A Phase 3b, Randomized, Open-label Study of the Antiviral Activity and Safety of Dolutegravir Compared to Lopinavir/Ritonavir Both Administered With Dual Nucleoside Reverse Transcriptase Inhibitor Therapy in HIV-1 Infected Adult Subjects With Treatment Failure on First Line Therapy
Phase: PHASE3
Conditions: HIV Infections
Sponsor: ViiV Healthcare

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Vii V H e alt h c ar e a n d t h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
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TI T L E P A G E
Di visi o n: W orl d w i de De vel o p me nt
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt
Title:
A P hase 3 b, ra n d o mise d, o pe n -la bel st u dy of t he a nti viral 
acti vit y a n d safety of d ol ute gra vir c o m pare d t o 
l o pi na vir/rit o na vir b ot h a d mi nistere d wit h d ual n ucle osi de 
re verse tra nscri ptase i n hi bit or t hera p y i n HI V- 1 i nfecte d a d ult 
s u bjects wit h treat me nt fail ure o n first li ne t hera p y
C o m p o u n d N u m ber:
G S K 1 3 4 9 5 7 2
De vel o p me nt P h ase:
IIIB
Effecti ve D ate:
1 9- J U N-2 0 1 8
Pr ot oc ol A me n d me nt N u m ber: 3
A ut h or (s):
C o p y ri g ht 20 1 8 Vii V Healt hcare a n d t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All 
ri g hts reser ve d.  U na ut h orise d c o pyi n g or use of t his i nf or mati o n is pr o hi bite d.
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ViiV Healthcare and the GlaxoSmithKline group of companies
200304
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N172672_00
2014-APR-01
Original
2013N172672_01
2014-APR-30
Amendment No. 1
This amendment includes the removal of exclusion criterion 18 (subject has creatinine 
clearance of <50 mL/min via the CKD-EPI method).  Allergic reaction criteria are 
referred to in Section 4.5 “Withdrawal criteria”.  Furthermore, the sequence of 
administration of the HIVTSQ status and change versions has been amended.  Other 
minor clarifications and corrections have been incorporated.
2013N172672_02
2017-APR-19
Amendment No. 2
This amendment includes a change in the study design giving subjects originally 
randomised to the LPV/RTV arm the option to switch to the DTG arm prior to study 
completion.  This change is being implemented following an IDMC recommendation to 
discontinue the LPV/RTV arm.  Revisions to the Suicidality Monitoring and data analysis 
sections and edits to the Time and Events Table are also included.  Other minor 
clarifications and corrections have been incorporated.
2013N172672_03
2018-JUN-19
Amendment No. 3
This amendment includes changes 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. The changes include updates to the 
Risk Assessment and acceptable methods of contraception, and a reminder that females 
of childbearing potential who change their minds and desire to be pregnant or who do not 
wish to comply with the approved pregnancy avoidance methods, should be withdrawn 
from the study.  Investigators are also reminded to check at every visit that females of 
childbearing potential are avoiding pregnancy. Other minor clarifications and corrections 
have been incorporated.

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M E DI C A L M O NI T O R /S P O N S O R I N F O R M A T I O N P A G E
Cli nic al St u d y I de ntifier: 2 0 0 3 0 4
T his st u d y  is s p o ns ore d b y Vii V Healt hcare.  Gla x o S mit h Kli ne is s u p p orti n g Vii V 
Healt hcare i n t he c o n d uct of t h is st u d y.
S p o ns or N a me a n d Le g al Re gistere d A d dress (e xcl u di n g U S) :
Vii V Healt hcare U K L i mite d
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
U S I N D S p o ns or N a me a n d Le g al Re gistere d A d dress:
Vii V Healt hcare C o m pa n y
Fi ve M o ore Dri ve 
P. O. 1 3 3 9 8
Resea rc h Tria n gle Par k, N C 2 7 7 0 9-3 3 9 8, U S A
Tele p h o ne: + 1 9 1 9 4 8 3 2 1 0 0
I n s o me c o u ntries, l ocal la w re q uires t hat t he Cli nical Trial s p o ns or is a l ocal c o m pa ny 
le gal e ntit y. I n t hese i nsta nces, t he a p pr o priate c o m pa n y t o be i de ntifie d as s p o ns or m ust 
be a gree d wit h t he gl o bal Vii V Healt hcare cli nical tea m a n d si g ne d off b y t he V P a n d 
Hea d, Gl o bal Researc h a n d Me dical Strate g y .
Me dic al M o nit or C o nt act I nf or m ati o n a n d Seri o us A d verse E ve nts ( S A E) C o nt act 
I nf or m ati o n: 
, M D, P h D 
Vii V Healt h care
9 8 0 Great West R oa d
Bre ntf or d , 
Mi d dlese x , T W 8 9 G S
U K
M o bile: +
Sec o n dar y  c o ntact:
, M D
Vii V Healt hcare
5 M o ore Dri ve
Researc h Tria n gle Par k, N C 2 7 7 0 9
U S A
M o bile: +
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):
E u dra C T: 2 0 1 4 - 0 0 1 0 5 7- 1 7
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200304
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....................................................................................................18
1.1.
Background ................................................................................................18
1.2.
Rationale ....................................................................................................20
1.3.
Benefit:Risk Assessment ............................................................................20
1.3.1.
Risk Assessment .........................................................................20
1.3.2.
Benefit Assessment.....................................................................25
1.3.2.1.
Analysis of subjects receiving DTG + 1-2 
NRTIs in SAILING ......................................................25
1.3.3.
Overall Benefit:Risk Conclusion...................................................26
2.
OBJECTIVES.........................................................................................................26
3.
INVESTIGATIONAL PLAN.....................................................................................27
3.1.
Study Design ..............................................................................................27
3.2.
Discussion of Design ..................................................................................31
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................32
4.1.
Number of Subjects ....................................................................................32
4.2.
Inclusion Criteria.........................................................................................32
4.3.
Exclusion Criteria........................................................................................35
4.4.
Other Eligibility Criteria Considerations.......................................................36
4.5.
Withdrawal Criteria .....................................................................................37
4.6.
Virologic Criteria for Subject Management and Viral Resistance 
Testing........................................................................................................38
4.6.1.
Virologic Withdrawal Criteria........................................................39
4.6.2.
Managing Subjects Meeting Suspected Virologic 
Withdrawal Criteria ......................................................................39
4.6.3.
Managing Subjects Meeting Confirmed Virologic 
Withdrawal Criteria ......................................................................40
4.7.
Retest Criteria for Subjects with Plasma HIV-1 RNA Levels between 
50 c/mL and <400 c/mL at Week 48..........................................................41
4.8.
Screening Failures......................................................................................41
5.
STUDY TREATMENTS..........................................................................................41
5.1.
Investigational Product and Other Study Treatment....................................41
5.1.1.
Tablet Formulation of DTG ..........................................................42
5.1.2.
Tablet Formulation of LPV/RTV ...................................................42
5.1.3.
Background NRTIs ......................................................................42
5.1.4.
Dosage and Administration..........................................................43
5.1.5.
Protocol-Permitted Substitutions..................................................43
5.2.
Treatment Assignment................................................................................44
5.3.
Blinding.......................................................................................................44
5.4.
Product Accountability ................................................................................44
5.5.
Treatment Compliance................................................................................45

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5.6.
Concomitant Medications and Non-Drug Therapies....................................45
5.6.1.
Permitted Medications and Non-Drug Therapies..........................45
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................46
5.6.3.
Prohibited medications for subjects randomised to DTG..............46
5.6.4.
Prohibited medications for subjects randomised to 
LPV/RTV......................................................................................47
5.7.
Treatment of Tuberculosis ..........................................................................48
5.8.
Treatment after the End of the Study ..........................................................48
5.9.
Treatment of Study Treatment Overdose....................................................49
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................50
6.1.
Time and Events Schedule .........................................................................50
6.2.
Critical Screening and Baseline Assessments ............................................54
6.2.1.
Screening Assessments ..............................................................54
6.2.2.
Baseline (Day 1) Assessments ....................................................55
6.2.3.
Subjects Co-infected with Hepatitis B Virus (HBV).......................55
6.2.4.
Subjects Co-infected with Hepatitis C Virus (HCV) ......................56
6.3.
Efficacy.......................................................................................................56
6.3.1.
Efficacy Evaluations.....................................................................56
6.3.2.
Primary Endpoint .........................................................................57
6.3.3.
Secondary Efficacy Endpoints .....................................................57
6.4.
Safety .........................................................................................................57
6.4.1.
Safety Evaluations.......................................................................57
6.4.2.
Safety Endpoints..........................................................................58
6.4.3.
Toxicity Management...................................................................59
6.4.4.
Specific Toxicities/Adverse Event Management...........................60
6.4.4.1.
Liver chemistry stopping and follow up criteria............61
6.4.4.2.
Restarting investigational product...............................63
6.4.4.3.
Hypertriglyceridemia/hypercholesterolemia ................64
6.4.4.4.
CPK elevation.............................................................64
6.4.4.5.
Decline in renal function .............................................64
6.4.4.6.
Allergic reaction..........................................................65
6.4.4.7.
Rash...........................................................................65
6.4.5.
Adverse Events............................................................................66
6.4.5.1.
Definition of an AE......................................................66
6.4.5.2.
Definition of an SAE ...................................................67
6.4.6.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................68
6.4.7.
Cardiovascular Events.................................................................69
6.4.8.
Death Events...............................................................................69
6.4.9.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................69
6.4.10.
Suicidality Monitoring...................................................................70
6.4.11.
Pregnancy ...................................................................................70
6.4.11.1.
Pregnancy testing.......................................................70
6.4.11.2.
Action to be taken if pregnancy occurs .......................71
6.4.11.3.
Time period for collecting pregnancy
information .................................................................71
6.4.12.
Time Period and Frequency of Detecting AEs and SAEs.............71
6.4.13.
Method of Detecting AEs and SAEs.............................................72
6.4.14.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................72

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6.4.14.1.
Regulatory reporting requirements for SAEs ..............73
6.4.15.
Other Safety Outcomes ...............................................................74
6.5.
Health Outcomes........................................................................................74
6.5.1.
Health Outcome Endpoints ..........................................................75
6.6.
Viral Genotyping and Phenotyping..............................................................75
6.6.1.
Virology Endpoint.........................................................................75
6.6.2.
HIV-1 Pol Viral Genotyping and Phenotyping...............................75
6.6.3.
HIV-1 Exploratory Analysis ..........................................................76
6.7.
Pharmacogenetic Research........................................................................76
7.
DATA MANAGEMENT ...........................................................................................76
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................77
8.1.
Hypotheses.................................................................................................77
8.2.
Study Design Considerations......................................................................77
8.2.1.
Sample Size Assumptions ...........................................................77
8.2.2.
Sample Size Sensitivity................................................................79
8.2.3.
Sample Size Re-estimation..........................................................79
8.3.
Data Analysis Considerations .....................................................................79
8.3.1.
Analysis Populations....................................................................79
8.3.2.
Analysis Data Sets.......................................................................80
8.3.3.
Treatment Comparisons ..............................................................81
8.3.3.1.
Primary comparisons of interest .................................81
8.3.3.2.
Other comparisons of interest.....................................81
8.3.3.3.
Secondary comparisons .............................................81
8.3.4.
Interim Analysis ...........................................................................82
8.3.4.1.
Week 24 data cut .......................................................82
8.3.4.2.
IDMC interim analyses ...............................................82
8.3.5.
Key Elements of Analysis Plan ....................................................84
8.3.5.1.
Efficacy analyses........................................................84
8.3.5.2.
Safety analyses..........................................................86
8.3.5.3.
Health outcomes analyses..........................................86
8.3.5.4.
Viral genotyping/phenotyping analyses.......................87
8.3.5.5.
Pharmacogenetic analyses.........................................87
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) ..............................................................88
9.4.
Quality Assurance.......................................................................................89
9.5.
Study and Site Closure ...............................................................................89
9.6.
Records Retention......................................................................................90
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................90
9.8.
Independent Data Monitoring Committee (IDMC) .......................................91
10. REFERENCES.......................................................................................................92
11. APPENDICES........................................................................................................96
11.1.
Appendix 1: Child-Pugh Classification ........................................................96
11.2.
Appendix 2: CDC Classification System for HIV-1 Infections (1993) ...........97

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11.3.
Appendix 3: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events...................................................................100
11.4.
Appendix 4: Liver Safety Drug Restart or Rechallenge Guidelines............118
11.5.
Appendix 5: Pharmacogenetic Research ..................................................124
11.6.
Appendix 6: Country Specific Requirements.............................................130
11.7.
Appendix 7: Protocol Changes..................................................................131
11.7.1.
Protocol Amendment 01 ............................................................131
11.7.2.
Protocol Amendment 02 ............................................................134
11.7.3.
Protocol Amendment 03 ............................................................142

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LIST OF ABBREVIATIONS
3TC
Lamivudine, EPIVIR
AE
Adverse event
ABC
Abacavir, ZIAGEN
ABC/3TC 
Abacavir/Lamivudine, EPZICOM, KIVEXA
ACTG
AIDS Clinical Trials Group
AIDS
Acquired immune deficiency syndrome
ALT
Alanine aminotransferase
anti-HBc
Antibody to hepatitis B core antigen
anti-HCV
Antibody to hepatitis C virus
APAP
Acetaminophen
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
ATV
Atazanavir, Reyataz
BUN
Blood urea nitrogen
c/mL
Copies/millilitre
CD4+
Helper-inducer T-lymphocyte having surface antigen CD4 
(cluster of differentiation 4)
CDC
Centers for Disease Control and Prevention
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
COBI
Cobicistat, Tybost
CPK
Creatine phosphokinase
CRF/eCRF
Case report form/electronic case report form
CSR
Clinical study report
C-SSRS
Columbia Suicidality Severity Rating Scale
d4T
Stavudine
DAIDS
Division of Acquired Immune Deficiency Syndrome
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
DTG
Dolutegravir
ECG
Electrocardiograph
EFV
Efavirenz
ELV
Elvitegravir
EMA
European Medicines Agency
FDA
Food and Drug Administration
FTC
Emtricitabine
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance  
GFR
Glomerular filtration rate
GI
Gastrointestinal
GSK
GlaxoSmithKline
GSRS
Gastrointestinal Symptom Rating Scale
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus

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HDL
High density lipoprotein
HDPE
High density polyethylene
HIV-1
Human immunodeficiency virus type 1
HIVTSQ
HIV Treatment Satisfaction Questionnaire
HIVTSQs
HIVTSQ status version
HIVTSQc
HIVTSQ change version
HLA
Human leukocyte antigen
HSR
Hypersensitivity reaction
IB
Investigator’s brochure
ICH
International Conference on Harmonization 
IDMC
Independent data monitoring committee
IEC
Independent ethics committee
IgM
Immunoglobulin M
INI
Integrase inhibitor
IP
Investigational product
IRB
Institutional review board
IRIS
Immune reconstitution inflammatory syndrome
ITT
Intent to Treat
IUD
Intrauterine device
IVRS
Interactive voice recognition system
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
LLOD
Lower limit of detection
LPV/RTV
Lopinavir/ritonavir, Kaletra
LSLV
Last subject’s last visit
MCV
Mean corpuscular volume
MMAS-8
Morisky 8-Item Medication Adherence Scale
MSDF
Missing, switch or discontinuation = failure
MSDS
Material safety data sheet 
mg
Milligram
mL
Millilitre
NCEP
National Cholesterol Education Program
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTI
Nucleoside reverse transcriptase inhibitor
OC
Observed case
OCT2
Organic cation transporter 2
PBMC
Peripheral blood mononuclear cell
PDVF
Protocol defined virologic failure
PGx
Pharmacogenetic
PI
Protease inhibitor
PK
Pharmacokinetic
Pol
Polymerase
PP
Per protocol
PRO
Protease
PSRAE
Possible suicidality related adverse event
QTC
Corrected QT interval
RAL
Raltegravir, Isentress
RAP
Reporting and analysis plan

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RBC
Red blood cells
RNA
Ribonucleic acid
RT
Reverse transcriptase
RTV
Ritonavir, Norvir
SAE
Serious adverse event
SDAC
Statistics Data Analysis Centre
SJS
Stevens Johnson Syndrome
SPM
Study procedure manual
STR
Single tablet regimen
TAM
Thymidine analogue mutation
TC
Total cholesterol
TEN
Toxic epidermal necrolysis
TDF
Tenofovir disoproxil fumarate, Viread
ULN
Upper limit of normal
US
United States
VSLC
ViiV Safety and Labeling Committee
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
EPIVIR
Atripla 
(efavirenz/tenofovir/emtricitabine)
EPZICOM
GenoSure
KIVEXA
Isentress (raltegravir)
TIVICAY
Kaletra (lopinavir/ritonavir)
TRIZIVIR
Monogram Biosciences
ZIAGEN
Norvir (ritonavir)
Phenosense
Quest Diagnostics
Reyataz (atazanavir)
Stribild (elvitegravir/cobicistat/ 
tenofovir/emtricitabine)
Tybost (cobicistat)
Vitekta (elvitegravir)

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PROTOCOL SUMMARY
Rationale
Access to antiretroviral therapy (ART) in low-income and middle-income countries has 
been scaled-up effectively over recent years. Despite these advances, the number of 
patients failing on their first-line regimen is increasing thereby requiring a switch to 
second-line treatment to reduce accumulation of drug-resistance mutations, disease 
progression, human immunodeficiency virus (HIV) transmission, and death.  Publicly 
funded programmes tend to follow World Health Organization (WHO) guidelines to use 
a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside 
reverse transcriptase inhibitors (NRTIs) for first-line ART; however, there is a need for 
further data on the best treatment options for people with HIV-1 who have virological 
failure with this first-line regimen.  WHO guidelines recommend second-line 
antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease 
inhibitor (PI); atazanavir plus ritonavir (ATV+RTV) or lopinavir (LPV)/RTV are the 
preferred boosted PI options.
Several studies have been conducted or are currently underway to investigate novel 
treatment strategies (i.e. NRTI-sparing regimens) in patients requiring second-line ART.  
There are currently no studies ongoing to explore the potential option of PI-sparing 
second-line ART.  This strategy, especially with the availability of agents from non-PI 
classes with a high barrier to resistance, may have some advantages over PI-based 
regimens, particularly from a safety and tolerability perspective.  This study compares a 
second-line regimen of dolutegravir (DTG) plus two NRTIs with a WHO-recommended 
regimen of LPV/RTV plus two NRTIs.
Objectives
Primary Objective

To demonstrate non-inferior antiviral activity at 48 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a WHO-recommended 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy.
Secondary Objectives

To demonstrate non-inferior antiviral activity at 24 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a recommended WHO 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy;

To evaluate the antiviral and immunological activity and incidence of disease 
progression (HIV-associated conditions, AIDS and death) of DTG compared to 
LPV/RTV over time;

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
To assess the development of viral resistance in subjects meeting confirmed 
virologic withdrawal criteria;

To evaluate the safety, tolerability, and laboratory parameters of DTG compared to 
LPV/RTV over time; 

To compare the effects of DTG and LPV/RTV on fasting lipids over time;

To compare the effects of DTG and LPV/RTV on the occurrence of gastrointestinal 
adverse events over time;

To compare the change in gastrointestinal symptom rating score for subjects treated 
with DTG and LPV/RTV over time;

To compare the satisfaction with treatment of patients with DTG compared to the 
LPV/RTV over time;

To compare patients’ adherence with DTG compared to the LPV/RTV over time;

To evaluate the effect of patient demographics and baseline characteristics (e.g. 
demographic factors, HIV-1 subtype, baseline CD4+ cell count) on response to DTG 
compared to LPV/RTV over time.
Study Design
This study is a Phase IIIb, randomised, open-label, active-controlled, multicenter, parallel 
group, non-inferiority study.  Approximately 612 adult patients with confirmed virologic 
failure (HIV-1 RNA 400 copies/mL [c/mL] on two occasions) on their first 
antiretroviral regimen consisting of one NNRTI + two NRTIs will be recruited.  Subjects 
will be randomised 1:1 to receive DTG 50 mg once daily or LPV/RTV (800/200 mg once 
daily or 400/100 mg twice daily, in accordance with investigator decision and local 
label), each added to an investigator selected background regimen consisting of two 
NRTIs.  The background regimen shall be constructed by the investigator based on viral 
resistance testing at Screening and be composed of at least one fully active NRTI plus 
one more NRTI which may or may not be active.  In consultation with the medical 
monitor, lamivudine (3TC) may be added as a third NRTI to a dual-NRTI background 
regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC 
(e.g. M184V).  3TC cannot be added to regimens that include FTC. 
Randomisation will be stratified by Screening plasma HIV-1 RNA (100,000 c/mL or 
>100,000 c/mL) and number of fully active NRTIs in the investigator selected study 
background regimen (2 versus <2).
The study will comprise a Screening Phase (approximately 28 to 42 days), a Randomised 
Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase.
The 4-week treatment extension up to Week 52 within the Randomised Phase is to allow 
for the collection of a confirmatory viral load measurement in subjects presenting with 
HIV-1 RNA 50 c/mL at the Week 48 visit.  The primary efficacy endpoint corresponds 

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to viral load measurements collected within a 6 week window around the Week 48 visit 
(including data from the Week 52 visit), as per the FDA’s Snapshot algorithm, and for 
this reason, the primary analysis is denoted as occurring at Week 48 with the 
understanding that data from the Week 52 visit may be included.
The primary analysis at Week 48 will take place after the last subject completes 52 weeks 
on therapy (Day 1 to Week 48 plus a 4-week treatment extension). An interim analysis 
and data cut will be conducted after the last subject completes 24 weeks on therapy, with 
the intent to provide an earlier assessment of efficacy to inform the Sponsor and 
clinicians.  A switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily 
and the opposite switch and a single change of one of the background NRTIs for toxicity 
or tolerability management is allowed.  Any NRTI change must ensure a fully active 
NRTI is still present based on Screening resistance testing. A switch from 3TC to 
emtricitabine (FTC) (or vice versa) will not be considered a background NRTI change 
and is permitted.  No other dose reductions, modifications in dosage, or changes in the 
frequency of dosing will be allowed in this study.
Subjects randomised to receive DTG who successfully complete 52 weeks of treatment 
will continue to have access to DTG (Continuation Phase) until it is either locally 
approved and commercial supplies are available to patients (e.g. through public health 
services), the patient no longer derives clinical benefit, or the patient meets a protocol-
defined reason for discontinuation.  Subjects randomised to the LPV/RTV arm will 
receive LPV/RTV through their Week 48 visit and during the 4-week treatment extension
only, after which they will complete the study and will need to have alternate 
arrangements in place to access antiretroviral medication.
An IDMC has been instituted to perform periodic reviews of the accumulating data to 
ensure that subjects are not being sub-optimally treated.  The IDMC completed two of 
the three pre-planned analyses.  Prior to interim analysis #3, the IDMC conducted 
an ad-hoc review of trial data and observed significant, clinically relevant 
differences between treatment arms in favour of DTG.  The IDMC recommended to 
the sponsor that the LPV/RTV treatment arm be discontinued and subjects
currently receiving LPV/RTV in the study be switched to a regimen with DTG as 
the third drug, if considered appropriate by the Investigator.  As per Protocol 
Amendment No. 2, subjects randomised to the LPV/RTV arm will either (i) continue 
receiving LPV/RTV and complete the study after the 4-week treatment extension 
(see above), or (ii) switch to the DTG arm prior to study completion at Week 52 and
continue to have access to DTG in the Continuation Phase until DTG is either 
locally approved and commercial supplies are available to patients (e.g. through 
public health services), the patient no longer derives clinical benefit, or the patient 
meets a protocol-defined reason for discontinuation.  Subjects originally randomised 
to DTG and receiving DTG in the Randomised Phase or in the Continuation Phase 
are not affected by this IDMC recommendation and Protocol Amendment No. 2.

