ING117175: a Phase IIIb, Randomized, Open-label Study of the Safety and Efficacy of Dolutegravir or Efavirenz Each Administered With Two NRTIs in HIV-1-infected Antiretroviral Therapy-naïve Adults Starting Treatment for Rifampicin-sensitive Tuberculosis
Phase: PHASE3
Conditions: Infection, Human Immunodeficiency Virus, HIV Infections
Sponsor: ViiV Healthcare

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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
ING117175: a Phase IIIb, randomized, open-label study of the 
safety and efficacy of dolutegravir or efavirenz each 
administered with two NRTIs in HIV-1-infected antiretroviral 
therapy-naïve adults starting treatment for rifampicin-sensitive 
tuberculosis
Compound Number:
GSK1349572
Development Phase:
IIIb
Effective Date:
10-JUL-2018
Protocol Amendment Number:  02
Author (s):
 
 
Copyright 2018 ViiV Healthcare group of companies.  All rights reserved.  Unauthorised 
copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N190475_00
2014-APR-24
Original
2014N190475_01
2016-MAR-21
Amendment No 1
Amended to include: change to the sample size from ~125 to ~115 (5%) to alleviate the 
enrolment difficulties while maintaining a high power for the sample size assumption; 
clarification that the 2 month sputum TB culture to be performed on solid medium is 
preferred rather than mandated, correction of the list of participating countries, some 
minor clarifications to inclusion and exclusion criteria, clarification on the ability to 
perform GeneXpert testing (or equivalent validated test) at the Screening Visit, addition 
of investigator instructions on the new SAE review requirement in the eCRF, 
reformatting of Figure 6 to improve readability, and other minor clarifications and 
corrections of typographical errors.
2014N190475_02
2018-JUL-10
Amendment No 2
Changes were made to the protocol to manage and mitigate risks following identification 
of a potential safety issue related to neural tube defects in infants born to women with 
exposure to dolutegravir at the time of conception. Changes were also made to update 
references to the DTG IB to reflect the most current versions.  

The Risk Assessment table (Section 1.3.1, Table 1) was updated to include language 
regarding risk and mitigation of neural tube defects.

The inclusion criteria (Section 4.2) were updated to align the pregnancy information 
with more recent protocols.

The withdrawal criteria (Section 4.5) were updated to include a reminder that females 
of reproductive potential who change their minds and desire to be pregnant, or who 
state they no longer are willing to comply with the approved pregnancy avoidance 
methods, should also be withdrawn from the study.

The Time and Events table (Section 6.1, Table 2). was updated to include a reminder 
for investigators to check at every visit that females of reproductive potential are 
avoiding pregnancy.

A new appendix was added detailing pregnancy information, including the modified 
list of highly effective methods for avoiding pregnancy in FRP and the collection of 
pregnancy data (Appendix 9, Section 11.9.1). The double barrier method of 
contraception, which does not meet updated GSK/ViiV criteria for a highly effective 
method, was excluded.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier: ING117175
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is implementing and 
managing all aspects of this study.
Sponsor Legal Registered Address:
ViiV Healthcare UK Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Telephone: 
Sponsor Contact Address
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, local law requires that the Clinical Trial sponsor is a local company 
legal entity. In these instances, the appropriate company to be identified as Sponsor must 
be agreed with the global ViiV Healthcare clinical team and signed off by the Vice 
President, Global Research and Medical Strategy
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is supporting ViiV 
Healthcare in the conduct of this study
Medical Monitor and Serious Adverse Events (SAE) Contact Information:
 MD, PhD
PPD
3900 Paramount Parkway, South Building, 3rd Floor, Office 352
Morrisville, NC 27560-8408
Phone: 
Fax: 
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number ING117175:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SUMMARY...............................................................................................13
1.
INTRODUCTION....................................................................................................16
1.1.
Background ................................................................................................16
1.2.
Rationale ....................................................................................................17
1.3.
Benefit:Risk Assessment ............................................................................18
1.3.1.
Risk Assessment .........................................................................19
1.3.2.
Benefit Assessment.....................................................................24
1.3.3.
Overall Benefit:Risk Conclusion...................................................25
2.
OBJECTIVES.........................................................................................................25
2.1.
Primary Objective .......................................................................................25
2.2.
Secondary Objectives.................................................................................25
2.3.
Tertiary Objectives......................................................................................25
3.
INVESTIGATIONAL PLAN.....................................................................................26
3.1.
Study Design ..............................................................................................26
3.1.1.
Screening Period .........................................................................27
3.1.2.
Randomized Phase (Day 1 to Week 48 plus 4-Week 
Extension)....................................................................................27
3.1.3.
DTG Open-Label Extension.........................................................28
3.1.4.
Study Completion ........................................................................29
3.1.5.
Follow-up.....................................................................................29
3.2.
Discussion of Design ..................................................................................29
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................30
4.1.
Number of Subjects ....................................................................................30
4.2.
Inclusion Criteria.........................................................................................31
4.3.
Exclusion Criteria........................................................................................33
4.4.
Other Eligibility Criteria Considerations.......................................................35
4.5.
Withdrawal Criteria .....................................................................................35
4.6.
Virologic Criteria for Subject Management and Viral Resistance 
Testing........................................................................................................37
4.6.1.
Management of Subjects Meeting Suspected Virologic 
Withdrawal Criteria ......................................................................39
4.7.
Retest Criteria for Subjects With Plasma HIV-1 RNA Levels 
50 c/mL at Week 48....................................................................................39
4.8.
Protocol-Defined Failure of TB Treatment...................................................40
4.9.
Screening Failures......................................................................................40
5.
STUDY TREATMENTS..........................................................................................41
5.1.
Investigational Product and Other Study Treatment....................................41
5.1.1.
Tablet Formulation of DTG ..........................................................41
5.1.2.
Tablet Formulation of EFV...........................................................41
5.1.3.
Background NRTIs ......................................................................42
5.1.4.
Dosage and Administration..........................................................42
 
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5.1.5.
Protocol-Permitted Substitutions..................................................42
5.2.
Treatment Assignment................................................................................43
5.3.
Blinding.......................................................................................................43
5.4.
Product Accountability ................................................................................43
5.5.
Treatment Compliance................................................................................43
5.6.
Concomitant Medications and Non-Drug Therapies....................................43
5.6.1.
Permitted Medications and Non-Drug Therapies..........................44
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................44
5.6.3.
Prohibited Medications for Subjects Randomly Assigned 
to DTG.........................................................................................45
5.6.4.
Prohibited Medications for Subjects Randomly Assigned 
to EFV .........................................................................................45
5.7.
Treatment After the End of the Study..........................................................45
5.8.
Treatment of Study Treatment Overdose....................................................46
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................47
6.1.
Time and Events Schedule .........................................................................47
6.1.1.
TB Time and Events Schedule.....................................................52
6.2.
Critical Baseline Assessments....................................................................52
6.2.1.
Screening Assessments ..............................................................52
6.2.2.
Baseline Assessments (Day 1) ....................................................53
6.3.
Efficacy.......................................................................................................54
6.3.1.
Efficacy Evaluations.....................................................................54
6.3.2.
Primary Efficacy Endpoint............................................................54
6.3.3.
Secondary Efficacy Endpoints .....................................................55
6.3.4.
Tertiary Efficacy Endpoints ..........................................................55
6.4.
Safety .........................................................................................................55
6.4.1.
Safety Endpoints..........................................................................56
6.4.2.
Toxicity Management...................................................................57
6.4.3.
Specific Toxicity Management .....................................................59
6.4.3.1.
Liver Chemistry Stopping and Follow-up 
Criteria........................................................................59
6.4.3.1.1.
Alternate RIF-Containing TB 
Treatment Regimen and Bridging 
Regimen.................................................62
6.4.3.2.
Restarting Investigational Product ..............................63
6.4.3.3.
TB-Associated IRIS Toxicity Management..................64
6.4.3.4.
Decline in Renal Function...........................................64
6.4.3.5.
Allergic Reaction ........................................................65
6.4.3.6.
Hypertriglyceridemia/Hypercholesterolemia................65
6.4.3.7.
Creatine Phosphokinase Elevation.............................65
6.4.3.8.
Rash...........................................................................66
6.4.3.9.
Petechial Rash ...........................................................67
6.4.4.
Adverse Events............................................................................67
6.4.4.1.
Definition of an AE......................................................67
6.4.4.2.
Definition of an SAE ...................................................68
6.4.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................69
6.4.6.
TB-Associated Immune Reconstitution Inflammatory 
Syndrome ....................................................................................69
6.4.7.
Cardiovascular Events.................................................................71
6.4.8.
Death Events...............................................................................71
 
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6.4.9.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................72
6.4.10.
Suicidality Monitoring...................................................................72
6.4.11.
Pregnancy ...................................................................................73
6.4.11.1.
Pregnancy Testing......................................................73
6.4.11.2.
Time Period for Collecting Pregnancy 
Information .................................................................73
6.4.11.3.
Action to be Taken if Pregnancy Occurs.....................73
6.4.12.
Time Period and Frequency of Detecting AEs and SAEs.............74
6.4.13.
Method of Detecting AEs and SAEs.............................................74
6.4.14.
Prompt Reporting of Serious Adverse Events and Other 
Events .........................................................................................74
6.4.14.1.
Regulatory Reporting Requirements for SAEs............76
6.4.14.2.
Reporting of ABC Hypersensitivity Reactions .............76
6.4.15.
Other Safety Outcomes ...............................................................76
6.5.
Pharmacokinetics .......................................................................................77
6.5.1.
Pharmacokinetic Endpoints .........................................................77
6.5.2.
Pharmacokinetic Sample Collection.............................................77
6.5.3.
Bioanalysis of DTG and EFV PK Samples...................................79
6.6.
Viral Genotyping and Phenotyping..............................................................79
6.6.1.
Viral Endpoint ..............................................................................79
6.6.2.
HIV-1 Polymerase Viral Genotyping and Phenotyping .................80
6.6.3.
HIV-1 Exploratory Analysis ..........................................................80
6.7.
Pharmacogenetic Research........................................................................80
7.
DATA MANAGEMENT ...........................................................................................80
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................81
8.1.
Hypotheses.................................................................................................81
8.1.1.
Sample Size Assumptions ...........................................................81
8.2.
Study Design Considerations......................................................................82
8.2.1.
Sample Size Sensitivity................................................................82
8.2.2.
Sample Size Re-estimation..........................................................84
8.2.3.
Analysis Populations....................................................................84
8.2.3.1.
Intent-to-Treat Exposed (ITT-E) Population ................84
8.2.3.2.
Modified Intent-to-Treat Exposed (MITT-E) 
Population ..................................................................85
8.2.3.3.
Per-Protocol Population..............................................85
8.2.3.4.
Safety Population .......................................................85
8.2.3.5.
PK Population.............................................................85
8.2.3.5.1.
DTG PK Population ................................85
8.2.3.5.2.
EFV PK Population.................................85
8.2.4.
Analysis Data Sets.......................................................................85
8.2.5.
Treatment Comparisons ..............................................................86
8.2.6.
Interim Analysis ...........................................................................86
8.2.7.
Key Elements of Analysis Plan ....................................................86
8.2.7.1.
Efficacy Analyses .......................................................86
8.2.7.2.
Safety Analyses..........................................................87
8.2.7.3.
Pharmacokinetic and 
Pharmacokinetic/Pharmacodynamic Analyses ...........87
8.2.7.4.
Viral Genotyping/Phenotyping Analyses.....................88
8.2.7.5.
Pharmacogenetic Analyses ........................................88
 
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9.
STUDY CONDUCT CONSIDERATIONS ...............................................................88
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............88
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................88
9.3.
Quality Control (Study Monitoring) ..............................................................89
9.4.
Quality Assurance.......................................................................................89
9.5.
Study and Site Closure ...............................................................................90
9.6.
Records Retention......................................................................................90
9.7.
Provision of Study Results to Investigators, and Posting of 
Information on Publicly Available Clinical Trials Registers and 
Publication..................................................................................................91
10. REFERENCES.......................................................................................................92
11. APPENDICES........................................................................................................96
11.1.
Appendix 1 Pharmacogenetic Research .....................................................96
11.2.
Appendix 2 CDC Classification System for HIV-1 Infections (1993) ..........102
11.3.
Appendix 3 Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events...................................................................105
11.4.
Appendix 4 Country-Specific Requirements..............................................130
11.5.
Appendix 5 Liver Safety Drug Restart or Rechallenge Guidelines.............131
11.6.
Appendix 6 Alternate RIF-Containing TB Treatment Regimens ................136
11.7.
Appendix 7 Karnofsky Performance Status Scale.....................................137
11.8.
Appendix 8 Child-Pugh Classification .......................................................138
11.9.
Appendix 9:  Pregnancy Information .........................................................139
11.9.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) 
and Collection of Pregnancy Information ...................................139
11.9.2.
Collection of Pregnancy Information ..........................................139
11.10. Appendix 10 Protocol Changes.................................................................141
11.10.1. Amendment 01: A global protocol amendment applicable 
to all participating countries:.......................................................141
11.10.2. Protocol changes for Amendment 02 from Amendment 01:.......144
 
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LIST OF ABBREVIATIONS
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
ART
Antiretroviral therapy
BUN
Blood urea nitrogen
c/mL
Copies/milliliter
CDC
Centers for Disease Control and Prevention
CD4+
Helper-inducer T-lymphocyte having surface antigen CD4 
(cluster of differentiation 4)
C-SSRS
Columbia-Suicidality Severity Rating Scale
CI
Confidence interval
CPK
Creatine phosphokinase
CrCL
Creatinine clearance
CYP
Cytochrome P450
DAIDS
Division of Acquired Immunodeficiency Syndrome
DHHS
United States Department of Health and Human Services
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DRV
Darunavir, Prezista
DRV/r
Darunavir + Ritonavir
DTG
Dolutegravir
ECG
Electrocardiograph
eCRF
Electronic case report form
EFV
Efavirenz, Sustiva
FDA
US Food and Drug Administration
FTC
Emtricitabine, Emtriva
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus 
HIV-1
Human immunodeficiency virus type 1
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INI
Integrase inhibitor
INR
International normalized ratio
IP
Investigational product
 
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IRB
Institutional Review Board
IRIS
Immune reconstitution inflammatory syndrome
ITT
Intent-to-treat
ITT-E
Intent-to-treat-exposed
IVRS
Interactive voice response system
LDL
Low-density lipoprotein
LN
Lymph node
mg
Milligram
MITT-E
Modified intent-to-treat
mL
Milliliter
MTB
Mycobacterium tuberculosis
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OLE
Open-label extension
PCR
Polymerase chain reaction
PGx
Pharmacogenetic
PI
Protease inhibitor
PK
Pharmacokinetic
PRO
Protease
PSRAE
Possible suicidality-related adverse event
PT
Prothrombin time
RAL
Raltegravir, Isentress
RAP
Reporting and analysis plan
RIF
Rifampicin
RNA
Ribonucleic acid
RT
Reverse transcriptase
SAE
Serious adverse event
SPM
Study Procedures Manual
TB
Tuberculosis
TDF
Tenofovir disoproxil fumarate, Viread
TDF/FTC
Tenofovir disoproxil fumarate/Emtricitabine, Truvada
TMP-SMX
Trimethoprim-sulfamethoxazole
ULN
Upper limit of normal
VSLC
ViiV Safety and Labeling Committee
WHO
World Health Organization
 
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Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Atripla
EPZICOM
Complera 
KIVEXA
Efavirenz
TIVICAY
Emtriva
TRIZIVIR
GeneXpert
ZIAGEN
GenoSure
Isentress 
MedDRA
Monogram Biosciences
PhenoSense
Quest Diagnostics
SAS
Standard Phenosense
 
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PROTOCOL SUMMARY
Rationale
Study ING117175 is being conducted to assess the antiretroviral activity of a dolutegravir 
(DTG)-containing regimen (50 mg twice-daily during tuberculosis [TB] treatment and for 
2 weeks following discontinuation of TB treatment, then 50 mg once-daily, with 
2 nucleoside reverse transcriptase inhibitors [NRTIs]) in antiretroviral therapy 
(ART)-naïve patients with human immunodeficiency virus (HIV)-1 infection taking 
rifampicin (RIF)-containing first-line treatment for pulmonary, pleural, and lymph node 
(LN) RIF-sensitive TB. Safety, TB-associated immune reconstitution inflammatory 
syndrome (IRIS), and tolerability will also be explored. This study is designed to assess 
the antiviral activity of DTG and efavirenz (EFV) ART-containing regimens through 
48 weeks.
Objectives
Primary Objective
To assess the antiviral activity at 48 weeks of a DTG-containing regimen (50 mg twice 
daily during TB treatment and for 2 weeks following discontinuation of TB treatment, 
then 50 mg once daily, with 2 NRTIs) in ART-naïve patients with HIV-1 infection taking 
RIF-containing TB treatment.
Secondary Objectives

To assess the antiviral activity of DTG and EFV both administered with 2 NRTIs at 
Week 24;

To assess the antiviral activity of EFV administered with 2 NRTIs at Week 48;

To evaluate immunological activity (CD4+ lymphocyte [CD4 counts]) at Week 24 
and Week 48;

To evaluate the safety, TB-associated IRIS, and tolerability in subjects treated with a 
DTG- or EFV-based regimen concurrently with treatment for TB over time;

To assess the development of HIV-1 resistance in subjects who meet confirmed 
virologic withdrawal criteria over 24 and 48 weeks.
Tertiary Objectives

To evaluate the incidence of disease progression (HIV-associated conditions, 
acquired immunodeficiency syndrome [AIDS], and death) over time;

To describe rates of TB treatment success (using the World Health Organization 
[WHO] definition) for all subjects;

To describe the proportion of subjects with pulmonary tuberculosis who are sputum 
culture-negative 2 months after starting TB treatment; 
 
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
To evaluate concentrations of DTG and EFV using sparse sampling and to 
characterize DTG pharmacokinetics and variability during and post TB treatment 
and to explore the association between DTG and EFV concentrations and antiviral 
activity at Week 24 and Week 48.
Study Design
This is a Phase IIIb, randomized, open-label study describing the efficacy and safety of 
DTG and EFV-containing ART regimens in HIV/TB co-infected patients. The study will 
be conducted in approximately (5%) 115 HIV-1 infected individuals who are ART-
naïve with a CD4+ cell count 50 cells/mm3 and newly diagnosed with confirmed 
pulmonary, pleural, or LN Mycobacterium TB (MTB) taking RIF-containing first-line TB 
treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined 
by GeneXpert (or equivalent approved molecular test) or mycobacterial culture. Eligible 
subjects will be randomly assigned in a 3:2 ratio to receive DTG plus 2 NRTIs 
(approximately 69 subjects) or EFV plus 2 NRTIs (approximately 46 subjects). The dual 
NRTI backbone will be selected by the investigator in accordance with local standard of 
care and per current WHO or national guidelines for the treatment of HIV/TB co-infected 
adults. Subjects randomization will be stratified by screening plasma HIV-1 RNA 
(100,000 c/mL or >100,000 c/mL) and screening CD4+ cell count (100 cells/mm3 or 
>100 cells/mm3). An interim analysis will be conducted when all subjects complete their 
Week 24 visit, the primary Week 48 analysis will be conducted when the last subject 
completes the Randomized Phase, and a final end-of-study analysis will be conducted 
when the final subject randomly assigned to DTG has transitioned from the Open-Label 
Extension (OLE) to commercial supplies of DTG or is withdrawn for the study. 
This study will include a Screening Period, a Randomized Phase (Day 1 to Week 48 plus 
a 4-week extension), and a DTG OLE.
Only protocol-defined dose reductions, modifications, or changes in the frequency of any 
components of each HIV regimen or TB treatment will be allowed at any time in this 
study, including during the Screening Period. 
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table are essential and 
required for study conduct. If deviations are required for the management of immediate 
safety concerns, these should be promptly communicated to the study medical monitor.
Study Endpoints/Assessments
The primary endpoint for this study will be the proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E population in the 
DTG arm.
 
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Secondary Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm in the EFV arm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related adverse event (AE), safety stopping criteria, or 
lack of efficacy);

Changes from baseline in CD4+ counts at Week 24 and Week 48.
Tertiary Efficacy Endpoints

Incidence of disease progression (HIV-associated conditions, new AIDS diagnoses, 
and death);

Proportion of subjects with TB treatment success (using the WHO definition);

Proportion of subjects with pulmonary tuberculosis who are sputum culture-negative 
2 months after starting TB treatment.
Safety endpoints will include: incidence and severity of AEs and laboratory 
abnormalities, proportion of subjects who discontinue treatment due to AEs, and 
proportion of subjects with TB-associated IRIS.
Pharmacokinetic endpoint will include an evaluation of concentrations of DTG and EFV 
measured at Weeks 8, 24, 36, and 48 using sparse sampling.
Virologic endpoint will be the incidence of treatment-emergent genotypic and phenotypic 
resistance to DTG, EFV, and other on-study ART in subjects meeting confirmed 
virologic withdrawal criteria over 24 and 48 weeks.
 
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1.
INTRODUCTION
1.1.
Background
Approximately 14 million individuals worldwide are estimated to be dually infected with 
human immunodeficiency virus (HIV) and tuberculosis (TB). The yearly incidence of TB 
infection is about 10% among patients with HIV and TB is the most common cause of 
death in patients with HIV worldwide. HIV and TB co-infection have profound effects on 
the host’s immune system. Recent studies evaluating the optimal timing for initiation of 
antiretroviral therapy (ART) in patients requiring treatment for active TB demonstrated a 
survival benefit for starting ART soon after TB treatment initiation rather than waiting 
until TB treatment completion. More specifically, current United States Department of 
Health and Human Services (DHHS) guidelines [DHHS, 2014] suggest that for patients 
with a CD4+ cell count <50 cells/mm3, ART should be started within 2 weeks of starting 
TB treatment; for patients with a CD4+ cell count 50 cells/mm3, ART should be started 
within 2 months of starting TB treatment [Török, 2011]. British guidelines suggest 
starting as soon as possible for patients with a CD4+ cell count 100 cells/mm3 [British 
HIV Association (BHIVA) Guidelines, 2011]. As a result of the aforementioned studies 
and guidelines, there is an increase in the number of co-infected individuals being treated 
concurrently.
Currently, rifamycins (such as rifampicin [RIF]) serve as the cornerstone of TB therapy 
because of their unique sterilizing activity. No drug can adequately substitute for 
rifamycins in the TB regimen; if rifamycins cannot be used, treatment duration must be 
substantially prolonged (from 6 months to 9 to 24 months in most cases). TB treatment is 
given in 2 stages: during the first 2 months (intensive phase), patients with RIF-sensitive 
TB receive isoniazid (H), RIF (R), pyrazinamide (Z), and ethambutol (E) (HRZE), and 
during the subsequent 4 months (TB treatment continuation phase), patients receive 
isoniazid and RIF (HR). Some national guidelines recommend a TB treatment 
continuation phase of HR extended to 7 months in HIV and TB co-infected patients. 
Rifampicin is the most commonly used rifamycin for TB treatment. It is a potent inducer 
of cytochrome P450 enzyme activity. By activating the pregnane X receptor (PXR), RIF 
can induce multiple metabolic enzymes, including cytochrome P450 (CYP) isoenzyme 
3A (CYP3A), other CYP enzymes, Phase II drug-metabolizing enzymes, 
UDP-glucosyltransferases, sulfonyltransferases, and drug transporters. Since most 
protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) used 
to treat HIV are metabolized by CYP3A, induction of CYP3A by RIF can lead to reduced 
serum concentrations of antiretroviral drugs with risk of treatment failure or emergence 
of resistance to antiretroviral drugs. Nucleoside reverse transcriptase inhibitor (NRTI) 
concentrations, though, are not reduced by RIF in a clinically meaningful way. In patients 
who must be treated with RIF-containing TB therapy and require concurrent ART, 
efavirenz (EFV)-based ART can be used safely and effectively [Boulle, 2008; DHHS, 
2013; WHO, 2010]. However, because the side effect profile of EFV (which includes
treatment-related rash, CNS effects, and liver enzyme elevations) overlaps with the 
adverse effect profile of HRZE therapy, management of toxicity is complex. Integrase 
inhibitors (INI) may offer an important alternative to EFV-based therapy in TB co-
 
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infected patients. Although the BHIVA guidelines recommend an increased dose of EFV 
of 800 mg for HIV/TB co-infected patients [BHIVA Guidelines, 2011], the DHHS, 
Centers for Disease Control and Prevention (CDC), and WHO TB guidelines do not 
recommend a dose increase of EFV [DHHS, 2014; WHO, 2010; CDC, 2013], because 
the evidence that RIF treatment impacts HIV antiviral responses with EFV-based 
combination ART is weak. In addition, among the minority of patients with lower levels 
of EFV during TB therapy, EFV concentrations remain above the required levels for 
adequate antiviral activity and an even lower dose of EFV has recently been shown to be 
effective. In the ENCORE study, the 400-mg once-daily dose of EFV in combination 
with tenofovir/emtricitabine (TDF/FTC) has been shown to be non-inferior to EFV 
600 mg once daily with TDF/FTC at Week 48 in ART-naive patients [ENCORE1 Study 
Group, 2014]. 
Further, for those with contraindications or resistance to NNRTIs, there are few treatment 
options, as RIF cannot be used safely or effectively with PIs, even with dose adjustment. 
Substitution of rifabutin (RBT) for RIF is a reasonable TB treatment option for HIV/TB 
co-infected adults; however, because RBT is metabolized by CYP3A4, it requires 
bidirectional dose adjustment when given with PIs, and the optimal RBT dosing 
frequency is unknown. In addition, access to rifabutin is difficult in most resource-limited 
settings. The same potential drug interaction problem may occur when treating HIV/TB 
co-infection using recently developed antituberculosis drugs such as the diarylquinoline 
antimycobacterial drug bedaquiline, as exposure to this drug may be reduced during 
co-administration with inducers of CYP3A4 and increased during co-administration with 
inhibitors of CYP3A4 [Sirturo Product Information, 2013]. An antiretroviral drug that 
could be taken with an NRTI backbone and be used safely and effectively with RIF in the 
treatment of HIV/TB co-infection without the need for adjustments to the patient’s TB 
regimen would give physicians and patients an important treatment option. 
1.2.
Rationale
In a Phase II open-label, randomized clinical study, the HIV INI raltegravir (RAL) was 
shown to be a suitable antiretroviral drug alternative to EFV for HIV/TB co-infected 
patients undergoing TB therapy study after 48 weeks of treatment (Grinsztejn, 2014). 
These results support the investigation of other INIs such as dolutegravir (DTG) in 
HIV/TB co-infection. 
DTG is approved in the United States, Canada, the EU, Brazil, and in other countries, and 
is under review with other countries’ regulatory agencies. Two Phase III studies, 
ING114467 (SINGLE) and ING113086 (SPRING-2) evaluated safety and efficacy of 
DTG in HIV-infected adults who were ART-naïve. ING114467 (SINGLE) evaluated the 
safety and efficacy of DTG 50 mg once daily plus FDC abacavir/lamivudine (ABC/3TC) 
600 mg/300 mg compared with Atripla (EFV/FTC/TDF). Following 48 weeks of 
treatment, 88% of the subjects receiving DTG (50 mg once daily plus ABC/3TC) 
compared with 81% of the subjects receiving EFV/FTC/TDF had plasma HIV-1 RNA 
levels of <50 copies/mL; test for superiority had a p=0.003 [Walmsley, 2013]. 
ING113086 (SPRING-2) evaluated antiviral efficacy of DTG 50 mg once daily plus dual 
NRTI. After 48 weeks of treatment, 88% of the subjects receiving DTG (50 mg once 
daily plus TDF/FTC 300 mg/200 mg or ABC/3TC 600 mg/300 mg) compared with 85% 
 
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of those taking RAL (400 mg twice daily plus TDF/FTC 300 mg/200 mg or ABC/3TC 
600 mg/300 mg) had plasma HIV-1 RNA levels of <50 copies/mL [Raffi, 2013a]. DTG 
was shown to be efficacious and non-inferior to RAL in combination with a dual NRTI. 
Non-inferiority between DTG and RAL was also demonstrated at Week 96 [Raffi, 
2013b]. DTG 50 mg twice daily has also been studied in patients with INI-resistant virus 
in the VIKING and VIKING-3 studies and shown to be effective and well tolerated, with 
a safety profile comparable to that of DTG 50 mg once daily [Eron, 2013; Castagna, 
2014]. Rates of discontinuation due to adverse events (AEs) were 2% in the DTG 50 mg 
once a day arms of the ART-naïve studies and 4% in the treatment-experienced 
population in the VIKING-3 study on DTG 50 mg twice a day with an optimized 
background regimen. 
DTG is primarily metabolized by UGT1A1 with CYP3A4 as a minor route, and both 
enzymes are induced by RIF. Therefore a Phase I open-label, 3-period, fixed-sequence 
study was conducted in healthy, HIV-seronegative subjects, evaluating the 
pharmacokinetic (PK) and safety of DTG given alone at a dose of 50 mg once daily to 
that of DTG given at a dose of 50 mg twice daily together with steady-state RIF [Dooley, 
2013]. Twice-daily DTG plus RIF achieved mean DTG concentrations that were 20%-
33% higher than once-daily DTG dosing alone. Specifically, the geometric mean ratio for 
the 24-hour area under the time-concentration curve (AUC0-24), comparing DTG twice 
daily plus RIF with DTG once daily, was 1.33 (90% confidence interval [CI] 1.14 to 
1.54). The GMR for the trough concentration at the end of the dosing interval (C) was 
1.22 (90% CI 1.01 to 1.48). There were no discontinuations for AEs and any Grade 3 or 
higher AEs. In summary, in this Phase I study, DTG at 50 mg twice daily given together 
with standard-dose RIF was well-tolerated and resulted in DTG concentrations similar to 
those of DTG 50 mg given once daily alone. Based on these results and as specified in 
the DTG prescribing information, the dose selection of twice-daily DTG 50 mg plus dual 
NRTI tablet during TB treatment was selected. The twice-daily regimen will be 
maintained for 2 weeks following discontinuation of TB treatment in order to eliminate 
(i.e., washout) the effects of RIF on the induction of UGT1A1 and CYP3A4; thereafter; 
once-daily DTG 50 mg with the same NRTI backbone will be administered through 
Week 48. 
ART regimens using DTG 50 mg twice daily may represent a new treatment option for 
TB-infected patients who require concurrent treatment for HIV infection. This study will 
examine the use of DTG-based regimen among patients with HIV/TB co-infection.
1.3.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with DTG 
can be found in the most current version of the Investigator’s Brochure (IB) [GSK 
Document Number RM2007/00683/11, GSK Document Number 2017N352880_00, 
GSK Document Number 2017N352880_01]];. The following section outlines the risk 
assessment and mitigation strategy for the use of DTG as described in this protocol. 
The approved country product labels should be referenced for RIF and all other 
components of the TB regimen, NRTIs, and EFV. 
 
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1.3.1.
Risk Assessment
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment. Considerations when using DTG are presented in 
Table 1. 
 
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Table 1
Considerations When Using DTG
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
Hypersensitivity and Rash
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. 
Subjects with history of allergy/sensitivity to any of the study drugs 
are excluded (Section 4.3).
Specific/detailed toxicity management guidance is provided for HSR 
(Section 6.4.3.5) and rash (Section 6.4.3.8).
The subject informed consent form includes information on this risk 
and the actions subjects should take in the event of a rash or 
associated signs and symptoms.
Drug induced liver injury 
(DILI) and other clinically 
significant liver chemistry 
elevations
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 subjects with 
hepatitis C virus (HCV) co-infection, improvements in immunosuppression as 
a result of HIV virologic and immunologic responses to DTG- containing ART 
contributed to significant elevations in liver chemistries.  
Drug-induced liver injury is a well-described adverse outcome of TB treatment. 
The risk of DILI from TB treatment is higher if the subject is also co-infected 
with HIV.
Subjects meeting either of the following criteria during the Screening 
Period are excluded from participating (Section 4.3).

Alanine aminotransferase (ALT) 2 times the upper limit of 
normal (ULN)

Subjects with an anticipated need for hepatitis C virus (HCV) 
therapy during the Randomized Phase (Day 1 to Week 48 plus 
a 4-week treatment extension)
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Section 6.4.3.1).  
Theoretical serious drug 
interaction with dofetilide and
pilsicainide
Co-administration of DTG may increase dofetilide/pilsicainide plasma 
concentration via inhibition of organic cation transporter 2 (OCT2), resulting in 
potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide is 
prohibited in the study (Section 5.6.2).
GI intolerance
Non-clinical studies showed upper and lower GI toxicity, including vomiting, 
diarrhoea and gastric erosions observed in monkey toxicology studies (thought 
to be related to local and not systemic toxicity).  
Mild to moderate GI intolerance (mainly diarrhoea and nausea) is associated 
Routine monitoring of GI symptoms will be performed.
 
 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
with DTG treatment in a small proportion of subjects; however there were no 
indications of an increased risk for peptic ulcers or serious erosions.
Renal function
Mild elevations of creatinine have been observed with DTG which are related 
to a likely benign effect on creatinine secretion with blockade of OCT2 
receptor. DTG has been shown to have no significant effect on glomerular 
filtration rate (GFR) or effective renal plasma flow. 
Specific/detailed toxicity management guidance is provided for 
subjects who develop a decline in renal function (Section 6.4.3.4). 
Psychiatric disorders
Psychiatric disorders including suicide ideation and behaviours are common in 
HIV-infected patients. The psychiatric profile for DTG (including suicidality, 
depression, bipolar and hypomania, anxiety and abnormal dreams) was 
similar or favourable compared with other ART. 
The reporting rate for insomnia was statistically higher for blinded 
DTG+ABC/3TC compared with EFV/TDF/FTC in ING114467; however, this 
was not duplicated in any other Phase IIb/III study conducted with DTG.  
Subjects who in the investigator’s judgment, poses a significant 
suicidality risk, are excluded from participating (Section 4.3).
Because of the elevated risk in the HIV- infected population, 
treatment emergent assessment of suicidality will be monitored 
during this study. Investigators are advised to consider mental 
health consultation or referral for subjects who experience signs of 
suicidal ideation or behaviour (Section 6.4.10).
Creatine phosphokinase 
(CPK)  elevations
Asymptomatic CPK elevations mainly in association with exercise have been 
reported with DTG therapy.
Specific detailed toxicity management guidance is provided for 
subjects who develop Grade 3 to 4 CPK elevations 
(Section 6.4.3.7).
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 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 female subject is eligible to participate if she is not pregnant, 
not lactating, and, if she is a female of reproductive potential, 
agrees to follow one of the options listed in the Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 9, Section 11.9.1)
during treatment and until 2 weeks after the last dose of study 
medication 
2. Women who are breastfeeding or plan to become pregnant or 
breastfeed during the study are excluded.
3. Women who become pregnant, or 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 
 
 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
have study treatment discontinued and be withdrawn from the 
study.
4. Females of reproductive potential are reminded re: pregnancy 
avoidance and adherence to contraception requirements at 
every study visit.
5. Pregnancy status is monitored at every study visit
Increased occurrence of 
immune reconstitution 
inflammatory syndrome 
(IRIS)
With rapid HIV-1 RNA decline and early recovery of CD4+ cell counts there 
could theoretically, be an increase in cases of IRIS. 
Based on medical adjudication of IRIS-like events in ING111762, ART-
experienced (INI-naïve) subjects with hepatitis C virus co-infection receiving 
DTG may be at greater risk for IRIS than those receiving RAL, due to 
improved HIV virologic and immunologic responses with DTG compared with 
RAL. 
Subjects will be monitored for signs and symptoms of TB-associated 
IRIS. Definitions on criteria for diagnosing these cases are provided 
in Section 6.4.6. Subjects will also have frequent liver chemistry 
monitoring. Robust liver chemistry stopping criteria and liver event 
follow-up assessments are included. 
 
 
 
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3TC = lamivudine, ABC = abacavir, ART = antiretroviral therapy, ALT = alanine aminotransferase, CPK = creatine phosphokinase, DILI = drug induced liver injury, DTG = dolutegravir, 
EFV = efavirenz, FTC = emtricitabine, GFR = glomerular filtration rate, GI = gastrointestinal, HCV = hepatitis C virus, IRIS = immune reconstitution inflammatory syndrome, 
TDF = tenofovir, OCT2 = organic cation transporter 2, ULN = upper limit of normal
a.
Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3/4 laboratory toxicities (per Division of Acquired Immune 
Deficiency Syndrome [DAIDS] toxicity gradings for HIV-infected patients). Serious/severe events will be managed appropriately including, but not limited to, withdrawal of 
investigational product (IP), and will be followed to resolution as per sponsor’s standard medical monitoring practices. Clinical safety data will be routinely reviewed in GSK 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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Events will be monitored using SAE reports and alerts for Grade 3/4 laboratory toxicities 
(according to the Division of Acquired Immune Deficiency Syndrome [DAIDS] toxicity 
grading for HIV-infected patients as described in Section 11.3). Serious/severe events 
will be managed appropriately including, but not limited to, IP being withdrawn, and will 
be followed to resolution by the medical monitor. Further information on SAE reporting 
is described in Section 6.4.14.
Clinical safety data will be routinely reviewed in GSK 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.
1.3.2.
Benefit Assessment
Early initiation of HAART together with HRZE therapy significantly reduces mortality in 
HIV-TB co-infected patients [DHHS, 2013]. Both EFV-based and RAL-based therapy 
have been shown to be effective for HIV/TB co-infected patients; in the REFLATE 
study, 48 week success rates with RAL 400 twice daily was 76% (95% CI 65-88), 63% 
(95% CI 49-76) with RAL 800 mg twice daily; and 67% (95% CI 54-80) with EFV, with 
no significant differences among the groups. Thirty-three percent to 37% of the subjects 
in each treatment group developed Grade 3 or higher AEs. These results suggest the 
possibility for improvements in treatment outcomes.
The safety profile for DTG 50 mg once daily was comparable to RAL and 
darunavir + ritonavir (DRV/r) and generally favorable to the EFV/TDF/FTC STR 
(Atripla) in both ART-naïve and ART-experienced (INI-naïve) patients (studies 
ING113086 [SPRING-2], ING111762 [SAILING], ING114915 [FLAMINGO] and 
ING114467 [SINGLE]). The most frequently observed AEs across patient populations 
were diarrhea, nausea, and headache, which were generally Grade 1 or 2 in severity, and 
typically did not lead to discontinuation from studies. With regards to antiviral efficacy, 
in treatment-naïve HIV-infected adult subjects, DTG 50 mg once daily was shown to be 
non-inferior to RAL in combination with a dual NRTI background regimen (SPRING-2). 
In study ING114915 (FLAMINGO), virologic suppression (HIV-1 RNA <50 c/mL) in 
the DTG arm (90%) was statistically superior to the DRV/r arm (83%) at Week 48. When 
used in combination with ABC/3TC, DTG was shown to be superior to EFV/TDF/FTC, a 
result driven by better tolerability of the DTG based regimen (SINGLE). In study 
ING111762 (SAILING), 71% of in INI-naïve ART-experienced patients receiving DTG 
achieved undetectable viral load (<50 c/ml) compared with 64% of those taking RAL at 
Week 48, reaching the threshold for statistical superiority [Cahn, 2013]. In the
ING112574 (VIKING-3) study, DTG administered at 50 mg twice daily was 
demonstrated to be safe and effective in patients with INI resistance [Castagna, 2014, 
GlaxoSmithKline Document Number 2013N177327_00].
Study participants may also benefit from the medical tests and screening procedures 
performed as part of the study.
 
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1.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with the DTG are justified by the 
anticipated benefits that may be afforded to HIV-1/TB co-infected ART-naïve adults.
2.
OBJECTIVES
2.1.
Primary Objective
To assess the antiviral activity at 48 weeks of a DTG-containing regimen (50 mg twice 
daily during TB treatment and for 2 weeks following discontinuation of TB treatment, 
then 50 mg once daily, with 2 NRTIs) in ART-naïve patients with HIV-1 infection taking 
RIF-containing TB treatment.
2.2.
Secondary Objectives

To assess the antiviral activity of DTG and EFV both administered with 2 NRTIs at 
Week 24;

To assess the antiviral activity of EFV administered with 2 NRTIs at Week 48;

To evaluate immunological activity (CD4+ lymphocyte [CD4 counts]) at Week 24 
and Week 48;

To evaluate the safety, TB-associated immune reconstitution inflammatory syndrome 
(IRIS), and tolerability in subjects treated with a DTG- or EFV-based regimen 
concurrently with treatment for TB over time;

To assess the development of HIV-1 resistance in subjects who meet confirmed 
virologic withdrawal criteria over 24 and 48 weeks.
2.3.
Tertiary Objectives

To evaluate the incidence of disease progression (HIV-associated conditions, 
acquired immunodeficiency syndrome [AIDS], and death) over time;

To describe rates of TB treatment success (using the WHO definition [WHO, 2010]) 
for all subjects;

To describe the proportion of subjects with pulmonary tuberculosis who are sputum 
culture-negative 2 months after starting TB treatment; 

To evaluate concentrations of DTG and EFV using sparse sampling and to 
characterize DTG PK and variability during and post TB treatment and to explore the 
association between DTG and EFV concentrations and antiviral activity at Week 24 
and Week 48.
 
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3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This is a Phase IIIb, randomized, open-label study describing the efficacy and safety of 
DTG and EFV-containing ART regimens in HIV/TB co-infected patients. The study will 
be conducted in approximately (5%) 115 HIV-1 infected individuals who are ART-
naïve with a CD4+ cell count 50 cells/mm3 and newly diagnosed with confirmed 
pulmonary, pleural, or LN Mycobacterium TB (MTB) taking RIF-containing first-line TB 
treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined 
by GeneXpert (or equivalent approved molecular test) or mycobacterial culture. 
Figure 1
Study Schematic
DTG = dolutegravir; EFV = efavirenz; max = maximum; mg = milligram; min = minimum; NRTI = nucleoside reverse 
transcriptase inhibitor; NTP = National TB Control Program; RIF = rifampicin; TB = tuberculosis
Note: TB treatment including isoniazid, RIF, pyrazinamide, and ethambutol will be provided at standard doses by the 
NTP under program conditions.
Eligible subjects will be randomly assigned in a 3:2 ratio to receive DTG plus 2 NRTIs 
(approximately 69 subjects) or EFV plus 2 NRTIs (approximately 46 subjects). The dual 
NRTI backbone will be selected by the investigator in accordance with local standard of 
care and per current WHO or national guidelines for the treatment of HIV/TB co-infected 
adults. Subjects randomization will be stratified by screening plasma HIV-1 RNA 
 
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(100,000 c/mL or >100,000 c/mL) and screening CD4+ cell count (100 cells/mm3 or 
>100 cells/mm3). An interim analysis will be conducted when all subjects complete their 
Week 24 visit, the primary Week 48 analysis will be conducted when the last subject 
completes the Randomized Phase, and a final end-of-study analysis will be conducted 
when the final subject randomly assigned to DTG has transitioned from the Open-Label 
Extension (OLE) to commercial supplies of DTG or is withdrawn for the study. 
This study will include a Screening Period, a Randomized Phase (Day 1 to 48 weeks plus 
a 4-week extension), and a DTG OLE.
Only protocol-defined dose reductions, modifications, or changes in the frequency of any 
components of HIV regimen or TB treatment will be allowed at any time in this study, 
including during the Screening Period (Section 5.1.5). 
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table (Table 2), are 
essential and required for study conduct. If deviations are required for the management of 
immediate safety concerns, these should be promptly communicated to the study medical 
monitor.
3.1.1.
Screening Period
TB diagnosis and confirmation of RIF-sensitive MTB infection must be performed 
locally. If the result confirming MTB infection is not available before the subject is 
screened, the assessment can be performed simultaneously in order to screen the subject 
for the study. Subjects with RIF-resistant TB are not eligible to enter the study. 
GeneXpert or other molecular test result is required to rule out RIF resistance prior to 
entry. Mycobacterial culture may be used to confirm RIF-sensitivity (as an alternative to 
GeneXpert or molecular testing) provided the culture results are available prior to 
randomization. The 14-day Screening Period may be extended to 28 days to allow receipt 
of all screening assessment results and to accommodate scheduling. Subjects are allowed 
to re-screen for this study one time; this will require a new subject ID number. A single 
repeat test (retest) per analyte or assessment is allowed during the Screening Period to 
determine eligibility, except for HIV drug resistance testing.
3.1.2.
Randomized Phase (Day 1 to Week 48 plus 4-Week Extension)
As soon as all screening results are available, subjects who fulfill all eligibility 
requirements will be randomly assigned in a 3:2 ratio to receive either DTG or EFV-
containing regimens, respectively. DTG or EFV regimens will be started up to 8 weeks 
after TB treatment initiation and will continue for 48 weeks, plus a 4-week extension.
TB treatment consisting of HRZE for 2 months (i.e., TB treatment intensive phase) 
followed by HR for 4 or 7 months (i.e., TB treatment continuation phase) will be 
administered according to local guidelines with TB treatment provided by the National 
TB Control Programs (NTP) in accordance with national guidelines. Sputum will be 
collected from subjects with pulmonary tuberculosis 2 months after initiating TB 
treatment (solid media culture testing is preferred). Sputum will also be collected at 
 
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4 months, 6 months, and 9 months (for subjects who receive TB treatment for 9 months) 
for smear and culture, for as long as the subject is able to produce sputum. Sputum 
samples are not required from subjects diagnosed only from pleural or LN aspirates that 
do not also have pulmonary disease. The same laboratory and method of MTB culture 
must be used during the study.
Subjects assigned to Arm 1 will receive DTG 50 mg twice-daily with 2 NRTIs until 
2 weeks after TB therapy is completed then they will receive DTG 50 mg once daily 
(with the same NRTI backbone) through the end of the Randomized Phase. Subjects 
randomized to Arm 2 will receive EFV 600 mg once daily plus 2 NRTIs through the end 
of the Randomized Phase. The NRTI background regimen selected by the investigator 
must be determined and documented prior to randomization and should be composed of 
2 NRTIs in accordance with the local standard of care and per the WHO or national 
treatment guidelines for HIV/TB co-infection. Following Day 1, no changes or 
intensification of background regimen will be permitted prior to meeting confirmed 
virologic withdrawal criteria or Week 52, with the exception of one allowed background 
NRTI change for management of drug toxicity as described in Section 6.4.3.
Subjects randomization will be stratified by screening plasma HIV-1 RNA 
(100,000 c/mL or >100,000 c/mL) and screening CD4+ cell count (100 cells/mm3 or 
>100 cells/mm3). DTG and EFV will be administered in an open-label fashion throughout 
the Randomized Phase.
During the Randomized Phase, subjects will attend the clinic at Baseline/Day 1 and at 
Weeks 4, 8, 12, 24, 36, 48, and 52 of treatment.
Following the Week 48 visit, subjects will remain on their DTG or EFV-containing 
regimen for an additional 4 weeks. All subjects will attend the Week 52 visit, although 
only those with a viral load of 50 c/mL at Week 48 will have their viral load confirmed 
by an assessment at the Week 52 visit. This treatment extension will allow for a more 
accurate assessment of treatment response for the Week 48 analysis window, as transient 
increases of HIV-1 RNA levels 50 c/mL will not be classified as virologic failure.
To determine DTG and EFV concentrations, sparse plasma samples will be collected at 
Weeks 8, 24, 36, and 48 in as many subjects as possible. If a subject meets virologic 
withdrawal criteria, HIV-1 resistance testing will be performed to assess treatment 
emergent mutations for INIs, NNRTIs, and NRTIs.
3.1.3.
DTG Open-Label Extension
Only those subjects randomized to receive DTG plus 2 NRTIs will enter into the DTG 
OLE.
If DTG is locally approved and commercially available when a subject successfully 
completes the Randomized Phase, the subject will be considered to have completed the 
study (see Section 3.1.5) and will need to have alternate arrangements in place to access 
DTG and NRTIs. If DTG is not locally approved and commercially available when a 
subject successfully completes the Randomized Phase, he/she will have the opportunity 
 
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to enter into the DTG OLE. During the DTG OLE, subjects will be supplied with DTG 
until it is locally approved and commercially available, the subject no longer derives 
clinical benefit, or the subject meets a protocol-defined reason for discontinuation. 
Subjects who enter the DTG OLE will be monitored accordingly every 12 weeks.
3.1.4.
Study Completion
Subjects are considered to have completed the study if they satisfy one of the following:

Randomized to EFV plus 2 NRTIs and completed the Randomized Phase including 
the Week 52 visit; 

Randomized to DTG plus 2 NRTIs and completed the Randomized Phase including 
the Week 52 visit; and did not enter the DTG OLE;

Randomized to DTG plus 2 NRTIs, completed the Randomized Phase, including the 
Week 52 study visit, and entered and completed the DTG OLE (defined as remaining 
on study until commercial supplies of DTG become locally available).
3.1.5.
Follow-up
Subjects with ongoing AEs or laboratory abnormalities will attend a Follow-up visit 
approximately 4 weeks after their last dose of investigational product (IP) (DTG or EFV). 
Assessments at the Follow-up visit should reflect any ongoing complaints (e.g., blood 
draws to follow a laboratory abnormality). The Follow-up visit is not required for 
successful completion of the study.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
This randomized, open-label, multicenter, parallel group study design aims at assessing 
DTG antiviral activity in a sufficient number of subjects to demonstrate a clinically 
acceptable level of activity in HIV/TB co-infected patients receiving concomitant TB 
therapy.
Adult subjects diagnosed (smear positive) and proven RIF-sensitive TB who are initiating 
TB treatment with HRZE will be recruited at sites in Brazil, Mexico, Russia, Argentina, 
Peru, South Africa and Thailand. These areas were selected based on epidemiology 
which suggests high rates of HIV and TB co-infection (WHO). Global Tuberculosis 
Report, 2013).
The primary endpoint, proportion of subjects at Week 48 with plasma HIV-1 RNA 
<50 c/mL, is a well-established surrogate endpoint for prognosis of HIV-1 infection and 
disease progression.
 
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Efavirenz-based regimens are the preferred regimens for patients with HIV and TB 
coinfection because of complications arising from drug interactions with other agents. In 
this study, the use of EFV as the active control in (HIV) therapy-naïve patients with TB is 
justified based on its indication as an appropriate agent as first-line therapy in treatment-
naïve HIV-1-infected adults in WHO, CDC, and EACS guidelines.
DTG has been extensively studied in Phase II and Phase III studies in a variety of HIV-1 
patient populations (e.g., treatment-naïve, treatment-experienced [integrase naïve], and 
treatment-experienced [integrase resistant]). DTG with dual NRTI therapy has not been 
evaluated in HIV/TB co-infected subjects taking RIF. This study will provide important 
information regarding the efficacy, safety and tolerability, incidence of TB-associated 
IRIS, and PK of DTG plus 2 NRTIs as a first-line ART regimen in HIV/TB co-infected 
subjects receiving concomitant TB therapy. 
The use of DTG at the 50 mg twice-daily dose is in accordance with DTG global labeling 
information (i.e., United States and the EU) [DTG US Prescribing Information, 2013; EU 
SmPC, 2014] when dosed with RIF and is based on the results of the PK drug-drug 
interaction study with both drugs [Dooley, 2013]. The DTG 50 mg twice-daily dose is 
continued 2 weeks after completion of the TB treatment course, after which RIF enzyme 
induction would be minimal. 
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
A sufficient number of subjects will be screened in order to ensure that a total of 
approximately (5%) 115 subjects will be randomly assigned in a 3:2 ratio to DTG 
(approximately 69 subjects) and EFV (approximately 46 subjects), respectively. 
Assuming 55% of subjects do not meet eligibility criteria, this will require the screening 
of approximately 255 subjects. Subjects will be enrolled from Brazil, Mexico, Russia, 
Argentina, Peru, South Africa and Thailand.
Subjects
Screened
~255
Randomized
~115
Evaluable
~115
The primary analysis will use all subjects in the intent-to-treat exposed (ITT-E) 
population, consisting of randomly assigned subjects who receive at least one dose of 
study drug. Since the intent is for all randomly assigned subjects to receive study drug, 
the number of evaluable subjects should equal the number randomized subjects.
Further details of sample size assumptions are found in Section 8.1.1.
 
