), emtricitabine (or 
lamivudine) as initial rapid therapy.  Because of concerns about transmitted drug 
resistance (e.g., K103N mutation), immediate ART should not be nonnucleoside reverse 
transcriptase inhibitor (NNRTI)–based.  Participants requiring abacavir should not begin 
until the result of testing for the HLAB* 5701 allele is available [Saag, 2018].
Phase 3 Studies GEMINI 1 and GEMINI 2 demonstrated that a 2-drug regimen of 
DTG + 3TC was non-inferior to DTG + TDF/FTC in HIV-1 infected ART naïve 
participants, with comparable safety results observed between the 2 treatment groups
[Cahn, 2019]. In both studies, Kaplan-Meier estimates of the time to viral suppression 
(<50 c/mL) through Week 48 indicated that participants reached viral suppression at a 
similar time point, irrespective of whether they received DTG + 3TC or a standard of care 
triple drug regimen in both treatment groups, with a median time to viral suppression of 
 
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29.0 days.  The proportion of participants with HIV-1 RNA <50 c/mL by visit in the 
DTG + 3TC group in GEMINI 1/GEMINI 2 was 73%/71% at Week 4, 85%/ 89% at 
Week 8, 87%/90% at Week 12 and 92%/94% at Week 24.  No statistically significant 
evidence of heterogeneity between the Baseline HIV-1 RNA subgroups (or >100,000 
c/mL) was observed for the difference in the proportion of participants with HIV-1 RNA 
<50 c/mL at Week 48 between arms.  2% of participants in both groups had baseline viral 
loads of 500,000 c/mL or more, Week 48 efficacy outcomes in these participants were 
similar in the two-drug regimen group (11 [85%] of 13) and three-drug regimen group 
(12 [80%] of 15).  At Week 12, the median (IQR) log 10 c/mL change from baseline was 
-2.840 (-3.290, -2.450) in GEMINI 1 and -2.800 (-3.250, -2.360) in GEMINI 2.  
However, there are possible barriers to DTG + 3TC use in a rapid Test and Treat model 
of care due to concerns over transmitted M184V, M184I and K65R resistance mutations 
and/or HBV-HIV co infection.  Study 212355 is a pilot study being conducted to assess 
the feasibility, effectiveness, safety and ease of use of DTG + 3TC FDC as a first line 
therapy in a rapid Test and Treat model of care. 
Study 212355 is a multi-center, open-label, one arm pilot study in newly diagnosed adult 
HIV-1 participants.  Participants will start study treatment at the time of or within 14 days 
of the initial diagnosis and prior to the availability of Screening/Day 1 labs.  The 
Screening/Day 1 Visit is to review participant inclusion/exclusion criteria and initiate 
study intervention.  The Screening/Day 1 Visit will be no more than 14 days since the 
initial day of diagnosis.  Study visits at Week 1 and Week 4 are included so that all 
participants will have a review of central labs and resistance genotypic data as they 
become available from Baseline Visit labs to confirm that DTG + 3TC FDC is an 
appropriate therapy (see also Section 7.2.1 and Section 7.2.2).  Study visits will also 
occur at Week 8, Week 12 and then every 12-weeks through Week 48 to ensure 
compliance with study treatment, and to assess the efficacy and safety and tolerability of 
DTG + 3TC FDC.  
4.3.
Justification for Dose
The efficacy, PK, safety, and drug interaction potential of DTG and 3TC as individual 
agents and in combination (DTG + 3TC) have been evaluated in extensive clinical 
development programmes.  DTG + 3TC FDC is approved in the US and marketed as 
DOVATO.  In addition, DTG and 3TC are approved and marketed as TIVICAY 50 mg 
once daily and EPIVIR 300 mg once daily, respectively.  
4.4.
End of Study Definition
A participant is considered to have completed the study if they have completed all study 
visits to Week 52, which includes the Week 48 HIV-1 RNA retest if needed.
The end of the study is defined as the date of the last visit of the last participant in the 
study.
A Week 52 Visit is included to allow for the collection of any viral load re-test from the 
Week 48 Visit and to collect the end date of study intervention.
 
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An in-clinic Follow-Up Visit will be conducted approximately 4 weeks after the last dose 
of study medication only for participants with ongoing AEs of interest or SAEs 
regardless of attributability (as defined in Section 2.3.1) at the last on-study visit.  
Assessments at the Follow-up Visit should reflect any ongoing complaints (e.g., blood 
draws to follow a laboratory abnormality). The investigator, in consultation with the 
medical monitor, should follow-up with the participant until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up.
5.
STUDY POPULATION
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational product or other study interventions 
that may impact participant eligibility is provided in the Product Insert(s) for DTG and 
3TC.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety.  Therefore, adherence to the criteria as specified in the protocol is 
essential. Prospective approval of protocol deviations to recruitment and enrolment 
criteria, also known as protocol waivers or exemptions, is not permitted.
The following are study specific eligibility criteria unless stated otherwise.  In addition to 
these criteria, Investigators must exercise clinical discretion regarding selection of 
appropriate study participants, taking into consideration any local treatment practices or 
guidelines and good clinical practice (GCP).
5.1.
Inclusion Criteria
Eligible participants must:
be able to understand and comply with protocol requirements, instructions, and 
restrictions;
be likely to complete the study as planned;
be considered appropriate candidates for participation in an investigative clinical 
trial with oral medication (e.g. no active problematic substance abuse, acute major 
organ disease, or potential long-term work assignments out of the country).  
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2.
Participants must have a new confirmed diagnosis of HIV-1 infection based on the 
criterion below, and are willing to initiate ART immediately (or, for those 
 
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participants referred from another site, within 14 days of initial diagnosis at the 
external clinic/testing center); as documented in source documents.
Participant must have an initial positive rapid HIV test
NOTE: This includes participants whose first rapid test was positive either at the 
study site or those who are referred to the study site with a single positive rapid 
HIV test. The study site must have viewable documentation of the positive rapid 
test available and placed into the study source documents.
AND
Participant has a second positive confirmatory rapid HIV test, using a test kit from 
a different manufacturer than the first test 
NOTE: If the second Rapid HIV test is nonreactive, the participant is presumed to 
be HIV-negative.  If both tests are reactive, the participant is confirmed HIV-
infected.
OR
Participant has been identified as HIV-1 infected using an FDA-approved 4th
generation assay antigen/antibody combination immunoassay or 3rd generation 
immunoassay that detects and differentiates HIV-1 and HIV-2 antibodies 
AND
has a confirmatory HIV western blot OR an HIV-1 RNA  
OR
Participant has a positive FDA-approved 4th generation assay and a positive 3rd
generation immunoassay that detects and differentiates HIV-1 and HIV-2 
antibodies.
3.
Antiretroviral-naïve.  Participants who received HIV post-exposure prophylaxis 
(PEP) or pre-exposure prophylaxis (PrEP) in the past are allowed as long as the last 
PEP/PrEP dose was >6 months from HIV diagnosis or there is documented HIV 
seronegativity at least 2 months after the last prophylactic dose and prior to the date 
of HIV diagnosis.  The study site must have viewable documentation of the 
seronegative test available and placed into the study source documents.
Sex
4.
Male and/or female
Participants who are female at birth: 
Participants who are female at birth are eligible to participate if at least one of the 
following conditions applies:

Not pregnant, as confirmed by a negative urine human chorionic gonadotropin 
(hCG) test at Screening/Day 1
 
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
Pregnant and post the first trimester (the physician and patient should decide 
whether enrolling in this study is in the participants best interest during the 
consent process)

Not a participant of childbearing potential (POCBP) (see Section 10.5.1).
OR

A POCBP who agrees to follow the contraceptive guidance as defined in 
Section 10.5.2, is currently taking hormonal contraceptives and continues for at 
least 2 weeks after the last dose of study medication.  
Participants who are female at birth and who are in the following categories are not 
considered POCBP
a) Premenarchal
b) Premenopausal with ONE of the following: 
Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s
medical records, medical examination, or medical history interview.
c) Postmenopausal:
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in participants who 
are female at birth and not using hormonal contraception or hormonal 
replacement therapy (HRT). 
Participants who are female at birth on HRT and whose menopausal status 
is in doubt will be required to use one of the non-hormonal highly 
effective contraception methods if they wish to continue their HRT during 
the study. 
The investigator is responsible for ensuring that participants understand how to properly 
use these methods of contraception.
All participants in the study should be counselled on safer sexual practices including the 
use and benefit/risk of effective barrier methods (e.g., male condom) and on the risk of 
HIV transmission to an uninfected partner.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a participants who are female at 
birth with an early undetected pregnancy.
 
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Informed Consent
5.
Capable of giving signed informed consent as described in Section 10.1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Participants who are breastfeeding, plan to become pregnant or breastfeed during the 
study
2. Participants who are in their first trimester of pregnancy;
3. HIV-1 drug resistance genotype test results are known prior to Screening/Day 1;  
4. Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3 
disease [CDC, 2014], except for esophageal candidiasis and cutaneous Kaposi’s 
sarcoma not requiring systemic therapy;
5. Participants with known or suspected Hepatitis B infection;
6. Known or suspected severe hepatic impairment or unstable liver disease (as defined 
by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary 
abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones);
7. Known moderate to severe renal impairment (creatinine clearance 
<30ml/min/1.73m2);
8. Ongoing malignancy other than basal cell carcinoma, or resected, non-invasive 
cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial 
neoplasia; other localised malignancies require agreement between the investigator 
and the Study Medical Monitor for inclusion of the participant;
9. Participants who in the investigator’s judgment, poses a significant suicidality risk. 
10. Any pre-existing physical or mental condition which, in the opinion of the 
Investigator, may interfere with the participant’s ability to comply with the dosing 
schedule and/or protocol evaluations or which may compromise the safety of the 
participant. 
11. Participants with substance abuse disorders or social restraints that the Investigator 
considers to be possible deterrents to successful initiation of ART. 
12. History or presence of allergy or intolerance to the study drugs or their components
 
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Exclusionary Treatments Prior to Initiation of DTG + 3TC FDC
13. Treatment with any of the following agents within 28 days of the first dose of study 
treatment

radiation therapy,

cytotoxic chemotherapeutic agents,

any systemic immune suppressant.
14. Participants receiving any prohibited medication (see Section 10.7) and who are 
unwilling or unable to switch to an alternate medication.
15. Exposure to an experimental drug or experimental vaccine within either 28 days, 5 
half-lives of the test agent, or twice the duration of the biological effect of the test 
agent, whichever is longer, prior to the first dose of study treatment.
5.3.
Lifestyle Considerations
This section is not applicable to this study.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but do not meet all inclusion criteria or meet at least one of the exclusion criteria. A 
minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs).
Participants are not allowed to re-screen for this study.  
Source documentation to verify entry criteria must be reviewed by the Principal 
Investigator or designee prior to first study treatment dose.  If a participant is referred to 
the site for treatment, evidence of HIV-1 infection must be confirmed and documented in 
source documents prior to starting study treatment.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
In this study, study intervention refers to DTG + 3TC FDC.  All study interventions will 
be administered at the approved dosages.  The study intervention DTG + 3TC FDC will 
be supplied by ViiV Healthcare/GSK as the fixed dose combination tablet. For subjects 
requiring ART modification as part of this trial, provisions will be in place, as needed and 
 
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after discussion with the study team, to provide financial assistance for patients in 
obtaining their additional ART during the study.
DTG + 3TC FDC must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and dispensing of the DTG+ 3TC FDC will be
limited to the investigator and authorized site staff.  Study intervention must be dispensed 
or administered only to participants enrolled in the study and in accordance with the 
protocol.  For further details on storage, access and administration of study interventions, 
refer to the SRM.
Study intervention, 50 mg DTG + 300 mg 3TC FDC will be provided to all participants 
as first line therapy.  DTG + 3TC FDC will be taken orally, once daily, with or without 
food.
6.1.
Study Intervention Administered
Table 1
Study Intervention
ARM Name
DTG + 3TC FDC
Intervention 
Name
Dolutegravir + Lamivudine = GSK3515864
Type 
Drug
Dose 
Formulation
Tablet
Unit Dose 
Strength(s)
50mg DTG, 300mg 3TC
Dosage Level(s)
Take one tablet daily
Route of 
Administration
oral
IMP 
Yes
Sourcing
Provided centrally by the Sponsor.
Packaging and
Labeling
White oval film-coated tablets, debossed with ‘SV 137’ on one side and plain 
on the other, are packed in high density polyethylene (HDPE) bottles with 
induction seals and child-resistant closures.  Each 60mL bottle contains 30 
tablets and a 2-gram silica gel desiccant.  Each bottle will be labelled as 
required per country requirement.
 
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6.2.
Preparation/Handling/Storage/Accountability
No special preparation of study intervention is required.
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2.
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3.
The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability and record 
maintenance (i.e., receipt and final disposition records).
4.
Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
ViiV/GSK.

DTG + 3TC FDC accountability will not be evaluated using pill counts.  Adherence 
will be assessed by participant recall on number of doses missed over the 7 days 
prior to the visit.
6.3.
Measures to Minimize Bias: Study Intervention and Blinding
This is an open-label, single arm study.  The site will contact the IWRS prior to the 
initiation of DTG + 3TC FDC at the Screening/Day 1 Visit and record the intervention 
assignment on the applicable CRF.
6.4.
Study Intervention Compliance
Compliance with DTG + 3TC FDC will be assessed through querying the participant 
during the site visits and documented in the source documents and CRF.  Participants will 
be asked about any missed doses in the previous 7 days.  A record of the number of 
DTG + 3TC FDC tablets dispensed to each participant must be maintained with study 
intervention and compliance records.  Intervention start and stop dates, including dates 
for intervention delays and/or dose reductions will also be recorded in the CRF.
 
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6.5.
Dose Modification
No dose modifications are allowed for DTG + 3TC FDC.  Section 7 details 
discontinuation and additional ART interventions allowed in this study.
6.6.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
Refer to Section 10.7 for a full list of prohibited medications.  The Medical Monitor 
should be contacted if there are any questions regarding concomitant or prior therapy.
Participants should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
DDIs between such treatments and the study interventions.  The investigator should 
evaluate any potential DDIs at every visit, including reviewing the most current version 
of the U.S. or local prescribing information for DTG and 3TC, especially if any new 
concomitant medications are reported by participants.  All concomitant medications 
(including oral contraception, implants or oral or topical hormone replacement therapy) 
taken during the study will be recorded in the eCRF.  
Concomitant medications (prescription and non-prescription) should be prescribed by the 
relevant health care provider/investigator and administered only as medically necessary 
during the Randomized and Continuation phases of the study (except prohibited 
medications described in Section 10.7).  Chemoprophylaxis for HIV-associated 
conditions is encouraged, if appropriate, at the discretion of the participant and their 
physician. All concomitant medications, blood products, and vaccines taken during the 
study will be recorded in the eCRF with dates of administration.
6.6.1.
Permitted Medications and Non-Drug Therapies
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma 
RNA, it is highly recommended that a vaccine, if necessary, be given during or 
immediately after a scheduled visit after all laboratory tests have been drawn and only 
when scheduled visits are ≥4 weeks apart.  This approach will minimize the risk of non-
specific increases in the level of HIV-1 plasma RNA at the next scheduled assessment.
DTG + 3TC FDC should be administered 2 hours before or 6 hours after taking antacid 
or laxative products containing polyvalent cations (e.g. aluminium and magnesium),
sucralfate, or calcium supplements.  Proton pump inhibitors and H2-antagonists may be 
used in place of antacids with no scheduling restrictions.  Concurrent administration with 
multivitamins is acceptable.  Iron supplements can be taken with study treatment
 
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provided that all are taken together with a meal. Under fasted conditions, DTG +3TC 
FDC should be given 2 hours prior to OR 6 hours after iron supplements.
Metformin concentrations may be increased by DTG.  A dose adjustment of metformin 
should be considered when starting and stopping co-administration of dolutegravir with 
metformin, to maintain glycaemic control.
Clinical monitoring is recommended for participants taking methadone, as methadone 
maintenance therapy may need to be adjusted in some participants.
Non-protocol defined treatments or medical interventions (e.g., physical therapy, 
radiotherapy, surgical procedures) are permitted during the study for appropriate medical 
management of the participant.
6.7.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the 
poststudy care of the subject’s medical condition, whether or not ViiV Healthcare/GSK is 
providing specific post-study treatment.
7.
STUDY INTERVENTION DISCONTINUATION CRITERIA
7.1.
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. If 
study intervention is permanently discontinued, the participant will remain in the study. 
7.2.
Additional Intervention Criteria
7.2.1.
Baseline Laboratory Safety Criteria:
Participants meeting any of the below safety criteria based on the Baseline
(Screening/Day 1) laboratory results as they become available (Week 1 Visit) will be 
evaluated for potential modification in their current DTG + 3TC FDC treatment and will 
remain in the study.  See Section 1.3.1 for the assessments required when ART is 
modified.