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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 (Missing, Switch or 
Discontinuation = Failure) for the intent-to-treat exposed (ITT-E) population.
Secondary efficacy endpoints will include: 

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 <400 c/mL at Weeks 24 and 48 
using the Snapshot algorithm;

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, safety stopping criteria, and lack 
of efficacy);

Time to viral suppression (HIV-1 RNA <50 c/mL);

Absolute values and changes from Baseline in CD4+ cell counts at Weeks 24 and 48;

Incidence of disease progression (HIV-associated conditions, AIDS and death).
Safety endpoints will include: 

Incidence and severity of AEs and laboratory abnormalities; 

Absolute values and changes over time in laboratory parameters; 

Change from Baseline in fasting LDL cholesterol at Weeks 24 and 48; 

Change from Baseline in fasting TC/HDL ratio at Weeks 24 and 48;

Incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Weeks 24 and 48; 

Incidence of maximum post-Baseline emergent Grade 2 or greater drug-related 
diarrhoea by Weeks 24 and 48;

Proportion of subjects who discontinue treatment due to AEs. 
Health outcome endpoints will include: 

Change from Baseline, using the Gastrointestinal Symptom Rating Scale (GSRS), at 
Week 4, Week 24, and Week 48; 

Change from Baseline in treatment satisfaction, using the HIV-Treatment 
Satisfaction Questionnaire (HIVTSQ), at Weeks 4, 24, and 48;

Change from Baseline in adherence with treatment, using the Morisky Medication 
Adherence eight item scale (MMAS-8), at Weeks 4, 24 and 48.
Virology endpoints will include:

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
Incidence of treatment-emergent genotypic and phenotypic resistance to DTG, 
LPV/RTV and other on-study ART in subjects meeting confirmed virologic 
withdrawal criteria.

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1.
INTRODUCTION
1.1.
Background
Integrase inhibitors (INIs) are a relatively new class of antiretroviral drugs designed to 
block the action of the integrase viral enzyme, which catalyzes several key steps in the 
human immunodeficiency virus type 1 (HIV-1) life cycle and is responsible for insertion 
of the viral genome into the deoxyribonucleic acid (DNA) of the host cell. Since 
integration is an essential step in retroviral replication, it is an attractive target for HIV 
therapy.  The first HIV INI, raltegravir (RAL) [Isentress Package Insert, 2013; Isentress, 
Summary of Product Characteristics, 2013], was approved by the United States (US) 
Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2007.  
Elvitegravir (ELV), another HIV INI, was approved by the US FDA in 2012 and by the 
EMA in 2013 as part of a single tablet regimen (STR) with cobicistat (COBI), tenofovir 
(TDF), and emtricitabine (FTC) [Stribild Package Insert, 2013; Stribild Summary of 
Product Characteristics, 2013] as well as for use as an individual drug by the EMA in 
November 2013 [Vitekta Summary of Product Characteristics, 2013].  
Dolutegravir (DTG) is a next-generation INI with low-moderate inter-subject 
pharmacokinetic variability, a predictable exposure-response relationship and a 14-hour 
plasma half-life that supports once daily dosing without the need for the PK boosters that 
are required with ELV.  DTG was approved by the US FDA in August 2013 and by the 
EMA in January 2014 [TIVICAY Package Insert, 2017; TIVICAY Summary of Product 
Characteristics, 2017].
To date, the efficacy, pharmacokinetics, safety and drug interaction potential of DTG 
have been evaluated in an extensive program of Phase I to III clinical trials.  Data are 
summarised in the Investigator’s Brochure (IB [GlaxoSmithKline Document Number 
.RM2007/00683/11]; IB Supplement 01 [GlaxoSmithKline Document Number
[2017N352880_00]; IB Supplement 02 [GlaxoSmithKline Document Number
2017N352880_01]).  In both antiretroviral therapy (ART)-naïve and ART-experienced 
(INI- naïve) patients, the safety profile for DTG 50 mg once daily was comparable to 
RAL and darunavir plus ritonavir (DRV+RTV) and generally favourable to the STR of 
efavirenz (EFV)/TDF/FTC (Atripla) (studies ING113086 [SPRING-2], ING111762 
[SAILING], ING114915 [FLAMINGO] and ING114467 [SINGLE]).  The most 
frequently observed AEs across patient populations were diarrhoea, 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 efficacious, and non-
inferior to RAL in combination with a dual nucleoside reverse transcriptase inhibitor 
(NRTI) background regimen [SPRING-2].  In study ING114915 [FLAMINGO], 
virologic suppression (HIV-1 RNA <50 copies/mL [c/mL]) in the DTG arm was 
statistically superior to the DRV+RTV arm at Week 48.  DTG used in combination with 
abacavir/lamivudine (ABC/3TC, EPZICOM/KIVEXA™) was also shown to be superior 
to EFV/TDF/FTC at Week 48, a result driven by better tolerability of the DTG-based 
regimen [SINGLE].  DTG also demonstrated superior virologic suppression (HIV-1 RNA 
<50 c/mL) compared with RAL in combination with investigator selected two drug 
background regimen for INI-naïve treatment experienced patients in the Phase III study 

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ING111762 [SAILING].  Finally, DTG also showed good efficacy in ART-experienced 
patients with INI resistance in ING112574 [VIKING-3].  
Furthermore, DTG 50 mg once daily may have a higher barrier to resistance in INI-naive 
patients, as suggested in the treatment-experienced (INI-naive) SAILING study where 
significantly fewer virologic failures with INI resistance were observed when compared 
with RAL. Data from Phase III studies [SPRING-2, SINGLE and FLAMINGO] in 
treatment-naive subjects are also supportive of a high barrier to resistance.
Access to ART in low-income and middle-income countries has been scaled-up 
effectively over recent years reaching 8 million people by the end of 2011 [UNAIDS, 
2012]. Despite these advances, the number of patients failing on their first-line regimen is 
increasing thereby requiring a switch to second-line treatment to reduce accumulation of 
drug-resistance mutations, disease progression, HIV transmission, and death [WHO, 
2011].  Publicly funded programmes tend to follow WHO guidelines to use a non-
nucleoside reverse transcriptase inhibitor (NNRTI) combined with two NRTIs for first-
line ART [WHO, 2013; WHO, 2016]; however, there is a need for further data on the 
best treatment options for people with HIV-1 who have virological failure with this first-
line regimen. WHO guidelines recommend second-line ART for adults consisting of two 
NRTIs + a ritonavir-boosted protease inhibitor (PI) with atazanavir (ATV)+RTV or 
LPV/RTV as the preferred boosted PI options [WHO, 2013; WHO, 2016].
In many low to middle income countries, LPV/RTV is the most widely used PI for 
second-line ART although the use of ATV+RTV is increasing. LPV/RTV is associated 
with lipid and gastrointestinal side effects [Molina, 2008; Ortiz, 2008; Mills, 2009].  PIs 
have also been associated with increased risk of decreased bone mineral density, renal 
impairment and cardiovascular disease, although the pathogenesis of complications in 
each organ is multi-factorial and complex [Brown, 2006; Ryom, 2013; Currier, 2008].  
A sequence of second-line NRTI options are recommended based on the likely activity of 
each NRTI against predicted resistance to ZDV/stavudine (d4T), 3TC/FTC and/or TDF 
when used in first line treatment [WHO, 2013; WHO, 2016]. This strategy is particularly 
useful in settings where resistance testing is not available. Depending on the development 
of resistance and taking into account local standard of care as well as drug availability, 
other NRTIs such as abacavir (ABC) may be considered in other settings.
Several studies have been conducted or are currently underway to investigate novel 
treatment strategies (i.e. NRTI-sparing regimens) in patients requiring second-line ART.  
The SECOND-LINE Study is a randomised clinical trial, which has demonstrated that the 
efficacy of a novel dual-treatment approach combining LPV/RTV with the integrase 
inhibitor (INI) raltegravir (RAL) was non-inferior to a WHO-recommended second-line 
treatment regimen of LPV/RTV plus two or three NRTIs over 96 weeks [SECOND-LINE 
Study Group, 2013]. Findings from this study show that the WHO-recommended second-
line treatment is an efficacious rescue regimen and also provide evidence for an 
alternative NRTI-sparing approach. In the Europe-Africa Research Network for 
Evaluation of Second-line Therapy (EARNEST) Trial, a second-line regimen consisting 
of LPV/RTV (400 mg/100 mg twice daily) plus two NRTIs has also led to good 

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outcomes; the NRTI-sparing regimen with LPV/RTV plus RAL evaluated in the study 
was not superior, and LPV/RTV monotherapy was inferior [Paton, 2013].
The HIV STAR study showed that in patients failing initial therapy on an NNRTI + two 
NRTI regimen, treatment with LPV/RTV monotherapy led to a significantly lower 
proportion of patients achieving HIV RNA <50 c/mL at Week 48 compared to LPV/RTV 
+ TDF/FTC treatment [Bunupuradah, 2012].
The 2LADY study (ANRS 12169) is a clinical trial evaluating three different second-line 
combinations (LPV/RTV + TDF/FTC, LPV/RTV + ABC + ddI, and DRV + RTV + 
TDF/FTC) in Sub-Saharan Africa enrolling patients on ART who meet the WHO 
immunologic or clinical failure criteria.  After undergoing a month of adherence support, 
patients are randomised to one of the three arms of the study unless they show a 
significant decrease of viral load and are kept on first-line therapy [Mazoyer, 2010]. The 
96-week SELECT Study (A5273) compares, like the SECOND-LINE Study, two second-
line regimens, LPV/RTV with RAL versus LPV/RTV plus two or three NRTIs [ACTG, 
2014].
1.2.
Rationale
There are currently no studies ongoing to explore the potential option of PI-sparing 
second-line ART.  This strategy, especially with the availability of agents from non-PI 
classes with a high barrier to resistance, may have some advantages over PI-based 
regimens, particularly from a safety and tolerability perspective.  This study compares a 
second-line regimen of DTG plus two NRTIs with a WHO-recommended regimen of 
LPV/RTV with two NRTIs.
1.3.
Benefit:Risk Assessment
Summaries of DTG can be found in the IB [GlaxoSmithKline Document Number
RM2007/00683/11, GlaxoSmithKline Document Number 2017N352880_00, and 
GlaxoSmithKline Document Number 2017N352880_01].  The following section outlines 
the risk assessment and mitigation strategy for DTG in this protocol.  Where available, 
the approved country product label should be referenced.
For LPV/RTV and background NRTIs, the approved country product labels should be 
referenced.  The comparator regimen, LPV/RTV plus two NRTIs, is a preferred treatment 
regimen for HIV-infected patients requiring second-line ART according to current WHO 
guidelines [WHO, 2013; WHO, 2016].
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 as follows:

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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1
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 6.4.4.6) and rash (Section 6.4.4.7).
The subject informed consent form includes information on this risk 
and the actions subjects should take in the event of an HSR 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 B virus (HBV) and/or hepatitis C virus (HCV) co-infection, 
improvements in immunosuppression as a result of HIV virologic and 
immunologic responses to DTG- containing ART, along with inadequate 
therapy for HBV co-infected subjects, likely contributed to significant 
elevations in liver chemistries.  
Subjects meeting either of the following criteria during the screening 
period are excluded from participating (Section 4.3).

Alanine aminotransferase (ALT) 5 times the upper limit of 
normal (ULN) or ALT 3xULN and bilirubin 1.5xULN (with 
>35% direct bilirubin)

Subjects with an anticipated need for hepatitis C virus (HCV) 
therapy during the Randomised Phase (Day 1 to Week 48 plus 
a 4-week treatment extension)
Investigators should consult current treatment guidelines when 
considering choice of NRTIs for subjects with chronic HBV infection.  
Additional treatment considerations should be guided by local 
treatment guidelines.  Adequate HBV therapy must be administered 
to subjects with chronic HBV infection (see Section 6.2.3).
Specific/detailed liver stopping criteria and toxicity management 
guidance is provided for suspected DILI or other clinically significant 
liver chemistry elevations (Section 6.4.4.1).  

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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
Theoretical serious drug 
interaction with dofetilide and
pilsicainide
Co-administration of DTG may increase dofetilide/pilsicainide plasma 
concentration via inhibition of organic cation transporter (OCT2) transporter, 
resulting in potentially life-threatening toxicity. 
The co-administration of DTG with dofetilide or pilsicainide is 
prohibited in the study (Section 5.6.3).
Gastrointestinal (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 
with DTG treatment in a small proportion of subjects; however there were no 
indications of an increased risk for peptic ulcers or serious erosions.
Routine monitoring of GI symptoms will be performed.
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 6.4.4.5). 
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 to RAL- or favourable compared with EFV-based regimens. 
The reporting rate for insomnia was statistically higher for blinded 
DTG+ABC/3TC compared to 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 
6.4.4.4).

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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on DTG
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 B or 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 to 
RAL, and withdrawal (or lack) of HBV active therapy in HIV/HBV co-infected 
subjects.  
Subjects will have frequent liver chemistry monitoring.  Robust liver 
chemistry stopping criteria and liver event follow up assessments 
are included.  Investigators are expected to follow local HBV and 
HCV treatment guidelines (see Section 6.2.3. and Section 6.2.4).
Functional monotherapy with 
DTG or LPV/RTV
Subjects are at risk of receiving functional monotherapy with their second-line 
regimen due to recycling of NRTIs to which their virus has already developed 
partial or full resistance.
The study requires that eligible subjects receive at least one fully 
active NRTI within the background regimen based on Screening 
genotypic resistance testing results as well as prior treatment history 
and, if available, any previous genotypic (and phenotypic) results 
showing resistance to an agent; a lack of resistance in previous 
results does not confirm susceptibility.  
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, 
and, if she is a female of childbearing potential, agrees to follow 
one of the options for prevention of pregnancy listed in the
Inclusion Criterion 2 (see Section 4.2) during treatment with 
study drug and until at least 2 weeks after the last dose of 
study medication.
2. Women who become pregnant, or who desire to be pregnant 
while in the study will have study treatment discontinued and 
be withdrawn from the study.
3. Females of childbearing potential are reminded re: pregnancy 
avoidance and adherence to contraception requirements at 
every study visit.
4. Pregnancy status is monitored at every study visit.

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1. 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 GlaxoSmithKline (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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1.3.2.
Benefit Assessment
DTG is conveniently dosed once daily, without need for a PK booster or food/fluid 
restrictions, and with limited safety implications resulting from theoretical or actual drug: 
drug interactions compared to other antiretroviral agents (including EFV and those 
requiring a PK booster).
The safety profile for DTG 50 mg once daily was comparable to RAL and DRV+RTV 
and generally favourable 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 diarrhoea, 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+RTV 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]. Excellent antiviral activity 
of DTG in patients with INI resistance was demonstrated in study ING112574 [VIKING-
3].  
Furthermore, DTG 50 mg once daily may have a higher barrier to resistance than RAL in 
INI-naïve patients. 
Uncertainty remains about the best treatment for HIV-1 infected patients who have 
virological failure with first-line ART of an NNRTI + two NRTIs. This study compares a 
new PI-sparing second-line regimen with a WHO-recommended regimen. This strategy, 
especially with the availability of agents from non-PI classes with a high barrier to 
resistance, may have some advantages over PI-based regimens, particularly from a safety 
and tolerability perspective.
The study requires that eligible subjects receive at least one fully active NRTI within the 
background regimen based on Screening genotypic resistance testing results. Previous 
genotypic (and phenotypic) results can provide evidence of resistance but cannot provide 
proof of a lack of resistance.  
Study participants may also benefit from the medical tests and screening procedures 
performed as part of the study.
1.3.2.1.
Analysis of subjects receiving DTG + 1-2 NRTIs in SAILING
In order to inform the study design, an exploratory analysis of subjects receiving DTG + 
1-2 NRTIs in ING111762 (SAILING) was conducted.  SAILING compared DTG and 

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raltegravir (RAL) in combination with up to two investigator selected background 
antiretroviral drugs (at least 1 being fully active) in antiretroviral therapy-experienced, 
integrase inhibitor-naïve adults with ongoing virologic failure and at least two-class drug 
resistance [Cahn, 2013].  Of the 715 subjects randomised, 32 subjects in each arm 
received an NRTI-based background regimen; all subjects received two NRTIs except for 
one subject in the DTG arm receiving only one NRTI. 
None of the 32 subjects in the DTG arm experienced protocol defined virologic failure 
(PDVF) by Week 48, including no cases of virologic failure in 13 subjects receiving less 
than 2 fully active NRTIs by phenotype (12 received one fully active NRTI and 1 
received two inactive NRTIs).  In the RAL arm, 7/32 (22%) of subjects experienced 
PDVF by Week 48, of which 4/13 (31%) experienced failure with 1 fully active NRTI 
and 3/19 (16%) failed with 2 fully active NRTIs.  Of the 13 subjects who had the M184V 
mutation detected at baseline and received DTG + 3TC/FTC + a second NRTI, none met 
PDVF criteria, including 10 subjects for whom the second NRTI was active (by 
phenotype) and 3 subjects with 2 or more thymidine analogue mutations (TAMs). Four of 
12 subjects (33%) who received RAL + 3TC/FTC + a second NRTI in the setting of 
baseline M184V experienced PDVF, despite the fact that the second NRTI was active by 
phenotype in all these cases.   
Based on this exploratory analysis, DTG + two NRTIs appears to have good activity 
through 48 weeks in treatment-experienced patients who are experiencing virologic 
failure when at least one of NRTIs was fully active by phenotype.  However, the sample 
size is small, and an increased risk of virologic failure in subjects receiving DTG with 
less than two fully active NRTIs cannot be ruled out based on these data alone.
1.3.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the potential risks identified in association with DTG are justified by the 
anticipated benefits that may be afforded to HIV-1 infected adults with treatment failure 
on first line therapy.
2.
OBJECTIVES
Primary Objective

To demonstrate non-inferior antiviral activity at 48 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a WHO-recommended 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy.
Secondary Objectives

To demonstrate non-inferior antiviral activity at 24 weeks of a DTG containing 
regimen (DTG 50 mg once daily + two NRTIs) compared to a recommended WHO 
standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-
1 infected patients failing first line therapy;

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
To evaluate the antiviral and immunological activity and incidence of disease 
progression (HIV-associated conditions, AIDS and death) of DTG compared to 
LPV/RTV over time;

To assess the development of viral resistance in subjects meeting confirmed 
virologic withdrawal criteria;

To evaluate the safety, tolerability, and laboratory parameters of DTG compared to 
LPV/RTV over time; 

To compare the effects of DTG and LPV/RTV on fasting lipids over time;

To compare the effects of DTG and LPV/RTV on the occurrence of gastrointestinal 
adverse events over time;

To compare the change in gastrointestinal symptom rating score for subjects treated 
with DTG and LPV/RTV over time;

To compare the satisfaction with treatment of patients with DTG compared to the 
LPV/RTV over time;

To compare patients’ adherence with DTG compared to the LPV/RTV over time;

To evaluate the effect of patient demographics and baseline characteristics (e.g. 
demographic factors, HIV-1 subtype, baseline CD4+ cell count) on response to DTG 
compared to LPV/RTV over time.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This study is a Phase IIIb, randomised, open-label, active-controlled, multicenter, parallel 
group, non-inferiority study.  
Approximately 612 adult patients with confirmed virologic failure (HIV-1 RNA 400 
c/mL on two occasions) on their first antiretroviral regimen consisting of one NNRTI + 
two NRTIs will be recruited.
Subjects will be randomised 1:1 to receive DTG 50 mg once daily or LPV/RTV (800/200 
mg once daily or 400/100 mg twice daily, in accordance with investigator decision and 
local label), each added to an investigator selected background regimen consisting of two 
NRTIs with at least one fully active NRTI (see Section 5.1.3).  In consultation with the 
medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background 
regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC 
(e.g. M184V) (see Section 6.2.3).
The primary analysis at Week 48 will take place after the last subject completes 52 weeks 
on therapy (Day 1 to Week 48 plus a 4-week treatment extension). An interim analysis 
and data cut will be conducted after the last subject completes 24 weeks on therapy, with 