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4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GlaxoSmithKline (GSK) investigational product or other 
study treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
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 subjects, taking into consideration any local treatment practices or 
guidelines and Good Clinical Practice (GCP). Specifically, investigators must follow 
national treatment guidelines for ART initiation for HIV/TB co-infected adults. 
Investigators must also ensure that HIV care for study subjects is available and will be 
provided locally after study completion. Study completion is described in Section 3.1.4.
Eligible subjects 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 substance abuse, acute major organ 
disease). It is of note that alcohol abuse would make these subjects more prone to 
develop TB-treatment–related liver-related toxicities.
Except for TB diagnosis laboratory test to determine eligibility that is to be performed 
locally, laboratory results from the central laboratory services provided by this study will 
be used to assess eligibility. Subjects not meeting all inclusion and exclusion criteria at 
the initial Screening visit may be rescreened only once; the subject will receive a new 
subject number. With the exception of a disqualifying viral genotype, a single repeat test 
(re-test) per analyte or assessment is allowed during the Screening Period to determine 
eligibility.  
Subjects eligible for enrollment in this study must meet all of the following:
1.
Subject or the subject’s legal representative is willing and able to understand and 
provide signed and dated written informed consent prior to Screening;
2.
Subject has plasma HIV-1 RNA 1000 copies/mL at Screening;
3.
CD4+ cell count is 50 cells/mm3 at Screening;
4.
Subject is ≥18 years of age;
5.
HIV-1-infected, ART-naïve; (10 days of prior therapy with any antiretroviral drug 
following a diagnosis of HIV-1 infection);
6.
A female subject may be eligible to enter and participate in the study if she:
 
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a. is of non-childbearing potential defined as either postmenopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of 
becoming pregnant with documented tubal ligation, hysterectomy, or bilateral 
oophorectomy or,
b. is of childbearing potential, with a negative pregnancy test at both Screening and 
Day 1, and agrees to use one of the following methods of contraception to avoid 
pregnancy throughout the study and for at least two weeks after discontinuation 
of all study medication (see Appendix 9, Section 11.9):

Complete abstinence from penile-vaginal intercourse from 2 weeks prior to 
administration of IP, throughout the study, and for at least 2 weeks after 
discontinuation of all study medications. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception

Approved hormonal contraception (see Appendix 9, Section 11.9)plus a 
barrier method while receiving RIF-containing TB treatment for subjects 
randomly assigned to the DTG arm and then regardless of use of a barrier 
method after discontinuation of RIF-containing TB treatment, or approved 
hormonal contraception plus a barrier method for subjects randomly assigned 
to the EFV arm (regardless of RIF-containing TB treatment). Approved 
hormonal contraception including:
o
Combined oestrogen and progestogen oral contraceptive [Hatcher, 
2011])
o
Contraceptive subdermal implant
o
Injectable progestogen [Hatcher, 2011]
o
Contraceptive vaginal ring [Hatcher, 2011]
o
Percutaneous contraceptive patches [Hatcher, 2011] ;

Any intrauterine device (IUD) or intrauterine system;

Male partner sterilization with documentation of azoospermia prior to the 
female subject’s entry into the study and this male is the sole partner for that 
subject [Hatcher, 2011]. The documentation on male sterility can come from 
the site personnel’s review of subject’s medical records, medical 
examination, and/or semen analysis, or medical history interview provided by 
her or her partner.;

Any other method with published data showing that the expected failure rate 
is <1% per year.
Any contraception method must be used consistently, in accordance with the 
approved product label and for at least 2 weeks after discontinuation of study drug. A 
childbearing potential female subject who starts the study using complete abstinence 
as her contraceptive method and decides to become sexually active must use the 
double barrier method either as a bridge to an approved hormonal contraception (if 
possible) or as a method of choice to be maintained from that moment onwards.
All subjects participating in the study should be counseled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/ spermicide).
 
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Note: these contraceptive requirements do not apply to females of childbearing 
potential with same sex partners only, when this is their preferred and usual lifestyle.
7.
New diagnosis of pulmonary, pleural, or LN tuberculosis based on identification of 
Mycobacterium tuberculosis using culture methods or GeneXpert (or other approved 
molecular test) on sputum or on samples collected by needle aspirate of pleural fluid 
or an affected LN; 
8.
RIF sensitivity of Mycobacterium tuberculosis either by culture or Gene Xpert (or 
other approved nucleic acid amplification test);
9.
RIF-containing first-line TB treatment or an alternate RIF-containing TB treatment 
as described in Section 11.6 started up to a maximum of 8 weeks before 
randomization and no later than the screening date;
10. Karnofsky score 70% before randomization (see Section 11.7).
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary Medical Conditions
1.
Any previous TB treatment (not including treatment for latent disease);
2.
Evidence of RIF resistance of Mycobacterium tuberculosis either by culture or Gene 
Xpert (or other validated nucleic acid amplification test);
3.
Expected requirement for TB treatment >9 months;
4.
Concomitant disorders or conditions for which isoniazid, RIF, pyrazinamide, or 
ethambutol are contraindicated;
5.
Central nervous system, miliary, or pericardial TB;
6.
Women who are pregnant or breastfeeding; 
7.
Any evidence of an active AIDS-defining disease (CDC Category C; see 
Section 11.2). Exceptions include TB, cutaneous Kaposi’s sarcoma not requiring 
systemic therapy, and historic CD4+ cell counts of <200 cells/mm3;
8.
Subjects with moderate to severe hepatic impairment (Class B or C) as determined 
by Child-Pugh classification (see Section 11.8); unstable liver disease (as defined by 
the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, 
esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
9.
Subjects positive for hepatitis B surface antigen (HBsAg) at screening;
10. Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase 
of the study;
 
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11. History or presence of allergy or intolerance to the study drugs or their components 
or drugs of their class;
12. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial 
neoplasia; other localized malignancies require agreement between the investigator 
and the study medical monitor for inclusion of the subject;
13. Subjects who, in the investigator’s judgment, pose a significant suicidality risk. 
Recent history of suicidal behavior and/or suicidal ideation may be considered as 
evidence of serious suicide risk.
Exclusionary Treatments Prior to Screening or Day 1
14. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
15. Treatment with any of the following agents within 28 days of Screening: radiation 
therapy, cytotoxic chemotherapeutic agents, any immunomodulators that alter 
immune response;
16. Treatment with any agent, other than licensed ART as allowed above (Section 4.2, 
inclusion criterion 5), with documented activity against HIV-1 in vitro/vivo within 
28 days of first dose of the investigational product (IP);
17. 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 IP;
Exclusionary Laboratory Values or Clinical Assessments at Screening
18. Any evidence of primary viral resistance to NRTIs, NNRTIs, or PIs based on the 
presence of any major resistance-associated mutation [IAS USA, 2013] in the 
Screening result or, if known, any historical resistance test result. Note: Retests of 
Screening genotypes are not allowed;
19. Any verified Grade 4 laboratory abnormality with the exception of Grade 4 
triglycerides.  A single repeat test is allowed during the Screening period to verify a 
result; 
20. Any acute laboratory abnormality at Screening, which, in the opinion of the 
investigator, would preclude the subject’s participation in the study of an 
investigational compound;
21. Alanine aminotransferase (ALT) 2 × upper limit of normal (ULN);
22. Hemoglobin 7.4 g/dL;
23. Platelet count <50,000/mm3.
Notwithstanding these minimum inclusion and exclusion criteria, investigators must 
also follow country-specific guidelines where they exist when making decisions 
about subjects who are eligible for study participation.
 
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4.4.
Other Eligibility Criteria Considerations
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the IB and supplements, approved product labels, and/or local prescribing 
information for detailed information regarding warnings, precautions, contraindications, 
AEs, drug interactions, and other significant data pertaining to the IP, background NRTIs, 
and TB treatment.
4.5.
Withdrawal Criteria
A subject may voluntarily discontinue participation in this study at any time. The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time. Withdrawn subjects will not be replaced.
Subjects permanently discontinuing study treatments prior to Week 52 are considered to 
be withdrawn from the study treatments and also from the study. Similarly, subjects in 
the DTG arm who enter the DTG OLE but permanently discontinue participation prior to 
commercial supplies of DTG becoming locally available (e.g., through public health 
services) are considered to be withdrawn from study treatment as well as from the study.
Subjects may be prematurely discontinued from the study for any of the following 
reasons:

Subject or investigator non-compliance;

At the request of the subject, investigator, or sponsor;

The subject requires concurrent prohibited medications during the course of the 
study. However, the subject 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 subject.
Subjects must be prematurely discontinued from the study for any of the following 
reasons:

Confirmed virologic withdrawal criteria as specified in Section 4.6.1.

Subject requires changes (i.e., substitution or dose modification) of DTG or EFV. 
Permitted NRTI substitutions due to toxicity management are discussed in 
Section 5.1.5.

Subject requires a TB treatment regimen that does not contain RIF.

Subject requires interruption to RIF-containing regimens for longer than 14 days and 
is not on a bridging regimen. Permitted RIF-containing regimens are described in 
Section 11.6. Suitable bridging regimens are described in Section 6.4.3.1.1.

Liver toxicity where stopping criteria specified in Section 6.4.3.1 are met and no 
compelling alternate cause is identified;

Grade 4 clinical AE considered causally related to study drug or any component of 
TB treatment;
 
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
Renal stopping criteria as described in Section 6.4.3.4 are met and no compelling 
alternate cause is identified;

Hypersensitivity and rash criteria as described in Section 6.4.3.5 and Section 6.4.3.8, 
respectively are met and no compelling alternate cause is identified;

Petechial rash due to RIF-induced thrombocytopenia as described in Section 6.4.3.9

Pregnancy (intrauterine), regardless of termination status of pregnancy. As a 
reminder, females of reproductive potential who change their minds and desire to be 
pregnant, or who state they no longer are willing to comply with the approved 
pregnancy avoidance methods, should also be withdrawn from the study.
If a subject is withdrawn from the study, the protocol-defined assessments (if withdrawn 
at a routine study visit), the Withdrawal visit assessments, and if necessary the Follow-up 
visit assessments described in the Time and Events Table (Table 2) should be performed. 
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any subject from the study. A 
Follow-up visit may occur approximately 4 weeks after the last dose of study treatment 
and is only required in subjects with ongoing serious AEs (SAEs) or non-serious 
laboratory or clinical AEs at the time of withdrawal.
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study based 
on previous non-compliance. In cases where the subject does not return for the 
rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (e.g., telephone calls and if necessary 
a certified letter to the subject’s last known mailing address) so that they can 
appropriately be withdrawn from the study. These contact attempts should be 
documented in the subject’s medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the 
study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing 
from the study, an alternative reason for discontinuation should be recorded in the 
electronic case report form (eCRF).
Subjects are not obligated to state the reason for withdrawal. However, the reasons for 
withdrawal, or failure to provide a reason, must be documented by the investigator on the 
Completion/Withdrawal section of the eCRF. Every effort should be made by the 
investigator to follow-up with subjects who withdraw from the study. In the event that a 
subject is prematurely discontinued from the study at any time due to an AE (see 
Section 6.4.4.1), the procedures stated in the Time and Events Table (Table 2) must be 
followed. Subjects who are withdrawn from the study will not be replaced.
Subjects may have a temporary interruption to their study treatment for management of 
toxicities.
 
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4.6.
Virologic Criteria for Subject Management and Viral 
Resistance Testing
Subjects with plasma HIV-1 RNA levels 50 c/mL at Week 24 or beyond must have 
HIV-1 levels re-assessed using the algorithms in Figure 2 and Figure 3, which detail 
virologic criteria for clinical management of subjects who either require more careful 
monitoring (e.g., meet “4-6 week plasma HIV-1 RNA testing criterion”) or have met a 
“suspected or confirmed virologic withdrawal criterion.” Investigators should not 
schedule re-assessment blood draws to take place in the presence of factors that could be 
associated with HIV-1 RNA levels 50 c/mL, such as intercurrent acute infection, 
treatment interruption due to toxicity management or non-compliance, or vaccination. 
Subjects should have received full doses of IP for at least 2 weeks at the time of HIV-1 
RNA re-assessment for any HIV-1 RNA level 50 c/mL.
If a subject meets the confirmed virologic withdrawal criteria, the plasma ‘for storage 
sample’ from the “suspected virologic withdrawal criterion” visit and the Day 1 sample 
will be used for HIV-1 genotype/phenotype testing. Subjects may continue to receive IP 
at the discretion of the investigator until results of resistance testing are available, at 
which time the subject must be discontinued from the study. If a subject is prematurely 
discontinued from the study, the investigator must make every effort to perform the 
evaluations outlined in the Time and Events Table (Section 6.1). These data will be 
recorded as they comprise essential evaluations needed to be done before discharging any 
subject from the study.
Note: Plasma samples with <400 c/mL of HIV-1 RNA will not be analyzed for viral 
resistance, as the protease/reverse transcriptase/integrase assays used in this study are not 
validated for plasma HIV-1 RNA levels <400 c/mL.
 
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Figure 2
Virologic Criteria for Subject Management at Week 24
Week 24 Visit
HIV-1 RNA is <50 c/mL
HIV-1 RNA is 50 c/mL but <400 c/mL
HIV-1 RNA is 400 c/mL
Maintain scheduled visit at 
Week 36
Perform an unscheduled visit in approximately 2 to 4 
weeks to reassess plasma HIV-1 RNA
Proceed to Figure 3
Perform an unscheduled visit in approximately 
2 to 4 weeks to reassess plasma HIV-1 RNA
Subject has met “Suspected Virologic 
Withdrawal Criterion”
Proceed to Figure 3
Figure 3
Virologic Criteria for Subject Management After Week 24
Any Visit (scheduled or unscheduled) After Week 24
Current plasma HIV-1 RNA <50 c/mL
Current plasma HIV-1 RNA 
50 c/mL but<400 c/mL 
Current plasma HIV-1 RNA 400 c/mL
Regardless of previous plasma HIV-1 
RNA result, proceed to next scheduled 
visit per Time and Events Table 2
Regardless of previous plasma 
HIV-1 RNA result, perform an 
unscheduled visit in approximately 
4-6 weeks to reassess plasma
HIV-1 RNAa
Subject has met “4 to 6 Week 
Plasma HIV-1 RNA Testing 
Criterion”
If previous plasma HIV-1 RNA was 
<400 c/mL, perform a scheduled or 
an unscheduled visit in 
approximately 4-6 weeks to 
reassess plasma HIV-1 RNAa
Subject has met “Suspected 
Virologic Withdrawal Criterion”
If previous plasma HIV-1 RNA was 
400 c/mL, discontinue the subject 
from study once resistance test 
results are available
Subject has met “Confirmed 
Virologic Withdrawal Criterion”
a.
If current visit is the Week 48 scheduled visit then retest will occur at the Week 52 visit.
 
 
 
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4.6.1.
Management of Subjects Meeting Suspected Virologic 
Withdrawal Criteria
Only plasma HIV-1 RNA levels determined by the central laboratory (or a laboratory 
contracted by the central laboratory) will be used to assess virologic withdrawal criteria. 
Upon notification that a subject’s plasma HIV-1 RNA level qualifies as meeting a 
suspected virologic withdrawal criterion, the investigator should query the subject 
regarding intercurrent illness, recent immunization, or interruption of therapy as 
inadequate adherence is a common cause of elevated HIV-1 RNA measurements.
All cases that meet a suspected virologic withdrawal criterion must be confirmed by 
a second measurement performed 4 to 6 weeks apart from the date of the original 
sample, unless one of the extenuating circumstances outlined below applies.
The following guidelines will be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of any 
intercurrent illness, during which time the subject should receive full dose of all IP.

Confirmatory testing should be scheduled at least 4 weeks following any 
immunization, during which time the subject should receive full dose of IP.

If therapy is interrupted due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2 to 4 weeks following resumption 
of full dose of IP.  

The subject should have received full doses of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA testing is done.
Sites should contact GSK to discuss individual subjects, whenever necessary.
At Week 48, repeat HIV-1 RNA testing is required for any HIV-1 RNA 50 c/mL and 
must be performed at the Week 52 study visit (Section 4.7).
4.7.
Retest Criteria for Subjects With Plasma HIV-1 RNA Levels 
50 c/mL at Week 48
Subjects with plasma HIV-1 RNA levels 50 c/mL at Week 48 must have HIV-1 levels 
re-assessed by a second measurement performed at the Week 52 visit. Subjects should 
have received full doses of IP for at least 2 weeks at the time of HIV-1 RNA 
re-assessment for any HIV-1 RNA level 50 c/mL.
Subjects with plasma HIV-1 RNA levels ≥400 c/mL should have a second measurement 
performed as outlined in Section 4.6.1.
 
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4.8.
Protocol-Defined Failure of TB Treatment
Tuberculosis treatment failure is defined by WHO [WHO, 2010] as patients whose 
sputum smear or culture is positive at 5 months or later during treatment. Also included 
in this definition are patients found to harbour a multidrug-resistant strain at any point of 
time during the treatment, whether they are smear-negative or smear-positive.
Subjects with suspected TB treatment failure should be evaluated with a history, physical 
examination, sputum smear and culture with drug-susceptibility testing, and chest 
radiograph (TB treating physicians caring for the subject and local investigators should 
also use clinical judgment to determine if other evaluations are required) to determine 
whether they have clinically responded to therapy, even though their cultures have not 
converted or were not tested. The initial culture results and drug-resistance tests, 
treatment regimen, and adherence also should be reviewed. Samples from all available 
sites should be taken for repeat culture and drug-susceptibility testing, and strong 
consideration should be given to performing rapid resistance testing on direct specimens 
or positive cultures to identify acquired drug resistance or superinfection with a drug-
resistant strain. If the results of repeat cultures and rapid resistance testing confirm, in 
consultation with an expert in the field, that the subject will require broadening of TB 
treatment by switching to a second-line TB treatment regimen without RIF then the 
subject must be withdrawn from the study.
4.9.
Screening Failures
A subject is considered a screen failure if after providing informed consent, the subject’s 
circumstances or conditions change or the outcome of a test or assessment becomes 
available which results in the subject’s failure to meet one or more of the entry criteria, or 
results in the investigator deciding that the subject is no longer an appropriate study 
candidate.
Subjects who meet all entry criteria are randomized and assigned a randomization 
number. Subjects not meeting all inclusion and exclusion criteria at the initial screen may 
be rescreened only once and the subject will receive a new subject number at that time. 
With the exception of disqualifying viral genotype or TB culture or nucleic-acid–based 
RIF-susceptibility results indicating RIF resistance, a single repeat test (retest) per analyte 
or assessment is allowed during the Screening Period to determine eligibility. Subjects 
who are randomized into the study and subsequently withdrawn from the study for any 
reason may not be rescreened.
Except for results to confirm MTB which are analyzed locally, laboratory results from the 
central laboratory services provided by this study will be used to assess eligibility. 
 
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5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Investigational product in this protocol refers to the investigational drugs DTG and the 
active control EFV. These will be supplied by GSK. For the purpose of this protocol, 
other ARTs administered in the study are not considered IP and will not be supplied by 
GSK. These will be sourced as local commercial material. Investigators will select a dual 
NRTI background for each subject. Tuberculosis drugs are also not considered IP and 
will be provided by the local TB program in accordance with national and local 
guidelines.
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of the IP will be limited to the 
investigator and authorized site staff. Investigational product must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
Adequate precautions must be taken to avoid direct contact with the investigational 
product which should be used in accordance with the manufacturer’s instructions detailed 
in the prescribing information.
5.1.1.
Tablet Formulation of DTG
DTG tablets are packaged as a full count of 30 film-coated tablets in a 45 cc high density 
polyethylene (HDPE) bottles with induction seal and child-resistant 33 mm closure. 
Tablets must be stored in the original package with the bottle tightly closed. The bottles 
contain a desiccant that must be kept in the bottle to protect tablets from moisture. The 
recommended storage conditions and expiry date where required, are stated on the 
product label.
Subjects must keep all IP in its original pack container. GSK will notify sites if and when 
data are available to support the use of pill boxes.
5.1.2.
Tablet Formulation of EFV
EFV [Sustiva (efavirenz) US Product Information, 2013; Sustiva Summary of Product 
Information, 2014] is supplied as the EFV oral tablet, which contains 600 mg of EFV. 
EFV tablets, as manufactured by Bristol Myers Squibb, are yellow film-coated capsule-
shaped tablets printed with “SUSTIVA” on both sides. Each pack/bottle will contain 
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5.1.3.
Background NRTIs
The investigator-selected dual NRTI background regimen must be determined and 
documented prior to randomization. 
All background NRTIs are locally registered products. GSK will not reimburse or supply 
the investigator-selected background regimen unless required by the local regulatory 
authority or Institutional Review Board/Independent Ethics Committee (IRB/IEC) or 
unless previously agreed with study sites.
Those subjects for whom abacavir (ABC) is being considered as a component of the 
NRTI backbone should have been screened and be negative for the human leukocyte 
antigen (HLA)-B*5701 allele before randomization takes place. This testing may be 
conducted as part of the study or may be performed by local laboratories. Results must be 
available for source document verification.
5.1.4.
Dosage and Administration
IP and background NRTI Dose and Dose Interval
Treatment Arm 1
GSK1349572 
(dolutegravir, DTG)
Twice-daily DTG 50 mg plus dual NRTI during TB treatment and for 2 weeksa following 
discontinuation of TB treatment, then once-daily DTG 50 mg with the same NRTI 
backbone through Week 52 and continued during the DTG OLE until DTG is locally 
approved and commercially available
Treatment Arm 2
Efavirenz (EFV) 
Once-daily EFV 600 mg plus dual NRTI through Week 52
Note: TB treatment including isoniazid, RIF, pyrazinamide, and ethambutol will be provided at standard doses by the 
NTP under program conditions.
a.
Delays in switching from DTG twice daily to DTG once daily will not be considered an overdose.
DTG may be administered with or without food. EFV must be administered without food. 
For the dual NRTIs refer to the appropriate NRTI product information for treatment 
administration.
5.1.5.
Protocol-Permitted Substitutions
A substitution of or switch between DTG or EFV is not allowed.
After consultation with the study medical monitor, switch of background NRTI therapy 
to an alternate approved NRTI therapy for toxicity or tolerability management is allowed 
one time. Switches of a background NRTI for any reason other than toxicity or 
tolerability management are not permitted in the study. The date of the decision to switch 
background NRTI for toxicity or tolerability management must be documented in the 
eCRF. 
Note: Protocol-permitted substitutions (as described above), will not be coded as failures 
in this study regardless of the subject’s HIV-1 RNA results at the time of the 
protocol-permitted substitution (Section 8.2.4).
Further information regarding alternate RIF-containing TB treatment regimens are 
described in Section 11.6.
 
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5.2.
Treatment Assignment
Informed consent must be obtained prior to any study procedures, including any 
screening assessment.
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. Randomization will be conducted using a central randomization procedure 
following confirmation of fulfillment of study entry criteria. Subjects will be assigned 
(3:2 ratio to DTG or EFV-containing regimens, respectively) to study treatment in 
accordance with the computer-generated randomization schedule. The central 
randomization schedule will be generated by biostatistics using a validated SAS 
developed program. The stratification will be generated using an interactive voice 
response system (IVRS). Study site personnel will be required to contact the central 
randomization service for assignment of a unique identifier (designating the subject’s 
randomization code) for each subject participating in the study. A unique treatment 
number will be assigned for each subject participating in the study. 
Subjects who are randomly assigned into the study and subsequently withdrawn may not 
be rescreened. 
5.3.
Blinding
This will be an open-label study.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of study 
drug dispensed and/or administered to study subjects, the amount returned by study 
subjects, and the amount received from and returned to PPD, when applicable. Product 
accountability records must be maintained throughout the course of the study.
5.5.
Treatment Compliance
Treatment adherence will be evaluated using pill counts of unused study drug (DTG and 
EFV). This assessment will be conducted each time the subject receives a new (refill) 
supply of study drug through the Withdrawal visit or study completion. These data will 
be recorded in the subject’s eCRF but will not be summarized for analysis purposes.
Data on start and end dates for TB treatment or ART including periods of interruptions (if 
applicable) will be documented.
5.6.
Concomitant Medications and Non-Drug Therapies
Subjects should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
drug-drug interactions between such treatments and the study drugs. All concomitant 
medications taken during the study will be recorded in the eCRF. The minimum 
requirement is that the drug name and the dates of administration are to be recorded.
 
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5.6.1.
Permitted Medications and Non-Drug Therapies
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications described in 
Section 5.6.2). Chemoprophylaxis for HIV-associated conditions is encouraged, if 
appropriate, at the discretion of the subject and their physician. All concomitant 
medications, blood products, and vaccines taken during the study will be recorded in the 
eCRF with dates of administration.
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn and only once scheduled 
visits are ≥4 weeks apart. This approach will minimize the risk of nonspecific increases 
in the level of HIV-1 plasma RNA at the next scheduled assessment.
Daily doses of RIF should be given at least 1 hour before the ingestion of antacids. 
DTG should be administered 2 hours before or 6 hours after taking antacid products or 
sucralfate containing divalent cations (e.g., aluminum and magnesium) or calcium or iron 
supplements; alternatively, DTG can be taken together with calcium or iron supplement 
with a meal. Proton pump inhibitors and H2-antagonists may be used in place of antacids 
with no scheduling restrictions. Concurrent administration of DTG with multivitamins is 
acceptable.
Metformin concentrations may be increased by DTG. Subjects taking DTG should be 
monitored for glucose control during therapy and a metformin dose adjustment may be 
required.
5.6.2.
Prohibited Medications and Non-Drug Therapies
The following concomitant medications or therapies are not permitted at any time during 
the study:

HIV immunotherapeutic vaccines (see Section 5.6.1 for guidance regarding non-HIV 
vaccines)

Other experimental agents, antiretroviral drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or radiation therapy (see Exclusion Criteria, 
Section 4.3)

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited through the Randomized Phase (Day 1 to Week 48 plus a 
4-week treatment extension) of the study. This includes topical agents with 
substantial systemic exposure and systemic effects. After the Randomized Phase 
(Day 1 to Week 48 plus a 4-week treatment extension), immunomodulators may be 
administered after discussion and agreement with the study medical monitor

HCV therapy during the study is prohibited

Chronic use of systemic (oral or parenteral) glucocorticoids should be avoided; 
however, short treatment courses of 30 days or less (e.g., for treatment of IRIS), 
replacement therapy (e.g., for Addison’s Disease), and topical, inhaled, or intranasal 
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5.6.3.
Prohibited Medications for Subjects Randomly Assigned to DTG
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

St. John’s wort (Hypericum perforatum)
Dofetilide and pilsicainide are prohibited as DTG may inhibit renal tubular secretion 
resulting in increased dofetilide/pilsicainide concentrations and potential for toxicity.
For prohibited medications related to TB therapy components, please refer to the local 
prescribing information for information on concurrent therapies.
For a detailed list of prohibited medications, please consult the SPM.
5.6.4.
Prohibited Medications for Subjects Randomly Assigned to EFV
Efavirenz has the potential to impact the following drugs potentially requiring monitoring 
and dose adjustment:

HMG-CoA reductase inhibitors are prohibited due to potential for decreased plasma 
concentrations; dosage should be individualized based on the goal of therapy and 
response.

Methadone is prohibited due to potential for decreased plasma concentrations; 
subjects should be monitored for signs of withdrawal and methadone dose should be 
adjusted as appropriate

Warfarin is prohibited because warfarin concentrations may be increased or 
decreased; international normalized ratio (INR) should be monitored and dosage 
should be adjusted as appropriate
5.7.
Treatment After the End of the Study
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition whether or not ViiV/GSK is providing 
specific post-study treatment.
All subjects randomly assigned to receive DTG who have not prematurely discontinued 
from the study and who successfully complete 52 weeks of treatment will continue to 
have access to DTG (during the DTG OLE) until it is either locally approved and 
commercially available, the subject no longer derives clinical benefit, or the subject 
meets a protocol-defined reason for discontinuation. Investigative sites must make 
arrangements for provision of background NRTIs to all subjects to ensure continued 
 
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access to these medications during the DTG OLE (unless provision by the sponsor is 
mandated by local regulation).
Subjects randomized to the EFV arm will receive EFV through their Week 52 visit only, 
after which subjects will complete the study and will need to have alternate arrangements 
in place to access EFV and NRTIs (unless mandated by local regulation).
5.8.
Treatment of Study Treatment Overdose
For this open-label study, any tablet intake exceeding the recommended daily number of 
tablets for study drug will be considered an overdose.
For the purposes of this study, an overdose is not an AE (refer to Section 6.4.4.1) unless 
it is accompanied by a clinical manifestation associated with the overdose. If the clinical 
manifestation presents with serious criteria, the event is a serious AE (SAE) (see 
Section 6.4.4.2).
If an overdose occurs and is associated with an AE requiring action, all study drugs 
should be temporarily discontinued until the AE resolves. The investigator should use 
clinical judgment in treating overdose and also refer to the prescribing information for 
current ARTs, as ViiV/GSK is unable to recommend specific treatment.
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
6.1.
Time and Events Schedule
Table 2
Time and Events Table
Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
Clinical and other assessments
Written informed consent
X
Subject demography
X
Document pulmonary, 
pleural, or LN TB 
diagnosisd
X
Document pre-TB 
treatment MTB culture 
result (e.g., sputum, LN, 
or pleural aspirate)e
X
X
Document pre-TB 
treatment sputum smear 
results, if available
X
Perform GeneXpert or 
equivalent and/or 
Document GeneXpert or 
equivalent RIF-sensitive 
MTB
X
 
 
 
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Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
Document the subject is 
on a RIF-containing first-
line TB treatment and 
record TB regimen 
components
Xf
Record pre-specified TB 
regimen duration
X
Documentation of TB 
regimen start date
X
Inclusion/Exclusion 
criteriaf
X
X
Prior ART history
X
Medical historyg
X
CDC HIV-1 classification
X
X
Physical examinationh
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and height
X
Current medical 
conditions
X
Cardiovascular risk 
assessmenti
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
HIV associated 
conditions
X
X
X
X
X
X
X
X
X
Columbia Suicidality 
Severity Rating Scalej
Xj
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
SAEs
Xk
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
TB-associated IRIS 
assessmentl
X
X
X
Laboratory assessments
Quantitative plasma HIV-
1 RNA PCR
X
X
X
X
X
X
X
X
Xm
X
X
Lymphocyte subsets 
X
X
X
X
X
X
X
X
X
X
X
Plasma for storagen
X
X
X
X
X
X
X
X
X
X
X
Plasma for HIV 
genotyping
X
HLA-B* 5701 testingo
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucosep
X
X
X
Pregnancy testq,r
S
U
S
S
S
S
S
S
S
S
S
HBsAg and hepatitis C 
(anti-HCV Ab)
X
Pharmacogenetic 
samples
X
Pharmacokinetic plasma 
samplet
X
X
X
X
Dispense PK dosing
diary card
X
X
X
X
Xu
 
 
 
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Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
Investigational product
IVRS
X
X
X
X
X
X
X
X
X
Xv
X
X
X
Dispense IP
X
X
X
X
X
X
X
Xv
X
Xvw
IP accountability (pill 
counts)
X
X
X
X
X
X
X
X
X
X
ART = antiretroviral therapy; CDC = Centers for Disease Control; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV-1 = human immunodeficiency virus-1; 
HLA-B = human leukocyte antigen-B; INR = international normalized ratio; IP = investigational product; IVRS = interactive voice response system; LN = lymph node; MTB = 
Mycobacterium tuberculosis; PCR = polymerase chain reaction; PT = prothrombin time; RIF = rifampicin; RNA = ribonucleic acid; SAE = serious adverse event; TB = tuberculosis
a.
The 14-day Screening Period may be extended to 28 days. Randomization may occur as soon as all Screening results are available and up to 8 weeks after TB treatment 
initiation
b.
Subjects randomly assigned to the DTG arm and complete the Randomized Phase through the Week 52 visit will enter into the DTG OLE. Subjects completing the DTG OLE 
must return to the clinic when transitioning to commercial supplies for an end of OLE visit. Study assessments will be conducted as specified for the withdrawal visit.
c.
A Follow-up visit will be conducted 4 weeks after the last dose of study provided IP and is required only if a subject has ongoing AEs or laboratory abnormalities at the last on-
study visit. The assessments performed should reflect what is considered medically necessary to assess the event(s).
d.
Smear positive or culture positive, including sample source recorded in eCRF.
e.
Results may be documented any time between Screening and Day 1.
f.
Inclusion/exclusion criteria will be fully assessed at the Screening visit (to include Karnofsky assessment). Changes between the screening visit and the Day 1 visit should be 
assessed to ensure eligibility, including additional assessments performed at Day 1.
g.
Full medical history will be collected. Targeted medical history assessments will include cardiovascular, gastrointestinal (e.g., GI bleeding, PUD), metabolic (e.g., Type I or II 
DM), psychiatric (e.g. depression), renal (e.g. nephrolithiasis, nephropathy, renal failure) and neurological disorders. 
h.
Limited physical examination to include blood pressure at Baseline (recorded in eCRF) for Framingham score assessment. Blood pressure to be measured after resting in a 
semi-supine position for at least 5 minutes.
i.
Assessment for cardiovascular risk will include height, weight, blood pressure, smoking history, medical conditions, and family history of premature cardiovascular disease. 
j.
The Columbia-Suicidality Severity Rating Scale (subject completed questionnaire) is to be administered if a validated version in the appropriate language is available for the 
subject. The assessment will be performed only in countries where the validated questionnaire exists in the appropriate language. On Day 1, the questionnaire should be 
 
 
 
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completed prior to randomization. 
k.
Only SAEs related to study participation or to a concomitantly administered GSK/ViiV product will be collected between obtaining informed consent and administration of IP at 
Day 1.
l.
TB-associated IRIS criteria are described in Section 6.4.6; if any of the major and/or minor criteria are identified they will be captured and reported as AEs. Toxicity management 
related to TB-associated IRIS cases are described in Section 6.4.3.3.
m.
Quantitative plasma HIV-1 RNA are ONLY for subjects who had HIV-1 RNA >50 c/mL at the Week 48 visit. 
n.
Plasma samples for storage will be collected at each visit for possible future analyses (including but not limited to HIV-1 RNA genotypic and phenotypic analyses, 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. Plasma for storage 
sample should also be collected at the unscheduled visit for retesting suspected virologic withdrawal. Additionally, for genotypic and phenotypic resistance analyses baseline 
samples from all subjects will be used and later samples in cases of confirmed virologic withdrawal criteria met (for paired baseline and endpoint genotypes). 
o.
Subjects starting ABC as one of the NRTIs must have been screened and be negative for the HLA-B*5701 allele.
p.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
q.
Pregnancy testing will be conducted (women of childbearing potential only) on serum samples with the exception of Day 1, which must be a urine test to confirm status prior to 
administration of IP.
r.
Remind females of reproductive potential of the need to avoid pregnancy while in the study and adherence to the study’s contraceptive requirements.
s.
Informed consent for optional pharmacogenetics (PGx) research must be obtained before collecting a sample. Collection of the PGx sample at Day 1 is preferred; however, this 
sample may be collected at any time during the study.
t.
For subjects randomly assigned to EFV, mid-dosing interval samples will be collected at Weeks 8, 24, 36, and 48. For subjects randomly assigned to DTG, 1 sample each for 
pre-dose, 1 to 3 hours post-dose, 4 to 12 hours post-dose will be collected at Weeks 8 and 36, and 1 sample pre-dose will be collected at Weeks 24 and 48. If PK sampling is not 
performed the visit will be rescheduled to collect the PK sample and if applicable the subject will be provided a new diary card. Instructions on PK sample collection are 
described in Section 6.5.2. Blood samples should be collected into K2EDTA tubes.
u.
Collect DTG twice daily PK diary card and provide the subject with the DTG once daily PK diary card. 
v.
The IVRS will capture the point at which the subject is within 2 weeks of completing their TB treatment and the site will notify the subject to return to the clinic for the DTG switch 
visit in order to dispense the DTG 50 mg once daily dose.
w.
For subjects receiving DTG during the DTG OLE only.
 
 
 
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6.1.1.
TB Time and Events Schedule
Table 3
TB Time and Events Table
Procedures
TB Treatment Intensive Phase
TB Treatment Continuation Phase
Baseline
Month 2
Month 4
Month 6
Month 9
Laboratory assessments
Collection of sputum samples for 
MTB smear and culture testinga
X
X
X
X
X
TB regimen assessments
TB medicationsb
X
X
X
X
X
TB treatment interruptionsc
X
X
X
X
TB treatment re-introductiond
X
X
X
X
Document RIF-sensitivitye
X
X
X
X
X
MTB = Mycobacterium tuberculosis, TB = tuberculosis
a.
To be performed at the local laboratory. The laboratory and method for that subject should remain the same 
throughout the study. Results of testing will be recorded in the eCRF. Sputum does not need to be collected from 
subjects with pleural or lymph node TB who do not also have pulmonary TB. If subjects are no longer producing 
sputum at 4 months, 6 months, and 9 months and no sputum sample can therefore be collected, then this fact 
must be recorded in the eCRF. Subjects who complete their TB treatment at 6 months, do not require a sputum 
sample to be collected at 9 months, unless clinically indicated (investigator decision).
b.
Record all TB treatment medications taken during the intensive and continuation phases on the TB treatment 
medication eCRF.
c.
Any missed doses or changes to the regimen should be recorded on the TB treatment medication eCRF. If the TB 
regimen is interrupted for more than 14 days, the subject must be withdrawn from the study.
d.
Re-introduction guidelines are described in Section 6.4.3.1.1.
e.
Rifampicin susceptibility testing at baseline is mandatory. The investigator may repeat RIF susceptibility testing at 
other times, as clinically indicated. If at any time, an isolate is found to be RIF-resistant, then the subject must be 
withdrawn from the study.
6.2.
Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject (or 
his/her legal representative) 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/IEC. After signing an informed consent, subjects will complete 
Screening assessments to determine subject eligibility. Each subject being screened for 
study enrollment evaluation will be assigned a subject number at the Screening visit. This 
number will be given sequentially in chronological order of subject presentation 
according to a numeric roster provided by PPD.
6.2.1.
Screening Assessments
Assessments to be conducted at Screening are provided in the Time and Events schedule 
(Table 2). 
All subjects will complete the Screening Period approximately 14 days prior to Baseline 
(Day 1) during which time all clinical and laboratory assessments of eligibility must be 
performed and reviewed. The Screening Period may be extended to 28 days to 
 
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accommodate availability of all Screening assessment results and scheduling. All 
Screening results must be available prior to randomization. 
Eligibility criteria must be carefully assessed at the Screening visit. Physical 
examinations should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF. Smear-positive sample, site from which sample was 
obtained (e.g., sputum, LN, or pleural aspirate) and sputum smear grade result, culture 
date of collection and result (if available), results of Gene Xpert test, including RIF 
genotypic susceptibility testing will be recorded at the Screening visit. 
Subjects who meet all entry criteria are randomly assigned to treatment and assigned a 
randomization number. Subjects not meeting all inclusion and exclusion criteria at the 
initial screen may be rescreened only once and the subject will receive a new subject 
number at that time. With the exception of a disqualifying viral genotype or 
documentation of RIF resistance, a single repeat test (re-test) per analyte or assessment is 
allowed during the Screening Period to determine eligibility. Subjects who are 
randomized into the study and subsequently withdrawn from the study for any reason 
may not be rescreened.
Note: Where HLA-B*5701 screening is considered standard of care, it is recommended 
that investigators screen for presence of the HLA-B*5701 allele in any subject for whom 
an ABC-containing product (e.g., ZIAGEN™, EPZICOM™, KIVEXA™) may be 
considered as part of background regimen and HLA-B*5701 status is unknown (even if 
the subject has previously tolerated ABC). Use of ABC in subjects known to carry 
HLA-B*5701 is not recommended and should be considered only under exceptional 
circumstances where potential benefit outweighs the risk and only under close medical 
supervision.
6.2.2.
Baseline Assessments (Day 1)
Assessments to be conducted at Baseline (Day 1) are provided in the Time and Events 
schedule (Table 2).
At Day 1 and prior to randomization, any changes to the eligibility parameters must be 
assessed and any results required prior to randomization (e.g., Day 1 urine pregnancy test 
for women of childbearing potential) must be available and reviewed.
Cardiovascular risk factors will be assessed at Baseline and assessments will include 
smoking status and history and family history of cardiac events. 
For subjects who agree to the optional assessment, a whole blood sample for 
pharmacogenetic (PGx) research should be collected at Day 1; however this sample may 
be collected at any time during the study (see Section 11.1).
 
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6.3.
Efficacy
6.3.1.
Efficacy Evaluations
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
Table (Table 2). Methods to be used may include but are not limited to the Abbott 
Realtime HIV-1 Assay with lower limit of detection (LLOD) 40 c/mL. In some cases 
(e.g., where the HIV-1 RNA is below the LLOD for a given assay) additional exploratory 
methods may be used to further characterize plasma HIV-1 RNA levels.
Lymphocyte Subsets
Blood samples will be collected for assessment of lymphocyte subsets by flow cytometry 
(total lymphocyte counts, percentage, and absolute CD4+ lymphocyte counts) according 
to the Time and Events Table (Table 2).
Sputum MTB Cultures 
Sputum samples will be collected for assessment of positive TB cultures according to the 
TB Time and Events Table (Table 3). TB cultures are to be performed locally and results 
will be collected in the eCRF.
CDC HIV-1 Classification and HIV Associated Conditions
HIV-associated conditions will be recorded as per the Time and Events Table (Table 2). 
HIV associated conditions will be assessed according to the 1993 CDC Revised 
Classification System for HIV Infection in Adults (see Section 11.2). Indicators of 
clinical disease progression are defined as:
CDC Category A at enrollment→ Category B event;
CDC Category A at enrollment→ Category C event;
CDC Category B at enrollment→ Category C event;
CDC Category C at enrollment→ New Category C Event;
CDC Category A, B or C at enrollment→ Death
6.3.2.
Primary Efficacy Endpoint
The primary endpoint will be the proportion of subjects with plasma HIV-1 RNA 
<50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E population in the DTG 
arm. This endpoint will also be evaluated in the modified ITT-E (MITT-E) population.
 
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6.3.3.
Secondary Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm in the EFV arm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related AE, safety stopping criteria, or lack of 
efficacy);

Changes from baseline in CD4+ counts at Week 24 and Week 48.
6.3.4.
Tertiary Efficacy Endpoints

Incidence of disease progression (HIV-associated conditions, new AIDS diagnoses 
and death);

Proportion of subjects with TB treatment success (using the WHO definition, to be 
detailed in the reporting and analysis plan [RAP]);

Proportion of subjects with pulmonary MTB who are sputum culture-negative 
2 months after starting TB treatment.
6.4.
Safety
Safety assessments will be conducted according to the Time and Events Table (Table 2) 
and will include the following:

Monitoring and recording all AEs and SAEs. Additional information on the time 
period and frequency of detecting AEs and SAEs is provided in Section 6.4.12; 

Regular monitoring of hematology and blood chemistry parameters;

Periodic assessment of fasting lipids and glucose;

Physical examinations should be conducted as part of normal routine clinical care 
but will not be entered systematically in the eCRF. Abnormalities noted during any 
examination must be recorded in the eCRF (e.g., in the current medical conditions or 
AE logs);

Evaluation and documentation of all concomitant medications and blood products 
received;

Suicidality monitoring using the Columbia-Suicide Severity Rating Scale (C-SSRS; 
Section 6.4.10).
Any appropriately qualified site personnel (e.g., investigator, sub-investigator, or study 
coordinator/nurse) can perform assessments. With the exception of TB culture, a central 
laboratory chosen by GSK/ViiV will undertake all routine scheduled laboratory 
evaluations within the study. Refer to the central laboratory manual for specific 
instructions on sample collection, processing, storage and shipping for each laboratory 
test.
 
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Table 4
Laboratory Assessments
Hematology
Platelet count 
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
Clinical Chemistry
BUN
Potassium
AST 
Total bilirubina
Creatinine
Chloride
ALT 
Albumin 
Glucoseb
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
Creatininec
PT/INRd
Fasting Lipid Panele
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Other Tests
Plasma HIV-1 RNA
CD4+ cell counts
Hepatitis B (HBsAg) and hepatitis C (anti-HCV Ab)d
Pregnancy test for women of childbearing potentialf
HLA-B*5701 screeningd
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; HDL = high density 
lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; MCV = mean corpuscular volume; 
PT = prothrombin time; RBC = red blood cells; WBC = white blood cells.
a.
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN.
b.
Fasting glucose will be collected at Day 1 and Weeks, 24, and 48 during the study. For fasting glucose 
assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable for subjects with 
afternoon appointments.
c.
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the CKD-EPI formula using serum 
creatinine [Inker, 2012].
d.
Screening visit only
e.
For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable 
for subjects with afternoon appointments.
f.
Urine pregnancy test and serum pregnancy test will be performed according to Table 2.
6.4.1.
Safety Endpoints

Incidence and severity of all AEs, SAEs, and laboratory abnormalities; 

Proportion of subjects who permanently discontinue IP or TB treatment due to AEs 
or death;

Proportion of subjects who temporarily discontinue IP and/or TB therapy due to 
AEs;

Proportion of subjects with TB-associated IRIS 
Note: the clinical team will review the AE terms and HIV conditions in order to 
identify TB-associated IRIS cases. TB-associated IRIS criteria are described in 
Section 6.4.6 and toxicity management for TB-associated IRIS cases are described in 
Section 6.4.3.3.
 
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6.4.2.
Toxicity Management
Adverse events that occur during the study should be evaluated by the investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (see Section 11.3). 
Additional information regarding detecting, documenting, and reporting AEs and SAEs 
are available in Section 6.4.3.9.
Investigational product may be interrupted at the discretion of the investigator and 
according to the severity of the AE. If one or more antiretroviral drugs are held due to 
toxicity or AEs, generally, all antiretroviral drugs should be held to reduce the risk of 
development of resistance taking into account the length of the planned interruptions and 
the PK half-life of each antiretroviral drug of the regimen. In some cases (e.g., EFV), 
short continuation of the dual NRTI components of the regimen after interruption of the 
third antiretroviral drug may be appropriate in order to minimize the risk of development 
of resistance.
No toxicity-related dose reductions of IP will be allowed. Investigational product 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 IP or temporary interruption of one or more but not all drugs 
within the ART regimen 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 subject management and IP interruptions based on the severity of the 
AE; for specific toxicities, please refer to Section 6.4.3. All changes in IP must be 
accurately recorded in the subject’s eCRF.
When possible, concomitant medications (like TB treatment components) should be held 
first at the discretion of the principal investigator if he/she suspects they are contributing 
to the toxicity
Toxicities That the Investigator Considers Related or Possibly Related to TB 
Treatment
Toxicities that the investigator considers related or possibly related to TB treatment 
should be managed with reference to applicable product labeling and local guidelines.
Note: In instances where both IP and TB treatments are interrupted due to either a clinical 
or laboratory toxicity, and it is decided to re-introduce these agents e.g., upon event 
improvement or resolution (following consultation with the medical monitor for Grade 3 
toxicities), the TB treatment should be restarted first according to Section 11.6, followed 
by trimethoprim-sulfamethoxazole (TMP-SMX), and then ART.
Toxicities That the Investigator Considers Related or Possibly Related to one or 
More NRTIs
Toxicities that the investigator considers related or possibly related to one of the 
background NRTIs may be addressed by substitution of the medication for another 
approved NRTI one time during the study (Section 5.1.5). In addition, toxicities that the 
 
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investigator considers related or possibly related to any NRTI should be managed with 
reference to applicable product labeling.
Note: For subjects receiving an ABC-containing product as part of the background 
regimen, in the event of a discontinuation of ABC for any reason, reinitiation of this drug 
should be undertaken with caution. The investigator should obtain a complete history of 
the events surrounding the discontinuation of the ABC-containing product, evaluate for 
the possibility of a clinically suspected hypersensitivity reaction (HSR), and initiate 
subject management as outlined in the local country prescribing information, regardless 
of a subject’s HLA-B*5701 status. Screening for the presence of HLA-B*5701 is 
recommended prior to reinitiating treatment with ABC-containing products in subjects of 
unknown HLA-B*5701 status who have previously tolerated ABC.
Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the 
discretion of the investigator. For exceptions to this guideline see Section 6.4.3. 
Subjects who voluntarily decide to terminate their participation in the study due to a 
Grade 1 or 2 AE should complete the Withdrawal and Follow-up visit.
Grade 3 Toxicity/Adverse Event
Subjects who develop a Grade 3 AE or Grade 3 toxicity should be managed as follows: 
If the investigator has compelling evidence that the Grade 3 AE or toxicity has not been 
caused by IP, dosing may continue after discussion with the medical monitor.
Subjects who develop a Grade 3 AE or toxicity that the investigator considers related or 
possibly related to the IP should have the IP withheld and be rechecked each week until 
the AE returns to Grade 2. Once the AE is Grade ≤2, IP may be restarted.
Should the same Grade 3 AE recur within 28 days in the same subject, the IP should be 
permanently discontinued and the subject withdrawn from study. Subjects experiencing 
Grade 3 AEs requiring permanent discontinuation of IP should be followed weekly until 
resolution of the AE and encouraged to complete the Withdrawal visit. A Follow-up visit 
should be performed 4 weeks after the last dose of IP.
Subjects with Grade 3 asymptomatic laboratory abnormalities should be investigated for 
all potential non-drug-related causes, and, following discussion with the medical monitor, 
may continue IP if the investigator has compelling evidence that the toxicity is not related 
to IP.
Exceptions are noted for lipid abnormalities in Section 6.4.3.6.
 
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Grade 4 Toxicity/Adverse Event
Subjects who develop a Grade 4 AE or toxicity should have IP permanently discontinued. 
However, if the investigator has compelling evidence that the AE is not causally related 
to the IP, dosing may continue after discussion with and assent from the medical monitor. 
Subjects should be rechecked each week until the AE returns to Grade 2.
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of IP should be 
followed weekly until resolution of the AE and are encouraged to complete the 
Withdrawal and Follow-up visit as noted above.
Subjects with Grade 4 asymptomatic 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 IP. Exceptions are noted for lipid abnormalities in Section 6.4.3.6. A Follow-up 
visit should be performed 4 weeks after the last dose of IP if AEs or laboratory 
abnormalities are ongoing.
6.4.3.
Specific Toxicity Management
General guidelines are described below for the management of specific toxicities that are 
considered to be related or possibly related to IP, background NRTIs, and TB treatment 
and include the following: 

Liver chemistry stopping and follow-up criteria (Section 6.4.3.1)

IRIS (Section 6.4.3.3)

Decline in renal function (Section 6.4.3.4)

Allergic reaction (Section 6.4.3.5)

Hypertriglyceridemia/hypercholesterolemia (Section 6.4.3.6)

Creatine phosphokinase (CPK) elevation (Section 6.4.3.7)

Rash (Section 6.4.3.8)

Petechial rash due to RIF-induced thrombocytopenia (Section 6.4.3.9)
Subjects who permanently discontinue IP for reasons of toxicity should be followed 
weekly until resolution or stabilization of the AE and encouraged to complete the 
withdrawal and Follow-Up study evaluations as noted above.
6.4.3.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of IP and the Follow-up period. 
If ALT >2 × ULN, liver chemistries should be monitored weekly for 2 weeks, then every 
2 weeks thereafter until normalized.
While receiving IP co-administered with TB treatment, both will be stopped if any of the 
following liver chemistry criteria are met:
 
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
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin; bilirubin 
fractionation required)

NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. If 
testing is unavailable and a subject meets the criterion of total bilirubin 2 × 
ULN, then the event meets liver stopping criteria;

ALT 3 × ULN with symptoms or worsening of acute hepatitis or hypersensitivity 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia, OR

ALT ≥5 × ULN; regardless of symptoms
After completion of TB treatment, while receiving IP, ART will be stopped if any of the 
following liver chemistry criteria are met:

ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin; bilirubin 
fractionation required)

NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. If 
testing is unavailable and a subject meets the criterion of total bilirubin 
2 × ULN, then the event meets liver stopping criteria;

ALT 3 × ULN (if baseline ALT is <ULN) with symptoms or worsening of acute 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia, OR

ALT 3 × baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;

ALT 5 × ULN and <8 × ULN (after TB treatment is complete) that persists 
2 weeks (with bilirubin <2 × ULN and no signs or symptoms of acute hepatitis or 
hypersensitivity); ALT 5 × ULN but <8 × ULN (after TB treatment is complete) 
and cannot be monitored weekly for >2 weeks; and subjects who develop ALT 5 × 
ULN should be followed weekly until resolution or stabilization (ALT <5 × ULN on 
2 consecutive evaluations);

ALT > 8 × ULN; regardless of symptoms.
When liver chemistry stopping criteria are met, do the following:

Immediately hold IP;

According to guidelines, isoniazid, pyrazinamide, RIF, and TMP-SMX should be 
stopped simultaneously (when applicable) with the interruption of the ART;

Report the event to the medical monitor within 24 hours of learning its occurrence 
(see Table 7 and Section 6.4.14);
 
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
Complete the liver event and SAE eCRFs, where applicable, (see Section 6.4.14);

Complete the liver imaging, liver biopsy, or both eCRFs if these tests are performed;

Perform liver event follow-up assessments (described in this section), and monitor 
the subject until liver chemistries resolve, stabilize, or return to baseline values as 
described below;

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow-up assessments (described in this section), 
and close monitoring;

A specialist or hepatology consultation is recommended;

Monitor subjects twice weekly until liver chemistries (ALT, aspartate 
aminotransferase, and bilirubin) resolve, stabilize, or return to within baseline values;
Make every attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

HBsAg and hepatitis B core antibody (IgM);

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;

Blood sample for PK analysis, obtained within 60 hours of last dose. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of IP prior 
to blood draw on the eCRF. If the date or time of the last dose is unclear, provide the 
subject’s best approximation. If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SPM;

Serum acetaminophen test (APAP adduct test). Please refer to the SPM and Quest 
Diagnostics Laboratory manual for further details;

Serum CPK and lactate dehydrogenase;

Fractionate bilirubin, if total bilirubin is 1.5 × ULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
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
Liver imaging (ultrasound, magnetic resonance, or computed tomography) to 
evaluate liver disease;

Record the appearance or worsening of clinical symptoms of hepatitis, 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, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. Record alcohol use on the liver event alcohol intake case report form.
6.4.3.1.1.
Alternate RIF-Containing TB Treatment Regimen and Bridging Regimen
In cases of TB treatment interruption due to hepatotoxicity, until the cause of the 
hepatotoxicity is identified it may be necessary to treat the subject’s tuberculosis with a 
bridging non-RIF–containing anti-tuberculosis regimen with low risk of hepatotoxicity. 
Drugs that may be used include (i) ethambutol, (ii) an injectable: e.g., aminoglycoside 
(such as streptomycin, amikacin, and kanamycin) or capreomycin or (iii) a 
fluoroquinolone (e.g., moxifloxacin or levofloxacin). A bridging regimen should be used 
to avoid reaching the 14-day treatment interruption limit and therefore avoid having to 
withdraw a study subject from the study.
Both CDC and BHIVA guidelines recommend that patients be treated with two or more 
active drugs drawn from each of the groups listed (i) to (iii) above (i.e., ethambutol and 
streptomycin, or ethambutol and moxifloxacin) while waiting for standard therapy to be 
reintroduced in consultation with a local expert. A note for caution comes from reports of 
severe hepatotoxicity with moxifloxacin. 
Tuberculosis treatment may be re-introduced when ALT <2 × ULN. Suggested re-
introduction regimen schedules after TB treatment interruption are provided in Table 5
and Table 6, which describe options excluding ethambutol (12) or isoniazid (13) for 
testing re-exposure to TB drugs, respectively. TB treatment should be restarted first 
[BHIVA Guidelines, 2011], followed by TMP-SMX, if required for patient care, 
followed by ART. Daily monitoring of the patient’s condition and liver chemistries 
(ALT, AST, total bilirubin, alkaline phosphatase) is required during the reintroduction. 
Guidance from a local expert should be sought.
The time on the standard regimen (i.e., the initial WHO first-line TB regimen) should 
count towards time on the acceptable alternate RIF-containing TB treatment, provided the 
treatment interruption was no longer than 14 days [CDC 2003 Guidelines]. Only time on 
full-dose of the WHO first-line regimen or listed in Section 11.6 counts towards time on a 
TB regimen. Time on partial doses of TB drugs as part of the reintroduction does not 
count, but time on the bridging regimen does count. Further information on alternate RIF-
containing TB treatment regimens are described in Section 11.6.
 