Creatinine clearance of <30 mL/min/1.73 m2 via the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) method.

Evidence of active chronic HBV infection (Investigator should consider either adding 
tenofovir or modifying to a tenofovir-based regimen):
o
Participants positive for HBsAg.
o
Participants negative for HBsAg and anti-HBs, positive for anti-HBc and 
positive for HBV DNA.  
 
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NOTE: If these results are not available for the Week 1 Visit, they should be 
reviewed at Week 4.  Participants who are diagnosed with active chronic hepatitis B 
infection will have samples from the ART Modification Visit and Baseline Visit sent 
for HBV 3TC-resistance testing.

Any Grade 3 or Grade 4 laboratory abnormality from the Baseline Visit, which, in the 
opinion of the Investigator, would end the participant’s participation in this study.
7.2.2.
Baseline Resistance Mutation Criteria:
Participants meeting any of the HIV-1 resistance mutation criteria based on Baseline 
laboratory assessments will be evaluated for additional ART interventions as the data are
made available (Week 4).  See Section 1.3.1 for the assessments required when ART is 
modified.
Participants with Baseline mutations that confer resistance to 3TC (e.g. M184V/I, K65R, 
etc.) or with DTG primary resistance associated mutation will discontinue study 
treatment but remain in the study.  Investigators should modify the participants regimen 
based on the Baseline genotype results, in consultation with the medical monitor.  A 
plasma sample will be obtained at Week 4 and will be sent for genotypic and phenotypic 
resistance testing and the result made known to the study investigator when available.  
7.3.
Virologic Failure Criteria
For the purposes of clinical management in this study, the criteria detailed below will 
apply:
Suspected Virologic Failure: A single HIV-1 RNA value as defined by Virologic Non-
response or Virologic Rebound
Confirmed Virologic Failure:  Any of the below conditions are met once the 
Investigator has confirmed participant compliance: 

Virologic Non-Response Criteria:
o
A decrease in Baseline plasma HIV-1 RNA of less than 2.0 log10 c/mL at Week 8, 
with subsequent confirmation, unless plasma HIV-1 RNA is <200 c/mL.  
o
Confirmed plasma HIV-1 RNA 1000 c/mL at Week 12.
o
Confirmed plasma HIV-1 RNA 200 c/mL on or after Week 24. 

Virologic Rebound Criteria: 
o
Confirmed rebound in plasma HIV-1 RNA to 200 c/mL after prior suppression to 
<200 c/mL.
 
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7.3.1.
Confirmatory testing of virologic non-response:
The participant must have received full doses of study treatment for at least two weeks at 
the time confirmatory plasma HIV-1 RNA is conducted, if at all possible. DTG + 3TC 
FDC (or current ART regimen) should continue to be administered and no additional 
ART should be added during re-testing.
Upon notification that a participant’s HIV-1 RNA plasma level initially meets one of the 
above criteria, the investigator should query the participant regarding intercurrent illness, 
recent immunization, interruption of therapy or inadequate adherence.
All cases meeting “virologic management” criterion must be confirmed by a second 
measurement performed at least two weeks but not more than 4 weeks apart from 
the date of the original sample, unless delay is necessary to meet the requirements of 
confirmatory HIV-1 RNA testing as outlined below.  
The following guidelines should be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled 2-4 weeks following resolution of any 
intercurrent illness, during which time the participant should receive full dose of all 
antiretrovirals in the regimen.

Confirmatory testing should be scheduled at least 4 weeks following any 
immunization, during which time the participant should receive full dose of all 
antiretrovirals in the regimen.

If therapy is interrupted due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2-4 weeks following resumption of 
full dose of all antiretrovirals in the regimen.

The participant should have received full doses of study interventions for at least 
2 weeks at the time confirmatory plasma HIV-1 RNA is done.  
Sites should contact the Medical Monitor to discuss individual participants, whenever 
necessary.
7.3.2.
Management of Virologic Non-Response
Once a participant has been determined as meeting a protocol defined virologic failure 
criterion, a plasma sample from the Suspected Virologic Failure time point, will be sent 
for genotypic and phenotypic HIV-1 resistance testing and the result made known to the 
study investigator when available to advise on a new ARV-regimen.  Plasma samples 
from storage will also be obtained at unscheduled visits including the time of Confirmed 
Virologic Failure criteria.
Plasma HIV-1 RNA values determined by the central laboratory only will be used to 
assess virologic management criteria.  Upon notification that a participant’s HIV-1 RNA 
plasma level qualifies him/her as meeting a virologic failure criterion, the Investigator 
 
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should query the participant regarding intercurrent illness, recent immunisation, 
adherence, or interruption of therapy.  
Participants may continue to receive study intervention at the discretion of the 
investigator until results of HIV-1 resistance testing are available.  Based on the results of
the resistance testing, the ART regimen may be modified (see Section 7.2.2). 
When the Investigator is modifying a participants ART regimen between scheduled 
visits, the study assessments shown in the SoA in Section 1.3.1 should be followed.  
A participant who meets virologic failure criterion (Section 7.3) can remain in the study.  
Selection of ART regimen for participants meeting confirmed virologic failure criteria 
will be recorded in the eCRF.  
The protease (PRO)/reverse transcriptase (RT)/integrase assays used in this study are not 
validated for plasma HIV-1 RNA levels <500 c/mL.  Nevertheless, for all participants 
who meet confirmed virologic failure criteria, plasma samples will be analysed in an 
attempt to obtain genotype/phenotype data on samples with HIV-1 RNA ≥200 c/mL, as 
possible.  Participants with confirmed HIV-1 RNA levels between 200 c/mL and 
<500 c/mL should be transitioned off study intervention within 30 days even if no HIV-1 
resistance mutation results become available, as genotype/phenotype data may not be 
reliably generated from plasma samples collected from these participants.  
Participants who meet a suspected or confirmed virologic failure can remain in the study.  
For participants meeting confirmed virologic failure, “Meeting Confirmed Virologic 
Failure” will be recorded in the eCRF as reason for the modification to a new ARV-
regimen. 
If a participant is prematurely discontinued from participation in the study, the 
Investigator must make every effort to perform the evaluations outlined in the Schedule 
of Activities.  These data will be recorded, as they comprise an essential evaluation that 
needs to be done before discharging any participant from the study.
7.4.
Other Additional Intervention Criteria:
Participants that meet any of the following criteria should discontinue DTG + 3TC FDC 
and will remain in the study.  The Investigator and Medical Monitor should consult on 
how to medically manage these participants.

A pregnancy (intrauterine) detected in the first trimester, should have DTG + 3TC 
FDC immediately discontinued and an alternative regimen that does not contain DTG 
should be started unless no suitable alternative is available [DHHS, 2018].
Pregnancies detected after the first trimester may continue DTG + 3TC FDC.  All 
participants will remain in the study and will be followed until completion of 
pregnancy.  As a reminder, participants of childbearing potential (POCBP) who 
change their minds and desire to be pregnant, or who state they are no longer willing 
to comply with the approved pregnancy avoidance methods, should have DTG + 3TC 
FDC discontinued and start an alternate ART regimen. 
 
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
Liver toxicity where stopping criteria are met and no compelling alternate cause is 
identified, these participants will discontinue study treatment and will continue in the 
study (see Section 10.6). 

Renal toxicity criteria are met, and no compelling alternate cause is identified (see 
Section 10.4.1.3);

Grade 4 clinical AE considered causally related to study drug;

Allergic reaction or rash criteria are met, and no compelling alternate cause is 
identified.

The participant requires concurrent prohibited medications during the course of the 
study.  The participant will discontinue study treatment and may remain in the study.
7.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Discontinuation of study intervention for abnormal liver tests is required when:
o
a participant meets conditions outlined in Section 10.6.
o
when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.
Liver Safety Required Actions and Follow up Assessments can be found in Section 10.6.
7.5.1.
Temporary Discontinuation
Participants may have a temporary interruption to their study intervention for 
management of toxicities.  Such interruption of study intervention does not require 
withdrawal from the study.  However, consultation with the Medical Monitor is required.  
Start and stop dates of study treatment and reason for temporary interruption will be 
recorded in the eCRF.
7.5.2.
Study Intervention Restart 
If participant meets liver chemistry stopping criteria do not restart the participant with 
study intervention unless:

ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted,
 
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
Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the participant.

Refer to Section 10.6.2 for full guidance.
If GSK/ViiV Medical Governance approval to restart/re-challenge participant with study
intervention is not granted, then participant must discontinue study intervention and may 
continue in the study with alternate ART interventions. 
7.6.
Participant Discontinuation/Withdrawal from the Study
Participants may be discontinued from the study for any of the following reasons:

Participant or Investigator non-compliance;

A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance or administrative reasons. This is expected to be uncommon.
At the time of discontinuing from the study, if possible, an early Withdrawal Visit should 
be conducted, as shown in the SoA (Section 1.3). The SoA has the data to be collected at 
the time of study discontinuation and follow-up and for any further evaluations that need 
to be completed.
The participant may be permanently discontinued both from the study intervention and 
from the study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.

At the request of, GSK or ViiV Healthcare;

The participant requires concurrent prohibited medications during the course of the 
study (Section 10.7).  The participant may remain in the study if in the opinion of the 
Investigator and the medical monitor, such medication will not interfere with the 
conduct or interpretation of the study or compromise the safety of the participant.  
Alternatively, the participant can have study intervention discontinued and remain in 
the study with additional ART interventions.
Refer to the SoA (Section 1.3) for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed.
All data from the Withdrawal Visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any participant from the study.  An in-
clinic Follow-Up Visit will be conducted 4 weeks after the last dose of study medication 
for participants with ongoing SAEs regardless of attributability, and any laboratory 
abnormalities that are considered to be AEs or potentially harmful to the participant (as 
defined in Section 2.3.1), at the last on-study visit.  The investigator, in consultation with 
 
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the medical monitor, should follow-up with the participant until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up.
Participants are not obligated to state the reason for withdrawal.  However, a reason for 
withdrawal must be documented by the Investigator on the Completion/Withdrawal 
section of the electronic case report form (eCRF).  Every effort should be made by the 
Investigator to follow-up participants who withdraw from the study. 
7.7.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA in Section 1.3. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for Screening/Day 1
purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.
 
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Screening/Day 1 Assessments
Written informed consent must be obtained from each potentially eligible participant by 
study site personnel prior to the initiation of any Screening procedures as outlined in this 
protocol.  The consent form must have been approved by the IRB.  After signing an 
informed consent, participants will complete Screening assessments to determine 
participant eligibility. Each participant being screened for enrolment evaluation will be 
assigned a participant number at this Visit. This number will be given sequentially in 
chronological order of participant presentation according to a numeric roster provided by 
PPD.
Eligibility criteria must be assessed carefully at the Screening/Day 1 Visit (Section 5.1
and Section 5.2).  Physical examinations should be conducted as part of normal routine 
clinical care but will not be collected systematically in the eCRF.  Cardiovascular 
medical history/risk factors, including vital signs (as detailed in the eCRF) will be 
assessed and assessments will include height, weight, blood pressure, smoking status and 
history, pertinent medical conditions (e.g., hypertension, diabetes mellitus), and family 
history of premature cardiovascular disease.  Background information to be collected 
includes demography (year of birth, sex at birth and current reported gender, race and 
ethnicity), prior PEP/PrEP history, medical history and current medical conditions, 
menopause history, concomitant medications, and an assessment of CDC HIV-1 
classification, as detailed in Section 1.3.
Participants are considered HIV-1 infected when they have positive results from 2 
different HIV Rapid tests (different assay or manufacturer), or they are positive with an 
FDA-approved antigen/antibody combination immunoassay (4th generation assay) or an 
FDA approved HIV antibody immunoassay that detects HIV-1 and HIV-2 antibodies (3rd
generation assay) confirmed by an FDA-approved antibody immunoassay that 
differentiates HIV-1 antibodies from HIV-2 antibodies or an HIV western blot or an 
HIV-1 RNA.  See Inclusion Criteria for additional information (Section 5.1).

For participants who are referred to the study site with a single positive Rapid 
HIV test, a second and different Rapid HIV test should be conducted.  If the 
second Rapid HIV test is nonreactive, the participant is presumed to be HIV-
negative. If both tests are reactive, the participant is confirmed HIV-infected.
Medical records/Source documents from external testing centers or medical 
facilities must be received, reviewed and included in the site source documentation 
to confirm participant has a new diagnosis of HIV-1 infection.
Other Screening/Day 1 information to be collected prior to the first dose of study 
intervention includes assessment of HIV risk factors and mode of transmission, general 
medical history and current medical conditions.  Laboratory and health outcomes 
assessments will also be collected.  Questionnaire/surveys are recommended to be 
administered at the beginning of the visit before any other assessments are conducted.  
Refer to the SoA Section 1.3 for a summary of all procedures at the Screening/Day 1 
Visit.
 
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Week 1 Review of Baseline laboratory results
The Investigator should review the Screening/Day 1 laboratory findings as they become 
available and schedule a study visit (Week 1 Visit).   
A review of creatinine clearance and HBV surface antigen (HBsAg) or HBV core 
antibody (anti-HBc), and HBV DNA if available, (if not available at Week 1, review at 
Week 4) and grade 3 or 4 laboratory abnormalities should be completed to determine if 
the participant should stop study intervention and initiate an alternate ART regimen (see 
Section 7.2.1). 
Subjects Co-infected with Hepatitis B Virus (HBV) 

Investigators should consult current treatment guidelines [Saag, 2018]) and Section 
7.2.1 when considering choice of ART regimen for subjects with chronic HBV 
infection (HBsAg positive OR anti-HBc positive with HBV DNA present).  

In addition, clinical trial and marketed use of 3TC, FTC and TDF have shown that 
some subjects with chronic HBV disease may experience clinical or laboratory 
evidence of recurrent hepatitis upon discontinuation of 3TC, FTC or TDF, which may 
have more severe consequences in subjects with decompensated liver disease.  
Subjects with HBV co-infection should be advised against self-discontinuation of any 
medications with anti-HBV activity.  If 3TC, FTC, TDF or TAF is discontinued in 
subjects co-infected with HBV, periodic monitoring of both liver chemistry tests and 
markers of HBV replication should be performed. 

Entecavir and telbivudine are permitted, in appropriate clinical situations, for 
treatment of hepatitis B (e.g. prior intolerance or viral resistance to TDF or TAF, viral 
resistance to 3TC/FTC) after discussion and agreement between the investigator and 
the medical monitor.  
Subjects Co-infected with Hepatitis C Virus (HCV) 

Investigators should consult current treatment guidelines when considering choice of 
therapy for subjects with chronic HCV infection.  

For participants with a requirement for HCV therapy during the conduct of the study, 
the Investigator must consult with the medical monitor.  HCV treatment based on 
interferon or any other medications that have a potential for adverse drug-drug 
interactions with study treatment, is prohibited during the conduct of the study.  
Review of Resistance Mutation Data when available (Week 4)
A visit should be scheduled when the central laboratory data from Screening/Day 1
genotypic HIV-1 drug resistance mutation data are available (Week 4) and additional 
intervention should be performed if required (see Section 7.2.2).  The investigator should 
also review the tolerance to DTG + 3TC FDC, AEs, assess adherence to study treatment 
and enforce the importance of adherence.  
 
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At Week 8, if the decrease HIV-1 RNA is less than 2.0 log10 c/mL, a plasma HIV-1 
RNA retest should be scheduled 2-4 weeks later, unless plasma HIV-1 RNA is <200 
c/mL; after the retest the Investigator in consultation with the Medical Monitor should 
determine if a modification in ART intervention is warranted.
If a subject requires a regimen modification (e.g., based on Baseline labs or a Confirmed 
Virologic Failure), a plasma HIV-1 RNA retest should be scheduled 4 weeks after the 
regimen modification (Section 1.3.1).  Post the retest, the participant should continue the 
regular study visit schedule.
Participants who have an ART modification due to Baseline laboratory or HIV-1 
resistance data as described in Section 7.2.1 and Section 7.2.2, respectively, and require 
subsequent modification(s) will remain in the study.  
8.1.
Efficacy Assessments
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Schedule of 
Activities (Section 1.3).  Methods to be used may include but are not limited to the 
Abbott Realtime HIV-1 Assay lower limit of quantitation 40 c/mL.  In some cases, (e.g., 
where the plasma HIV-1 RNA is below the lower limit of detection for a given assay) 
additional exploratory methods may be used to further characterize plasma HIV-1 RNA 
levels.
See Section 7.3 (Virologic Failure Criteria) for HIV-1 RNA re-test criterion.
Lymphocyte Subsets
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage, and absolute CD4+ and CD8+ lymphocyte counts, 
CD4+/CD8+ ratio) according to the Schedule of Activities (Section 1.3).
CDC HIV-1 Classification and HIV Associated Conditions
HIV-associated conditions will be recorded as per the Schedule of Activities 
(Section 1.3).  HIV associated conditions will be assessed according to the 2014 CDC 
Revised Classification System for HIV Infection in Adults (see Section 10.9).  When 
assessing CDC stage at Screening/Day 1, consider only the latest available CD4+ T-cell 
count, except when the participant had an active Stage 3 event. Indicators of clinical 
disease progression are defined as:
CDC Stage 1 at enrolment → Stage 3 event;
CDC Stage 2 at enrolment → Stage 3 event;
CDC Stage 3 at enrolment → New Stage 3 Event;
CDC Stage 1, 2 or 3 at enrolment → Death.
 