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the intent to provide an earlier assessment of efficacy to inform the Sponsor and 
clinicians.  A switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily 
and the opposite switch and a single change of one of the background NRTIs for toxicity 
or tolerability management is allowed.  Any NRTI change must ensure a fully active 
NRTI is still present based on Screening resistance testing.  A switch from 3TC to FTC 
(or vice versa) will not be considered a background NRTI change and is permitted.  No 
other dose reductions, modifications in dosage, or changes in the frequency of dosing will 
be allowed in this study.
An IDMC has been instituted to perform periodic reviews of the accumulating data to 
ensure that subjects are not being sub-optimally treated.  The IDMC completed the first 
two of the three pre-planned analyses (see Section 8.3.4.2).  Prior to the third 
interim analysis, the IDMC conducted an ad hoc review of trial data and the IDMC 
observed significant, clinically relevant differences between treatment arms in 
favour of DTG.  The IDMC recommended to the sponsor that the LPV/RTV 
treatment arm be discontinued and subjects currently receiving LPV/RTV in the 
study be switched to a regimen with DTG as the third drug, if considered 
appropriate by the Investigator.
Assuming a true response rate of 70% for both DTG and LPV/r arms, the study requires 
306 subjects per arm to have 90% power with a 12% non-inferiority margin and a one-
sided 2.5% significance level (see Section 8.2.1).
The study design is summarised in Figure 1 and comprises the following Phases:
Screening Period
Randomisation may occur as soon as all Screening procedures have been completed and 
results are available and on file.  Subjects will participate in a Screening period of up to 
28 days, which may be extended to 42 days to ensure eligibility (e.g. receipt of final 
Screening laboratory results) and scheduling.  Eligibility criteria must be fulfilled by 
current resistance testing, i.e. Screening results.
Subjects are allowed to re-screen for this study one time; this will require a new subject 
number. A single repeat test (re-test) per analyte or assessment is allowed during the 
screening period to determine eligibility (with the exception of a disqualifying Screening 
genotype which may not be retested; however, a single repeat test for a failed genotype 
[no result] is permitted during the Screening period).
Randomised Phase: Day 1 to Week 48 + 4-week treatment extension
Subjects who fulfil eligibility requirements will be randomised 1:1 to receive DTG once 
daily + two NRTIs or LPV/RTV once or twice daily + two NRTIs.  The investigator 
selected background regimen must be determined and documented prior to randomisation 
and should take into account Screening genotypic resistance testing results as well as 
prior treatment history and, if available, any previous genotypic (and phenotypic) results.  
The background regimen shall be composed of at least one fully active NRTI based on 
Screening resistance testing plus one more NRTI which may or may not be active (as 

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defined in Section 5.1.3).  For further detail on the definition of full or partial activity, see
Section 5.1.3.
When constructing a subject’s background NRTI regimen, certain combinations of 
NRTIs are prohibited (see Section 5.1.3).  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 6.4.4, “Specific 
Toxicities/Adverse Event Management”.  Any NRTI change must ensure a fully active 
NRTI is still present based on Screening resistance testing.  A switch from 3TC to FTC 
(or vice versa) will not be considered a background NRTI change and will not incur a 
penalty as per the FDA’s Snapshot algorithm (Missing, Switch or Discontinuation = 
Failure) (see Section 6.3.2 and Section 8.3.2). 
In order to achieve balance across the two treatment groups of the study, randomisation 
will be stratified by:

Screening plasma HIV-1 RNA (100,000 c/mL or >100,000 c/mL);

Number of fully active NRTIs in the investigator selected background regimen 
based on Screening genotype (as defined in Section 5.1.3): 2 versus <2.
During the Randomised Phase, subjects will attend the clinic at Baseline/Day 1 and at 
Weeks 4, 8, 16, 24, 36, 48 and 52 of treatment. 
Subjects are considered to have completed the Randomised Phase of the study if they 
remain on therapy (i.e. have not permanently discontinued IP) through completion of the 
Week 52 visit.
Following the Week 48 visit, subjects will stay on their DTG or LPV/RTV-based 
regimen for another 4 weeks (i.e. the 4-week treatment extension).  Any subject with a 
viral load of 50 c/mL at Week 48 will have their viral load confirmed by a second 
measurement performed at the Week 52 visit.  As per the primary endpoint, if the retest 
viral load is <50 c/mL then the subject will be considered to have met the primary 
endpoint of virologic responder by FDA’s Snapshot algorithm at Week 48 (see Section 
6.3.2). If the retest viral load is 50 c/mL then the subject will be considered to be a 
virologic non-responder at Week 48 by Snapshot analysis.  Thus, the treatment extension 
up to Week 52 will allow for a robust assessment of treatment response in the primary 
endpoint analysis at Week 48 (windowed) as transient blips in HIV RNA 50 c/mL are 
censored.
All subjects will attend the clinic at Week 52.
Following the IDMC’s recommendation and as per Protocol Amendment No. 2, 
subjects randomised to the LPV/RTV arm will either (i) continue receiving 
LPV/RTV and complete the study after the 4-week treatment extension at Week 52, 
or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to 
have access to DTG in the Continuation Phase.

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The primary efficacy endpoint corresponds to viral load measurements collected within a 
6 week window around the Week 48 visit (including data from the Week 52 visit), as 
per the FDA’s Snapshot algorithm, and for this reason, the primary analysis is denoted as 
occurring at Week 48 with the understanding that data from the Week 52 visit may be 
included.
DTG Continuation Phase
Subjects randomised to receive DTG who successfully complete 52 weeks of treatment 
and subjects originally randomised to receive LPV/RTV but switched to DTG prior to 
Week 52 (as per Protocol Amendment No. 2) will continue to have access to DTG 
(Continuation Phase) until it is either locally approved and commercial supplies are 
available to patients (e.g. through public health services), the patient no longer derives 
clinical benefit, or the patient meets a protocol-defined reason for discontinuation.  
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure continued access to these medications during the DTG Continuation 
Phase (unless provision by the sponsor is mandated by local regulation).
Subjects randomised to the LPV/RTV arm will receive LPV/RTV + two NRTIs through 
their Week 52 visit only, after which subjects will complete the study and will need to 
have alternate arrangements in place to access antiretroviral medication (unless mandated 
by local regulation).  Subjects randomised to the LPV/RTV arm, who switch to the DTG 
arm prior to study completion at Week 52, will continue to have access to DTG 
(Continuation Phase) as mentioned above.
Study Completion
Subjects are considered to have completed the study if they satisfy one of the following:

Randomised to LPV/RTV + two NRTIs and completed the Randomised Phase 
including the Week 52 study visit;

Randomised to LPV/RTV + two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase including the Week 52 study visit, and did not enter 
the Continuation Phase;

Randomised to LPV/RTV+ two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase, including the Week 52 study visit, entered and 
completed the Continuation Phase (defined as remaining on study until commercial 
supplies of DTG become locally available to patients [e.g. through public health 
services]).

Randomised to DTG + two NRTIs, completed the Randomised Phase including the 
Week 52 study visit, and did not enter the Continuation Phase;

Randomised to DTG + two NRTIs, completed the Randomised Phase, including the 
Week 52 study visit, entered and completed the Continuation Phase (defined as 
remaining on study until commercial supplies of DTG become locally available to 
patients [e.g. through public health services]).

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Follow Up
Subjects with ongoing AEs or laboratory abnormalities considered to be AEs will attend 
a Follow-up visit approximately four weeks after their last dose of IP (DTG or 
LPV/RTV).  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.
Figure 1
Study Schematic
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 6.1), are essential and required for study 
conduct. 
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
The design of this study (1:1 randomised, open-label, active-controlled, multicentre, 
parallel group) is well established for confirming the non-inferiority of an investigational 
agent compared to an active comparator and is generally accepted by regulatory 
authorities as rigorous proof of antiviral activity.
The primary endpoint, proportion of subjects at Week 48 with plasma HIV-1 RNA below 
the assay lower limit of detection (LLOD, e.g. <50 c/mL), is a reasonable well-
established surrogate endpoint for prognosis of HIV-1 infection and disease progression.
LPV/RTV is one of two PIs currently recommended by WHO for treatment of patients 
experiencing virologic failure on a first line regimen [WHO, 2013; WHO, 2016] and is 
widely used (in combination with NRTIs) for second line treatment in low to middle 

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income countries. Several ongoing studies exploring the role of alternative treatment 
strategies in this patient group have similarly included LPV/RTV as the comparator 
[SECOND-LINE Study Group, 2013; Paton, 2013].
Consistent with other Phase IIIb and IV studies for other antiretrovirals, the potential for 
once or twice daily dosing of LPV/RTV and because of the concerns about pill burden, 
this study will be open-label.  However, no summaries of the study data according to 
actual randomised treatment groups will be available to sponsor staff prior to the planned 
Week 24 interim analysis.
An IDMC will be used to provide independent review of the accumulating data to ensure 
subjects are not being sub-optimally treated in either arm (see Section 8.3.4.2 and Section 
9.8). 
This study is designed to show the potency and safety of DTG compared to LPV/RTV in 
patients failing first-line ART and to explore the potential of DTG to be used as an 
alternative option to boosted PIs in second-line treatment regimens.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Sufficient subjects will be screened in order to ensure a total of approximately 612 
subjects will be randomised, approximately 306 to each study arm. Subjects will be 
enrolled from multiple geographic regions.
Subjects
Screened
~815
Randomised
~612
Evaluable
~612
All randomised and treated subjects (per the ITT-E definition, see Section 8.3.1) are 
considered evaluable for the primary efficacy analysis, with subjects who discontinue 
from the study prior to Week 48 being imputed as non-responders.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB, IB supplements, 
product labels, and/or local prescribing information.
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
Subjects are allowed to re-screen for this study one time; this will require a new subject 
number. A single repeat test (re-test) per analyte or assessment is allowed during the 

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Screening period to determine eligibility (with the exception of a disqualifying Screening 
genotype which may not be retested; however, a single repeat test for a failed genotype 
[no result] is permitted during the Screening period).  A subject that does not have a fully 
active NRTI based on a resistance test which is successful during Screening should not 
re-screen.
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).
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).
Laboratory results from central laboratory services provided by this trial will be used to 
assess eligibility.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
HIV-1 infected subjects 18 years of age.
2.
A female subject may be eligible to enter and participate in the study if she:
a.
is of non-childbearing potential defined as either post-menopausal (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 child-bearing 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 2 weeks after 
discontinuation of all study medication:

Complete abstinence from intercourse from 2 weeks prior to administration 
of IP.

Approved hormonal contraception for subjects randomised to the DTG arm 
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]

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o
Percutaneous contraceptive patches [Hatcher, 2011]

Approved hormonal contraception (as for subjects randomised to the DTG 
arm; see above) and a barrier method for subjects randomised to the 
LPV/RTV arm.

Intrauterine device or intrauterine system.

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.

Any other method with published data showing that the expected failure rate 
is <1% per year.
Any contraception method must be used consistently and in accordance with the 
approved product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception. Periodic abstinence (e.g. 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 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.
All subjects participating in the study should be counselled on safer sexual practices 
including the use of effective barrier methods (e.g. male condom/spermicide).
3.
HIV-1 infection as documented by HIV-1 RNA 400 c/mL at Screening. 
4.
Subject has been on a first-line treatment regimen consisting of an NNRTI plus two 
NRTIs for at least 6 months and is currently experiencing virologic failure to this 
first-line regimen defined as two consecutive (7 days apart) HIV-1 RNA results of 
400 c/mL (which can include Screening HIV-1 RNA results).
In addition to HIV-1 RNA 400 c/mL at Screening, at least one previous HIV-1 
RNA result of 400 c/mL within the 3 months prior to Screening must be 
documented.  If an additional HIV-1 RNA within 3 months prior to Screening is not 
available, a second HIV-1 RNA must be performed and have results 400 c/mL 
during the Screening period [after the first result is available and 7 days apart] to 
serve as a confirmatory sample.
5.
Subjects must receive at least one fully active agent within the dual-NRTI 
background regimen for second line treatment. Fully active is defined by the 
Screening genotypic resistance report of the central laboratory (or a laboratory 
contracted by the central laboratory) showing no evidence of full or of partial 
resistance for a given NRTI which will be taken on study.

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6.
Subject is PI-naïve and INI-naïve, defined as no prior or current exposure to any PI 
or INI.
7.
Subject or the subject’s legal representative is willing and able to understand and 
provide signed and dated written informed consent prior to screening.
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
A single repeat test (re-test) per analyte is allowed during the Screening period (with the 
exception of a disqualifying Screening genotype which may not be retested; however, a 
single repeat test for a failed genotype [no result] is permitted during the Screening 
period).
Subjects meeting any of the following criteria must not be enrolled in the study:
Exclusionary medical conditions
1.
Women who are breastfeeding.
2.
Any evidence of an active Centers for Disease Control and Prevention (CDC) 
Category C disease (Section 11.2). Exceptions include cutaneous Kaposi’s sarcoma 
not requiring systemic therapy and historic or current CD4+ cell levels <200 
cells/mm3.
3.
Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh 
classification (see Appendix 1, Section 11.1).
4.
Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's 
syndrome or asymptomatic gallstones).
5.
Anticipated need for hepatitis C virus (HCV) therapy during the Randomised Phase 
of the study.
6.
History or presence of allergy or intolerance to the study drugs or their components 
or drugs of their class.
7.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or 
resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial 
neoplasia; other localised malignancies require agreement between the investigator 
and the Study medical monitor for inclusion of the subject.
8.
Subjects who in the investigator’s judgment, poses a significant suicidality risk. 
Recent history of suicidal behaviour and/or suicidal ideation may be considered as 
evidence of serious suicide risk.

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Exclusionary Treatments prior to Screening or Day 1
9. Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
10. Treatment with any of the following agents within 28 days of Screening: 
radiation therapy,
cytotoxic chemotherapeutic agents,
systemically administered immunomodulators.
11. Treatment with any agent, other than licensed ART as allowed above (Section 4.2), 
with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of 
IP.  The exception is use of entecavir, in appropriate clinical situations, for treatment 
of hepatitis B (e.g. prior intolerance to TDF, viral resistance to 3TC /FTC) after 
discussion and agreement between the investigator and the medical monitor.
12. 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
13. Any evidence of primary viral resistance to PIs or INIs based on the presence of any 
major resistance-associated mutation [Johnson, 2013].
14. The subject’s virus does not yield results using genotype at Screening (assay data is 
essential for eligibility determination). 
15. 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. 
16. 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.
17. Alanine aminotransferase (ALT) 5 times the upper limit of normal (ULN) or ALT 
3xULN and bilirubin 1.5xULN (with >35% direct bilirubin).
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.

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4.5.
Withdrawal Criteria
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 Continuation Phase but permanently discontinue 
participation in the Continuation Phase prior to commercial supplies of DTG becoming 
available to patients (e.g. through public health services), are considered to be withdrawn 
from study treatment and also from the study.
A subject may voluntarily discontinue participation in this study at any time. The 
Investigator may also, at their discretion, discontinue the subject from participating in this 
study at any time. Withdrawn subjects will not be replaced.
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. 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 discontinued from the study for any of the following reasons:

Confirmed virologic withdrawal criteria as described in Section 4.6.1 are met;

Subject requires substitution or dose modification of DTG, or substitution of 
LPV/RTV (a switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice 
daily or the opposite switch is allowed; as per Protocol Amendment No. 2, a switch 
from LPV/RTV to DTG will also be allowed);

Subject requires a second switch of background therapy prior to Week 52 (one 
switch in NRTIs is allowed for toxicity management but any NRTI change must 
ensure a fully active NRTI is still present based on Screening resistance testing, see 
Section 6.4.4).  A switch from 3TC to FTC (or vice versa) will not be considered a 
background NRTI change and will not incur a penalty as per the Snapshot algorithm 
(see Section 6.3.2 and Section 8.3.2).

Liver toxicity where stopping criteria specified in Section 6.4.4.1 are met and no 
compelling alternate cause is identified;

Grade 4 clinical AE considered causally related to IP (see Section 6.4.3);

Renal toxicity criteria as specified in Section 6.4.4.5 are met and no compelling 
alternate cause is identified;

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
Allergic reaction or rash criteria as described in Section 6.4.4.6 and Section 6.4.4.7
respectively, are met and no compelling alternate cause is identified;

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
6.4.11).  As a reminder, females of childbearing potential who changed their minds 
and desire to become pregnant, or who state they are no longer willing to comply
with the approved pregnancy avoidance methods, should also be withdrawn from the 
study.
If a subject is prematurely or permanently withdrawn from the study, perform the 
procedures described in the Time and Events Table (Section 6.1) for the Withdrawal visit 
and if necessary the Follow Up visit. 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 clinical or 
laboratory 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 re-schedule 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. via telephone calls and/or 
sending 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 he/she will 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 CRF. Every effort should be made by the 
Investigator to follow up 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 
6.4.3) the procedures stated in the Time and Events Table (Section 6.1) 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 (Section 6.4.3).
4.6.
Virologic Criteria for Subject Management and Viral 
Resistance Testing
For the purposes of clinical management in this study, suspected or confirmed virologic 
withdrawal criteria are defined in Section 4.6.1 wherein the virologic withdrawal criteria 

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defined below revolve around the HIV-1 RNA cut-off of 400 c/mL. Notably, this allows 
for more reliable generation of data required for subject management as the primary 
genotypic and phenotypic resistance assays are not validated for RNA levels near the 
limits of detection (50 c/mL).
Following Day 1, no changes, or intensification of ART will be permitted prior to 
meeting confirmed virologic withdrawal criteria or Week 52, with the exception of a 
switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily or the opposite 
switch, a switch from LPV/RTV to DTG as per Protocol Amendment No. 2, and one 
allowed background NRTI change for management of drug toxicity as described in 
Section 6.4.4., “Specific Toxicities/Adverse Event Management”.  Any NRTI change 
must ensure a fully active NRTI is still present based on Screening resistance testing.  A 
switch from 3TC to FTC (or vice versa) will not be considered a background NRTI 
change and is permitted.  Subjects unable to manage drug toxicity or tolerate IP (DTG or 
LPV/RTV) must be discontinued from the study as described in Section 6.4.
4.6.1.
Virologic Withdrawal Criteria
Virologic withdrawal criteria must be confirmed for each criterion by a repeat and 
consecutive plasma HIV-1 RNA measurement between one and four weeks after the 
subject met a suspected virologic withdrawal criterion.  Subjects should receive full dose 
of IP across all plasma sampling times used for determining virologic non-response or 
rebound.  For these definitions, Baseline viral load is defined as the Day 1 HIV-1 RNA 
measurement.  For the purposes of clinical management in this study, virologic 
withdrawal criteria are defined as any of the following:
Virologic Non-response

A decrease in plasma HIV-1 RNA of less than 1 log10 c/mL by Week 16, with 
subsequent confirmation, unless plasma HIV-1 RNA is <400 c/mL.

Confirmed plasma HIV-1 RNA levels ≥400 c/mL on or after Week 24.
Virologic Rebound

Confirmed rebound in plasma HIV-1 RNA levels to ≥400 c/mL after prior confirmed 
suppression to <400 c/mL.
Subjects who meet any confirmed virologic withdrawal criterion must be discontinued 
from the study.
Cases of subjects meeting confirmed virologic withdrawal criteria will trigger virologic 
resistance testing.  Investigators should use their discretion as to the most appropriate 
clinical management of their subjects, if more stringent local guidelines apply.
4.6.2.
Managing Subjects Meeting Suspected Virologic Withdrawal 
Criteria
Only plasma HIV-1 RNA values determined by the central laboratory (or a laboratory 
contracted by the central laboratory) will be used to assess virologic withdrawal criteria.  

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Upon notification that a subject’s HIV-1 RNA plasma level qualifies him/her as meeting 
a suspected virologic withdrawal criterion, the Investigator should query the subject 
regarding intercurrent illness, recent immunisation, 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 at least one week but not more than 4 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 
immunisation, 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 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 between 50 
c/mL and <400 c/mL and must be performed at the Week 52 study visit (see Section 4.7).
4.6.3.
Managing Subjects Meeting Confirmed Virologic Withdrawal 
Criteria
Once a subject has been confirmed as meeting a virologic withdrawal criterion, a ‘plasma 
for storage’ sample from the virologic failure visit and the Day 1 sample will be sent as 
soon as possible for genotypic and phenotypic resistance testing and the result made 
known to the Investigator when available.
A subject who meets a confirmed virologic withdrawal criterion must be 
discontinued from the study.
If a subject is prematurely discontinued from participation in the study, the Investigator 
must make every effort to perform the evaluations outlined in the Time and Events 
Schedule (Section 6.1).  These data will be recorded, as they comprise an essential 
evaluation that needs to be done before discharging any subject from the study.