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Table 5
Re-Introduction Guidelines for Regimen 1
Day
Rifampicin 
Isoniazid 
Pyrazinamide 
1
50 mg 
2
150 mg 
3
full dose
4
75 mg 
full dose
5
150 mg 
full dose
6
300 mg 
full dose
7
full dose
full dose
8
full dose
full dose
250 mg 
9
full dose
full dose
500 mg 
10
full dose
full dose
1 g 
11
full dose
full dose
full dose
12
full dose
full dose
full dose
13
full dose
full dose
full dose
kg = kilogram; mg = milligram; g = gram
Table 6
Re-Introduction Guidelines for Regimen 2
Day
Rifampicin
Ethambutol 
Pyrazinamide 
1
75 mg 
2
150 mg 
3
300 mg 
4
450 mg <50 kg or 600 mg >50 kg 
5
450 mg/600 mg 
5 mg/kg 
6
450 mg/600 mg
10 mg/kg 
7
450 mg/600 mg 
15 mg/kg 
8
450 mg/600 mg 
15 mg/kg 
250 mg 
9
450 mg/600 mg 
15 mg/kg 
500 mg 
10
450 mg/600 mg 
15 mg/kg 
1 g 
11
450 mg/600 mg 
15 mg/kg 
1.5 g <50 kg or 2 g >50 kg 
12
450 mg/600 mg 
15 mg/kg 
1.5 g/2 g 
kg = kilogram; mg = milligram; g = gram
6.4.3.2.
Restarting Investigational Product
Drug restart/rechallenge following liver events that are possibly related to IP
Liver toxicity in the setting of concomitant TB treatment and ART is most commonly 
related to the antituberculosis medications rather than the HIV medications. As described 
above, TB treatment (isoniazid, RIF, and pyrazinamide) should all be discontinued 
(Section 11.6 for alternate TB therapy recommendations), along with all antiretrovirals 
and TMP-SMX, if being administered, when liver stopping criteria are met. In some 
cases (e.g., EFV), short continuation of the dual NRTI components of the regimen after 
interruption of the third antiretroviral drug may be appropriate in order to minimize the 
risk of development of resistance. Liver chemistries should be followed at least twice 
weekly until they have returned to <2 × ULN. Re-introduction of TB treatment should 
then be undertaken first as described in Section 11.6, followed by TMP-SMX, and then 
ART should be restarted. 
 
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If liver toxicity is due to TB treatment and an alternative anti-TB treatment containing 
RIF can be successfully introduced, the authorization for restarting the IP may be 
discussed between the investigator and the study medical monitor, without the need for 
approval from the ViiV Safety and Labeling Committee (VSLC) (see details in Section 
11.5). If liver toxicity is not due to TB treatment, the case will need VSLC approval to 
restart DTG (this approval can be ad hoc).
For Grade 4 ALT elevations (10 × ULN) it is recommended that the subject not be 
rechallenged with pyrazinamide. Alternate RIF-containing TB treatment regimens are 
described in Section 11.6 [BHIVA Guidelines Section 7.2, 2011 and CDC, 2003 
Section 8.8.2].
The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge. Documentation of informed consent must be recorded in the study 
chart.
Subjects approved by ViiV/GSK for rechallenge of IP must return to the clinic twice a 
week for liver chemistry tests for 1 month or for as long as clinically indicated and then 
laboratory monitoring may resume as per protocol.
Refer to Section 11.5 for further details.
Drug restart following transient resolving liver events not related to IP 
Refer to Section 11.5 for further details.
6.4.3.3.
TB-Associated IRIS Toxicity Management
Subjects presenting with Grade 3 (except Grade 3 TB-associated IRIS toxicity manifested 
only by respiratory signs and symptoms) and Grade 4 TB-associated IRIS toxicity should 
have the IP withheld and be rechecked each week until the AE returns to Grade 2. Once 
the AE is Grade 2, IP may be restarted.
Grade 3 TB-associated IRIS toxicity restricted to respiratory signs and symptoms may be 
managed by the investigator including, but not limited to, assessment of treatment failure 
and therapy with steroids, for a period of 1 week without having the IP withheld. After 
this period, if the event persists as a Grade 3 event, withholding the IP and having weekly 
follow-ups until the AE returns to Grade 2 would be required.
6.4.3.4.
Decline in Renal Function
Subjects who experience an increase in creatinine from Baseline of 45 Mol/L (or 
0.5 mg/dL) should return for a confirmatory assessment within 2 to 4 weeks. A urinalysis 
and urine albumin/creatinine ratio should 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.
Subjects who have a decline in estimated GFR (using the CKD-EPI method) of >50% 
must return for a confirmatory creatinine assessment as soon as possible. A urinalysis and 
 
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urine albumin/creatinine ratio should be done at this confirmatory visit. If the estimated 
GFR has declined by >50% (confirmed), then IP should be withheld and the investigator 
should contact the study medical monitor to discuss the rationale for restarting IP (if 
appropriate). Consideration for confounding factors (e.g., other medications, dehydration, 
concurrent medications) should be taken into account and a nephrology consult may be 
obtained. If a subject is also receiving TDF, then a switch to an alternate NRTI should be 
considered if restarting IP. One background NRTI change is allowed for management of 
drug toxicity as described in Section 5.1.5. If IP is not reinitiated the subject must be 
withdrawn.
6.4.3.5.
Allergic Reaction
Grade 1 or 2: Subjects may continue IP at the discretion of the investigator. The subject 
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.
Grade ≥3: Subjects with allergic reactions that are considered to be possibly or probably 
related to the IP should permanently discontinue the IP regimen and the subject should be 
withdrawn from the study. Subjects should be treated as clinically appropriate and 
followed until resolution of the AE.
Allergic reactions that the investigator considers related or possibly related to TB 
treatment should be managed with reference to applicable product labeling, local 
guidelines and, where the re-introduction of TB treatment is applicable, the 
recommendations outlined in Section 11.6.
Subjects receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC HSR and managed appropriately as 
outlined in the local prescribing information.
6.4.3.6.
Hypertriglyceridemia/Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events Table (Table 2). Subjects who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP.
6.4.3.7.
Creatine Phosphokinase Elevation
Grade 3: Subjects with an elevation in CPK should result in a repeat assessment 
within 2 to 4 weeks to ensure the result is transient or due to exercise and will not require 
a change in study treatment. 
Grade 4: Subjects with an elevation in CPK should have a repeat assessment after the 
subject has abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations 
that are considered possibly or probably related to the IP, IP should be discontinued and 
the subject withdrawn from the study.
A history regarding use of drugs known to cause an increase in CPK (such as statins) and 
physical activity or exercise preceding the CPK evaluation should be obtained. 
 
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6.4.3.8.
Rash
Mild to moderate rash is an expected adverse reaction for DTG-containing ART. 
Episodes generally occur within the first 10 weeks of treatment, rarely require 
interruptions or discontinuations of therapy and tend to resolve within 2 to 3 weeks. No 
instances of serious skin reaction, including Stevens-Johnson syndrome, toxic epidermal 
necrolysis and erythema multiforme, have been reported for DTG in clinical trials. 
Additional information on characterization of HSR and rash observed with DTG-
containing ART is in the current version of the IB [GSK Document Number
RM2007/00683/11, GSK Document Number 2017N352880_00, GSK Document Number
2017N352880_01]]. Approximately one-fourth of adult subjects treated with EFV in 
clinical studies presented rash of any grade, with rare cases (<1%) being Grade 3 or 
higher. For information on rashes observed in EFV treated subjects refer to EFV product 
information [Sustiva (efavirenz) US Product Information, May 2013; Sustiva Package 
Insert, 2013; Sustiva Summary of Product Information, 2014].
TB treatment regimens commonly cause rashes that are typically mild/moderate in 
severity and usually start within the first 2 months of treatment initiation. Mild rashes 
without mucosal involvement can be treated symptomatically. More widespread 
worsening rashes or those with systemic symptoms require all drug cessation. It is 
recommended that when TB drugs, HIV drugs, and TMP-SMX are interrupted 
concomitantly due to treatment emerging rash that TB drugs be reintroduced first, then 
TMP-SMX, and finally the ART, in a similar regimen as the one suggested for 
hepatotoxicity management (Section 6.4.3.1.1).
Grade 1: Subjects with an isolated Grade 1 rash may continue IP at the investigator’s 
discretion. The subject should be advised to contact the investigator immediately if there 
is any worsening of the rash, if any systemic signs or symptoms worsen, or if mucosal 
involvement develops.
Grade 2: Subjects may continue IP for an isolated Grade 2 rash. However, IP (and all 
other concurrent medication(s) suspected in the investigators causality assessment 
including TB treatment medications) should be permanently discontinued for any Grade
≥2 rash that is associated with an increase in ALT (see Section 6.4.3.1). The subject 
should be advised to contact the physician immediately if rash fails to resolve (after more 
than 2 weeks), if there is any worsening of the rash, if any systemic signs or allergic 
symptoms develop, or if mucosal involvement develops.
Grade 3 or 4: Subjects should permanently discontinue IP (and all other concurrent 
medication(s) suspected in the investigators causality assessment should be interrupted) 
for an isolated Grade 3 or 4 rash, and the subject should be withdrawn from the study. 
Subjects should be treated as clinically appropriate and followed until resolution of the 
AE.
The rash and any associated symptoms should be reported as AEs (see Section 6.4.3.9) 
and appropriate toxicity ratings should be used to grade the events (see Section 11.3).
 
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If the etiology of the rash can be definitely diagnosed as being unrelated to IP and due to 
a specific medical event or a concomitant non-study medication, routine management 
should be performed and documentation of the diagnosis provided.
A rash that the investigator considers related or possibly related to TB treatment should 
be managed with reference to applicable product labeling, local guidelines and, where the 
re-introduction of TB treatment is applicable, the recommendations outlined in Section 
11.6. 
Subjects receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC HSR and managed appropriately as 
outlined in the local prescribing information. In any subject treated with ABC, the 
clinical diagnosis of suspected HSR must remain the basis of clinical decision making. 
Regardless of HLA-B*5701 status, it is important to permanently discontinue ABC and 
not re-challenge with ABC (i.e., ABC/DTG/3TC, Ziagen, EPZICOM/KIVEXA, or 
TRIZIVIR™), if a HSR cannot be ruled out on clinical grounds, due to the potential for a 
severe or even fatal reaction.
6.4.3.9.
Petechial Rash
Thrombocytopenia induced by RIF and manifested by petechial rash has been described 
with high-dose intermittent therapy and also after resumption of interrupted treatment. As 
this event is reversible and potentially serious, RIF should be immediately and 
permanently withdrawn. This would also require discontinuation from the study, as the 
subject must be on a RIF-containing TB treatment regimen.
6.4.4.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE.
6.4.4.1.
Definition of an AE
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation subject, temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
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 medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

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 treatment administration even 
though it may have been present prior to the start of the study
 
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
Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE or SAE) unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This 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. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where 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

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
6.4.4.2.
Definition of an SAE
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
NOTE: The term “life threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject 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 out-patient setting. Complications that occur during hospitalization are AEs. 
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.
d.
Results in disability/incapacity, or
 
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NOTE: 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 significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.     Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These should also be 
considered serious. Examples of such events are 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.
g.
All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT 3 × ULN and bilirubin 2 × ULN (>35% direct) (or ALT 3 × ULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
Note: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2 × ULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.4.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and 
scientific judgement of the investigator are to be recorded as AEs or SAEs. However, any 
clinically significant safety assessments that are associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs.
Additionally, diagnostic test results that represent a sign of a clinical condition that is 
already reported as an AE need not be reported as this would be redundant.
6.4.6.
TB-Associated Immune Reconstitution Inflammatory Syndrome
The assessment of the frequency of TB-associated IRIS is one of the secondary study 
objectives (Section 2.2). In order to achieve this goal, investigators need to carefully 
 
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document and manage signs and symptoms that could be related to TB-associated IRIS. 
In addition, the clinical team will review the AE terms and HIV conditions in order to 
identify TB-associated IRIS cases. Information on X-ray findings and repeat sputum 
culture and susceptibility testing may be helpful in distinguishing IRIS from worsening 
TB disease or development of TB resistance.
This section provides guidance on criteria for TB-associated IRIS diagnosis during the 
study. TB-associated IRIS assessments will be performed according to the Time and 
Events schedule (Table 3). If any of the major and/or minor criteria described in this 
section occur, they should be captured and reported as AEs. 
Details on toxicity management for TB-associated IRIS cases are described in Section 
6.4.3.3.
IRIS is associated with the initiation of highly active ART for subjects co-infected with 
HIV-1 and TB. IRIS appears to be associated with severe immunosuppression, the speed 
of immune reconstitution, and TB severity. The diagnosis of this syndrome is actually a 
diagnosis of exclusion, after ruling out other diagnoses such as non-response to treatment 
(including failure to TB treatment due to drug resistance), poor adherence to TB 
treatment, recurrence of TB, toxicity or drug reaction, neoplasia, and opportunistic 
infections or other causes of fever. In biological terms, the IRIS could be associated with 
a burst of specific Th1 CD4+ T cells to tuberculin purified protein derivative, detectable 
by ELISPOT for IFN-.
There are 3 components of the existing case definition for paradoxical TB-associated 
IRIS [Meintjes, 2008]:
a.
Preliminary Requirements
     Both of the following requirements must be met:

Diagnosis of TB, meeting WHO criteria for the diagnosis of either positive or 
negative sputum smear-positive pulmonary TB or extrapulmonary TB before 
starting the ART

Initial response to TB treatment: the subject's condition should be stabilized or 
improved in the presence of appropriate treatment for TB before starting the 
ART (e.g., remission of night sweats, fever, cough, weight loss). (Note: This 
does not apply to subjects starting ART within the first 2 weeks of TB treatment, 
since this is not sufficient time for the occurrence of clinical response)
b.
Clinical Criteria
The onset of IRIS signs and symptoms related to TB should occur within the first 
3 months of starting, restarting, or changing the ART regimen for treatment failure.
At least 1 major criterion or 2 of the minor criteria listed below must be present:
Major criteria

New lymph nodes or increase in existing lymph nodes, cold abscesses, or other 
focal tissue involvement (e.g., tuberculous arthritis)
 
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
New x-ray findings suggestive of TB or worsening of existing images (e.g. chest 
x-ray, abdominal ultrasonography, computed tomography or magnetic resonance 
imaging)

New onset of CNS TB or worsening of existing disease (meningitis or focal 
neurological deficit caused by tuberculoma)

New onset or worsening serositis (pleural effusion, ascites, or pericardial 
effusion)
Minor criteria

New constitutional symptoms or worsening of existing symptoms, such as fever, 
night sweats, or weight loss

New respiratory symptoms or worsening of existing symptoms such as 
coughing, dyspnea, or rhonchi

Recent onset or worsening abdominal pain accompanied by peritonitis, 
hepatomegaly, splenomegaly, or abdominal adenopathy
6.4.7.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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
This information should be recorded in the specific cardiovascular eCRF within 1 week 
of when the AE/SAE(s) are first reported.
6.4.8.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed. 
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
 
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6.4.9.
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 
(see Section 11.2) 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 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 6.4.4.2), or

The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, 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.
6.4.10.
Suicidality Monitoring
Subjects with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behavior). Therefore, it is appropriate to monitor 
subjects for suicidality before and during treatment. It is recommended that the 
investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behavior.
Assessment of treatment-emergent suicidality will be monitored during this study using 
the C-SSRS, if a validated version in the appropriate language is available for the subject. 
The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia Suicide History Form [Oquendo, 2003]. Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation. Day 1 (Baseline) visit questions will 
be in relation to lifetime experiences and current experiences (within the past 2 months) 
and all subsequent questioning in relation to the last assessment. The C-SSRS is to be 
administered as a patient-completed questionnaire specified in the Time and Events Table 
(Table 2). Refer to the SPM for further details on questionnaire delivery and follow-ups.
Additionally, the investigator will collect information using the Possible 
Suicidality-Related AE (PSRAE) eCRF form in addition to the AE (nonserious or SAE) 
eCRF form on any subject that experiences a PSRAE 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 behavior, 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 PSRAE.
 
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6.4.11.
Pregnancy
6.4.11.1.
Pregnancy Testing
Women of childbearing potential must have a negative pregnancy test at Screening and 
Day 1 to be eligible for administration of IP. Pregnancy testing will also be conducted 
according to the Time and Events Table (Table 2) and at any time during the study when 
pregnancy is suspected.
Additionally, a pregnancy test should also be performed prior to IP re-administration, 
when IP administration is disrupted for more than 7 days.
6.4.11.2.
Time Period for Collecting Pregnancy Information
Information on the occurrence of pregnancies in female subjects will be collected over 
the period starting at Screening and ending at the final Follow-up visit. Only those 
pregnancies that occur following the first dose of IP will be reported to the medical 
monitor. Follow-up information will only be collected for pregnancies occurring from 
Day 1 to the final Follow-up visit.
6.4.11.3.
Action to be Taken if Pregnancy Occurs
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study. Subjects using DTG must immediately discontinue the IP.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported within 
2 weeks of learning of its occurrence. 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. Spontaneous abortions must be reported as SAEs.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to ViiV/GSK.
ViiV/GSK’s central safety department will also forward this information to the 
Antiretroviral Pregnancy Registry. The international registry is jointly sponsored by 
manufacturers or licensees of antiretroviral products. Additional information and a list of 
participating manufacturers/licensees are available from http://apregistry.com/index.htm.
 
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6.4.12.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff personnel are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.
Beginning at Day 1 and continuing until the follow-up contact, AEs will be recorded. 
Serious AEs will be collected throughout the entire study. Any SAE assessed as related
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a ViiV/GSK concomitant medication, 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. All SAEs will be reported to medical monitor within 
24 hours, as indicated in Section 6.4.14. 
6.4.13.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?”
6.4.14.
Prompt Reporting of Serious Adverse Events and Other Events
Serious AEs, pregnancies, and liver function abnormalities meeting pre-defined criteria 
will be reported promptly by the investigator to the medical monitor as described in Table 
7 once the investigator determines that the event meets the protocol definition for that 
event.
Criteria for liver chemistry stopping and follow-up criteria are in Section 6.4.3.1.
 
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Table 7
Reporting of Serious Adverse Events and Other Events
Initial Reports
Follow-up Information on a Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data collection 
tool
24 hours
Updated “SAE” data 
collection tool
Cardiovascular or death 
event
Initial and follow-
up reports to be 
completed within 
1 week of when 
the 
cardiovascular 
event or death is 
reported 
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Initial and follow-up 
reports to be 
completed within 
1 week of when the 
cardiovascular event 
or death is reported
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-up 
Form”
Suspected ABC HSRa
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF
ALT3×ULN and
bilirubin2×ULN (>35% 
direct) (or ALT3×ULN
24 hoursb
“SAE” data collection 
tool. “Liver Event 
eCRF” and “Liver 
Imaging” and/or “Liver 
Biopsy” eCRFs, if 
applicablec
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” documentsc
ALT≥5×ULN that persists 
≥2 weeks 
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ALT ≥8×ULN 
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ALT ≥3×ULN or ALT ≥3 
fold increase from 
baseline value with 
appearance or worsening 
of symptoms of hepatitis 
or hypersensitivity
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ABC = abacavir; CV = cardiovascular; eCRF = electronic case report form; HSR = hypersensitivity reaction; 
SAE = serious adverse event; ULN = upper limit of normal.
a.
ABC HSR eCRF required only if event meets one of the definitions in Section 6.4.4.2.
b.
PPD must be contacted at onset of liver chemistry elevations to discuss subject safety.
c.
Liver event documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, as 
applicable) should be completed as soon as possible.
The investigator will be required to confirm review of the SAE causality by ticking the 
‘For Investigators ONLY’ box at the bottom of the eCRF page within 72 hours of 
submission of the SAE.
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM. Procedures 
for post-study AEs/SAEs are provided in the SPM. 
 
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6.4.14.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
ViiV/GSK has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. 
ViiV/GSK will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from ViiV/GSK will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Reporting of SAEs and other events to ViiV/GSK/PPD is addressed in Table 7.
6.4.14.2.
Reporting of ABC Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC develops in subjects receiving ABC as part 
of their NRTI background regimen, and meets the definition of an SAE as described in 
Section 6.4.4, then, in addition to reporting the case as an SAE, the ABC HSR eCRF 
should also be completed within 1 week of the onset of the HSR (see Section 6.4.14).
6.4.15.
Other Safety Outcomes
Laboratory Assessments
All protocol-required laboratory assessments, as defined in Table 4, must be performed 
by the central laboratory, Quest Diagnostics, or a laboratory contracted by the central 
laboratory. Laboratory assessments must be conducted in accordance with the Central 
Laboratory Manual and Protocol Time and Events schedule (Table 2). Laboratory 
requisition forms must be completed and samples must be clearly labeled with the subject 
number, protocol number, site/center number, and visit date. Details for the preparation 
and shipment of samples will be provided in the Quest Diagnostic Laboratory manual. 
Reference ranges for all safety parameters will be provided to the site by Quest 
Diagnostics.
Mycobacterium TB laboratory assessments are to be performed locally and the results 
must be recorded in the subject’s eCRF in accordance with Time and Events schedules 
(Table 2 and Table 3).
All study-required laboratory assessments will be performed by a central laboratory. If 
required for cardiovascular events, additional specific local laboratory assessments will 
be recorded in the specific cardiovascular eCRF (see Section 6.4.7).
 
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6.5.
Pharmacokinetics
6.5.1.
Pharmacokinetic Endpoints
DTG and EFV concentrations will be evaluated at Weeks 8, 24, 36, and 48 using sparse 
PK sampling.
DTG and EFV drug concentrations will be analyzed using a population PK modeling 
approach to evaluate the effects of demographic factors (e.g., weight, age, gender, and 
race), subject characteristics, and on/off RIF treatment on DTG and EFV PK parameters 
and variability. DTG PK data obtained from this study may be combined with DTG PK 
data from previous Phase 3 studies for the population PK modeling. Plasma DTG and 
EFV PK parameters (AUC0-, Cmax, and C) estimated by population PK modeling 
based on sparse PK sampling will be reported and used in the analysis of correlation with 
antiviral activities at Weeks 24 and 48.
6.5.2.
Pharmacokinetic Sample Collection
Blood samples (2 mL each) will be collected from as many subjects as possible for 
evaluation of DTG and EFV plasma PK levels. Blood samples should be collected into 
K2EDTA tubes. The PK sampling visits will occur at Weeks 8, 24, 36, and 48 during the 
Randomized Phase. For the EFV arm, mid-dosing interval samples will be collected at 
Weeks 8, 24, 36, and 48. For the DTG arm, 1 sample will be collected for each of the 
following time points relative to IP dose: pre-dose, 1 to 3 hours post-dose, and 4 to 12 
hours post-dose at Weeks 8 and 36 as well as 1 sample pre-dose at Weeks 24 and 48 
Table 8. If PK sampling is not performed at the planned visit for any reason then the PK 
sample collection visit will be rescheduled within 4 weeks of the originally scheduled PK 
visit. The subject will be provided a new diary card at the rescheduled visit for the next 
PK visit, if applicable.
Table 8
Pharmacokinetic Sample Schedule
Treatment Arm
Week
Sample Times Relative to Dose
DTG PK
8 and 36
1 sample pre-dosea
1 sample 1 to 3 h post-doseb
1 sample 4 to12 h post-doseb,c
24 and 48
1 sample pre-dosea
EFV PK
8, 24, 36, and 48
1 sample mid-dosing intervald
DTG = dolutegravir; EFV = efavirenz; h = hour; PK = pharmacokinetic
a.
Pre-dose samples to be collected immediately before the morning dose (i.e. within 15 minutes) which will be taken 
under observation at the clinic. DTG twice-daily pre-dose sample be drawn as close as possible to 12 hours after 
the previous dose and DTG once-daily pre-dose sample should be drawn as close as possible to 24 hours after 
the previous dose.
b.
Both sample time points must be obtained from each subject.
c.
It is acceptable to draw the 4 to 12 hour sample any time between 4 and 12 hours post-dose.
d.
Mid-dosing interval samples should be collected in the morning at about 12 hours after the evening EFV dose on 
previous day.
 
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The Week 8 PK visit is to collect PK data during the TB treatment. If the subject is not on 
TB treatment at Week 8 due to temporary interruption for the management of toxicity, 
then PK data should instead be collected 14 to 21 days after RIF reintroduction. The 
Week 36 PK visit is to collect PK data when the subject has completed TB treatment (i.e., 
the subject is no longer taking RIF). If the treatment course has been extended because of 
interruptions, collection of Week 36 data should be delayed until TB treatment 
completion.  The Week 24 and 48 PK data will correspond with the primary and 
secondary efficacy analysis, respectively. Collection of PK data at multiple visits will 
provide more robust analysis of inter-occasional variability as well as possible evaluation 
of dosing compliance.
It is important to collect PK samples according to the following specified procedure.
For subjects randomly assigned to the DTG arm 
DTG twice daily - While taking DTG twice daily following TB treatment completion it 
is critical that the pre-dose sample should be drawn as close as possible to 12 hours after 
the previous dose (target window = 10 to 14 hours after the last dose) and before that 
morning’s dose (i.e., within 15 minutes of the next dose). For the 3 days in advance of a 
PK clinic visit, the subject must be instructed to plan the dosing of DTG at a time that 
corresponds with the scheduled PK visit time to allow for a pre-dose sample collection as 
close to 12 hours after the previous dose. 
DTG once daily - While taking DTG once daily following TB treatment completion it is 
critical that the pre-dose sample should be drawn as close as possible to 24 hours after the 
previous dose (target window = 22 to 26 hours after the last dose) and before that 
morning’s dose (i.e., within 15 minutes of the next dose). For the 3 days in advance of a 
PK clinic visit, the subject must be instructed to plan the dosing of DTG at a time that 
corresponds with the scheduled PK visit time to allow for a pre-dose sample collection as 
close to 24 hours after the previous dose. 
After the pre-dose sample is taken, the next dose will be taken under observation at the 
clinic. 
To enhance the quality of PK data collection, subjects will be asked to complete a diary 
card with the date and time of IP administration prior to the scheduled PK clinic visits. 
The actual dates and times of DTG dosing during the 3 days of prior to PK sampling as 
well as the observed dose taken at the clinic, if the subject vomited, and the actual date 
and time of the PK samples must be recorded on the eCRF.
Note: If a subject presents at the clinic for pre-dose PK sample collection having already 
taken the morning dose or having missed doses within the previous 3 days, it is 
recommended to reschedule PK sampling at the earliest next clinic visit. It is not 
recommended to collect PK samples if date and time of dosing for the previous 3 days 
cannot be reliably confirmed. Such samples will be discarded and will not contribute to 
any analyses.
Flexibility is allowed in collecting the post-dose sample (anywhere from 1 to 3 hours and 
4 to 12 hours post-dose) so that a range of sample times can be obtained. To achieve this, 
subjects may choose to remain in clinic until at least 1 hour after taking the DTG dose 
and may choose to return to the clinic 4 to 12 hours after taking the medication.
 
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For subjects randomly assigned to the EFV arm 
For subjects on EFV, the mid-dose samples will be collected in the morning, 
approximately 12 hours after the previous day’s dose. The date and time of the EFV 
mid-dose sample, as well as the date and time the subject had taken the previous 3 doses 
of EFV, will be collected and recorded on the CRF.
6.5.3.
Bioanalysis of DTG and EFV PK Samples
Plasma will be extracted from the blood samples collected and shipped for determination 
of DTG and EFV plasma concentrations by validated LC/MS/MS assays under the 
control of GSK PTS DMPK/Scinovo, the details of which will be included in the SPM. 
Raw data will be archived at the bioanalytical site (detailed in the SPM).
Once the plasma has been analyzed for DTG and EFV, any plasma may be analyzed for 
other compound-related metabolites and the results reported under a separate GSK PTS 
DMPK protocol.
6.6.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject at Screening for 
resistance testing at the central laboratory (or a laboratory contracted by the central 
laboratory) and on study ‘plasma for storage samples’ according to the Time and Events 
schedule in Section 6.1 for potential viral genotypic and phenotypic analyses. In addition, 
whole venous blood samples will be obtained from each subject to provide plasma for 
storage samples at the time of re-test for suspected protocol-defined virologic failure as 
specified in the Quest Laboratory manual. 
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately. Viral genotype will be performed at Screening for study eligibility 
determination through Quest Diagnostics as well as at location(s) to be described in the 
SPM. Genotypic and phenotypic analyses may be carried out by Monogram Biosciences 
using, but not limited to, their Standard Phenosense and GenoSure testing methods for 
protease (PRO), reverse transcriptase (RT), and integrase assays. In addition, where 
Monogram Biosciences resistance testing is not possible, resistance testing may also be 
performed at location(s) to be described in the SPM.
6.6.1.
Viral Endpoint
A secondary endpoint of this study will be the incidence of treatment-emergent genotypic 
and phenotypic resistance to DTG, EFV, and other on-study ART in subjects meeting 
confirmed virologic withdrawal criteria.
 
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6.6.2.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Subjects meeting ‘confirmed virologic withdrawal criterion’ 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 
withdrawal criterion’ (additional subsequent samples may be analyzed); these results will 
be reported to the investigator as soon as available to provide guidance for election of an 
alternate regimen.
HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and 
phenotype will also be determined on the Baseline isolates from all subjects, if possible. 
When samples cannot be analyzed by Monogram Biosciences, Baseline isolate resistance 
testing may be performed at location(s) to be described in the SPM.
6.6.3.
HIV-1 Exploratory Analysis
Additional analyses for HIV-1 resistance may, for example, be carried on stored plasma 
samples from Baseline and other relevant time points. These 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, and measurement of viral replicative capacity. HIV-1 PRO and RT genotype 
and phenotype and HIV-1 integrase genotype and phenotype will also be determined on 
the Baseline and the last on-treatment isolates from subjects who have HIV-1 RNA 
>400 c/mL regardless of confirmatory HIV-1 RNA.
6.7.
Pharmacogenetic Research
Information regarding pharmacogenetic (PGx) research is included in Section 11.1.  
The IEC/IRB and, where required, the applicable regulatory agency, must approve the 
PGx assessments before these can be conducted at the site. The approval(s) must be in 
writing and will clearly specify approval of the PGx assessments (see Section 11.1). In 
some cases, approval of the PGx assessments can occur after approval is obtained for the 
rest of the study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and, therefore, PGx assessments will not be conducted.
7.
DATA MANAGEMENT
For this study subject data will be entered into GSK-defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system. 
Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal validated medication dictionary, GSKDrug. Electronic CRFs (including queries 
and audit trails) will be sent at the end of the study in CD format to GSK to be retained. 
Each investigator will receive a copy of his or her site-specific data in the same format to 
maintain as the investigator copy. In all cases, subject initials will not be collected or 
transmitted to ViiV/GSK according to ViiV/GSK policy.
 
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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This study is designed to assess the antiviral effect of treatment with a DTG-containing 
regimen (50 mg twice daily during TB treatment and for 2 weeks following 
discontinuation of TB treatment, then 50 mg once daily) at Week 48, when administered 
in combination with dual NRTI therapy. No formal statistical hypothesis testing will be 
performed.
8.1.1.
Sample Size Assumptions
Data from recent DTG studies in treatment-naïve subjects have shown consistent 
response rates of 88% to 90% at Week 48 with a dose of 50 mg once daily (Table 9). 
Primary analyses in these studies have shown non-inferiority to RAL 400 mg once daily 
and superiority to both EFV/TDF/FTC once daily and DRV/r once daily. The proportion 
of subjects with baseline HIV-1 RNA >100,000 c/mL in the Phase III studies ranged 
from 25% to 32%; there were few subjects with baseline CD4+ cell counts 
<50 cells/mm3.
Table 9
Week 48 Results From Recent Treatment-Naïve DTG Studies
Study
Back-
ground 
NRTI
Endpoint
Active 
Treatment 
Responsea
Comparator/
Control 
Response
Notes
SINGLE
Phase III
n=833
HIV-1 RNA
<50 c/mL;
FDA 
Snapshot
DTG 50 mg
+ABC/3TC 
once daily
88%
(87%)a
EFV/TDF/FTC 
once daily
81%
(80%)a
DTG superior (at 
Wk 48/96)
Baseline:
32% >100,000 c/mL HIV-1 
RNA
SPRING-2
Phase III
n=822
ABC/3TC
or
TDF/FTC
HIV-1 RNA
<50 c/mL;
FDA 
Snapshot
DTG 50 mg 
once daily
88%
(87%)a
RAL 400 mg BID
85%
(86%)a
DTG non-inferior (at 
Wk 48/96)
Baseline:
28% >100,000 c/mL HIV-1 
RNA
FLAMINGO
Phase IIIb
n=484
ABC/3TC
or
TDF/FTC
HIV-1 RNA
<50 c/mL;
FDA 
Snapshot
DTG 50 mg 
once daily
90%
(88%)a
DRV/r 
800 mg/100 mg 
once daily
83%
(80%)a
DTG superior at Wk 48 
(study continuing to 
Wk 96)
Baseline:
25% >100,000 c/mL HIV-1 
RNA
SPRING-1
Phase IIb
n=205
ABC/3TC
or
TDF/FTC
HIV-1 RNA 
<50 c/mL;
TLOVR
DTG 50 mg 
once daily
90%
EFV 600 mg once 
daily
82%
DTG 10 mg 91%
DTG 25 mg 88%
Baseline:
21% >100,000 c/mL HIV-1 
RNA
ABC/3TC = abacavir/lamivudine; c = copies; CD4 = helper-inducer T-lymphocyte having surface antigen CD4 (cluster 
of differentiation 4); DRV/r = darunavir + ritonavir; DTG = dolutegravir; EFV = efavirenz; 
EFV/TDF/FTC = efavirenz/tenofovir disoproxil fumarate/emtricitabine; FDA = Food and Drug Administration 
(United States); HIV = human immunodeficiency virus; mL = milliliter; NRTI = nucleoside reverse transcriptase 
inhibitor; RAL = raltegravir; RNA = ribonucleic acid; TDF/FTC = tenofovir disoproxil fumarate/emtricitabine; 
TLOVR = time to loss of virologic response; Wk = week.
a.
Response rate for subjects with baseline CD4+ cell count ≥50 to <500 cells/mm3, where available.
 
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Response rates <50 c/mL in the REFLATE study at Week 48 were much lower than seen 
in the DTG studies (Table 10). The study population included higher proportions of 
subjects with baseline HIV-1 RNA >100,000 c/mL (46%) and with baseline CD4+ cell 
counts <50 cells/mm3 (20%); in particular, the EFV treatment arm had more such 
subjects than either of the RAL treatment arms. These characteristics are typically 
associated with a lower response rate for achieving virologic suppression.
Table 10
Week 48 Results from the REFLATE Study
Back-
ground 
NRTI
Endpoint
EFV
Once Daily 
(Response Rate)
RAL
Twice-Daily 
(Response Rate)
Notes
TDF/FTC
<50 c/mL;
Missing=Failure
600 mg (67%)
400 mg (76%)
800 mg (63%)
n=51 in each arm
Baseline:
CD4+ cells <50 c/mL: 27%, 24%, 
and 10%a
HIV-1 RNA >100,000 c/mL: 51%, 
39%, 47%a
c = copies; EFV = efavirenz; HIV = human immunodeficiency virus; mL = milliliter; NRTI = nucleoside reverse 
transcriptase inhibitor; RAL = raltegravir; RNA = ribonucleic acid; TDF/FTC = tenofovir disoproxil 
fumarate/emtricitabine.
a.
Percentage of subjects at Baseline in EFV 600 mg, RAL 400 mg, and RAL 800 mg treatment groups, respectively
Rates of withdrawal due to non-fatal AEs were comparable between REFLATE and the 
DTG studies. There was a higher incidence of deaths in REFLATE (approximately 5% 
overall versus <1% in DTG studies) with many owing to complications with TB 
co-infection. Even accounting for differences in the study population, the REFLATE 
response rates are lower than would be expected based on results seen in the DTG 
studies. The smaller sample sizes in REFLATE are more sensitive to what may be other 
chance findings.
Given the exposure data, it is anticipated that DTG twice daily co-administered with RIF 
will have efficacy comparable to DTG once daily, but a study population with higher 
proportions of subjects with baseline HIV-1 RNA >100,000 c/mL and lower CD4+ cell 
counts would have slightly lower responses than seen in the prior DTG studies.  
Assuming an 85% response rate for DTG at Week 48, a sample size of 66 to 72 subjects 
in the DTG arm would have >85% power to detect a response rate of greater than 70%
(Figure 4). Although the objective of the study is not to test a statistical hypothesis, the 
sample size has been chosen to provide an adequate number of subjects for assessing the 
antiretroviral activity of DTG.
8.2.
Study Design Considerations
8.2.1.
Sample Size Sensitivity
Figure 4 shows the relationship between study power and sample size, assuming an 85% 
response rate for DTG, to detect a response rate of greater than 70%. A sample size of 
69 subjects has >90% power. Smaller samples (e.g., 65 or greater) have at least 86% 
power, which is relevant when assessing the primary endpoint in alternate analysis 
populations (i.e., modified ITT-E).
 
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Figure 4
Relationship Between Study Power and Sample Size
Figure 5 shows the relationship between minimum sample size required and the assumed 
response rate; different targets for power are considered.
 
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Figure 5
Relationship Between Minimum Sample Size Required and the 
Assumed Response Rate
8.2.2.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.2.3.
Analysis Populations
The following populations will be assessed; other analysis populations (e.g., per-protocol, 
genotypic/phenotypic) will be fully described in the RAP.
8.2.3.1.
Intent-to-Treat Exposed (ITT-E) Population
The intent-to-treat exposed (ITT-E) population will consist of all randomly assigned 
subjects who receive at least one dose of IP. Subjects will be assessed according to their 
randomized treatment, regardless of the treatment they received. Unless stated otherwise, 
the ITT-E population will be used for summaries of efficacy. 
 
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8.2.3.2.
Modified Intent-to-Treat Exposed (MITT-E) Population
The modified intent-to-treat exposed (MITT-E) population will consist of all subjects in 
ITT-E population with confirmed RIF-sensitive MTB. This population will be used in an 
additional evaluation of the primary endpoint.
8.2.3.3.
Per-Protocol Population
The per-protocol (PP) population will consist of subjects in the ITT-E population with the 
exception of major protocol violators, e.g. violations which could affect the assessment of 
antiviral activity. The PP population will be used for sensitivity analyses of the primary 
efficacy endpoint.
8.2.3.4.
Safety Population
The safety population is defined as all subjects who receive at least one dose of IP. 
Subjects will be analyzed according to the actual treatments received.
8.2.3.5.
PK Population
8.2.3.5.1.
DTG PK Population
All subjects enrolled in the study who received at least 1 dose and for whom any 
pre-dose, post-dose, or mid-dose sample was taken for PK analysis with evaluable drug 
concentration data reported.
8.2.3.5.2.
EFV PK Population
All subjects enrolled in the study who received at least 1 dose and for whom any 
mid-dose sample was taken for PK analysis with evaluable drug concentration data 
reported.
8.2.4.
Analysis Data Sets
Final analysis will be performed after the completion of the study and authorization of 
final dataset.
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by subject, study period or phase, day, and time, noting 
treatment arm; summaries will be presented by treatment arm, day, and time. 
For the primary efficacy analysis, each subject’s response (i.e., HIV-1 RNA <50 c/mL) 
will be calculated according to the US Food and Drug Administration (FDA)’s Snapshot 
algorithm. This algorithm treats all subjects without HIV-1 RNA data at the visit of 
interest (due to missing data or discontinuation of IP prior to visit window) as 
non-responders, as well as subjects with ART substitutions not permitted per protocol 
(see Section 5.1.5). 
 
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Otherwise, virologic success or failure will be determined by the last available HIV-1 
RNA assessment while the subject is on-treatment within the visit window of interest (to 
be specified in the RAP). Full details on this Snapshot algorithm will be contained in the 
RAP. 
For this study, all protocol-permitted substitutions, regardless of HIV-1 RNA results at 
the time of the substitution, will have no effect on the analysis.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise. If there are multiple assessments collected on the 
same scheduled time, the average of these assessments will be used. For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.1 or higher of the SAS system will be used to analyze the data and to generate 
tables, figures, and listings.
Complete details will be documented in the RAP.
8.2.5.
Treatment Comparisons
No formal treatment comparisons will be performed in this study.
8.2.6.
Interim Analysis
The first interim analysis will be conducted when all subjects complete their Week 24 
visit. The primary analysis will be conducted when all subjects complete their Week 52 
visit. A final end-of-study analysis will be conducted when the final subject randomly 
assigned to the DTG OLE has transitioned to commercial supplies of DTG or has been 
withdrawn from the study. Further data cuts and analyses may be conducted as necessary 
in order to support regulatory submissions and publications.
8.2.7.
Key Elements of Analysis Plan
When descriptive statistics are used to summarize group characteristics or differences, the 
following statistics will be included: for categorical variables, the number and percent in 
each category; for continuous variables, the mean, median, standard deviation, quartiles, 
and range (minimum, maximum). 
8.2.7.1.
Efficacy Analyses
The primary efficacy endpoint, the proportion of subjects from the ITT-E population with 
plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm in the DTG arm, 
will be presented with its 95% CI.
The following secondary efficacy endpoints will be summarized using descriptive 
statistics:
 
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
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm in the EFV arm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 
48, where failure equals treatment-related discontinuation (meeting confirmed 
virologic withdrawal criteria, treatment-related AE, safety stopping criteria, or 
lack of efficacy);

Changes from baseline in CD4+ counts at Week 24 and Week 48.
The following tertiary efficacy endpoint will be summarized by event type and treatment 
arm using descriptive statistics:

Incidence of disease progression (HIV-associated conditions, new AIDS 
diagnoses, and death);

Proportion of subjects with TB treatment success (using the WHO definition);

Proportion of subjects with pulmonary tuberculosis who are sputum 
culture-negative 2 months after starting TB treatment.
8.2.7.2.
Safety Analyses
Exposure to IP, measured by the number of weeks on IP, will be summarized by 
treatment arm. The proportion of subjects reporting AEs will be tabulated by treatment 
arm. The following summaries of AEs will be provided:

Incidence and severity of all AEs, SAEs, and laboratory abnormalities; 

Proportion of subjects who permanently discontinue IP due to AEs or death;

Proportion of subjects who temporarily discontinue IP and/or TB therapy due to 
AEs;

Proportion of subjects with TB-associated IRIS.
In addition, absolute values and changes over time in laboratory parameters will be 
analyzed. Laboratory data will be summarized by visit and treatment arm. The number 
and percentage of subjects with graded laboratory toxicities (based on DAIDS categories, 
see Section 11.3) will be summarized by treatment arm. 
Further details of safety analyses will be included in the RAP.
8.2.7.3.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses
Concentrations of DTG and EFV at Weeks 8, 24, 36, and 48 upon initiation of DTG or 
EFV therapy will be analyzed using population PK modeling approach to estimate AUC, 
Cmax, and Cfor individual subjects at Week 48 final analysis. The population PK 
analysis result will be presented in a separate PK report.
 
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Week 24 interim analyses and Week 48 final analyses of DTG and EFV concentrations 
based on sparse PK sampling will be summarized using descriptive statistics.
The relationship between DTG/EFV IP exposure and the Week 24 and Week 48 anti-HIV 
responses (Snapshot) may be evaluated using univariate (and multivariate) logistic 
regression analysis as well as graphic exploration. 
Detailed analysis will be provided in the RAP.
8.2.7.4.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment-emergent genotypic and phenotypic resistance to DTG, EFV, 
and other on-study ART in subjects meeting confirmed virologic withdrawal criteria will 
be summarized using descriptive statistics.
8.2.7.5.
Pharmacogenetic Analyses
See Section 11.1 for details about the pharmacogenetics analysis plan.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, ViiV/GSK will obtain favorable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with ICH E6(R1) 
GCP guidelines and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/IEC review and approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
ViiV/GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 
 
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Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described Section 11.1, unless otherwise indicated. Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study. If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated. When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and PPD procedures, PPD monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and ViiV, 
GSK, or PPD requirements. When reviewing data collection procedures, the discussion 
will include identification, agreement, and documentation of data items for which the 
eCRF will serve as the source document.
PPD will monitor the study to ensure the following:

Data are authentic, accurate, and complete;

Safety and rights of subjects are being protected;

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, 
ViiV/GSK/PPD may conduct a quality assurance assessment and/or audit of the site 
records, and the regulatory agencies may conduct a regulatory inspection at any time 
during or after completion of the study. In the event of an assessment, audit, or 
inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s), 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss the conduct of the study, any findings/relevant issues, and to 
implement any corrective and/or preventative actions to address any findings/issues 
identified.
 
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9.5.
Study and Site Closure
Unless terminated early, this study will be considered completed after the last subject 
transitions to commercial supplies of DTG. Upon completion or termination of the study, 
the PPD monitor will conduct site closure activities with the investigator or site staff (as 
appropriate), in accordance with applicable regulations, GCP, and PPD SOPs.
ViiV/GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
non-compliance. If ViiV/GSK determines that such action is required, ViiV/GSK will 
discuss the reasons for taking such action with the investigator or head of the medical 
institution (where applicable). When feasible, ViiV/GSK will provide advance notice to 
the investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, ViiV/GSK will promptly inform 
all investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study. ViiV/GSK will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a ViiV/GSK audit or regulatory inspection) 
and must be available for review in conjunction with assessment of the facility, 
supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
ViiV, GSK, or PPD will inform the investigator of the time period for retaining the site 
records in order to comply with all applicable regulatory requirements. The minimum 
retention time will meet the strictest standard applicable to a particular site, as dictated by 
local laws/regulations, ViiV/GSK standard operating procedures, and/or institutional 
requirements.
The investigator must notify ViiV, GSK, or PPD of any changes in the archival 
arrangements, including, but not limited to archival of records at an off-site facility or 
transfer of ownership of the records in the event that the investigator is no longer 
associated with the site.
 
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9.7.
Provision of Study Results to Investigators, and Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
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 subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register no later than 8 months 
after the final primary completion date, the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome. In addition, a manuscript will be submitted to a peer reviewed journal for 
publication no later than 18 months after the last subject’s last visit (LSLV). When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.
 
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Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection 
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Raffi F, Rachlis A, Stellbrink HJ et al. Once-daily dolutegravir versus raltegravir in 
antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, 
double-blind, non-inferiority SPRING-2 study. Lancet. 2013b;381(9868):735-43.
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Török ME and Farrar J. When to start antiretroviral therapy in HIV-associated 
tuberculosis. N Engl J of Med 2011;365(16):1538-40.
Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir/lamivudine for the 
treatment of HIV-1 infection. N Engl J Med. 2013;369(19):1807-18. 
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http://www.who.int/tb/publications/global_report/en/. Accessed on 28 Mar 2014
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28 Mar 2014
 
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11.
APPENDICES
11.1.
Appendix 1 Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations. There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), pharmacodynamics (relationship between concentrations 
and pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir. 
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity. Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity. HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
 
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Drug
Disease
Gene Variant
Outcome
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis. 
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment. The irinotecan drug label 
indicates that individuals who have 2 copies of 
the UGT1A1*28 variant are at increased risk 
of neutropenia. A genetic blood test is 
available that can detect variations in the 
gene. 
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to DTG. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to DTG. If 
at any time it appears there is potential variability in response in this clinical study or in a 
series of clinical studies with DTG, the following objectives may be investigated – the 
relationship between genetic variants and study treatment with respect to:

Efficacy

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety (tolerability and IRIS monitoring) 
 
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Study Population
Any subject who is enrolled in the clinical study can participate in PGx research. Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
Study Assessments and Procedures
Blood samples can be taken for DNA extraction and used in PGx assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (approximately 6 mL) will be collected for the PGx research using a 
tube containing EDTA. It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomized and provided informed consent for PGx 
research, but may be taken at any time while the subject is participating in the clinical 
study.
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff. Coded samples do not carry 
personal identifiers (such as name or social security number). The blood sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis. This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples. If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
DTG has been completed and the clinical study data reviewed. In some cases, the 
samples may not be studied. e.g., no questions are raised about how people respond to 
DTG.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers) will use samples collected from the study for the 
purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
 
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Subject Withdrawal from Study
If a subject who has consented to participate in PGx research withdraws from the clinical 
study for any reason other than being lost to follow-up, the subject will be given a choice 
of one of the following options concerning the PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process. In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (absorption, distribution, metabolism and excretion) 
genes that are studied to determine the relationship between gene variants or 
treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to DTG. The genes that may code for these 
proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
 
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of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarised as appropriate to the data. A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study. PGx informed consent must be obtained prior to any blood being taken for 
PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarise the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
References
Chung WH, Hung SI, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010;9:15-21.
Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations. 
Pharmacogenomics. 2008;9:1543-6.
Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and 
hypersensitivity reactions to abacavir. Lancet. 2002;359:1121-2.
Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the 
UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of 
irinotecan. J Clin Oncol. 2004;22:1382-8.
Liu CY, Chen PM, Chiou TJ, et al. UGT1A1*28 polymorphism predicts irinotecan-
induced severe toxicities without affecting treatment outcome and survival in patients 
with metastatic colorectal carcinoma. Cancer. 2008;112:1932-40.
Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-
DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor 
abacavir. Lancet. 2002;359:727-32.
 
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Mallal S, Phillips E, Carosi G, et al. PREDICT-1 Study Team. HLA-B*5701 screening 
for hypersensitivity to abacavir. N Engl J Med. 2008;358:568-79.
Schulz C, Heinemann V, Schalhorn A, et al. UGT1A1 gene polymorphism: Impact on 
toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World 
J. Gastroenterol. 2009;15:5058-66.
 
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11.2.
Appendix 2 CDC Classification System for HIV-1 Infections 
(1993)
Clinical Categories
The clinical categories of HIV infection are defined as follows:
Category A
Category A consists of one or more of the conditions listed below in an adolescent or 
adult (>13 years) with documented HIV infection. Conditions listed in Categories B and 
C must not have occurred.