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8.1.1.
Primary Efficacy Endpoint
The primary endpoint will be the proportion of participants with plasma HIV-1 RNA 
<50 c/mL at Week 24, regardless of ART Regimen (Observed Analysis) (see 
Section 9.5).
8.1.2.
Secondary Efficacy Endpoints

Proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 48, 
regardless of ART Regimen (Observed Analysis).

Proportion of participants with plasma HIV-1 RNA <50 c/mL at Weeks 24 and 48
using the FDA Snapshot algorithm.

Time to suppression of HIV-1 RNA <50 c/mL.

Proportion of participants who modify first line regimen of DTG + 3TC FDC due to 
Baseline lab or HIV-1 resistance mutation data (see Section 7.2).

Change from Baseline in CD4+ cell counts and CD4+/CD8+ ratio at Week 24 and 
Week 48.

Incidence of disease progression (HIV-associated conditions, AIDS and death).
8.2.
Safety Assessments

Incidence and severity of AEs and laboratory abnormalities.

Proportion of participants who discontinue treatment due to AEs and drug-related 
AEs over 48 weeks of treatment
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations
A brief physical examination at the Screening/Day 1 Visit will include, at a minimum, 
assessments of the [e.g., skin, lungs, cardiovascular system].  Investigators should pay 
special attention to clinical signs related to previous serious illnesses.
Physical exams should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF.  Abnormalities noted during any exam must be 
recorded in the eCRF (e.g. in the current medical conditions or AE logs).
8.2.2.
Vital Signs

At the Screening/Day 1 Visit, vital signs will be measured in semi-supine position 
after 5 minutes rest and will include height, weight, systolic and diastolic blood 
pressure and Body Mass Index (BMI). Vital signs and body weight will also be 
assessed at each visit according to the Schedule of Activities (SoA) (Section 1.3).
 
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8.2.3.
Clinical Safety Laboratory Assessments
Refer to Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency. 

All protocol required laboratory assessments must be performed by central 
laboratory services.  Laboratory assessments must be conducted in accordance with 
the Laboratory Manual, and SoA (Section 1.3). Laboratory requisition forms must 
be completed, and samples must be clearly labelled with the participant number, 
protocol number, site/centre number, and visit date. Details for the preparation and 
shipment of samples will be provided by Q2 Solutions and are detailed in the 
laboratory manual.  Reference ranges for all safety parameters will be provided to 
the site by Q2 Solutions.

If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification) the results must be recorded in the eCRF.

Labs will be graded automatically by the central laboratory according to the DAIDS 
toxicity scales (See Section 10.8 “Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events”).

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 days after the last dose of study intervention 
should be repeated until the values return to normal or Baseline or are no longer 
considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/Baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

Refer to the SRM for appropriate processing and handling of samples to avoid 
duplicate and/or additional blood draws.

Haematology, clinical chemistry, urinalysis and additional parameters to be tested 
are listed in Section 10.2. 
8.2.4.
Suicidal Ideation and Behaviour Risk Monitoring
Participants with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour).  In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in people with a 
pre-existing history of depression or psychiatric illness) in some people being treated 
with INIs, including DTG.  Therefore, it is appropriate to monitor and closely observe 
 
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participants prospectively before and during treatment for suicidal ideation and/or 
behaviour, or any other unusual changes in behaviour.  
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behaviour or any other unusual changes in behaviour. Investigator must assess 
participant suicidality using their usual clinical practice.  It is recommended that the 
investigator consider mental health consultation or referral for participants who 
experience signs of suicidal ideation or behaviour. Participants presenting with new 
onset/treatment emergent depression should be advised to contact the investigator 
immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the study 
medication may be required.
The investigator will collect information using the Possible Suicidality-Related AE 
(PSRAE) eCRF form in addition to the AE (non-serious or SAE) eCRF form on any 
participant that experiences a possible suicidality-related AE while participating in this 
study.  This may include, but is not limited to, an event that involves suicidal ideation, a 
preparatory act toward imminent suicidal behaviour, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly suicide-related. PSRAE forms should be 
completed and reported to ViiV/GSK within 1 week of the investigator diagnosing a 
possible suicidality-related AE. All sites should have a plan in place for managing 
possible risks for suicide related events.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Section 10.3.1 and Section 10.3.2, 
respectively.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see Section 7.2
and Section 7.4).
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information
The time period and frequency for collecting AE and SAE information is as follows:

All SAEs will be collected from the start of intervention until the Follow-up Visit at 
the time points specified in the SoA (Section 1.3).  However, any SAEs assessed as 
related to study participation (e.g., study intervention, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a ViiV/GSK product will 
be recorded from the time a participant consents to participate in the study.

All AEs will be collected from the start of study intervention until the Follow-up 
Visit, at the time points specified in the SoA (Section 1.3).
 
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
Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 10.3. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion of 
the study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor.
8.3.2.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 2.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.7). Further information on follow-up procedures is given in Section 10.3.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB) and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB, if appropriate according to local requirements.
 
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8.3.5.
Pregnancy
Details of all pregnancies in participants will be collected after the start of study 
intervention and ending at the final Follow-up Visit.  If a pregnancy is reported, the 
investigator should inform ViiV/GSK/PPD within 24 hours of learning of the pregnancy 
and should follow the procedures outlined in Section 10.5.3.  Participants who become 
pregnant and are in the first trimester should immediately discontinue DTG + 3TC FDC 
and an alternate ART regimen that does not contain DTG should be started, unless no 
suitable alternative is available, in consultation with the Medical Monitor.  If the 
pregnancy is after the first trimester, the participant can continue study treatment.  Any 
participant who becomes pregnant during the study can remain in the study, including 
those who needed to modify the ART Regimen.  
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. The pregnancy must be followed up to determine outcome 
(including premature termination) and status of mother and child(ren). Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or 
SAE.  Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and must be reported.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the participant has completed the study and considered by the investigator 
as possibly related to the study intervention must be reported promptly to ViiV/GSK (or 
designee).

GSK’s central safety department will forward this information to the ART Pregnancy 
Registry.  The international registry is jointly sponsored by manufacturers or 
licensees of ARV products.  Additional information and a list of participating 
manufacturers/licensees are available from http://www.apregistry.com/.  
8.3.6.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 10.3.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
 
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8.3.7.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
The events or outcomes listed in the CDC Classification System for HIV-1 Infections 
(Section 10.9) will be recorded on the HIV-Associated Conditions eCRF page if they 
occur. However, these individual events or outcomes, as well as any sign, symptom, 
diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these 
events or outcomes are not reported to ViiV/GSK as AEs and SAEs even though such 
event or outcome may meet the definition of an AE or SAE, unless the following 
conditions apply:

The investigator determines that the event or outcome qualifies as an SAE under part 
‘f’ of the SAE definition (see Section 10.3), or

The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual participant, or

Death occurring for any reason during a study, including death due to a 
disease-related event, will always be reported promptly.

Lymphomas and invasive cervical carcinomas are excluded from this exemption; they 
must be reported as SAEs even if they are considered to be HIV-related.
8.4.
Treatment of Overdose
For this open-label study, any tablet intake exceeding the daily tablet of DTG + 3TC 
FDC will be considered an overdose [TIVICAY Product Insert, 2018; EPIVIR Product 
Information, 2018].  ViiV Healthcare does not recommend specific treatment for an 
overdose of DTG + 3TC FDC. As appropriate, the Investigator should use clinical 
judgment in the treatment of an overdose.
For the purposes of this study, an overdose is not an AE unless it is accompanied by a 
clinical manifestation associated with the overdose.  If the clinical manifestation presents 
with serious criteria, the event is a SAE (see Section 10.3).  If an overdose occurs and is 
associated with an adverse event requiring action, all study medications should be 
temporarily discontinued until the adverse event resolves.
In the event of an overdose, the investigator or treating physician should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
DTG + 3TC FDC can no longer be detected systemically (at least 2 days).
3. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
 
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8.5.
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not being evaluated in this study.
8.9.
Health Economics and Outcome Research
Health outcomes assessments will be conducted according to the SoA (Section 1.3). In 
the event of translations being unavailable, no such assessments will be conducted, and 
the responses will be considered as missing in the final analyses. Assessments are 
recommended to be administered at the beginning of the visit prior to collection of blood 
for analysis and other scheduled assessments.  
Questionnaires will be administered on paper and should be completed by participant 
without the assistance of others where possible.  If a subject is unable to read, it is 
acceptable for site personnel to read the questions and response options directly as 
written with no further interpretation or assistance.  In these situations, subject must 
clearly indicate their responses which may be recorded on paper form by site personnel.
Sites should enter participant responses into eCRF and retain the paper forms in the 
participants chart.  
The following health outcomes assessment will be utilized in this study:
The Symptom Distress Module (also called the HIV Symptom Index or Symptoms 
Impact Questionnaire) is a 20-item self-reported measure that addresses the presence and 
perceived distress linked to symptoms commonly associated with HIV or its treatment 
[Justice, 2001].
8.10.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each participant to provide plasma 
for storage samples according to the Schedule of Activities in Section 1.3 (for potential 
viral genotypic and phenotypic analyses).  Participants meeting Confirmed Virologic 
Failure criteria or having HIV-1 resistance mutations to study drugs detected at Baseline
will have plasma samples tested for HIV-1 PRO and RT genotype and phenotype and 
HIV-1 integrase genotype and phenotype from samples collected at the time of meeting 
Suspected Virologic Failure criteria; these results will be reported to the investigator as 
 
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soon as available to provide guidance for selection of an alternative regimen (see 
Section 7.3)
Details concerning the handling, labelling and shipping of these samples will be supplied 
separately.  Genotypic and phenotypic analyses may be carried out by Monogram 
Biosciences using, but not limited to, their Standard PhenoSense and GenoSure testing 
methods for PRO, RT, and integrase assays.
A secondary endpoint of the study will be the incidence of observed genotypic and 
phenotypic resistance to DTG or 3TC in participants meeting Confirmed Virologic 
Failure criteria.  If participants meet a second Confirmed Virologic Failure after initiating
a new ART regimen during the study, susceptibility to any ART therapy received will 
also be assessed.  
8.10.1.
HIV-1 Exploratory Analysis
HIV-1 exploratory analysis may be carried out for participants meeting virologic failure 
criteria, and for all participants to more broadly assess the contribution of Baseline 
genotypic information on study results.  These tests may be carried out on whole blood or 
stored plasma samples collected at Baseline and/or from other relevant time points as 
long as this is feasible per local country and laboratory practices.  These exploratory tests 
and analyses may include but are not limited to additional viral genotyping and/or 
phenotyping, as well as other virologic evaluations such as linkage and minority species 
analyses, low level HIV-1 RNA quantitation, viral DNA quantitation, and measurement 
of viral replicative capacity.  
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
This is a single arm study; no formal statistical hypothesis will be tested.
9.2.
Sample Size 
The study will recruit approximately 120 individuals.  It is expected around 150 
individuals to be screened to meet this number of enrolled individuals.  If less than 120 
individuals have been enrolled after 150 individuals have been screened, screening will 
continue until enrolment of approximately 120 individuals is met. 
9.2.1.
Sample Size Considerations
This is a single-arm study with no statistical testing being performed therefore the sample 
size is not statistically powered.  The study will enrol approximately (±5%) 120 HIV-1 
treatment naïve individuals.  The sample size of 120 participants allows estimation of the
response rate at Weeks 24 and 48 (i.e. HIV-1 RNA <50 c/ml), with precision shown in 
Table 2, assuming a high number of participants (i.e. ≥80% of participants) will be 
responders.  Table 2 shows the estimated response rate, 95% Confidence Interval (CI) 
based on the Clopper-Pearson method and precision measured by 95% CI width,
assuming various numbers of responders for the given sample size of 120 participants. 
 
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Table 2
Estimated Response Rate, 95% Confidence Interval and precision 
assuming various number of responders
Sample 
Size
Number of 
Responders
Response 
Rate
95% Confidence 
Interval
Precision
(95% CI Width)
120
96
80%
71.7% - 86.7%
15.0%
120
102
85%
77.3% - 90.9%
13.5%
120
108
90%
83.2% - 94.7%
11.5%
120
114
95%
89.4% - 98.1%
8.7%
9.2.2.
Sample Size Sensitivity
Figure 2 shows sensitivity of expected response rate precision (measured by the width of 
the 95% CI) versus sample size, assuming four population response rates (i.e. 80%, 85%, 
90% and 95%).  Note that a much larger sample size than 120 participants is required to 
achieve higher precision in the estimated response rate for all four assumed observed 
rates.  For example, to get a ~40% more precise response rate estimate (for any of the 
four assumed response rates) a sample size of ~300 participants is needed.
Figure 2
Sample Size Sensitivity
Figure 2: Expected precision (measured by 95% CI width) of estimated proportion of 
participants with HIV-1 RNA < 50 c/mL assuming four population response rates (i.e. 80%, 
85%, 90%, 95%) versus sample size.  Clopper-Pearson 95% CI widths have been calculated.  
The vertical grey dash line corresponds to a sample size of 120 participants which is the 
sample size used in the current study.
 
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9.3.
First-line DTG + 3TC FDC Regimen Modification
Participants meeting any of the safety criteria described in Section 7.2.1 (i.e. Creatinine 
clearance of <30 mL/min/1.73m2, evidence of active HBV infection, Grade 3 or 4 
laboratory abnormality) will be evaluated for potential modification in their current first 
line DTG + 3TC FDC treatment and participants with Screening/Day 1 genotypic data 
that confer resistance to 3TC (e.g. M184V/I, K65R etc.) or with DTG primary resistance 
associated mutation will discontinue study treatment.  Assuming that the probability a 
participant to have a modification from first line DTG + 3TC FDC regimen because of 
any of the above reasons ranges from 1% to 5%, the probability at least one participant to 
modifying ART because of the above reasons ranges from 70% to 100%, assuming a 
sample size of 120 participants.
9.4.
Data Analysis Considerations 
9.4.1.
Analysis Populations
For purposes of analysis, the following populations are defined:
Table 3
Analysis Populations
Population
Description
Enrolled
All participants who sign the ICF
Intent to Treat Exposed 
(ITT-E)
All participants who receive at least one dose of study drug. This 
population will be used in all efficacy analyses.
Safety
This population will be the same as the ITT-E population and will be 
used in all Safety analyses
The analysis populations for genotypic and phenotypic analyses and other populations 
potentially needed for other analyses will be fully described in the reporting and analysis 
plan (RAP).
9.5.
Key Elements of the Analysis Plan
9.5.1.
Efficacy Analysis
Primary analysis will be conducted when all Week 24 assessments have been performed 
at the Week 24 Visit, including any viral load re-test, if needed.
The primary analysis will be the proportion of participants with plasma HIV-1 RNA 
<50 c/mL at Week 24 Visit, regardless of the ART regimen (Observed Analysis).
 