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4.7.
Retest Criteria for Subjects with Plasma HIV-1 RNA Levels 
between 50 c/mL and <400 c/mL at Week 48
Subjects with plasma HIV-1 RNA levels between 50 c/mL and <400 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 4.6.2 “Managing Subjects Meeting Suspected Virologic 
Withdrawal Criteria”.
4.8.
Screening Failures
A subject is considered a screening 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 are allowed to re-screen for this study one time (so long as the first screening 
does not exclude the subject based on lack of a fully active drug); re-screening will 
require a new subject number. There is no timeline restriction for re-screening.  
A single repeat test (re-test) per analyte or assessment is allowed during the screening 
period to determine eligibility (with the exception of a disqualifying Screening genotype 
which may not be retested; however, a single repeat test for a failed genotype [no result] 
is permitted during the Screening period to determine eligibility).
Laboratory results from central laboratory services provided by this trial will be used to 
assess eligibility.
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Investigational product (IP) in this protocol refers to the investigational study drug DTG 
and the comparator drug LPV/RTV. These will be supplied by GlaxoSmithKline. For this 
protocol, other antiretrovirals administered in the study are not considered IP.
Investigators will choose a dual NRTI background regimen for each subject (see Section 
5.1.3).  Background antiretroviral therapy will be recorded on the Concomitant 
Antiretroviral Therapy (ConART) eCRF page.  For additional details, please consult the 
SPM.
Under normal conditions of handling and administration, IP is not expected to pose 
significant safety risks to site staff.  A Material Safety Data Sheet (MSDS) describing the 
occupational hazards and recommended handling precautions will be provided to site 
staff if required by local laws or will otherwise be available from GSK upon request.

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IP 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 
authorised site staff.  IP must be dispensed or administered only to subjects enrolled in 
the study and in accordance with the protocol. 
The contents of the label will be in accordance with all applicable regulatory 
requirements.
5.1.1.
Tablet Formulation of DTG
DTG tablets are packaged into high density polyethylene (HDPE) bottles with child-
resistant closures that include induction seals.  The bottles may contain a desiccant. The 
recommended storage conditions and expiry date where required, are stated on the 
product label.
In general, subjects should keep IP in the original container.  However, subjects may use 
pill boxes for short term storage of 7 days.
5.1.2.
Tablet Formulation of LPV/RTV
LPV/RTV [Kaletra Package Insert, 2016; Kaletra EU Summary of Product 
Characteristics, 2017] is supplied as the LPV/RTV oral tablet, which contains 200 mg of 
LPV and 50 mg of RTV.  LPV/RTV tablets are manufactured by Abbvie.  Each HDPE 
bottle is closed with a propylene cap and contains 120 tablets.
5.1.3.
Background NRTIs
The investigator selected dual NRTI background regimen must be determined and 
documented prior to randomisation.  While Screening resistance test results must be used 
to determine one fully active agent, all available data (prior treatment history, Screening 
and historical resistance results) should be considered for selection of the background 
therapy.  The background regimen shall be composed of one of the following:

one fully active NRTI plus one inactive or partially active NRTI;

two fully active NRTIs;

one of the above plus, where required in subjects co-infected with HBV, 3TC. 
Note: In consultation with the medical monitor, 3TC may be added as a third NRTI to a 
dual-NRTI background regimen in subjects with chronic HBV infection and evidence of 
HIV resistance to 3TC (e.g. M184V) (see Section 6.2.3).  3TC cannot be added to 
regimens that include FTC.
Fully active is defined by the genotypic resistance report of the central laboratory (or a 
laboratory contracted by the central laboratory) showing no evidence of full or of partial 
resistance for a given NRTI. For additional details, please consult the SPM.
All triple NRTI (except for adding 3TC to a dual NRTI combination in subjects co-
infected with HBV; see Section 6.2.3) and the following dual NRTI combinations will be 

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prohibited in this protocol per current treatment guidelines and recommendations [HHS
2013; Gallant, 2005; Barnas, 2010]: 

ABC+TDF, 

3TC+FTC, 

AZT+d4T, 

ddI+ABC, 

ddI+TDF, 

ddI+d4T, 

ddI+3TC, 

ddI+FTC,

d4T+3TC,

d4T+FTC.
All background NRTIs are locally registered products.  GSK will not reimburse or supply 
the investigator selected background regimen unless requested by the local regulatory 
authority or IRB/IEC or unless previously agreed with study sites.
Those subjects for whom ABC is being considered as a component of the NRTI 
backbone should have been screened and be negative for the HLA-B*5701 allele before 
randomisation takes place (see Section 6.2.1).  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
Details of dosing for both randomised arms are outlined in the following table:
Treatment Arm
IP Dose and Dose Interval and background NRTI 
DTG
1 x 50 mg DTG tablet once daily plus 2 NRTIs selected by the investigator
LPV/RTV
4 x 200/50 mg LPV/RTV tablets once daily or 2 x 200/50 mg LPV/RTV 
tablets twice daily plus 2 NRTIs selected by the investigator 
IP may be administered with or without food.
5.1.5.
Protocol-Permitted Substitutions
A switch of DTG or LPV/RTV is not allowed except for a switch from LPV/RTV 
800/200 mg once daily to LPV/RTV 400/100 mg twice daily or the opposite switch.  As 
per Protocol Amendment No. 2, a switch from LPV/RTV to DTG will be allowed.
Switch of one background NRTI to an alternative approved NRTI for toxicity or 
tolerability management is allowed one time.  After the switch, based on Screening 
resistance testing results background ART must still consist of at least one fully active 

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NRTI and a second single NRTI  which may or may not be active (as defined in Section 
5.1.3).  A switch from 3TC to FTC (or vice versa) will not be considered a background 
NRTI change and is permitted.  The date of the decision to switch one background NRTI 
for toxicity or tolerability management must be documented in the eCRF.
Local prescribing information should be consulted for information regarding use of these 
medications. 
For more details on IP and protocol-permitted switch medications, refer to the SPM.
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 randomisation 
schedule. Randomisation will occur at the Baseline (Day 1) visit and will be conducted 
via a central randomisation procedure following confirmation of fulfilment of study entry 
criteria. Subjects will be assigned (1:1) to study treatment in accordance with the 
computer generated randomisation schedule. The central randomisation schedule, 
including stratification, will be generated using the GSK validated randomisation 
software RandAll NG. Study site personnel will be required to contact the central 
randomisation service for assignment of a unique identifier (designating the subject’s 
randomisation code) for each subject participating in the study. A unique treatment 
number will be assigned for each subject participating in the study.  Subjects will 
maintain the assigned treatment group throughout the Randomised Phase (Day 1 to Week 
48 plus a 4-week treatment extension) and if applicable the Continuation Phase (after 
Week 52 for subjects randomised to the DTG arm).
Subjects who are randomised into the trial and subsequently withdrawn may not be re-
screened.
5.3.
Blinding
As this is an open-label study, blinding is not required.  No summaries of the study data 
according to actual randomised treatment groups will be available to sponsor staff prior 
to the planned Week 24 interim analysis.  According to the IDMC Charter, ViiV 
Healthcare/GSK personnel having direct responsibility for the conduct of the study and 
its analysis may however review summaries of data by treatment group if the IDMC 
recommends to the sponsor the termination of a treatment arm or the entire 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 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.

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5.5.
Treatment Compliance
Treatment compliance will be evaluated through the Morisky 8-Item Medication 
Adherence Scale (MMAS-8), a self-report measure of medication-taking behaviour (see 
Section 6.5).  Pill counts of unused IP will be assessed for monitoring purposes each time 
the subject receives a new (refill) supply of study medication through the Withdrawal 
visit or study completion. These data will be recorded in the subject’s CRF, but will not 
be summarised for analysis purposes.
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 
for interactions between such treatments and the study medications. All concomitant 
medications taken during the study will be recorded in the CRF. The minimum 
requirement is that the drug name and the dates of administration are to be recorded. 
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 
CRF 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.  This approach will 
minimise the risk of non-specific increases in the level of HIV-1 plasma RNA at the next 
scheduled assessment.
Entecavir and telbivudine are permitted, in appropriate clinical situations, for treatment of 
hepatitis B (e.g. prior intolerance or viral resistance to TDF, viral resistance to 3TC/FTC) 
after discussion and agreement between the investigator and the medical monitor (also 
see Section 6.2.3).
Approved hormonal contraception may be administered with DTG. However, the 
investigator should consult local prescribing information for guidance on the use of 
hormonal contraceptives with background ART as some antiretrovirals have clinically 
significant drug interactions with these products.
DTG should be administered 2 hours before or 6 hours after taking antacid products or 
sucralfate containing divalent cations (e.g. aluminum and magnesium).  Proton pump 
inhibitors and H2-antagonists may be used in place of antacids with no scheduling 
restrictions. Concurrent administration with multivitamins is acceptable.

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DTG can be co-administered with calcium or iron supplements if taken with a meal.  
Under fasted conditions, DTG should be given 2 hours prior to OR 6 hours after calcium 
or iron supplements. 
Metformin concentrations may be increased by DTG. Subjects should be monitored 
during therapy and a dose adjustment of metformin may be considered.
Both LPV and RTV are inhibitors of the P450 isoform CYP3A. LPV/RTV is likely to 
increase plasma concentrations of medicinal products that are primarily metabolised by 
CYP3A. These increases of plasma concentrations of co-administered medicinal products 
could increase or prolong their therapeutic effect and adverse events. It is important to 
consult the current prescribing information for LPV/RTV prior to administering any 
concomitant medication together with LPV/RTV.
5.6.2.
Prohibited Medications and Non-Drug Therapies
HIV immunotherapeutic vaccines are not permitted at any time during the study (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 may not be administered (see Exclusion Criteria, Section 4.3). 
Systemically administered immunomodulators are prohibited with the following 
exception.  HCV therapy will not be permitted during the Randomised Phase (Day 1 to 
Week 48 plus a 4-week treatment extension) of the study.  If HCV therapy is required 
during the Continuation Phase, subjects may be allowed to continue on study after 
discussion and agreement between the investigator and the medical monitor.
Chronic use of systemic (oral or parenteral) glucocorticoids must be avoided; however, 
short treatment courses (for example, 30 days or less), replacement therapy (e.g. for 
Addison’s Disease), and topical, inhaled, or intranasal use of glucocorticosteroids will be 
allowed.
Acetaminophen is not to be used in patients with acute viral hepatitis.
For a detailed list of prohibited medications, please consult the SPM.
5.6.3.
Prohibited medications for subjects randomised 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

Rifampicin or rifapentine (see Section 5.7 for substitutes for treatment of TB)

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
St. John’s wort (Hypericum perforatum)
Dofetilide and pilsicainide are prohibited as DTG may inhibit their renal tubular secretion 
resulting in increased dofetilide/pilsicainide concentrations and potential for toxicity.
For NRTIs used as background therapy, please refer to the local prescribing information 
for information on concurrent therapies.
5.6.4.
Prohibited medications for subjects randomised to LPV/RTV
Both LPV and RTV are inhibitors of the P450 isoform CYP3A. LPV/RTV should not be 
co-administered with medicinal products that are highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious 
and/or life threatening events.  For subjects randomised to LPV/RTV, the following 
medications or their equivalents must not be administered concurrently:

Alfuzosin

Amiodarone

Antihistamines (astemizole, terfenadine)

Cisapride

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

Fusidic acid (in dermatological infections)

HMG Co-A reductase inhibitors (specifically lovastatin, simvastatin)

Pimozide

Rifampicin (see Section 5.7 for substitutes for treatment of TB)

Sildenafil (when used for the treatment of pulmonary arterial hypertension)

Vardenafil

Avanafil

Midazolam (oral)

Triazolam

St John’s wort (Hypericum perforatum)
Refer to the most up to date prescribing information for LPV/RTV for a listing of drugs 
with established or other potentially significant interactions with LPV/RTV.
For NRTIs used as background therapy, please refer to the local prescribing information 
for information on concurrent therapies.

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5.7.
Treatment of Tuberculosis
Patients who developed tuberculosis (TB) during the study may be managed according to 
local treatment guidelines with rifabutin substituted for rifampicin.  Rifabutin may be 
reimbursed by GSK.
Switching to DTG twice daily dosing in subjects who receive DTG in this study and 
require rifampicin treatment for tuberculosis, will not be allowed in this study. 
5.8.
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 patient’s medical condition whether or not GSK is providing specific 
post study treatment.
Subjects randomised to DTG
To provide continued access to unapproved investigational drug to subjects deriving 
therapeutic benefit, subjects randomised to receive DTG and who have successfully 
completed the Randomised Phase (Day 1 to Week 48 plus a 4-week treatment extension)
will be given the opportunity to continue to receive DTG until one of the following 
occurs:

DTG is locally approved and commercial supplies are available to patients (e.g. 
through public health services),

The subject no longer derives clinical benefit from treatment with DTG, 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 access to these medications during and post study.
Subjects who complete the DTG Continuation Phase must return to clinic when 
transitioning to ART available, e.g. through public health services, to have the 
assessments performed as noted in the Continuation Phase schedule (see Section 6.1).
Subjects randomised to LPV/RTV
As subjects receiving LPV/RTV in the Randomised Phase (Day 1 to Week 48 plus a 4-
week treatment extension) complete the Week 52 visit, they will also complete the study.  
Investigative sites must make arrangements for provision of LPV/RTV early during the 
study to ensure continued access to medication post study.  Investigative sites must make 
arrangements for provision of background NRTIs to all subjects to ensure access to these 
medications during and post study. 
Subjects originally randomised to receive LPV/RTV but switched to the DTG arm prior 
to Week 52 (as per Protocol Amendment No. 2) will continue to have access to DTG 
(Continuation Phase) until it is either locally approved and commercial supplies are 

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available to patients (e.g. through public health services), the patient no longer derives 
clinical benefit, or the patient meets a protocol-defined reason for discontinuation.  
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure continued access to these medications during the DTG Continuation 
Phase (unless provision by the sponsor is mandated by local regulation).
5.9.
Treatment of Study Treatment Overdose
Any tablet intake exceeding the randomised daily number of tablets for IP will be 
considered an overdose.
For the purposes of this study, an overdose is not an AE (see Section 6.4.5.1) unless it is 
accompanied by a clinical manifestation associated with the overdose. If the clinical 
manifestation presents with serious criteria, the event is a SAE (see Section 6.4.5.2).
If an overdose occurs and is associated with an adverse event requiring action, all study 
medications should be temporarily discontinued until the adverse event resolves. 
The Investigator should use clinical judgment and also refer to the prescribing 
information for approved ARTs, as appropriate in treating overdose, as GSK is unable to 
recommend specific treatment.

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6.
STUDY ASSESSMENTS AND PROCEDURES
6.1.
Time and Events Schedule
Table 1
Time and Events Table
Procedures
Randomised Phase
Continuation 
Phaseb
Withdrawal
Follow-
upc
Screeninga
Baseline 
(Day 1)
Day 1 to Week 48
4-week 
Treatment 
Extension
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
48
Week 52
Week 
60
Every 12 
weeks 
thereafter
Clinical and Other Assessments
Written informed 
consent
X
Inclusion/Exclusion 
criteriad
X
Subject 
demography
X
Medical historye
X
Prior ART history
X
CDC HIV-1 
classification
X
X
Limited physical 
examinationf
X
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and 
height
X
Current medical 
conditions
X
CV risk 
assessmentg
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X

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Procedures
Randomised Phase
Continuation 
Phaseb
Withdrawal
Follow-
upc
Screeninga
Baseline 
(Day 1)
Day 1 to Week 48
4-week 
Treatment 
Extension
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
48
Week 52
Week 
60
Every 12 
weeks 
thereafter
HIV associated 
conditions
X
X
X
X
X
X
X
X
X
X
Columbia 
Suicidality Severity 
Rating Scale
Xh
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
SAEs
Xi
X
X
X
X
X
X
X
X
X
X
X
X
GSRS
X
X
X
X
Xj
HIVTSQs
X
X
X
X
Xj
HIVTSQc
X
Xj
MMAS-8
X
X
X
X
Xj
Laboratory Assessments
Quantitative 
plasma HIV-1 RNA 
PCR
X
X
X
X
X
X
X
X
Xk
X
X
X
Lymphocyte subset 
X
X
X
X
X
X
X
X
X
X
X
X
Plasma for HIV 
genotyping
X
Plasma for storagel
X
X
X
X
X
X
X
X
X
X
X
X
HLA-B* 5701 
testingm
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Fasting lipids and 
glucosen
X
X
X
X
Pregnancy testo
S
U
S
S
S
S
S
S
S
S
S
S
S
HBsAg, anti-HBc 
and anti-HCVp
X

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Procedures
Randomised Phase
Continuation 
Phaseb
Withdrawal
Follow-
upc
Screeninga
Baseline 
(Day 1)
Day 1 to Week 48
4-week 
Treatment 
Extension
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
48
Week 52
Week 
60
Every 12 
weeks 
thereafter
HBV DNAq
X
Pharmacogenetic 
sampler
X
PBMCss
X
Investigational product
Interactive voice 
recognition 
system (IVRS)
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
X
X
Xt
X
X
IP accountability 
(pill counts)
X
X
X
X
X
X
X
X
X
X
a.
The 28-day Screening period may be extended to 42 days. Randomisation may occur as soon as all Screening results are available.
b.
For subjects who completed randomised DTG through Week 52 and entered into the DTG Continuation Phase: subjects completing the DTG Continuation Phase must return to 
the clinic when transitioning to commercial supplies. Conduct study assessments, with the exception of dispensing IP, as specified for all Continuation Phase visits at this end of 
Continuation Phase 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.
Inclusion/exclusion criteria will be fully assessed at the Screening visit. Changes between the screening visit and the Day 1 visit should be assessed to ensure eligibility, including 
additional assessments performed at Day 1.
e.
Full medical history will be collected. Targeted Medical History assessments will include cardiovascular, gastrointestinal (e.g. GI bleeding, PUD, etc), metabolic (e.g. Type I or II 
DM), psychiatric (e.g. depression), renal (e.g. nephrolithiasis, nephropathy, renal failure) and neurological disorders. 
f.
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.
g.
Assessment for cardiovascular risk will include height, weight, blood pressure, smoking history, medical conditions, and family history of premature cardiovascular disease.
h.
On Day 1, the Columbia Suicidality Severity Rating Scale is to be administered prior to randomisation.
i.
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.
j.
Health outcomes assessments will only be conducted at Withdrawal if the Withdrawal visit occurs at or prior to Week 48.

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k.
At Week 52, repeat HIV-1 RNA testing will only be performed for subjects with HIV-1 RNA 50 c/mL at Week 48.
l.
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. 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).
m.
Subjects starting ABC as one of the NRTIs should have been screened and be negative for the HLA-B*5701 allele.
n.
An overnight fast is preferred, however a minimum of a 6 hour fast is acceptable.
o.
Pregnancy testing will be conducted (women of child bearing potential only) on serum (S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of IP. Remind females of childbearing potential of the need to avoid pregnancy while on study and adherence to the study’s contraception requirements.
p.
Subjects who are hepatitis B surface antigen (HBsAg) positive require appropriate HBV therapy based on local guidelines (see Section 6.2.3 for details).
q.
HBV DNA testing will be performed on Day 1 for subjects with negative HBsAg and positive hepatitis B core antibody (anti-HBc) results at Screening.  Subjects with positive anti-
HBc and positive HBV DNA results require appropriate HBV therapy based on local guidelines (see Section 6.2.3 for details).
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.
Whole blood collection (please refer to the SPM).
t.
For subjects receiving DTG during the Continuation Phase only.

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6.2.
Critical Screening and 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 Institutional Review Board/Independent Ethics Committee (IRB/IEC). 
After signing an informed consent, subjects will complete Screening assessments to 
determine subject eligibility. Each subject being screened for study enrolment evaluation 
will be assigned a subject number. This number will be given sequentially in 
chronological order of subject presentation according to a numeric roster provided by 
GSK.
Eligibility criteria must be carefully assessed at the Screening visit.  Physical exams 
should be conducted as part of normal routine clinical care but will not be collected 
systematically in the CRF.
6.2.1.
Screening Assessments
Assessments to be conducted at Screening are provided in the Time and Events Table 
(Section 6.1).  
Eligible subjects may be randomised as soon as all Screening assessments are complete 
and the results are available and documented. All subjects will complete a Screening 
period of approximately 28 days prior to Baseline (Day 1) during which all clinical and 
laboratory assessments of eligibility must be performed and reviewed.  The Screening 
period may be extended to 42 days to accommodate availability of all Screening 
assessment results and scheduling.  All Screening results must be available prior to 
randomisation.
All subjects must provide a plasma sample for determination of viral genotypic resistance 
at the central laboratory (or a laboratory contracted by the central laboratory).  For 
eligibility the resistance report must show no evidence of either full or of partial 
resistance for at least one NRTI which will be taken by the subject during study.
Severe hepatic impairment is exclusionary and will be assessed by Child-Pugh grading at 
Screening (see Appendix 1, Section 11.1).  
Hepatitis B surface antigen (HBsAg) will be obtained at Screening to ensure that subjects 
with chronic active hepatitis B receive appropriate hepatitis B treatment in conjunction 
with appropriate HIV background regimens for the study.  For subjects with positive 
hepatitis B core antibody (anti-HBc) and negative HBsAg at Screening, HBV DNA 
testing will be performed on Day 1.
Subjects who meet all entry criteria are randomised and assigned a randomisation 
number. Subjects not meeting all inclusion and exclusion criteria at initial screen may be 
re-screened and receive a new subject number one time.  Subjects, who are randomised 
into the trial and subsequently withdrawn from the study for any reason, may not be re-
screened.