Asymptomatic HIV infection

Persistent generalized lymphadenopathy

Acute (primary) HIV infection with accompanying illness or history of acute HIV 
infection
Category B (Symptomatic non-AIDS conditions)
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult 
that are not included among conditions listed in clinical Category C and that meet at least 
one of the following criteria: a) the conditions are attributed to HIV infection or are 
indicative of a defect in cell-mediated immunity; or b) the conditions are considered by 
physicians to have a clinical course or to require management that is complicated by HIV 
infection. Examples of conditions in clinical Category B include, but are not limited to:

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 month

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least 2 distinct episodes or more than 
1 dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

Peripheral neuropathy
For classification purposes, Category B conditions take precedence over those in 
Category A. For example, someone previously treated for oral or persistent vaginal 
 
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candidiasis (and who has not developed a Category C disease) but who is now 
asymptomatic should be classified in clinical Category B.
Category C (AIDS indicator conditions as defined by diagnostic or presumptive 
measures).
Category C includes the clinical conditions listed in the AIDS surveillance case 
definition. For classification purposes, once a Category C condition has occurred, the 
person will remain in Category C.
Conditions in Category C include:

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related

Herpes simplex: chronic ulcer(s) (>1 month’s duration);or bronchitis, pneumonitis, 
or esophagitis

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 M. kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis carinii pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent
 
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
Toxoplasmosis of brain

Wasting syndrome due to HIV

Non-CDC, HIV-associated conditions.
Reference:
Castro GK, Ward JW, Slutsker L, et al. 1993 revised classification system for HIV 
infection and expanded surveillance case definition for AIDS among adolescents and 
adults. MMWR Recomm Rep. 1992;41(No. RR-17):1-19.
 
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11.3.
Appendix 3 Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events
VERSION 1.0, DECEMBER 2004; CLARIFICATION AUGUST 2009
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 utilized 
for adverse event (AE) reporting. A grading (severity) scale is provided for each AE 
term.
 
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CLINICAL 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event NOT 
identified elsewhere in this 
DAIDS AE grading table 
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 
Medical or operative intervention 
indicated to prevent permanent 
impairment, persistent disability, or 
death 
SYSTEMIC 
Acute systemic allergic reaction 
Localized urticaria (wheals) 
with no medical intervention 
indicated 
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated 
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild bronchospasm 
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & functional 
activities 
NA 
Fatigue Malaise 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & functional 
activities 
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care functions 
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
39.4 – 40.5°C 
> 40.5°C 
Pain (indicate body site) DO 
NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site pain) 
See also Headache, Arthralgia, 
Pain causing no or minimal 
interference with usual social & 
functional activities 
Pain causing greater than 
minimal interference with usual 
social & functional activities 
Pain causing inability to perform 
usual social & functional activities 
Disabling pain causing inability to 
perform basic self-care functions OR 
Hospitalization (other than 
emergency room visit) indicated 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
and Myalgia 
Unintentional weight loss 
NA 
5 – 9% loss in body weight from 
baseline 
10 – 19% loss in body weight from 
baseline 
≥ 20% loss in body weight from 
baseline OR Aggressive intervention 
indicated [e.g., tube feeding or total 
parenteral nutrition (TPN)] 
INFECTION 
Infection (any other than HIV 
infection) 
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual social & 
functional activities 
Systemic antimicrobial treatment 
indicated OR Symptoms causing 
greater than minimal interference 
with usual social & functional 
activities 
Systemic antimicrobial treatment 
indicated AND Symptoms causing 
inability to perform usual social & 
functional activities OR Operative 
intervention (other than simple 
incision and drainage) indicated 
Life-threatening consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain (pain without 
touching) Or Tenderness (pain 
when area is touched) 
Pain/tenderness causing no or 
minimal limitation of use of limb 
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social & 
functional activities 
Pain/tenderness causing inability 
to perform usual social & 
functional activities 
Pain/tenderness causing inability to 
perform basic self-care function OR 
Hospitalization (other than 
emergency room visit) indicated for 
management of pain/tenderness 
Injection site reaction (localized) 
Adult >15 years 
Erythema OR Induration of 5x5 
cm – 9x9 cm (or 25 cm2 –
Erythema OR Induration OR 
Edema > 9 cm any diameter (or 
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess 
Necrosis (involving dermis and 
deeper tissue) 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
81cm2) 
> 81 cm2) 
OR Drainage 
Pediatric ≤15 Years 
Erythema OR Induration OR 
Edema present but ≤ 2.5 cm 
diameter 
Erythema OR Induration OR 
Edema > 2.5 cm diameter but < 
50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) 
Erythema OR Induration OR 
Edema involving ≥ 50% surface 
area of the extremity segment 
(e.g., upper arm/thigh) OR 
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess 
OR Drainage 
Necrosis (involving dermis and 
deeper tissue) 
Pruritis associated with 
injection See also Skin: Pruritis 
(itching - no skin lesions) 
Itching localized to injection site 
AND Relieved spontaneously 
or with < 48 hours treatment 
Itching beyond the injection site 
but not generalized OR Itching 
localized to injection site 
requiring ≥ 48 hours treatment 
Generalized itching causing 
inability to perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable by study 
participant (or by caregiver for 
young children and disabled 
adults) 
Thinning or patchy hair loss 
detectable by health care 
provider 
Complete hair loss 
NA 
Cutaneous reaction – rash 
Localized macular rash 
Diffuse macular, maculopapular, 
or morbilliform rash OR Target 
lesions 
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae OR 
Superficial ulcerations of mucous 
membrane limited to one site 
Extensive or generalized bullous 
lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous 
membrane involving two or more 
distinct mucosal sites OR Toxic 
epidermal necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Pruritis (itching – no skin 
lesions) (See also Injection Site 
Reactions: Pruritis associated 
with injection) 
Itching causing no or minimal 
interference with usual social & 
functional activities 
Itching causing greater than 
minimal interference with usual 
social & functional activities 
Itching causing inability to perform 
usual social & functional activities 
NA 
CARDIOVASCULAR 
Cardiac arrhythmia (general) 
(By ECG or physical exam) 
Asymptomatic AND No 
intervention indicated 
Asymptomatic AND Non-urgent 
medical intervention indicated 
Symptomatic, non-life-threatening 
AND Non-urgent medical 
intervention indicated 
Life-threatening arrhythmia OR 
Urgent intervention indicated 
Cardiac-ischemia/infarction
NA 
NA 
Symptomatic ischemia (stable 
angina) OR Testing consistent with 
ischemia 
Unstable angina OR Acute 
myocardial infarction 
Hemorrhage (significant acute 
blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND Transfusion of 
≤ 2 units packed RBCs (for 
children ≤ 10 cc/kg) indicated 
Life-threatening hypotension OR 
Transfusion of > 2 units packed 
RBCs (for children >10 cc/kg) 
indicated 
Hypertension 
Adult >17 years (with 
repeat testing at same 
visit) 
> 140 – 159 mmHg systolic OR 
> 90 – 99 mmHg diastolic 
> 160 – 179 mmHg systolic OR > 
100 – 109 mmHg diastolic 
> 180 mmHg systolic OR > 110 
mmHg diastolic 
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit) 
Pediatric ≤17 Years (with 
repeat testing at same 
NA 
91st – 94th percentile adjusted 
for age, height, and gender 
95th percentile adjusted for age, 
height, and gender (systolic and/or 
Life-threatening consequences (e.g., 
malignant hypertension) OR 
 
 
 
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GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
visit) 
(systolic and/or diastolic) 
diastolic) 
Hospitalization indicated (other than 
emergency room visit) 
Hypotension 
NA 
Symptomatic, corrected with oral 
fluid replacement 
Symptomatic, IV fluids indicated 
Shock requiring use of vasopressors 
or mechanical assistance to 
maintain blood pressure 
Pericardial effusion 
Asymptomatic, small effusion 
requiring no intervention 
Asymptomatic, moderate or 
larger effusion requiring no 
intervention 
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening consequences (e.g., 
tamponade) OR Urgent intervention 
indicated 
Prolonged PR interval 
Adult >16 years 
PR interval 0.21 – 0.25 sec 
PR interval > 0.25 sec 
Type II 2nd degree AV block OR 
Ventricular pause > 3.0 sec 
Complete AV block 
Pediatric ≤16 Years 
1st degree AV block (PR > 
normal for age and rate) 
Type I 2nd degree AV block 
Type II 2nd degree AV block 
Complete AV block 
Prolonged QTc 
Adult >16 years 
Asymptomatic, QTc interval 
0.45 – 0.47 sec OR Increase 
interval < 0.03 sec above 
baseline 
Asymptomatic, QTc interval 0.48 
– 0.49 sec OR Increase in 
interval 0.03 – 0.05 sec above 
baseline 
Asymptomatic, QTc interval ≥ 0.50 
sec OR Increase in interval ≥ 0.06 
sec above baseline 
Life-threatening consequences, e.g. 
Torsade de pointes or other 
associated serious ventricular 
dysrhythmia 
Pediatric ≤16 years 
Asymptomatic, QTc interval 
0.450 – 0.464 sec 
Asymptomatic, QTc interval 
0.465 – 0.479 sec 
Asymptomatic, QTc interval ≥ 
0.480 sec 
Life-threatening consequences, e.g. 
Torsade de pointes or other 
associated serious ventricular 
dysrhythmia 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Thrombosis/embolism 
NA 
Deep vein thrombosis AND No 
intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g., pulmonary 
embolism, life-threatening thrombus) 
Vasovagal episode (associated 
with a procedure of any kind) 
Present without loss of 
consciousness 
Present with transient loss of 
consciousness 
NA 
NA 
Ventricular dysfunction 
(congestive heart failure) 
NA 
Asymptomatic diagnostic finding 
AND intervention indicated 
New onset with symptoms OR 
Worsening symptomatic 
congestive heart failure 
Life-threatening congestive heart 
failure 
GASTROINTESTINAL 
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 or total parenteral 
nutrition (TPN)]
Ascites 
Asymptomatic 
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis) 
Symptomatic despite intervention 
Life-threatening consequences 
Cholecystitis 
NA 
Symptomatic AND Medical 
intervention indicated 
Radiologic, endoscopic, or 
operative intervention indicated 
Life-threatening consequences (e.g., 
sepsis or perforation) 
Constipation 
NA 
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated 
Life-threatening consequences (e.g., 
obstruction) 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Diarrhea
Adult and Pediatric ≥1 
year 
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 – 6 stools over baseline per 
24-hour period 
Bloody diarrhea OR Increase of 7 
stools per 24-hour period OR IV 
fluid replacement indicated 
Life-threatening consequences (e.g., 
hypotensive shock) 
Pediatric <1 year 
Liquid stools (more unformed 
than usual) but usual number 
of stools 
Liquid stools with increased 
number of stools OR Mild 
dehydration 
Liquid stools with moderate 
dehydration 
Liquid stools resulting in severe 
dehydration with aggressive 
rehydration indicated OR 
Hypotensive shock 
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet 
Symptoms causing altered 
dietary intake without medical 
intervention indicated 
Symptoms causing severely 
altered dietary intake with medical 
intervention indicated 
Life-threatening reduction in oral 
intake 
Mucositis/stomatitis (clinical 
exam) Indicate site (e.g., 
larynx, oral) See Genitourinary 
for Vulvovaginitis See also 
Dysphagia-Odynophagia and 
Proctitis 
Erythema of the mucosa 
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes or 
ulcerations OR Mucosal bleeding 
with minor trauma 
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding OR 
Life-threatening consequences (e.g., 
aspiration, choking) 
Nausea 
Transient (< 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake 
Persistent nausea resulting in 
decreased oral intake for 24 – 48 
hours 
Persistent nausea resulting in 
minimal oral intake for > 48 hours 
OR Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not indicated 
(other than emergency room 
Symptomatic AND Hospitalization 
indicated (other than emergency 
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
visit) 
room visit) 
sepsis) 
Proctitis (functional-
symptomatic) Also see 
Mucositis/stomatitis for clinical 
exam 
Rectal discomfort AND No 
intervention indicated 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Operative 
intervention indicated 
Life-threatening consequences (e.g., 
perforation) 
Vomiting 
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake 
Frequent episodes of vomiting 
with no or mild dehydration 
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration indicated 
(e.g., IV fluids) 
Life-threatening consequences (e.g., 
hypotensive shock) 
NEUROLOGIC 
Alteration in personality-
behavior or in mood (e.g., 
agitation, anxiety, depression, 
mania, psychosis) 
Alteration causing no or 
minimal interference with usual 
social & functional activities 
Alteration causing greater than 
minimal interference with usual 
social & functional activities 
Alteration causing inability to 
perform usual social & functional 
activities 
Behavior potentially harmful to self 
or others (e.g., suicidal and 
homicidal ideation or attempt, acute 
psychosis) OR Causing inability to 
perform basic self-care functions 
Altered Mental Status For 
Dementia, see Cognitive and 
behavioral/attentional
disturbance (including dementia 
and attention deficit disorder) 
Changes causing no or minimal 
interference with usual social & 
functional activities 
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social & 
functional activities 
Confusion, memory impairment, 
lethargy, or somnolence causing 
inability to perform usual social & 
functional activities 
Delirium OR obtundation, OR coma 
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with usual 
social & functional activities 
Symptomatic ataxia causing 
greater than minimal interference 
with usual social & functional 
activities 
Symptomatic ataxia causing 
inability to perform usual social & 
functional activities 
Disabling ataxia causing inability to 
perform basic self-care functions 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Cognitive and 
behavioral/attentional 
disturbance (including dementia 
and attention deficit disorder) 
Disability causing no or minimal 
interference with usual social & 
functional activities OR 
Specialized resources not 
indicated 
Disability causing greater than 
minimal interference with usual 
social & functional activities OR 
Specialized resources on part-
time basis indicated 
Disability causing inability to 
perform usual social & functional 
activities OR Specialized 
resources on a full-time basis 
indicated 
Disability causing inability to perform 
basic self-care functions OR 
Institutionalization indicated 
CNS ischemia (acute) 
NA 
NA 
Transient ischemic attack 
Cerebral vascular accident (CVA, 
stroke) with neurological deficit 
Developmental delay 
Mild developmental delay, 
either 
Moderate developmental delay, 
Severe developmental delay, 
either 
Developmental regression, either 
– Pediatric ≤16 Years 
motor or cognitive, as 
determined by comparison with 
a developmental screening tool 
appropriate for the setting 
either motor or cognitive, as 
determined by comparison with a 
developmental screening tool 
appropriate for the setting 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting 
motor or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting 
Headache 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & functional 
activities 
Symptoms causing inability to 
perform basic self-care functions OR 
Hospitalization indicated (other than 
emergency room visit) OR 
Headache with significant 
impairment of alertness or other 
neurologic function 
Insomnia 
NA 
Difficulty sleeping causing 
greater than minimal interference 
with usual social & functional 
activities 
Difficulty sleeping causing inability 
to perform usual social & 
functional activities 
Disabling insomnia causing inability 
to perform basic self-care functions 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Neuromuscular weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weakness causing no 
or minimal interference with 
usual social & functional 
activities 
Muscle weakness causing 
greater than minimal interference 
with usual social & functional 
activities 
Muscle weakness causing inability 
to perform usual social & 
functional activities 
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation 
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy) 
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or 
minimal interference with usual 
social & functional activities 
Sensory alteration or paresthesia 
causing greater than minimal 
interference with usual social & 
functional activities 
Sensory alteration or paresthesia 
causing inability to perform usual 
social & functional activities 
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care functions 
Seizure: (new onset) 
NA 
1 seizure 
2 – 4 seizures 
Seizures of any kind which are 
– Adult ≥18 years 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control 
(e.g., 
See also Seizure: (known pre-
refractory epilepsy) 
existing seizure disorder) 
Seizure: (known pre-existing 
seizure disorder) – Adult ≥ 18 
years For worsening of existing 
epilepsy the grades should be 
based on an increase from 
previous level of control to any 
of these levels. 
NA 
Increased frequency of pre-
existing seizures (non-repetitive) 
without change in seizure 
character OR Infrequent break-
through seizures while on stable 
medication in a previously 
controlled seizure disorder 
Change in seizure character from 
baseline either in duration or 
quality (e.g., severity or focality) 
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control 
(e.g., refractory epilepsy) 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Seizure – Pediatric <18 years 
Seizure, generalized onset with 
or without secondary 
generalization, lasting < 5 
minutes with < 24 hours post-
ictal state 
Seizure, generalized onset with 
or without secondary 
generalization, lasting 5 – 20 
minutes with <24 hours post ictal 
state 
Seizure, generalized onset with or 
without secondary generalization,
lasting >20 minutes 
Seizure, generalized onset with or 
without Secondary generalization, 
requiring intubation and sedation 
Syncope (not associated with a 
procedure) 
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no or minimal 
interference with usual social & 
functional activities 
Vertigo causing greater than 
minimal interference with usual 
social & functional activities 
Vertigo causing inability to perform 
usual social & functional activities 
Disabling vertigo causing inability to 
perform basic self-care Functions 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow reduced to 
70 – 80% 
FEV1 or peak flow 50 – 69% 
FEV1 or peak flow 25 – 49% 
Cyanosis OR FEV1 or peak flow < 
25% OR Intubation 
Dyspnea or respiratory distress 
Adult ≥14 years 
Dyspnea on exertion with no or 
minimal interference with usual 
social & functional activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing inability to 
perform usual social & functional 
activities 
Respiratory failure with ventilatory 
support Indicated 
Pediatric <14 years 
Wheezing OR minimal increase 
in respiratory rate for age 
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 90 
– 95% 
Dyspnea at rest causing inability to 
perform usual social & functional 
activities OR Pulse oximetry < 
90% 
Respiratory failure with ventilatory 
support indicated 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
MUSCULOSKELETAL 
Arthralgia See also Arthritis 
Joint pain causing no or 
minimal interference with usual 
social & functional activities 
Joint pain causing greater than 
minimal interference with usual 
social & functional activities 
Joint pain causing inability to 
perform usual social & functional 
activities 
Disabling joint pain causing inability 
to perform basic self-care Functions 
Arthritis See also Arthralgia 
Stiffness or joint swelling 
causing no or minimal 
interference with usual social & 
functional activities 
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities 
Stiffness or joint swelling causing 
inability to perform usual social & 
functional activities 
Disabling joint stiffness or swelling 
causing inability to perform basic 
self-care functions 
Bone Mineral Loss 
Adult ≥ 21 years 
BMD t-score -2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture (including 
loss of vertebral height) 
Pathologic fracture causing life-
threatening Consequences 
Pediatric < 21 years 
BMD z-score -2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture (including 
loss of vertebral height) 
Pathologic fracture causing life-
threatening Consequences 
Myalgia (non-injection site) 
Muscle pain causing no or 
minimal interference with usual 
social & functional activities 
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities 
Muscle pain causing inability to 
perform usual social & functional 
activities 
Disabling muscle pain causing 
inability to perform basic self-care 
functions 
Osteonecrosis 
NA 
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated 
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention indicated 
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-care 
functions 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
GENITOURINARY 
Cervicitis (symptoms) (For use 
in studies evaluating topical 
study agents) For other 
cervicitis see Infection: Infection 
(any other than HIV infection) 
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 
Cervicitis (clinical exam) (For 
use in studies evaluating 
topical study agents) For other 
cervicitis see Infection: Infection 
(any other than HIV infection) 
Minimal cervical abnormalities 
on examination (erythema, 
Mucopurulent discharge, or 
friability) OR Epithelial 
disruption < 25% of total 
surface 
Moderate cervical abnormalities 
on examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption 
of 25 – 49% total surface 
Severe cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption 
50 – 75% total surface 
Epithelial disruption > 75% total 
surface 
Inter-menstrual bleeding (IMB) 
Spotting observed by 
participant OR Minimal blood 
observed during clinical or 
colposcopic examination 
Inter-menstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle 
Inter-menstrual bleeding greater in 
duration or amount than usual 
menstrual cycle 
Hemorrhage with life-threatening 
hypotension OR Operative 
intervention indicated 
Urinary tract obstruction (e.g., 
stone) 
NA 
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction 
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or 
renal dysfunction 
Obstruction causing life-threatening 
consequences 
Vulvovaginitis (symptoms) (Use 
in studies evaluating topical 
study agents) For other 
vulvovaginitis see Infection: 
Infection (any other than HIV 
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 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
infection) 
Vulvovaginitis (clinical exam) 
(Use in studies evaluating 
topical study agents) For other 
vulvovaginitis see Infection: 
Infection (any other than HIV 
infection) 
Minimal vaginal abnormalities 
on examination OR Epithelial 
disruption <25% of total surface 
Moderate vaginal abnormalities 
on examination OR Epithelial 
disruption of 25 - 49% total 
surface 
Severe vaginal abnormalities on 
examination OR Epithelial 
disruption 50 - 75% total surface 
Vaginal perforation OR Epithelial 
disruption > 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but detectable 
on exam 
Symptomatic anterior uveitis OR 
Medical intervention indicated 
Posterior or pan-uveitis OR 
Operative intervention indicated 
Disabling visual loss in affected 
eye(s) 
Visual changes (from baseline) 
Visual changes causing no or 
minimal interference with usual 
social & functional activities 
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities 
Visual changes causing inability to 
perform usual social & functional 
activities 
Disabling visual loss in affected 
eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat accumulation 
(e.g., back of neck, breasts, 
abdomen) 
Detectable by study participant 
(or by caregiver for young 
children and disabled adults) 
Detectable on physical exam by 
health care provider 
Disfiguring OR Obvious changes 
on casual visual inspection 
NA 
Diabetes mellitus 
NA 
New onset without need to 
initiate medication OR 
Modification of current 
medications to regain glucose 
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non-
ketotic coma) 
 
 
 
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CLINICAL 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
control 
modification 
Gynecomastia 
Detectable by study participant 
or caregiver (for young children 
and disabled adults) 
Detectable on physical exam by 
health care provider 
Disfiguring OR Obvious on casual 
visual inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
suppression therapy indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification 
Life-threatening consequences (e.g., 
thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
replacement therapy indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification 
Life-threatening consequences (e.g., 
myxedema coma) 
Lipoatrophy (e.g., fat loss from 
the face, extremities, buttocks) 
Detectable by study participant 
(or by caregiver for young 
children and disabled adults) 
Detectable on physical exam by 
health care provider 
Disfiguring OR Obvious on casual 
visual inspection 
NA 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
HEMATOLOGY Standard International Units are listed in italics 
Absolute CD4+ count – Adult 
and Pediatric >13 years (HIV 
NEGATIVE ONLY) 
300 – 400/mm3
300 – 400/µL
200 – 299/ mm3
200 – 299/µL
100 – 199/ mm3
100 – 199/µL
< 100/ mm3
< 100/µL
Absolute lymphocyte count –
Adult and Pediatric >13 years 
(HIV NEGATIVE ONLY) 
600 – 650/ mm3
0.600 x 109 – 0.650 x 109/L
500 – 599/ mm3
0.500 x 109 – 0.599 x 
109/L
350 – 499/ mm3
0.350 x 109 – 0.499 x 109/L
< 350/ mm3
< 0.350 x 109/L
Absolute neutrophil count (ANC) 
Adult and Pediatric, >7 
days 
1,000 – 1,300/ mm3
1.000 x 109 – 1.300 x 109/L
750 – 999/ mm3
0.750 x 109 – 0.999 x 
109/L
500 – 749/ mm3
0.500 x 109 – 0.749 x 109/L
< 500/ mm3
< 0.500 x 109/L
Infant†, 2 – 7 days 
1,250 – 1,500/ mm3
1.250 x 109 – 1.500 x 109/L
1,000 – 1,249/ mm3
1.000 x 109 – 1.249 x 
109/L
750 – 999/ mm3
0.750 x 109 – 0.999 x 109/L
< 750/ mm3
< 0.750 x 109/L
Infant†, 1 day 
4,000 – 5,000/ mm3
4.000 x 109 – 5.000 x 109/L
3,000 – 3,999/ mm3
3.000 x 109 – 3.999 
x109/L
1,500 – 2,999/ mm3
1.500 x 109 – 2.999 x 109/L
< 1,500/ mm3
< 1.500 x 109/L
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L
OR 0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 0.25 – 0.49 x LLN 
< 50 mg/dL 
< 0.50 g/L 
OR < 0.25 x LLN OR Associated 
with gross bleeding 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Hemoglobin (Hgb) 
Adult and Pediatric 
≥57 days (HIV POSITIVE 
ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
7.5 – 8.4 g/dL 
4.62 – 5.23 mmol/L 
6.50 – 7.4 g/dL 
4.03 – 4.61 mmol/L 
< 6.5 g/dL 
< 4.03 mmol/L 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Adult and Pediatric 
≥57 days (HIV 
NEGATIVE ONLY) 
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR
Any decrease 
2.5 – 3.4 g/dL
1.58 – 2.13mmol/L 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease 
3.5 – 4.4 g/dL
2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 
2.14 – 2.78 mmol/L
OR
Any decrease 
≥ 4.5 g/dL
> 2.79 mmol/L 
< 7.0 g/dL 
< 4.34 mmol/L 
Infant†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL
5.24 – 5.86 mmol/L 
7.0 – 8.4 g/dL
4.31 – 5.23 mmol/L 
6.0 – 6.9 g/dL
3.72 – 4.30 mmol/L 
< 6.00 g/dL
< 3.72 mmol/L 
Infant†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL
5.87 – 6.54 mmol/L 
8.0 – 9.4 g/dL
4.93 – 5.86 mmol/L 
7.0 – 7.9 g/dL
4.34 – 4.92 mmol/L 
< 7.00 g/dL
< 4.34 mmol/L 
Infant†, 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL
7.42 – 8.09 mmol/L 
10.0 – 11.9 g/dL
6.18 – 7.41 mmol/L 
9.0 – 9.9 g/dL
5.59 – 6.17 mmol/L 
< 9.0 g/dL
< 5.59 mmol/L 
International Normalized 
Ratio of prothrombin time 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
(INR) 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 124,999/mm3
100.000 x 109 – 124.999 x 109/L 
50,000 – 99,999/mm3
50.000 x 109 – 99.999 x 109/L 
25,000 – 49,999/mm3
25.000 x 109 – 49.999 x 109/L 
< 25,000/mm3
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3
2.000 x 109 – 2.500 x 109/L 
1,500 – 1,999/mm3
1.500 x 109 – 1.999 x 109/L 
1,000 – 1,499/mm3
1.000 x 109 – 1.499 x 109/L 
< 1,000/mm3
< 1.000 x 109/L 
CHEMISTRIES 
Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3 without life-threatening 
consequences 
pH < 7.3 with life-threatening 
consequences 
LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN†
2.6 – 5.0 x ULN†
5.1 – 10.0 x ULN†
> 10.0 x ULN†
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Alkalosis
NA 
pH > normal, but ≤ 7.5 
pH > 7.5 without life-threatening 
consequences 
pH > 7.5 with life-threatening 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Bilirubin (Total) 
Adult and Pediatric >14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant†, ≤14 days (non-
hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
25.1 – 30.0 mg/dL 
429 – 513 µmol/L 
> 30.0 mg/dL 
> 513.0 µmol/L 
Infant†, ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.0 mg/dL 
> 428 µmol/L 
Calcium, serum, high (corrected for albumin) 
Adult and Pediatric ≥7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L
Infant†, <7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low (corrected for albumin) 
Adult and Pediatric ≥7 days 
7.8 – 8.4 mg/dL 
7.0 – 7.7 mg/dL 
6.1 – 6.9 mg/dL 
< 6.1 mg/dL 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
1.95 – 2.10 mmol/L 
1.75 – 1.94 mmol/L 
1.53 – 1.74 mmol/L 
< 1.53 mmol/L
Infant†, <7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with myocardial 
infarction or unstable angina as 
defined by the manufacturer 
LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Cardiac troponin T (cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL OR Levels consistent 
with myocardial infarction or 
unstable angina as defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric <18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Fasting 
110 – 125 mg/dL
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Glucose, serum, low 
Adult and Pediatric ≥ 1 
month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L
Infant†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
ULN - < 2.0 x 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 
LDL cholesterol (fasting) 
Adult ≥18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥4.91 mmol/L 
NA 
Pediatric >2 – <18 years 
110 – 129 mg/dL 
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric >14 
years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 years 
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Pediatric <1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
125 – 129 mEq/L 
121 – 124 mEq/L 
≤ 120 mEq/L 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
130 – 135 mmol/L 
125 – 129 mmol/L 
121 – 124 mmol/L 
≤120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS Standard International Units are listed in italics 
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without clots OR 
with RBC casts 
Transfusion indicated 
Proteinuria, random Collection 
1 + 
2 – 3 + 
4 + 
NA 
LABORATORY 
PARAMETER
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY 
LIFE-THREATENING 
Proteinuria, 24 hour collection 
Adult and Pediatric ≥10 
years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
>3.500 g/d 
Pediatric > 3 mo -<10 years 
201 – 499 mg/m2/24 h 
500 – 799 mg/m2/24 h 
800 – 1,000 mg/m2/24 h 
> 1,000 mg/ m2/24 h 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
0.201 – 0.499 g/d 
0.500 – 0.799 g/d 
0.800 – 1.000 g/d 
> 1.000 g/d 
 
 
 
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11.4.
Appendix 4 Country-Specific Requirements
No country-specific requirements exist.
 
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11.5.
Appendix 5 Liver Safety Drug Restart or Rechallenge 
Guidelines
GUIDELINES FOR DRUG RESTART OR RECHALLENGE AFTER STOP FOR 
LIVER CRITERIA
1.
IP rechallenge may be considered for a subject exhibiting compelling benefit for a 
critical medicine following drug-induced liver injury, if favorable benefit: risk and 
no alternate medicine available. (Figure 6 and Table 11).
2.
IP restart may be considered for liver safety events with a clear underlying cause 
(e.g. biliary, pancreatic events, hypotension, acute viral hepatitis), if not associated 
with drug-induced liver injury, alcoholic hepatitis, or hypersensitivity [fever, rash or 
eosinophilia] and drug not associated with HLA genetic marker of liver injury, when 
liver chemistries have improved to normal or are within 1.5 × baseline and 
ALT<2 × ULN).
3.
Subjects meeting liver chemistry stopping criteria that present rebound of ALT 
elevation upon stepwise re-exposure to TB treatment regimen (see Section 6.4.3.1
for suggestion on TB treatment re-introduction regimens) will be considered as 
having the anti-TB treatment as the likely cause of ALT elevation. If the TB 
treatment component considered to be the likely cause of the ALT elevation is not 
RIF and an alternative anti-TB treatment containing RIF can be successfully 
introduced, the authorization for restarting the IP may be discussed between the 
investigator and the study medical monitor without the need for approval from the 
VSLC. If there is no evidence of a relationship between one of the antituberculosis 
anti-TB treatment regimen components (other than RIF) and the ALT elevation, the 
case will need VSLC approval to restart DTG (this approval can be ad hoc).
Background: Following drug-induced liver injury, drug rechallenge is associated with 
a 13% mortality across all drugs in prospective studies. Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane re-administered in 1 month of initial injury 
[Andrade, 2009]. However, some drugs seldom result in recurrent liver injury or fatality.
Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andrade, 2009]

Jaundice or bilirubin 2 × ULN with initial liver injury

Prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay, 2009; Hunt, 2010]

Evidence of drug-related preclinical liability (e.g., reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
 
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Decision Process for Drug Rechallenge Approval or Disapproval

Principal investigator (PI) requests consideration of drug rechallenge for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits liver 
chemistry elevation meeting subject stopping criteria, with no alternate treatment.

Medical monitor and Global Clinical Safety and Pharmacovigilance (GCSP) 
physician to review the subject’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 11).

The medical monitor and GCSP physician are accountable to review and agree on 
the following:
1.
Compelling benefit of the IP for this subject and no alternate therapy 
2.
Relative benefit-risk of drug rechallenge, with consideration of the following 
high risk factors:

Initial liver injury event included: fever, rash, eosinophilia, or bilirubin 
>2 × ULN (or direct bilirubin >35% of total, if available)

Subject currently exhibits severe liver injury defined by: ALT >3 × ULN, 
bilirubin >2 × ULN (direct bilirubin >35% of total, if available), or INR>1.5

SAE or fatality has earlier been observed with IP rechallenge

IP associated with known preclinical hepatic liability/injury

Relevant physicians must review and agree on request for drug rechallenge:

Safety Team Leader, study medical monitor and Physician Product Leader 
Medicines Development Leader, and Project Physician Leader (GSK).

Medicines Development Leader and Project Physician Leader (GSK).

Request is taken to full VSLC for final decision
 
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Figure 6
VSLC Process for Drug Rechallenge Approval or Disapproval
Subject exhibits liver injury on drug, while disease condition stable or 
improving
Clear evidence of a relationship between one of the antituberculosis 
drugs (other than RIF) and the ALT elevation?
Authorization for restarting the IP may be 
discussed between the investigator and the 
study medical monitor, without the need for 
approval from the VSLC
YES
NO
Authorization for restarting the IP requires 
approval from the VSLC
Medical Monitor & Safety Physician(s) to discuss benefit : risk and:
Any fever, rash or eosinophilia, hypersensitivity with initial liver injury in the patient?
Bilirubin 2 × ULN or INR>1.5 in this patient, suggesting failing liver?
Any prior severe / fatal outcomes reported on drug rechallenges with this drug?
Any evidence of preclinical hepatic liability / injury with this drug?
Request is submitted to VSLC
Who approve IP re-initiation
VSLC do not approve IP re-initiation
PI promptly informed of decision & dosing regimen Ethics Com.  or IRB review, 
if needed Benefits/risks discussed with subject & consent recorded in chart 
Liver chemistries obtained twice weekly for one month or for as long as 
clinically indicated Safety Review Team records rechallenge outcome VSLC 
notified of rechallenge outcomes
PI promptly informed of decision
The local operating company (LOC) medical director (ViiV and GSK where applicable) should be informed that IP rechallenge is under 
consideration and of the final decision, whether or not to proceed.
 
 
 
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Table 11
Checklist for IP Rechallenge for Critical Medicine (Following Drug-
Induced Liver Injury, IP Rechallenge is Associated with 13% 
Mortality Across all Drugs in Prospective Studies)
Yes
No
Relative benefit-risk favorable for drug rechallenge, after considering the 
following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin 2 × ULN (direct bilirubin >35% of total)
o
Subject currently exhibits ALT 3xULN, bilirubin 2 × ULN 
(direct bilirubin >35% of total, if available), or INR 1.5
o
SAE or fatality has earlier been observed with IP rechallenge
If yes, please provide brief explanation:
o
IP associated with known preclinical hepatic liability/injury
o
Source data defining the subjects current resistance profile
o
Previous drug history
Medical monitor, GCSP Physician, and PI actions for Restart or 
Rechallenge following VSLC decision
Medical Monitor and (Global Clinical Safety and Pharmacovigilance) GCSP 
Physician Actions

Medical Monitor must notify PI of VSLC’s rechallenge (or restart) decision and 
recommended dosing regimen in writing and medical monitor must record note 
in study files.

The Safety Review Team must record rechallenge (or restart) outcomes and the 
GCSP Physician must send these to the VSLC

All severe reactions (rechallenge associated with bilirubin >2 × ULN or 
jaundice, or INR ≥1.5), SAEs, or fatalities with drug rechallenge (or 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 IRB or IEC approval of IP rechallenge or restart, as required. 

If IP re-initiation is approved, the subject 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.
Targeted IP rechallenge or IP restart informed consent form must be used.

The subject’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by medical monitor.
 
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
Liver chemistries must be followed twice weekly for ‘rechallenge’ cases and 
once weekly for ‘restart’ cases for one month or for as long as clinically 
indicated following drug re-initiation. If the subject exhibits protocol-defined 
liver chemistry elevations, IP should be discontinued as protocol specified.
VSLC and the IRB/IEC must be informed of the subject’s outcome following drug 
rechallenge or restart.
Rechallenge/restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject 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;8:709-14.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatology. 
2010;52:2216-22.
Papay JI, Clines D, Rafi R, et al. Drug-induced liver injury following positive drug 
rechallenge. Regul Tox Pharm. 2009;54:84-90. 
 
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11.6.
Appendix 6 Alternate RIF-Containing TB Treatment 
Regimens
The WHO-recommended first-line regimen for drug-sensitive TB is a combination 
regiment of isoniazid and RIF for six months, with ethambutol and pyrazinamide for the 
first two months. This regimen may be given daily or intermittently according to local or 
national guidelines. In case alternate TB treatments need to be considered due to 
tolerability/toxicity issues to one of the agents on the WHO-recommended first line 
regimen or due to antibiotic resistance, alternative TB treatment regimens are suggested 
below. The doses used should follow local or national guidelines. For additional 
information on alternate RIF-containing TB treatment regimens see Section 6.4.3.1.1. 
None of the alternate RIF-containing TB treatment regimens listed below should be used 
as the first-line TB treatment.

Regimen 1 (omitting pyrazinamide): isoniazid, RIF, and ethambutol for 2 months, 
followed by RIF and isoniazid, for 7 months (9 months in total) [BTA, 1982; BTS, 
1984; Slutkin, 1988].

Regimen 2 (omitting isoniazid): RIF, pyrazinamide, ethambutol, and streptomycin 
for 2 months, followed by RIF and ethambutol for 7 months (9 months in total) 
[Babu, 1988].
The investigator may find Regimen 2 suitable in cases where isoniazid is found to 
have precipitated hepatotoxicity (i.e., in the course of TB drug re-introduction for 
Regimen 1) [BTS, 1984]. In which case, the investigator may choose to use the 
schedule suggested in Table 6. Guidance from a local expert should be sought.
This is also a suitable regimen for use when the study subject is found to be infected 
with isoniazid-resistant TB. If the WHO first-line regimen was well-tolerated prior to 
the discovery of isoniazid-resistance, then it is reasonable for all drugs in Regimen 2 
to be introduced simultaneously instead of using the schedule displayed Table 6.

Regimen 3 (omitting ethambutol): RIF, isoniazid, and pyrazinamide for 2 months, 
followed by RIF and isoniazid for 4 months [Combs, 1990]. 
The investigator may choose to use Regimen 3 for those subjects who are intolerant 
to ethambutol (the principal adverse effect of ethambutol being optic neuritis). 
Provided other components of Regimen 3 have been well-tolerated, conversion from 
the WHO first-line regimen only requires that ethambutol be stopped. Otherwise, the 
schedule in Table 5 is suitable if there has been a drug-interruption and the 
investigator feels that a gradual reintroduction is required. Consultation from a local 
expert should be sought.
When making changes to TB treatment, national or local guidelines on the treatment of 
tuberculosis should always be followed and take precedence over the recommendations 
made in this section. Should the subject need to go on a regimen that excludes the use of 
RIF (e.g., for reasons of tolerability/toxicity or antibiotic resistance), then the subject will 
have to be withdrawn from the study. Further details describing withdrawal criteria are 
described in Section 4.5.
 
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11.7.
Appendix 7 Karnofsky Performance Status Scale
 
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11.8.
Appendix 8 Child-Pugh Classification
A subject is classified with mild hepatic impairment (Class A) if their overall sum of 
scores is 5-6 points, moderate hepatic impairment (Class B) if their overall sum of scores 
is 7-9 points, and severe hepatic impairment (Class C) if their overall sum of scores is 
10-15 based on the Child-Pugh system [Pugh, 1973] scoring described in the following 
table (Table 13). For subjects requiring anticoagulation therapy, discussion with the study 
medical monitor will be required.
Table 13
Child-Pugh System
Finding 
Points Scored for Each Observed Finding 
1
2
3
Encephalopathy Grade 1a 
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum bilirubin, SI units (μmol/L), 
Serum bilirubin, conventional units (mg/dL) 
<34
<2
34 to 52
2 to 3
>52
>3
Serum albumin, SI units (g/L) 
Serum albumin, conventional units (mg/dL) 
>35
>3.5
28 to 35
2.8 to 3.5
<28
<2.8
Prothrombin Time (seconds prolonged) or 
INR 
<4
<1.7
4 to 6
1.7 to 2.3
>6
>2.3
a.
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity
[Pugh, 1973; Lucey, 1997]
References
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on 
the liver transplant waiting list: a report of a national conference organized by the 
American Society of Transplant Physicians and the American Association for the Study 
of Liver Diseases. Liver Transpl Surg. 1997 Nov;3(6):628-637 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg 1973;60:649-649.
 
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11.9.
Appendix 9:  Pregnancy Information
11.9.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP) and Collection of 
Pregnancy Information
The list does not apply to FRP with same sex partners or for subjects 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, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilisation with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination, and/or 
semen analysis, or medical history interview provided by her or her partner.
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 subjects understand how to properly use these methods of contraception.
11.9.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to 
ViiV/GSK/PPD within 2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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 also will forward this information to the Antiretroviral Pregnancy 
Registry.  The international registry is jointly sponsored by manufacturers or 
licensees of antiretroviral products.  Additional information and a list of participating 
manufacturers/licensees are available from http://www.apregistry.com/.  
 
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
Any termination of pregnancy will be reported, regardless of foetal 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 will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.    

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to the 
Medical Monitor. 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.
Any female subject who becomes pregnant (intrauterine) while participating in this 
study must be withdrawn from the study and must immediately discontinue study 
drug.
Reference
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 
20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2. 
 
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11.10.
Appendix 10 Protocol Changes
11.10.1.
Amendment 01: A global protocol amendment applicable to all 
participating countries:
Summary of Changes in Protocol Amendment 01 and Rationale

Mailing address of study medical monitor was updated.

Changes were made to the protocol text in the following sections to reflect the 
revision of the number of subjects to be randomized from ~125 to ~115 to alleviate
enrolment difficulties and recruit the study in a timely manner. The reduced sample 
size will allow timely availability of the data while maintaining a high power for the 
sample size assumption. The changes were made in Protocol Summary Study Design 
Section, in Section 3.1, in Section 4.1, in Section 8.1.1 and in Section 8.2.1.

Minor clarifications in the study conduct include clarification of the use of solid 
media for the 2 month TB culture to be preferred rather than mandated to be aligned 
with the original study intent to follow national recommendations for TB testing and 
management. Change was made in Section 3.1.1.

Correction of the list of participating countries in Section 3.2 and Section 4.1.

Minor clarifications on GeneXpert testing or equivalent validated test and the ability 
to perform the test at the Screening visit in alignment with the original the study 
design and intent and described in Section 3.1. Changes were made in Section 4.2 
and Section 6.1.

Addition of instructions for investigators on the new GSK/ViiV procedure requiring 
investigator to confirm and document their review of the SAE causality within 72 
hours of submission of the SAE. Change was made in Section 6.4.14.

Minor clarification and/or corrections of typographical errors were made in inclusion 
criteria 19 and 23 Section 4.3, in Section 6.4.14.2 and in Section 8.1 Table 9.

Figure 6 in Appendix 5 was replaced by an identical and reformatted figure to 
improve readability.
List of Changes (Old deleted text shown as strike through and new 
text shown in bold)

Page 3, SPONSOR INFORMATION PAGE last paragraph:
 MD, PhD
PPD
1800 Perimeter Park Drive, Suite 2753900 Paramount Parkway, South Building, 3rd
Floor, Office 352

Protocol Summary Study Design and Section 3.1 first and second paragraph:
 
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This is a Phase IIIb, randomized, open-label study describing the efficacy and safety of 
DTG and EFV-containing ART regimens in HIV/TB co-infected patients. The study will 
be conducted in approximately (5%) 1125 HIV-1 infected individuals who are ART-
naïve with a CD4+ cell count 50 cells/mm3 and newly diagnosed with confirmed 
pulmonary, pleural, or LN Mycobacterium TB (MTB) taking RIF-containing first-line TB 
treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined 
by GeneXpert (or equivalent approved molecular test) or mycobacterial culture. Eligible 
subjects will be randomly assigned in a 3:2 ratio to receive DTG plus 2 NRTIs 
(approximately 6975 subjects) or EFV plus 2 NRTIs (approximately 4650 subjects).

Section 3.1.2, 2nd Paragraph, 2nd sentence:
Sputum will be collected from subjects with pulmonary tuberculosis 2 months after 
initiating TB treatment (solid media culture testing is preferred required).

Section 3.2 Discussion of Design, 2nd paragraph, 1st sentence:
Adult subjects diagnosed (smear positive) and proven RIF-sensitive TB who are initiating 
TB treatment with HRZE will be recruited at sites in Brazil, Mexico, Russia, Argentina, 
Peru, South Africa, Malawi and Thailand.

Section 4.1, 1st and 2nd paragraph and Table:
A sufficient number of subjects will be screened in order to ensure that a total of 
approximately (5%) 1125 subjects will be randomly assigned in a 3:2 ratio to DTG 
(approximately 6975 subjects) and EFV (approximately 4650 subjects), respectively. 
Assuming 55% of subjects do not meet eligibility criteria, this will require the screening 
of approximately 2575 subjects. Subjects will be enrolled from Brazil, Mexico, Russia, 
Argentina, Peru, South Africa, Malawi, and Thailand.
Subjects
Screened
~2575
Randomized
~1125
Evaluable
~1125

Section 4.2, Inclusion criteria 7 and 8:
3.
New diagnosis of pulmonary, pleural, or LN tuberculosis based on identification of 
Mycobacterium tuberculosis using culture methods or GeneXpert (or other 
approved molecular test) on sputum or on samples collected by needle aspirate of 
pleural fluid or an affected LN; 
4.
RIF sensitivity of Mycobacterium tuberculosis either by culture or Gene Xpert (or 
other validated approved nucleic acid amplification test);

Section 4.3, Exclusion criteria 19 and 23:
 
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19. Any verified Grade 4 laboratory abnormality with the exception of Grade 4 
triglycerides.  A single repeat test is allowed during the Screening period to 
verify a result; 
23. Platelet count <50,000/mm3.

Section 6.1, Table 2, row 8, column 1:
Perform GeneXpert or equivalent and/or Document GeneXpert or equivalent RIF-
sensitive MTB.

Section 6.4.14, new sentence added after Table 7:
The investigator will be required to confirm review of the SAE causality by ticking 
the ‘For Investigators ONLY’ box at the bottom of the eCRF page within 72 hours 
of submission of the SAE.

Section 6.4.14.2, typo corrected:
If a clinically suspected case of HSR to ABC develops in subjects receiving ABC as part 
of their NRTI background regimen, and meets the definition of an AE/SAE as described 
in Section 6.4.4, then, in addition to reporting the case as an SAE, the ABC HSR eCRF 
should also be completed within 1 week of the onset of the HSR (see Section 6.4.14).

Section 8.1.1, Table 9, 3rd column, rows 2 to 5, typo corrected:
CD4+ cell countHIV-1 RNA <50 c/mL

Section 8.1.1, 5th and last paragraph:
Assuming an 85% response rate for DTG at Week 48, a sample size of 75 66 to 
72 subjects in the DTG arm would have >9085% power to detect a response rate of 
greater than 70% (Figure 4). Although the objective of the study is not to test a statistical 
hypothesis, the sample size has been chosen to provide an adequate number of subjects 
for assessing the antiretroviral activity of DTG.

Section 8.2.1, 1st paragraph, 2nd sentence:
A sample size of 6975 subjects has >90% power. Smaller samples (e.g., 659 or greater) 
have at least 868% power, which is relevant when assessing the primary endpoint in 
alternate analysis populations (i.e., modified ITT-E).

Figure 6 in Appendix 5:
Figure 6 was reformatted.
 
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11.10.2.
Protocol changes for Amendment 02 from Amendment 01: 
A global amendment applicable to all participating countries
Summary of Key Changes in Protocol Amendment 02 and Rationale
Changes were made to the protocol to manage and mitigate risks following identification 
of a potential safety issue related to neural tube defects in infants born to women with 
exposure to dolutegravir at the time of conception. Changes were also made to update 
references to the DTG IB to reflect the most current versions.  

The Risk Assessment table (Section 1.3.1, Table 1) was updated to include language 
regarding risk and mitigation of neural tube defects.

The inclusion criteria (Section 4.2) were updated to align the pregnancy information 
with more recent protocols.

The withdrawal criteria (Section 4.5) were updated to include a reminder that females 
of reproductive potential who change their minds and desire to be pregnant, or who 
state they no longer are willing to comply with the approved pregnancy avoidance 
methods, should also be withdrawn from the study.

The Time and Events table (Section 6.1, Table 2). was updated to include a reminder 
for investigators to check at every visit that females of reproductive potential are 
avoiding pregnancy.

A new Appendix was added detailing the modified list of highly effective methods 
for avoiding pregnancy in FRP and the collection of pregnancy data (Appendix 9, 
Section 11.9.1). The double barrier method of contraception, which does not meet 
updated GSK/ViiV criteria for a highly effective method, was excluded.
List of Specific Changes. Unless stated otherwise, new text is represented in bold 
font.
Section 1.3.1 Risk Assessment:
Added the following text:
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 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 female subject is eligible 
to participate if she is not 
pregnant, not lactating, 
and, if she is a female of 
reproductive potential, 
agrees to follow one of the 
options listed in the 
Modified List of Highly 
Effective Methods for 
Avoiding Pregnancy in 
 
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Females of Reproductive 
Potential (FRP) (see 
Appendix 9, Section 
11.9.1) until the last dose 
of study medication.
2. Women who are 
breastfeeding or plan to 
become pregnant or 
breastfeed during the 
study are excluded.
3. Women who become 
pregnant, or 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 study 
treatment discontinued 
and be withdrawn from 
the study.
4. Females of reproductive 
potential are reminded re: 
pregnancy avoidance and 
adherence to 
contraception 
requirements at every 
study visit.
5. Pregnancy status is 
monitored at every study 
visit.
Section 4.2 Inclusion Criteria
Previous Text
6.
A female subject may be eligible to enter and participate in the study if she:
a
is of non-childbearing potential defined as either postmenopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of becoming 
pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or,
b
is of childbearing potential, with a negative pregnancy test at both Screening and 
Day 1, and agrees to use one of the following methods of contraception to avoid 
pregnancy:
 
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
Complete abstinence from intercourse from 2 weeks prior to administration 
of IP, throughout the study, and for at least 2 weeks after discontinuation of 
all study medications;

Double-barrier method (male condom/spermicide, male condom/diaphragm, 
diaphragm/spermicide); 

Approved hormonal contraception (see the SPM for a listing of examples of 
approved hormonal contraception) plus a barrier method while receiving 
RIF-containing TB treatment for subjects randomly assigned to the DTG arm, 
or approved hormonal contraception plus a barrier method for subjects 
randomly assigned to the EFV arm (regardless of RIF-containing TB 
treatment);

Any intrauterine device (IUD) with published data showing that the expected 
failure rate is <1% per year (not all IUDs meet this criterion; see the SPM for 
an example listing of approved IUDs);

Male partner sterilization prior to the female subject’s entry into the study 
and this male is the sole partner for that subject;

Any other method with published data showing that the expected failure rate 
is <1% per year.
Any contraception method must be used consistently, in accordance with the 
approved product label and for at least 2 weeks after discontinuation of study drug. A 
childbearing potential female subject who starts the study using complete abstinence 
as her contraceptive method and decides to become sexually active must use the 
double barrier method either as a bridge to an approved hormonal contraception (if
possible) or as a method of choice to be maintained from that moment onwards.
All subjects participating in the study should be counseled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/ spermicide).
Current text:
6.
A female subject may be eligible to enter and participate in the study if she:
a. is of non-childbearing potential defined as either postmenopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of becoming 
pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or,
b. is of childbearing potential, with a negative pregnancy test at both Screening and 
Day 1, and agrees to use one of the following methods of contraception to avoid 
pregnancy throughout the study and for at least two weeks after discontinuation of all 
study medication (see Appendix 9, Section 11.9):

Complete abstinence from penile-vaginal intercourse from 2 weeks prior to 
administration of IP, throughout the study, and for at least 2 weeks after 
discontinuation of all study medications. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception
 
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
Approved hormonal contraception (see Appendix 9 Section 11.9 and the 
SPM for a listing of examples of approved hormonal contraception) plus a 
barrier method while receiving RIF-containing TB treatment for subjects 
randomly assigned to the DTG arm, and then regardless of use of a barrier 
method after discontinuation of RIF-containing TB treatment or approved 
hormonal contraception plus a barrier method for subjects randomly 
assigned to the EFV arm (regardless of RIF-containing TB treatment).
Approved hormonal contraception including:
o
Combined oestrogen and progestogen oral contraceptive [Hatcher, 
2011])
o
Contraceptive subdermal implant
o
Injectable progestogen [Hatcher, 2011]
o
Contraceptive vaginal ring [Hatcher, 2011]
o
Percutaneous contraceptive patches [Hatcher, 2011] ;

Any intrauterine device (IUD); or intrauterine system

Male partner sterilization with documentation of azoospermia prior to the 
female subject’s entry into the study and this male is the sole partner for that 
subject [Hatcher, 2011]. The documentation on male sterility can come from 
the site personnel’s review of subject’s medical records, medical 
examination, and/or semen analysis, or medical history interview provided by 
her or her partner.;

Any other method with published data showing that the expected failure rate 
is <1% per year.
Any contraception method must be used consistently, in accordance with the 
approved product label and for at least 2 weeks after discontinuation of study drug. A 
childbearing potential female subject who starts the study using complete abstinence 
as her contraceptive method and decides to become sexually active must use the 
double barrier method either as a bridge to an approved hormonal contraception (if 
possible) or as a method of choice to be maintained from that moment onwards.
All subjects participating in the study should be counseled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/ spermicide).
Note: these contraceptive requirements do not apply to females of childbearing 
potential with same sex partners only, when this is their preferred and usual lifestyle.
Section 4.5 Withdrawal Criteria:
Previous text: 

Pregnancy (intrauterine), regardless of termination status of pregnancy.
 