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The primary Week 24 Observed Analysis will classify participants into Virologic Success 
or Virologic Failure categories as follows: 
Virologic Success
Participants with HIV-1 RNA < 50 c/mL at Week 24 will be classified as Virologic 
Successes irrespective of the ART regimen they take at Week 24 (switch from DTG 
+ 3TC FDC to another ART is not penalised); re-test at Week 24 will be considered. 
Virologic Failure
The following cases will be classified as Virologic Failure:

Participants with plasma HIV-1 RNA ≥ 50 c/mL at Week 24 (re-test 
considered)

Participants with missing plasma HIV-1 RNA assessment at Week 24, but 
still on study

Participants who withdrew from study for any reason before Week 24 visit
Further details of the primary analysis will be provided in the RAP.
9.5.2.
Secondary Analyses
Analysis of proportion of participants with HIV-1 RNA <50 c/mL at Week 48 Visit, 
regardless of the ART Regimen (Observed Analysis, similar to the primary analysis at 
Week 24).
Analysis of proportion of participants with plasma HIV-1 RNA <50 c/mL at Week 24 
and Week 48, using the FDA’s Snapshot algorithm.
FDA’s Snapshot algorithm will classify all participants without plasma HIV-1 RNA data 
at the visit of interest, i.e. Week 24/48, either due to missing plasma HIV-1 RNA 
assessment but on study, or due to permanent discontinuation of study treatment prior to 
visit window as Virologic non-Success.  Participants who will switch from first line 
regimen of DTG + 3TC FDC for any reason prior to the visit of interest will also be 
classified as Virologic non-Successes.  Participants still on DTG + 3TC FDC at the time 
of last HIV-1 RNA assessment at the visit interest will be classified as Virologic 
Successes if plasma HIV-1 RNA < 50 c/mL, or as Virologic Failures if plasma HIV-1 
RNA ≥50 c/mL.
Full details of the FDA’s Snapshot algorithm will be provided in the RAP. 
Other key efficacy secondary analyses:

Proportion of participants with ART modifications from the first line regimen due 
to abnormal Baseline laboratory or Baseline genotypic resistance data.  Proportion 
of participants with a modification from the first line regimen due to any reason.
 
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
The incidence of HIV-1 disease progression (AIDS and death). 

Subgroup analyses of proportion of participants with plasma HIV-1 RNA 
<50 c/mL using the Observed Analysis and changes from Baseline in CD4+ cell 
count will be summarised by age, gender, race, Baseline CD4 counts and Baseline 
HIV-1 RNA levels.

A time to event analysis for the time to first HIV-1 RNA < 50 c/ml. 
Full details of all secondary efficacy endpoints will be provided in the RAP.
Given that participants are allowed to remain in the study after ART modification (e.g.
due to Baseline laboratory or HIV-1 resistance mutation results, meet Suspected or 
Confirmed Virologic Failure criteria, toxicity etc.) or protocol deviations (e.g. 
administration of prohibited medication, first trimester pregnancy etc.) a very small 
number of early study withdrawals is expected (mainly due to lost to follow-up or 
withdraw consent).  Data will be allocated to visit windows using actual visit dates rather 
than nominal visit dates.  Data collected from extra visits within a visit window will be 
listed and will be included in the derivation of the Observed and Snapshot response at 
analysis visits of interest, but summary tables (e.g. change in CD4+) using observed case
datasets will only use the data captured closest to the target visit date.  Detailed 
explanations of the definition of visit windows will be included in the RAP.  Any 
deviations from planned analyses will be detailed in the clinical study report (CSR).
9.5.3.
Safety Analyses
The observed case dataset will be the primary dataset used for analysis of safety 
endpoints.  All safety analyses will be based on the Safety analysis population.
All Safety analyses will be based on period under treatment with DTG + 3TC FDC.  In 
addition, selected safety endpoints will also be analysed including data after participants 
have ART modifications from DTG + 3TC FDC. 
Exposure to first line regimen of DTG + 3TC FDC, measured by the number of weeks on 
study drug, will be summarized. 
The proportion of participants reporting AEs will be tabulated.  The following summaries 
of AEs will be provided for AEs with onset under treatment with DTG + 3TC FDC (i.e. 
AEs occurred after DTG + 3TC FDC modification will be excluded) at the analysis time 
period:
o
Incidence and severity of all AEs;
o
Incidence and severity of treatment related AEs;
o
Incidence and severity of AEs leading to withdrawal; and
o
Incidence of SAEs.
 
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In addition, the following summaries of AEs will be provided including those occurring 
after treatment modification from DTG + 3TC FDC:
o
Incidence and severity of all AES;
o
Incidence and severity of treatment related AEs;
o
Incidence and severity of AEs leading to withdrawal; and
o
Incidence of SAEs
Laboratory and vital signs data will be summarised by visit including data under 
treatment with DTG + 3TC FDC (i.e. data after ART modification to be excluded) only.  
In addition, the number and percentage of participants with graded laboratory toxicities 
(based on DAIDS categories; Section 10.8) will be summarised for those occurring when 
under treatment with DTG + 3TC FDC and for the overall period under study treatment 
(i.e. data after DTG + 3TC FDC modification to be considered).  Further details of safety 
analyses will be included in the RAP.
9.5.3.1.
Viral Genotyping/Phenotyping Analyses 
The incidence of treatment-emergent genotypic and phenotypic resistance to DTG and 
3TC will be summarised for participants meeting Confirmed Virologic Failure criteria 
(Section 7.3).  Details of genotypic/phenotypic analyses to be performed will be specified 
in the RAP.
9.5.4.
Other Analyses
The Symptom Bother analysis will be described in the reporting and analysis plan.  
9.6.
Interim Analyses
One analysis will be conducted to evaluate the primary objective of the protocol when all 
subjects have completed their Week 24 Visit.
A Week 12 interim analysis may be conducted after the last participant completes the 
Week 12 Visit.  It is not required for participants to have completed a Week 12 viral load 
re-tested, if needed, for this analysis.  The main purpose of the analysis, if conducted, will 
be to assess the proportion of participants that required a modification in the first line 
ART regimen, following the evaluation of Baseline laboratory and Baseline genotypic 
resistance mutation results.  Results of the potential Week 12 analysis may be publicly 
presented before the publication of primary Week 24 results. There are no planned 
modifications to the study based on the interim analysis results.  
A Week 48 analysis will be conducted when all participants have had their Week 52 Visit 
and follow-up visit (if required).  This includes any visits for viral load re-test following 
the Week 48 Visit.  The Week 48 analysis will be the last (End of Study) analysis and the 
only planned analysis after the primary Week 24 analysis.  Results from Week 24 and 48 
analyses will be publicly presented.
 
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As the potential Week 12 analysis and the Week 48 analysis are secondary and the study 
is single arm with no statistical hypothesis testing performed, no adjustment for 
multiplicity is needed.
The Reporting and Analysis Plan will describe the planned analyses in greater detail.
 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS 
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB by the investigator 
and reviewed and approved by the IRB before the study is initiated. 

Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB.

Notifying the IRB of SAE or other significant safety findings as required by 
IRB procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
 
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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities.
10.1.5.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
 
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
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.1.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a ViiV/GSK site or other 
mutually-agreeable location.

ViiV/GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the study 
participants, as appropriate.

The procedures and timing for public disclosure of the protocol and results summary 
and for development of a manuscript for publication for this study will be in 
accordance with ViiV/GSK Policy.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data).
The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
 
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Study Report (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).
10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.

Definition of what constitutes source data can be found in the SRM.
10.1.9.
Study and Site Closure
ViiV/GSK or its designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of ViiV/GSK. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents 
and study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
 
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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 4 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same 
time.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 

Refer to Section 5.1 Inclusion Criteria for Screening/Day 1 pregnancy criteria.

Pregnancy testing (urine and/or serum) should be conducted at all study visits. 

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator, to establish the absence of pregnancy at any time 
during the participant's participation in the study.

Study intervention should be discontinued if a pregnancy is detected in the first 
trimester, and the participant can remain in the study on a modified (new, non-
DTG based) ART regimen.  Pregnancies detected after the first trimester can 
continue DTG + 3TC FDC.
 
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Table 4
Protocol-Required Safety Laboratory Assessments
Hematology:
Platelet count
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute)
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
MCH
Clinical Chemistry:
BUN
Potassium
AST
Total bilirubin
Direct bilirubina
Creatinine
Chloride
ALTa
Albumin
Glucose
Total CO2
Alkaline phosphatase
GFR/Creatinine clearanceb
Sodium
Phosphate
Cystatin-C (Day 1 only)
Calcium
Protein
Lipid Panel
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Urinalysis
specific gravity, pH, glucose, protein, blood and ketones by dipstick (with microscopic examination if blood 
or protein is abnormal), urine albumin/creatinine ratio, urine protein/creatinine ratio
Other Tests
Plasma HIV-1 RNAc
CD4+ and CD8+ lymphocyte counts, CD4+/CD8+ cell count ratio
Hepatitis B (HBsAg, anti-HBc, anti-HBs, HBV DNA); HBV 3TC Resistancee, HBV DNAe
Hepatitis C (anti-HCV)
Pregnancy test for participants of childbearing potentiald
HLA B5701 testf
1.
MCV = mean corpuscular volume, MCH = mean corpuscular haemoglobin, RBC = red blood cells, WBC = white 
blood cells, BUN = Blood urea nitrogen, AST=aspartate aminotransferase, ALT = alanine aminotransferase, CO2 = 
carbon dioxide, HDL = high density lipoprotein, LDL = low density lipoprotein, HbsAg= hepatitis B virus surface antigen, 
anti-HBc = Hepatitis B Core Antibody, HBV = Hepatitis B virus.
a)
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.5 and Section 10.6.  Direct bilirubin will be reflexively performed for all 
total bilirubin values >1.5 × ULN.
b)
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI-creatinine) [Levey, 2009]. In addition, GFR will be estimated by the central 
laboratory using the CKD-EPI-cystatin C [Inker, 2012] at Screening/Day 1 and when indicated by renal toxicity 
criteria.
c)
For participants meeting virologic failure criteria, plasma samples and whole blood may be analyzed in attempt to 
obtain genotype/phenotype data.
d)
Urine pregnancy test/ serum pregnancy test will be performed according to the Schedule of Activities. 
e)
For participants with chronic HBV infection, testing for HBV 3TC resistance will be performed using samples from 
Week 1 and Week 4 (depending on when ART modification occurs) as well as Screening/Day 1 samples.  HBV 
DNA will also be obtained at the Week 1 or Week 4 visit.
f)
Please consult with the Medical Monitor.
 
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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
 
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investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:

Results in death

Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
 
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significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
10.3.4.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
 
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related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the categories in the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE Grading 
Table”) in Section 10.8:

Grade 1 / Mild:

Grade 2 / Moderate

Grade 3 / Severe

Grade 4 / Potentially life threatening

Grade 5 / Death
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment [TIVICAY Package Insert, 
 
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2018; EPIVIR Package Insert, 2018; DOVATO Package Insert, 2019].

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to ViiV/GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to ViiV/GSK/PPD.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
ViiV/GSK/PPD to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide ViiV/GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
10.3.5.
Reporting of SAE and other events to ViiV/GSK/PPD
Reporting of SAEs and other events to ViiV/GSK/PPD

The primary mechanism for reporting SAE to ViiV/GSK/PPD will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to study intervention/study participation (causality) within 
 
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72 hours of SAE entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to ViiV/GSK/PPD via Paper CRF

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and scan and email it to the Medical Monitor

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the SRM.
 
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10.4.
Appendix 4: Toxicity Management
Adverse events that occur during the trial should be evaluated by the investigator and 
graded according to the DAIDS toxicity scales (see Section 10.8).  Additional 
information regarding detecting, documenting and reporting AEs and SAEs are available 
in Section 10.3.
Study intervention may be interrupted at the discretion of the investigator and according 
to the severity of the AE. If DTG + 3TC FDC is held due to toxicity or AEs, all 
additional ART medications that were added per protocol, should be held to reduce the 
risk of development of HIV-1 resistance taking into account the length of the planned 
interruptions and the PK half-life of each ART of the regimen, in order to minimize the 
risk of development of resistance.
No toxicity-related dose reductions of study interventions will be allowed.  Study 
intervention should be restarted as soon as medically appropriate; in general, this should 
be no longer than 4 weeks after interruption (unless Grade 3 or 4 toxicities persist).  
Decisions regarding sequential reintroduction of study intervention or temporary 
interruption of one but not all drugs within the ART regimen must be discussed with the 
Medical Monitor and should be made with the understanding that these changes may 
result in incomplete viral suppression and selection of resistant virus.  Guidance is 
provided below on participant management and study intervention interruptions based on 
the severity of the AE for specific toxicities.  All modifications in study intervention must 
be accurately recorded in the participant’s eCRF.
Grade 1 or Grade 2 Toxicity/Adverse Event
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study 
intervention at the discretion of the investigator.  The investigator may also choose to 
discontinue DTG + 3TC FDC and change to an alternate ART and participant can remain 
in the study.  Participants who choose to withdraw from the study due to a Grade 1 or 2 
AE should have the study Withdrawal and Follow-up evaluations completed.
Grade 3 Toxicity/Adverse Event
Participants who develop a Grade 3 AE or toxicity should be managed as follows: 
If the investigator has compelling evidence that the Grade 3 AE or toxicity has not been 
caused by study intervention, dosing may continue after discussion with the medical 
monitor.
Participants who develop a Grade 3 AE or toxicity that the investigator considers related 
or possibly related to the interventions should have study intervention withheld and be 
rechecked each week until the AE returns to Grade 2.  Once the AE is Grade ≤2, study 
intervention may be restarted. 
Should the same Grade 3 AE recur within 28 days in the same participant, study 
intervention should be permanently discontinued, evaluated to have a new ART treatment 
initiated, and can remain in the study.  Participants experiencing Grade 3 AEs requiring 
 
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permanent discontinuation of study intervention should be followed weekly until 
resolution of the AE.  Participants who choose to withdraw from the study should have 
the Follow-up Visit performed 4 weeks after the last dose of study interventions.
Participants with asymptomatic Grade 3 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue study intervention if the investigator has compelling evidence that 
the toxicity is not related to study intervention.
Exceptions are noted for rash in Section 10.4.1.6 and lipid abnormalities in 
Section 10.4.1.7.
Grade 4 Toxicity/Adverse Event
Participants who develop a Grade 4 AE or toxicity should have study intervention 
discontinued.  However, if the investigator has compelling evidence that the AE is not 
causally related to the study interventions, dosing may continue after discussion with and 
assent from the medical monitor.  Participants should be rechecked each week until the 
AE returns to Grade 2.
Participants experiencing Grade 4 AEs requiring permanent discontinuation of study 
intervention should have a new ART regimen initiated and can remain in the study.  
These participants should be followed weekly until resolution of the AE.  Participants 
who choose to withdraw from the study are encouraged to complete the Withdrawal and 
Follow-up evaluations.
Participants with asymptomatic Grade 4 laboratory abnormalities should be investigated 
for all potential non-drug related causes, and, following discussion with the medical 
monitor, may continue therapy if the investigator has compelling evidence that the 
toxicity is not related to study intervention.  Exceptions are noted for lipid abnormalities 
in Section 10.4.1.7.  
An in-clinic Follow-Up Visit will be conducted approximately 4 weeks after the last dose 
of study medication for participants with ongoing AEs, serious adverse events (SAEs) 
regardless of attributability, and any laboratory abnormalities that are considered to be 
AEs or potentially harmful to the participant (as defined in Section 2.3.1), at the last on-
study visit.  The investigator, in consultation with the medical monitor, should follow-up 
with the participant until the event is resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up.
10.4.1.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
related or possibly related to study intervention are provided below. 
Participants who permanently discontinue study intervention for reasons of toxicity may 
remain in the study and have a new ART regimen initiated.  The participant should be 
followed weekly until resolution of the AE.  Participants who choose to withdraw from 
the study are encouraged to complete the Withdrawal and Follow-up evaluations.
 
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10.4.1.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure participant 
safety and to evaluate liver event aetiology during administration of study intervention 
and the follow-up period. For a complete listing of stopping and follow-up criteria refer 
to Section 10.6.1.
10.4.1.2.
Restarting Study Intervention
Refer to Section 10.6.2 for details on drug restart following transient resolving liver 
events not related to study intervention.
10.4.1.3.
Decline in Renal Function
Participants who experience an increase in serum creatinine from Baseline of 
45 micromoles/liter (Mol/L) (or 0.5 milligrams/deciliter [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis, urine albumin/creatinine and 
urine total protein/creatinine ratios, serum cystatin C and an estimated GFR using the 
CKD-EPI (cystatin C) [Inker , 2012] should also be done at this confirmatory visit.  If the 
creatinine increase is confirmed, the investigator should contact the study medical 
monitor to discuss additional follow-up and medical management.
Participants who experience progression to an estimated GFR (using the CKD-EPI-
creatinine) of <30 mL/min/1.73m2 must return for a confirmatory assessment within 
2 weeks [Levey, 2009].  A urinalysis, urine albumin/creatinine and urine 
protein/creatinine ratios, serum cystatin C and an estimated GFR using the CKD-EPI 
(cystatin C) [Inker , 2012] should be done at this confirmatory visit.  If an estimated GFR 
of <30 mL/min/1.73m2 is confirmed using the CKD-EPI (cystatin C), then study 
intervention should be discontinued, and new ART initiated.  
10.4.1.4.
Proteinuria
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, >300 mg/g, or 
>34 mg/mmol) that represents a change from Baseline and no associated increase in 
creatinine, should have a repeat spot urine albumin/creatinine ratio performed within 2-4 
weeks.  If confirmed, then consideration should be given to additional evaluation after 
consultation with the study medical monitor. Additional evaluation may include a 24-
hour urine protein and creatinine measurement and nephrology referral.
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, 300 mg/g, or 
>34 mg/mmol and representing a change from Baseline) and a serum creatinine increase 
>45 μmol/L (or 0.5 mg/dL) should have confirmation of both results within 2 weeks. If 
confirmed, the study medical monitor should be contacted immediately.  Agreement on 
further management should be agreed between the investigator and medical monitor.
Refer to the SPM for details on the collection and processing of these urine samples.
 