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Investigators must ensure subjects are prepared for randomisation on Day 1, including 
confirming arrangements for provision of the dual NRTI background regimen and 
ensuring that these medications will be available for use at the time of the Day 1 visit.  
Screening resistance test results must be used to determine one fully active agent, but all 
available data (prior treatment history, Screening and, if available, historical resistance 
results) should also be considered for selection of the background therapy.  Also see 
Section 5.1.3 for dual NRTI combinations prohibited in this trial.
Selection of the background regimen must be complete prior to randomisation; therefore, 
after successfully completing all screening procedures, the investigator will determine the 
most appropriate background regimen for use in the study.
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 abacavir (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 (Day 1) Assessments
Assessments to be conducted at Baseline (Day1) are provided in the Time and Events 
Table (Section 6.1). 
At Day 1 and prior to randomisation, any changes to the eligibility parameters must be 
assessed and any results required prior to randomisation (e.g. Day 1 urine pregnancy test 
for women of child bearing potential) must be available and reviewed.  
Cardiovascular medical history/risk factors will be assessed at Baseline, to include 
smoking status and history and family history of cardiac events. 
6.2.3.
Subjects Co-infected with Hepatitis B Virus (HBV)
Investigators should consult current treatment guidelines (e.g. [Thompson, 2012]) when 
considering choice of NRTIs for subjects with chronic HBV infection (HBsAg positive 
OR anti-HBc positive with HBV DNA present).  
In addition, clinical trial and marketed use of 3TC, FTC and TDF have shown that some 
subjects with chronic HBV disease may experience clinical or laboratory evidence of 
recurrent hepatitis upon discontinuation of 3TC, FTC or TDF, which may have more 
severe consequences in subjects with decompensated liver disease.  Subjects with HBV 
co-infection should be advised against self-discontinuation of any medications with anti-
HBV activity.  If 3TC, FTC or TDF is discontinued in subjects co-infected with HBV, 
periodic monitoring of both liver chemistry tests and markers of HBV replication should 
be performed.

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Entecavir and telbivudine are permitted, in appropriate clinical situations, for treatment of 
hepatitis B (e.g. prior intolerance or viral resistance to TDF, viral resistance to 3TC/FTC) 
after discussion and agreement between the investigator and the medical monitor.  
In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-
NRTI background regimen in subjects with chronic HBV infection and evidence of HIV 
resistance to 3TC (e.g. M184V).  3TC cannot be added to regimens that include FTC.
6.2.4.
Subjects Co-infected with Hepatitis C Virus (HCV)
Investigators should consult current treatment guidelines when considering choice of 
therapy for subjects with chronic HCV infection.  Subjects with an anticipated need for 
HCV therapy during the Randomised Phase (Day 1 to Week 48 plus a 4-week treatment 
extension) may not be enrolled into this study.
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 (Section 6.1).  Methods to be used may include but are not limited to the Abbott 
RealTime HIV 1 Assay lower limit of detection (LLOD) 40 c/mL. In some cases (e.g. 
where the HIV-1 RNA is below the lower limit of detection for a given assay) additional 
exploratory methods may be used to further characterise HIV-1 RNA levels.
Lymphocyte Subsets
Lymphocyte subsets will be collected for assessment by flow cytometry (total 
lymphocyte counts, percentage and absolute CD4+ lymphocyte counts) according to the 
Time and Events Table (Section 6.1).
HIV-associated Conditions
HIV-associated conditions will be recorded as per the Time and Events Table (Section 
6.1) and assessed according to the 1993 CDC Revised Classification System for HIV 
Infection in Adults (Appendix 2, Section 11.2).  Indicators of clinical disease progression 
are defined as:
CDC Category A at enrolment Category C event;
CDC Category B at enrolment Category C event;
CDC Category C at enrolment New Category C Event;
CDC Category A, B or C at enrolment Death.

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6.3.2.
Primary Endpoint
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 (Missing, Switch or 
Discontinuation = Failure) for the ITT-E population (see Section 8.3.3.1).
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 <400 c/mL at Weeks 24 and 48 
using the Snapshot algorithm;

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, safety stopping criteria, and lack 
of efficacy;

Time to viral suppression (HIV-1 RNA <50 c/mL);

Absolute values and changes from Baseline in CD4+ cell counts at Weeks 24 and 48;

Incidence of disease progression (HIV-associated conditions, AIDS and death).
6.4.
Safety
6.4.1.
Safety Evaluations
Safety assessments 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 haematology, blood chemistry and fasting lipids (parameters 
to be tested listed in Table 2 below);

Physical exams should be conducted as part of normal routine clinical care but will 
not be collected systematically in the CRF.  Abnormalities noted during any exam 
must be recorded in the CRF (e.g. in the current medical conditions or AE logs);

Evaluation and documentation of all concomitant medications and blood products;

Suicidality monitoring using the Columbia Suicide-Severity Rating Scale (Section
6.4.10).
Any appropriately qualified site personnel (e.g. Investigator, sub-Investigator or study 
coordinator/nurse) can perform assessments.  A central laboratory chosen by GSK (or a 
laboratory contracted by this central laboratory) will undertake all routine scheduled 
laboratory evaluations within the study.  Refer to the Laboratory Manual for specific 
instructions on sample collection, processing, storage and shipping for each laboratory 
test.

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Table 2
Laboratory Assessments
Haematology
Platelet Count
Automated WBC Differential:
RBC Count
Neutrophils
WBC Count (absolute) 
Lymphocytes
Haemoglobin
Monocytes
Haematocrit
Eosinophils
MCV
Basophils
MCV = mean corpuscular volume, RBC = red blood cells, WBC = white blood cells
Clinical Chemistry
BUN
Potassium
AST
Total bilirubina
Creatinineb
Chloride
ALT 
Albumin 
Glucose
Total CO2
Alkaline phosphatase
Creatine phosphokinase
Sodium
Lipase
Phosphate
BUN = blood urea nitrogen
a. Direct bilirubin will be reflexively performed for all total bilirubin values > 1.5X ULN.
b. Glomerular Filtration Rate (GFR) will be estimated by the central laboratory using the CKD-EPI method [Levey, 
2009].
Fasting Lipid Panela
Total cholesterol
HDL cholesterol
LDL cholesterol
Triglycerides
a. For fasting lipids assessments, an overnight fast is preferred; however, a minimum of a 6 hour fast is acceptable. 
Other tests
Plasma HIV-1 RNA
CD4+ cell counts
Hepatitis B (HBsAg, anti-HBc) and Hepatitis C (anti-HCV)a
Hepatitis B (HBV DNA)b
Pregnancy test for women of child bearing potentialc
HLA-B*5701 screeningd
a. Screening visit only.
b. Baseline visit only (subjects with negative HBsAg and positive anti-HBc results at Screening only).
c. Urine pregnancy test on Day 1; serum pregnancy test at Screening and Weeks 4, 8, 16, 24, 36, 48, and 52 (and at 
Week 60 and at 12 weeks intervals thereafter if applicable).
d. HLA-B*5701 screening will be only performed to examine candidates for ABC at discretion of the investigator.
6.4.2.
Safety Endpoints

Incidence and severity of AEs and laboratory abnormalities; 

Absolute values and changes over time in laboratory parameters;

Change from Baseline in fasting LDL cholesterol at Weeks 24 and 48;

Change from Baseline in fasting TC/HDL ratio at Weeks 24 and 48;

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
The incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Weeks 24 and 48;

The incidence of maximum post-Baseline emergent Grade 2 or greater drug-related 
diarrhoea by Weeks 24 and 48;

The proportion of subjects who discontinue treatment due to AEs.
6.4.3.
Toxicity Management
Adverse events that occur during the trial should be evaluated by the Investigator and 
graded according to the Division of AIDS (DAIDS) toxicity scales (Appendix 3, Section 
11.3). Additional information regarding detecting, documenting and reporting AEs and 
SAEs are available in Section 6.4.5.
IP may be interrupted at the discretion of the Investigator and according to the severity of 
the AE. If one or more antiretroviral medication is held due to toxicity or adverse events, 
all antiretroviral medications should be held to reduce the risk of development of 
resistance taking into account both the length of the planned interruptions and the 
pharmacokinetic half-life of each antiretroviral of the regimen, in a way to minimise the 
risk of development of resistance.
No toxicity-related dose reductions of IP will be allowed (except for switch from 
LPV/RTV 800/200 mg once daily to LPV/RTV 400/100 mg twice daily or the opposite 
switch). IP 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 general subject management and IP interruptions 
based on the severity of the AE; for specific toxicities, please refer to Section 6.4.4
“Specific Toxicities/Adverse Event Management”. All changes in the IP must be 
accurately recorded in the subject’s eCRF.
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 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. (Note: see Section 6.4.4 “Specific Toxicities/Adverse 
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from study due to a Grade 1 or 2 AE should have study withdrawal and follow-up 
evaluations completed.
Grade 3 Toxicity/Adverse Event
Subjects who develop a Grade 3 AE or toxicity should be managed as follows:
If the Investigator has compelling evidence that the Grade 3 AE or toxicity has not been 
caused by IP, dosing may continue after discussion with the medical monitor.
Subjects who develop a Grade 3 AE or toxicity, which 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 re-started.
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 have withdrawal study evaluations completed.  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 below for lipid abnormalities (Section 6.4.4.3).
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 encouraged to complete the withdrawal 
and follow-up study evaluations 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 below for lipid abnormalities (Section 6.4.4.3).  A 
follow-up visit should be performed 4 weeks after the last dose of study medication if 
AEs or laboratory abnormalities are ongoing.
6.4.4.
Specific Toxicities/Adverse Event Management
General guidelines for the management of specific toxicities that are considered to be 
related or possibly related to IP are provided below. 

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A switch from LPV/RTV 800/200 mg once daily to LPV/RTV 400/100 mg twice daily or 
the opposite switch is allowed.
Toxicities that the Investigator considers related or possibly related to one of the 
background NRTIs may be addressed by substitutions of the medication for another 
approved NRTI one time during the study, as indicated in Section 5.1.5 “Protocol-
Permitted Substitutions”.  Additional background substitutions for toxicity management 
are permitted after Week 52, but must be agreed first with the study medical monitor.
Toxicities that the Investigator considers related or possibly related to any background 
NRTI should be managed with reference to applicable product labelling.
Subjects who permanently discontinue IP for reasons of toxicity should be followed 
weekly until resolution of the AE and encouraged to complete the withdrawal and 
Follow-Up study evaluations as noted above.
6.4.4.1.
Liver chemistry stopping and follow up criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event aetiology during administration of IP and the follow-up 
period. IP will be stopped if any of the following liver chemistry criteria are met:

ALT ≥ 3xULN and bilirubin ≥2xULN (>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 ≥2xULN, then the 
event meets liver stopping criteria;

ALT ≥8xULN;

ALT ≥3xULN (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 ≥3x baseline ALT (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;

ALT ≥5xULN and <8xULN that persists 2 weeks (with bilirubin <2xULN and no 
signs or symptoms of acute hepatitis or hypersensitivity);

ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks;
Subjects who develop ALT ≥5xULN should be followed weekly until resolution or 
stabilisation (ALT <5xULN on 2 consecutive evaluations).

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When a liver chemistry stopping criterion is met, do the following:

Immediately hold IP;  

Report the event to the medical monitor within 24 hours of learning its occurrence 
(see Table 3 and Table 4, Section 6.4.14);

Complete the liver event eCRF and SAE eCRF, where applicable (see Section 
6.4.14);

Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed;

Perform liver event follow up assessments (described below), and monitor the 
subject until liver chemistries resolve, stabilise, 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 (see below), and close 
monitoring;

A specialist or hepatology consultation is recommended;

Monitor subjects twice weekly until liver chemistries (ALT, aspartate 
aminotransferase (AST), alkaline phosphatase, bilirubin) resolve, stabilise or return 
to within baseline values;
Consider the following additional tests to further evaluate the liver event:

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;

Serum acetaminophen test (APAP adduct test). The site must contact GSK when this 
test is required. Please refer to the SPM.

Blood sample for pharmacokinetic (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 CRF.  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.

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
Serum CPK and lactate dehydrogenase (LDH);

Fractionate bilirubin, if total bilirubin is greater than 1.5xULN;

Obtain complete blood count with differential to assess eosinophilia;

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies;

Liver imaging (ultrasound, magnetic resonance, or computerised 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.
6.4.4.2.
Restarting investigational product
Drug Restart/Rechallenge Following Liver Events that are Possibly Related to IP
Approval by the ViiV Safety and Labeling Committee (VSLC) for drug restart can be 
considered where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and 
no effective alternative therapy is available. Ethics Committee or Institutional 
Review Board approval of drug restart/rechallenge must be obtained, as required.

If the restart/rechallenge is approved by the VSLC in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.

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.

Study drug must be administered at the dose specified by the VSLC.

Subjects approved by the VSLC for rechallenge of IP must return to the clinic twice 
a week for liver chemistry tests for one month or for as long as clinically indicated 
and then laboratory monitoring may resume as per protocol.
Refer to Appendix 4, Section 11.4 for further details. 
Drug Restart Following Transient Resolving Liver Events Not Related to IP
Approval by the VSLC for drug restart can be considered where:

Liver chemistries have a clear underlying cause (e.g. biliary obstruction, hypotension 
and liver chemistries have improved to normal or are within 1.5x baseline and 

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ALT <3xULN). Ethics Committee or Institutional Review Board approval of drug 
restart/rechallenge must be obtained, as required.

If restart of drug is approved by the VSLC in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, 
including the possibility of recurrent, more severe liver injury or death.

The subject must also provide signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study chart.

Study drug must be administered at the dose specified by the VSLC.

Subjects approved by the VSLC for restarting IP must return to the clinic once a 
week for liver chemistry tests for one month or for as long as clinically indicated and 
then laboratory monitoring may resume as per protocol.  If protocol defined stopping 
criteria for liver chemistry elevations are met, study drug must be stopped.
Refer to Appendix 4, Section 11.4 for further details.
6.4.4.3.
Hypertriglyceridemia/hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the Time 
and Events Table (Section 6.1). Subjects who experience asymptomatic triglyceride or 
cholesterol elevations may continue to receive IP.
6.4.4.4.
CPK elevation
A Grade 3 or higher 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. A history regarding use of drugs known to cause increase of CPK (such 
as statins) physical activity or exercise preceding the CPK evaluation should be obtained. 
Grade 4 elevations 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.
6.4.4.5.
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 and urine total protein/albumin ratios 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 the estimated GFR (using the CKD-EPI method) of >50% 
must return for a confirmatory assessment as soon as possible. A urinalysis and urine 
albumin/creatinine and urine protein/creatinine ratios 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 study drugs (if appropriate).  Consideration for confounding 

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factors (e.g. background therapy, other medications, dehydration, concurrent conditions) 
should be taken into account, and a nephrology consult may be obtained.  If a subject is 
also receiving TDF, then a switch to an alternative nucleoside should be considered if 
restarting IP. One background NRTI change is allowed for management of drug toxicity 
as described in Section 6.4.4, “Specific Toxicities/Adverse Event Management”.   If IP is 
reinitiated, it should have been withheld for no more than 4 weeks.  If IP is not reinitiated 
the subject must be withdrawn.
6.4.4.6.
Allergic reaction
Subjects may continue IP for Grade 1 or 2 allergic reactions 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. 
Subjects with Grade ≥3 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.
Subjects receiving ABC as part of their NRTI background regimen should be evaluated 
for the possibility of a clinically suspected ABC hypersensitivity reaction (HSR) and 
managed appropriately as outlined in the local prescribing information.
6.4.4.7.
Rash
Mild to moderate rash is an expected adverse reaction for DTG-containing ART.  
Episodes generally occur within the first ten weeks of treatment, rarely require 
interruptions or discontinuations of therapy and tend to resolve within two to three weeks.  
No instances of serious skin reaction, including SJS, TEN and erythema multiforme, have 
been reported for DTG in clinical trials.  For further characterisation of HSR and rash 
observed with DTG-containing ART, please see the current version of the IB 
[GlaxoSmithKline Document Number RM2007/00683/11, GlaxoSmithKline Document 
Number 2017N352880_00, and GlaxoSmithKline Document Number 2017N352880_01].
TEN, SJS and erythema multiforme have been reported in patients receiving LPV/RTV 
[Kaletra US Package Insert, 2016; Kaletra EU Summary of Product Characteristics, 
2017].
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.
Subjects may continue IP for an isolated Grade 2 rash. However, IP (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) should be 
permanently discontinued for any Grade ≥2 rash that is associated with an increase in 
ALT (see Section 6.4.4.1). The subject should be advised to contact the physician 
immediately if rash fails to resolve (after more than two weeks), if there is any worsening 

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of the rash, if any systemic signs or allergic symptoms develop, or if mucosal 
involvement develops.
Subjects should permanently discontinue IP (and all other concurrent medication(s) 
suspected in the Investigators causality assessment) 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 adverse events (see 
Section 6.4.5) and appropriate toxicity ratings should be used to grade the events (see 
Appendix 3, Section 11.3).
If the aetiology 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.
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.
6.4.5.
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.
6.4.5.1.
Definition of an AE
Any untoward medical occurrence in a patient 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 unfavourable 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 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.

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“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
6.4.5.2.
Definition of an SAE
A serious adverse event 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 hospitalisation or prolongation of existing hospitalisation
Note:  In general, hospitalisation 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 hospitalisation are 
AEs.  If a complication prolongs hospitalisation or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
Hospitalisation 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 may 
interfere or prevent everyday life functions but do not constitute a substantial
disruption.

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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 hospitalisation but may jeopardise 
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 hospitalisation, or development of 
drug dependency or drug abuse.
g.
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN 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 patients 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 2xULN, 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.
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 one of the International Conference on 
Harmonization (ICH)-E2A definitions of seriousness listed above, then, in addition to 
reporting the case as an SAE, the ABC HSR CRF should also be completed within one 
week of the onset of the hypersensitivity reaction (see Section 6.4.14).
6.4.6.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 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.
It is important to note that grading for laboratory abnormalities (see Section 11.3) is an 
objective assessment conducted at the central laboratory (or a laboratory contracted by 
the central laboratory) and does not translate directly into similarly graded AEs.

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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

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one 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 noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
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 
(Appendix 2, Section 11.2 [CDC, 1992]) will be recorded on the HIV Associated 
Conditions CRF 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 6.4.5.2), 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.

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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
Patients with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour). In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in patients with a pre-
existing history of depression or psychiatric illness) in some patients being treated with 
INIs, including DTG.  Therefore, it is appropriate to monitor subjects for suicidality 
before and during treatment. 
Subjects should be monitored appropriately and observed closely for suicidal ideation 
and behaviour or any other unusual changes in behaviour.  It is recommended that the 
Investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behaviour.  Subjects presenting with new onset/treatment-
emergent depression should be advised to contact the investigator immediately if 
symptoms of severe acute depression (including suicidal ideation/attempts) develop, 
because medical intervention and discontinuation of the study medication may be 
required.
Assessment of treatment emergent suicidality will be monitored during this study using 
the Columbia Suicide Severity Rating Scale (C-SSRS). The definitions of behavioural 
suicidal events used in this scale are based on those used in the Columbia Suicide History 
Form [Oquendo, 2003]. Questions are asked on suicidal behaviour, 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 at the time-points specified in Section 6.1.
Additionally, the investigator will collect information using the Possible Suicidality-
Related AE (PSRAE) eCRF form in addition to the AE (non-serious or SAE) eCRF form 
on any subject that experiences a possible suicidality-related AE while participating in 
this study. This may include, but is not limited to, an event that involves suicidal ideation, 
a preparatory act toward imminent suicidal behaviour, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly suicide-related.  PSRAE forms should be 
completed and reported to GSK within one week of the investigator diagnosing a possible 
suicidality-related AE.
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 as 
per the Time and Events Table (see Section 6.1) and at anytime during the trial when 
pregnancy is suspected.

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Additionally, a pregnancy test should also be performed prior to study drug re-
administration, when administration is disrupted for more than 7 days (e.g. temporary 
interruption of study drug).
6.4.11.2.
Action to be taken if pregnancy occurs
Any female who becomes pregnant (intrauterine) while participating in this study must be 
withdrawn from the study and discontinue 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 to GSK 
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.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
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 GSK.
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.
6.4.11.3.
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 on-study or Follow-up visit. Only 
those pregnancies that occur following the first dose of IP will be reported to GSK. 
Follow-up information will only be collected for pregnancies occurring from Day 1 to the 
final on-study or Follow-up visit.
6.4.12.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of study treatment and until the follow up contact.  
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g. study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a 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 GSK within 24 
hours, as indicated in Section 6.4.14. 

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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 
to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in Table 3 and Table 4 once 
the investigator determines that the event meets the protocol definition for that event.
Table 3
Events and Reporting Time Periods for SAEs
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
ALT3xULN and
Bilirubin2xULN (>35% 
direct)
24 hours1
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver Imaging” 
and/or “Liver 
Biopsy” CRFs, if 
applicable2
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” Documents2
1.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
2.
Liver Event Documents (i.e. “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as applicable) 
should be completed as soon as possible.

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Table 4
Other Events Requiring Prompt Reporting
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Cardiovascular or death 
event
Initial and follow 
up reports to be 
completed within 
one 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 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Suspected ABC HSR1
1 week
ABC HSR CRF
1 week
Updated ABC HSR 
CRF
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
ALT ≥5xULN and 
<8xULN that persists 
≥2 weeks 
24 hours2
Liver Event CRF3
24 hours 
Updated Liver Event 
CRF3
ALT ≥8xULN 
24 hours2
Liver Event CRF3
24 hours 
Updated Liver Event 
CRF3
ALT ≥3xULN (if 
baseline ALT ≤ULN) or 
ALT ≥3 fold increase 
from baseline value (if 
baseline ALT >ULN) 
with appearance or 
worsening of symptoms 
of hepatitis or 
hypersensitivity
24 hours2
Liver Event CRF3
24 hours 
Updated Liver Event 
CRF3
1.
ABC HSR CRF required only if event meets one of the ICH-E2A definitions of ‘seriousness’.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e. “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as applicable) 
should be completed as soon as possible.
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.
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.
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.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.