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Current text:

Pregnancy (intrauterine), regardless of termination status of pregnancy. As a 
reminder, females of reproductive potential who change their minds and desire 
to be pregnant, or who state they no longer are willing to comply with the 
approved pregnancy avoidance methods, should also be withdrawn from the 
study. 
Section 6.1 Time and Events Table:
Inserted footnote r: Remind females of reproductive potential of the need to avoid 
pregnancy while in study and adherence to the study’s contraception requirements.
Section 10: References
References to the DTG IB have been updated to add DTG IB version 11, supplement 01 
and 02 as follows:
GlaxoSmithKline (GSK) Document Number RM2007/00683/11:  Clinical Investigator's 
Brochure for GSK1349572 (Dolutegravir) Version 11. October 2017.
GlaxoSmithKline Document Number 2017N352880_00: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 01, 11 December 2017.
GlaxoSmithKline Document Number 2017N352880_01: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 02, June 2018.
Section 11.9: Appendix 9 Pregnancy
New Text:
11.9
Appendix 9:  Pregnancy Information
11.9.1 Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP) and Collection of Pregnancy Information
The list does not apply to FRP with same sex partners or for subjects 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, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]
 
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
Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilisation with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s review of subject’s medical records, medical examination, and/or 
semen analysis, or medical history interview provided by her or her partner.
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 subjects understand how to properly use these methods of contraception.
11.9.2 Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to 
ViiV/GSK/PPD within 2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, 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 also will forward this information to the Antiretroviral Pregnancy 
Registry.  The international registry is jointly sponsored by manufacturers or 
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 foetal 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 will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.    

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to the 
Medical Monitor. 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.
Any female subject who becomes pregnant (intrauterine) while participating in this 
study must be withdrawn from the study and must immediately discontinue study 
drug.
 
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Reference
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 
20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2. 
 
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ING117175
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
ING117175: a Phase IIIb, randomized, open-label study of the 
safety and efficacy of dolutegravir or efavirenz each 
administered with two NRTIs in HIV-1-infected antiretroviral 
therapy-naïve adults starting treatment for rifampicin-sensitive 
tuberculosis
Compound Number:
GSK1349572
Development Phase:
IIIb
Effective Date:
21-MAR-2016
Protocol Amendment Number:  01
Author (s):
 
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N190475_00
2014-APR-24
Original
2014N190475_01
2016-MAR-21
Amendment No 1
Amended to include: change to the sample size from ~125 to ~115 (+/-5%) to alleviate 
the enrolment difficulties while maintaining a high power for the sample size assumption; 
clarification that the 2 month sputum TB culture to be performed on solid medium is 
preferred rather than mandated, correction of the list of participating countries, some 
minor clarifications to inclusion and exclusion criteria, clarification on the ability to 
perform GeneXpert testing (or equivalent validated test) at the Screening Visit, addition 
of investigator instructions on the new SAE review requirement in the eCRF, 
reformatting of Figure 6 to improve readability, and other minor clarifications and 
corrections of typographical errors.
Copyright 2016 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorised copying or use of this information is prohibited.
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier: ING117175
This study is sponsored by ViiV Healthcare. GlaxoSmithKline is implementing and 
managing all aspects of this study.
Sponsor Legal Registered Address:
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Telephone: 
Sponsor Contact Address
ViiV Healthcare
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Medical Monitor and Serious Adverse Events (SAE) Contact Information:
 MD, PhD
PPD
3900 Paramount Parkway, South Building, 3rd Floor, Office 352
Morrisville, NC 27560-8408
Phone: 
Fax: 
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number ING117175:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................12
1.
INTRODUCTION....................................................................................................15
1.1.
Background ................................................................................................15
1.2.
Rationale ....................................................................................................16
1.3.
Benefit:Risk Assessment ............................................................................17
1.3.1.
Risk Assessment .........................................................................18
1.3.2.
Benefit Assessment.....................................................................22
1.3.3.
Overall Benefit:Risk Conclusion...................................................23
2.
OBJECTIVES.........................................................................................................23
2.1.
Primary Objective .......................................................................................23
2.2.
Secondary Objectives.................................................................................23
2.3.
Tertiary Objectives......................................................................................23
3.
INVESTIGATIONAL PLAN.....................................................................................24
3.1.
Study Design ..............................................................................................24
3.1.1.
Screening Period .........................................................................25
3.1.2.
Randomized Phase (Day 1 to Week 48 plus 4-Week 
Extension)....................................................................................25
3.1.3.
DTG Open-Label Extension.........................................................26
3.1.4.
Study Completion ........................................................................27
3.1.5.
Follow-up.....................................................................................27
3.2.
Discussion of Design ..................................................................................27
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................28
4.1.
Number of Subjects ....................................................................................28
4.2.
Inclusion Criteria.........................................................................................29
4.3.
Exclusion Criteria........................................................................................31
4.4.
Other Eligibility Criteria Considerations.......................................................32
4.5.
Withdrawal Criteria .....................................................................................33
4.6.
Virologic Criteria for Subject Management and Viral Resistance 
Testing........................................................................................................34
4.6.1.
Management of Subjects Meeting Suspected Virologic 
Withdrawal Criteria ......................................................................37
4.7.
Retest Criteria for Subjects With Plasma HIV-1 RNA Levels 
50 c/mL at Week 48....................................................................................37
4.8.
Protocol-Defined Failure of TB Treatment...................................................38
4.9.
Screening Failures......................................................................................38
5.
STUDY TREATMENTS..........................................................................................39
5.1.
Investigational Product and Other Study Treatment....................................39
5.1.1.
Tablet Formulation of DTG ..........................................................39
5.1.2.
Tablet Formulation of EFV...........................................................39
5.1.3.
Background NRTIs ......................................................................40
5.1.4.
Dosage and Administration..........................................................40
 
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5.1.5.
Protocol-Permitted Substitutions..................................................40
5.2.
Treatment Assignment................................................................................41
5.3.
Blinding.......................................................................................................41
5.4.
Product Accountability ................................................................................41
5.5.
Treatment Compliance................................................................................41
5.6.
Concomitant Medications and Non-Drug Therapies....................................41
5.6.1.
Permitted Medications and Non-Drug Therapies..........................42
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................42
5.6.3.
Prohibited Medications for Subjects Randomly Assigned 
to DTG.........................................................................................43
5.6.4.
Prohibited Medications for Subjects Randomly Assigned 
to EFV .........................................................................................43
5.7.
Treatment After the End of the Study..........................................................43
5.8.
Treatment of Study Treatment Overdose....................................................44
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
6.1.
Time and Events Schedule .........................................................................45
6.1.1.
TB Time and Events Schedule.....................................................50
6.2.
Critical Baseline Assessments....................................................................50
6.2.1.
Screening Assessments ..............................................................50
6.2.2.
Baseline Assessments (Day 1) ....................................................51
6.3.
Efficacy.......................................................................................................52
6.3.1.
Efficacy Evaluations.....................................................................52
6.3.2.
Primary Efficacy Endpoint............................................................52
6.3.3.
Secondary Efficacy Endpoints .....................................................53
6.3.4.
Tertiary Efficacy Endpoints ..........................................................53
6.4.
Safety .........................................................................................................53
6.4.1.
Safety Endpoints..........................................................................54
6.4.2.
Toxicity Management...................................................................55
6.4.3.
Specific Toxicity Management .....................................................57
6.4.3.1.
Liver Chemistry Stopping and Follow-up 
Criteria........................................................................57
6.4.3.1.1.
Alternate RIF-Containing TB 
Treatment Regimen and Bridging 
Regimen.................................................60
6.4.3.2.
Restarting Investigational Product ..............................61
6.4.3.3.
TB-Associated IRIS Toxicity Management..................62
6.4.3.4.
Decline in Renal Function...........................................62
6.4.3.5.
Allergic Reaction ........................................................63
6.4.3.6.
Hypertriglyceridemia/Hypercholesterolemia................63
6.4.3.7.
Creatine Phosphokinase Elevation.............................63
6.4.3.8.
Rash...........................................................................63
6.4.3.9.
Petechial Rash ...........................................................65
6.4.4.
Adverse Events............................................................................65
6.4.4.1.
Definition of an AE......................................................65
6.4.4.2.
Definition of an SAE ...................................................66
6.4.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................67
6.4.6.
TB-Associated Immune Reconstitution Inflammatory 
Syndrome ....................................................................................67
6.4.7.
Cardiovascular Events.................................................................69
6.4.8.
Death Events...............................................................................69
 
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6.4.9.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................70
6.4.10.
Suicidality Monitoring...................................................................70
6.4.11.
Pregnancy ...................................................................................71
6.4.11.1.
Pregnancy Testing......................................................71
6.4.11.2.
Time Period for Collecting Pregnancy 
Information .................................................................71
6.4.11.3.
Action to be Taken if Pregnancy Occurs.....................71
6.4.12.
Time Period and Frequency of Detecting AEs and SAEs.............72
6.4.13.
Method of Detecting AEs and SAEs.............................................72
6.4.14.
Prompt Reporting of Serious Adverse Events and Other 
Events .........................................................................................72
6.4.14.1.
Regulatory Reporting Requirements for SAEs............74
6.4.14.2.
Reporting of ABC Hypersensitivity Reactions .............74
6.4.15.
Other Safety Outcomes ...............................................................74
6.5.
Pharmacokinetics .......................................................................................75
6.5.1.
Pharmacokinetic Endpoints .........................................................75
6.5.2.
Pharmacokinetic Sample Collection.............................................75
6.5.3.
Bioanalysis of DTG and EFV PK Samples...................................77
6.6.
Viral Genotyping and Phenotyping..............................................................77
6.6.1.
Viral Endpoint ..............................................................................77
6.6.2.
HIV-1 Polymerase Viral Genotyping and Phenotyping .................78
6.6.3.
HIV-1 Exploratory Analysis ..........................................................78
6.7.
Pharmacogenetic Research........................................................................78
7.
DATA MANAGEMENT ...........................................................................................78
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................79
8.1.
Hypotheses.................................................................................................79
8.1.1.
Sample Size Assumptions ...........................................................79
8.2.
Study Design Considerations......................................................................80
8.2.1.
Sample Size Sensitivity................................................................80
8.2.2.
Sample Size Re-estimation..........................................................82
8.2.3.
Analysis Populations....................................................................82
8.2.3.1.
Intent-to-Treat Exposed (ITT-E) Population ................82
8.2.3.2.
Modified Intent-to-Treat Exposed (MITT-E) 
Population ..................................................................83
8.2.3.3.
Per-Protocol Population..............................................83
8.2.3.4.
Safety Population .......................................................83
8.2.3.5.
PK Population.............................................................83
8.2.3.5.1.
DTG PK Population ................................83
8.2.3.5.2.
EFV PK Population.................................83
8.2.4.
Analysis Data Sets.......................................................................83
8.2.5.
Treatment Comparisons ..............................................................84
8.2.6.
Interim Analysis ...........................................................................84
8.2.7.
Key Elements of Analysis Plan ....................................................84
8.2.7.1.
Efficacy Analyses .......................................................84
8.2.7.2.
Safety Analyses..........................................................85
8.2.7.3.
Pharmacokinetic and 
Pharmacokinetic/Pharmacodynamic Analyses ...........85
8.2.7.4.
Viral Genotyping/Phenotyping Analyses.....................86
8.2.7.5.
Pharmacogenetic Analyses ........................................86
 
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9.
STUDY CONDUCT CONSIDERATIONS ...............................................................86
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............86
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................86
9.3.
Quality Control (Study Monitoring) ..............................................................87
9.4.
Quality Assurance.......................................................................................87
9.5.
Study and Site Closure ...............................................................................88
9.6.
Records Retention......................................................................................88
9.7.
Provision of Study Results to Investigators, and Posting of 
Information on Publicly Available Clinical Trials Registers and 
Publication..................................................................................................89
10. REFERENCES.......................................................................................................90
11. APPENDICES........................................................................................................94
11.1.
Appendix 1 Pharmacogenetic Research .....................................................94
11.2.
Appendix 2 CDC Classification System for HIV-1 Infections (1993) ..........100
11.3.
Appendix 3 Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events...................................................................103
11.4.
Appendix 4 Country-Specific Requirements..............................................128
11.5.
Appendix 5 Liver Safety Drug Restart or Rechallenge Guidelines.............129
11.6.
Appendix 6 Alternate RIF-Containing TB Treatment Regimens ................134
11.7.
Appendix 7 Karnofsky Performance Status Scale.....................................135
11.8.
Appendix 8 Child-Pugh Classification .......................................................136
11.9.
Appendix 9 Protocol Changes...................................................................137
 
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LIST OF ABBREVIATIONS
3TC
Lamivudine, EPIVIR
ABC
Abacavir, ZIAGEN
ABC/3TC
Abacavir/lamivudine, EPZICOM, KIVEXA
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALT
Alanine aminotransferase
ART
Antiretroviral therapy
BUN
Blood urea nitrogen
c/mL
Copies/milliliter
CDC
Centers for Disease Control and Prevention
CD4+
Helper-inducer T-lymphocyte having surface antigen CD4 
(cluster of differentiation 4)
C-SSRS
Columbia-Suicidality Severity Rating Scale
CI
Confidence interval
CPK
Creatine phosphokinase
CrCL
Creatinine clearance
CYP
Cytochrome P450
DAIDS
Division of Acquired Immunodeficiency Syndrome
DHHS
United States Department of Health and Human Services
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DRV
Darunavir, Prezista
DRV/r
Darunavir + Ritonavir
DTG
Dolutegravir
ECG
Electrocardiograph
eCRF
Electronic case report form
EFV
Efavirenz, Sustiva
FDA
US Food and Drug Administration
FTC
Emtricitabine, Emtriva
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus 
HIV-1
Human immunodeficiency virus type 1
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INI
Integrase inhibitor
INR
International normalized ratio
IP
Investigational product
 
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IRB
Institutional Review Board
IRIS
Immune reconstitution inflammatory syndrome
ITT
Intent-to-treat
ITT-E
Intent-to-treat-exposed
IVRS
Interactive voice response system
LDL
Low-density lipoprotein
LN
Lymph node
mg
Milligram
MITT-E
Modified intent-to-treat
mL
Milliliter
MTB
Mycobacterium tuberculosis
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OLE
Open-label extension
PCR
Polymerase chain reaction
PGx
Pharmacogenetic
PI
Protease inhibitor
PK
Pharmacokinetic
PRO
Protease
PSRAE
Possible suicidality-related adverse event
PT
Prothrombin time
RAL
Raltegravir, Isentress
RAP
Reporting and analysis plan
RIF
Rifampicin
RNA
Ribonucleic acid
RT
Reverse transcriptase
SAE
Serious adverse event
SPM
Study Procedures Manual
TB
Tuberculosis
TDF
Tenofovir disoproxil fumarate, Viread
TDF/FTC
Tenofovir disoproxil fumarate/Emtricitabine, Truvada
TMP-SMX
Trimethoprim-sulfamethoxazole
ULN
Upper limit of normal
VSLC
ViiV Safety and Labeling Committee
WHO
World Health Organization
 
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Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Atripla
EPZICOM
Complera 
KIVEXA
Efavirenz
TIVICAY
Emtriva
TRIZIVIR
GeneXpert
ZIAGEN
GenoSure
Isentress 
MedDRA
Monogram Biosciences
PhenoSense
Quest Diagnostics
SAS
Standard Phenosense
 
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PROTOCOL SUMMARY
Rationale
Study ING117175 is being conducted to assess the antiretroviral activity of a dolutegravir 
(DTG)-containing regimen (50 mg twice-daily during tuberculosis [TB] treatment and for 
2 weeks following discontinuation of TB treatment, then 50 mg once-daily, with 
2 nucleoside reverse transcriptase inhibitors [NRTIs]) in antiretroviral therapy 
(ART)-naïve patients with human immunodeficiency virus (HIV)-1 infection taking 
rifampicin (RIF)-containing first-line treatment for pulmonary, pleural, and lymph node 
(LN) RIF-sensitive TB. Safety, TB-associated immune reconstitution inflammatory 
syndrome (IRIS), and tolerability will also be explored. This study is designed to assess 
the antiviral activity of DTG and efavirenz (EFV) ART-containing regimens through 
48 weeks.
Objectives
Primary Objective
To assess the antiviral activity at 48 weeks of a DTG-containing regimen (50 mg twice 
daily during TB treatment and for 2 weeks following discontinuation of TB treatment, 
then 50 mg once daily, with 2 NRTIs) in ART-naïve patients with HIV-1 infection taking 
RIF-containing TB treatment.
Secondary Objectives

To assess the antiviral activity of DTG and EFV both administered with 2 NRTIs at 
Week 24;

To assess the antiviral activity of EFV administered with 2 NRTIs at Week 48;

To evaluate immunological activity (CD4+ lymphocyte [CD4 counts]) at Week 24 
and Week 48;

To evaluate the safety, TB-associated IRIS, and tolerability in subjects treated with a 
DTG- or EFV-based regimen concurrently with treatment for TB over time;

To assess the development of HIV-1 resistance in subjects who meet confirmed 
virologic withdrawal criteria over 24 and 48 weeks.
Tertiary Objectives

To evaluate the incidence of disease progression (HIV-associated conditions, 
acquired immunodeficiency syndrome [AIDS], and death) over time;

To describe rates of TB treatment success (using the World Health Organization 
[WHO] definition) for all subjects;

To describe the proportion of subjects with pulmonary tuberculosis who are sputum 
culture-negative 2 months after starting TB treatment; 
 
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
To evaluate concentrations of DTG and EFV using sparse sampling and to 
characterize DTG pharmacokinetics and variability during and post TB treatment 
and to explore the association between DTG and EFV concentrations and antiviral 
activity at Week 24 and Week 48.
Study Design
This is a Phase IIIb, randomized, open-label study describing the efficacy and safety of 
DTG and EFV-containing ART regimens in HIV/TB co-infected patients. The study will 
be conducted in approximately (+/- 5%) 115 HIV-1 infected individuals who are ART-
naïve with a CD4+ cell count 50 cells/mm3 and newly diagnosed with confirmed 
pulmonary, pleural, or LN Mycobacterium TB (MTB) taking RIF-containing first-line TB 
treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined 
by GeneXpert (or equivalent approved molecular test) or mycobacterial culture. Eligible 
subjects will be randomly assigned in a 3:2 ratio to receive DTG plus 2 NRTIs 
(approximately 69 subjects) or EFV plus 2 NRTIs (approximately 46 subjects). The dual 
NRTI backbone will be selected by the investigator in accordance with local standard of 
care and per current WHO or national guidelines for the treatment of HIV/TB co-infected 
adults. Subjects randomization will be stratified by screening plasma HIV-1 RNA 
(100,000 c/mL or >100,000 c/mL) and screening CD4+ cell count (100 cells/mm3 or 
>100 cells/mm3). An interim analysis will be conducted when all subjects complete their 
Week 24 visit, the primary Week 48 analysis will be conducted when the last subject 
completes the Randomized Phase, and a final end-of-study analysis will be conducted 
when the final subject randomly assigned to DTG has transitioned from the Open-Label 
Extension (OLE) to commercial supplies of DTG or is withdrawn for the study. 
This study will include a Screening Period, a Randomized Phase (Day 1 to Week 48 plus 
a 4-week extension), and a DTG OLE.
Only protocol-defined dose reductions, modifications, or changes in the frequency of any 
components of each HIV regimen or TB treatment will be allowed at any time in this 
study, including during the Screening Period. 
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table are essential and 
required for study conduct. If deviations are required for the management of immediate 
safety concerns, these should be promptly communicated to the study medical monitor.
Study Endpoints/Assessments
The primary endpoint for this study will be the proportion of subjects with plasma HIV-1 
RNA <50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E population in the 
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Secondary Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm in the EFV arm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related adverse event (AE), safety stopping criteria, or 
lack of efficacy);

Changes from baseline in CD4+ counts at Week 24 and Week 48.
Tertiary Efficacy Endpoints

Incidence of disease progression (HIV-associated conditions, new AIDS diagnoses, 
and death);

Proportion of subjects with TB treatment success (using the WHO definition);

Proportion of subjects with pulmonary tuberculosis who are sputum culture-negative 
2 months after starting TB treatment.
Safety endpoints will include: incidence and severity of AEs and laboratory 
abnormalities, proportion of subjects who discontinue treatment due to AEs, and 
proportion of subjects with TB-associated IRIS.
Pharmacokinetic endpoint will include an evaluation of concentrations of DTG and EFV 
measured at Weeks 8, 24, 36, and 48 using sparse sampling.
Virologic endpoint will be the incidence of treatment-emergent genotypic and phenotypic 
resistance to DTG, EFV, and other on-study ART in subjects meeting confirmed 
virologic withdrawal criteria over 24 and 48 weeks.
 
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1.
INTRODUCTION
1.1.
Background
Approximately 14 million individuals worldwide are estimated to be dually infected with 
human immunodeficiency virus (HIV) and tuberculosis (TB). The yearly incidence of TB 
infection is about 10% among patients with HIV and TB is the most common cause of 
death in patients with HIV worldwide. HIV and TB co-infection have profound effects on 
the host’s immune system. Recent studies evaluating the optimal timing for initiation of 
antiretroviral therapy (ART) in patients requiring treatment for active TB demonstrated a 
survival benefit for starting ART soon after TB treatment initiation rather than waiting 
until TB treatment completion. More specifically, current United States Department of 
Health and Human Services (DHHS) guidelines [DHHS, 2014] suggest that for patients 
with a CD4+ cell count <50 cells/mm3, ART should be started within 2 weeks of starting 
TB treatment; for patients with a CD4+ cell count 50 cells/mm3, ART should be started 
within 2 months of starting TB treatment [Török, 2011]. British guidelines suggest 
starting as soon as possible for patients with a CD4+ cell count 100 cells/mm3 [British 
HIV Association (BHIVA) Guidelines, 2011]. As a result of the aforementioned studies 
and guidelines, there is an increase in the number of co-infected individuals being treated 
concurrently.
Currently, rifamycins (such as rifampicin [RIF]) serve as the cornerstone of TB therapy 
because of their unique sterilizing activity. No drug can adequately substitute for 
rifamycins in the TB regimen; if rifamycins cannot be used, treatment duration must be 
substantially prolonged (from 6 months to 9 to 24 months in most cases). TB treatment is 
given in 2 stages: during the first 2 months (intensive phase), patients with RIF-sensitive 
TB receive isoniazid (H), RIF (R), pyrazinamide (Z), and ethambutol (E) (HRZE), and 
during the subsequent 4 months (TB treatment continuation phase), patients receive 
isoniazid and RIF (HR). Some national guidelines recommend a TB treatment 
continuation phase of HR extended to 7 months in HIV and TB co-infected patients. 
Rifampicin is the most commonly used rifamycin for TB treatment. It is a potent inducer 
of cytochrome P450 enzyme activity. By activating the pregnane X receptor (PXR), RIF 
can induce multiple metabolic enzymes, including cytochrome P450 (CYP) isoenzyme 
3A (CYP3A), other CYP enzymes, Phase II drug-metabolizing enzymes, 
UDP-glucosyltransferases, sulfonyltransferases, and drug transporters. Since most 
protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) used 
to treat HIV are metabolized by CYP3A, induction of CYP3A by RIF can lead to reduced 
serum concentrations of antiretroviral drugs with risk of treatment failure or emergence 
of resistance to antiretroviral drugs. Nucleoside reverse transcriptase inhibitor (NRTI) 
concentrations, though, are not reduced by RIF in a clinically meaningful way. In patients 
who must be treated with RIF-containing TB therapy and require concurrent ART, 
efavirenz (EFV)-based ART can be used safely and effectively [Boulle, 2008; DHHS, 
2013; WHO, 2010]. However, because the side effect profile of EFV (which includes 
treatment-related rash, CNS effects, and liver enzyme elevations) overlaps with the 
adverse effect profile of HRZE therapy, management of toxicity is complex. Integrase 
inhibitors (INI) may offer an important alternative to EFV-based therapy in TB co-
 
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infected patients. Although the BHIVA guidelines recommend an increased dose of EFV 
of 800 mg for HIV/TB co-infected patients [BHIVA Guidelines, 2011], the DHHS, 
Centers for Disease Control and Prevention (CDC), and WHO TB guidelines do not 
recommend a dose increase of EFV [DHHS, 2014; WHO, 2010; CDC, 2013], because 
the evidence that RIF treatment impacts HIV antiviral responses with EFV-based 
combination ART is weak. In addition, among the minority of patients with lower levels 
of EFV during TB therapy, EFV concentrations remain above the required levels for 
adequate antiviral activity and an even lower dose of EFV has recently been shown to be 
effective. In the ENCORE study, the 400-mg once-daily dose of EFV in combination 
with tenofovir/emtricitabine (TDF/FTC) has been shown to be non-inferior to EFV 
600 mg once daily with TDF/FTC at Week 48 in ART-naive patients [ENCORE1 Study 
Group, 2014]. 
Further, for those with contraindications or resistance to NNRTIs, there are few treatment 
options, as RIF cannot be used safely or effectively with PIs, even with dose adjustment. 
Substitution of rifabutin (RBT) for RIF is a reasonable TB treatment option for HIV/TB 
co-infected adults; however, because RBT is metabolized by CYP3A4, it requires 
bidirectional dose adjustment when given with PIs, and the optimal RBT dosing 
frequency is unknown. In addition, access to rifabutin is difficult in most resource-limited 
settings. The same potential drug interaction problem may occur when treating HIV/TB 
co-infection using recently developed antituberculosis drugs such as the diarylquinoline 
antimycobacterial drug bedaquiline, as exposure to this drug may be reduced during 
co-administration with inducers of CYP3A4 and increased during co-administration with 
inhibitors of CYP3A4 [Sirturo Product Information, 2013]. An antiretroviral drug that 
could be taken with an NRTI backbone and be used safely and effectively with RIF in the 
treatment of HIV/TB co-infection without the need for adjustments to the patient’s TB 
regimen would give physicians and patients an important treatment option. 
1.2.
Rationale
In a Phase II open-label, randomized clinical study, the HIV INI raltegravir (RAL) was 
shown to be a suitable antiretroviral drug alternative to EFV for HIV/TB co-infected 
patients undergoing TB therapy study after 48 weeks of treatment (Grinsztejn, 2014). 
These results support the investigation of other INIs such as dolutegravir (DTG) in 
HIV/TB co-infection. 
DTG is approved in the United States, Canada, the EU, Brazil, and in other countries, and 
is under review with other countries’ regulatory agencies. Two Phase III studies, 
ING114467 (SINGLE) and ING113086 (SPRING-2) evaluated safety and efficacy of 
DTG in HIV-infected adults who were ART-naïve. ING114467 (SINGLE) evaluated the 
safety and efficacy of DTG 50 mg once daily plus FDC abacavir/lamivudine (ABC/3TC) 
600 mg/300 mg compared with Atripla (EFV/FTC/TDF). Following 48 weeks of 
treatment, 88% of the subjects receiving DTG (50 mg once daily plus ABC/3TC) 
compared with 81% of the subjects receiving EFV/FTC/TDF had plasma HIV-1 RNA 
levels of <50 copies/mL; test for superiority had a p=0.003 [Walmsley, 2013]. 
ING113086 (SPRING-2) evaluated antiviral efficacy of DTG 50 mg once daily plus dual 
NRTI. After 48 weeks of treatment, 88% of the subjects receiving DTG (50 mg once 
daily plus TDF/FTC 300 mg/200 mg or ABC/3TC 600 mg/300 mg) compared with 85% 
 
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of those taking RAL (400 mg twice daily plus TDF/FTC 300 mg/200 mg or ABC/3TC 
600 mg/300 mg) had plasma HIV-1 RNA levels of <50 copies/mL [Raffi, 2013a]. DTG 
was shown to be efficacious and non-inferior to RAL in combination with a dual NRTI. 
Non-inferiority between DTG and RAL was also demonstrated at Week 96 [Raffi, 
2013b]. DTG 50 mg twice daily has also been studied in patients with INI-resistant virus 
in the VIKING and VIKING-3 studies and shown to be effective and well tolerated, with 
a safety profile comparable to that of DTG 50 mg once daily [Eron, 2013; Castagna, 
2014]. Rates of discontinuation due to adverse events (AEs) were 2% in the DTG 50 mg 
once a day arms of the ART-naïve studies and 4% in the treatment-experienced 
population in the VIKING-3 study on DTG 50 mg twice a day with an optimized 
background regimen. 
DTG is primarily metabolized by UGT1A1 with CYP3A4 as a minor route, and both 
enzymes are induced by RIF. Therefore a Phase I open-label, 3-period, fixed-sequence 
study was conducted in healthy, HIV-seronegative subjects, evaluating the 
pharmacokinetic (PK) and safety of DTG given alone at a dose of 50 mg once daily to 
that of DTG given at a dose of 50 mg twice daily together with steady-state RIF [Dooley, 
2013]. Twice-daily DTG plus RIF achieved mean DTG concentrations that were 20%-
33% higher than once-daily DTG dosing alone. Specifically, the geometric mean ratio for 
the 24-hour area under the time-concentration curve (AUC0-24), comparing DTG twice 
daily plus RIF with DTG once daily, was 1.33 (90% confidence interval [CI] 1.14 to 
1.54). The GMR for the trough concentration at the end of the dosing interval (C) was 
1.22 (90% CI 1.01 to 1.48). There were no discontinuations for AEs and any Grade 3 or 
higher AEs. In summary, in this Phase I study, DTG at 50 mg twice daily given together 
with standard-dose RIF was well-tolerated and resulted in DTG concentrations similar to 
those of DTG 50 mg given once daily alone. Based on these results and as specified in 
the DTG prescribing information, the dose selection of twice-daily DTG 50 mg plus dual 
NRTI tablet during TB treatment was selected. The twice-daily regimen will be 
maintained for 2 weeks following discontinuation of TB treatment in order to eliminate 
(i.e., washout) the effects of RIF on the induction of UGT1A1 and CYP3A4; thereafter; 
once-daily DTG 50 mg with the same NRTI backbone will be administered through 
Week 48. 
ART regimens using DTG 50 mg twice daily may represent a new treatment option for 
TB-infected patients who require concurrent treatment for HIV infection. This study will 
examine the use of DTG-based regimen among patients with HIV/TB co-infection.
1.3.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with DTG 
can be found in the most current version of the Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number RM2007/00683/07]. The following section 
outlines the risk assessment and mitigation strategy for the use of DTG as described in 
this protocol. 
The approved country product labels should be referenced for RIF and all other 
components of the TB regimen, NRTIs, and EFV. 
 
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1.3.1.
Risk Assessment
All medications have AE profiles that must be assessed prior to use, allowing for an 
appropriate risk/benefit assessment. Considerations when using DTG are presented in 
Table 1. 
 
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Table 1
Considerations When Using DTG
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
Hypersensitivity and Rash
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. 
Subjects with history of allergy/sensitivity to any of the study drugs 
are excluded (Section 4.3).
Specific/detailed toxicity management guidance is provided for HSR 
(Section 6.4.3.5) and rash (Section 6.4.3.8).
The subject informed consent form includes information on this risk 
and the actions subjects should take in the event of a rash or 
associated signs and symptoms.
Drug induced liver injury 
(DILI) and other clinically 
significant liver chemistry 
elevations
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 subjects with 
hepatitis C virus (HCV) co-infection, improvements in immunosuppression as 
a result of HIV virologic and immunologic responses to DTG- containing ART 
contributed to significant elevations in liver chemistries.  
Drug-induced liver injury is a well-described adverse outcome of TB treatment. 
The risk of DILI from TB treatment is higher if the subject is also co-infected 
with HIV.
Subjects meeting either of the following criteria during the Screening 
Period are excluded from participating (Section 4.3).

Alanine aminotransferase (ALT) 2 times the upper limit of 
normal (ULN)

Subjects with an anticipated need for hepatitis C virus (HCV) 
therapy during the Randomized Phase (Day 1 to Week 48 plus 
a 4-week treatment extension)
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Section 6.4.3.1).  
Theoretical serious drug 
interaction with dofetilide and
pilsicainide
Co-administration of DTG may increase dofetilide/pilsicainide plasma 
concentration via inhibition of organic cation transporter 2 (OCT2), resulting in 
potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide is 
prohibited in the study (Section 5.6.2).
GI intolerance
Non-clinical studies showed upper and lower GI toxicity, including vomiting, 
diarrhoea and gastric erosions observed in monkey toxicology studies (thought 
to be related to local and not systemic toxicity).  
Mild to moderate GI intolerance (mainly diarrhoea and nausea) is associated 
Routine monitoring of GI symptoms will be performed.
 
 
 
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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategya
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
with DTG treatment in a small proportion of subjects; however there were no 
indications of an increased risk for peptic ulcers or serious erosions.
Renal function
Mild elevations of creatinine have been observed with DTG which are related 
to a likely benign effect on creatinine secretion with blockade of OCT2 
receptor. DTG has been shown to have no significant effect on glomerular 
filtration rate (GFR) or effective renal plasma flow. 
Specific/detailed toxicity management guidance is provided for 
subjects who develop a decline in renal function (Section 6.4.3.4). 
Psychiatric disorders
Psychiatric disorders including suicide ideation and behaviours are common in 
HIV-infected patients. The psychiatric profile for DTG (including suicidality, 
depression, bipolar and hypomania, anxiety and abnormal dreams) was 
similar or favourable compared with other ART. 
The reporting rate for insomnia was statistically higher for blinded 
DTG+ABC/3TC compared with EFV/TDF/FTC in ING114467; however, this 
was not duplicated in any other Phase IIb/III study conducted with DTG.  
Subjects who in the investigator’s judgment, poses a significant 
suicidality risk, are excluded from participating (Section 4.3).
Because of the elevated risk in the HIV- infected population, 
treatment emergent assessment of suicidality will be monitored 
during this study. Investigators are advised to consider mental 
health consultation or referral for subjects who experience signs of 
suicidal ideation or behaviour (Section 6.4.10).
Creatine phosphokinase 
(CPK)  elevations
Asymptomatic CPK elevations mainly in association with exercise have been 
reported with DTG therapy.
Specific detailed toxicity management guidance is provided for 
subjects who develop Grade 3 to 4 CPK elevations 
(Section 6.4.3.7).
Increased occurrence of 
immune reconstitution 
inflammatory syndrome 
(IRIS)
With rapid HIV-1 RNA decline and early recovery of CD4+ cell counts there 
could theoretically, be an increase in cases of IRIS. 
Based on medical adjudication of IRIS-like events in ING111762, ART-
experienced (INI-naïve) subjects with hepatitis C virus co-infection receiving 
DTG may be at greater risk for IRIS than those receiving RAL, due to 
improved HIV virologic and immunologic responses with DTG compared with 
RAL. 
Subjects will be monitored for signs and symptoms of TB-associated 
IRIS. Definitions on criteria for diagnosing these cases are provided 
in Section 6.4.6. Subjects will also have frequent liver chemistry 
monitoring. Robust liver chemistry stopping criteria and liver event 
follow-up assessments are included. 
 
 
 
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3TC = lamivudine, ABC = abacavir, ART = antiretroviral therapy, ALT = alanine aminotransferase, CPK = creatine phosphokinase, DILI = drug induced liver injury, DTG = dolutegravir, 
EFV = efavirenz, FTC = emtricitabine, GFR = glomerular filtration rate, GI = gastrointestinal, HCV = hepatitis C virus, IRIS = immune reconstitution inflammatory syndrome, 
TDF = tenofovir, OCT2 = organic cation transporter 2, ULN = upper limit of normal
a.
Careful monitoring of events will be conducted using serious adverse event (SAE) reports and alerts for Grade 3/4 laboratory toxicities (per Division of Acquired Immune 
Deficiency Syndrome [DAIDS] toxicity gradings for HIV-infected patients). Serious/severe events will be managed appropriately including, but not limited to, withdrawal of 
investigational product (IP), and will be followed to resolution as per sponsor’s standard medical monitoring practices. Clinical safety data will be routinely reviewed in GSK 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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Events will be monitored using SAE reports and alerts for Grade 3/4 laboratory toxicities 
(according to the Division of Acquired Immune Deficiency Syndrome [DAIDS] toxicity 
grading for HIV-infected patients as described in Section 11.3). Serious/severe events 
will be managed appropriately including, but not limited to, IP being withdrawn, and will 
be followed to resolution by the medical monitor. Further information on SAE reporting 
is described in Section 6.4.14.
Clinical safety data will be routinely reviewed in GSK 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.
1.3.2.
Benefit Assessment
Early initiation of HAART together with HRZE therapy significantly reduces mortality in 
HIV-TB co-infected patients [DHHS, 2013]. Both EFV-based and RAL-based therapy 
have been shown to be effective for HIV/TB co-infected patients; in the REFLATE 
study, 48 week success rates with RAL 400 twice daily was 76% (95% CI 65-88), 63% 
(95% CI 49-76) with RAL 800 mg twice daily; and 67% (95% CI 54-80) with EFV, with 
no significant differences among the groups. Thirty-three percent to 37% of the subjects 
in each treatment group developed Grade 3 or higher AEs. These results suggest the 
possibility for improvements in treatment outcomes.
The safety profile for DTG 50 mg once daily was comparable to RAL and 
darunavir + ritonavir (DRV/r) and generally favorable to the EFV/TDF/FTC STR 
(Atripla) in both ART-naïve and ART-experienced (INI-naïve) patients (studies 
ING113086 [SPRING-2], ING111762 [SAILING], ING114915 [FLAMINGO] and 
ING114467 [SINGLE]). The most frequently observed AEs across patient populations 
were diarrhea, nausea, and headache, which were generally Grade 1 or 2 in severity, and 
typically did not lead to discontinuation from studies. With regards to antiviral efficacy, 
in treatment-naïve HIV-infected adult subjects, DTG 50 mg once daily was shown to be 
non-inferior to RAL in combination with a dual NRTI background regimen (SPRING-2). 
In study ING114915 (FLAMINGO), virologic suppression (HIV-1 RNA <50 c/mL) in 
the DTG arm (90%) was statistically superior to the DRV/r arm (83%) at Week 48. When 
used in combination with ABC/3TC, DTG was shown to be superior to EFV/TDF/FTC, a 
result driven by better tolerability of the DTG based regimen (SINGLE). In study 
ING111762 (SAILING), 71% of in INI-naïve ART-experienced patients receiving DTG 
achieved undetectable viral load (<50 c/ml) compared with 64% of those taking RAL at 
Week 48, reaching the threshold for statistical superiority [Cahn, 2013]. In the 
ING112574 (VIKING-3) study, DTG administered at 50 mg twice daily was 
demonstrated to be safe and effective in patients with INI resistance [Castagna, 2014, 
GlaxoSmithKline Document Number 2013N177327_00].
Study participants may also benefit from the medical tests and screening procedures 
performed as part of the study.
 
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1.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with the DTG are justified by the 
anticipated benefits that may be afforded to HIV-1/TB co-infected ART-naïve adults.
2.
OBJECTIVES
2.1.
Primary Objective
To assess the antiviral activity at 48 weeks of a DTG-containing regimen (50 mg twice 
daily during TB treatment and for 2 weeks following discontinuation of TB treatment, 
then 50 mg once daily, with 2 NRTIs) in ART-naïve patients with HIV-1 infection taking 
RIF-containing TB treatment.
2.2.
Secondary Objectives

To assess the antiviral activity of DTG and EFV both administered with 2 NRTIs at 
Week 24;

To assess the antiviral activity of EFV administered with 2 NRTIs at Week 48;

To evaluate immunological activity (CD4+ lymphocyte [CD4 counts]) at Week 24 
and Week 48;

To evaluate the safety, TB-associated immune reconstitution inflammatory syndrome 
(IRIS), and tolerability in subjects treated with a DTG- or EFV-based regimen 
concurrently with treatment for TB over time;

To assess the development of HIV-1 resistance in subjects who meet confirmed 
virologic withdrawal criteria over 24 and 48 weeks.
2.3.
Tertiary Objectives

To evaluate the incidence of disease progression (HIV-associated conditions, 
acquired immunodeficiency syndrome [AIDS], and death) over time;

To describe rates of TB treatment success (using the WHO definition [WHO, 2010]) 
for all subjects;

To describe the proportion of subjects with pulmonary tuberculosis who are sputum 
culture-negative 2 months after starting TB treatment; 

To evaluate concentrations of DTG and EFV using sparse sampling and to 
characterize DTG PK and variability during and post TB treatment and to explore the 
association between DTG and EFV concentrations and antiviral activity at Week 24 
and Week 48.
 
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3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This is a Phase IIIb, randomized, open-label study describing the efficacy and safety of 
DTG and EFV-containing ART regimens in HIV/TB co-infected patients. The study will 
be conducted in approximately (+/-5%) 115 HIV-1 infected individuals who are ART-
naïve with a CD4+ cell count 50 cells/mm3 and newly diagnosed with confirmed 
pulmonary, pleural, or LN Mycobacterium TB (MTB) taking RIF-containing first-line TB 
treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined 
by GeneXpert (or equivalent approved molecular test) or mycobacterial culture. 
Figure 1
Study Schematic
DTG = dolutegravir; EFV = efavirenz; max = maximum; mg = milligram; min = minimum; NRTI = nucleoside reverse 
transcriptase inhibitor; NTP = National TB Control Program; RIF = rifampicin; TB = tuberculosis
Note: TB treatment including isoniazid, RIF, pyrazinamide, and ethambutol will be provided at standard doses by the 
NTP under program conditions.
Eligible subjects will be randomly assigned in a 3:2 ratio to receive DTG plus 2 NRTIs 
(approximately 69 subjects) or EFV plus 2 NRTIs (approximately 46 subjects). The dual 
NRTI backbone will be selected by the investigator in accordance with local standard of 
care and per current WHO or national guidelines for the treatment of HIV/TB co-infected 
adults. Subjects randomization will be stratified by screening plasma HIV-1 RNA 
 
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(100,000 c/mL or >100,000 c/mL) and screening CD4+ cell count (100 cells/mm3 or 
>100 cells/mm3). An interim analysis will be conducted when all subjects complete their 
Week 24 visit, the primary Week 48 analysis will be conducted when the last subject 
completes the Randomized Phase, and a final end-of-study analysis will be conducted 
when the final subject randomly assigned to DTG has transitioned from the Open-Label 
Extension (OLE) to commercial supplies of DTG or is withdrawn for the study. 
This study will include a Screening Period, a Randomized Phase (Day 1 to 48 weeks plus 
a 4-week extension), and a DTG OLE.
Only protocol-defined dose reductions, modifications, or changes in the frequency of any 
components of HIV regimen or TB treatment will be allowed at any time in this study, 
including during the Screening Period (Section 5.1.5). 
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table (Table 2), are 
essential and required for study conduct. If deviations are required for the management of 
immediate safety concerns, these should be promptly communicated to the study medical 
monitor.
3.1.1.
Screening Period
TB diagnosis and confirmation of RIF-sensitive MTB infection must be performed 
locally. If the result confirming MTB infection is not available before the subject is 
screened, the assessment can be performed simultaneously in order to screen the subject 
for the study. Subjects with RIF-resistant TB are not eligible to enter the study. 
GeneXpert or other molecular test result is required to rule out RIF resistance prior to 
entry. Mycobacterial culture may be used to confirm RIF-sensitivity (as an alternative to 
GeneXpert or molecular testing) provided the culture results are available prior to 
randomization. The 14-day Screening Period may be extended to 28 days to allow receipt 
of all screening assessment results and to accommodate scheduling. Subjects are allowed 
to re-screen for this study one time; this will require a new subject ID number. A single 
repeat test (retest) per analyte or assessment is allowed during the Screening Period to 
determine eligibility, except for HIV drug resistance testing.
3.1.2.
Randomized Phase (Day 1 to Week 48 plus 4-Week Extension)
As soon as all screening results are available, subjects who fulfill all eligibility 
requirements will be randomly assigned in a 3:2 ratio to receive either DTG or EFV-
containing regimens, respectively. DTG or EFV regimens will be started up to 8 weeks 
after TB treatment initiation and will continue for 48 weeks, plus a 4-week extension.
TB treatment consisting of HRZE for 2 months (i.e., TB treatment intensive phase) 
followed by HR for 4 or 7 months (i.e., TB treatment continuation phase) will be 
administered according to local guidelines with TB treatment provided by the National 
TB Control Programs (NTP) in accordance with national guidelines. Sputum will be 
collected from subjects with pulmonary tuberculosis 2 months after initiating TB 
treatment (solid media culture testing is preferred). Sputum will also be collected at 
 
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4 months, 6 months, and 9 months (for subjects who receive TB treatment for 9 months) 
for smear and culture, for as long as the subject is able to produce sputum. Sputum 
samples are not required from subjects diagnosed only from pleural or LN aspirates that 
do not also have pulmonary disease. The same laboratory and method of MTB culture 
must be used during the study.
Subjects assigned to Arm 1 will receive DTG 50 mg twice-daily with 2 NRTIs until 
2 weeks after TB therapy is completed then they will receive DTG 50 mg once daily 
(with the same NRTI backbone) through the end of the Randomized Phase. Subjects 
randomized to Arm 2 will receive EFV 600 mg once daily plus 2 NRTIs through the end 
of the Randomized Phase. The NRTI background regimen selected by the investigator 
must be determined and documented prior to randomization and should be composed of 
2 NRTIs in accordance with the local standard of care and per the WHO or national 
treatment guidelines for HIV/TB co-infection. Following Day 1, no changes or 
intensification of background regimen will be permitted prior to meeting confirmed 
virologic withdrawal criteria or Week 52, with the exception of one allowed background 
NRTI change for management of drug toxicity as described in Section 6.4.3.
Subjects randomization will be stratified by screening plasma HIV-1 RNA 
(100,000 c/mL or >100,000 c/mL) and screening CD4+ cell count (100 cells/mm3 or 
>100 cells/mm3). DTG and EFV will be administered in an open-label fashion throughout 
the Randomized Phase.
During the Randomized Phase, subjects will attend the clinic at Baseline/Day 1 and at 
Weeks 4, 8, 12, 24, 36, 48, and 52 of treatment.
Following the Week 48 visit, subjects will remain on their DTG or EFV-containing 
regimen for an additional 4 weeks. All subjects will attend the Week 52 visit, although 
only those with a viral load of 50 c/mL at Week 48 will have their viral load confirmed 
by an assessment at the Week 52 visit. This treatment extension will allow for a more 
accurate assessment of treatment response for the Week 48 analysis window, as transient 
increases of HIV-1 RNA levels 50 c/mL will not be classified as virologic failure.
To determine DTG and EFV concentrations, sparse plasma samples will be collected at 
Weeks 8, 24, 36, and 48 in as many subjects as possible. If a subject meets virologic 
withdrawal criteria, HIV-1 resistance testing will be performed to assess treatment 
emergent mutations for INIs, NNRTIs, and NRTIs.
3.1.3.
DTG Open-Label Extension
Only those subjects randomized to receive DTG plus 2 NRTIs will enter into the DTG 
OLE.
If DTG is locally approved and commercially available when a subject successfully 
completes the Randomized Phase, the subject will be considered to have completed the 
study (see Section 3.1.5) and will need to have alternate arrangements in place to access 
DTG and NRTIs. If DTG is not locally approved and commercially available when a 
subject successfully completes the Randomized Phase, he/she will have the opportunity 
 
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to enter into the DTG OLE. During the DTG OLE, subjects will be supplied with DTG 
until it is locally approved and commercially available, the subject no longer derives 
clinical benefit, or the subject meets a protocol-defined reason for discontinuation. 
Subjects who enter the DTG OLE will be monitored accordingly every 12 weeks.
3.1.4.
Study Completion
Subjects are considered to have completed the study if they satisfy one of the following:

Randomized to EFV plus 2 NRTIs and completed the Randomized Phase including 
the Week 52 visit; 

Randomized to DTG plus 2 NRTIs and completed the Randomized Phase including 
the Week 52 visit; and did not enter the DTG OLE;

Randomized to DTG plus 2 NRTIs, completed the Randomized Phase, including the 
Week 52 study visit, and entered and completed the DTG OLE (defined as remaining 
on study until commercial supplies of DTG become locally available).
3.1.5.
Follow-up
Subjects with ongoing AEs or laboratory abnormalities will attend a Follow-up visit 
approximately 4 weeks after their last dose of investigational product (IP) (DTG or EFV). 
Assessments at the Follow-up visit should reflect any ongoing complaints (e.g., blood 
draws to follow a laboratory abnormality). The Follow-up visit is not required for 
successful completion of the study.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
This randomized, open-label, multicenter, parallel group study design aims at assessing 
DTG antiviral activity in a sufficient number of subjects to demonstrate a clinically 
acceptable level of activity in HIV/TB co-infected patients receiving concomitant TB 
therapy.
Adult subjects diagnosed (smear positive) and proven RIF-sensitive TB who are initiating 
TB treatment with HRZE will be recruited at sites in Brazil, Mexico, Russia, Argentina, 
Peru, South Africa and Thailand. These areas were selected based on epidemiology 
which suggests high rates of HIV and TB co-infection (WHO). Global Tuberculosis 
Report, 2013).
The primary endpoint, proportion of subjects at Week 48 with plasma HIV-1 RNA 
<50 c/mL, is a well-established surrogate endpoint for prognosis of HIV-1 infection and 
disease progression.
 
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Efavirenz-based regimens are the preferred regimens for patients with HIV and TB 
coinfection because of complications arising from drug interactions with other agents. In 
this study, the use of EFV as the active control in (HIV) therapy-naïve patients with TB is 
justified based on its indication as an appropriate agent as first-line therapy in treatment-
naïve HIV-1-infected adults in WHO, CDC, and EACS guidelines.
DTG has been extensively studied in Phase II and Phase III studies in a variety of HIV-1 
patient populations (e.g., treatment-naïve, treatment-experienced [integrase naïve], and 
treatment-experienced [integrase resistant]). DTG with dual NRTI therapy has not been 
evaluated in HIV/TB co-infected subjects taking RIF. This study will provide important 
information regarding the efficacy, safety and tolerability, incidence of TB-associated 
IRIS, and PK of DTG plus 2 NRTIs as a first-line ART regimen in HIV/TB co-infected 
subjects receiving concomitant TB therapy. 
The use of DTG at the 50 mg twice-daily dose is in accordance with DTG global labeling 
information (i.e., United States and the EU) [DTG US Prescribing Information, 2013; EU 
SmPC, 2014] when dosed with RIF and is based on the results of the PK drug-drug 
interaction study with both drugs [Dooley, 2013]. The DTG 50 mg twice-daily dose is 
continued 2 weeks after completion of the TB treatment course, after which RIF enzyme 
induction would be minimal. 
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
A sufficient number of subjects will be screened in order to ensure that a total of 
approximately (+/-5%) 115 subjects will be randomly assigned in a 3:2 ratio to DTG 
(approximately 69 subjects) and EFV (approximately 46 subjects), respectively. 
Assuming 55% of subjects do not meet eligibility criteria, this will require the screening 
of approximately 255 subjects. Subjects will be enrolled from Brazil, Mexico, Russia, 
Argentina, Peru, South Africa and Thailand.
Subjects
Screened
~255
Randomized
~115
Evaluable
~115
The primary analysis will use all subjects in the intent-to-treat exposed (ITT-E) 
population, consisting of randomly assigned subjects who receive at least one dose of 
study drug. Since the intent is for all randomly assigned subjects to receive study drug, 
the number of evaluable subjects should equal the number randomized subjects.
Further details of sample size assumptions are found in Section 8.1.1.
 