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10.4.1.5.
Allergic reaction
Participants may continue study intervention for Grade 1 or 2 allergic reactions at the 
discretion of the Investigator.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop.  Antihistamines, topical corticosteroids, or antipruritic agents 
may be prescribed. 
Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the study intervention should permanently discontinue study 
intervention, and a new ART regimen initiated. Participants should be treated as 
clinically appropriate and followed until resolution of the AE.  Participants who choose to 
withdraw from the study are encouraged to complete the Withdrawal and Follow-up 
evaluations.
10.4.1.6.
Rash
Mild to moderate rash is an expected adverse reaction for DTG-containing ART.  
Episodes generally occur within the first ten weeks of treatment, rarely require 
interruptions or discontinuations of therapy and tend to resolve within two to three weeks.  
No instances of serious skin reaction, including SJS, TEN and erythema multiforme, have 
been reported for DTG in clinical trials.  For further characterisation of HSR and rash 
observed with DTG-containing ART, please see the current version of the IB and any IB 
supplements [DTG IB, 2018; TIVICAY Product Insert, 2018].
Participants with an isolated Grade 1 rash may continue study intervention at the 
Investigator’s discretion.  The participant should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
appear, or if mucosal involvement develops.
Participants may continue study intervention for an isolated Grade 2 rash.  However, 
study intervention (and all other concurrent medication(s) suspected in the Investigators 
causality assessment) should be permanently discontinued for any Grade ≥2 rash that is 
associated with an increase in ALT.  The participant should be advised to contact the 
physician immediately if rash fails to resolve (after more than two weeks), if there is any 
worsening of the rash, if any systemic signs or allergic symptoms develop, or if mucosal 
involvement develops.
Participants should permanently discontinue study intervention [and all other concurrent 
medication(s) suspected in the Investigators causality assessment] for an isolated Grade 3 
or 4 rash, except where the aetiology of the rash has been definitively diagnosed as NOT 
attributable to study intervention (see below).  Participants should be treated as clinically 
appropriate and followed until resolution of the AE.  Every effort should be made to 
collect as much information as possible about the evolution of the event and any 
relationship with potentially related medical events (e.g., viral infection) or start of 
concomitant medication.  
 
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The rash and any associated symptoms should be reported as adverse events and 
appropriate toxicity ratings should be used to grade the events (based on DAIDS toxicity 
gradings, Section 10.8.
However, if the aetiology of the rash has been definitively diagnosed as being unrelated 
to study intervention and due to a specific medical event or a concomitant infection or a 
concomitant non-study medication, routine management should be performed, and 
documentation of the diagnosis provided. In this situation, the study intervention should 
be continued. 
10.4.1.7.
Hypertriglyceridemia/Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the 
Schedule of Activities (Section 1.3).  Participants who experience asymptomatic 
triglyceride or cholesterol elevations may continue to receive study intervention.
REFERENCE:
Inker LA, Schmid CH, Tighiouart H, Eckfeldt J.H, Feldman H.I, Greene T, et al; 
Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C. N Engl J 
Med. 2012;367:20-9.
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro III A.F, Feldman H.I, et.al. A new 
equation to estimate glomerular filtration rate.  Ann Int Med. 2009;150:604-12.
 
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10.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
10.5.1.
Definitions:
Participants of Childbearing Potential (POCBP)
A female at birth is considered fertile following menarche and until becoming post-
menopausal unless permanently sterile (see below).
Participants who are female at birth in the following categories are not considered 
POCBP
1.
Premenarchal
2.
Premenopausal with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview.
3.
Postmenopausal 

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in participants who 
were females at birth and not using hormonal contraception or hormonal 
replacement therapy (HRT). 

Females at birth on HRT and whose menopausal status is in doubt will be 
required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
10.5.2.
Contraception Guidance:
Participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 
5.
The list does not apply to participants of child bearing potential who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
 
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ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Table 5
List of Highly Effective Contraceptive Methods

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency 

Failure rate of <1% per year when used consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the participant of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulation
oral
injectable

Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant
a.
Contraceptive use by participants should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
1.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)
 
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These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that participants understand how to properly use these methods of contraception.
10.5.3.
Collection of Pregnancy Information:
Participants who become pregnant and are in the first trimester should immediately 
discontinue DTG + 3TC FDC and an alternate ART regimen that does not contain 
DTG should be started, unless no suitable alternative is available, in consultation 
with the Medical Monitor.  If the pregnancy is after the first trimester, the 
participant can continue study treatment.  Any participant who becomes pregnant 
during the study can remain in the study, including those who needed to modify the 
ART Regimen.  

Investigator will collect pregnancy information on any female participant at birth, 
who becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to 
ViiV/GSK/PPD within 24 hours of learning of a participant's pregnancy. 

Participants will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to ViiV/GSK/PPD.  Generally, follow-up will not be required for 
longer than 6 to 8 weeks beyond the estimated delivery date.  GSK’s central safety 
department will forward this information to the Antiretroviral Pregnancy Registry.  
The international registry is jointly sponsored by manufacturers and licensees of 
antiretroviral products.  Additional information and a list of participating
manufacturers/licensees are available from http://www.apregistry.com/.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 

A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age), congenital anomalies, or ectopic 
pregnancy are considered SAEs and must be reported. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Section 10.3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting. 
 
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10.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge 
Guidelines
Study treatment refers to all drugs evaluated in the study and therefore includes ViiV 
study intervention and non-ViiV ART therapies that can be used in combination with 
ViiV products or other ART interventions.
A liver stopping event is an occurrence of predefined liver chemistry changes (ALT, 
bilirubin and or INR) that trigger discontinuation of study treatment and requirement of 
additional actions and follow up assessments to be performed.
A liver monitoring event is as an occurrence of predefined liver chemistry changes (ALT, 
bilirubin and or INR) that triggers increased monitoring of the participant’s liver 
chemistries, but no action is taken with study treatment unless liver chemistry stopping 
criteria are met.
10.6.1.
Liver Chemistry Stopping Criteria:  Required Actions and Follow 
up Assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
If baseline ALT ≤1.5x ULN
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks (with bilirubin <2xULN and no 
signs or symptoms of acute hepatitis or hypersensitivity)
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored every 1 - 2 weeks
Symptomatic3
ALT 3xULN with symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity
If baseline ALT >1.5x ULN
ALT-absolute
ALT ≥5x baseline OR >500 U/L (whichever occurs first)
ALT Increase
ALT ≥3x baseline but <5x baseline persists for ≥2 weeks (with bilirubin <2xULN 
and no signs or symptoms of acute hepatitis or hypersensitivity)
Bilirubin1, 2
ALT ≥3x baseline OR >300 U/L (whichever occurs first) and bilirubin ≥2xULN
Cannot 
Monitor
ALT ≥3x baseline but <5x baseline and cannot be monitored every 1 - 2 weeks
 
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Symptomatic3
ALT ≥3x baseline and symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity.
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study intervention.

Report the event to the Medical Monitor
within 24 hours.

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2.

Complete the liver imaging and/or liver biopsy 
eCRFs if these tests are performed.

Perform liver event follow up assessments. 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below).

Do not restart participant with study 
intervention unless allowed per protocol and 
VSLC approval is granted (refer to 
Section 10.6.2).

If restart is not allowed or not granted, 
permanently discontinue study intervention 
and may continue participant in the study for 
any protocol specified follow up assessments.
MONITORING:

Make every reasonable attempt to have 
participants return to clinic within 24 hours
for repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments. 

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline.

A specialist or hepatology consultation is 
recommended.
Make every attempt to carry out liver event 
follow-up assessments at the central 
laboratory as described below:

Viral hepatitis serology, including:

Hepatitis A immunoglobulin M (IgM) 
antibody;

HBsAg and hepatitis B core 
antibody;

Hepatitis C RNA;

Hepatitis E IgM antibody.

Cytomegalovirus IgM antibody.

Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).

Syphilis screening.

Drugs of abuse screen, including alcohol.

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in participants 
with definite or likely acetaminophen use 
in the preceding week [James, 2009]).  
The site must contact the Medical Monitor 
when this test is required.

Serum CPK and lactate dehydrogenase 
(LDH).

Fractionate bilirubin, if total bilirubin 
1.5xULN.

Obtain complete blood count with 
differential to assess eosinophilia.

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
 
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globulins).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, fatigue, decreased 
appetite, nausea, vomiting, abdominal 
pain, jaundice, fever, or rash as relevant 
on the AE report form.

Record use of concomitant medications 
on the concomitant medications report 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake eCRF.
1.
CPK - creatine phosphokinase
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required, and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)  
 
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Liver Chemistry Increased Monitoring Criteria with Continued Therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
If baseline ALT ≤1.5x ULN, 
ALT ≥5x ULN and <8xULN and 
bilirubin <2xULN without symptoms 
believed to be related to liver injury 
or hypersensitivity, monitor 
participant every 2 weeks until 
resolution to ALT <5x ULN.

Notify the Medical Monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 

Participant can continue study intervention  

Participant must return every 1 – 2 weeks for 
repeat liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) until resolution or 
stabilisation (ALT <5×ULN on 2 consecutive 
evaluations) 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above
If baseline ALT >1.5x ULN, 
ALT ≥3x baseline and <5x baseline 
and bilirubin <2xULN without 
symptoms believed to be related to 
liver injury or hypersensitivity, 
monitor participant every 2 weeks 
until resolution to ALT <3x baseline
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et.al...
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
10.6.2.
Study Intervention Restart after Stopping for Liver Criteria
If a participant meets liver chemistry stopping criteria do not restart/rechallenge 
participant with study treatment unless:

ViiV Healthcare Safety and Labelling Committee (VSLC) approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the participant
If VSLC approval to restart/rechallenge subject with study treatment is not granted, then 
subject must permanently discontinue study treatment and may continue in the study for 
protocol-specified follow up assessments.
Drug restart may be considered for liver events with a clear underlying cause (e.g., 
biliary, pancreatic events, hypotension, acute viral hepatitis), if not associated with drug-
 
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induced liver injury, alcoholic hepatitis or hypersensitivity, and drug not associated with 
human leukocyte antigen (HLA) marker of liver injury, when liver chemistries improve 
to within 1.5x Screening/Day 1 and ALT<3xULN) (Table 6, Figure 3).
Drug Restart
Phase III “drug restart” can be approved by the VSLC for transient, defined non-drug-
induced liver injury if no evidence of:
•
immunoallergic injury /HLA association with injury
•
drug-induced liver injury (DILI)
•
alcoholic hepatitis
Study intervention is held while labs and evaluation are completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval (Figure 3): 

Investigator requests consideration of drug re-initiation for a participant stable or 
improving on study intervention, who exhibits liver chemistry elevation meeting 
participant stopping criteria, which is transient, non-drug-related, and liver 
chemistries improve to within 1.5x baseline and ALT< 3xULN. 

In setting of a definitive non-study-drug-related diagnosis (e.g., acute viral or 
syphilitic hepatitis), restart will be considered once ALT <3x ULN (for 
participants with baseline ALT <1.5x ULN) or < 3x baseline ALT value (for 
participants with baseline ALT >1.5x ULN).

Medical monitor and Clinical Safety Physician to review the participant’s diagnosis, 
restart risk factors and complete checklist (Table 6).
The LOC medical director (ViiV Healthcare and GSK where applicable) should 
be informed that study intervention restart is under consideration and of the final 
decision, whether or not to proceed.
 
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Table 6
Checklist for Phase III drug restart after well-explained liver injury 
(e.g., biliary, pancreatic, hypotensive events, congestive heart 
failure, acute viral hepatitis), improving to liver chem.1.5x baseline 
& ALT<3xULN
Yes
No
Was participant stable or improving on study intervention?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)

study intervention has an HLA genetic marker associated with liver injury 
(e.g., lapatinib, abacavir, amoxicillin/clavulanate)
Previous drug history

Relevant physicians must review and agree on request for drug restart:  

Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader.

Hepatotoxicity Panel consultation is available.

Justification for drug restart outlining the benefit and risk for this participant must be 
recorded by GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) Physician 
and sent to the VSLC Secretary.
VSLC must approve drug re-initiation and dosing regimen
 
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Figure 3
VSLC process for drug restart approval or disapproval
1. Andrade, 2009; 2. Papay 2009; 3. Hunt, 2010
Medical Monitor, GCSP Physician and PI actions for Restart following VSLC 
decision
Medical Monitor and (Global Clinical Safety and Pharmacovigilance) GCSP 
Physician Actions

Medical Monitor must notify PI of VSLC’s restart decision and recommended 
dosing regimen in writing and Medical Monitor must record note in study files.

The Safety Review Team must record restart outcomes and the GCSP Physician 
must send these to the VSLC
All severe reactions (restart associated with bilirubin>2xULN or jaundice, or 
INR1.5), SAEs or fatalities with drug restart must be immediately reported to 
Line Management, VSLC Chair, VP Global Medical Strategy and EU Qualified 
Person for Pharmacovigilance. 
Principal Investigator Actions:

The PI must obtain Ethics Committee or Institutional Review Board approval of drug
restart, as required. 
 
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
If drug re-initiation VSLC-approved, the participant must provide informed consent 
with a clear description of possible benefits and risks of drug administration 
including recurrent, more severe liver injury or possible death.

The participant’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by Medical Monitor.

Liver chemistries must be followed once weekly for ‘restart’ cases for one month or 
for as long as clinically indicated following drug re-initiation.  If participant exhibits 
protocol-defined liver chemistry elevations, study intervention should be 
discontinued as protocol specified.
VSLC and the IRB must be informed of the participant’s outcome following drug 
restart.
Restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting participant stopping criteria

2 = recurrent liver chemistry elevation meeting participant stopping criteria

3 = serious adverse event

4 = fatality
References
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009; 8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010; 
52:2216-2222. 
Papay JI, Clines D, Rafi R, Yuen N., Britt S.D., Walsh J.S., Hunt C.M.  Drug-induced 
liver injury following positive drug rechallenge.  Regul Tox Pharm. 2009; 54:84-90. 
 
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10.7.
Appendix 7: Prohibited Medications
The following concomitant medications or therapies are not permitted at any time during 
the study:

HIV immunotherapeutic vaccines are not permitted at any time during the study. 

Other experimental agents, cytotoxic chemotherapy, or radiation therapy may not 
be administered. 

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited (a list of examples is provided in the SRM).  This includes 
topical agents with substantial systemic exposure and systemic effects.  Use of 
topical imiquimod is permitted. 

For participants with an unanticipated requirement for HCV therapy during 
study, interferon or any other medications that have a potential for adverse drug-
drug interactions with study intervention are prohibited during the conduct of the 
study.  

Acetaminophen (paracetamol) cannot be used in participants with acute viral 
hepatitis [James, 2009].
The following medications or their equivalents may cause decreased concentrations of 
DTG. Therefore, the following medications must not be administered concurrently with 
DTG.

Carbamazepine

Oxcarbamazepine

Phenobarbital

Phenytoin

Rifampin

St. John’s wort (Hypericum perforatum)
Dofetilide is prohibited as DTG may inhibit their renal tubular secretion resulting in 
increased dofetilide concentrations and potential for toxicity.
Note:  Any prohibited medication should be discontinued for a minimum of two weeks or 
a minimum of three half-lives (whichever is longer) prior to the first dose.  
For information on concurrent therapies and interactions suspected to be relevant to 
other antiretroviral therapy added during the study, please consult the local prescribing 
information.
 