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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 a SAE(s) or other 
specific safety information (e.g. summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.4.15.
Other Safety Outcomes
Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 2, 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 
Laboratory Manual and Protocol Time and Events Schedule. Laboratory requisition 
forms must be completed and samples must be clearly labelled with the subject number, 
protocol number, site/centre number, and visit date. Details for the preparation and 
shipment of samples will be provided by Quest Diagnostics. Reference ranges for all 
safety parameters will be provided to the site by Quest Diagnostics.
If required for cardiovascular events, additional specific local laboratory assessments will 
be recorded in the specific cardiovascular eCRF (see Section 6.4.7).   
6.5.
Health Outcomes
Health outcomes assessments will be conducted in all countries according the schedule in 
the Time and Events Table (Section 6.1).  Assessments are recommended to be 
administered at the beginning of the visit.
HIVTSQ: The HIV treatment satisfaction questionnaire status version (HIVTSQs) and 
HIVTSQ change version (HIVTSQc) are self-reported scales that measure overall 
satisfaction with treatment and by specific domains, e.g. convenience, flexibility 
[Woodcock, 2001; Woodcock, 2006]. The change version of the HIVTSQ was developed 
to overcome ceiling effects (i.e. where respondents score maximum or near-maximum 
satisfaction at Baseline and can show little or no improvement at follow-up.  The 
HIVTSQ will be administered as a paper questionnaire.
MMAS-8: The Morisky 8-Item Medication Adherence Scale (MMAS-8) is a self-report 
measure of medication-taking behaviour and addresses barriers to medication-taking 
[Morisky, 2008].  The MMAS-8 will be administered as a paper questionnaire. 
GSRS: The Gastrointestinal Symptom Rating Scale (GSRS) is a disease-specific 
instrument of 15 items combined into five symptom clusters depicting Reflux, 
Abdominal pain, Indigestion, Diarrhoea and Constipation [Svedlund, 1988].  The GSRS 
will be administered as a paper questionnaire. 

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6.5.1.
Health Outcome Endpoints

Change from Baseline, using the Gastrointestinal Symptom Rating Scale (GSRS), at 
Week 4, Week 24, and Week 48; 

Change from Baseline in treatment satisfaction, using the HIV-Treatment 
Satisfaction Questionnaire (HIVTSQ), at Week 4, Week 24, and Week 48;

Change from Baseline in adherence with treatment, using the Morisky 8-Item 
Medication Adherence Scale (MMAS-8), at Week 4, Week 24, and Week 48.
6.6.
Viral Genotyping and Phenotyping
Whole venous blood samples will be obtained from each subject for Screening 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 viral genotypic and phenotypic analyses as required.
Details concerning the handling, labelling and shipping of these samples will be supplied 
separately.  Screening viral genotype will be performed 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) and 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.
Screening will include only viral genotype for eligibility determination and to guide the 
choice of NRTIs.
6.6.1.
Virology Endpoint

Incidence of treatment-emergent genotypic and phenotypic resistance to DTG, 
LPV/RTV and other on-study ART in subjects meeting confirmed virologic 
withdrawal criteria.
6.6.2.
HIV-1 Pol Viral Genotyping and Phenotyping
Subjects meeting a ‘confirmed virologic withdrawal criterion’ (see Section 4.6.3) will 
have plasma samples tested for HIV-1 PRO and RT genotype and phenotype and HIV-1 
integrase genotype and phenotype from both Baseline samples and from samples 
collected at the time of meeting a ‘suspected virologic withdrawal criterion’; these results 
will be reported to the Investigator as soon as available to provide guidance for election 
of an alternative regimen.
HIV-1 PRO and RT genotype and phenotype will also be determined on the Baseline 
isolates from all subjects, if possible.  When samples cannot be analysed by Monogram 
Biosciences, Baseline isolate resistance testing may be performed at location(s) to be 
described in the SPM.  

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6.6.3.
HIV-1 Exploratory Analysis
Additional analyses for HIV-1 resistance may, for example, be carried out on peripheral 
blood mononuclear cell (PBMC) samples collected at Baseline and/or 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 Appendix 5, 
Section 11.5.
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 (i.e. approval of 
Appendix 5, Section 11.5).  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 GSK 
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 MedDRA and an internal validated medication dictionary, 
GSKDrug.  eCRFs (including queries and audit trails) will be retained by GSK, and 
copies will be sent to the investigator to maintain as the investigator copy.  In all cases, 
subject initials will not be collected or transmitted to GSK according to GSK policy.

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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This study is designed to show that the antiviral effect of a regimen of DTG 
(administered once daily) + two NRTIs is non-inferior to LPV/RTV + two NRTIs. 
If rd is the response rate on DTG + two NRTIs and ra is the response rate on LPV/RTV + 
two NRTIs then the hypotheses can be written as follows:
H0: rd – ra ≤ -12% 
H1: rd – ra > -12%.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
Rationale for non-inferiority margin
The non-inferiority margin of 12% was chosen based on historical data from well-
controlled superiority trials in treatment naïve subjects which established a large 
quantitative contribution to viral suppression of a PI when added as a third drug to a dual 
NRTI background (approximately 45% using the lower confidence bounds) and the 
negligible viral load response (less than 5%) in regimens containing dual NRTIs alone 
[HHS, 2013].  In second-line therapy, the efficacy of optimised dual NRTI alone would 
be expected to be similar or worse than that seen in treatment naïve studies in light of 
possible emergence of resistance to NRTIs during virologic failure with first line therapy.   
Therefore, a non-inferiority margin of 12% is an acceptable margin since it is well below 
the expected treatment effect for LPV/RTV plus two NRTIs vs. two NRTIs alone. 
Response rate assumptions
There are limited randomised prospective study data to indicate response rates of patients 
receiving second line treatment.  Retrospective and cohort analyses of LPV/RTV 
containing regimens in treatment experienced patients have showed responses between 
56.4% and 85.7% at 48 weeks.  These studies mostly contained small numbers of patients 
and differed in their use of backbone agents and the degree of treatment experience of 
subjects.
The estimated treatment response rate chosen for the comparator (70%) is based on the 
results from comparable studies of second line ART and the most recent relevant studies 
of DTG and LPV/RTV in patient population with treatment experience greater than 
second-line ART. 
Studies evaluating second-line therapy

HIV STAR was a study conducted in Thailand (n=195, ITT) to compare LPV/RTV + 
TDF/FTC with LPV/RTV monotherapy in patients failing initial therapy on an 
NNRTI + two NRTI regimen [Bunupuradah, 2012].  In this trial, the primary 
endpoint of non-inferiority according to mean reduction in HIV RNA from Baseline 

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over 48 weeks was met with a 1.89 log decrease for the LPV/RTV +TDF/FTC arm 
compared with a decrease of 1.74 log in the monotherapy arm (difference: 0.15 log; 
95% CI: 0.04 to 0.33).  For the secondary outcome of proportion of subjects <50 
c/mL a lower response was seen for the monotherapy arm.  In this analysis, 83% of 
subjects achieved HIV-1 RNA <50 c/mL (ITT) at Week 48 in the triple therapy arm 
compared with 61% in the LPV/RTV monotherapy arm (difference: -22.2%, 95% CI 
-33.5 to -9.0, p <0.01) based on a missing equals failure imputation.  As noted in the 
above manuscript, the high virologic suppression rate in the LPV + TDF/FTC arm 
may not be applicable to those with a much more extensive duration of NNRTI-
based failure.  For the LPV + TDF/FTC, the median (IQR) duration of NNRTI-based 
HAART before enrolment was 2.3 years (1.2-4.0).

The SECOND LINE study compares the antiviral efficacy of second-line ART 
comprising LPV/RTV + 2-3 NRTIs with LPV/RTV + RAL, as measured by the 
proportion of participants with plasma HIV-1 RNA <200 c/mL at Week 48 (n=541) 
[SECOND-LINE Study Group, 2013].  In this study, the LPV/RTV + RAL arm was 
found to be non-inferior to LPV/RTV + NRTIs at 48 weeks with 82.6% vs. 80.8% of 
patients respectively, achieving HIV-1 RNA  <200 c/mL (mITT, p=0.59).  Similarly, 
71.1% and 70.5% of participants achieved an HIV-1 RNA <50 c/mL (mITT, p=0.87) 
[Note: NC=F analysis or Snapshot equivalent showed 68.1% (184/270) vs 66.4% 
(180/271) of patients achieved HIV-1 RNA <50 c/mL at Week 48].  For the 
LPV/RTV + 2-3 NRTIs arm, the median (IQR) duration of NNRTI-based HAART 
before enrolment was 3.3 years (1.8-5.4) years.

The EARNEST study (ongoing, n=1270), conducted in sub-Saharan Africa was 
powered on 75% for the composite endpoint of ‘good HIV disease control’ at Week 
96.  At Week 96, 74% achieved HIV-1 RNA <50 c/mL with LPV/r + 2-3 NRTIs 
[Paton, 2013].
Studies in more treatment experienced populations

The TITAN study (LPV/RTV vs DRV+RTV):  the response rate for LPV/RTV arm 
was 68% (< 50 c/mL at 48 weeks, n=595) [Madruga, 2007]. This study population 
was more treatment experienced than the current study, with 47% of subjects having 
prior 3-class experience (NRTI + NNRTI + PI). 

The SAILING study (DTG vs RAL): in subjects receiving DTG in combination with 
1-2 investigator-selected background agents, the proportion of subjects with plasma 
HIV-1 RNA < 50 c/mL at Week 48 (Snapshot) was 71% (251/354) [Cahn, 2013].  
This study population had documented genotypic or phenotypic resistance to at least 
one member of each of at least two ART drug classes (NRTI, NNRTI, PI, fusion or 
entry inhibitor).
This study will randomise at least 306 subjects per arm.  Assuming a true response rate of 
70% in each arm, this sample size will provide 90% power to show non-inferiority for the 
proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 48 with a 12% non-
inferiority margin and a one-sided 2.5% significance level.  If we observe a 70% response 
rate in the LPV arm then non-inferiority would be declared if the observed treatment 
difference (DTG - LPV) was better than -4.6 percentage points.

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8.2.2.
Sample Size Sensitivity
Figure 2 shows the sensitivity of the required sample size to the true response rate for the 
control arm (assuming no true difference between arms).  Assuming identical response 
rates in each arm, if the true response rate is as low as 65%, the study will still have 88% 
power to meet its primary objective.  In this case, an extra 50 subjects (25 per arm) would 
be required to restore 90% power.
Figure 2
Sample Size Sensitivity
Power (%)
55
60
65
70
75
85
86
87
88
89
90
91
92
93
Control arm response rate (%)
a) How power changes with
control response (N=306/arm)
55
60
65
70
75
280
300
320
340
360
Subjects per arm
55
60
65
70
75
280
290
300
310
320
330
340
350
360
Control arm response rate (%)
b) Sample size needed
to guarantee 90% power
8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The following populations will be assessed.  The analysis population for genotypic and 
phenotypic analyses as well as for health outcomes assessments will be fully described in 
the reporting and analysis plan (RAP).
Intent-to-Treat Exposed (ITT-E) Population
This population will consist of all randomised subjects who receive at least one dose of 
study medication.  Subjects will be assessed according to their randomised treatment, 
regardless of the treatment they receive.  Unless stated otherwise, the ITT-E population 
will be used for summaries and analyses of efficacy.
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.

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Per-Protocol Population
This 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 Per-Protocol (PP) population will be used for sensitivity analyses of the 
primary efficacy endpoint.
ITT Population (ITT)
This population will consist of all randomised subjects.  Subjects will be assessed 
according to their randomised treatment even if no study treatment was taken or the 
wrong treatment was received.  The ITT population will be used for sensitivity analyses 
of the primary efficacy endpoint.
8.3.2.
Analysis Data Sets
For the primary efficacy analysis, each subjects responses (e.g. <50 c/mL) will be 
calculated according to the FDA’s Snapshot algorithm.  This algorithm treats all subjects 
without HIV 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 who switch their 
concomitant ART prior to the visit of interest as follows:

Background ART substitutions not permitted per protocol;

Background ART substitutions permitted per protocol after Week 4 (or date of first 
on-treatment viral load collection, if earlier) where the last HIV-1 RNA result prior to 
the date of decision to switch is ≥50 c/mL.  
Note: if the last HIV-1 RNA result prior to the date of decision to switch is <50 c/mL 
then the permitted change in background ART will have no effect on the analysis.
Note: A switch from 3TC to FTC (or vice versa) will not be considered a background 
NRTI change and will not incur a penalty in the Snapshot algorithm, regardless of reason 
or date of switch, as these agents are assumed to be of equal efficacy.
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 of interest window (to 
be specified in the RAP).
Full details on this Snapshot algorithm will be contained in the RAP.
The observed case (OC) dataset, which uses only data that is available at a particular time 
point with no imputation for missing values, will be the primary dataset for assessing 
safety and will also be used for some analyses of efficacy and health outcomes.
Full details on methods to address missing data for secondary efficacy and health 
outcomes endpoints will be discussed in the RAP.

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8.3.3.
Treatment Comparisons
8.3.3.1.
Primary comparisons of interest
The primary analysis will be based on the ITT-E population using the Snapshot dataset.   
The primary comparison will be made at a one-sided 2.5% level of significance.  
Treatment with DTG + two NRTIs will be declared non-inferior to treatment with 
LPV/RTV + two NRTIs if the lower end of a two-sided 95% confidence interval for the 
difference between the two groups in response rates at Week 48 lies above -12%.
8.3.3.2.
Other comparisons of interest
The analysis described above in Section 8.3.3.1 will also be performed using the PP 
population and the results will be compared for consistency with the results from the ITT-
E population.  If both analyses show non-inferiority then the hypothesis that the antiviral 
effect of treatment with DTG + two NRTIs is superior to treatment with LPV/RTV + two 
NRTIs will be tested using the same level of significance as for the tests of non-
inferiority.  Superiority will be declared if the lower end of the confidence internal is 
above 0%.  The primary comparison will also be performed using the ITT population and 
will be compared for consistency with the results from the ITT-E and PP populations.
The supportive analysis using the ITT population will classify subjects randomised but 
not exposed to study treatment as non-responders and therefore conservatively addresses 
any selection bias that may occur given the open-label study design.
8.3.3.3.
Secondary comparisons
The following key secondary comparisons will be tested:

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to change from Baseline in fasting LDL cholesterol at Week 48 using the Safety 
population;

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to the incidence of maximum post-Baseline emergent Grade 2 or greater laboratory 
abnormalities in fasting LDL cholesterol by Week 48 using the Safety population;

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to change from Baseline in fasting TC/HDL ratio at Week 48 using the Safety 
population;

Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to the incidence of maximum post-Baseline emergent Grade 2 or greater drug-related 
diarrhoea by Week 48 using the Safety population;

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, safety stopping criteria, and lack 
of efficacy);

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
Superiority of DTG + two NRTIs compared to LPV/RTV + two NRTIs with respect 
to time to viral suppression (HIV-1 RNA <50 c/mL) using ITT-E population.
8.3.4.
Interim Analysis
The main analysis will be conducted to evaluate the primary objective of the protocol 
when all subjects have completed their Week 52 visit.  
8.3.4.1.
Week 24 data cut
An interim analysis will be conducted when all subjects have completed their Week 24 
visit in order to provide an earlier assessment of efficacy to inform the Sponsor and 
clinicians.  The analyses described in Section 8.3.3 and Section 8.3.5 will be performed 
with the sole difference being that the timepoint for these analyses will be Week 24 
instead of Week 48.  
No adjustment for multiplicity will be made for this analysis because the Week 24 
endpoints represent secondary objectives for the study which are subordinate to the 
primary analysis at Week 48.
8.3.4.2.
IDMC interim analyses
An IDMC has been instituted to provide independent review of the accumulating data, 
primarily to ensure subjects are not being sub-optimally treated in either arm. 
Three formal interim analyses were planned for review by the IDMC (Table 5).
Table 5
Timing of Planned IDMC Interim Analyses and Statistical Stopping 
Guidelines
Interim 
Analysis
Timing
Endpoint
Evaluation (guideline)
#1
Once 100 subjects (total) 
have completed their Week 
16 visit
Proportion of subjects with 
HIV-1 RNA <50 c/mL
at Week 16
(Snapshot algorithm)
Inferioritya (one-sided p<0.01)
#2
Once 300 subjects (total) 
have completed their Week 
24 visit
Proportion of subjects with
HIV-1 RNA <50 c/mL
at Week 24
(Snapshot algorithm)
Inferioritya (one-sided p<0.01)
#3
Once all subjects have 
completed their Week 24 
visit
Proportion of subjects with 
HIV-1 RNA <50 c/mL
at Week 48
(Snapshot algorithm)
Inferioritya (one-sided p<0.01)
Superiorityb (one-sided p<0.0001)
a.
Inferiority: significantly lower response rate with DTG than LPV/r.
b.
Superiority: significantly higher response rate with DTG than LPV/r.
It is intended that the second interim analysis will occur roughly halfway between the 
second and third interim analyses, although this will be affected by the actual rate of 
study recruitment.     

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The third interim analysis will occur after all subjects have completed Week 24, but the 
stopping guideline is provided for the proportion of subjects with suppression at Week 48 
(including all subjects randomised at least 48 weeks prior to the last subject completing 
Week 24). For this reason, the number of subjects with week 48 data at the third interim 
analysis cannot be specified in advance.
The IDMC completed interim analyses #1 and #2.  Prior to interim analysis #3, the 
IDMC conducted an ad hoc review of trial data and observed significant, clinically 
relevant differences between treatment arms in favour of DTG.  The IDMC 
recommended to the sponsor that the LPV/RTV treatment arm be discontinued and 
subjects currently receiving LPV/RTV in the study be switched to a regimen with 
DTG as the third drug, if considered appropriate by the Investigator. Interim
analysis #3 will no longer take place.
Stopping Guidelines
Proposed p-value boundaries that may lead to an IDMC recommendation to stop the 
study at each interim analysis are provided in Table 5.  These have been provided as a 
guide only, with the expectation that the IDMC will base its recommendation to stop or 
continue the study based on all available evidence and the IDMC’s collective judgment. 
This stopping guidance is not a substitute for the medical, scientific or statistical expertise 
of the IDMC.  Moreover, if a guideline boundary is crossed then the IDMC will be asked 
to undertake a thorough review of the data, including all available data on treatment- and 
efficacy-related discontinuations (discontinuations due to virologic failure, lack of 
efficacy, drug-related adverse events), viral load data at all timepoints, and response by 
number of fully active background NRTIs.
Formal assessments of inferiority will be conducted at each interim analysis.  Inferiority 
for this study is defined as evidence that DTG has a substantially lower response rate than 
LPV.  A statistical guideline of p<0.01 (one-sided) will be used for each inferiority 
evaluation.
A formal assessment for superiority will be conducted only at the third interim analysis.  
Superiority is defined as substantial evidence that DTG has a higher response rate than 
LPV.  A statistical guideline of p<0.0001 (one-sided) will be used for this evaluation of 
DTG superiority.
No adjustment for multiple comparisons will be made since the impact of these 
guidelines do not alter the Type I error rate in favour of DTG to any measurable degree 
(Table 6).
The analysis method for these comparisons will be the same as that used in the final 
primary analysis (i.e. adjusted difference in proportion based on stratified analysis). 
The statistical properties of the proposed stopping guidelines are explored below.  For 
illustrative purposes only, the p-value boundaries are assumed to be binding (i.e. if 
crossed the study must be stopped).  However, in practice, the p-value boundaries are not 
binding and are to be used as guides only: signaling that additional exploration of the data 
is warranted, as described previously.