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4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GlaxoSmithKline (GSK) investigational product or other 
study treatment that may impact subject eligibility is provided in the IB.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
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 subjects, taking into consideration any local treatment practices or 
guidelines and Good Clinical Practice (GCP). Specifically, investigators must follow 
national treatment guidelines for ART initiation for HIV/TB co-infected adults. 
Investigators must also ensure that HIV care for study subjects is available and will be 
provided locally after study completion. Study completion is described in Section 3.1.4.
Eligible subjects 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 substance abuse, acute major organ 
disease). It is of note that alcohol abuse would make these subjects more prone to 
develop TB-treatment–related liver-related toxicities.
Except for TB diagnosis laboratory test to determine eligibility that is to be performed 
locally, laboratory results from the central laboratory services provided by this study will 
be used to assess eligibility. Subjects not meeting all inclusion and exclusion criteria at 
the initial Screening visit may be rescreened only once; the subject will receive a new 
subject number. With the exception of a disqualifying viral genotype, a single repeat test 
(re-test) per analyte or assessment is allowed during the Screening Period to determine 
eligibility.  
Subjects eligible for enrollment in this study must meet all of the following:
1.
Subject or the subject’s legal representative is willing and able to understand and 
provide signed and dated written informed consent prior to Screening;
2.
Subject has plasma HIV-1 RNA 1000 copies/mL at Screening;
3.
CD4+ cell count is 50 cells/mm3 at Screening;
4.
Subject is ≥18 years of age;
5.
HIV-1-infected, ART-naïve; (10 days of prior therapy with any antiretroviral drug 
following a diagnosis of HIV-1 infection);
6.
A female subject may be eligible to enter and participate in the study if she:
 
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a. is of non-childbearing potential defined as either postmenopausal (12 months of 
spontaneous amenorrhea and 45 years of age) or physically incapable of 
becoming pregnant with documented tubal ligation, hysterectomy, or bilateral 
oophorectomy or,
b. is of childbearing potential, with a negative pregnancy test at both Screening and 
Day 1, and agrees to use one of the following methods of contraception to avoid 
pregnancy:

Complete abstinence from intercourse from 2 weeks prior to administration 
of IP, throughout the study, and for at least 2 weeks after discontinuation of 
all study medications;

Double-barrier method (male condom/spermicide, male condom/diaphragm, 
diaphragm/spermicide); 

Approved hormonal contraception (see the SPM for a listing of examples of 
approved hormonal contraception) plus a barrier method while receiving 
RIF-containing TB treatment for subjects randomly assigned to the DTG arm, 
or approved hormonal contraception plus a barrier method for subjects 
randomly assigned to the EFV arm (regardless of RIF-containing TB 
treatment);

Any intrauterine device (IUD) with published data showing that the expected 
failure rate is <1% per year (not all IUDs meet this criterion; see the SPM for 
an example listing of approved IUDs);

Male partner sterilization prior to the female subject’s entry into the study 
and this male is the sole partner for that subject;

Any other method with published data showing that the expected failure rate 
is <1% per year.
Any contraception method must be used consistently, in accordance with the 
approved product label and for at least 2 weeks after discontinuation of study drug. A 
childbearing potential female subject who starts the study using complete abstinence 
as her contraceptive method and decides to become sexually active must use the 
double barrier method either as a bridge to an approved hormonal contraception (if 
possible) or as a method of choice to be maintained from that moment onwards.
All subjects participating in the study should be counseled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/ spermicide).
7.
New diagnosis of pulmonary, pleural, or LN tuberculosis based on identification of 
Mycobacterium tuberculosis using culture methods or GeneXpert (or other approved 
molecular test) on sputum or on samples collected by needle aspirate of pleural fluid 
or an affected LN; 
8.
RIF sensitivity of Mycobacterium tuberculosis either by culture or Gene Xpert (or 
other approved nucleic acid amplification test);
9.
RIF-containing first-line TB treatment or an alternate RIF-containing TB treatment 
as described in Section 11.6 started up to a maximum of 8 weeks before 
randomization and no later than the screening date;
10. Karnofsky score 70% before randomization (see Section 11.7).
 
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4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary Medical Conditions
1.
Any previous TB treatment (not including treatment for latent disease);
2.
Evidence of RIF resistance of Mycobacterium tuberculosis either by culture or Gene 
Xpert (or other validated nucleic acid amplification test);
3.
Expected requirement for TB treatment >9 months;
4.
Concomitant disorders or conditions for which isoniazid, RIF, pyrazinamide, or 
ethambutol are contraindicated;
5.
Central nervous system, miliary, or pericardial TB;
6.
Women who are pregnant or breastfeeding; 
7.
Any evidence of an active AIDS-defining disease (CDC Category C; see 
Section 11.2). Exceptions include TB, cutaneous Kaposi’s sarcoma not requiring 
systemic therapy, and historic CD4+ cell counts of <200 cells/mm3;
8.
Subjects with moderate to severe hepatic impairment (Class B or C) as determined 
by Child-Pugh classification (see Section 11.8); unstable liver disease (as defined by 
the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, 
esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
9.
Subjects positive for hepatitis B surface antigen (HBsAg) at screening;
10. Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase 
of the study;
11. History or presence of allergy or intolerance to the study drugs or their components 
or drugs of their class;
12. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial 
neoplasia; other localized malignancies require agreement between the investigator 
and the study medical monitor for inclusion of the subject;
13. Subjects who, in the investigator’s judgment, pose a significant suicidality risk. 
Recent history of suicidal behavior and/or suicidal ideation may be considered as 
evidence of serious suicide risk.
Exclusionary Treatments Prior to Screening or Day 1
14. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening;
 
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15. Treatment with any of the following agents within 28 days of Screening: radiation 
therapy, cytotoxic chemotherapeutic agents, any immunomodulators that alter 
immune response;
16. Treatment with any agent, other than licensed ART as allowed above (Section 4.2, 
inclusion criterion 5), with documented activity against HIV-1 in vitro/vivo within 
28 days of first dose of the investigational product (IP);
17. 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 IP;
Exclusionary Laboratory Values or Clinical Assessments at Screening
18. Any evidence of primary viral resistance to NRTIs, NNRTIs, or PIs based on the 
presence of any major resistance-associated mutation [IAS USA, 2013] in the 
Screening result or, if known, any historical resistance test result. Note: Retests of 
Screening genotypes are not allowed;
19. Any verified Grade 4 laboratory abnormality with the exception of Grade 4 
triglycerides.  A single repeat test is allowed during the Screening period to verify a 
result; 
20. Any acute laboratory abnormality at Screening, which, in the opinion of the 
investigator, would preclude the subject’s participation in the study of an 
investigational compound;
21. Alanine aminotransferase (ALT) 2 × upper limit of normal (ULN);
22. Hemoglobin 7.4 g/dL;
23. Platelet count <50,000/mm3.
Notwithstanding these minimum inclusion and exclusion criteria, investigators must 
also follow country-specific guidelines where they exist when making decisions 
about subjects who are eligible for study participation.
4.4.
Other Eligibility Criteria Considerations
To assess any potential impact on subject eligibility with regard to safety, the investigator 
must refer to the IB and supplements, approved product labels, and/or local prescribing 
information for detailed information regarding warnings, precautions, contraindications, 
AEs, drug interactions, and other significant data pertaining to the IP, background NRTIs, 
and TB treatment.
 
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4.5.
Withdrawal Criteria
A subject may voluntarily discontinue participation in this study at any time. The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time. Withdrawn subjects will not be replaced.
Subjects permanently discontinuing study treatments prior to Week 52 are considered to 
be withdrawn from the study treatments and also from the study. Similarly, subjects in 
the DTG arm who enter the DTG OLE but permanently discontinue participation prior to 
commercial supplies of DTG becoming locally available (e.g., through public health 
services) are considered to be withdrawn from study treatment as well as from the study.
Subjects may be prematurely discontinued from the study for any of the following 
reasons:

Subject or investigator non-compliance;

At the request of the subject, investigator, or sponsor;

The subject requires concurrent prohibited medications during the course of the 
study. However, the subject 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 subject.
Subjects must be prematurely discontinued from the study for any of the following 
reasons:

Confirmed virologic withdrawal criteria as specified in Section 4.6.1.

Subject requires changes (i.e., substitution or dose modification) of DTG or EFV. 
Permitted NRTI substitutions due to toxicity management are discussed in 
Section 5.1.5.

Subject requires a TB treatment regimen that does not contain RIF.

Subject requires interruption to RIF-containing regimens for longer than 14 days and 
is not on a bridging regimen. Permitted RIF-containing regimens are described in 
Section 11.6. Suitable bridging regimens are described in Section 6.4.3.1.1.

Liver toxicity where stopping criteria specified in Section 6.4.3.1 are met and no 
compelling alternate cause is identified;

Grade 4 clinical AE considered causally related to study drug or any component of 
TB treatment;

Renal stopping criteria as described in Section 6.4.3.4 are met and no compelling 
alternate cause is identified;

Hypersensitivity and rash criteria as described in Section 6.4.3.5 and Section 6.4.3.8, 
respectively are met and no compelling alternate cause is identified;

Petechial rash due to RIF-induced thrombocytopenia as described in Section 6.4.3.9

Pregnancy (intrauterine), regardless of termination status of pregnancy.
 
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If a subject is withdrawn from the study, the protocol-defined assessments (if withdrawn 
at a routine study visit), the Withdrawal visit assessments, and if necessary the Follow-up 
visit assessments described in the Time and Events Table (Table 2) should be performed. 
All data from the Withdrawal visit will be recorded, as they comprise an essential 
evaluation that should be done prior to discharging any subject from the study. A 
Follow-up visit may occur approximately 4 weeks after the last dose of study treatment 
and is only required in subjects with ongoing serious AEs (SAEs) or non-serious 
laboratory or clinical AEs at the time of withdrawal.
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study based 
on previous non-compliance. In cases where the subject does not return for the 
rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (e.g., telephone calls and if necessary 
a certified letter to the subject’s last known mailing address) so that they can 
appropriately be withdrawn from the study. These contact attempts should be 
documented in the subject’s medical record. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the 
study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing 
from the study, an alternative reason for discontinuation should be recorded in the 
electronic case report form (eCRF).
Subjects are not obligated to state the reason for withdrawal. However, the reasons for 
withdrawal, or failure to provide a reason, must be documented by the investigator on the 
Completion/Withdrawal section of the eCRF. Every effort should be made by the 
investigator to follow-up with subjects who withdraw from the study. In the event that a 
subject is prematurely discontinued from the study at any time due to an AE (see 
Section 6.4.4.1), the procedures stated in the Time and Events Table (Table 2) must be 
followed. Subjects who are withdrawn from the study will not be replaced.
Subjects may have a temporary interruption to their study treatment for management of 
toxicities.
4.6.
Virologic Criteria for Subject Management and Viral 
Resistance Testing
Subjects with plasma HIV-1 RNA levels 50 c/mL at Week 24 or beyond must have 
HIV-1 levels re-assessed using the algorithms in Figure 2 and Figure 3, which detail 
virologic criteria for clinical management of subjects who either require more careful 
monitoring (e.g., meet “4-6 week plasma HIV-1 RNA testing criterion”) or have met a 
“suspected or confirmed virologic withdrawal criterion.” Investigators should not 
schedule re-assessment blood draws to take place in the presence of factors that could be 
associated with HIV-1 RNA levels 50 c/mL, such as intercurrent acute infection, 
treatment interruption due to toxicity management or non-compliance, or vaccination. 
Subjects should have received full doses of IP for at least 2 weeks at the time of HIV-1 
RNA re-assessment for any HIV-1 RNA level 50 c/mL.
 
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If a subject meets the confirmed virologic withdrawal criteria, the plasma ‘for storage 
sample’ from the “suspected virologic withdrawal criterion” visit and the Day 1 sample 
will be used for HIV-1 genotype/phenotype testing. Subjects may continue to receive IP 
at the discretion of the investigator until results of resistance testing are available, at 
which time the subject must be discontinued from the study. If a subject is prematurely 
discontinued from the study, the investigator must make every effort to perform the 
evaluations outlined in the Time and Events Table (Section 6.1). These data will be 
recorded as they comprise essential evaluations needed to be done before discharging any 
subject from the study.
Note: Plasma samples with <400 c/mL of HIV-1 RNA will not be analyzed for viral 
resistance, as the protease/reverse transcriptase/integrase assays used in this study are not 
validated for plasma HIV-1 RNA levels <400 c/mL.
 
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Figure 2
Virologic Criteria for Subject Management at Week 24
Week 24 Visit
HIV-1 RNA is <50 c/mL
HIV-1 RNA is 50 c/mL but <400 c/mL
HIV-1 RNA is 400 c/mL
Maintain scheduled visit at 
Week 36
Perform an unscheduled visit in approximately 2 to 4 
weeks to reassess plasma HIV-1 RNA
Proceed to Figure 3
Perform an unscheduled visit in approximately 
2 to 4 weeks to reassess plasma HIV-1 RNA
Subject has met “Suspected Virologic 
Withdrawal Criterion”
Proceed to Figure 3
Figure 3
Virologic Criteria for Subject Management After Week 24
Any Visit (scheduled or unscheduled) After Week 24
Current plasma HIV-1 RNA <50 c/mL
Current plasma HIV-1 RNA 
50 c/mL but<400 c/mL 
Current plasma HIV-1 RNA 400 c/mL
Regardless of previous plasma HIV-1 
RNA result, proceed to next scheduled 
visit per Time and Events Table 2
Regardless of previous plasma 
HIV-1 RNA result, perform an 
unscheduled visit in approximately 
4-6 weeks to reassess plasma
HIV-1 RNAa
Subject has met “4 to 6 Week 
Plasma HIV-1 RNA Testing 
Criterion”
If previous plasma HIV-1 RNA was 
<400 c/mL, perform a scheduled or 
an unscheduled visit in 
approximately 4-6 weeks to 
reassess plasma HIV-1 RNAa
Subject has met “Suspected 
Virologic Withdrawal Criterion”
If previous plasma HIV-1 RNA was 
400 c/mL, discontinue the subject 
from study once resistance test 
results are available
Subject has met “Confirmed 
Virologic Withdrawal Criterion”
a.
If current visit is the Week 48 scheduled visit then retest will occur at the Week 52 visit.
 
 
 
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4.6.1.
Management of Subjects Meeting Suspected Virologic 
Withdrawal Criteria
Only plasma HIV-1 RNA levels determined by the central laboratory (or a laboratory 
contracted by the central laboratory) will be used to assess virologic withdrawal criteria. 
Upon notification that a subject’s plasma HIV-1 RNA level qualifies as meeting a 
suspected virologic withdrawal criterion, the investigator should query the subject 
regarding intercurrent illness, recent immunization, or interruption of therapy as 
inadequate adherence is a common cause of elevated HIV-1 RNA measurements.
All cases that meet a suspected virologic withdrawal criterion must be confirmed by 
a second measurement performed 4 to 6 weeks apart from the date of the original 
sample, unless one of the extenuating circumstances outlined below applies.
The following guidelines will be followed for scheduling confirmatory HIV-1 RNA 
testing in an effort to avoid false-positive results:

Confirmatory testing should be scheduled 2 to 4 weeks following resolution of any 
intercurrent illness, during which time the subject should receive full dose of all IP.

Confirmatory testing should be scheduled at least 4 weeks following any 
immunization, during which time the subject should receive full dose of IP.

If therapy is interrupted due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2 to 4 weeks following resumption 
of full dose of IP.  

The subject should have received full doses of IP for at least 2 weeks at the time 
confirmatory plasma HIV-1 RNA testing is done.
Sites should contact GSK to discuss individual subjects, whenever necessary.
At Week 48, repeat HIV-1 RNA testing is required for any HIV-1 RNA 50 c/mL and 
must be performed at the Week 52 study visit (Section 4.7).
4.7.
Retest Criteria for Subjects With Plasma HIV-1 RNA Levels 
50 c/mL at Week 48
Subjects with plasma HIV-1 RNA levels 50 c/mL at Week 48 must have HIV-1 levels 
re-assessed by a second measurement performed at the Week 52 visit. Subjects should 
have received full doses of IP for at least 2 weeks at the time of HIV-1 RNA 
re-assessment for any HIV-1 RNA level 50 c/mL.
Subjects with plasma HIV-1 RNA levels ≥400 c/mL should have a second measurement 
performed as outlined in Section 4.6.1.
 
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4.8.
Protocol-Defined Failure of TB Treatment
Tuberculosis treatment failure is defined by WHO [WHO 2010] as patients whose 
sputum smear or culture is positive at 5 months or later during treatment. Also included 
in this definition are patients found to harbour a multidrug-resistant strain at any point of 
time during the treatment, whether they are smear-negative or smear-positive.
Subjects with suspected TB treatment failure should be evaluated with a history, physical 
examination, sputum smear and culture with drug-susceptibility testing, and chest 
radiograph (TB treating physicians caring for the subject and local investigators should 
also use clinical judgment to determine if other evaluations are required) to determine 
whether they have clinically responded to therapy, even though their cultures have not
converted or were not tested. The initial culture results and drug-resistance tests, 
treatment regimen, and adherence also should be reviewed. Samples from all available 
sites should be taken for repeat culture and drug-susceptibility testing, and strong 
consideration should be given to performing rapid resistance testing on direct specimens 
or positive cultures to identify acquired drug resistance or superinfection with a drug-
resistant strain. If the results of repeat cultures and rapid resistance testing confirm, in 
consultation with an expert in the field, that the subject will require broadening of TB 
treatment by switching to a second-line TB treatment regimen without RIF then the 
subject must be withdrawn from the study.
4.9.
Screening Failures
A subject is considered a screen failure if after providing informed consent, the subject’s 
circumstances or conditions change or the outcome of a test or assessment becomes 
available which results in the subject’s failure to meet one or more of the entry criteria, or 
results in the investigator deciding that the subject is no longer an appropriate study 
candidate.
Subjects who meet all entry criteria are randomized and assigned a randomization 
number. Subjects not meeting all inclusion and exclusion criteria at the initial screen may 
be rescreened only once and the subject will receive a new subject number at that time. 
With the exception of disqualifying viral genotype or TB culture or nucleic-acid–based 
RIF-susceptibility results indicating RIF resistance, a single repeat test (retest) per analyte 
or assessment is allowed during the Screening Period to determine eligibility. Subjects 
who are randomized into the study and subsequently withdrawn from the study for any 
reason may not be rescreened.
Except for results to confirm MTB which are analyzed locally, laboratory results from the 
central laboratory services provided by this study will be used to assess eligibility. 
 
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5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Investigational product in this protocol refers to the investigational drugs DTG and the 
active control EFV. These will be supplied by GSK. For the purpose of this protocol, 
other ARTs administered in the study are not considered IP and will not be supplied by 
GSK. These will be sourced as local commercial material. Investigators will select a dual 
NRTI background for each subject. Tuberculosis drugs are also not considered IP and 
will be provided by the local TB program in accordance with national and local 
guidelines.
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of the IP will be limited to the 
investigator and authorized site staff. Investigational product must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
Adequate precautions must be taken to avoid direct contact with the investigational 
product which should be used in accordance with the manufacturer’s instructions detailed 
in the prescribing information.
5.1.1.
Tablet Formulation of DTG
DTG tablets are packaged as a full count of 30 film-coated tablets in a 45 cc high density 
polyethylene (HDPE) bottles with induction seal and child-resistant 33 mm closure. 
Tablets must be stored in the original package with the bottle tightly closed. The bottles 
contain a desiccant that must be kept in the bottle to protect tablets from moisture. The 
recommended storage conditions and expiry date where required, are stated on the 
product label.
Subjects must keep all IP in its original pack container. GSK will notify sites if and when 
data are available to support the use of pill boxes.
5.1.2.
Tablet Formulation of EFV
EFV [Sustiva (efavirenz) US Product Information, 2013; Sustiva Summary of Product 
Information, 2014] is supplied as the EFV oral tablet, which contains 600 mg of EFV. 
EFV tablets, as manufactured by Bristol Myers Squibb, are yellow film-coated capsule-
shaped tablets printed with “SUSTIVA” on both sides. Each pack/bottle will contain 
30 film-coated tablets.
 
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5.1.3.
Background NRTIs
The investigator-selected dual NRTI background regimen must be determined and 
documented prior to randomization. 
All background NRTIs are locally registered products. GSK will not reimburse or supply 
the investigator-selected background regimen unless required by the local regulatory 
authority or Institutional Review Board/Independent Ethics Committee (IRB/IEC) or 
unless previously agreed with study sites.
Those subjects for whom abacavir (ABC) is being considered as a component of the 
NRTI backbone should have been screened and be negative for the human leukocyte 
antigen (HLA)-B*5701 allele before randomization takes place. This testing may be 
conducted as part of the study or may be performed by local laboratories. Results must be 
available for source document verification.
5.1.4.
Dosage and Administration
IP and background NRTI Dose and Dose Interval
Treatment Arm 1
GSK1349572 
(dolutegravir, DTG)
Twice-daily DTG 50 mg plus dual NRTI during TB treatment and for 2 weeksa following 
discontinuation of TB treatment, then once-daily DTG 50 mg with the same NRTI 
backbone through Week 52 and continued during the DTG OLE until DTG is locally 
approved and commercially available
Treatment Arm 2
Efavirenz (EFV) 
Once-daily EFV 600 mg plus dual NRTI through Week 52
Note: TB treatment including isoniazid, RIF, pyrazinamide, and ethambutol will be provided at standard doses by the 
NTP under program conditions.
a.
Delays in switching from DTG twice daily to DTG once daily will not be considered an overdose.
DTG may be administered with or without food. EFV must be administered without food. 
For the dual NRTIs refer to the appropriate NRTI product information for treatment 
administration.
5.1.5.
Protocol-Permitted Substitutions
A substitution of or switch between DTG or EFV is not allowed.
After consultation with the study medical monitor, switch of background NRTI therapy 
to an alternate approved NRTI therapy for toxicity or tolerability management is allowed 
one time. Switches of a background NRTI for any reason other than toxicity or 
tolerability management are not permitted in the study. The date of the decision to switch 
background NRTI for toxicity or tolerability management must be documented in the 
eCRF. 
Note: Protocol-permitted substitutions (as described above), will not be coded as failures 
in this study regardless of the subject’s HIV-1 RNA results at the time of the 
protocol-permitted substitution (Section 8.2.4).
Further information regarding alternate RIF-containing TB treatment regimens are 
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5.2.
Treatment Assignment
Informed consent must be obtained prior to any study procedures, including any 
screening assessment.
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. Randomization will be conducted using a central randomization procedure 
following confirmation of fulfillment of study entry criteria. Subjects will be assigned 
(3:2 ratio to DTG or EFV-containing regimens, respectively) to study treatment in 
accordance with the computer-generated randomization schedule. The central 
randomization schedule will be generated by biostatistics using a validated SAS 
developed program. The stratification will be generated using an interactive voice 
response system (IVRS). Study site personnel will be required to contact the central 
randomization service for assignment of a unique identifier (designating the subject’s 
randomization code) for each subject participating in the study. A unique treatment 
number will be assigned for each subject participating in the study. 
Subjects who are randomly assigned into the study and subsequently withdrawn may not 
be rescreened. 
5.3.
Blinding
This will be an open-label study.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of study 
drug dispensed and/or administered to study subjects, the amount returned by study 
subjects, and the amount received from and returned to PPD, when applicable. Product 
accountability records must be maintained throughout the course of the study.
5.5.
Treatment Compliance
Treatment adherence will be evaluated using pill counts of unused study drug (DTG and 
EFV). This assessment will be conducted each time the subject receives a new (refill) 
supply of study drug through the Withdrawal visit or study completion. These data will 
be recorded in the subject’s eCRF but will not be summarized for analysis purposes.
Data on start and end dates for TB treatment or ART including periods of interruptions (if 
applicable) will be documented.
5.6.
Concomitant Medications and Non-Drug Therapies
Subjects should be advised to notify their investigator of any current or proposed 
concomitant medication, whether prescribed or over-the-counter, because of the potential 
drug-drug interactions between such treatments and the study drugs. All concomitant 
medications taken during the study will be recorded in the eCRF. The minimum 
requirement is that the drug name and the dates of administration are to be recorded.
 
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5.6.1.
Permitted Medications and Non-Drug Therapies
Concomitant medications (prescription and non-prescription) should be administered 
only as medically necessary during the study (except prohibited medications described in 
Section 5.6.2). Chemoprophylaxis for HIV-associated conditions is encouraged, if 
appropriate, at the discretion of the subject and their physician. All concomitant 
medications, blood products, and vaccines taken during the study will be recorded in the 
eCRF with dates of administration.
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma 
RNA, it is recommended that a vaccine, if necessary, be given during or immediately 
after a scheduled visit after all laboratory tests have been drawn and only once scheduled 
visits are ≥4 weeks apart. This approach will minimize the risk of nonspecific increases 
in the level of HIV-1 plasma RNA at the next scheduled assessment.
Daily doses of RIF should be given at least 1 hour before the ingestion of antacids. 
DTG should be administered 2 hours before or 6 hours after taking antacid products or 
sucralfate containing divalent cations (e.g., aluminum and magnesium) or calcium or iron 
supplements; alternatively, DTG can be taken together with calcium or iron supplement 
with a meal. Proton pump inhibitors and H2-antagonists may be used in place of antacids 
with no scheduling restrictions. Concurrent administration of DTG with multivitamins is 
acceptable.
Metformin concentrations may be increased by DTG. Subjects taking DTG should be 
monitored for glucose control during therapy and a metformin dose adjustment may be 
required.
5.6.2.
Prohibited Medications and Non-Drug Therapies
The following concomitant medications or therapies are not permitted at any time during 
the study:

HIV immunotherapeutic vaccines (see Section 5.6.1 for guidance regarding non-HIV 
vaccines)

Other experimental agents, antiretroviral drugs not otherwise specified in the 
protocol, cytotoxic chemotherapy, or radiation therapy (see Exclusion Criteria, 
Section 4.3)

Systemically administered immunomodulators (such as interleukin and interferon 
agents) are prohibited through the Randomized Phase (Day 1 to Week 48 plus a 
4-week treatment extension) of the study. This includes topical agents with 
substantial systemic exposure and systemic effects. After the Randomized Phase 
(Day 1 to Week 48 plus a 4-week treatment extension), immunomodulators may be 
administered after discussion and agreement with the study medical monitor

HCV therapy during the study is prohibited

Chronic use of systemic (oral or parenteral) glucocorticoids should be avoided; 
however, short treatment courses of 30 days or less (e.g., for treatment of IRIS), 
replacement therapy (e.g., for Addison’s Disease), and topical, inhaled, or intranasal 
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5.6.3.
Prohibited Medications for Subjects Randomly Assigned to DTG
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

St. John’s wort (Hypericum perforatum)
Dofetilide and pilsicainide are prohibited as DTG may inhibit renal tubular secretion 
resulting in increased dofetilide/pilsicainide concentrations and potential for toxicity.
For prohibited medications related to TB therapy components, please refer to the local 
prescribing information for information on concurrent therapies.
For a detailed list of prohibited medications, please consult the SPM.
5.6.4.
Prohibited Medications for Subjects Randomly Assigned to EFV
Efavirenz has the potential to impact the following drugs potentially requiring monitoring 
and dose adjustment:

HMG-CoA reductase inhibitors are prohibited due to potential for decreased plasma 
concentrations; dosage should be individualized based on the goal of therapy and 
response.

Methadone is prohibited due to potential for decreased plasma concentrations; 
subjects should be monitored for signs of withdrawal and methadone dose should be 
adjusted as appropriate

Warfarin is prohibited because warfarin concentrations may be increased or 
decreased; international normalized ratio (INR) should be monitored and dosage 
should be adjusted as appropriate
5.7.
Treatment After the End of the Study
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the subject’s medical condition whether or not ViiV/GSK is providing 
specific post-study treatment.
All subjects randomly assigned to receive DTG who have not prematurely discontinued 
from the study and who successfully complete 52 weeks of treatment will continue to 
have access to DTG (during the DTG OLE) until it is either locally approved and 
commercially available, the subject no longer derives clinical benefit, or the subject 
meets a protocol-defined reason for discontinuation. Investigative sites must make 
arrangements for provision of background NRTIs to all subjects to ensure continued 
 
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access to these medications during the DTG OLE (unless provision by the sponsor is 
mandated by local regulation).
Subjects randomized to the EFV arm will receive EFV through their Week 52 visit only, 
after which subjects will complete the study and will need to have alternate arrangements 
in place to access EFV and NRTIs (unless mandated by local regulation).
5.8.
Treatment of Study Treatment Overdose
For this open-label study, any tablet intake exceeding the recommended daily number of 
tablets for study drug will be considered an overdose.
For the purposes of this study, an overdose is not an AE (refer to Section 6.4.4.1) unless 
it is accompanied by a clinical manifestation associated with the overdose. If the clinical 
manifestation presents with serious criteria, the event is a serious AE (SAE) (see 
Section 6.4.4.2).
If an overdose occurs and is associated with an AE requiring action, all study drugs 
should be temporarily discontinued until the AE resolves. The investigator should use 
clinical judgment in treating overdose and also refer to the prescribing information for 
current ARTs, as ViiV/GSK is unable to recommend specific treatment.
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
6.1.
Time and Events Schedule
Table 2
Time and Events Table
Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
Clinical and other assessments
Written informed consent
X
Subject demography
X
Document pulmonary, 
pleural, or LN TB 
diagnosisd
X
Document pre-TB 
treatment MTB culture 
result (e.g., sputum, LN, 
or pleural aspirate)e
X
X
Document pre-TB 
treatment sputum smear 
results, if available
X
Perform GeneXpert or 
equivalent and/or 
Document GeneXpert or 
equivalent RIF-sensitive 
MTB
X
 
 
 
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Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
Document the subject is 
on a RIF-containing first-
line TB treatment and 
record TB regimen 
components
Xf
Record pre-specified TB 
regimen duration
X
Documentation of TB 
regimen start date
X
Inclusion/Exclusion 
criteriaf
X
X
Prior ART history
X
Medical historyg
X
CDC HIV-1 classification
X
X
Physical examinationh
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and height
X
Current medical 
conditions
X
Cardiovascular risk 
assessmenti
X
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
HIV associated 
conditions
X
X
X
X
X
X
X
X
X
Columbia Suicidality 
Severity Rating Scalej
Xj
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
SAEs
Xk
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
TB-associated IRIS 
assessmentl
X
X
X
Laboratory assessments
Quantitative plasma HIV-
1 RNA PCR
X
X
X
X
X
X
X
X
Xm
X
X
Lymphocyte subsets 
X
X
X
X
X
X
X
X
X
X
X
Plasma for storagen
X
X
X
X
X
X
X
X
X
X
X
Plasma for HIV 
genotyping
X
HLA-B* 5701 testingo
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucosep
X
X
X
Pregnancy testq
S
U
S
S
S
S
S
S
S
S
S
HBsAg and hepatitis C 
(anti-HCV Ab)
X
Pharmacogenetic 
sampler
X
Pharmacokinetic plasma 
samples
X
X
X
X
Dispense PK dosing 
diary card
X
X
X
X
Xt
 
 
 
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Procedures
Screeninga
Randomized Phase
DTG Open-Label 
Extensionb
Withdrawal
Follow-upc
Week
4-week 
Treatment 
Extension
DTG Dose Switch
(2 weeks post TB 
treatment 
completion) 
Day 
1
4
8
12
24
36
48
52
May occur any 
time after the 12 
week visit 
Week 60
and every 12 
weeks thereafter
Investigational product
IVRS
X
X
X
X
X
X
X
X
X
Xu
X
X
X
Dispense IP
X
X
X
X
X
X
X
Xv
X
Xv
IP accountability (pill 
counts)
X
X
X
X
X
X
X
X
X
X
ART = antiretroviral therapy; CDC = Centers for Disease Control; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV-1 = human immunodeficiency virus-1; 
HLA-B = human leukocyte antigen-B; INR = international normalized ratio; IP = investigational product; IVRS = interactive voice response system; LN = lymph node; MTB = 
Mycobacterium tuberculosis; PCR = polymerase chain reaction; PT = prothrombin time; RIF = rifampicin; RNA = ribonucleic acid; SAE = serious adverse event; TB = tuberculosis
a.
The 14-day Screening Period may be extended to 28 days. Randomization may occur as soon as all Screening results are available and up to 8 weeks after TB treatment 
initiation
b.
Subjects randomly assigned to the DTG arm and complete the Randomized Phase through the Week 52 visit will enter into the DTG OLE. Subjects completing the DTG OLE 
must return to the clinic when transitioning to commercial supplies for an end of OLE visit. Study assessments will be conducted as specified for the withdrawal visit.
c.
A Follow-up visit will be conducted 4 weeks after the last dose of study provided IP and is required only if a subject has ongoing AEs or laboratory abnormalities at the last on-
study visit. The assessments performed should reflect what is considered medically necessary to assess the event(s).
d.
Smear positive or culture positive, including sample source recorded in eCRF.
e.
Results may be documented any time between Screening and Day 1.
f.
Inclusion/exclusion criteria will be fully assessed at the Screening visit (to include Karnofsky assessment). Changes between the screening visit and the Day 1 visit should be 
assessed to ensure eligibility, including additional assessments performed at Day 1.
g.
Full medical history will be collected. Targeted medical history assessments will include cardiovascular, gastrointestinal (e.g., GI bleeding, PUD), metabolic (e.g., Type I or II 
DM), psychiatric (e.g. depression), renal (e.g. nephrolithiasis, nephropathy, renal failure) and neurological disorders. 
h.
Limited physical examination to include blood pressure at Baseline (recorded in eCRF) for Framingham score assessment. Blood pressure to be measured after resting in a 
semi-supine position for at least 5 minutes.
i.
Assessment for cardiovascular risk will include height, weight, blood pressure, smoking history, medical conditions, and family history of premature cardiovascular disease. 
j.
The Columbia-Suicidality Severity Rating Scale (subject completed questionnaire) is to be administered if a validated version in the appropriate language is available for the 
subject. The assessment will be performed only in countries where the validated questionnaire exists in the appropriate language. On Day 1, the questionnaire should be 
 
 
 
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completed prior to randomization. 
k.
Only SAEs related to study participation or to a concomitantly administered GSK/ViiV product will be collected between obtaining informed consent and administration of IP at 
Day 1.
l.
TB-associated IRIS criteria are described in Section 6.4.6; if any of the major and/or minor criteria are identified they will be captured and reported as AEs. Toxicity management 
related to TB-associated IRIS cases are described in Section 6.4.3.3.
m.
Quantitative plasma HIV-1 RNA are ONLY for subjects who had HIV-1 RNA >50 c/mL at the Week 48 visit. 
n.
Plasma samples for storage will be collected at each visit for possible future analyses (including but not limited to HIV-1 RNA genotypic and phenotypic analyses, 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. Plasma for storage 
sample should also be collected at the unscheduled visit for retesting suspected virologic withdrawal. Additionally, for genotypic and phenotypic resistance analyses baseline 
samples from all subjects will be used and later samples in cases of confirmed virologic withdrawal criteria met (for paired baseline and endpoint genotypes). 
o.
Subjects starting ABC as one of the NRTIs must have been screened and be negative for the HLA-B*5701 allele.
p.
An overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable.
q.
Pregnancy testing will be conducted (women of childbearing potential only) on serum samples with the exception of Day 1, which must be a urine test to confirm status prior to 
administration of IP.
r.
Informed consent for optional pharmacogenetics (PGx) research must be obtained before collecting a sample. Collection of the PGx sample at Day 1 is preferred; however, this 
sample may be collected at any time during the study.
s.
For subjects randomly assigned to EFV, mid-dosing interval samples will be collected at Weeks 8, 24, 36, and 48. For subjects randomly assigned to DTG, 1 sample each for 
pre-dose, 1 to 3 hours post-dose, 4 to 12 hours post-dose will be collected at Weeks 8 and 36, and 1 sample pre-dose will be collected at Weeks 24 and 48. If PK sampling is not 
performed the visit will be rescheduled to collect the PK sample and if applicable the subject will be provided a new diary card. Instructions on PK sample collection are 
described in Section 6.5.2. Blood samples should be collected into K2EDTA tubes.
t.
Collect DTG twice daily PK diary card and provide the subject with the DTG once daily PK diary card. 
u.
The IVRS will capture the point at which the subject is within 2 weeks of completing their TB treatment and the site will notify the subject to return to the clinic for the DTG switch 
visit in order to dispense the DTG 50 mg once daily dose.
v.
For subjects receiving DTG during the DTG OLE only.
 
 
 
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6.1.1.
TB Time and Events Schedule
Table 3
TB Time and Events Table
Procedures
TB Treatment Intensive Phase
TB Treatment Continuation Phase
Baseline
Month 2
Month 4
Month 6
Month 9
Laboratory assessments
Collection of sputum samples for 
MTB smear and culture testinga
X
X
X
X
X
TB regimen assessments
TB medicationsb
X
X
X
X
X
TB treatment interruptionsc
X
X
X
X
TB treatment re-introductiond
X
X
X
X
Document RIF-sensitivitye
X
X
X
X
X
MTB = Mycobacterium tuberculosis, TB = tuberculosis
a.
To be performed at the local laboratory. The laboratory and method for that subject should remain the same 
throughout the study. Results of testing will be recorded in the eCRF. Sputum does not need to be collected from 
subjects with pleural or lymph node TB who do not also have pulmonary TB. If subjects are no longer producing 
sputum at 4 months, 6 months, and 9 months and no sputum sample can therefore be collected, then this fact 
must be recorded in the eCRF. Subjects who complete their TB treatment at 6 months, do not require a sputum 
sample to be collected at 9 months, unless clinically indicated (investigator decision).
b.
Record all TB treatment medications taken during the intensive and continuation phases on the TB treatment 
medication eCRF.
c.
Any missed doses or changes to the regimen should be recorded on the TB treatment medication eCRF. If the TB 
regimen is interrupted for more than 14 days, the subject must be withdrawn from the study.
d.
Re-introduction guidelines are described in Section 6.4.3.1.1.
e.
Rifampicin susceptibility testing at baseline is mandatory. The investigator may repeat RIF susceptibility testing at 
other times, as clinically indicated. If at any time, an isolate is found to be RIF-resistant, then the subject must be 
withdrawn from the study.
6.2.
Critical Baseline Assessments
Written informed consent must be obtained from each potentially eligible subject (or 
his/her legal representative) 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/IEC. After signing an informed consent, subjects will complete 
Screening assessments to determine subject eligibility. Each subject being screened for 
study enrollment evaluation will be assigned a subject number at the Screening visit. This 
number will be given sequentially in chronological order of subject presentation 
according to a numeric roster provided by PPD.
6.2.1.
Screening Assessments
Assessments to be conducted at Screening are provided in the Time and Events schedule 
(Table 2). 
All subjects will complete the Screening Period approximately 14 days prior to Baseline 
(Day 1) during which time all clinical and laboratory assessments of eligibility must be 
performed and reviewed. The Screening Period may be extended to 28 days to 
 
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accommodate availability of all Screening assessment results and scheduling. All 
Screening results must be available prior to randomization. 
Eligibility criteria must be carefully assessed at the Screening visit. Physical 
examinations should be conducted as part of normal routine clinical care but will not be 
collected systematically in the eCRF. Smear-positive sample, site from which sample was 
obtained (e.g., sputum, LN, or pleural aspirate) and sputum smear grade result, culture 
date of collection and result (if available), results of Gene Xpert test, including RIF 
genotypic susceptibility testing will be recorded at the Screening visit. 
Subjects who meet all entry criteria are randomly assigned to treatment and assigned a 
randomization number. Subjects not meeting all inclusion and exclusion criteria at the 
initial screen may be rescreened only once and the subject will receive a new subject 
number at that time. With the exception of a disqualifying viral genotype or 
documentation of RIF resistance, a single repeat test (re-test) per analyte or assessment is 
allowed during the Screening Period to determine eligibility. Subjects who are 
randomized into the study and subsequently withdrawn from the study for any reason 
may not be rescreened.
Note: Where HLA-B*5701 screening is considered standard of care, it is recommended 
that investigators screen for presence of the HLA-B*5701 allele in any subject for whom 
an ABC-containing product (e.g., ZIAGEN™, EPZICOM™, KIVEXA™) may be 
considered as part of background regimen and HLA-B*5701 status is unknown (even if 
the subject has previously tolerated ABC). Use of ABC in subjects known to carry 
HLA-B*5701 is not recommended and should be considered only under exceptional 
circumstances where potential benefit outweighs the risk and only under close medical 
supervision.
6.2.2.
Baseline Assessments (Day 1)
Assessments to be conducted at Baseline (Day 1) are provided in the Time and Events 
schedule (Table 2).
At Day 1 and prior to randomization, any changes to the eligibility parameters must be 
assessed and any results required prior to randomization (e.g., Day 1 urine pregnancy test 
for women of childbearing potential) must be available and reviewed.
Cardiovascular risk factors will be assessed at Baseline and assessments will include 
smoking status and history and family history of cardiac events. 
For subjects who agree to the optional assessment, a whole blood sample for 
pharmacogenetic (PGx) research should be collected at Day 1; however this sample may 
be collected at any time during the study (see Section 11.1).
 
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6.3.
Efficacy
6.3.1.
Efficacy Evaluations
Plasma HIV-1 RNA
Plasma for quantitative HIV-1 RNA will be collected according to the Time and Events 
Table (Table 2). Methods to be used may include but are not limited to the Abbott 
Realtime HIV-1 Assay with lower limit of detection (LLOD) 40 c/mL. In some cases 
(e.g., where the HIV-1 RNA is below the LLOD for a given assay) additional exploratory 
methods may be used to further characterize plasma HIV-1 RNA levels.
Lymphocyte Subsets
Blood samples will be collected for assessment of lymphocyte subsets by flow cytometry 
(total lymphocyte counts, percentage, and absolute CD4+ lymphocyte counts) according 
to the Time and Events Table (Table 2).
Sputum MTB Cultures 
Sputum samples will be collected for assessment of positive TB cultures according to the 
TB Time and Events Table (Table 3). TB cultures are to be performed locally and results 
will be collected in the eCRF.
CDC HIV-1 Classification and HIV Associated Conditions
HIV-associated conditions will be recorded as per the Time and Events Table (Table 2). 
HIV associated conditions will be assessed according to the 1993 CDC Revised 
Classification System for HIV Infection in Adults (see Section 11.2). Indicators of 
clinical disease progression are defined as:
CDC Category A at enrollment→ Category B event;
CDC Category A at enrollment→ Category C event;
CDC Category B at enrollment→ Category C event;
CDC Category C at enrollment→ New Category C Event;
CDC Category A, B or C at enrollment→ Death
6.3.2.
Primary Efficacy Endpoint
The primary endpoint will be the proportion of subjects with plasma HIV-1 RNA 
<50 c/mL at Week 48 using the Snapshot algorithm for the ITT-E population in the DTG 
arm. This endpoint will also be evaluated in the modified ITT-E (MITT-E) population.
 
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6.3.3.
Secondary Efficacy Endpoints

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm in the EFV arm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 48, 
where failure equals treatment-related discontinuation (meeting confirmed virologic 
withdrawal criteria, treatment-related AE, safety stopping criteria, or lack of 
efficacy);

Changes from baseline in CD4+ counts at Week 24 and Week 48.
6.3.4.
Tertiary Efficacy Endpoints

Incidence of disease progression (HIV-associated conditions, new AIDS diagnoses 
and death);

Proportion of subjects with TB treatment success (using the WHO definition, to be 
detailed in the reporting and analysis plan [RAP]);

Proportion of subjects with pulmonary MTB who are sputum culture-negative 
2 months after starting TB treatment.
6.4.
Safety
Safety assessments will be conducted according to the Time and Events Table (Table 2) 
and will include the following:

Monitoring and recording all AEs and SAEs. Additional information on the time 
period and frequency of detecting AEs and SAEs is provided in Section 6.4.12; 

Regular monitoring of hematology and blood chemistry parameters;

Periodic assessment of fasting lipids and glucose;

Physical examinations should be conducted as part of normal routine clinical care 
but will not be entered systematically in the eCRF. Abnormalities noted during any 
examination must be recorded in the eCRF (e.g., in the current medical conditions or 
AE logs);

Evaluation and documentation of all concomitant medications and blood products 
received;

Suicidality monitoring using the Columbia-Suicide Severity Rating Scale (C-SSRS; 
Section 6.4.10).
Any appropriately qualified site personnel (e.g., investigator, sub-investigator, or study 
coordinator/nurse) can perform assessments. With the exception of TB culture, a central 
laboratory chosen by GSK/ViiV will undertake all routine scheduled laboratory 
evaluations within the study. Refer to the central laboratory manual for specific 
instructions on sample collection, processing, storage and shipping for each laboratory 
test.
 
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Table 4
Laboratory Assessments
Hematology
Platelet count 
Automated WBC differential:
RBC count
Neutrophils
WBC count (absolute) 
Lymphocytes
Hemoglobin
Monocytes
Hematocrit
Eosinophils
MCV
Basophils
Clinical Chemistry
BUN
Potassium
AST 
Total bilirubina
Creatinine
Chloride
ALT 
Albumin 
Glucoseb
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
Creatininec
PT/INRd
Fasting Lipid Panele
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
Other Tests
Plasma HIV-1 RNA
CD4+ cell counts
Hepatitis B (HBsAg) and hepatitis C (anti-HCV Ab)d
Pregnancy test for women of childbearing potentialf
HLA-B*5701 screeningd
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; HDL = high density 
lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; MCV = mean corpuscular volume; 
PT = prothrombin time; RBC = red blood cells; WBC = white blood cells.
a.
Direct bilirubin will be reflexively performed for all total bilirubin values >1.5 × ULN.
b.
Fasting glucose will be collected at Day 1 and Weeks, 24, and 48 during the study. For fasting glucose 
assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable for subjects with 
afternoon appointments.
c.
Glomerular filtration rate (GFR) will be estimated by the central laboratory using the CKD-EPI formula using serum 
creatinine [Inker, 2012].
d.
Screening visit only
e.
For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast is acceptable 
for subjects with afternoon appointments.
f.
Urine pregnancy test and serum pregnancy test will be performed according to Table 2.
6.4.1.
Safety Endpoints

Incidence and severity of all AEs, SAEs, and laboratory abnormalities; 

Proportion of subjects who permanently discontinue IP or TB treatment due to AEs 
or death;

Proportion of subjects who temporarily discontinue IP and/or TB therapy due to 
AEs;

Proportion of subjects with TB-associated IRIS 
Note: the clinical team will review the AE terms and HIV conditions in order to 
identify TB-associated IRIS cases. TB-associated IRIS criteria are described in 
Section 6.4.6 and toxicity management for TB-associated IRIS cases are described in 
Section 6.4.3.3.
 
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6.4.2.
Toxicity Management
Adverse events that occur during the study should be evaluated by the investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (see Section 11.3). 
Additional information regarding detecting, documenting, and reporting AEs and SAEs 
are available in Section 6.4.3.9.
Investigational product may be interrupted at the discretion of the investigator and 
according to the severity of the AE. If one or more antiretroviral drugs are held due to 
toxicity or AEs, generally, all antiretroviral drugs should be held to reduce the risk of 
development of resistance taking into account the length of the planned interruptions and 
the PK half-life of each antiretroviral drug of the regimen. In some cases (e.g., EFV), 
short continuation of the dual NRTI components of the regimen after interruption of the 
third antiretroviral drug may be appropriate in order to minimize the risk of development 
of resistance.
No toxicity-related dose reductions of IP will be allowed. Investigational product 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 IP or temporary interruption of one or more but not all drugs 
within the ART regimen 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 subject management and IP interruptions based on the severity of the 
AE; for specific toxicities, please refer to Section 6.4.3. All changes in IP must be 
accurately recorded in the subject’s eCRF.
When possible, concomitant medications (like TB treatment components) should be held 
first at the discretion of the principal investigator if he/she suspects they are contributing 
to the toxicity
Toxicities That the Investigator Considers Related or Possibly Related to TB 
Treatment
Toxicities that the investigator considers related or possibly related to TB treatment 
should be managed with reference to applicable product labeling and local guidelines.
Note: In instances where both IP and TB treatments are interrupted due to either a clinical 
or laboratory toxicity, and it is decided to re-introduce these agents e.g., upon event 
improvement or resolution (following consultation with the medical monitor for Grade 3 
toxicities), the TB treatment should be restarted first according to Section 11.6, followed 
by trimethoprim-sulfamethoxazole (TMP-SMX), and then ART.
Toxicities That the Investigator Considers Related or Possibly Related to one or 
More NRTIs
Toxicities that the investigator considers related or possibly related to one of the 
background NRTIs may be addressed by substitution of the medication for another 
approved NRTI one time during the study (Section 5.1.5). In addition, toxicities that the 
 
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investigator considers related or possibly related to any NRTI should be managed with 
reference to applicable product labeling.
Note: For subjects receiving an ABC-containing product as part of the background 
regimen, in the event of a discontinuation of ABC for any reason, reinitiation of this drug 
should be undertaken with caution. The investigator should obtain a complete history of 
the events surrounding the discontinuation of the ABC-containing product, evaluate for 
the possibility of a clinically suspected hypersensitivity reaction (HSR), and initiate 
subject management as outlined in the local country prescribing information, regardless 
of a subject’s HLA-B*5701 status. Screening for the presence of HLA-B*5701 is 
recommended prior to reinitiating treatment with ABC-containing products in subjects of 
unknown HLA-B*5701 status who have previously tolerated ABC.
Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the 
discretion of the investigator. For exceptions to this guideline see Section 6.4.3. 
Subjects who voluntarily decide to terminate their participation in the study due to a 
Grade 1 or 2 AE should complete the Withdrawal and Follow-up visit.
Grade 3 Toxicity/Adverse Event
Subjects who develop a Grade 3 AE or Grade 3 toxicity should be managed as follows: 
If the investigator has compelling evidence that the Grade 3 AE or toxicity has not been 
caused by IP, dosing may continue after discussion with the medical monitor.
Subjects who develop a Grade 3 AE or toxicity that the investigator considers related or 
possibly related to the IP should have the IP withheld and be rechecked each week until 
the AE returns to Grade 2. Once the AE is Grade ≤2, IP may be restarted.
Should the same Grade 3 AE recur within 28 days in the same subject, the IP should be 
permanently discontinued and the subject withdrawn from study. Subjects experiencing 
Grade 3 AEs requiring permanent discontinuation of IP should be followed weekly until 
resolution of the AE and encouraged to complete the Withdrawal visit. A Follow-up visit 
should be performed 4 weeks after the last dose of IP.
Subjects with Grade 3 asymptomatic laboratory abnormalities should be investigated for 
all potential non-drug-related causes, and, following discussion with the medical monitor, 
may continue IP if the investigator has compelling evidence that the toxicity is not related 
to IP.
Exceptions are noted for lipid abnormalities in Section 6.4.3.6.
 