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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et.al.. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
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10.8.
Appendix 8:  Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, March 
2017
VERSION 2.1, March 2017
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term [DAIDS, 2017].
Estimating Severity Grade for Parameters Not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5.
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Clinical adverse
event NOT
identified 
elsewhere in the
grading table
Mild symptoms
causing no or 
minimal 
interference with
usual social & 
functional
activities with
intervention not
indicated
Moderate symptoms
causing greater than 
minimal interference 
with usual social &
functional activities 
with intervention 
indicated
Severe symptoms
causing inability to 
perform usual
social & functional
activities with
intervention or 
hospitalization 
indicated
Potentially life-
threatening symptoms 
causing inability to
perform basic self-care 
functions with
intervention indicated to
prevent permanent
impairment, persistent
disability, or death
Major Clinical Conditions Cardiovascular
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Arrhythmia
(by ECG or physical
examination)
Specify type, if 
applicable
No symptoms
AND No
intervention 
indicated
No symptoms
AND Non-urgent 
intervention 
indicated
Non-life-
threatening 
symptoms AND
Non-urgent
intervention
indicated
Life-threatening 
arrhythmia OR
Urgent intervention
indicated
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Blood Pressure
Abnormalities1
Hypertension (with 
the lowest reading 
taken after repeat 
testing during a
visit)
≥ 18 years of
age
140 to < 160
mmHg systolic
OR
90 to < 100
mmHg 
diastolic
≥ 160 to
< 180 mmHg
systolic OR
≥ 100 to < 110 
mmHg
diastolic
≥ 180 mmHg
systolic
OR ≥ 110 mmHg 
diastolic
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
< 18 years of
age
> 120/80
mmHg
≥ 95th to < 99th 
percentile + 5
mmHg adjusted for
age, height, and
gender (systolic 
and/or diastolic)
≥99th percentile
+5mmHg adjusted 
for age, height, 
and gender
(systolic and/or
diastolic)
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
Hypotension
No symptoms
Symptoms 
corrected with oral
fluid replacement
Symptoms AND IV
fluids indicated
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood
pressure
Cardiac Ischemia
or Infarction
Report only one
NA
NA
New symptoms
with ischemia 
(stable angina)
OR New testing
consistent with
ischemia
Unstable angina OR
Acute myocardial 
infarction
Heart Failure
No symptoms
AND
Laboratory or 
cardiac 
imaging 
abnormalities
Symptoms with
mild to moderate 
activity or exertion
Symptoms at rest
or with minimal
activity or
exertion (e.g., 
hypoxemia) OR
Intervention
indicated (e.g., 
oxygen)
Life-threatening 
consequences OR
Urgent intervention 
indicated (e.g., 
vasoactive
medications,
ventricular assist
device, heart
transplant)
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 
2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C
 
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Cardiovascular
PARAMETER
GRADE 1 
MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Hemorrhage
(with significant
acute blood loss)
NA
Symptoms AND
No transfusion
indicated
Symptoms
AND
Transfusion of
≤2 units
packed RBCs 
indicated
Life-threatening 
hypotension OR
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs
> 10 cc/kg) indicated
Prolonged PR 
Interval or AV
Block
Report only one
> 16 years of age
PR interval 0.21
to < 0.25
seconds
PR interval
≥0.25 seconds 
OR Type I 2nd
degree AV block
Type II 2nd
degree AV
block OR
Ventricular
pause ≥3.0
seconds
Complete AV block
≤ 16 years of age
1st degree AV
block
(PR interval > 
normal for age 
and rate)
Type I 2nd degree
AV block
Type II 2nd
degree AV
block OR
Ventricular
pause ≥3.0
seconds
Complete AV block
Prolonged QTc
Interval2
0.45 to 0.47
seconds
> 0.47 to
0.50 
seconds
> 0.50 seconds OR
≥ 0.06 seconds 
above baseline
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated serious 
ventricular
dysrhythmia)
Thrombosis or
Embolism
Report only one
NA
Symptoms AND
No intervention 
indicated
Symptoms
AND
Intervention 
indicated
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus)
2 As per Bazett’s formula
 
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Dermatologic
PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Alopecia (scalp only) Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference
with usual
social & 
functional
activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
NA
NA
Bruising
Localized to
one area
Localized to
more than one 
area
Generalized
NA
Cellulitis
NA
Non-parenteral 
treatment
indicated (e.g.,
oral antibiotics, 
antifungals, 
antivirals)
IV treatment 
indicated
(e.g., IV 
antibiotics, 
antifungals, 
antivirals)
Life-threatening 
consequences 
(e.g., sepsis, tissue 
necrosis)
Hyperpigmentation
Slight or
localized 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Hypopigmentation
Slight or
localized 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Petechiae
Localized to
one area
Localized to
more than one 
area
Generalized
NA
 
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PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Pruritus3
(without skin lesions)
Itching causing
no or minimal 
interference
with usual
social & 
functional
activities
Itching causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Itching causing 
inability to
perform usual
social & 
functional
activities
NA
Rash
Specify 
type, if 
applicable
Localized rash
Diffuse rash
OR Target
lesions
Diffuse rash
AND Vesicles 
or limited 
number of
bullae or 
superficial 
ulcerations of 
mucous 
membrane 
limited to one 
site
Extensive or
generalized bullous
lesions OR Ulceration
of mucous membrane 
involving
two or more 
distinct mucosal
sites OR
Stevens-Johnson
syndrome OR
Toxic epidermal
necrolysis
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions
section (page 23 in source DAIDS Table).
Endocrine and Metabolic
PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus
Controlled
without 
medication
Controlled with 
medication OR
Modification of 
current
medication 
regimen
Uncontrolled
despite treatment 
modification OR
Hospitalization
for immediate 
glucose control
indicated
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end
organ failure)
Gynecomastia
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on visual 
inspection AND
Causing pain with 
greater than
minimal 
interference with 
usual social & 
functional
activities
Disfiguring
changes AND
Symptoms 
requiring
intervention or
causing inability to 
perform usual
social
& 
functional 
activities
NA
 
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PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Hyperthyroidism
No symptoms
AND Abnormal 
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
suppression
therapy indicated
Symptoms 
causing inability
to perform usual
social & 
functional
activities OR
Uncontrolled 
despite treatment 
modification
Life-threatening 
consequences 
(e.g., thyroid
storm)
Hypothyroidism
No symptoms
AND Abnormal 
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
replacement
therapy indicated
Symptoms 
causing inability
to perform usual
social & 
functional
activities OR
Uncontrolled 
despite treatment 
modification
Life-threatening 
consequences 
(e.g., myxedema 
coma)
Lipoatrophy4
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference
with usual
social &
functional
activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
Lipohypertrophy5
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on visual 
inspection AND
Causing greater
than minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and
abdomen
 
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Gastrointestinal
PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Anorexia
Loss of appetite 
without
decreased oral
intake
Loss of appetite 
associated with 
decreased oral
intake without
significant weight
loss
Loss of
appetite 
associated with 
significant
weight loss
Life-threatening 
consequences OR
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total
parenteral nutrition)
Ascites
No symptoms
Symptoms
AND
Intervention 
indicated (e.g.,
diuretics,
therapeutic 
paracentesis)
Symptoms recur
or persist
despite 
intervention
Life-
threatening 
consequences
Bloating or 
Distension
Report only one
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional activities
Symptoms 
causing inability
to perform usual
social & 
functional
activities
NA
Cholecystitis
NA
Symptoms AND
Medical
intervention 
indicated
Radiologic, 
endoscopic,
or operative
intervention
indicated
Life-threatening 
consequences 
(e.g., sepsis,
perforation)
Constipation
NA
Persistent 
constipation 
requiring regular
use of dietary 
modifications, 
laxatives, or
enemas
Obstipation
with manual
evacuation 
indicated
Life-threatening 
consequences 
(e.g., 
obstruction)
Diarrhea
≥ 1 year of age
Transient or 
intermittent 
episodes of
unformed stools 
OR Increase of ≤ 
3 stools over
baseline
per 24-hour period
Persistent episodes 
of unformed to 
watery stools OR
Increase of 4 to 6 
stools over
baseline per 24-
hour period
Increase of ≥7 
stools per 24-
hour period OR
IV fluid 
replacement 
indicated
Life-threatening 
consequences (e.g., 
hypotensive shock)
 
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PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
< 1 year of age
Liquid stools 
(more unformed
than usual) but
usual number of
stools
Liquid stools with 
increased number
of stools OR Mild 
dehydration
Liquid stools with 
moderate 
dehydration
Life-threatening 
consequences (e.g., 
liquid stools 
resulting in severe 
dehydration, 
hypotensive shock)
Dysphagia or
Odynophagia
Report only one
and specify 
location
Symptoms but
able to eat usual
diet
Symptoms causing 
altered dietary
intake with no
intervention 
indicated
Symptoms causing 
severely altered 
dietary intake with 
intervention
indicated
Life-threatening 
reduction in oral
intake
Gastrointestinal
Bleeding
Not requiring 
intervention
other than iron 
supplement
Endoscopic 
intervention 
indicated
Transfusion  
indicated
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
Mucositis or 
Stomatitis
Report only
one and 
specify 
location
Mucosal erythema Patchy 
pseudomembranes 
or ulcerations
Confluent 
pseudomembranes 
or ulcerations OR
Mucosal bleeding 
with minor trauma
Life-threatening 
consequences (e.g., 
aspiration, choking)
OR Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding
Nausea
Transient (< 24 
hours) or 
intermittent
AND No or
minimal 
interference
with oral intake
Persistent
nausea resulting
in
decreased oral
intake for 24 to 48
hours
Persistent nausea 
resulting in
minimal oral
intake for > 48 
hours OR
Rehydration 
indicated (e.g.,
IV fluids)
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
Pancreatitis
NA
Symptoms with 
hospitalization
not indicated
Symptoms
with 
hospitalization 
indicated
Life-threatening 
consequences 
(e.g., circulatory
failure, 
hemorrhage,
sepsis)
Perforation
(colon or rectum)
NA
NA
Intervention 
indicated
Life-
threatening 
consequences 
 
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PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING
Proctitis
Rectal discomfort 
with no
intervention 
indicated
Symptoms causing 
greater than
minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated
Symptoms causing 
inability to
perform usual
social & 
functional
activities OR
Operative 
intervention
indicated
Life-threatening 
consequences 
(e.g., 
perforation)
Rectal Discharge
Visible discharge
Discharge 
requiring the use 
of pads
NA
NA
Vomiting
Transient or 
intermittent
AND No or
minimal 
interference
with oral intake
Frequent
episodes with no
or mild 
dehydration
Persistent
vomiting resulting
in orthostatic 
hypotension OR
Aggressive 
rehydration
indicated (e.g., IV
fluids)
Life-threatening 
consequences 
(e.g., 
hypotensive 
shock)
Musculoskeletal
PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Arthralgia
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional
activities
Joint pain
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Joint pain
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint pain 
causing inability to 
perform basic self-
care functions
Arthritis
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference 
with usual social 
& functional 
activities
Stiffness or 
joint swelling 
causing 
inability to 
perform usual 
social & 
functional 
activities
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-
care functions
 
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PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Myalgia
(generalized)
Muscle pain 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Muscle pain
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Muscle pain
causing inability
to perform usual
social & 
functional
activities
Disabling muscle 
pain causing inability
to perform basic self-
care functions
Osteonecrosis
NA
No symptoms 
but with
radiographic 
findings AND
No operative 
intervention 
indicated
Bone pain with 
radiographic 
findings OR
Operative 
intervention
indicated
Disabling bone
pain with
radiographic 
findings causing 
inability to
perform
basic self-care
functions
Osteopenia6
≥ 30 years of age BMD t-score
-2.5 to -1
NA
NA
NA
< 30 years of age BMD z-score
-2 to -1
NA
NA
NA
Osteoporosis6
≥ 30 years of age
NA
BMD t-score < -
2.5
Pathologic 
fracture (e.g.,
compression 
fracture causing
loss of vertebral
height)
Pathologic fracture 
causing life-
threatening 
consequences
< 30 years of
age
NA
BMD z-score < -2 Pathologic 
fracture (e.g.,
compression 
fracture causing
loss of vertebral
height)
Pathologic fracture 
causing life-
threatening 
consequences
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific 
Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK.
2007: Printed by the University of Sheffield
 
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Neurologic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute CNS Ischemia NA
NA
Transient
ischemic attack
Cerebral vascular 
accident (e.g.,
stroke with
neurological deficit)
Altered Mental
Status (for
Dementia, see 
Cognitive,
Behavioral, or 
Attentional
Disturbance below)
Changes 
causing no or
minimal 
interference
with usual
social & 
functional
activities
Mild lethargy or 
somnolence 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Confusion,
memory 
impairment,
lethargy, or 
somnolence 
causing inability
to perform usual
social & 
functional 
activities
Delirium OR
Obtundation OR
Coma
Ataxia
Symptoms 
causing no or
minimal 
interference
with usual
social & 
functional
activities OR
No symptoms 
with ataxia 
detected on
examination
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing inability
to perform usual
social & 
functional
activities
Disabling symptoms 
causing inability to 
perform basic self-
care functions
Cognitive,
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention 
deficit disorder)
Specify type, if
applicable
Disability
causing no or
minimal
interference
with usual
social & 
functional
activities OR
Specialized 
resources not 
indicated
Disability
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Specialized 
resources on part-
time basis 
indicated
Disability
causing inability
to perform usual
social & 
functional
activities OR
Specialized 
resources on a 
full- time basis 
indicated
Disability causing 
inability to perform
basic self-care
functions OR
Institutionalization 
indicated
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Developmental
Delay
< 18 years of
age
Specify type,
if applicable
Mild
developmental 
delay, either
motor or
cognitive, as 
determined by 
comparison
with a 
developmental 
screening tool 
appropriate 
for the setting
Moderate 
developmental
delay, either
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for
the setting
Severe
developmental
delay, either motor
or cognitive, as 
determined by 
comparison with a 
developmental
screening tool 
appropriate for the 
setting
Developmental 
regression, either
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Headache
Symptoms 
causing no or
minimal 
interference
with usual
social & 
functional
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing inability
to perform usual
social & 
functional
activities
Symptoms causing 
inability to perform
basic self-care
functions OR
Hospitalization 
indicated OR
Headache with
significant 
impairment of
alertness or other
neurologic 
function
Neuromuscular 
Weakness 
(includes 
myopathy and 
neuropathy)
Specify type, if
applicable
Minimal
muscle 
weakness 
causing no or
minimal 
interference
with usual
social & 
functional
activities OR
No symptoms 
with
decreased 
strength on 
examination
Muscle weakness 
causing greater
than minimal
interference with
usual social & 
functional
activities
Muscle 
weakness 
causing inability
to perform usual
social & 
functional 
activities
Disabling muscle 
weakness causing 
inability to perform
basic self-care
functions OR
Respiratory muscle 
weakness 
impairing
ventilation
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Neurosensory 
Alteration
(includes 
paresthesia and
painful 
neuropathy)
Specify type, if
applicable
Minimal
paresthesia 
causing no or 
minimal
interference
with usual
social & 
functional
activities OR
No symptoms 
with sensory 
alteration on 
examination
Sensory
alteration or 
paresthesia 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Sensory
alteration or 
paresthesia 
causing inability
to perform usual
social & 
functional
activities
Disabling sensory 
alteration or
paresthesia causing
inability to perform
basic self-care 
functions
Seizures
New Onset Seizure
≥ 18 years of age
NA
NA
1 to 3 seizures
Prolonged and
repetitive seizures (e.g.,
status epilepticus) OR
Difficult to control
(e.g., refractory
< 18 years of
age (includes 
new or pre-
existing febrile 
seizures)
Seizure 
lasting < 5 
minutes with
< 24 hours 
postictal state
Seizure lasting 5 to
<
20 minutes with
< 24 hours 
postictal state
Seizure lasting ≥ 
20 minutes OR
> 24 hours 
postictal state
Prolonged and
repetitive seizures (e.g.,
status epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
Pre-existing Seizure
NA
Increased
frequency from
previous level of
control without 
change in seizure 
character
Change in
seizure 
character either
in duration or
quality (e.g.,
severity or 
focality)
Prolonged and
repetitive seizures (e.g.,
status epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
Syncope
Near syncope 
without loss 
of 
consciousness 
(e.g., pre-
syncope)
Loss of 
consciousness 
with no
intervention 
indicated
Loss of 
consciousness 
AND
Hospitalization or 
intervention
required
NA
 
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Pregnancy, Puerperium, and Perinatal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Stillbirth
(report using 
mother’s 
participant ID)
Report only one
NA
NA
Fetal death 
occurring at ≥ 20
weeks gestation
NA
Preterm
Birth (report 
using
mother’s 
participant
ID)
Live birth at 34 to
< 37 weeks 
gestational age
Live birth at 28 to
< 34 weeks 
gestational age
Live birth at 24 to
< 28 weeks 
gestational age
Live birth at < 24 weeks 
gestational age
Spontaneous 
Abortion or 
Miscarriage7
(report using
mother’s 
participant ID)
Report only
one
Chemical 
pregnancy
Uncomplicated 
spontaneous 
abortion or
miscarriage
Complicated 
spontaneous 
abortion or
miscarriage
NA
7 Definition: A pregnancy loss occurring at < 20 weeks gestational age
 