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Table 6 presents simulated probabilities of crossing the p-value boundaries at each 
interim analysis, and for declaring non-inferiority/superiority at the final primary Week 
48 analysis.
Table 6
Probability of crossing boundary at each analysis time-point for the 
ITT-E population
Interim 
Analysis
Week 48 
True treatment effect= -12%
(null hypothesis)
Week 48
True treatment effect = 0% (alternative 
hypothesis)
Inferiority
Superiority
Non-
inferiority
Inferiority
Superiority
Non-
inferiority
1
2
3
Final
5.02%
13.3%
30.3%
-
-
-
0
0
-
-
-
2.35%
1.18%
0.97%
0.89%
-
-
-
0.01%
2.49%
-
-
-
88.2%
When the true treatment difference is -12% (i.e. under the null hypothesis that DTG is 
inferior to LPV), the probability of wrongfully claiming non-inferiority is estimated to be 
2.35%, which is conservatively below the desired false positive error of 2.5%.  The 
probability that the inferiority boundary will be crossed at any one of the three interim 
analyses is estimated to be 49%.
When the true treatment effect is 0% (i.e. under the alternative hypothesis that both arms 
have response rates of 70%), the probability to correctly claim non-inferiority (i.e. power) 
is estimated to be 88.2%, slightly below the planned 90% level.  The probability that an 
inferiority boundary will be wrongfully crossed at any one of the three interim analyses is 
estimated to be 3%.  The probability that the superiority boundary will be crossed at the 
third interim analysis is 0.01% and 2.49% at the final analysis, if the true population 
response rate is 70% in each arm.
The unblinded interim analysis will be performed and delivered to the IDMC by an 
independent Statistics Data Analysis Centre (SDAC) external to the sponsor, so that the 
IDMC is able to evaluate the questions described in the committee charter.  The IDMC 
will review the list of data to be assessed and potentially may decide to review other 
types of data. Further details regarding the operation of the IDMC, the use of a SDAC for 
generating unblinded data, and content of the reviews are described in the charter.
8.3.5.
Key Elements of Analysis Plan
The study design is open-label; however, the sponsor staff responsible for the conduct 
and analysis of the study will not review any summaries of data grouped by treatment 
prior to database freeze for the interim Week 24 analysis.
8.3.5.1.
Efficacy analyses
For the primary comparison, adjusted estimates of the difference in the rate of responders 
between the two arms will be presented along with CIs based on a stratified analysis 
using Cochran-Mantel-Haenszel (CMH) weights.  All CIs will be two-sided.  For the 

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statistical analysis, 4 strata (subgroups) will be formed according to the combinations of 
levels of the following categorical variables: 
Baseline plasma HIV-1 RNA (vs. >100,000 c/mL);
Number of fully active background NRTIs (<2 vs. 2) at Baseline.
For analysis purposes, fully active is defined at Baseline by the genotypic resistance 
reports of the central laboratory (or a laboratory contracted by the central laboratory) 
showing no evidence of full or of partial genotypic resistance for a given NRTI. If 
Baseline genotypic results are not available, then activity of the background regimen will 
be based on genotypic results at Screening. 
The CMH estimate of the common difference in rates across strata will be calculated as 
the weighted average of the strata-specific estimates of the difference in response rates 
between the two arms as follows:
If nk is the number of DTG treated subjects, mk is the number of LPV treated subjects, 
and Nk = nk + mk is the total number of subjects in the kth stratum, then the CMH 
estimate is given by



k
k
k
cmh
W
d
W
d
ˆ
ˆ
where
k
k
k
k
N
m
n
W 
are CMH weights and     are estimates of the differences in response rates between the 
two treatment arms, rd-ra, for the kth strata.
The corresponding two-sided 95% CI will be calculated as
)
ˆ
r(
aˆv
96
.1
ˆ
cmh
cmh
d
d


using the variance estimator           ,       given by [Sato, 1989], which is consistent in both 
sparse data and large strata.  The full equation for this variance estimate is provided in the 
RAP. 
The weighted least squares chi-squared statistic [Fleiss, 1981] will be used to test for one-
way homogeneity across the levels of each categorical variable, with each categorical 
variable considered separately. Following Lui and Kelly [Lui, 2000], ½ will be added to 
each cell in any strata for which the stratum-specific rate estimates of either rd or ra are 
zero or one, and tests will be one-sided. Full details will be contained in the RAP. Any 
heterogeneity found to be statistically significant will be explored and if necessary results 
will be reported for each level of the categorical variable. Investigation of heterogeneity 
k
dˆ
)
ˆ
r(
aˆ
v
cmh
d

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will be confined to the primary endpoint using the Week 48 Snapshot analysis. Tests of 
homogeneity will be assessed at the one-sided 10% level of significance.
Following the IDMC recommendation to switch LPV/RTV subjects to DTG, 
additional sensitivity analyses will be conducted for the primary endpoint.  Further 
details of these analyses and any other impacted analyses will be included in the 
RAP.
Details for secondary efficacy endpoints will be discussed in the RAP.
Data gathered after subjects withdraw from IP will be listed but will not be included in 
summary tables. Data will be allocated to visit windows using actual visit dates rather 
than nominal visit numbers. Data collected from extra visits within a window will be 
listed and will be included in the derivation of the Snapshot response at analysis visits of 
interest, but summary tables using OC datasets will only use the data captured closest to 
the target visit date. Detailed explanations of the derivation of visit windows will be 
included in the RAP. Any deviations from planned analyses will be detailed in the 
clinical study report (CSR).
8.3.5.2.
Safety analyses
Exposure to study medication, measured by the number of weeks on study drug, will be 
summarised by treatment group. The proportion of subjects reporting AEs will be 
tabulated for each treatment group. The following summaries of AEs will be provided:

Incidence and severity of all AEs

Incidence and severity of treatment related AEs

Incidence and severity of AEs leading to withdrawal

Incidence of SAEs
Laboratory and vital signs data will be summarised by visit and treatment group. In 
addition, the number and percentage of subjects with graded laboratory toxicities (based 
on DAIDS categories) will be summarised by treatment group. The proportion of subjects 
experiencing changes from Baseline in their National Cholesterol Education Program 
(NCEP) lipid categories will be summarised by treatment arm.
Further details of safety analyses will be included in the RAP.
8.3.5.3.
Health outcomes analyses
HIVTSQ
The HIVTSQ was developed to evaluate treatments for HIV and patient satisfaction 
[Woodcock, 2001; Woodcock, 2006].  The higher the score, the greater the improvement 
in treatment satisfaction as compared to the past few weeks.  A smaller score represents a 
decline in treatment satisfaction compared to the past few weeks.

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
8 7
T his st u d y  will use t he 1 4 -ite m HI V T S Qs (stat us versi o n) a n d t he 1 4- ite m HI V T S Qc 
(c ha n ge versi o n), b ot h i ncl u di n g t he 1 0 ite ms of t he sta n dar d HI V T S Q b ut ha vi n g f o ur 
a d diti o nal ite ms f or testi n g.  T hese meas ures will assess c ha n ge i n treat me nt satisfacti o n 
o ver ti me (i n t he sa me s u bjects) a n d c o m pare c urre nt satisfacti o n wit h pre vi o us treat me nt 
satisfacti o n, fr o m a n earlier ti me p oi nt.
M M A S- 8
T he ori gi nal M oris k y  Me dicati o n A d here nce Scale ( M M A S) was a f o ur ite m scale t hat 
was de vel o pe d t o assess me dicati o n a d here nce wit h c hr o nic c o n diti o ns, s uc h as 
a nti h yperte nsi ve a ge nts [ M oris k y , 1 9 8 6].  M ore rece ntl y, a n ei g ht-ite m self-re p orte d 
scale was de vel o pe d calle d t he M oris ky 8 -Ite m Me dicati o n A d here nce Scale ( M M A S-8) 
[M oris k y , 2 0 0 8].  Sc ores of 8 i n dicate 
, a n d sc ores of less 
t ha n 6 i n dicate 
 o n t he M M A S-8 scale.  
Sc ores will be s u m marise d a n d c o m pare d bet wee n t he treat me nt gr o u ps i n a n e x pl orat or y 
a nal ys is at eac h ti me p oi nt.
G S R S
T he Gastr oi ntesti nal S y m pt o m Rati n g Scale ( G S R S) has 1 5 ite ms a n d is di vi de d i nt o f o ur 
d o mai ns: a b d o mi nal pai n; d y s pe ptic sy n dr o me; i n di gesti o n s y n dr o me; a n d b o wel 
s yn dr o me.  T he scale ra n ges fr o m 
 (1 ) t o 
 ( 7). T he 
o verall sc ore is calc ulate d b y  a d di n g t he c o m plete d sc ores of i n di vi d ual ite ms i n eac h 
gr o u p, f or a p ossi ble t otal ra n gi n g fr o m 1 5 t o 1 0 5.  Hi g her sc ores s h o w greater se verit y of 
s ym pt o ms [ S ve dl u n d , 1 9 8 8].  T he G S R S has bee n use d a n d vali date d i n ot her 
a ntiretr o viral st u dies, w hic h e xa mi ne t he GI s y m pt o ms ass oc iate d wit h b o oste d PIs [Sáez 
de la F ue nte ; 2 0 0 9; Mta m b o , 2 0 1 3].
Sc ores will be s u m marise d a n d c o m pare d bet wee n t he treat me nt gr o u ps i n a n e x pl orat or y 
a nal ys is at eac h ti me p oi nt.
8. 3. 5. 4.
Vir al g e n ot y pi n g/ p h e n ot y pi n g a n al y s e s
T he i nci de nce of treat me nt e mer ge nt ge n ot y pic a n d p he n ot y pic resista nce t o N R TI s, PIs, 
a n d I NIs will be s u m marise d b y treat me nt ar m f or s u bjects meeti n g c o nfir me d vir ol o gic 
wit h dra wal criteria.  Details of t he a nalys es t o be perf or me d will be s pecifie d i n t he R A P.
8. 3. 5. 5.
P h ar m a c o g e n eti c a n al y s e s
See A p pe n di x 5 , Secti o n 1 1. 5 , f or details a b o ut t he P har mac o ge netics A nalysis Pla n.
C CI
C CI
C CI
C CI

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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, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) 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:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review 
and favourable opinion/approval of study protocol and any subsequent 
amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
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 in Appendix 5 (Section 11.5), 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 GSK procedures, GSK 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 GSK 
requirements.  When reviewing data collection procedures, the discussion will include 

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identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

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, GSK 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.
9.5.
Study and Site Closure
Unless terminated early, this study will be considered completed after the last subject 
completes the last study-related clinic visit or assessment.  Upon completion or 
termination of the study, the GSK monitor will conduct site closure activities with the 
investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, 
and GSK Standard Operating Procedures.
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 GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, 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, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  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.

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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 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.
GSK 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, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK 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.
9.7.
Provision of Study Results to Investigators, 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 GSK site or other mutually-
agreeable location.
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 eight 
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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9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilised in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  Planned stopping 
guidelines and schedule for interim analyses are provided in Section 8.3.4.2, with 
additional details described in the charter, which is available upon request.  
The IDMC completed pre-planned interim analyses #1 and #2 and following an ad hoc 
review of trial data prior to interim analysis #3, the IDMC observed significant, clinically 
relevant differences between treatment arms in favour of DTG.  The IDMC 
recommended that the LPV/RTV treatment arm be discontinued and subjects currently 
receiving LPV/RTV in the study be switched to a regimen with DTG as the third drug, if 
considered appropriate by the Investigator.  Interim analysis #3 will no longer take place.

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10.
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Barnas D, Koontz D, Bazmi H, Bixby C, Jemsek J, Mellors JW. Clonal resistance 
analyses of HIV type-1 after failure of therapy with didanosine, lamivudine and 
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Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and 
osteoporosis: a meta-analytic review. AIDS 2006; 20:2165-74.
Bunupuradah T, Chetchotisakd P, Ananworanich J, et al. A randomized comparison of 
second-line lopinavir/ritonavir monotherapy versus 
tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV 
STAR study. Antivir Ther 2012; 17:1351-61.
Cahn P, Pozniak AL, Mingrone H, et al.  Dolutegravir versus raltegravir in antiretroviral-
experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the 
randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382:700-8.
CDC. 1993 revised classification system for HIV infection and expanded surveillance 
case definition for AIDS among adolescents and adults. MMWR 1992; 41 (No. RR-
17):1-19.
Currier JS, Lundgren JD, Carr A, et al. Epidemiological evidence for cardiovascular 
disease in HIV-infected patients and relationship to highly active antiretroviral therapy. 
Circulation 2008; 118:e29-e35.
Fleiss JL. Statistical Methods for Rates and Proportions. 2 ed. New York: John Wiley; 
1981.  
Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, 
abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis 2005; 
192:1921-30.
GlaxoSmithKline Document Number RM2007/00683/11: GSK1349572 Clinical 
Investigator's Brochure, version 11. October 2017.
GlaxoSmithKline Document Number 2017N352880_00: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 01. December 2017.
GlaxoSmithKline Document Number 2017N352880_01: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 02. June 2018.
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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HHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the 
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of 
Health and Human Services. Available at:
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (accessed 30 August 
2013)
Isentress EU Summary of Product Characteristics, August 2013.
Isentress US Product Information, October 2013.
Johnson VA, Calvez V, Günthard HF, et al. Update of the drug resistance mutations in 
HIV-1: March 2013. Top Antivir Med 2013; 21:6-14.
Kaletra EU Summary of Product Characteristics, February 2017.
Kaletra US Product Information, November 2016.
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med 2009; 150:604-12.
Lui K-J, Kelly C. A Revisit on Tests for Homogeneity of the Risk Difference. 
Biometrics. 2000; 56:309-15.
Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir 
compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-
infected patients in TITAN: a randomised controlled phase III trial. Lancet 2007; 370:49-
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Mazoyer E, Manirakiza G, Bikie A, et al. Never too late for adherence support: 
experience from the recruitment phase in ANRS 12169 - 2LADY trial. 18th International 
AIDS Conference (AIDS 2010). Vienna, 18-23 July 2010. TUPE0187.
Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. 
lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS 
2009; 23:1679-88.
Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir 
versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and 
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week 
efficacy and safety results of the CASTLE study. Lancet 2008; 372:646-55.
Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive validity of a medication 
adherence measure for hypertension control. J Clin Hypertens 2008;10: 348-54.
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Mtambo A, Harris M, Toy J, Guillemi S, et al. Evaluation of treatment tolerability, 
satisfaction and laboratory parameters in HIV+ patients switching from ritonavir capsule 
to tablet formulation. Curr HIV Res 2013; 11:231-7.
Oquendo MA, Mann J. Risk Factors for suicidal behaviour: utility and limitations of 
research instruments (2003). In M.B. First [Ed] Standardized Evaluation in Clinical 
Practice, pp 103-30.
Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily 
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Paton N, Kityo C, Hoppe A, et al. A pragmatic randomised controlled strategy trial of 
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Sáez de la Fuente J, Granja V, Escobar I, et al. Study of the gastrointestinal tolerance of a 
new tablet formulation of the lopinavir/ritonavir antiretroviral in HIV-infected patients.  J 
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SECOND-LINE Study Group. Ritonavir-boosted lopinavir plus nucleoside or nucleotide 
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Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral Treatment of Adult HIV 
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TIVICAY US Product Information, March 2017.
UNAIDS. 2012 UNAIDS Report on the Global AIDS Epidemic. Available at: 
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2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
9 6
1 1.
A P P E N DI C E S
1 1. 1.
A p p e n di x 1: C hil d -P u g h Cl a s sifi c ati o n
A s u bject is cla ssifie d wit h 
 ( Class A) if t heir o verall s u m of 
sc ores is 5- 6 p oi nts, 
 ( Class B) if t heir o verall s u m of sc ores 
is 7- 9 p oi nts, a n d 
 ( Class C) if t heir o verall s u m of sc ores is 1 0-
1 5 base d o n t he C hil d- P u g h s ys te m [P u g h , 1 9 7 3] sc ori n g descri be d i n t he f oll o wi n g ta ble 
(Ta ble 7 ).  F or s u bjects re q uiri n g a ntic oa g ulati o n t hera p y, disc ussi o n wit h t he st u d y 
me dic al m o nit or will be re q uire d.
T a bl e 7
C hil d -P u g h S y st e m
[P u g h , 1 9 7 3; L uc ey , 1 9 9 7]
R ef er e n c e s
L uce y  M R, Br o w n K A, E vers o n G T, et al. Mi ni mal criteria f or place me nt of a d ults o n 
t he li ver tra ns pla nt waiti n g list: a re p ort of a nati o nal c o nfere nce or ga nize d b y  t he 
A merica n S ociet y of Tra ns pla nt P h y sicia ns a n d t he A merica n Ass ociati o n f or t he St u d y 
of L i ver Diseases. Li ver Tra ns pl S ur g 1 9 9 7; 3: 6 2 8-3 7.
P u g h R N H, M urra y -L y o n I M, Da ws o n J L,  Pietr o ni M C, Willia ms R. Tra nsecti o n of t he 
oes o p ha g us f or blee di n g oes o p ha geal varices. Br J S ur g 1 9 7 3; 6 0: 6 4 6 - 9.
C CI
C CI
C CI
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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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 generalised 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 two distinct episodes or more than one 
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 septicaemia, recurrent

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
Toxoplasmosis of brain

Wasting syndrome due to HIV

Non-CDC, HIV-associated conditions.
Reference
CDC. 1993 revised classification system for HIV infection and expanded surveillance 
case definition for AIDS among adolescents and adults. MMWR 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 utilised for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term.
CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
ESTIMATING SEVERITY GRADE1
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

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Pain (indicate body site)
DO NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site pain)
See also Headache, Arthralgia, 
and Myalgia
Pain causing no or minimal 
interference with usual social & 
functional activities
Pain causing greater than minimal 
interference with usual social & 
functional activities
Pain causing inability to perform 
usual social & functional activities
Disabling pain causing inability to 
perform basic self-care functions OR 
Hospitalization (other than emergency 
room visit) indicated
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

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
Injection site reaction (localized)
Adult > 15 years
Erythema OR Induration of 5x5 
cm – 9x9 cm (or 25 cm2 – 81cm2)
Erythema OR Induration OR Edema 
> 9 cm any diameter (or > 81 cm2)
Ulceration OR Secondary infection 
OR Phlebitis OR Sterile abscess OR 
Drainage
Necrosis (involving dermis and deeper
tissue)
Pediatric 15 Years
Erythema OR Induration OR 
Edema present but 2.5 cm 
diameter
Erythema OR Induration OR Edema 
> 2.5 cm diameter but < 50% 
surface area of the extremity 
segment (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
Hypopigmentation
Slight or localized
Marked or generalized
NA
NA
Pruritis (itching – no skin lesions)
(See also Injection Site Reactions: 
Pruritis associated with injection)
Itching causing no or minimal 
interference with usual social & 
functional activities
Itching causing greater than 
minimal interference with usual 
social & functional activities
Itching causing inability to perform 
usual social & functional activities
NA

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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 
visit)
NA
91st – 94th percentile adjusted for 
age, height, and gender (systolic 
and/or diastolic)
95th percentile adjusted for age, 
height, and gender (systolic and/or 
diastolic)
Life-threatening consequences (e.g., 
malignant hypertension) OR
Hospitalization indicated (other than 
emergency room visit)
Hypotension
NA
Symptomatic, corrected with oral 
fluid replacement
Symptomatic, IV fluids indicated
Shock requiring use of vasopressors or 
mechanical assistance to maintain 
blood pressure
Pericardial effusion
Asymptomatic, small effusion 
requiring no intervention
Asymptomatic, moderate or larger 
effusion requiring no intervention
Effusion with non-life threatening 
physiologic consequences OR 
Effusion with 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

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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)]
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when grading anorexia, this is not a requirement and should 
not be used as a substitute for clinical judgment.
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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CLINICAL
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 visit)
Symptomatic AND Hospitalization 
indicated (other than emergency 
room visit)
Life-threatening consequences (e.g., 
circulatory failure, hemorrhage, 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)

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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
– Pediatric 16 Years
Mild developmental delay, either 
motor or cognitive, as determined 
by comparison with a 
developmental screening tool 
appropriate for the setting
Moderate developmental delay, 
either motor or cognitive, as 
determined by comparison with a 
developmental screening tool 
appropriate for the setting
Severe developmental delay, either 
motor or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting
Developmental regression, either motor 
or cognitive, as determined by 
comparison with a developmental 
screening tool appropriate for the 
setting

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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)
– Adult 18 years
See also Seizure: (known pre-
existing seizure disorder)
NA
1 seizure
2 – 4 seizures
Seizures of any kind which are 
prolonged, repetitive (e.g., status 
epilepticus), or difficult to control (e.g., 
refractory epilepsy)
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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CLINICAL
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
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

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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
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

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CLINICAL
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-THREATENING
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 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
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 control
New onset with initiation of 
medication indicated OR Diabetes 
uncontrolled despite treatment 
modification
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
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
1. Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.
2. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement).
3. Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.
4. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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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
Comment:  Values in children 13 years are not given for the two parameters above because the absolute counts are variable.
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
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 – 2.13 mmol/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
4.34 – 5.54 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
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

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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
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 
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 
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
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

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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†
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
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
130 – 135 mmol/L
125 – 129 mEq/L
125 – 129 mmol/L
121 – 124 mEq/L
121 – 124 mmol/L
120 mEq/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

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LABORATORY
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
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
0.201 – 0.499 g/d
500 – 799 mg/m2/24 h
0.500 – 0.799 g/d
800 – 1,000 mg/m2/24 h
0.800 – 1.000 g/d
> 1,000 mg/ m2/24 h
> 1.000 g/d
Values are for term infants.  Preterm infants should be assessed using local normal ranges.
† Use age and sex appropriate values (e.g., bilirubin).
Reference
Division of AIDS, Regulatory Support Center. Manual for grading the severity of adult and pediatric adverse events. Version 1.0 -
December 2004 (Clarification dated August 2009) Bethesda, MD: DAIDS/RCC, 2009. Available at: http://rsc.tech-
res.com/safetyandpharmacovigilance/ (accessed 21 March, 2014)

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11.4.
Appendix 4: Liver Safety Drug Restart or Rechallenge 
Guidelines
VSLC GUIDELINES FOR DRUG RESTART OR RECHALLENGE AFTER 
STOP FOR LIVER CRITERIA
1.
Drug rechallenge may be considered for a subject exhibiting compelling benefit for 
a critical medicine following drug-induced liver injury, if favourable benefit: risk 
and no alternative medicine available (Table 8, Figure 3)
2.
In Phase III, drug restart may be considered for liver events with a clear underlying 
cause (e.g. biliary, pancreatic events, hypotension, acute viral hepatitis), if not 
associated with drug-induced liver injury, alcoholic hepatitis or hypersensitivity, and 
drug not associated with HLA marker of liver injury, when liver chemistries improve 
to within 1.5x baseline and ALT<3xULN) (Table 9, Figure 4).
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 one 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2xULN 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])
VSLC Decision Process for Drug Rechallenge Approval or 
Disapproval (Figure 3):

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 
alternative treatment

By definition treatment naïve subjects will only be considered for rechallenge if 
they were infected with a multi-resistant virus.

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 8).

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
The Medical Monitor and GCSP Physician are accountable to review and agree
on:
–
compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history 
–
Relative benefit-risk of drug rechallenge, with consideration of the following 
high risk factors:
Initial liver injury event included: fever, rash, eosinophilia, or 
bilirubin2xULN (or direct bilirubin >35% of total, if available)
subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total, if available), or INR1.5
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, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader.

Request is taken to full VSLC for final decision. 