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Grade 4 Toxicity/Adverse Event
Subjects who develop a Grade 4 AE or toxicity should have IP permanently discontinued. 
However, if the investigator has compelling evidence that the AE is not causally related 
to the IP, dosing may continue after discussion with and assent from the medical monitor. 
Subjects should be rechecked each week until the AE returns to Grade 2.
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of IP should be 
followed weekly until resolution of the AE and are encouraged to complete the 
Withdrawal and Follow-up visit as noted above.
Subjects with Grade 4 asymptomatic 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 IP. Exceptions are noted for lipid abnormalities in Section 6.4.3.6. A Follow-up 
visit should be performed 4 weeks after the last dose of IP if AEs or laboratory 
abnormalities are ongoing.
6.4.3.
Specific Toxicity Management
General guidelines are described below for the management of specific toxicities that are 
considered to be related or possibly related to IP, background NRTIs, and TB treatment 
and include the following: 

Liver chemistry stopping and follow-up criteria (Section 6.4.3.1)

IRIS (Section 6.4.3.3)

Decline in renal function (Section 6.4.3.4)

Allergic reaction (Section 6.4.3.5)

Hypertriglyceridemia/hypercholesterolemia (Section 6.4.3.6)

Creatine phosphokinase (CPK) elevation (Section 6.4.3.7)

Rash (Section 6.4.3.8)

Petechial rash due to RIF-induced thrombocytopenia (Section 6.4.3.9)
Subjects who permanently discontinue IP for reasons of toxicity should be followed 
weekly until resolution or stabilization of the AE and encouraged to complete the 
withdrawal and Follow-Up study evaluations as noted above.
6.4.3.1.
Liver Chemistry Stopping and Follow-up Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of IP and the Follow-up period. 
If ALT >2 × ULN, liver chemistries should be monitored weekly for 2 weeks, then every 
2 weeks thereafter until normalized.
While receiving IP co-administered with TB treatment, both will be stopped if any of the 
following liver chemistry criteria are met:
 
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
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin; bilirubin 
fractionation required)

NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. If 
testing is unavailable and a subject meets the criterion of total bilirubin 2 × 
ULN, then the event meets liver stopping criteria;

ALT 3 × ULN with symptoms or worsening of acute hepatitis or hypersensitivity 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, 
rash, or eosinophilia, OR

ALT ≥5 × ULN; regardless of symptoms
After completion of TB treatment, while receiving IP, ART will be stopped if any of the 
following liver chemistry criteria are met:

ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin; bilirubin 
fractionation required)

NOTE: Serum bilirubin fractionation should be performed if testing is available. 
If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. If 
testing is unavailable and a subject meets the criterion of total bilirubin 
2 × ULN, then the event meets liver stopping criteria;

ALT 3 × ULN (if baseline ALT is <ULN) with symptoms or worsening of acute 
hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, or eosinophilia, OR

ALT 3 × baseline ALT with symptoms or worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia;

ALT 5 × ULN and <8 × ULN (after TB treatment is complete) that persists 
2 weeks (with bilirubin <2 × ULN and no signs or symptoms of acute hepatitis or 
hypersensitivity); ALT 5 × ULN but <8 × ULN (after TB treatment is complete) 
and cannot be monitored weekly for >2 weeks; and subjects who develop ALT 5 × 
ULN should be followed weekly until resolution or stabilization (ALT <5 × ULN on 
2 consecutive evaluations);

ALT > 8 × ULN; regardless of symptoms.
When liver chemistry stopping criteria are met, do the following:

Immediately hold IP;

According to guidelines, isoniazid, pyrazinamide, RIF, and TMP-SMX should be 
stopped simultaneously (when applicable) with the interruption of the ART;

Report the event to the medical monitor within 24 hours of learning its occurrence 
(see Table 7 and Section 6.4.14);
 
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
Complete the liver event and SAE eCRFs, where applicable, (see Section 6.4.14);

Complete the liver imaging, liver biopsy, or both eCRFs if these tests are performed;

Perform liver event follow-up assessments (described in this section), and monitor 
the subject until liver chemistries resolve, stabilize, or return to baseline values as 
described below;

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow-up assessments (described in this section), 
and close monitoring;

A specialist or hepatology consultation is recommended;

Monitor subjects twice weekly until liver chemistries (ALT, aspartate 
aminotransferase, and bilirubin) resolve, stabilize, or return to within baseline values;
Make every attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

HBsAg and hepatitis B core antibody (IgM);

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;

Blood sample for PK analysis, obtained within 60 hours of last dose. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of IP prior 
to blood draw on the eCRF. If the date or time of the last dose is unclear, provide the 
subject’s best approximation. If the date/time of the last dose cannot be 
approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SPM;

Serum acetaminophen test (APAP adduct test). Please refer to the SPM and Quest 
Diagnostics Laboratory manual for further details;

Serum CPK and lactate dehydrogenase;

Fractionate bilirubin, if total bilirubin is 1.5 × ULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
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
Liver imaging (ultrasound, magnetic resonance, or computed tomography) to 
evaluate liver disease;

Record the appearance or worsening of clinical symptoms of hepatitis, 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, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. Record alcohol use on the liver event alcohol intake case report form.
6.4.3.1.1.
Alternate RIF-Containing TB Treatment Regimen and Bridging Regimen
In cases of TB treatment interruption due to hepatotoxicity, until the cause of the 
hepatotoxicity is identified it may be necessary to treat the subject’s tuberculosis with a 
bridging non-RIF–containing anti-tuberculosis regimen with low risk of hepatotoxicity. 
Drugs that may be used include (i) ethambutol, (ii) an injectable: e.g., aminoglycoside 
(such as streptomycin, amikacin, and kanamycin) or capreomycin or (iii) a 
fluoroquinolone (e.g., moxifloxacin or levofloxacin). A bridging regimen should be used 
to avoid reaching the 14-day treatment interruption limit and therefore avoid having to 
withdraw a study subject from the study.
Both CDC and BHIVA guidelines recommend that patients be treated with two or more 
active drugs drawn from each of the groups listed (i) to (iii) above (i.e., ethambutol and 
streptomycin, or ethambutol and moxifloxacin) while waiting for standard therapy to be 
reintroduced in consultation with a local expert. A note for caution comes from reports of 
severe hepatotoxicity with moxifloxacin. 
Tuberculosis treatment may be re-introduced when ALT <2 × ULN. Suggested re-
introduction regimen schedules after TB treatment interruption are provided in Table 5
and Table 6, which describe options excluding ethambutol (12) or isoniazid (13) for 
testing re-exposure to TB drugs, respectively. TB treatment should be restarted first 
[BHIVA Guidelines, 2011], followed by TMP-SMX, if required for patient care, 
followed by ART. Daily monitoring of the patient’s condition and liver chemistries 
(ALT, AST, total bilirubin, alkaline phosphatase) is required during the reintroduction. 
Guidance from a local expert should be sought.
The time on the standard regimen (i.e., the initial WHO first-line TB regimen) should 
count towards time on the acceptable alternate RIF-containing TB treatment, provided the 
treatment interruption was no longer than 14 days [CDC 2003 Guidelines]. Only time on 
full-dose of the WHO first-line regimen or listed in Section 11.6 counts towards time on a 
TB regimen. Time on partial doses of TB drugs as part of the reintroduction does not 
count, but time on the bridging regimen does count. Further information on alternate RIF-
containing TB treatment regimens are described in Section 11.6.
Table 5
Re-Introduction Guidelines for Regimen 1
Day
Rifampicin 
Isoniazid 
Pyrazinamide 
1
50 mg 
2
150 mg 
 
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Day
Rifampicin 
Isoniazid 
Pyrazinamide 
3
full dose
4
75 mg 
full dose
5
150 mg 
full dose
6
300 mg 
full dose
7
full dose
full dose
8
full dose
full dose
250 mg 
9
full dose
full dose
500 mg 
10
full dose
full dose
1 g 
11
full dose
full dose
full dose
12
full dose
full dose
full dose
13
full dose
full dose
full dose
kg = kilogram; mg = milligram; g = gram
Table 6
Re-Introduction Guidelines for Regimen 2
Day
Rifampicin
Ethambutol 
Pyrazinamide 
1
75 mg 
2
150 mg 
3
300 mg 
4
450 mg <50 kg or 600 mg >50 kg 
5
450 mg/600 mg 
5 mg/kg 
6
450 mg/600 mg
10 mg/kg 
7
450 mg/600 mg 
15 mg/kg 
8
450 mg/600 mg 
15 mg/kg 
250 mg 
9
450 mg/600 mg 
15 mg/kg 
500 mg 
10
450 mg/600 mg 
15 mg/kg 
1 g 
11
450 mg/600 mg 
15 mg/kg 
1.5 g <50 kg or 2 g >50 kg 
12
450 mg/600 mg 
15 mg/kg 
1.5 g/2 g 
kg = kilogram; mg = milligram; g = gram
6.4.3.2.
Restarting Investigational Product
Drug restart/rechallenge following liver events that are possibly related to IP
Liver toxicity in the setting of concomitant TB treatment and ART is most commonly 
related to the antituberculosis medications rather than the HIV medications. As described 
above, TB treatment (isoniazid, RIF, and pyrazinamide) should all be discontinued 
(Section 11.6 for alternate TB therapy recommendations), along with all antiretrovirals 
and TMP-SMX, if being administered, when liver stopping criteria are met. In some 
cases (e.g., EFV), short continuation of the dual NRTI components of the regimen after 
interruption of the third antiretroviral drug may be appropriate in order to minimize the 
risk of development of resistance. Liver chemistries should be followed at least twice 
weekly until they have returned to <2 × ULN. Re-introduction of TB treatment should 
then be undertaken first as described in Section 11.6, followed by TMP-SMX, and then 
ART should be restarted. 
If liver toxicity is due to TB treatment and an alternative anti-TB treatment containing 
RIF can be successfully introduced, the authorization for restarting the IP may be 
discussed between the investigator and the study medical monitor, without the need for 
 
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approval from the ViiV Safety and Labeling Committee (VSLC) (see details in Section 
11.5). If liver toxicity is not due to TB treatment, the case will need VSLC approval to 
restart DTG (this approval can be ad hoc).
For Grade 4 ALT elevations (10 × ULN) it is recommended that the subject not be 
rechallenged with pyrazinamide. Alternate RIF-containing TB treatment regimens are 
described in Section 11.6 [BHIVA Guidelines Section 7.2, 2011 and CDC 2003 
Section 8.8.2].
The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge. Documentation of informed consent must be recorded in the study
chart.
Subjects approved by ViiV/GSK for rechallenge of IP must return to the clinic twice a 
week for liver chemistry tests for 1 month or for as long as clinically indicated and then 
laboratory monitoring may resume as per protocol.
Refer to Section 11.5 for further details.
Drug restart following transient resolving liver events not related to IP 
Refer to Section 11.5 for further details.
6.4.3.3.
TB-Associated IRIS Toxicity Management
Subjects presenting with Grade 3 (except Grade 3 TB-associated IRIS toxicity manifested 
only by respiratory signs and symptoms) and Grade 4 TB-associated IRIS toxicity should 
have the IP withheld and be rechecked each week until the AE returns to Grade 2. Once 
the AE is Grade 2, IP may be restarted.
Grade 3 TB-associated IRIS toxicity restricted to respiratory signs and symptoms may be 
managed by the investigator including, but not limited to, assessment of treatment failure 
and therapy with steroids, for a period of 1 week without having the IP withheld. After 
this period, if the event persists as a Grade 3 event, withholding the IP and having weekly 
follow-ups until the AE returns to Grade 2 would be required.
6.4.3.4.
Decline in Renal Function
Subjects who experience an increase in creatinine from Baseline of 45 Mol/L (or 
0.5 mg/dL) should return for a confirmatory assessment within 2 to 4 weeks. A urinalysis 
and urine albumin/creatinine ratio should 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.
Subjects who have a decline in estimated GFR (using the CKD-EPI method) of >50% 
must return for a confirmatory creatinine assessment as soon as possible. A urinalysis and 
urine albumin/creatinine ratio should be done at this confirmatory visit. If the estimated 
GFR has declined by >50% (confirmed), then IP should be withheld and the investigator 
should contact the study medical monitor to discuss the rationale for restarting IP (if 
 
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appropriate). Consideration for confounding factors (e.g., other medications, dehydration, 
concurrent medications) should be taken into account and a nephrology consult may be 
obtained. If a subject is also receiving TDF, then a switch to an alternate NRTI should be 
considered if restarting IP. One background NRTI change is allowed for management of 
drug toxicity as described in Section 5.1.5. If IP is not reinitiated the subject must be 
withdrawn.
6.4.3.5.
Allergic Reaction
Grade 1 or 2: Subjects may continue IP at the discretion of the investigator. The subject 
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.
Grade ≥3: Subjects with allergic reactions that are considered to be possibly or probably 
related to the IP should permanently discontinue the IP regimen and the subject should be 
withdrawn from the study. Subjects should be treated as clinically appropriate and 
followed until resolution of the AE.
Allergic reactions that the investigator considers related or possibly related to TB 
treatment should be managed with reference to applicable product labeling, local 
guidelines and, where the re-introduction of TB treatment is applicable, the 
recommendations outlined in Section 11.6.
Subjects receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC HSR and managed appropriately as 
outlined in the local prescribing information.
6.4.3.6.
Hypertriglyceridemia/Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events Table (Table 2). Subjects who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP.
6.4.3.7.
Creatine Phosphokinase Elevation
Grade 3: Subjects with an elevation in CPK should result in a repeat assessment 
within 2 to 4 weeks to ensure the result is transient or due to exercise and will not require 
a change in study treatment. 
Grade 4: Subjects with an elevation in CPK should have a repeat assessment after the 
subject has abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations 
that are considered possibly or probably related to the IP, IP should be discontinued and 
the subject withdrawn from the study.
A history regarding use of drugs known to cause an increase in CPK (such as statins) and 
physical activity or exercise preceding the CPK evaluation should be obtained. 
6.4.3.8.
Rash
Mild to moderate rash is an expected adverse reaction for DTG-containing ART. 
Episodes generally occur within the first 10 weeks of treatment, rarely require 
 
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interruptions or discontinuations of therapy and tend to resolve within 2 to 3 weeks. No 
instances of serious skin reaction, including Stevens-Johnson syndrome, toxic epidermal 
necrolysis and erythema multiforme, have been reported for DTG in clinical trials. 
Additional information on characterization of HSR and rash observed with DTG-
containing ART is in the current version of the IB [GlaxoSmithKline Document Number 
RM2007/00683/07]. Approximately one-fourth of adult subjects treated with EFV in 
clinical studies presented rash of any grade, with rare cases (<1%) being Grade 3 or 
higher. For information on rashes observed in EFV treated subjects refer to EFV product 
information [Sustiva (efavirenz) US Product Information, May 2013; Sustiva Package 
Insert, 2013; Sustiva Summary of Product Information, 2014].
TB treatment regimens commonly cause rashes that are typically mild/moderate in 
severity and usually start within the first 2 months of treatment initiation. Mild rashes 
without mucosal involvement can be treated symptomatically. More widespread 
worsening rashes or those with systemic symptoms require all drug cessation. It is 
recommended that when TB drugs, HIV drugs, and TMP-SMX are interrupted 
concomitantly due to treatment emerging rash that TB drugs be reintroduced first, then 
TMP-SMX, and finally the ART, in a similar regimen as the one suggested for 
hepatotoxicity management (Section 6.4.3.1.1).
Grade 1: Subjects with an isolated Grade 1 rash may continue IP at the investigator’s 
discretion. The subject should be advised to contact the investigator immediately if there 
is any worsening of the rash, if any systemic signs or symptoms worsen, or if mucosal 
involvement develops.
Grade 2: Subjects may continue IP for an isolated Grade 2 rash. However, IP (and all 
other concurrent medication(s) suspected in the investigators causality assessment 
including TB treatment medications) should be permanently discontinued for any Grade 
≥2 rash that is associated with an increase in ALT (see Section 6.4.3.1). The subject 
should be advised to contact the physician immediately if rash fails to resolve (after more 
than 2 weeks), if there is any worsening of the rash, if any systemic signs or allergic 
symptoms develop, or if mucosal involvement develops.
Grade 3 or 4: Subjects should permanently discontinue IP (and all other concurrent 
medication(s) suspected in the investigators causality assessment should be interrupted) 
for an isolated Grade 3 or 4 rash, and the subject should be withdrawn from the study. 
Subjects should be treated as clinically appropriate and followed until resolution of the 
AE.
The rash and any associated symptoms should be reported as AEs (see Section 6.4.3.9) 
and appropriate toxicity ratings should be used to grade the events (see Section 11.3).
If the etiology of the rash can be definitely diagnosed as being unrelated to IP and due to 
a specific medical event or a concomitant non-study medication, routine management 
should be performed and documentation of the diagnosis provided.
A rash that the investigator considers related or possibly related to TB treatment should 
be managed with reference to applicable product labeling, local guidelines and, where the 
 
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re-introduction of TB treatment is applicable, the recommendations outlined in Section 
11.6. 
Subjects receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC HSR and managed appropriately as 
outlined in the local prescribing information. In any subject treated with ABC, the 
clinical diagnosis of suspected HSR must remain the basis of clinical decision making. 
Regardless of HLA-B*5701 status, it is important to permanently discontinue ABC and 
not re-challenge with ABC (i.e., ABC/DTG/3TC, Ziagen, EPZICOM/KIVEXA, or 
TRIZIVIR™), if a HSR cannot be ruled out on clinical grounds, due to the potential for a 
severe or even fatal reaction.
6.4.3.9.
Petechial Rash
Thrombocytopenia induced by RIF and manifested by petechial rash has been described 
with high-dose intermittent therapy and also after resumption of interrupted treatment. As 
this event is reversible and potentially serious, RIF should be immediately and 
permanently withdrawn. This would also require discontinuation from the study, as the 
subject must be on a RIF-containing TB treatment regimen.
6.4.4.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE.
6.4.4.1.
Definition of an AE
An AE is defined as any untoward medical occurrence in a subject or clinical 
investigation subject, temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
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 medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

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 treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
 
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AE or SAE) unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This 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. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where 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

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
6.4.4.2.
Definition of an SAE
An SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
NOTE: The term “life threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject 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 out-patient setting. Complications that occur during hospitalization are AEs. 
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.
d.
Results in disability/incapacity, or
NOTE: 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 significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which 
 
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may interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These should also be 
considered serious. Examples of such events are 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.
g.
All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT 3 × ULN and bilirubin 2 × ULN (>35% direct) (or ALT 3 × ULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
Note: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2 × ULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.4.5.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology or clinical chemistry) or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and 
scientific judgement of the investigator are to be recorded as AEs or SAEs. However, any 
clinically significant safety assessments that are associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs.
Additionally, diagnostic test results that represent a sign of a clinical condition that is 
already reported as an AE need not be reported as this would be redundant.
6.4.6.
TB-Associated Immune Reconstitution Inflammatory Syndrome
The assessment of the frequency of TB-associated IRIS is one of the secondary study 
objectives (Section 2.2). In order to achieve this goal, investigators need to carefully 
document and manage signs and symptoms that could be related to TB-associated IRIS. 
In addition, the clinical team will review the AE terms and HIV conditions in order to 
identify TB-associated IRIS cases. Information on X-ray findings and repeat sputum 
 
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culture and susceptibility testing may be helpful in distinguishing IRIS from worsening 
TB disease or development of TB resistance.
This section provides guidance on criteria for TB-associated IRIS diagnosis during the 
study. TB-associated IRIS assessments will be performed according to the Time and 
Events schedule (Table 3). If any of the major and/or minor criteria described in this 
section occur, they should be captured and reported as AEs. 
Details on toxicity management for TB-associated IRIS cases are described in Section 
6.4.3.3.
IRIS is associated with the initiation of highly active ART for subjects co-infected with 
HIV-1 and TB. IRIS appears to be associated with severe immunosuppression, the speed 
of immune reconstitution, and TB severity. The diagnosis of this syndrome is actually a 
diagnosis of exclusion, after ruling out other diagnoses such as non-response to treatment 
(including failure to TB treatment due to drug resistance), poor adherence to TB 
treatment, recurrence of TB, toxicity or drug reaction, neoplasia, and opportunistic 
infections or other causes of fever. In biological terms, the IRIS could be associated with 
a burst of specific Th1 CD4+ T cells to tuberculin purified protein derivative, detectable 
by ELISPOT for IFN-.
There are 3 components of the existing case definition for paradoxical TB-associated 
IRIS [Meintjes, 2008]:
h.
Preliminary Requirements
Both of the following requirements must be met:

Diagnosis of TB, meeting WHO criteria for the diagnosis of either positive or 
negative sputum smear-positive pulmonary TB or extrapulmonary TB before 
starting the ART

Initial response to TB treatment: the subject's condition should be stabilized or 
improved in the presence of appropriate treatment for TB before starting the 
ART (e.g., remission of night sweats, fever, cough, weight loss). (Note: This 
does not apply to subjects starting ART within the first 2 weeks of TB treatment, 
since this is not sufficient time for the occurrence of clinical response)
i.Clinical Criteria
The onset of IRIS signs and symptoms related to TB should occur within the first 
3 months of starting, restarting, or changing the ART regimen for treatment failure.
At least 1 major criterion or 2 of the minor criteria listed below must be present:
Major criteria

New lymph nodes or increase in existing lymph nodes, cold abscesses, or other 
focal tissue involvement (e.g., tuberculous arthritis)

New x-ray findings suggestive of TB or worsening of existing images (e.g. chest 
x-ray, abdominal ultrasonography, computed tomography or magnetic resonance 
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
New onset of CNS TB or worsening of existing disease (meningitis or focal 
neurological deficit caused by tuberculoma)

New onset or worsening serositis (pleural effusion, ascites, or pericardial 
effusion)
Minor criteria

New constitutional symptoms or worsening of existing symptoms, such as fever, 
night sweats, or weight loss

New respiratory symptoms or worsening of existing symptoms such as 
coughing, dyspnea, or rhonchi

Recent onset or worsening abdominal pain accompanied by peritonitis, 
hepatomegaly, splenomegaly, or abdominal adenopathy
6.4.7.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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
This information should be recorded in the specific cardiovascular eCRF within 1 week 
of when the AE/SAE(s) are first reported.
6.4.8.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed. 
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
 
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6.4.9.
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 
(see Section 11.2) 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 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 6.4.4.2), or

The event or outcome is in the investigator’s opinion of greater intensity, frequency 
or duration than expected for the individual subject, 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.
6.4.10.
Suicidality Monitoring
Subjects with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behavior). Therefore, it is appropriate to monitor 
subjects for suicidality before and during treatment. It is recommended that the 
investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behavior.
Assessment of treatment-emergent suicidality will be monitored during this study using 
the C-SSRS, if a validated version in the appropriate language is available for the subject. 
The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia Suicide History Form [Oquendo, 2003]. Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation. Day 1 (Baseline) visit questions will 
be in relation to lifetime experiences and current experiences (within the past 2 months) 
and all subsequent questioning in relation to the last assessment. The C-SSRS is to be 
administered as a patient-completed questionnaire specified in the Time and Events Table 
(Table 2). Refer to the SPM for further details on questionnaire delivery and follow-ups.
Additionally, the investigator will collect information using the Possible 
Suicidality-Related AE (PSRAE) eCRF form in addition to the AE (nonserious or SAE) 
eCRF form on any subject that experiences a PSRAE 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 behavior, 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 PSRAE.
 
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6.4.11.
Pregnancy
6.4.11.1.
Pregnancy Testing
Women of childbearing potential must have a negative pregnancy test at Screening and 
Day 1 to be eligible for administration of IP. Pregnancy testing will also be conducted 
according to the Time and Events Table (Table 2) and at any time during the study when 
pregnancy is suspected.
Additionally, a pregnancy test should also be performed prior to IP re-administration, 
when IP administration is disrupted for more than 7 days.
6.4.11.2.
Time Period for Collecting Pregnancy Information
Information on the occurrence of pregnancies in female subjects will be collected over 
the period starting at Screening and ending at the final Follow-up visit. Only those 
pregnancies that occur following the first dose of IP will be reported to the medical 
monitor. Follow-up information will only be collected for pregnancies occurring from 
Day 1 to the final Follow-up visit.
6.4.11.3.
Action to be Taken if Pregnancy Occurs
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study. Subjects using DTG must immediately discontinue the IP.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported within 
2 weeks of learning of its occurrence. 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. Spontaneous abortions must be reported as SAEs.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to ViiV/GSK.
ViiV/GSK’s central safety department will also forward this information to the 
Antiretroviral Pregnancy Registry. The international registry is jointly sponsored by 
manufacturers or licensees of antiretroviral products. Additional information and a list of 
participating manufacturers/licensees are available from http://apregistry.com/index.htm.
 
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6.4.12.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff personnel are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE.
Beginning at Day 1 and continuing until the follow-up contact, AEs will be recorded. 
Serious AEs will be collected throughout the entire study. Any SAE assessed as related
to study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or related to a ViiV/GSK concomitant medication, 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. All SAEs will be reported to medical monitor within 
24 hours, as indicated in Section 6.4.14. 
6.4.13.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?”
6.4.14.
Prompt Reporting of Serious Adverse Events and Other Events
Serious AEs, pregnancies, and liver function abnormalities meeting pre-defined criteria 
will be reported promptly by the investigator to the medical monitor as described in Table 
7 once the investigator determines that the event meets the protocol definition for that 
event.
Criteria for liver chemistry stopping and follow-up criteria are in Section 6.4.3.1.
 
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Table 7
Reporting of Serious Adverse Events and Other Events
Initial Reports
Follow-up Information on a Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data collection 
tool
24 hours
Updated “SAE” data 
collection tool
Cardiovascular or death 
event
Initial and follow-
up reports to be 
completed within 
1 week of when 
the 
cardiovascular 
event or death is 
reported 
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Initial and follow-up 
reports to be 
completed within 
1 week of when the 
cardiovascular event 
or death is reported
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-up 
Form”
Suspected ABC HSRa
1 week
ABC HSR eCRF
1 week
Updated ABC HSR 
eCRF
ALT3×ULN and
bilirubin2×ULN (>35% 
direct) (or ALT3×ULN
24 hoursb
“SAE” data collection 
tool. “Liver Event 
eCRF” and “Liver 
Imaging” and/or “Liver 
Biopsy” eCRFs, if 
applicablec
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” documentsc
ALT≥5×ULN that persists 
≥2 weeks 
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ALT ≥8×ULN 
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ALT ≥3×ULN or ALT ≥3 
fold increase from 
baseline value with 
appearance or worsening 
of symptoms of hepatitis 
or hypersensitivity
24 hoursa
Liver Event eCRFb
24 hours 
Updated Liver Event 
eCRFb
ABC = abacavir; CV = cardiovascular; eCRF = electronic case report form; HSR = hypersensitivity reaction; 
SAE = serious adverse event; ULN = upper limit of normal.
a.
ABC HSR eCRF required only if event meets one of the definitions in Section 6.4.4.2.
b.
PPD must be contacted at onset of liver chemistry elevations to discuss subject safety.
c.
Liver event documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, as 
applicable) should be completed as soon as possible.
The investigator will be required to confirm review of the SAE causality by ticking the 
‘For Investigators ONLY’ box at the bottom of the eCRF page within 72 hours of 
submission of the SAE.
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM. Procedures 
for post-study AEs/SAEs are provided in the SPM. 
 
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6.4.14.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
ViiV/GSK has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. 
ViiV/GSK will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from ViiV/GSK will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Reporting of SAEs and other events to ViiV/GSK/PPD is addressed in Table 7.
6.4.14.2.
Reporting of ABC Hypersensitivity Reactions
If a clinically suspected case of HSR to ABC develops in subjects receiving ABC as part 
of their NRTI background regimen, and meets the definition of an SAE as described in 
Section 6.4.4, then, in addition to reporting the case as an SAE, the ABC HSR eCRF 
should also be completed within 1 week of the onset of the HSR (see Section 6.4.14).
6.4.15.
Other Safety Outcomes
Laboratory Assessments
All protocol-required laboratory assessments, as defined in Table 4, must be performed 
by the central laboratory, Quest Diagnostics, or a laboratory contracted by the central 
laboratory. Laboratory assessments must be conducted in accordance with the Central 
Laboratory Manual and Protocol Time and Events schedule (Table 2). Laboratory 
requisition forms must be completed and samples must be clearly labeled with the subject 
number, protocol number, site/center number, and visit date. Details for the preparation 
and shipment of samples will be provided in the Quest Diagnostic Laboratory manual. 
Reference ranges for all safety parameters will be provided to the site by Quest 
Diagnostics.
Mycobacterium TB laboratory assessments are to be performed locally and the results 
must be recorded in the subject’s eCRF in accordance with Time and Events schedules 
(Table 2 and Table 3).
All study-required laboratory assessments will be performed by a central laboratory. If 
required for cardiovascular events, additional specific local laboratory assessments will 
be recorded in the specific cardiovascular eCRF (see Section 6.4.7).
 
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6.5.
Pharmacokinetics
6.5.1.
Pharmacokinetic Endpoints
DTG and EFV concentrations will be evaluated at Weeks 8, 24, 36, and 48 using sparse 
PK sampling.
DTG and EFV drug concentrations will be analyzed using a population PK modeling 
approach to evaluate the effects of demographic factors (e.g., weight, age, gender, and 
race), subject characteristics, and on/off RIF treatment on DTG and EFV PK parameters 
and variability. DTG PK data obtained from this study may be combined with DTG PK 
data from previous Phase 3 studies for the population PK modeling. Plasma DTG and 
EFV PK parameters (AUC0-, Cmax, and C) estimated by population PK modeling 
based on sparse PK sampling will be reported and used in the analysis of correlation with 
antiviral activities at Weeks 24 and 48.
6.5.2.
Pharmacokinetic Sample Collection
Blood samples (2 mL each) will be collected from as many subjects as possible for 
evaluation of DTG and EFV plasma PK levels. Blood samples should be collected into 
K2EDTA tubes. The PK sampling visits will occur at Weeks 8, 24, 36, and 48 during the 
Randomized Phase. For the EFV arm, mid-dosing interval samples will be collected at 
Weeks 8, 24, 36, and 48. For the DTG arm, 1 sample will be collected for each of the 
following time points relative to IP dose: pre-dose, 1 to 3 hours post-dose, and 4 to 12 
hours post-dose at Weeks 8 and 36 as well as 1 sample pre-dose at Weeks 24 and 48 
Table 8. If PK sampling is not performed at the planned visit for any reason then the PK 
sample collection visit will be rescheduled within 4 weeks of the originally scheduled PK 
visit. The subject will be provided a new diary card at the rescheduled visit for the next 
PK visit, if applicable.
Table 8
Pharmacokinetic Sample Schedule
Treatment Arm
Week
Sample Times Relative to Dose
DTG PK
8 and 36
1 sample pre-dosea
1 sample 1 to 3 h post-doseb
1 sample 4 to12 h post-doseb,c
24 and 48
1 sample pre-dosea
EFV PK
8, 24, 36, and 48
1 sample mid-dosing intervald
DTG = dolutegravir; EFV = efavirenz; h = hour; PK = pharmacokinetic
a.
Pre-dose samples to be collected immediately before the morning dose (i.e. within 15 minutes) which will be taken 
under observation at the clinic. DTG twice-daily pre-dose sample be drawn as close as possible to 12 hours after 
the previous dose and DTG once-daily pre-dose sample should be drawn as close as possible to 24 hours after 
the previous dose.
b.
Both sample time points must be obtained from each subject.
c.
It is acceptable to draw the 4 to 12 hour sample any time between 4 and 12 hours post-dose.
d.
Mid-dosing interval samples should be collected in the morning at about 12 hours after the evening EFV dose on 
previous day.
 
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The Week 8 PK visit is to collect PK data during the TB treatment. If the subject is not on 
TB treatment at Week 8 due to temporary interruption for the management of toxicity, 
then PK data should instead be collected 14 to 21 days after RIF reintroduction. The 
Week 36 PK visit is to collect PK data when the subject has completed TB treatment (i.e., 
the subject is no longer taking RIF). If the treatment course has been extended because of 
interruptions, collection of Week 36 data should be delayed until TB treatment 
completion.  The Week 24 and 48 PK data will correspond with the primary and 
secondary efficacy analysis, respectively. Collection of PK data at multiple visits will 
provide more robust analysis of inter-occasional variability as well as possible evaluation 
of dosing compliance.
It is important to collect PK samples according to the following specified procedure.
For subjects randomly assigned to the DTG arm 
DTG twice daily - While taking DTG twice daily following TB treatment completion it 
is critical that the pre-dose sample should be drawn as close as possible to 12 hours after 
the previous dose (target window = 10 to 14 hours after the last dose) and before that 
morning’s dose (i.e., within 15 minutes of the next dose). For the 3 days in advance of a 
PK clinic visit, the subject must be instructed to plan the dosing of DTG at a time that 
corresponds with the scheduled PK visit time to allow for a pre-dose sample collection as 
close to 12 hours after the previous dose. 
DTG once daily - While taking DTG once daily following TB treatment completion it is 
critical that the pre-dose sample should be drawn as close as possible to 24 hours after the 
previous dose (target window = 22 to 26 hours after the last dose) and before that 
morning’s dose (i.e., within 15 minutes of the next dose). For the 3 days in advance of a 
PK clinic visit, the subject must be instructed to plan the dosing of DTG at a time that 
corresponds with the scheduled PK visit time to allow for a pre-dose sample collection as 
close to 24 hours after the previous dose. 
After the pre-dose sample is taken, the next dose will be taken under observation at the 
clinic. 
To enhance the quality of PK data collection, subjects will be asked to complete a diary 
card with the date and time of IP administration prior to the scheduled PK clinic visits. 
The actual dates and times of DTG dosing during the 3 days of prior to PK sampling as 
well as the observed dose taken at the clinic, if the subject vomited, and the actual date 
and time of the PK samples must be recorded on the eCRF.
Note: If a subject presents at the clinic for pre-dose PK sample collection having already 
taken the morning dose or having missed doses within the previous 3 days, it is 
recommended to reschedule PK sampling at the earliest next clinic visit. It is not 
recommended to collect PK samples if date and time of dosing for the previous 3 days 
cannot be reliably confirmed. Such samples will be discarded and will not contribute to 
any analyses.
Flexibility is allowed in collecting the post-dose sample (anywhere from 1 to 3 hours and 
4 to 12 hours post-dose) so that a range of sample times can be obtained. To achieve this, 
subjects may choose to remain in clinic until at least 1 hour after taking the DTG dose 
and may choose to return to the clinic 4 to 12 hours after taking the medication.
 
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For subjects randomly assigned to the EFV arm 
For subjects on EFV, the mid-dose samples will be collected in the morning, 
approximately 12 hours after the previous day’s dose. The date and time of the EFV 
mid-dose sample, as well as the date and time the subject had taken the previous 3 doses 
of EFV, will be collected and recorded on the CRF.
6.5.3.
Bioanalysis of DTG and EFV PK Samples
Plasma will be extracted from the blood samples collected and shipped for determination 
of DTG and EFV plasma concentrations by validated LC/MS/MS assays under the 
control of GSK PTS DMPK/Scinovo, the details of which will be included in the SPM. 
Raw data will be archived at the bioanalytical site (detailed in the SPM).
Once the plasma has been analyzed for DTG and EFV, any plasma may be analyzed for 
other compound-related metabolites and the results reported under a separate GSK PTS 
DMPK protocol.
6.6.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject at Screening for 
resistance testing at the central laboratory (or a laboratory contracted by the central 
laboratory) and on study ‘plasma for storage samples’ according to the Time and Events 
schedule in Section 6.1 for potential viral genotypic and phenotypic analyses. In addition, 
whole venous blood samples will be obtained from each subject to provide plasma for 
storage samples at the time of re-test for suspected protocol-defined virologic failure as 
specified in the Quest Laboratory manual. 
Details concerning the handling, labeling and shipping of these samples will be supplied 
separately. Viral genotype will be performed at Screening for study eligibility 
determination through Quest Diagnostics as well as at location(s) to be described in the 
SPM. Genotypic and phenotypic analyses may be carried out by Monogram Biosciences 
using, but not limited to, their Standard Phenosense and GenoSure testing methods for 
protease (PRO), reverse transcriptase (RT), and integrase assays. In addition, where 
Monogram Biosciences resistance testing is not possible, resistance testing may also be 
performed at location(s) to be described in the SPM.
6.6.1.
Viral Endpoint
A secondary endpoint of this study will be the incidence of treatment-emergent genotypic 
and phenotypic resistance to DTG, EFV, and other on-study ART in subjects meeting 
confirmed virologic withdrawal criteria.
 
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6.6.2.
HIV-1 Polymerase Viral Genotyping and Phenotyping
Subjects meeting ‘confirmed virologic withdrawal criterion’ 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 
withdrawal criterion’ (additional subsequent samples may be analyzed); these results will 
be reported to the investigator as soon as available to provide guidance for election of an 
alternate regimen.
HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and 
phenotype will also be determined on the Baseline isolates from all subjects, if possible. 
When samples cannot be analyzed by Monogram Biosciences, Baseline isolate resistance 
testing may be performed at location(s) to be described in the SPM.
6.6.3.
HIV-1 Exploratory Analysis
Additional analyses for HIV-1 resistance may, for example, be carried on stored plasma 
samples from Baseline and other relevant time points. These 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, and measurement of viral replicative capacity. HIV-1 PRO and RT genotype 
and phenotype and HIV-1 integrase genotype and phenotype will also be determined on 
the Baseline and the last on-treatment isolates from subjects who have HIV-1 RNA 
>400 c/mL regardless of confirmatory HIV-1 RNA.
6.7.
Pharmacogenetic Research
Information regarding pharmacogenetic (PGx) research is included in Section 11.1.  
The IEC/IRB and, where required, the applicable regulatory agency, must approve the 
PGx assessments before these can be conducted at the site. The approval(s) must be in 
writing and will clearly specify approval of the PGx assessments (see Section 11.1). In 
some cases, approval of the PGx assessments can occur after approval is obtained for the 
rest of the study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and, therefore, PGx assessments will not be conducted.
7.
DATA MANAGEMENT
For this study subject data will be entered into GSK-defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system. 
Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal validated medication dictionary, GSKDrug. Electronic CRFs (including queries 
and audit trails) will be sent at the end of the study in CD format to GSK to be retained. 
Each investigator will receive a copy of his or her site-specific data in the same format to 
maintain as the investigator copy. In all cases, subject initials will not be collected or 
transmitted to ViiV/GSK according to ViiV/GSK policy.
 
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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This study is designed to assess the antiviral effect of treatment with a DTG-containing 
regimen (50 mg twice daily during TB treatment and for 2 weeks following 
discontinuation of TB treatment, then 50 mg once daily) at Week 48, when administered 
in combination with dual NRTI therapy. No formal statistical hypothesis testing will be 
performed.
8.1.1.
Sample Size Assumptions
Data from recent DTG studies in treatment-naïve subjects have shown consistent 
response rates of 88% to 90% at Week 48 with a dose of 50 mg once daily (Table 9). 
Primary analyses in these studies have shown non-inferiority to RAL 400 mg once daily 
and superiority to both EFV/TDF/FTC once daily and DRV/r once daily. The proportion 
of subjects with baseline HIV-1 RNA >100,000 c/mL in the Phase III studies ranged 
from 25% to 32%; there were few subjects with baseline CD4+ cell counts 
<50 cells/mm3.
Table 9
Week 48 Results From Recent Treatment-Naïve DTG Studies
Study
Back-
ground 
NRTI
Endpoint
Active 
Treatment 
Responsea
Comparator/
Control 
Response
Notes
SINGLE
Phase III
n=833
HIV-1 RNA
<50 c/mL;
FDA 
Snapshot
DTG 50 mg
+ABC/3TC 
once daily
88%
(87%)a
EFV/TDF/FTC 
once daily
81%
(80%)a
DTG superior (at 
Wk 48/96)
Baseline:
32% >100,000 c/mL HIV-1 
RNA
SPRING-2
Phase III
n=822
ABC/3TC
or
TDF/FTC
HIV-1 RNA
<50 c/mL;
FDA 
Snapshot
DTG 50 mg 
once daily
88%
(87%)a
RAL 400 mg BID
85%
(86%)a
DTG non-inferior (at 
Wk 48/96)
Baseline:
28% >100,000 c/mL HIV-1 
RNA
FLAMINGO
Phase IIIb
n=484
ABC/3TC
or
TDF/FTC
HIV-1 RNA
<50 c/mL;
FDA 
Snapshot
DTG 50 mg 
once daily
90%
(88%)a
DRV/r 
800 mg/100 mg 
once daily
83%
(80%)a
DTG superior at Wk 48 
(study continuing to 
Wk 96)
Baseline:
25% >100,000 c/mL HIV-1 
RNA
SPRING-1
Phase IIb
n=205
ABC/3TC
or
TDF/FTC
HIV-1 RNA 
<50 c/mL;
TLOVR
DTG 50 mg 
once daily
90%
EFV 600 mg once 
daily
82%
DTG 10 mg 91%
DTG 25 mg 88%
Baseline:
21% >100,000 c/mL HIV-1 
RNA
ABC/3TC = abacavir/lamivudine; c = copies; CD4 = helper-inducer T-lymphocyte having surface antigen CD4 (cluster 
of differentiation 4); DRV/r = darunavir + ritonavir; DTG = dolutegravir; EFV = efavirenz; 
EFV/TDF/FTC = efavirenz/tenofovir disoproxil fumarate/emtricitabine; FDA = Food and Drug Administration 
(United States); HIV = human immunodeficiency virus; mL = milliliter; NRTI = nucleoside reverse transcriptase 
inhibitor; RAL = raltegravir; RNA = ribonucleic acid; TDF/FTC = tenofovir disoproxil fumarate/emtricitabine; 
TLOVR = time to loss of virologic response; Wk = week.
a.
Response rate for subjects with baseline CD4+ cell count ≥50 to <500 cells/mm3, where available.
 
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Response rates <50 c/mL in the REFLATE study at Week 48 were much lower than seen 
in the DTG studies (Table 10). The study population included higher proportions of 
subjects with baseline HIV-1 RNA >100,000 c/mL (46%) and with baseline CD4+ cell 
counts <50 cells/mm3 (20%); in particular, the EFV treatment arm had more such 
subjects than either of the RAL treatment arms. These characteristics are typically 
associated with a lower response rate for achieving virologic suppression.
Table 10
Week 48 Results from the REFLATE Study
Back-
ground 
NRTI
Endpoint
EFV
Once Daily 
(Response Rate)
RAL
Twice-Daily 
(Response Rate)
Notes
TDF/FTC
<50 c/mL;
Missing=Failure
600 mg (67%)
400 mg (76%)
800 mg (63%)
n=51 in each arm
Baseline:
CD4+ cells <50 c/mL: 27%, 24%, 
and 10%a
HIV-1 RNA >100,000 c/mL: 51%, 
39%, 47%a
c = copies; EFV = efavirenz; HIV = human immunodeficiency virus; mL = milliliter; NRTI = nucleoside reverse 
transcriptase inhibitor; RAL = raltegravir; RNA = ribonucleic acid; TDF/FTC = tenofovir disoproxil 
fumarate/emtricitabine.
a.
Percentage of subjects at Baseline in EFV 600 mg, RAL 400 mg, and RAL 800 mg treatment groups, respectively
Rates of withdrawal due to non-fatal AEs were comparable between REFLATE and the 
DTG studies. There was a higher incidence of deaths in REFLATE (approximately 5% 
overall versus <1% in DTG studies) with many owing to complications with TB 
co-infection. Even accounting for differences in the study population, the REFLATE 
response rates are lower than would be expected based on results seen in the DTG 
studies. The smaller sample sizes in REFLATE are more sensitive to what may be other 
chance findings.
Given the exposure data, it is anticipated that DTG twice daily co-administered with RIF 
will have efficacy comparable to DTG once daily, but a study population with higher 
proportions of subjects with baseline HIV-1 RNA >100,000 c/mL and lower CD4+ cell 
counts would have slightly lower responses than seen in the prior DTG studies.  
Assuming an 85% response rate for DTG at Week 48, a sample size of 66 to 72 subjects 
in the DTG arm would have >85% power to detect a response rate of greater than 70%
(Figure 4). Although the objective of the study is not to test a statistical hypothesis, the 
sample size has been chosen to provide an adequate number of subjects for assessing the 
antiretroviral activity of DTG.
8.2.
Study Design Considerations
8.2.1.
Sample Size Sensitivity
Figure 4 shows the relationship between study power and sample size, assuming an 85% 
response rate for DTG, to detect a response rate of greater than 70%. A sample size of 
69 subjects has >90% power. Smaller samples (e.g., 65 or greater) have at least 86% 
power, which is relevant when assessing the primary endpoint in alternate analysis 
populations (i.e., modified ITT-E).
 
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Figure 4
Relationship Between Study Power and Sample Size
Figure 5 shows the relationship between minimum sample size required and the assumed 
response rate; different targets for power are considered.
 
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Figure 5
Relationship Between Minimum Sample Size Required and the 
Assumed Response Rate
8.2.2.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.2.3.
Analysis Populations
The following populations will be assessed; other analysis populations (e.g., per-protocol, 
genotypic/phenotypic) will be fully described in the RAP.
8.2.3.1.
Intent-to-Treat Exposed (ITT-E) Population
The intent-to-treat exposed (ITT-E) population will consist of all randomly assigned 
subjects who receive at least one dose of IP. Subjects will be assessed according to their 
randomized treatment, regardless of the treatment they received. Unless stated otherwise, 
the ITT-E population will be used for summaries of efficacy. 
 
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8.2.3.2.
Modified Intent-to-Treat Exposed (MITT-E) Population
The modified intent-to-treat exposed (MITT-E) population will consist of all subjects in 
ITT-E population with confirmed RIF-sensitive MTB. This population will be used in an 
additional evaluation of the primary endpoint.
8.2.3.3.
Per-Protocol Population
The per-protocol (PP) population will consist of subjects in the ITT-E population with the 
exception of major protocol violators, e.g. violations which could affect the assessment of 
antiviral activity. The PP population will be used for sensitivity analyses of the primary 
efficacy endpoint.
8.2.3.4.
Safety Population
The safety population is defined as all subjects who receive at least one dose of IP. 
Subjects will be analyzed according to the actual treatments received.
8.2.3.5.
PK Population
8.2.3.5.1.
DTG PK Population
All subjects enrolled in the study who received at least 1 dose and for whom any 
pre-dose, post-dose, or mid-dose sample was taken for PK analysis with evaluable drug 
concentration data reported.
8.2.3.5.2.
EFV PK Population
All subjects enrolled in the study who received at least 1 dose and for whom any 
mid-dose sample was taken for PK analysis with evaluable drug concentration data 
reported.
8.2.4.
Analysis Data Sets
Final analysis will be performed after the completion of the study and authorization of 
final dataset.
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by subject, study period or phase, day, and time, noting 
treatment arm; summaries will be presented by treatment arm, day, and time. 
For the primary efficacy analysis, each subject’s response (i.e., HIV-1 RNA <50 c/mL) 
will be calculated according to the US Food and Drug Administration (FDA)’s Snapshot 
algorithm. This algorithm treats all subjects without HIV-1 RNA data at the visit of 
interest (due to missing data or discontinuation of IP prior to visit window) as 
non-responders, as well as subjects with ART substitutions not permitted per protocol 
(see Section 5.1.5). 
 
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Otherwise, virologic success or failure will be determined by the last available HIV-1 
RNA assessment while the subject is on-treatment within the visit window of interest (to 
be specified in the RAP). Full details on this Snapshot algorithm will be contained in the 
RAP. 
For this study, all protocol-permitted substitutions, regardless of HIV-1 RNA results at 
the time of the substitution, will have no effect on the analysis.
Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise. If there are multiple assessments collected on the 
same scheduled time, the average of these assessments will be used. For tabulated safety 
summaries, only the scheduled assessments will be included in the summary tables.
Version 9.1 or higher of the SAS system will be used to analyze the data and to generate 
tables, figures, and listings.
Complete details will be documented in the RAP.
8.2.5.
Treatment Comparisons
No formal treatment comparisons will be performed in this study.
8.2.6.
Interim Analysis
The first interim analysis will be conducted when all subjects complete their Week 24 
visit. The primary analysis will be conducted when all subjects complete their Week 52 
visit. A final end-of-study analysis will be conducted when the final subject randomly 
assigned to the DTG OLE has transitioned to commercial supplies of DTG or has been 
withdrawn from the study. Further data cuts and analyses may be conducted as necessary 
in order to support regulatory submissions and publications.
8.2.7.
Key Elements of Analysis Plan
When descriptive statistics are used to summarize group characteristics or differences, the 
following statistics will be included: for categorical variables, the number and percent in 
each category; for continuous variables, the mean, median, standard deviation, quartiles, 
and range (minimum, maximum). 
8.2.7.1.
Efficacy Analyses
The primary efficacy endpoint, the proportion of subjects from the ITT-E population with 
plasma HIV-1 RNA <50 c/mL at Week 48 using the Snapshot algorithm in the DTG arm, 
will be presented with its 95% CI.
The following secondary efficacy endpoints will be summarized using descriptive 
statistics:
 
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
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24 using the 
Snapshot algorithm;

Proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 using the 
Snapshot algorithm in the EFV arm;

Proportion of subjects without virologic or tolerability failure by Weeks 24 and 
48, where failure equals treatment-related discontinuation (meeting confirmed 
virologic withdrawal criteria, treatment-related AE, safety stopping criteria, or 
lack of efficacy);

Changes from baseline in CD4+ counts at Week 24 and Week 48.
The following tertiary efficacy endpoint will be summarized by event type and treatment 
arm using descriptive statistics:

Incidence of disease progression (HIV-associated conditions, new AIDS 
diagnoses, and death);

Proportion of subjects with TB treatment success (using the WHO definition);

Proportion of subjects with pulmonary tuberculosis who are sputum 
culture-negative 2 months after starting TB treatment.
8.2.7.2.
Safety Analyses
Exposure to IP, measured by the number of weeks on IP, will be summarized by 
treatment arm. The proportion of subjects reporting AEs will be tabulated by treatment 
arm. The following summaries of AEs will be provided:

Incidence and severity of all AEs, SAEs, and laboratory abnormalities; 

Proportion of subjects who permanently discontinue IP due to AEs or death;

Proportion of subjects who temporarily discontinue IP and/or TB therapy due to 
AEs;

Proportion of subjects with TB-associated IRIS.
In addition, absolute values and changes over time in laboratory parameters will be 
analyzed. Laboratory data will be summarized by visit and treatment arm. The number 
and percentage of subjects with graded laboratory toxicities (based on DAIDS categories, 
see Section 11.3) will be summarized by treatment arm. 
Further details of safety analyses will be included in the RAP.
8.2.7.3.
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses
Concentrations of DTG and EFV at Weeks 8, 24, 36, and 48 upon initiation of DTG or 
EFV therapy will be analyzed using population PK modeling approach to estimate AUC, 
Cmax, and Cfor individual subjects at Week 48 final analysis. The population PK 
analysis result will be presented in a separate PK report.
 
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Week 24 interim analyses and Week 48 final analyses of DTG and EFV concentrations 
based on sparse PK sampling will be summarized using descriptive statistics.
The relationship between DTG/EFV IP exposure and the Week 24 and Week 48 anti-HIV 
responses (Snapshot) may be evaluated using univariate (and multivariate) logistic 
regression analysis as well as graphic exploration. 
Detailed analysis will be provided in the RAP.
8.2.7.4.
Viral Genotyping/Phenotyping Analyses
The incidence of treatment-emergent genotypic and phenotypic resistance to DTG, EFV, 
and other on-study ART in subjects meeting confirmed virologic withdrawal criteria will 
be summarized using descriptive statistics.
8.2.7.5.
Pharmacogenetic Analyses
See Section 11.1 for details about the pharmacogenetics analysis plan.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, ViiV/GSK will obtain favorable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with ICH E6(R1) 
GCP guidelines and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/IEC review and approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
ViiV/GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 
 
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Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described Section 11.1, unless otherwise indicated. Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study. If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated. When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and PPD procedures, PPD monitors will 
contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and ViiV, 
GSK, or PPD requirements. When reviewing data collection procedures, the discussion 
will include identification, agreement, and documentation of data items for which the 
eCRF will serve as the source document.
PPD will monitor the study to ensure the following:

Data are authentic, accurate, and complete;

Safety and rights of subjects are being protected;

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, 
ViiV/GSK/PPD may conduct a quality assurance assessment and/or audit of the site 
records, and the regulatory agencies may conduct a regulatory inspection at any time 
during or after completion of the study. In the event of an assessment, audit, or 
inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s), 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss the conduct of the study, any findings/relevant issues, and to 
implement any corrective and/or preventative actions to address any findings/issues 
identified.
 
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9.5.
Study and Site Closure
Unless terminated early, this study will be considered completed after the last subject 
transitions to commercial supplies of DTG. Upon completion or termination of the study, 
the PPD monitor will conduct site closure activities with the investigator or site staff (as 
appropriate), in accordance with applicable regulations, GCP, and PPD SOPs.
ViiV/GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
non-compliance. If ViiV/GSK determines that such action is required, ViiV/GSK will 
discuss the reasons for taking such action with the investigator or head of the medical 
institution (where applicable). When feasible, ViiV/GSK will provide advance notice to 
the investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, ViiV/GSK will promptly inform 
all investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study. ViiV/GSK will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a ViiV/GSK audit or regulatory inspection) 
and must be available for review in conjunction with assessment of the facility, 
supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
ViiV, GSK, or PPD will inform the investigator of the time period for retaining the site 
records in order to comply with all applicable regulatory requirements. The minimum 
retention time will meet the strictest standard applicable to a particular site, as dictated by 
local laws/regulations, ViiV/GSK standard operating procedures, and/or institutional 
requirements.
The investigator must notify ViiV, GSK, or PPD of any changes in the archival 
arrangements, including, but not limited to archival of records at an off-site facility or 
transfer of ownership of the records in the event that the investigator is no longer 
associated with the site.
 
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9.7.
Provision of Study Results to Investigators, and Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
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 subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register no later than 8 months 
after the final primary completion date, the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome. In addition, a manuscript will be submitted to a peer reviewed journal for 
publication no later than 18 months after the last subject’s last visit (LSLV). When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.
 