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Psychiatric
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
RADE 4
POTENTIALLY LIFE-
THREATENING
Insomnia
Mild difficulty 
falling asleep, 
staying asleep,
or waking up
early causing
no or minimal 
interference
with usual
social &
functional
activities
Moderate 
difficulty falling
asleep, staying
asleep, or 
waking up early 
causing more 
than
minimal
interference with
usual social & 
functional
activities
Severe difficulty 
falling asleep,
staying asleep, or
waking up early
causing
inability to
perform usual
social &
functional
activities
requiring
intervention or
hospitalization
NA
Psychiatric 
Disorders 
(includes 
anxiety, 
depression,
mania, and 
psychosis)
Specify 
disorder
Symptoms with 
intervention not 
indicated OR
Behavior
causing no or
minimal 
interference
with usual
social & 
functional
activities
Symptoms with 
intervention 
indicated OR
Behavior causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Symptoms with 
hospitalization 
indicated OR
Behavior
causing inability
to perform usual
social & 
functional
activities
Threatens harm to self 
or others OR Acute 
psychosis OR
Behavior causing
inability to perform
basic self-care 
functions
Suicidal
Ideation or
Attempt
Report only one
Preoccupied
with 
thoughts 
of death AND
No wish to kill
oneself
Preoccupied
with thoughts 
of death AND
Wish to kill 
oneself with no 
specific plan or 
intent
Thoughts of
killing oneself
with partial or
complete plans
but no attempt
to do so OR
Hospitalization
indicated
Suicide attempted
 
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Respiratory
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute 
Bronchospasm
Forced
expiratory 
volume in 1
second or peak
flow reduced to
≥ 70 to < 80%
OR Mild
symptoms
with intervention
not indicated
Forced expiratory 
volume in 1 second 
or peak flow 50 to
< 70% OR
Symptoms with
intervention
indicated OR
Symptoms causing 
greater than
minimal 
interference with
usual social &
functional activities
Forced
expiratory 
volume in 1
second or
peak flow 25
to
< 50% OR
Symptoms 
causing
inability to
perform usual
social & 
functional
activities
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR
Life-threatening 
respiratory or 
hemodynamic 
compromise OR
Intubation
Dyspnea or 
Respiratory
Distress
Report only one
Dyspnea on
exertion with
no or minimal 
interference
with usual
social &
functional
activities OR
Wheezing OR
Minimal
increase in
respiratory rate
for age
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR
Intercostal retractions 
OR Pulse oximetry
90 to < 95%
Dyspnea at
rest causing
inability to 
perform usual
social
& functional
activities OR
Pulse oximetry
< 90%
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation)
Sensory
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Hearing Loss
≥ 12 years of age
NA
Hearing aid or 
intervention
not indicated
Hearing aid or 
intervention
indicated
Profound bilateral 
hearing loss (> 80 dB at
2 kHz and above) OR
Non-serviceable hearing
(i.e., >50 dB audiogram 
and <50% speech 
discrimination)
< 12 years of
age
(based on a 1,
2, 3, 4, 6 and 8
kHz 
> 20 dB 
hearing loss 
at ≤ 4 kHz
> 20 dB hearing
loss at > 4 kHz
> 20 dB hearing
loss at ≥ 3 kHz in
one ear with
additional speech
language related
services indicated
Audiologic indication for
cochlear implant and 
additional speech-
language related services 
indicated (where 
available)
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
audiogram)
(where available)
OR Hearing loss 
sufficient to
indicate 
therapeutic 
intervention, 
including hearing 
aids
Tinnitus
Symptoms 
causing no or
minimal 
interference
with usual social
& functional
activities with
intervention not
indicated
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities with
intervention 
indicated
Symptoms 
causing inability
to perform usual
social & 
functional
activities
NA
Uveitis
No symptoms
AND Detectable 
on examination
Anterior uveitis 
with symptoms 
OR Medical
intervention 
indicated
Posterior or pan-
uveitis OR
Operative 
intervention
indicated
Disabling visual loss in 
affected eye(s)
Vertigo
Vertigo causing
no or minimal 
interference
with usual social
& functional
activities
Vertigo causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Vertigo causing 
inability to
perform usual
social & 
functional
activities
Disabling vertigo 
causing inability to 
perform basic self-care 
functions
Visual Changes
(assessed from
baseline)
Visual
changes 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Visual changes 
causing greater
than minimal
interference with
usual social & 
functional
activities
Visual changes 
causing inability
to perform usual
social
& functional
activities
Disabling visual loss in 
affected eye(s)
 
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Systemic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute Allergic
Reaction
Localized
urticaria (wheals)
with no medical
intervention 
indicated
Localized
urticaria with
intervention 
indicated OR
Mild 
angioedema
with no
intervention 
indicated
Generalized
urticaria OR
Angioedema
with intervention
indicated OR
Symptoms of
mild
bronchospasm
Acute anaphylaxis 
OR Life-threatening 
bronchospasm OR
Laryngeal edema
Chills
Symptoms causing
no or minimal 
interference with
usual social &
functional
activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA
Cytokine Release
Syndrome8
Mild signs and 
symptoms
AND Therapy
(i.e., antibody
infusion) 
interruption not 
indicated
Therapy (i.e., 
antibody
infusion) 
interruption 
indicated AND
Responds
promptly to
symptomatic 
treatment OR
Prophylactic 
medications 
indicated for ≤
24 hours
Prolonged
severe signs and
symptoms OR
Recurrence of 
symptoms
following initial
improvement
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator support)
Fatigue or 
Malaise
Report only one
Symptoms causing
no or minimal 
interference with
usual social &
functional activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Incapacitating
symptoms of fatigue or
malaise causing
inability to perform
basic self-care 
functions
Fever (non-
axillary 
temperatures 
only)
38.0 to < 38.6°C or
100.4 to < 101.5°F
≥ 38.6 to
< 39.3°C or
≥101.5 to
< 102.7°F
≥ 39.3 to < 40.0°C
or ≥ 102.7 to
< 104.0°F
≥ 40.0°C or ≥ 104.0°F
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Pain9 (not
associated with
study agent 
injections and
not specified
elsewhere)
Specify location
Pain causing no
or minimal
interference with
usual social & 
functional
activities
Pain causing 
greater than 
minimal 
interference
with usual
social &
functional
activities
Pain causing
inability to
perform usual 
social & 
functional 
activities
Disabling pain causing 
inability to perform
basic self-care
functions OR
Hospitalization
indicated
Serum Sickness
10
Mild signs 
and 
symptoms
Moderate signs 
and symptoms
AND
Intervention 
indicated (e.g., 
antihistamines)
Severe signs and 
symptoms AND
Higher level 
intervention
indicated (e.g.,
steroids or IV 
fluids)
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator support)
Underweight11
> 5 to 19 years of
age
WHO BMI z-score
< -1 to -2
WHO BMI z-score
< -2 to -3
WHO BMI z-score
< -3
WHO BMI z-score < -3
with life-threatening 
consequences
2 to 5 years of
age
WHO BMI z-score
< -1 to -2
WHO Weight-
for- height z-
score < -2 to -3
WHO Weight-
for- height z-
score < -3
WHO Weight-for-
height z-score < -3 with
life- threatening
consequences
< 2 years of age
WHO BMI z-score
< -1 to -2
WHO Weight-
for- length z-
score < -2 to -3
WHO Weight-
for- length z-
score < -3
WHO Weight-for-
length z-score < -3 with
life- threatening
consequences
Unintentional 
Weight Loss 
(excludes 
postpartum 
weight loss)
NA
5 to < 9% loss 
in body weight
from baseline
≥ 9 to < 20%
loss in body
weight from 
baseline
≥ 20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated
(e.g., tube feeding,
total parenteral 
nutrition)
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness 
of breath.
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section
(page 23 in source DAIDS Table).
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy,
marked discomfort, and/or dyspnea
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following
URLs:
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5
to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5
years of age.
 
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Urinary
PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Urinary Tract
Obstruction
NA
Signs or
symptoms of
urinary tract 
obstruction
without 
hydronephrosis 
or renal
dysfunction
Signs or
symptoms of 
urinary tract 
obstruction
with 
hydronephrosis 
or renal
dysfunction
Obstruction causing 
life-threatening 
consequences
Site Reactions to Injections and Infusions
PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain
or Tenderness
Report only one
Pain or
tenderness 
causing no or 
minimal
limitation of
use of limb
Pain or tenderness 
causing greater than 
minimal limitation
of use of limb
Pain or
tenderness 
causing
inability to 
perform usual
social
& functional
activities
Pain or tenderness 
causing inability to 
perform basic self-
care function OR
Hospitalization 
indicated
Injection Site 
Erythema or 
Redness12
Report only one
> 15 years of age
2.5 to < 5 cm in 
diameter OR
6.25 to < 25 cm2
surface area
AND Symptoms 
causing no or
minimal
interference with 
usual social & 
functional
activities
≥ 5 to < 10 cm in 
diameter OR ≥ 25
to < 100 cm2
surface area OR
Symptoms causing
greater than 
minimal
interference with
usual social &
functional activities
≥ 10 cm in
diameter OR ≥ 
100 cm2 
surface area OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage 
OR Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis 
involving dermis 
or deeper tissue)
 
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PARAMETER
GRADE 1 MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤ 15 years of age
≤ 2.5 cm
in 
diameter
> 2.5 cm in
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh)
≥ 50% surface 
area of the 
extremity 
segment
involved (e.g.,
upper arm or 
thigh) OR
Ulceration OR
Secondary 
infection OR
Phlebitis OR
Sterile
abscess OR
Drainage
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis 
involving dermis 
or deeper tissue)
Injection Site
Induration or 
Swelling
Report only one
> 15 years of
age
Same as for 
Injection
Site 
Erythema
or Redness,
> 15 years 
of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, > 15 years 
of age
≤15 years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for
Injection Site 
Erythema or 
Redness, ≤ 15 years
of age
Injection Site 
Pruritus
Itching localized
to the injection
site that is 
relieved 
spontaneously or
in < 48 hours of 
treatment
Itching beyond the 
injection site that
is not generalized
OR Itching
localized to the 
injection site 
requiring ≥48
hours treatment
Generalized 
itching causing
inability to 
perform usual
social & 
functional 
activities
NA
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area.
 
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Laboratory Values*
Chemistries
PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Acidosis
NA
pH ≥ 7.3 to < 
LLN
pH < 7.3 without
life- threatening 
consequences
pH < 7.3 with life-
threatening 
consequences
Albumin,
Low
(g/dL; g/L)
3.0 to < LLN
30 to < LLN
≥ 2.0 to < 3.0
≥ 20 to < 30
< 2.0
< 20
NA
Alkaline 
Phosphatase, 
High
1.25 to <
2.5 x ULN
2.5 to < 5.0 x
ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Alkalosis
NA
pH > ULN to ≤ 
7.5
pH > 7.5 without
life- threatening 
consequences
pH > 7.5 with life-
threatening 
consequences
ALT or SGPT,
High
Report only one
1.25 to <
2.5 x ULN
2.5 to < 5.0 x
ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Amylase 
(Pancreatic) or
Amylase (Total),
High
Report only one
1.1 to < 1.5 x
ULN
1.5 to < 3.0 x
ULN
3.0 to < 5.0 x ULN
≥ 5.0 x ULN
AST or SGOT,
High
Report only one
1.25 to
< 2.5 x
ULN
2.5 to < 5.0 x
ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to < LLN
16.0 to < LLN
11.0 to < 16.0
11.0 to < 16.0
8.0 to < 11.0
8.0 to < 11.0
< 8.0
< 8.0
Bilirubin
Direct Bilirubin13, 
High
> 28 days of age
NA
NA
> ULN with
other signs and
symptoms of
hepatotoxicity.
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure)
≤ 28 days of age ULN to ≤ 1 mg/dL > 1 to ≤ 1.5
mg/dL
> 1.5 to ≤2 mg/dL
> 2 mg/dL
Total Bilirubin,
High
> 28 days of
age
1.1 to < 1.6 x
ULN
1.6 to < 2.6 x
ULN
2.6 to < 5.0 x
ULN with other
signs and 
symptoms of 
hepatotoxicity.
≥ 5.0 x ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure).
 
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PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
≤ 28 days of age See
Appendix A in 
Source DAIDS 
Table. Total
Bilirubin for 
Term and
Preterm 
Neonates
See
Appendix A
in Source 
DAIDS Table. 
Total
Bilirubin for 
Term and
Preterm 
Neonates
See 
Appendix A in 
Source DAIDS 
Table. Total
Bilirubin for 
Term and
Preterm 
Neonates
See Appendix A in 
Source DAIDS Table.
Total Bilirubin for
Term and Preterm
Neonates
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6 to < 11.5
2.65 to < 2.88
11.5 to < 12.5
2.88 to < 3.13
12.5 to < 13.5
3.13 to < 3.38
≥ 13.5
≥ 3.38
< 7 days of age
11.5 to < 12.4
2.88 to < 3.10
12.4 to < 12.9
3.10 to < 3.23
12.9 to < 13.5
3.23 to < 3.38
≥ 13.5
≥ 3.38
Calcium (Ionized),
High
(mg/dL; mmol/L)
> ULN to < 6.0
> ULN to < 1.5
6.0 to < 6.4
1.5 to < 1.6
6.4 to < 7.2
1.6 to < 1.8
≥ 7.2
≥ 1.8
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age
7.8 to < 8.4
1.95 to < 2.10
7.0 to < 7.8
1.75 to < 1.95
6.1 to < 7.0
1.53 to < 1.75
< 6.
< 1.53
< 7 days of age
6.5 to < 7.5
1.63 to < 1.88
6.0 to < 6.5
1.50 to < 1.63
5.50 to < 6.0
1.38 to < 1.50
< 5.50
< 1.38
Calcium (Ionized),
Low
(mg/dL; mmol/L)
< LLN to 4.0
< LLN to 1.0
3.6 to < 4.0
0.9 to < 1.0
3.2 to < 3.6
0.8 to < 0.9
< 3.2
< 0.8
Cardiac 
Troponin I, 
High
NA
NA
NA
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory
Creatine Kinase,
High
3 to < 6 x ULN
6 to < 10x ULN
10 to < 20 x ULN
≥ 20 x ULN
Creatinine, High
*Report only one
1.1 to 1.3 x ULN
> 1.3 to 1.8 x
ULN OR
Increase to 1.3
to < 1.5 x
participant’s 
baseline
> 1.8 to < 3.5 x
ULN OR Increase 
to 1.5 to < 2.0 x 
participant’s
baseline
≥ 3.5 x ULN OR Increase 
of ≥ 2.0 x participant’s 
baseline
 
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PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Creatinine 
Clearance14or 
eGFR, Low
*Report only one
NA
< 90 to 60
ml/min or 
ml/min/1.73 m2
OR 10 to < 30%
decrease from
participant’s 
baseline
< 60 to 30 ml/min
or ml/min/1.73
m2 OR 30 to
< 50% decrease
from participant’s
baseline
< 30 ml/min or 
ml/min/1.73 m2
OR ≥ 50%
decrease from 
participant’s
baseline or 
dialysis needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to < 6.95
> 125 to 250
6.95 to < 13.89
> 250 to 500
13.89 to < 27.75
≥500
≥ 27.75
Nonfasting, High
116 to 160
6.44 to < 8.89
> 160 to 250
8.89 to < 13.89
> 250 to 500
13.89 to < 27.75
≥ 500
≥ 27.75
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55 to 64
3.05 to <3.55
40 to < 55
2.22 to < 3.05
30 to < 40
1.67 to < 2.22
< 30
< 1.67
< 1 month of age
50 to 54
2.78 to < 3.00
40 to < 50
2.22 to < 2.78
30 to < 40
1.67 to < 2.22
< 30
< 1.67
Lactate, High
ULN to < 2.0x
ULN without 
acidosis
≥ 2.0 x ULN
without acidosis
Increased lactate
with pH < 7.3
without life-
threatening 
consequences
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences
Lipase, High
1.1 to < 1.5 x
ULN
1.5 to < 3.0 x
ULN
3.0 to < 5.0 x ULN
≥ 5.0 x ULN
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol,
Fasting, High
≥ 18 years of age
200 to < 240
5.18 to < 6.19
240 to < 300
6.19 to < 7.77
≥ 300
≥ 7.77
NA
< 18 years of
age
170 to < 200
4.40 to < 5.15
200 to < 300
5.15 to < 7.77
≥ 300
≥ 7.77
NA
LDL, Fasting,
High
≥ 18 years of
age
130 to < 160
3.37 to < 4.12
160 to < 190
4.12 to < 4.90
≥ 190
≥4.90
NA
> 2 to < 18
years of age
110 to < 130
2.85 to < 3.34
130 to < 190
3.34 to < 4.90
≥ 190
≥ 4.90
NA
 
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PARAMETER
GRADE 1 MILD
GRADE 2 
MODERATE
GRADE 3 
SEVERE
GRADE 4 
POTENTIALLY LIFE-
THREATENING
Triglycerides,
Fasting, High
150 to 300
1.71 to 3.42
>300 to 500
>3.42 to 5.7
>500 to < 1,000
>5.7 to 11.4
> 1,000
> 11.4
Magnesium15,
Low
(mEq/L;
mmol/L)
1.2 to < 1.4
0.60 to < 0.70
0.9 to < 1.2
0.45 to < 0.60
0.6 to < 0.9
0.30 to < 0.45
< 0.6
< 0.30
Phosphate, Low
(mg/dL; mmol/L)
> 14 years of age
2.0 to < LLN
0.65 to < LLN
1.4 to < 2.0
0.45 to < 0.65
1.0 to < 1.4
0.32 to < 0.45
< 1.0
< 0.32
1 to 14 years of
age
3.0 to < 3.5
0.97 to < 1.13
2.5 to < 3.0
0.81 to < 0.97
1.5 to < 2.5
0.48 to < 0.81
< 1.5
< 0.48
< 1 year of age
3.5 to < 4.5
1.13 to < 1.45
2.5 to < 3.5
0.81 to < 1.13
1.5 to < 2.5
0.48 to < 0.81
< 1.5
< 0.48
Potassium, High
(mEq/L; mmol/L)
5.6 to < 6.0
5.6 to < 6.0
6.0 to < 6.5
6.0 to < 6.5
6.5 to < 7.0
6.5 to < 7.0
≥ 7.0
≥ 7.0
Potassium, Low
(mEq/L; mmol/L)
3.0 to < 3.4
3.0 to < 3.4
2.5 to < 3.0
2.5 to < 3.0
2.0 to < 2.5
2.0 to < 2.5
< 2.0
< 2.0
Sodium, High
(mEq/L; mmol/L)
146 to < 150
146 to < 150
150 to < 154
150 to < 154
154 to < 160
154 to < 160
≥ 160
≥160
Sodium, Low
(mEq/L; mmol/L)
130 to < 135
130 to < 135
125 to < 130
125 to < 130
121 to < 125
121 to < 125
≤ 120
≤ 120
Uric Acid, High
(mg/dL; mmol/L)
7.5 to < 10.0
0.45 to < 0.59
10.0 to < 12.0
0.59 to < 0.71
12.0 to < 15.0
0.71 to < 0.89
≥ 15.0
≥ 0.89
eGFR - estimated glomerular filtration rate
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be 
reported to DAIDS in an expedited time frame unless it meets protocol-specific reporting requirements.
13 Direct bilirubin > 1.5 mg/dL in a participant <28 days of age should be graded as grade 2, if < 10% of the 
total bilirubin
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in
mL/min/1.73m2). Sites should choose the method defined in their study and when not specified, use the 
method most relevant to the study population.
*Reminder: Choose the method that selects for the higher grade
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114
 
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Hematology
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Absolute CD4+
Count, Low
(cell/mm3;
cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to < 300
200 to < 300
100 to < 200
100 to < 200
< 100
< 100
Absolute 
Lymphocyte
Count, Low
(cell/mm3;
cells/L)
> 5 years of age 
(not HIV infected) 
600 to < 650
< 0.600 x 109 to 
< 0.650 x 109
500 to < 600
0.500 x 109 to 
< 0.600 x 109
350 to < 500
0350 x 109 to 
< 0.500 x 109
< 350
< 0.350 x 109
Absolute 
Neutrophil
Count (ANC),
Low
(cells/mm3;
cells/L)
> 7 days of
age
800 to 1,000
0.800 x 109 to
1.000 x 109
600 to 799
0.600 x 109 to
0.799 x 109
400 to 599
0.400 x 109 to
0.599 x 109
< 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to
1.500 x 109
1,000 to 1,249
1.000 x 109 to
1.249 x 109
750 to 999
0.750 x 109 to
0.999 x 109
< 750
< 0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109 to
5.000 x 109
3,000 to 3,999
3.000 x 109 to
3.999 x 109
1,500 to 2,999
1.500 x 109 to
2.999 x 109
< 1,500
< 1.500 x 109
Fibrinogen,
Decreased
(mg/dL; g/L)
100 to < 200
1.00 to < 2.00
OR
0.75 to < 1.00 x
LLN
75 to < 100
0.75 to < 1.00
OR
≥ 0.50 to < 0.75 x
LLN
50 to < 75
0.50 to < 0.75
OR
0.25 to < 0.50 x
LLN
< 50
< 0.50
OR
< 0.25 x LLN
OR Associated with gross
bleeding
Hemoglobin16,
Low
(g/dL;
mmol/L)17
≥ 13 years of
age (male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
57 days of age to
< 13 years of age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of
age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72
22 to 35 days of
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59
INR, High
(not on
anticoagulation
therapy)
1.1 to < 1.5 x
ULN
1.5 to < 2.0 x ULN 2.0 to < 3.0 x ULN ≥ 3.0 x ULN
Methemoglobin
(% hemoglobin)
5.0 to < 10.0%
10.0 to < 15.0%
15.0 to < 20.0%
≥ 20.0%
PTT, High
(not on
anticoagulation
therapy)
1.1 to
< 1.66 x
ULN
1.66 to
< 2.33 x
ULN
2.33 to
< 3.00 x
ULN
≥ 3.00 x ULN
Platelets, Decreased
(cells/mm3;
cells/L)
100,000 to
< 125,000
100.000 x 109 to
< 125.000 x 109
50,000 to
< 100,000
50.000 x 109 to
< 100.000 x 109
25,000 to < 50,000
25.000 x 109 to
< 50.000 x 109
< 25,000
< 25.000 x 109
PT, High
(not on
anticoagulation
therapy
1.1 to
< 1.25 x
ULN
1.25 to
< 1.50 x
ULN
1.50 to
< 3.00 x
ULN
≥ 3.00 x ULN
WBC,
Decreased
(cells/mm3;
cells/L)
> 7 days of
age
2,000 to 2,499
2.000 x 109 to
2.499 x 109
1,500 to 1,999
1.500 x 109 to
1.999 x 109
1,000 to 1,499
1.000 x 109 to
1.499 x 109
< 1,000
< 1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to
6.999 x 109
4,000 to 5,499
4.000 x 109 to
5.499 x 109
2,500 to 3,999
2.500 x 109 to
3.999 x 109
< 2,500
< 2.500 x 109
 
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16 Male and female sex are defined as sex at birth. For transgender participants 13 years of age who have 
been on hormone therapy for more than 6 consecutive months grade hemoglobin based on the gender with 
which they identify (i.e., a transgender female should be graded using the femaile sex at birth hemoglobin 
laboratory values).
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading
hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result
must be converted to g/dL using appropriate conversion factor for the particular laboratory
Urinalysis
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Glycosuria
(random 
collection tested
by dipstick)
Trace to 1+ or
≤250 mg
2+ or ˃ 250 to
≤ 500 mg
> 2+ or > 500 mg
NA
Hematuria (not to
be reported based
on dipstick
findings or on 
blood believed to
be of menstrual
origin)
6 to < 10 RBCs
per high power
field
≥ 10 RBCs per
high power field
Gross, with or 
without clots OR
With RBC casts 
OR Intervention 
indicated
Life-threatening 
consequences
Proteinuria
(random 
collection tested
by dipstick)
1+
2+
3+ or higher
NA
 
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Appendix A: Total Bilirubin Table for Term and Preterm Neonates
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Total Bilirubin18,
High
(mg/dL; 
µmol/L)19
Term 
Neonate20
< 24 hours of 
age
4 to < 7
68.4 to < 119.7
7 to < 10
119.7 to < 171
10 to < 17
171 to < 290.7
≥ 17
≥ 290.7
24 to < 48
hours of age
5 to < 8
85.5 to < 136.8
8 to < 12
136.8 to < 205.2
12 to < 19
205.2 to < 324.9
≥ 19
≥ 324.9
48 to < 72
hours of age
8.5 to < 13
145.35 to < 222.3
13 to < 15
222.3 to < 256.5
15 to < 22
256.5 to < 376.2
≥ 22
≥ 376.2
72 hours to < 7
days of age
11 to < 16
188.1 to < 273.6
16 to < 18
273.6 to < 307.8
18 to < 24
307.8 to < 410.4
≥ 24
≥ 410.4
7 to 28 days of
age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
≥ 25
≥ 427.5
7 to 28 days of
age
(not breast
feeding)
1.1 to < 1.6 x ULN 1.6 to < 2.6 x ULN 2.6 to < 5.0 x
ULN
≥5.0 x ULN
Preterm
Neonate20
35 to < 37 weeks 
gestational age
Same as for Total
Bilirubin, High,
Term Neonate 
(based on days of
age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based on days of
age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based on days of
age).
Same as for Total
Bilirubin, High, Term
Neonate (based on
days of age).
32 to < 35
weeks 
gestational age 
and < 7 days
of age
NA
NA
10 to < 14
171 to < 239.4
≥ 14
≥ 239.4
28 to < 32
weeks 
gestational age 
and < 7 days
of age
NA
NA
6 to < 10
102.6 to < 171
≥ 10
≥ 171
< 28 weeks 
gestational age 
and
< 7 days of age
NA
NA
5 to < 8
85.5 to < 136.8
≥ 8
≥ 136.8
 
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
7 to 28 days of
age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
≥ 25
≥ 427.5
7 to 28 days of
age
(not breast
feeding)
1.1 to < 1.6 x ULN 1.6 to < 2.6 x ULN 2.6 to < 5.0 x
ULN
≥5.0 x ULN
18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin
normal ranges in the first week of life followed by the benign phenomenon of breast milk jaundice after
the first week of life. Severity grading in this appendix corresponds approximately to cut-offs for
indications for phototherapy at grade 3 and for exchange transfusion at grade 4.
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L.
20 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks gestational age; 
preterm, as < 35 weeks gestational age; and neonate, as 0 to 28 days of age.
Reference
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.1. Jul 2017. Available from: https://rsc.tech-res.com/docs/default-source/safety/daids-
ae-grading-table-mar2017.pdf (date accessed: 5 Mar 2019).
 
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10.9.
Appendix 9:  CDC Classification for HIV-1 Infection (2014)
Note that the CD4+ T-lymphocyte count takes precedence over the CD4+ T-lymphocyte 
percentage in HIV infection stages 1, 2, and 3.  The CD4+ T-lymphocyte percentage 
should only be considered if the count is missing.

HIV infection, stage 0

Indicates early HIV infection, inferred from a negative or indeterminate HIV test 
result within 180 days of a positive result.  The criteria for stage 0 supersede and 
are independent of criteria used for other stages.

HIV infection, stage 1

Laboratory confirmation of HIV infection with no AIDS-defining condition, 
and
o
CD4+ T-lymphocyte count of ≥500 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of ≥26%.

HIV infection, stage 2

Laboratory confirmation of HIV infection with no AIDS-defining condition, and
o
CD4+ T-lymphocyte count of 200 to 499 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of 14% to 25%.

HIV infection, stage 3 (AIDS)

Laboratory confirmation of HIV infection, and
o
CD4+ T-lymphocyte count of <200 cells/L, or
o
CD4+ T-lymphocyte percentage of total lymphocytes of <14%, or
o
Documentation of an AIDS-defining condition (see below).

Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte 
count of >200 cells/L and a CD4+ T-lymphocyte percentage of total 
lymphocytes of >14%. 

HIV infection, stage unknown

Laboratory confirmation of HIV infection, and
o
No information on CD4+ T-lymphocyte count or percentage, and
o
No information on presence of AIDS-defining conditions.

Stage-3-defining opportunistic illnesses in HIV infection

Candidiasis of bronchi, trachea, or lungs 

Candidiasis of oesophagus 

Cervical cancer, invasive
 
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
Coccidioidomycosis, disseminated or extrapulmonary 

Cryptococcosis, extrapulmonary 

Cryptosporidiosis, chronic intestinal (>1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 
month

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related 

Herpes simplex: chronic ulcers (>1 month's duration) or bronchitis, pneumonitis, 
or oesophagitis (onset at age >1 month)

Histoplasmosis, disseminated or extrapulmonary 

Isosporiasis, chronic intestinal (>1 month's duration) 

Kaposi's sarcoma 

Lymphoma, Burkitt's (or equivalent term) 

Lymphoma, immunoblastic (or equivalent term) 

Lymphoma, primary, of brain 

Mycobacterium avium complex or Mycobacterium kansasii, disseminated or 
extrapulmonary 

Mycobacterium tuberculosis of any site, pulmonary, disseminated or 
extrapulmonary 

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis jirovecii pneumonia 

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy 

Salmonella septicaemia, recurrent 

Toxoplasmosis of brain, onset at age >1 month 

Wasting syndrome attributed to HIV.
 
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10.10.
Appendix 10: Abbreviations and Trademarks
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
ACTG
International AIDS Society
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
Anti-HBc
Hepatitis B Core Antibody
ARV
Antiretroviral
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
BIC
Bictegravir
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
c/mL
Copies/milliliter
CDC
Centers for Disease Control and Prevention
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRF
Case Report Form
COMBIVIR
Lamivudine and zidovudine
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CrCl
Creatinine Clearance
CSR
Clinical Study Report
CV
Cardiovascular
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDI
Drug-Drug Interaction
dL
Deciliter
DHHS
Department of Health and Human Services
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DTG
Dolutegravir, TIVICAY
EACS
European AIDS Clinical Society
ECG
Electrocardiogram
eCRF
Electronic case report form
EFV
Efavirenz
eGFR
Estimated glomerular filtration rate
FDA
Food and Drug Administration
FDC
Fixed-dose combination
FSH
Follicle stimulating hormone
FTC
Emtricitabine
GCP
Good Clinical Practice
GCSP
GSK’s Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
 
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GFR
Glomerular Filtration rate
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HDPE
High density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HRT
Hormonal replacement therapy
HSR
Hypersensitivity reaction
IAS
International AIDS Society
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICF
Informed Consent Form 
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMP
Investigational medicinal product
INI
Integrase inhibitor
INSTI
Integrase strand transfer inhibitor
INR
International normalized ratio
IQR
Interquartile range
IRB
Institutional Review Board
ITT-E
Intent-to-treat exposed
IUD
Intrauterine device
IUS
Intrauterine hormone-replacing system
IWRS/IWRS
Interactive Voice/Web Recognition System
LDL 
Low density lipoprotein
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
Mol/L
Micromole/Liter
Mg
Milligram
Mg/dL
Milligram per deciliter
Mg/min
Milligram per minute
MSDS
Material Safety Data Sheet
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed Case
OCT-2
Organic cation transporter
PEP
Post-exposure prophylaxis
PI
Protease inhibitor
PK
Pharmacokinetic
POCBP
Participants of childbearing potential
PPD
Pharmaceutical Product Development
 
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PrEP
Pre-exposure prophylaxis
PRO
Protease
PSRAE
Possible suicidality-related adverse event
QTc
Corrected QT interval 
RAL
Raltegravir
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RNA
Ribonucleic acid
RPR
Rapid plasma reagin
RT
Reverse transcriptase
SAE
Serious adverse event
SDM
Symptom Distress Module
SoA
Schedule of Activites
SJS
Stevens-Johnson syndrome
SRM
Study Reference Manual
SUSAR
Suspected unexpected serious adverse reactions
TAF
Tenofovir alafenamide 
TDF/FTC
Tenofovir disoproxil fumarate/Emtricitabine, Truvada
TEN
Toxic epidermal necrolysis
TRIUMEQ
Abacavir, dolutegravir, and lamivudine
ULN
Upper limit of normal
VSLC
ViiV Safety and Labelling Committee
WBC
White blood cell
WHO
World Health Organization
ZDV/3TC
Zidovudine/lamivudine, COMBIVIR
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
COMBIVIR
Abbot Realtime HIV-1
DOVATO
GenoSure
EPIVIR
Monogram Biosciences
EPZICOM/ KIVEXA
PhenoSense
TIVICAY
Symptom Distress Module
TRIUMEQ
Truvada
ZIAGEN
 
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10.11.
Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
 
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11.
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