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10.
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Boulle A, Van Cutsem G, Cohen K et al. Outcomes of nevirapine- and efavirenz-based 
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28 Mar 2014
 
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11.
APPENDICES
11.1.
Appendix 1 Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations. There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, and elimination), pharmacodynamics (relationship between concentrations 
and pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir. 
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity. Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity. HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
 
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Drug
Disease
Gene Variant
Outcome
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis. 
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment. The irinotecan drug label 
indicates that individuals who have 2 copies of 
the UGT1A1*28 variant are at increased risk 
of neutropenia. A genetic blood test is 
available that can detect variations in the 
gene. 
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in response to DTG. 
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to DTG. If 
at any time it appears there is potential variability in response in this clinical study or in a 
series of clinical studies with DTG, the following objectives may be investigated – the 
relationship between genetic variants and study treatment with respect to:

Efficacy

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety (tolerability and IRIS monitoring) 
 
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Study Population
Any subject who is enrolled in the clinical study can participate in PGx research. Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled.
Study Assessments and Procedures
Blood samples can be taken for DNA extraction and used in PGx assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (approximately 6 mL) will be collected for the PGx research using a 
tube containing EDTA. It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomized and provided informed consent for PGx 
research, but may be taken at any time while the subject is participating in the clinical 
study.
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff. Coded samples do not carry 
personal identifiers (such as name or social security number). The blood sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis. This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples. If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of
DTG has been completed and the clinical study data reviewed. In some cases, the 
samples may not be studied. e.g., no questions are raised about how people respond to 
DTG.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers) will use samples collected from the study for the 
purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
 
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Subject Withdrawal from Study
If a subject who has consented to participate in PGx research withdraws from the clinical 
study for any reason other than being lost to follow-up, the subject will be given a choice 
of one of the following options concerning the PGx sample, if already collected:

Continue to participate in the PGx research with the PGx sample retained for 
analysis 

Withdraw from the PGx research and destroy the PGx sample 
If a subject withdraws consent for PGx research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from the PGx research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process. In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (absorption, distribution, metabolism and excretion) 
genes that are studied to determine the relationship between gene variants or 
treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to DTG. The genes that may code for these 
proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
 
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of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarised as appropriate to the data. A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study. PGx informed consent must be obtained prior to any blood being taken for 
PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarise the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
References
Chung WH, Hung SI, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010;9:15-21.
Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations. 
Pharmacogenomics. 2008;9:1543-6.
Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and 
hypersensitivity reactions to abacavir. Lancet. 2002;359:1121-2.
Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the 
UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of 
irinotecan. J Clin Oncol. 2004;22:1382-8.
Liu CY, Chen PM, Chiou TJ, et al. UGT1A1*28 polymorphism predicts irinotecan-
induced severe toxicities without affecting treatment outcome and survival in patients 
with metastatic colorectal carcinoma. Cancer. 2008;112:1932-40.
Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-
DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor 
abacavir. Lancet. 2002;359:727-32.
 
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Mallal S, Phillips E, Carosi G, et al. PREDICT-1 Study Team. HLA-B*5701 screening 
for hypersensitivity to abacavir. N Engl J Med. 2008;358:568-79.
Schulz C, Heinemann V, Schalhorn A, et al. UGT1A1 gene polymorphism: Impact on 
toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World 
J. Gastroenterol. 2009;15:5058-66.
 
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11.2.
Appendix 2 CDC Classification System for HIV-1 Infections 
(1993)
Clinical Categories
The clinical categories of HIV infection are defined as follows:
Category A
Category A consists of one or more of the conditions listed below in an adolescent or 
adult (>13 years) with documented HIV infection. Conditions listed in Categories B and 
C must not have occurred.

Asymptomatic HIV infection

Persistent generalized lymphadenopathy

Acute (primary) HIV infection with accompanying illness or history of acute HIV 
infection
Category B (Symptomatic non-AIDS conditions)
Category B consists of symptomatic conditions in an HIV-infected adolescent or adult 
that are not included among conditions listed in clinical Category C and that meet at least 
one of the following criteria: a) the conditions are attributed to HIV infection or are 
indicative of a defect in cell-mediated immunity; or b) the conditions are considered by 
physicians to have a clinical course or to require management that is complicated by HIV 
infection. Examples of conditions in clinical Category B include, but are not limited to:

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 month

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least 2 distinct episodes or more than 
1 dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Pelvic inflammatory disease, particularly if complicated by tubo-ovarian abscess

Peripheral neuropathy
For classification purposes, Category B conditions take precedence over those in 
Category A. For example, someone previously treated for oral or persistent vaginal 
 
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candidiasis (and who has not developed a Category C disease) but who is now 
asymptomatic should be classified in clinical Category B.
Category C (AIDS indicator conditions as defined by diagnostic or presumptive 
measures).
Category C includes the clinical conditions listed in the AIDS surveillance case 
definition. For classification purposes, once a Category C condition has occurred, the 
person will remain in Category C.
Conditions in Category C include:

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV-related

Herpes simplex: chronic ulcer(s) (>1 month’s duration);or bronchitis, pneumonitis, 
or esophagitis

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 M. kansasii, disseminated or extrapulmonary

Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)

Mycobacterium, other species or unidentified species, disseminated or 
extrapulmonary

Pneumocystis carinii pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent
 
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
Toxoplasmosis of brain

Wasting syndrome due to HIV

Non-CDC, HIV-associated conditions.
Reference:

Castro GK, Ward JW, Slutsker L, et al. 1993 revised classification system for HIV 
infection and expanded surveillance case definition for AIDS among adolescents and 
adults. MMWR Recomm Rep. 1992;41(No. RR-17):1-19.
 
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11.3.
Appendix 3 Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events
VERSION 1.0, DECEMBER 2004; CLARIFICATION AUGUST 2009
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 utilized 
for adverse event (AE) reporting. A grading (severity) scale is provided for each AE 
term.
 
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CLINICAL 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event NOT 
identified elsewhere in this 
DAIDS AE grading table 
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 
Medical or operative intervention 
indicated to prevent permanent 
impairment, persistent disability, or 
death 
SYSTEMIC 
Acute systemic allergic reaction 
Localized urticaria (wheals) 
with no medical intervention 
indicated 
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated 
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild bronchospasm 
Acute anaphylaxis OR Life-
threatening bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & functional 
activities 
NA 
Fatigue Malaise 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & functional 
activities 
Incapacitating fatigue/malaise 
symptoms causing inability to 
perform basic self-care functions 
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
39.4 – 40.5°C 
> 40.5°C 
Pain (indicate body site) DO 
NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site pain) 
See also Headache, Arthralgia, 
Pain causing no or minimal 
interference with usual social & 
functional activities 
Pain causing greater than 
minimal interference with usual 
social & functional activities 
Pain causing inability to perform 
usual social & functional activities 
Disabling pain causing inability to 
perform basic self-care functions OR 
Hospitalization (other than 
emergency room visit) indicated 
 
 
 
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CLINICAL 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
and Myalgia 
Unintentional weight loss 
NA 
5 – 9% loss in body weight from 
baseline 
10 – 19% loss in body weight from 
baseline 
≥ 20% loss in body weight from 
baseline OR Aggressive intervention 
indicated [e.g., tube feeding or total 
parenteral nutrition (TPN)] 
INFECTION 
Infection (any other than HIV 
infection) 
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual social & 
functional activities 
Systemic antimicrobial treatment 
indicated OR Symptoms causing 
greater than minimal interference 
with usual social & functional 
activities 
Systemic antimicrobial treatment 
indicated AND Symptoms causing 
inability to perform usual social & 
functional activities OR Operative 
intervention (other than simple 
incision and drainage) indicated 
Life-threatening consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain (pain without 
touching) Or Tenderness (pain 
when area is touched) 
Pain/tenderness causing no or 
minimal limitation of use of limb 
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social & 
functional activities 
Pain/tenderness causing inability 
to perform usual social & 
functional activities 
Pain/tenderness causing inability to 
perform basic self-care function OR 
Hospitalization (other than 
emergency room visit) indicated for 
management of pain/tenderness 
Injection site reaction (localized) 
Adult >15 years 
Erythema OR Induration of 5x5 
cm – 9x9 cm (or 25 cm2 –
Erythema OR Induration OR 
Edema > 9 cm any diameter (or 
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess 
Necrosis (involving dermis and 
deeper tissue) 
 
 
 
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GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
81cm2) 
> 81 cm2) 
OR Drainage 
Pediatric ≤15 Years 
Erythema OR Induration OR 
Edema present but ≤ 2.5 cm 
diameter 
Erythema OR Induration OR 
Edema > 2.5 cm diameter but < 
50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) 
Erythema OR Induration OR 
Edema involving ≥ 50% surface 
area of the extremity segment 
(e.g., upper arm/thigh) OR 
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess 
OR Drainage 
Necrosis (involving dermis and 
deeper tissue) 
Pruritis associated with 
injection See also Skin: Pruritis 
(itching - no skin lesions) 
Itching localized to injection site 
AND Relieved spontaneously 
or with < 48 hours treatment 
Itching beyond the injection site 
but not generalized OR Itching 
localized to injection site 
requiring ≥ 48 hours treatment 
Generalized itching causing 
inability to perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable by study 
participant (or by caregiver for 
young children and disabled 
adults) 
Thinning or patchy hair loss 
detectable by health care 
provider 
Complete hair loss 
NA 
Cutaneous reaction – rash 
Localized macular rash 
Diffuse macular, maculopapular, 
or morbilliform rash OR Target 
lesions 
Diffuse macular, maculopapular, or 
morbilliform rash with vesicles or 
limited number of bullae OR 
Superficial ulcerations of mucous 
membrane limited to one site 
Extensive or generalized bullous 
lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous 
membrane involving two or more 
distinct mucosal sites OR Toxic 
epidermal necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
 
 
 
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GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Pruritis (itching – no skin 
lesions) (See also Injection Site 
Reactions: Pruritis associated 
with injection) 
Itching causing no or minimal 
interference with usual social & 
functional activities 
Itching causing greater than 
minimal interference with usual 
social & functional activities 
Itching causing inability to perform 
usual social & functional activities 
NA 
CARDIOVASCULAR 
Cardiac arrhythmia (general) 
(By ECG or physical exam) 
Asymptomatic AND No 
intervention indicated 
Asymptomatic AND Non-urgent 
medical intervention indicated 
Symptomatic, non-life-threatening 
AND Non-urgent medical 
intervention indicated 
Life-threatening arrhythmia OR 
Urgent intervention indicated 
Cardiac-ischemia/infarction
NA 
NA 
Symptomatic ischemia (stable 
angina) OR Testing consistent with 
ischemia 
Unstable angina OR Acute 
myocardial infarction 
Hemorrhage (significant acute 
blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND Transfusion of 
≤ 2 units packed RBCs (for 
children ≤ 10 cc/kg) indicated 
Life-threatening hypotension OR 
Transfusion of > 2 units packed 
RBCs (for children >10 cc/kg) 
indicated 
Hypertension 
Adult >17 years (with 
repeat testing at same 
visit) 
> 140 – 159 mmHg systolic OR 
> 90 – 99 mmHg diastolic 
> 160 – 179 mmHg systolic OR > 
100 – 109 mmHg diastolic 
> 180 mmHg systolic OR > 110 
mmHg diastolic 
Life-threatening consequences (e.g., 
malignant hypertension) OR 
Hospitalization indicated (other than 
emergency room visit) 
Pediatric ≤17 Years (with 
repeat testing at same 
NA 
91st – 94th percentile adjusted 
for age, height, and gender 
95th percentile adjusted for age, 
height, and gender (systolic and/or 
Life-threatening consequences (e.g., 
malignant hypertension) OR 
 
 
 
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GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
visit) 
(systolic and/or diastolic) 
diastolic) 
Hospitalization indicated (other than 
emergency room visit) 
Hypotension 
NA 
Symptomatic, corrected with oral 
fluid replacement 
Symptomatic, IV fluids indicated 
Shock requiring use of vasopressors 
or mechanical assistance to 
maintain blood pressure 
Pericardial effusion 
Asymptomatic, small effusion 
requiring no intervention 
Asymptomatic, moderate or 
larger effusion requiring no 
intervention 
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening consequences (e.g., 
tamponade) OR Urgent intervention 
indicated 
Prolonged PR interval 
Adult >16 years 
PR interval 0.21 – 0.25 sec 
PR interval > 0.25 sec 
Type II 2nd degree AV block OR 
Ventricular pause > 3.0 sec 
Complete AV block 
Pediatric ≤16 Years 
1st degree AV block (PR > 
normal for age and rate) 
Type I 2nd degree AV block 
Type II 2nd degree AV block 
Complete AV block 
Prolonged QTc 
Adult >16 years 
Asymptomatic, QTc interval 
0.45 – 0.47 sec OR Increase 
interval < 0.03 sec above 
baseline 
Asymptomatic, QTc interval 0.48 
– 0.49 sec OR Increase in 
interval 0.03 – 0.05 sec above 
baseline 
Asymptomatic, QTc interval ≥ 0.50 
sec OR Increase in interval ≥ 0.06 
sec above baseline 
Life-threatening consequences, e.g. 
Torsade de pointes or other 
associated serious ventricular 
dysrhythmia 
Pediatric ≤16 years 
Asymptomatic, QTc interval 
0.450 – 0.464 sec 
Asymptomatic, QTc interval 
0.465 – 0.479 sec 
Asymptomatic, QTc interval ≥ 
0.480 sec 
Life-threatening consequences, e.g. 
Torsade de pointes or other 
associated serious ventricular 
dysrhythmia 
 
 
 
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PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Thrombosis/embolism 
NA 
Deep vein thrombosis AND No 
intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Embolic event (e.g., pulmonary 
embolism, life-threatening thrombus) 
Vasovagal episode (associated 
with a procedure of any kind) 
Present without loss of 
consciousness 
Present with transient loss of 
consciousness 
NA 
NA 
Ventricular dysfunction 
(congestive heart failure) 
NA 
Asymptomatic diagnostic finding 
AND intervention indicated 
New onset with symptoms OR 
Worsening symptomatic 
congestive heart failure 
Life-threatening congestive heart 
failure 
GASTROINTESTINAL 
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 or total parenteral 
nutrition (TPN)]
Ascites 
Asymptomatic 
Symptomatic AND Intervention 
indicated (e.g., diuretics or 
therapeutic paracentesis) 
Symptomatic despite intervention 
Life-threatening consequences 
Cholecystitis 
NA 
Symptomatic AND Medical 
intervention indicated 
Radiologic, endoscopic, or 
operative intervention indicated 
Life-threatening consequences (e.g., 
sepsis or perforation) 
Constipation 
NA 
Persistent constipation requiring 
regular use of dietary 
modifications, laxatives, or 
enemas 
Obstipation with manual 
evacuation indicated 
Life-threatening consequences (e.g., 
obstruction) 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Diarrhea
Adult and Pediatric ≥1 
year 
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 – 6 stools over baseline per 
24-hour period 
Bloody diarrhea OR Increase of 7 
stools per 24-hour period OR IV 
fluid replacement indicated 
Life-threatening consequences (e.g., 
hypotensive shock) 
Pediatric <1 year 
Liquid stools (more unformed 
than usual) but usual number 
of stools 
Liquid stools with increased 
number of stools OR Mild 
dehydration 
Liquid stools with moderate 
dehydration 
Liquid stools resulting in severe 
dehydration with aggressive 
rehydration indicated OR 
Hypotensive shock 
Dysphagia-Odynophagia 
Symptomatic but able to eat 
usual diet 
Symptoms causing altered 
dietary intake without medical 
intervention indicated 
Symptoms causing severely 
altered dietary intake with medical 
intervention indicated 
Life-threatening reduction in oral 
intake 
Mucositis/stomatitis (clinical 
exam) Indicate site (e.g., 
larynx, oral) See Genitourinary 
for Vulvovaginitis See also 
Dysphagia-Odynophagia and 
Proctitis 
Erythema of the mucosa 
Patchy pseudomembranes or 
ulcerations 
Confluent pseudomembranes or 
ulcerations OR Mucosal bleeding 
with minor trauma 
Tissue necrosis OR Diffuse 
spontaneous mucosal bleeding OR 
Life-threatening consequences (e.g., 
aspiration, choking) 
Nausea 
Transient (< 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake 
Persistent nausea resulting in 
decreased oral intake for 24 – 48 
hours 
Persistent nausea resulting in 
minimal oral intake for > 48 hours 
OR Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not indicated 
(other than emergency room 
Symptomatic AND Hospitalization 
indicated (other than emergency 
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
visit) 
room visit) 
sepsis) 
Proctitis (functional-
symptomatic) Also see 
Mucositis/stomatitis for clinical 
exam 
Rectal discomfort AND No 
intervention indicated 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities OR 
Medical intervention indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Operative 
intervention indicated 
Life-threatening consequences (e.g., 
perforation) 
Vomiting 
Transient or intermittent 
vomiting with no or minimal 
interference with oral intake 
Frequent episodes of vomiting 
with no or mild dehydration 
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration indicated 
(e.g., IV fluids) 
Life-threatening consequences (e.g., 
hypotensive shock) 
NEUROLOGIC 
Alteration in personality-
behavior or in mood (e.g., 
agitation, anxiety, depression, 
mania, psychosis) 
Alteration causing no or 
minimal interference with usual 
social & functional activities 
Alteration causing greater than 
minimal interference with usual 
social & functional activities 
Alteration causing inability to 
perform usual social & functional 
activities 
Behavior potentially harmful to self 
or others (e.g., suicidal and 
homicidal ideation or attempt, acute 
psychosis) OR Causing inability to 
perform basic self-care functions 
Altered Mental Status For 
Dementia, see Cognitive and 
behavioral/attentional
disturbance (including dementia 
and attention deficit disorder) 
Changes causing no or minimal 
interference with usual social & 
functional activities 
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social & 
functional activities 
Confusion, memory impairment, 
lethargy, or somnolence causing 
inability to perform usual social & 
functional activities 
Delirium OR obtundation, OR coma 
Ataxia 
Asymptomatic ataxia 
detectable on exam OR 
Minimal ataxia causing no or 
minimal interference with usual 
social & functional activities 
Symptomatic ataxia causing 
greater than minimal interference 
with usual social & functional 
activities 
Symptomatic ataxia causing 
inability to perform usual social & 
functional activities 
Disabling ataxia causing inability to 
perform basic self-care functions 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Cognitive and 
behavioral/attentional 
disturbance (including dementia 
and attention deficit disorder) 
Disability causing no or minimal 
interference with usual social & 
functional activities OR 
Specialized resources not 
indicated 
Disability causing greater than 
minimal interference with usual 
social & functional activities OR 
Specialized resources on part-
time basis indicated 
Disability causing inability to 
perform usual social & functional 
activities OR Specialized 
resources on a full-time basis 
indicated 
Disability causing inability to perform 
basic self-care functions OR 
Institutionalization indicated 
CNS ischemia (acute) 
NA 
NA 
Transient ischemic attack 
Cerebral vascular accident (CVA, 
stroke) with neurological deficit 
Developmental delay 
Mild developmental delay, 
either 
Moderate developmental delay, 
Severe developmental delay, 
either 
Developmental regression, either 
– Pediatric ≤16 Years 
motor or cognitive, as 
determined by comparison with 
a developmental screening tool 
appropriate for the setting 
either motor or cognitive, as 
determined by comparison with a 
developmental screening tool 
appropriate for the setting 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting 
motor or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting 
Headache 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater than 
minimal interference with usual 
social & functional activities 
Symptoms causing inability to 
perform usual social & functional 
activities 
Symptoms causing inability to 
perform basic self-care functions OR 
Hospitalization indicated (other than 
emergency room visit) OR 
Headache with significant 
impairment of alertness or other 
neurologic function 
Insomnia 
NA 
Difficulty sleeping causing 
greater than minimal interference 
with usual social & functional 
activities 
Difficulty sleeping causing inability 
to perform usual social & 
functional activities 
Disabling insomnia causing inability 
to perform basic self-care functions 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Neuromuscular weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with decreased 
strength on exam OR Minimal 
muscle weakness causing no 
or minimal interference with 
usual social & functional 
activities 
Muscle weakness causing 
greater than minimal interference 
with usual social & functional 
activities 
Muscle weakness causing inability 
to perform usual social & 
functional activities 
Disabling muscle weakness causing 
inability to perform basic self-care 
functions OR Respiratory muscle 
weakness impairing ventilation 
Neurosensory Alteration 
(including paresthesia and 
painful neuropathy) 
Asymptomatic with sensory 
alteration on exam or minimal 
paresthesia causing no or 
minimal interference with usual 
social & functional activities 
Sensory alteration or paresthesia 
causing greater than minimal 
interference with usual social & 
functional activities 
Sensory alteration or paresthesia 
causing inability to perform usual 
social & functional activities 
Disabling sensory alteration or 
paresthesia causing inability to 
perform basic self-care functions 
Seizure: (new onset) 
NA 
1 seizure 
2 – 4 seizures 
Seizures of any kind which are 
– Adult ≥18 years 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control 
(e.g., 
See also Seizure: (known pre-
refractory epilepsy) 
existing seizure disorder) 
Seizure: (known pre-existing 
seizure disorder) – Adult ≥ 18 
years For worsening of existing 
epilepsy the grades should be 
based on an increase from 
previous level of control to any 
of these levels. 
NA 
Increased frequency of pre-
existing seizures (non-repetitive) 
without change in seizure 
character OR Infrequent break-
through seizures while on stable 
medication in a previously 
controlled seizure disorder 
Change in seizure character from 
baseline either in duration or 
quality (e.g., severity or focality) 
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control 
(e.g., refractory epilepsy) 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Seizure – Pediatric <18 years 
Seizure, generalized onset with 
or without secondary 
generalization, lasting < 5 
minutes with < 24 hours post-
ictal state 
Seizure, generalized onset with 
or without secondary 
generalization, lasting 5 – 20 
minutes with <24 hours post ictal 
state 
Seizure, generalized onset with or 
without secondary generalization,
lasting >20 minutes 
Seizure, generalized onset with or 
without Secondary generalization, 
requiring intubation and sedation 
Syncope (not associated with a 
procedure) 
NA 
Present 
NA 
NA 
Vertigo 
Vertigo causing no or minimal 
interference with usual social & 
functional activities 
Vertigo causing greater than 
minimal interference with usual 
social & functional activities 
Vertigo causing inability to perform 
usual social & functional activities 
Disabling vertigo causing inability to 
perform basic self-care Functions 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow reduced to 
70 – 80% 
FEV1 or peak flow 50 – 69% 
FEV1 or peak flow 25 – 49% 
Cyanosis OR FEV1 or peak flow < 
25% OR Intubation 
Dyspnea or respiratory distress 
Adult ≥14 years 
Dyspnea on exertion with no or 
minimal interference with usual 
social & functional activities 
Dyspnea on exertion causing 
greater than minimal interference 
with usual social & functional 
activities 
Dyspnea at rest causing inability to 
perform usual social & functional 
activities 
Respiratory failure with ventilatory 
support Indicated 
Pediatric <14 years 
Wheezing OR minimal increase 
in respiratory rate for age 
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 90 
– 95% 
Dyspnea at rest causing inability to 
perform usual social & functional 
activities OR Pulse oximetry < 
90% 
Respiratory failure with ventilatory 
support indicated 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
MUSCULOSKELETAL 
Arthralgia See also Arthritis 
Joint pain causing no or 
minimal interference with usual 
social & functional activities 
Joint pain causing greater than 
minimal interference with usual 
social & functional activities 
Joint pain causing inability to 
perform usual social & functional 
activities 
Disabling joint pain causing inability 
to perform basic self-care Functions 
Arthritis See also Arthralgia 
Stiffness or joint swelling 
causing no or minimal 
interference with usual social & 
functional activities 
Stiffness or joint swelling causing 
greater than minimal interference 
with usual social & functional 
activities 
Stiffness or joint swelling causing 
inability to perform usual social & 
functional activities 
Disabling joint stiffness or swelling 
causing inability to perform basic 
self-care functions 
Bone Mineral Loss 
Adult ≥ 21 years 
BMD t-score -2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture (including 
loss of vertebral height) 
Pathologic fracture causing life-
threatening Consequences 
Pediatric < 21 years 
BMD z-score -2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture (including 
loss of vertebral height) 
Pathologic fracture causing life-
threatening Consequences 
Myalgia (non-injection site) 
Muscle pain causing no or 
minimal interference with usual 
social & functional activities 
Muscle pain causing greater than 
minimal interference with usual 
social & functional activities 
Muscle pain causing inability to 
perform usual social & functional 
activities 
Disabling muscle pain causing 
inability to perform basic self-care 
functions 
Osteonecrosis 
NA 
Asymptomatic with radiographic 
findings AND No operative 
intervention indicated 
Symptomatic bone pain with 
radiographic findings OR 
Operative intervention indicated 
Disabling bone pain with 
radiographic findings causing 
inability to perform basic self-care 
functions 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
GENITOURINARY 
Cervicitis (symptoms) (For use 
in studies evaluating topical 
study agents) For other 
cervicitis see Infection: Infection 
(any other than HIV infection) 
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 
Cervicitis (clinical exam) (For 
use in studies evaluating 
topical study agents) For other 
cervicitis see Infection: Infection 
(any other than HIV infection) 
Minimal cervical abnormalities 
on examination (erythema, 
Mucopurulent discharge, or 
friability) OR Epithelial 
disruption < 25% of total 
surface 
Moderate cervical abnormalities 
on examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption 
of 25 – 49% total surface 
Severe cervical abnormalities on 
examination (erythema, 
mucopurulent discharge, or 
friability) OR Epithelial disruption 
50 – 75% total surface 
Epithelial disruption > 75% total 
surface 
Inter-menstrual bleeding (IMB) 
Spotting observed by 
participant OR Minimal blood 
observed during clinical or 
colposcopic examination 
Inter-menstrual bleeding not 
greater in duration or amount 
than usual menstrual cycle 
Inter-menstrual bleeding greater in 
duration or amount than usual 
menstrual cycle 
Hemorrhage with life-threatening 
hypotension OR Operative 
intervention indicated 
Urinary tract obstruction (e.g., 
stone) 
NA 
Signs or symptoms of urinary 
tract obstruction without 
hydronephrosis or renal 
dysfunction 
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or 
renal dysfunction 
Obstruction causing life-threatening 
consequences 
Vulvovaginitis (symptoms) (Use 
in studies evaluating topical 
study agents) For other 
vulvovaginitis see Infection: 
Infection (any other than HIV 
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 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
infection) 
Vulvovaginitis (clinical exam) 
(Use in studies evaluating 
topical study agents) For other 
vulvovaginitis see Infection: 
Infection (any other than HIV 
infection) 
Minimal vaginal abnormalities 
on examination OR Epithelial 
disruption <25% of total surface 
Moderate vaginal abnormalities 
on examination OR Epithelial 
disruption of 25 - 49% total 
surface 
Severe vaginal abnormalities on 
examination OR Epithelial 
disruption 50 - 75% total surface 
Vaginal perforation OR Epithelial 
disruption > 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but detectable 
on exam 
Symptomatic anterior uveitis OR 
Medical intervention indicated 
Posterior or pan-uveitis OR 
Operative intervention indicated 
Disabling visual loss in affected 
eye(s) 
Visual changes (from baseline) 
Visual changes causing no or 
minimal interference with usual 
social & functional activities 
Visual changes causing greater 
than minimal interference with 
usual social & functional 
activities 
Visual changes causing inability to 
perform usual social & functional 
activities 
Disabling visual loss in affected 
eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat accumulation 
(e.g., back of neck, breasts, 
abdomen) 
Detectable by study participant 
(or by caregiver for young 
children and disabled adults) 
Detectable on physical exam by 
health care provider 
Disfiguring OR Obvious changes 
on casual visual inspection 
NA 
Diabetes mellitus 
NA 
New onset without need to 
initiate medication OR 
Modification of current 
medications to regain glucose 
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non-
ketotic coma) 
 
 
 
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GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
control 
modification 
Gynecomastia 
Detectable by study participant 
or caregiver (for young children 
and disabled adults) 
Detectable on physical exam by 
health care provider 
Disfiguring OR Obvious on casual 
visual inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
suppression therapy indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification 
Life-threatening consequences (e.g., 
thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
replacement therapy indicated 
Symptoms causing inability to 
perform usual social & functional 
activities OR Uncontrolled despite 
treatment modification 
Life-threatening consequences (e.g., 
myxedema coma) 
Lipoatrophy (e.g., fat loss from 
the face, extremities, buttocks) 
Detectable by study participant 
(or by caregiver for young 
children and disabled adults) 
Detectable on physical exam by 
health care provider 
Disfiguring OR Obvious on casual 
visual inspection 
NA 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
HEMATOLOGY Standard International Units are listed in italics 
Absolute CD4+ count – Adult 
and Pediatric >13 years (HIV 
NEGATIVE ONLY) 
300 – 400/mm3
300 – 400/µL
200 – 299/ mm3
200 – 299/µL
100 – 199/ mm3
100 – 199/µL
< 100/ mm3
< 100/µL
Absolute lymphocyte count –
Adult and Pediatric >13 years 
(HIV NEGATIVE ONLY) 
600 – 650/ mm3
0.600 x 109 – 0.650 x 109/L
500 – 599/ mm3
0.500 x 109 – 0.599 x 
109/L
350 – 499/ mm3
0.350 x 109 – 0.499 x 109/L
< 350/ mm3
< 0.350 x 109/L
Absolute neutrophil count (ANC) 
Adult and Pediatric, >7 
days 
1,000 – 1,300/ mm3
1.000 x 109 – 1.300 x 109/L
750 – 999/ mm3
0.750 x 109 – 0.999 x 
109/L
500 – 749/ mm3
0.500 x 109 – 0.749 x 109/L
< 500/ mm3
< 0.500 x 109/L
Infant†, 2 – 7 days 
1,250 – 1,500/ mm3
1.250 x 109 – 1.500 x 109/L
1,000 – 1,249/ mm3
1.000 x 109 – 1.249 x 
109/L
750 – 999/ mm3
0.750 x 109 – 0.999 x 109/L
< 750/ mm3
< 0.750 x 109/L
Infant†, 1 day 
4,000 – 5,000/ mm3
4.000 x 109 – 5.000 x 109/L
3,000 – 3,999/ mm3
3.000 x 109 – 3.999 
x109/L
1,500 – 2,999/ mm3
1.500 x 109 – 2.999 x 109/L
< 1,500/ mm3
< 1.500 x 109/L
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L
OR 0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 0.25 – 0.49 x LLN 
< 50 mg/dL 
< 0.50 g/L 
OR < 0.25 x LLN OR Associated 
with gross bleeding 
Hemoglobin (Hgb) 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Adult and Pediatric 
≥57 days (HIV POSITIVE 
ONLY) 
8.5 – 10.0 g/dL 
5.24 – 6.23 mmol/L 
7.5 – 8.4 g/dL 
4.62 – 5.23 mmol/L 
6.50 – 7.4 g/dL 
4.03 – 4.61 mmol/L 
< 6.5 g/dL 
< 4.03 mmol/L 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Adult and Pediatric 
≥57 days (HIV 
NEGATIVE ONLY) 
10.0 – 10.9 g/dL 
6.18 – 6.79 mmol/L 
OR
Any decrease 
2.5 – 3.4 g/dL
1.58 – 2.13mmol/L 
9.0 – 9.9 g/dL 
5.55 - 6.17 mmol/L 
OR 
Any decrease 
3.5 – 4.4 g/dL
2.14 – 2.78 mmol/L 
7.0 – 8.9 g/dL 
2.14 – 2.78 mmol/L
OR
Any decrease 
≥ 4.5 g/dL
> 2.79 mmol/L 
< 7.0 g/dL 
< 4.34 mmol/L 
Infant†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL
5.24 – 5.86 mmol/L 
7.0 – 8.4 g/dL
4.31 – 5.23 mmol/L 
6.0 – 6.9 g/dL
3.72 – 4.30 mmol/L 
< 6.00 g/dL
< 3.72 mmol/L 
Infant†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL
5.87 – 6.54 mmol/L 
8.0 – 9.4 g/dL
4.93 – 5.86 mmol/L 
7.0 – 7.9 g/dL
4.34 – 4.92 mmol/L 
< 7.00 g/dL
< 4.34 mmol/L 
Infant†, 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL
7.42 – 8.09 mmol/L 
10.0 – 11.9 g/dL
6.18 – 7.41 mmol/L 
9.0 – 9.9 g/dL
5.59 – 6.17 mmol/L 
< 9.0 g/dL
< 5.59 mmol/L 
International Normalized 
Ratio of prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 – 124,999/mm3
100.000 x 109 – 124.999 x 109/L 
50,000 – 99,999/mm3
50.000 x 109 – 99.999 x 109/L 
25,000 – 49,999/mm3
25.000 x 109 – 49.999 x 109/L 
< 25,000/mm3
< 25.000 x 109/L 
WBC, decreased 
2,000 – 2,500/mm3
2.000 x 109 – 2.500 x 109/L 
1,500 – 1,999/mm3
1.500 x 109 – 1.999 x 109/L 
1,000 – 1,499/mm3
1.000 x 109 – 1.499 x 109/L 
< 1,000/mm3
< 1.000 x 109/L 
CHEMISTRIES 
Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3 without life-threatening 
consequences 
pH < 7.3 with life-threatening 
consequences 
LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN†
2.6 – 5.0 x ULN†
5.1 – 10.0 x ULN†
> 10.0 x ULN†
Alkalosis
NA 
pH > normal, but ≤ 7.5 
pH > 7.5 without life-threatening 
pH > 7.5 with life-threatening 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
consequences 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Bilirubin (Total) 
Adult and Pediatric >14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant†, ≤14 days (non-
hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
25.1 – 30.0 mg/dL 
429 – 513 µmol/L 
> 30.0 mg/dL 
> 513.0 µmol/L 
Infant†, ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.0 mg/dL 
> 428 µmol/L 
Calcium, serum, high (corrected for albumin) 
Adult and Pediatric ≥7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6 – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L
Infant†, <7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low (corrected for albumin) 
Adult and Pediatric ≥7 days 
7.8 – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0 – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1 – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Infant†, <7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with myocardial 
infarction or unstable angina as 
defined by the manufacturer 
LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Cardiac troponin T (cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL OR Levels consistent 
with myocardial infarction or 
unstable angina as defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric <18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Fasting 
110 – 125 mg/dL
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
Glucose, serum, low 
Adult and Pediatric ≥ 1 
month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L
Infant†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
ULN - < 2.0 x 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 
LDL cholesterol (fasting) 
Adult ≥18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥4.91 mmol/L 
NA 
Pediatric >2 – <18 years 
110 – 129 mg/dL 
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
Magnesium, serum, low 
1.2 – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric >14 
years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 years 
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Pediatric <1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
125 – 129 mEq/L 
121 – 124 mEq/L 
≤ 120 mEq/L 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
130 – 135 mmol/L 
125 – 129 mmol/L 
121 – 124 mmol/L 
≤120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS Standard International Units are listed in italics 
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without clots OR 
with RBC casts 
Transfusion indicated 
Proteinuria, random Collection 
1 + 
2 – 3 + 
4 + 
NA 
LABORATORY 
PARAMETER
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
MILD 
MODERATE 
SEVERE 
POTENTIALLY 
LIFE-THREATENING 
Proteinuria, 24 hour collection 
Adult and Pediatric ≥10 
years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
>3.500 g/d 
Pediatric > 3 mo -<10 years 
201 – 499 mg/m2/24 h 
500 – 799 mg/m2/24 h 
800 – 1,000 mg/m2/24 h 
> 1,000 mg/ m2/24 h 
 
 
 
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LABORATORY 
PARAMETER
GRADE 1 MILD 
GRADE 2 MODERATE 
GRADE 3 SEVERE 
GRADE 4 POTENTIALLY LIFE-
THREATENING 
0.201 – 0.499 g/d 
0.500 – 0.799 g/d 
0.800 – 1.000 g/d 
> 1.000 g/d 
 
 
 
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11.4.
Appendix 4 Country-Specific Requirements
No country-specific requirements exist.
 
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11.5.
Appendix 5 Liver Safety Drug Restart or Rechallenge 
Guidelines
GUIDELINES FOR DRUG RESTART OR RECHALLENGE AFTER STOP FOR 
LIVER CRITERIA
1.
IP rechallenge may be considered for a subject exhibiting compelling benefit for a 
critical medicine following drug-induced liver injury, if favorable benefit: risk and 
no alternate medicine available. (Figure 6 and Table 11).
2.
IP restart may be considered for liver safety events with a clear underlying cause 
(e.g. biliary, pancreatic events, hypotension, acute viral hepatitis), if not associated 
with drug-induced liver injury, alcoholic hepatitis, or hypersensitivity [fever, rash or 
eosinophilia] and drug not associated with HLA genetic marker of liver injury, when 
liver chemistries have improved to normal or are within 1.5 × baseline and 
ALT<2 × ULN).
3.
Subjects meeting liver chemistry stopping criteria that present rebound of ALT 
elevation upon stepwise re-exposure to TB treatment regimen (see Section 6.4.3.1
for suggestion on TB treatment re-introduction regimens) will be considered as 
having the anti-TB treatment as the likely cause of ALT elevation. If the TB 
treatment component considered to be the likely cause of the ALT elevation is not 
RIF and an alternative anti-TB treatment containing RIF can be successfully 
introduced, the authorization for restarting the IP may be discussed between the 
investigator and the study medical monitor without the need for approval from the 
VSLC. If there is no evidence of a relationship between one of the antituberculosis 
anti-TB treatment regimen components (other than RIF) and the ALT elevation, the 
case will need VSLC approval to restart DTG (this approval can be ad hoc).
Background: Following drug-induced liver injury, drug rechallenge is associated with 
a 13% mortality across all drugs in prospective studies. Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane re-administered in 1 month of initial injury 
[Andrade, 2009]. However, some drugs seldom result in recurrent liver injury or fatality.
Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andrade, 2009]

Jaundice or bilirubin 2 × ULN with initial liver injury

Prior serious adverse event or fatality has earlier been observed with drug 
rechallenge [Papay, 2009; Hunt, 2010]

Evidence of drug-related preclinical liability (e.g., reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
 
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Decision Process for Drug Rechallenge Approval or Disapproval

Principal investigator (PI) requests consideration of drug rechallenge for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits liver 
chemistry elevation meeting subject stopping criteria, with no alternate treatment.

Medical monitor and Global Clinical Safety and Pharmacovigilance (GCSP) 
physician to review the subject’s rechallenge risk factors (consultation with the 
Hepatotoxicity Panel is available) and complete checklist (Table 11).

The medical monitor and GCSP physician are accountable to review and agree on 
the following:
1.
Compelling benefit of the IP for this subject and no alternate therapy 
2.
Relative benefit-risk of drug rechallenge, with consideration of the following 
high risk factors:

Initial liver injury event included: fever, rash, eosinophilia, or bilirubin 
>2 × ULN (or direct bilirubin >35% of total, if available)

Subject currently exhibits severe liver injury defined by: ALT >3 × ULN, 
bilirubin >2 × ULN (direct bilirubin >35% of total, if available), or INR>1.5

SAE or fatality has earlier been observed with IP rechallenge

IP associated with known preclinical hepatic liability/injury

Relevant physicians must review and agree on request for drug rechallenge:

Safety Team Leader, study medical monitor and Physician Product Leader 
Medicines Development Leader, and Project Physician Leader (GSK).

Medicines Development Leader and Project Physician Leader (GSK).

Request is taken to full VSLC for final decision
 
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Figure 6
VSLC Process for Drug Rechallenge Approval or Disapproval
Subject exhibits liver injury on drug, while disease condition stable or 
improving
Clear evidence of a relationship between one of the antituberculosis 
drugs (other than RIF) and the ALT elevation?
Authorization for restarting the IP may be 
discussed between the investigator and the 
study medical monitor, without the need for 
approval from the VSLC
YES
NO
Authorization for restarting the IP requires 
approval from the VSLC
Medical Monitor & Safety Physician(s) to discuss benefit : risk and:
Any fever, rash or eosinophilia, hypersensitivity with initial liver injury in the patient?
Bilirubin 2 × ULN or INR>1.5 in this patient, suggesting failing liver?
Any prior severe / fatal outcomes reported on drug rechallenges with this drug?
Any evidence of preclinical hepatic liability / injury with this drug?
Request is submitted to VSLC
Who approve IP re-initiation
VSLC do not approve IP re-initiation
PI promptly informed of decision & dosing regimen Ethics Com.  or IRB review, 
if needed Benefits/risks discussed with subject & consent recorded in chart 
Liver chemistries obtained twice weekly for one month or for as long as 
clinically indicated Safety Review Team records rechallenge outcome VSLC 
notified of rechallenge outcomes
PI promptly informed of decision
The local operating company (LOC) medical director (ViiV and GSK where applicable) should be informed that IP rechallenge is under 
consideration and of the final decision, whether or not to proceed.
 
 
 
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Table 11
Checklist for IP Rechallenge for Critical Medicine (Following Drug-
Induced Liver Injury, IP Rechallenge is Associated with 13% 
Mortality Across all Drugs in Prospective Studies)
Yes
No
Relative benefit-risk favorable for drug rechallenge, after considering the 
following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin 2 × ULN (direct bilirubin >35% of total)
o
Subject currently exhibits ALT 3xULN, bilirubin 2 × ULN 
(direct bilirubin >35% of total, if available), or INR 1.5
o
SAE or fatality has earlier been observed with IP rechallenge
If yes, please provide brief explanation:
o
IP associated with known preclinical hepatic liability/injury
o
Source data defining the subjects current resistance profile
o
Previous drug history
Medical monitor, GCSP Physician, and PI actions for Restart or 
Rechallenge following VSLC decision
Medical Monitor and (Global Clinical Safety and Pharmacovigilance) GCSP 
Physician Actions

Medical Monitor must notify PI of VSLC’s rechallenge (or restart) decision and 
recommended dosing regimen in writing and medical monitor must record note 
in study files.

The Safety Review Team must record rechallenge (or restart) outcomes and the 
GCSP Physician must send these to the VSLC

All severe reactions (rechallenge associated with bilirubin >2 × ULN or 
jaundice, or INR ≥1.5), SAEs, or fatalities with drug rechallenge (or 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 IRB or IEC approval of IP rechallenge or restart, as required. 

If IP re-initiation is approved, the subject 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.
Targeted IP rechallenge or IP restart informed consent form must be used.

The subject’s informed consent must be recorded in the study chart, and the drug 
administered at agreed dose, as communicated by medical monitor.
 
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
Liver chemistries must be followed twice weekly for ‘rechallenge’ cases and 
once weekly for ‘restart’ cases for one month or for as long as clinically 
indicated following drug re-initiation. If the subject exhibits protocol-defined 
liver chemistry elevations, IP should be discontinued as protocol specified.
VSLC and the IRB/IEC must be informed of the subject’s outcome following drug 
rechallenge or restart.
Rechallenge/restart safety outcomes:

0 = no liver chemistry elevation

1 = recurrent liver chemistry elevation not meeting subject stopping criteria

2 = recurrent liver chemistry elevation meeting subject 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;8:709-14.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatology. 
2010;52:2216-22.
Papay JI, Clines D, Rafi R, et al. Drug-induced liver injury following positive drug 
rechallenge. Regul Tox Pharm. 2009;54:84-90. 
 
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11.6.
Appendix 6 Alternate RIF-Containing TB Treatment 
Regimens
The WHO-recommended first-line regimen for drug-sensitive TB is a combination 
regiment of isoniazid and RIF for six months, with ethambutol and pyrazinamide for the 
first two months. This regimen may be given daily or intermittently according to local or 
national guidelines. In case alternate TB treatments need to be considered due to 
tolerability/toxicity issues to one of the agents on the WHO-recommended first line 
regimen or due to antibiotic resistance, alternative TB treatment regimens are suggested 
below. The doses used should follow local or national guidelines. For additional 
information on alternate RIF-containing TB treatment regimens see Section 6.4.3.1.1. 
None of the alternate RIF-containing TB treatment regimens listed below should be used 
as the first-line TB treatment.

Regimen 1 (omitting pyrazinamide): isoniazid, RIF, and ethambutol for 2 months, 
followed by RIF and isoniazid, for 7 months (9 months in total) [BTA, 1982; BTS, 
1984; Slutkin, 1988].

Regimen 2 (omitting isoniazid): RIF, pyrazinamide, ethambutol, and streptomycin 
for 2 months, followed by RIF and ethambutol for 7 months (9 months in total) 
[Babu, 1988].
The investigator may find Regimen 2 suitable in cases where isoniazid is found to 
have precipitated hepatotoxicity (i.e., in the course of TB drug re-introduction for 
Regimen 1) [BTS, 1984]. In which case, the investigator may choose to use the 
schedule suggested in Table 6. Guidance from a local expert should be sought.
This is also a suitable regimen for use when the study subject is found to be infected 
with isoniazid-resistant TB. If the WHO first-line regimen was well-tolerated prior to 
the discovery of isoniazid-resistance, then it is reasonable for all drugs in Regimen 2 
to be introduced simultaneously instead of using the schedule displayed Table 6.

Regimen 3 (omitting ethambutol): RIF, isoniazid, and pyrazinamide for 2 months, 
followed by RIF and isoniazid for 4 months [Combs, 1990]. 
The investigator may choose to use Regimen 3 for those subjects who are intolerant 
to ethambutol (the principal adverse effect of ethambutol being optic neuritis). 
Provided other components of Regimen 3 have been well-tolerated, conversion from 
the WHO first-line regimen only requires that ethambutol be stopped. Otherwise, the 
schedule in Table 5 is suitable if there has been a drug-interruption and the 
investigator feels that a gradual reintroduction is required. Consultation from a local 
expert should be sought.
When making changes to TB treatment, national or local guidelines on the treatment of 
tuberculosis should always be followed and take precedence over the recommendations 
made in this section. Should the subject need to go on a regimen that excludes the use of 
RIF (e.g., for reasons of tolerability/toxicity or antibiotic resistance), then the subject will 
have to be withdrawn from the study. Further details describing withdrawal criteria are 
described in Section 4.5.
 
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11.7.
Appendix 7 Karnofsky Performance Status Scale
 
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third party copyright laws and therefore have been excluded.

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11.8.
Appendix 8 Child-Pugh Classification
A subject is classified with mild hepatic impairment (Class A) if their overall sum of 
scores is 5-6 points, moderate hepatic impairment (Class B) if their overall sum of scores 
is 7-9 points, and severe hepatic impairment (Class C) if their overall sum of scores is 
10-15 based on the Child-Pugh system [Pugh, 1973] scoring described in the following 
table (Table 13). For subjects requiring anticoagulation therapy, discussion with the study 
medical monitor will be required.
Table 13
Child-Pugh System
Finding 
Points Scored for Each Observed Finding 
1
2
3
Encephalopathy Grade 1a 
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum bilirubin, SI units (μmol/L), 
Serum bilirubin, conventional units (mg/dL) 
<34
<2
34 to 52
2 to 3
>52
>3
Serum albumin, SI units (g/L) 
Serum albumin, conventional units (mg/dL) 
>35
>3.5
28 to 35
2.8 to 3.5
<28
<2.8
Prothrombin Time (seconds prolonged) or 
INR 
<4
<1.7
4 to 6
1.7 to 2.3
>6
>2.3
a.
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cycles per second delta activity
[Pugh, 1973; Lucey, 1997]
References
Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on 
the liver transplant waiting list: a report of a national conference organized by the 
American Society of Transplant Physicians and the American Association for the Study 
of Liver Diseases. Liver Transpl Surg. 1997 Nov;3(6):628-637 
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for 
bleeding oesophageal varices. Br J Surg 1973;60:649-649.
 
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11.9.
Appendix 9 Protocol Changes
Amendment 01: A global protocol amendment applicable to all participating countries:
Summary of Changes in Protocol Amendment 01 and Rationale

Mailing address of study medical monitor was updated.

Changes were made to the protocol text in the following sections to reflect the 
revision of the number of subjects to be randomized from ~125 to ~115 to alleviate
enrolment difficulties and recruit the study in a timely manner. The reduced sample 
size will allow timely availability of the data while maintaining a high power for the 
sample size assumption. The changes were made in Protocol Summary Study Design 
Section, in Section 3.1, in Section 4.1, in Section 8.1.1 and in Section 8.2.1.

Minor clarifications in the study conduct include clarification of the use of solid 
media for the 2 month TB culture to be preferred rather than mandated to be aligned 
with the original study intent to follow national recommendations for TB testing and 
management. Change was made in Section 3.1.1.

Correction of the list of participating countries in Sections 3.2 and Section 4.1.

Minor clarifications on GeneXpert testing or equivalent validated test and the ability 
to perform the test at the Screening visit in alignment with the original the study 
design and intent and described in Section 3.1. Changes were made in Sections 4.2 
and Section 6.1.

Addition of instructions for investigators on the new GSK/ViiV procedure requiring 
investigator to confirm and document their review of the SAE causality within 72 
hours of submission of the SAE. Change was made in Section 6.4.14.

Minor clarification and/or corrections of typographical errors were made in inclusion 
criteria 19 and 23 Section 4.3, in Section 6.4.14.2 and in Section 8.1 Table 9.

Figure 6 in Appendix 5 was replaced by an identical and reformatted figure to 
improve readability.
List of Changes (Old deleted text shown as strike through and new 
text shown in bold)

Page 3, SPONSOR INFORMATION PAGE last paragraph:
 MD, PhD
PPD
1800 Perimeter Park Drive, Suite 2753900 Paramount Parkway, South Building, 3rd
Floor, Office 352

Protocol Summary Study Design and Section 3.1 first and second paragraph:
This is a Phase IIIb, randomized, open-label study describing the efficacy and safety of 
DTG and EFV-containing ART regimens in HIV/TB co-infected patients. The study will 
 
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be conducted in approximately (+/-5%) 1125 HIV-1 infected individuals who are ART-
naïve with a CD4+ cell count 50 cells/mm3 and newly diagnosed with confirmed 
pulmonary, pleural, or LN Mycobacterium TB (MTB) taking RIF-containing first-line TB 
treatment. Subjects should have confirmed RIF-sensitive MTB infection as determined 
by GeneXpert (or equivalent approved molecular test) or mycobacterial culture. Eligible 
subjects will be randomly assigned in a 3:2 ratio to receive DTG plus 2 NRTIs 
(approximately 6975 subjects) or EFV plus 2 NRTIs (approximately 4650 subjects).

Section 3.1.2, 2nd Paragraph, 2nd sentence:
Sputum will be collected from subjects with pulmonary tuberculosis 2 months after 
initiating TB treatment (solid media culture testing is preferred required).

Section 3.2 Discussion of Design, 2nd paragraph, 1st sentence:
Adult subjects diagnosed (smear positive) and proven RIF-sensitive TB who are initiating 
TB treatment with HRZE will be recruited at sites in Brazil, Mexico, Russia, Argentina, 
Peru, South Africa, Malawi and Thailand.

Section 4.1, 1st and 2nd paragraph and Table:
A sufficient number of subjects will be screened in order to ensure that a total of 
approximately (+/-5%) 1125 subjects will be randomly assigned in a 3:2 ratio to DTG 
(approximately 6975 subjects) and EFV (approximately 4650 subjects), respectively. 
Assuming 55% of subjects do not meet eligibility criteria, this will require the screening 
of approximately 2575 subjects. Subjects will be enrolled from Brazil, Mexico, Russia, 
Argentina, Peru, South Africa, Malawi, and Thailand.
Subjects
Screened
~2575
Randomized
~1125
Evaluable
~1125

Section 4.2, Inclusion criteria 7 and 8:
3.
New diagnosis of pulmonary, pleural, or LN tuberculosis based on identification of 
Mycobacterium tuberculosis using culture methods or GeneXpert (or other 
approved molecular test) on sputum or on samples collected by needle aspirate of 
pleural fluid or an affected LN; 
4.
RIF sensitivity of Mycobacterium tuberculosis either by culture or Gene Xpert (or 
other validated approved nucleic acid amplification test);

Section 4.3, Exclusion criteria 19 and 23:
 
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19. Any verified Grade 4 laboratory abnormality with the exception of Grade 4 
triglycerides.  A single repeat test is allowed during the Screening period to
verify a result; 
23. Platelet count <50,000/mm3.

Section 6.1, Table 2, row 8, column 1:
Perform GeneXpert or equivalent and/or Document GeneXpert or equivalent RIF-
sensitive MTB.

Section 6.4.14, new sentence added after Table 7:
The investigator will be required to confirm review of the SAE causality by ticking 
the ‘For Investigators ONLY’ box at the bottom of the eCRF page within 72 hours 
of submission of the SAE.

Section 6.4.14.2, typo corrected:
If a clinically suspected case of HSR to ABC develops in subjects receiving ABC as part 
of their NRTI background regimen, and meets the definition of an AE/SAE as described 
in Section 6.4.4, then, in addition to reporting the case as an SAE, the ABC HSR eCRF 
should also be completed within 1 week of the onset of the HSR (see Section 6.4.14).

Section 8.1.1, Table 9, 3rd column, rows 2 to 5, typo corrected:
CD4+ cell countHIV-1 RNA <50 c/mL

Section 8.1.1, 5th and last paragraph:
Assuming an 85% response rate for DTG at Week 48, a sample size of 75 66 to 
72 subjects in the DTG arm would have >9085% power to detect a response rate of 
greater than 70% (Figure 4). Although the objective of the study is not to test a statistical 
hypothesis, the sample size has been chosen to provide an adequate number of subjects 
for assessing the antiretroviral activity of DTG.

Section 8.2.1, 1st paragraph, 2nd sentence:
A sample size of 6975 subjects has >90% power. Smaller samples (e.g., 659 or greater) 
have at least 868% power, which is relevant when assessing the primary endpoint in 
alternate analysis populations (i.e., modified ITT-E).

Figure 6 in Appendix 5:
Figure 6 was reformatted.
 
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