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Figure 3
VSLC process for drug rechallenge approval or disapproval
The local operating company (LOC) medical director (ViiV and GSK where applicable) 
should be informed that study drug rechallenge is under consideration and of the final 
decision, whether or not to proceed.
Table 8
Checklist for drug rechallenge for critical medicine (Following drug-
induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy.  Provide brief explanation:
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2xULN (direct bilirubin >35% of total)
o
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (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 patients current resistance profile
o
Previous drug history

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Drug Restart
Phase III “drug restart” can be approved by the VSLC for transient, defined non-drug-
induced liver injury if no evidence of:
•
immunoallergic injury /HLA association with injury
•
drug-induced liver injury (DILI)
•
alcoholic hepatitis
Study drug is held while labs and evaluation is completed to assess diagnosis.
VSLC Decision Process for Drug Restart Approval or Disapproval 
(Figure 4):

PI requests consideration of drug re-initiation for a subject stable or improving 
on IP, who exhibits liver chemistry elevation meeting subject stopping criteria, 
which is transient, non-drug-related, and liver chemistries improve to within 
1.5x baseline and ALT< 3xULN. 

Medical Monitor and Clinical Safety Physician to review the subject’s 
diagnosis, restart risk factors and complete checklist (Table 9).
–
must present source data defining the patient’s current resistance profile 
with documented evidence of extensive drug resistance and previous drug 
history.

The LOC medical director (ViiV and GSK where applicable) should be 
informed that study drug restart is under consideration and of the final decision, 
whether or not to proceed.
Table 9
Checklist for Phase III drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, congestive heart 
failure, acute viral hepatitis), improving to liver chem1.5x baseline 
& ALT<3xULN.
Yes
No
Is subject stable or improving on the investigational product (IP)?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)

IP has an HLA genetic marker associated with liver injury (e.g. lapatinib, 
abacavir, amoxicillin/clavulanate)
Source data defining the patients current resistance profile
Previous drug history

Relevant physicians must review and agree on request for drug restart:  

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
Safety Team Leader, VP, or Senior Safety Physician

Medicines Development Leader and Project Physician Leader.

Hepatotoxicity Panel consultation is available.

Justification for drug restart outlining the benefit and risk for this subject must 
be recorded by GCSP Physician and sent to the VSLC Secretary.

VSLC must approve drug re-initiation and dosing regimen
Figure 4
VSLC process for drug restart approval or disapproval
1. Andrade, 2009; 2. Papay, 2009; 3. Hunt, 2010
Medical monitor, GCSP Physician and PI actions for Restart 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

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 2 3

All se vere reacti o ns (rec halle n ge ass ociate d wit h bilir u bi n > 2 x U L N or ja u n dice, 
or I N R 1. 5), S A Es or fatalities wit h dr u g rec halle n ge ( or restart) m ust be 
i m me diatel y re p orte d t o Li ne Ma na ge me nt, V S L C C hair, V P Gl o bal Me dical 
Strate g y  a n d E U Q ualifie d Pers o n f or P har mac o vi gila nce. 
Pri n ci p al I n v e sti g at or A cti o n s:

T he PI  m ust o btai n Et hics C o m mittee or Instit uti o nal Re vie w B oar d a p pr o val of 
dr u g rec halle n ge or restart, as re q uire d. 

If dr u g re-i nitiati o n V S L C-a p pr o ve d, t he patie nt m ust pr o vi de i nf or me d c o nse nt 
wit h a clear descri pti o n of p ossi ble be nefits a n d ris ks of dr u g a d mi nistrati o n 
i ncl u di n g rec urre nt, m ore se vere li ver i nj ur y or p ossi ble deat h.

T ar gete d dr u g rec h alle n ge or dr u g rest art c o nse nt f or m m ust be use d.

T he patie nt’s i nf or me d c o nse nt m ust be rec or de d i n t he st u d y  c hart, a n d t he dr u g 
a d mi nistere d at a gree d d ose, as c o m m u nicate d b y Me dical M o nit or.

Li ver c he mistries m ust be f oll o we d t wice wee kly f or ‘rec h alle n ge’ c ases a n d 
o nce wee kly f or ‘rest art’ c ases f or o ne m o nt h or f or as l o ng as cli nicall y 
i n dicate d f oll o wi n g dr u g re-i nitiati o n.  If s u bject e x hi bits pr ot oc ol-defi ne d li ver 
c he mistr y ele vati o ns, I P s h o ul d be disc o nti n ue d as pr ot oc ol s pecifie d.
V S L C a n d t he I R B/I E C m ust be i nf or me d of t he p atie nt’s o utc o me f oll o wi n g dr u g 
rec h all e n ge or rest art.
R e c h all e n g e/r e st art s af et y  o ut c o m e s:





R ef er e n c e s
A n dra de RJ, R o bles M, L uce na MI.  Rec halle n ge i n dr u g -i n d uce d li ver i nj ur y: t he 
attracti ve hazar d.  E x pert O pi n Dr u g Saf. 2 0 0 9; 8: 7 0 9- 7 1 4.
H u nt, C M.  Mit oc h o n drial a n d i m m u n oaller gic i nj ur y  i ncrease ris k of p ositi ve dr u g 
rec halle n ge after dr u g-i n d uce d li ver i nj ur y: A sys te matic re vie w.  He pat ol. 2 0 1 0; 
5 2: 2 2 1 6 - 2 2 2 2. 
Pa pa y  JI, Cli nes D, Rafi R, et al.  Dr u g-i n d uce d li ver i nj ur y f oll o wi n g p ositi ve dr u g 
rec halle n ge.  Re g ul T o x P har m. 2 0 0 9; 5 4: 8 4- 9 0. 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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11.5.
Appendix 5: 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, 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:

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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.
Carbamazepine
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 two 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 or any of the HIV medicines 
included in this study. 

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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 or 
any of the HIV medicines included in this study.  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:

Relationship between genetic variants and the pharmacokinetics and/or 
pharmacodynamics of DTG or other HIV medicines used in this study;

Relationship between genetic variants and safety and/or tolerability of DTG or other 
HIV medicines used in this study;

Relationship between genetic variants and efficacy of DTG or other HIV medicines 
used in this study.
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 Deoxyribonucleic acid (DNA) extraction and used in 
PGx assessments.
In addition to any blood samples taken for the clinical study, a whole blood sample (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 randomised 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 utilise 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.

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The need to conduct PGx analysis may be identified after a study (or a set of studies) of 
DTG (or any of the HIV medicines included in this study) 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 (or any of the HIV medicines 
included in this study).
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.
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. 

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In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to DTG or any of the HIV medicines included 
in this study.  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 
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 SL, 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: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.

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Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.

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11.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 1
1 1. 7.
A p p e n di x 7: Pr ot o c ol C h a n g e s
1 1. 7. 1.
Pr ot o c ol A m e n d m e nt 0 1
T his pr ot oc ol a me n d me nt a p plies t o all p artici p ati n g sites.
R ati o n ale f or Pr ot oc ol A me n d me nt 0 1:
i. Me dical M o nit or C o ntact I nf or mati o n a n d Seri o us A d verse E ve nts ( S A E) C o ntact 
I nf or mati o n has bee n u p date d wit h a sec o n dar y c o ntact.
ii. Re m o val of e xcl u si o n criteri o n 1 8 w hic h pr o hi bits e nr ol me nt of s u bject wit h 
creati ni ne cleara nce of < 5 0 m L / mi n via t he C K D-E PI  met h o d.  T his e xcl usi o n 
criteri o n was i ncl u de d i n err or.  B ot h D T G a n d L P V/ R T V ca n be a d mi nistere d i n 
patie nts wit h re nal i m pair me nt, a n d n o d osa ge a dj ust me nts are re q uire d.
iii.Refere nce t o aller gic reacti o n criteria i n Secti o n 4. 5 “ Wit h dra wal Criteria” w hic h was 
o mitte d i n t he ori gi nal pr ot oc ol.  As per Secti o n 6. 4. 4. 6, s u bjects wit h Gra de ≥3 
aller gic reacti o ns t hat are c o nsi dere d t o be p ossi bl y  or pr o ba bly relate d t o t he I P 
s h o ul d per ma ne ntly disc o nti n ue t he I P re gi me n a n d t he s u bject s h o ul d be wit h dra w n 
fr o m t he st u d y. 
i v.T he HI V treat me nt satisfacti o n q uesti o n naire stat us versi o n ( HI V T S Qs) a n d HI V T S Q 
c ha n ge versi o n ( HI V T S Qc) will be a d mi nistere d at differe nt ti mes f oll o wi n g fee d bac k 
of t he de vel o per of t hese q uesti o n naires.  T he HI V T S Qs will be a d mi nistere d at 
Ba seli ne ( Da y 1), Wee k 4, Wee k 2 4, Wee k 4 8 a n d wit h dra wal w hile t he HI V T S Qc 
will be a d mi nistere d at Wee k 4 8 a n d at wit h dra wal (i n a d diti o n t o t he HI V T S Qs) 
rat her t ha n at Wee k 2 4.  T he HI V T S Qs-1 4 ite m meas ure, w hic h i ncl u des t he 1 0 ite ms 
i n t he sta n dar d HI V T S Qs b ut has f o ur a d diti o nal ite ms f or testi n g, will be use d i n t he 
st u d y.
v. I n Secti o n 6. 4. 4. 5 “ Decli ne i n re nal f u ncti o n”, esti mate d G F R ( by t h e C K D -E PI  
met h o d) is referre d t o i nstea d of Cr Cl i n or der t o clarif y w hat f or m ula s h o ul d be use d 
t o e val uate re nal f u ncti o n.
vi. U p dates t o refere nce [ Kaletra E U S u m mar y  of Pr o d uct C haracteristics; Kaletra U S 
Pr o d uct I nf or mati o n].
A list of s pecific c ha n ges is pr o vi de d bel o w.  U nless state d ot her wise, ne w te xt is 
re prese nte d i n b ol d f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
S P O N S O R I N F O R M A TI O N P A G E
S p o ns or Me dical M o nit or C o ntact I nf or mati o n
a n d Seri o us A d verse E ve nts ( S A E) 
C o nt act I nf or m ati o n : 
 M D
Gl a x o S mit h Kli ne
Researc h Tria n gle Par k
P P D

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 2
Fi ve M o ore Dri ve, Researc h Tria n gle Par k, N C ( U S A)
Tele p h o ne: +
M o bile: +
Sec o n d ar y c o nt act:
 M D
Gl a x o S mit h Kli ne
C olle ge ville, P A ( U S A) 
Tele p h o ne: +
M o bile: +
S p o ns or Seri o us A d verse E ve nts ( S A E) C o nt act I nf or m ati o n:
Researc h Tria n gle Par k
Fi ve M o ore Dri ve, Researc h Tria n gle Par k, N C ( U S A)
Tele p h o ne: +
M o bile: +
4. 3. E x cl u si o n Crit eri a
T he f oll o wi n g te xt has bee n delete d:
1 8. S u bject has creati ni ne cleara nce of < 5 0 m L / mi n via t he C K D-E PI met h o d.
4. 5 Wit h dr a w al Crit eri a
S u bjects m ust be disc o nti n ue d fr o m t he st u d y  f or a n y of t he f oll o wi n g reas o ns:...

Aller gic re acti o n or ras h criteria as descri be d i n Secti o n 6. 4. 4. 6 a n d Secti o n 6. 4. 4. 7
res pecti vel y, are met a n d n o c o m pelli n g alter nate ca use is i de ntifie d;
6. 1. Ti m e a n d E v e nt s S c h e d ul e
Ta ble 1 Ti me a n d E ve nts Ta ble
I n a d diti o n t o Baseli ne ( Da y 1), Wee k 4, Wee k 4 8 a n d at wit h dra wal, t he HI V T S Qs will 
als o be a d mi nistere d at Wee k 2 4.  T he HI V T S Qc will be a d mi nistere d at Wee k 4 8 a n d 
als o at wit h dra wal rat her t ha n at Wee k 2 4.
Sa m ples f or q ua ntitati ve plas ma HI V -1 R N A P C R a n d l y m p h oc y te s u bset a n d plas ma f or 
st ora ge will n ot be c ollecte d at F oll o w- u p.
F o ot n ote b. has bee n a me n de d: F or s u bjects w h o c o m plete d ra n d o mise d D T G t hr o u g h 
Wee k 5 2 a n d e ntere d i nt o t he D T G C o nti n uati o n P hase: s u bjects c o m pleti n g t he D T G 
C o nti n uati o n P hase m ust ret ur n t o t he cl i nic w he n tra nsiti o ni n g t o c o m mercial s u p plies. 
C o n d uct st u d y  assess me nts, wit h t he e xce pti o n of dis pe nsi n g I P, as s pecifie d f or all 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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Continuation Phase visits per the follow-up visit schedule at this end of Continuation 
Phase visit.
6.4.4.5 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 and urine total protein/albumin ratios 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 CrCl the estimated GFR (using the CKD-EPI method) 
of >50% must return for a confirmatory assessment as soon as possible. A urinalysis and 
urine albumin/creatinine and urine protein/creatinine ratios should be done at this 
confirmatory visit.  If the estimated CrCl 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 study drugs (if appropriate).  Consideration for 
confounding factors (e.g. background therapy, other medications, dehydration, concurrent 
conditions) should be taken into account, and a nephrology consult may be obtained.  If a 
subject is also receiving TDF, then a switch to an alternative nucleoside should be 
considered if restarting IP.  One background NRTI change is allowed for management of 
drug toxicity as described in Section 6.4.4, “Specific Toxicities/Adverse Event 
Management”.   If IP is reinitiated, it should have been withheld for no more than 4 
weeks.  If IP is not reinitiated the subject must be withdrawn.
8.3.5.3. Health outcomes analyses
HIVTSQ
The HIVTSQ was developed to evaluate treatments for HIV and patient satisfaction 
[Woodcock, 2001; Woodcock, 2006].  The higher the score, the greater the improvement 
in treatment satisfaction as compared to the past few weeks.  A smaller score represents a 
decline in treatment satisfaction compared to the past few weeks.
This study will use the 14-item HIVTSQ(s) (status version) and the revised14-item
HIVTSQ(c) (change version), both including the 10 items of the standard HIVTSQ 
but having four additional items for testing.  These measures will assess change in 
treatment satisfaction over time (in the same subjects) and compare current satisfaction 
with previous treatment satisfaction, from an earlier time point.
10. REFERENCES
The following references have been updated.
Kaletra EU Summary of Product Characteristics, February 2014May2013.
Kaletra US Product Information, NovemberJanuary 2013.

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 4
1 1. 7. 2.
Pr ot o c ol A m e n d m e nt 0 2
Pr ot oc ol c h a n ges f or A me n d me nt 0 2, fr o m pr ot oc ol c h a n ges t o A me n d me nt 0 1 ( 3 0 -
A pr - 2 0 1 4)
T his pr ot oc ol a me n d me nt a p plies t o all p artici p ati n g sites.
A m e n d me nt 0 2 S u m m ar y a n d R at i o n ale:
i. T he a ut h or list has bee n u p date d.
ii. S p o ns or, Me dical M o nit or a n d Seri o us A d verse E ve nts ( S A E) C o ntact I nf or mati o n 
has bee n u p dat e d.
iii.F oll o wi n g a n I D M C rec o m me n dati o n t o disc o nti n ue t he LP V/ R T V ar m a n d s witc h 
s u bjects c urre ntl y recei vi n g L P V/ R T V i n t he st u d y t o a re gi me n wit h D T G, cha n ges t o 
t he st u d y desi g n ha ve bee n ma de acc or di n gly.   A d diti o nal se nsiti vit y  a nal yses are 
pla n ne d f or t he pri mar y e n d p oi nt as a c o nse q ue nce of t hese c ha n ges.
i v.T he secti o n o n S uici dalit y  m o nit ori n g has bee n u p date d wit h f urt her g ui da nce 
f oll o wi n g i ncl usi o n of a d diti o nal a d verse dr u g reacti o ns i n t he D T G i n vesti gat or’s 
br oc h ure : de pressi o n, s uici dal i deati o n or s uici de atte m pt ( partic ularl y i n patie nts wit h 
a pre-e xisti n g hist or y of de pressi o n or ps yc hi atric ill ness). 
v. U p dates t o t he Ti me & E ve nts Ta ble ( Secti o n 6. 1) a n d t he Healt h O utc o mes A nal yses 
secti o n t o pr o vi de clearer g ui da nce o n w he n healt h o utc o mes assess me nts will be 
c o n d ucte d i n t he case of earl y wit h dra wal fr o m t he st u d y a n d o n M M A S-8 a n d G S R S 
sc ores, res pecti vely.
vi. U p dates t o refere nce s: Kaletra E U S u m mar y  of Pr o d uct C haracteristics, Kaletra U S 
Pr o d uct I nf or mati o n , W H O treat me nt g ui deli nes, In vest i gat or’s Br oc h ure.
A list of s pecific c ha n ges is pr o vi de d bel o w.  U nless state d ot her wise, ne w te xt is 
re prese nte d i n b ol d f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
List of S pecific C h a n ges
TI T L E P A G E
A ut h or(s):
S P O N S O R I N F O R M A TI O N P A G E
T his st u d y  is s p o ns ore d b y Vii V Healt hcare.  Gla x o S mit h Kli ne is i m ple me nti n g a n d 
ma na gi n g all as pects of t his st u d y .Gl a x o S mit h Kli ne is s u p p orti n g Vii V He alt hc are i n 
t he c o n d uct of t his st u dy.
P P D
P P D

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 5
S p o ns or N a me a n d Le g al Re gistere d A d dress (e xcl u di n g U S) S p o ns or Le gal 
Re gistere d A d dress :
Vii V Healt hcare U K Li mite d
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
Tele p h o ne:  + 4 4 ( 0) 2 0 8 3 8 0 6 2 0 0
U S I N D S p o ns or N a me a n d Le g al Re gistere d A d dress S p o n s or C o ntact A d dress:
Vii V Healt hcare C o m p a n y
Fi ve M o ore Dri ve 
P. O. 1 3 3 9 8
Researc h Tria n gle Par k, N C 2 7 7 0 9 -3 3 9 8, U S A
Tele p h o ne: + 1 9 1 9 4 8 3 2 1 0 0
I n s o me c o u ntries, t he cli nical trial s p o ns or ma y be t he l ocal Vii V Healt hcare affiliate 
c o m pa n y ( or desi g nee) . W here a p plica ble, t he details of t he S p o ns or a n d c o ntact pers o n 
will be pr o vi de d t o t he rele va nt re g ulat or y  a ut h orit y as part of t he cli nical trial 
s u b missi o n. I n s o me c o u ntries, l oc al l a w re q uires t h at t he Cli nic al Tri al s p o ns or is a 
l oc al c o m p a n y le g al e ntit y. I n t hese i nst a nces, t he a p pr o pri ate c o m p a n y t o be 
i de ntifie d as s p o ns or m ust be a gree d wit h t he gl o b al Vii V He alt hc are cli nic al te a m 
a n d si g ne d off b y t he V P a n d He a d, Gl o b al Rese arc h a n d Me dic al Str ate g y.
Me dical M o nit or C o ntact I nf or mati o n a n d Seri o us A d verse E ve nts ( S A E) C o ntact 
I nf or mati o n: 
 M D, P h D 
Vii V He alt hc are
9 8 0 Gre at West R o a d
Bre ntf or d , Mi d dlese x
T W 8 9 G S
U K
M o bile: +
Gla x o S mit h Kli ne
Researc h Tr ia n gle Par k
Fi ve M o ore Dri ve, Researc h Tria n gle Par k, N C ( U S A)
Tele p h o ne: +
M o bile: +
Sec o n dar y  c o ntact:
 M D
Vii V He alt hc are
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 3 6
5 M o ore Dri ve
Rese arc h Tri a n gle P ar k, N C  2 7 7 0 9
U S A
M o bile: +
, M D
Gla x o S mit h Kli ne
C olle ge ville, P A ( U S A) 
Tele p h o ne: +
M o bile: +
P R O T O C O L S U M M A R Y
St u d y Desi g n
T he f oll o wi n g te xt has bee n a d de d:
T he I D M C c o m plete d t w o of t he t hree pre- pl a n ne d a n al yses.  Pri or t o i nteri m 
a n al ysis # 3, t he I D M C c o n d ucte d a n a d -h oc re vie w of tri al d at a a n d o bser ve d 
si g nific a nt, cli nic all y rele v a nt differe nces bet wee n tre at me nt ar ms i n f a v o ur of D T G.  
T he I D M C rec o m me n de d t o t he s p o ns or t h at t he L P V/ R T V tre at me nt ar m be 
disc o nti n ue d a n d s u bjects c urre ntl y recei vi n g L P V/ R T V i n t he st u d y be s witc he d t o 
a re gi me n wit h D T G as t he t hir d dr u g, if c o nsi dere d a p pr o pri ate b y t he 
I n vesti g at or.  As per P r ot oc ol A me n d me nt N o. 2 , s u bjects r an d o mise d t o t he 
L P V/ R T V ar m will eit her (i) c o nti n ue recei vi n g L P V/ R T V a n d c o m plete t he st u d y 
after t he 4- wee k tre at me nt e xte nsi o n (see a b o ve), or (ii) s witc h t o t he D T G ar m 
pri or t o st u d y c o m pleti o n at Wee k 5 2 a n d c o nti n ue t o h a ve access t o D T G i n t he 
C o n ti n u ati o n P h ase u ntil D T G is eit her l oc all y a p pr o ve d a n d c o m merci al s u p plies 
are a v ail a ble t o p atie nts (e. g. t hr o u g h p u blic he alt h ser vices), t he p atie nt n o l o n ger 
deri ves cli nic al be nefit, or t he p atie nt meets a pr ot oc ol -defi ne d re as o n f or 
disc o nti n u ati o n .  S u bjects ori gi n all y r a n d o mise d t o D T G a n d recei vi n g D T G i n t he 
R a n d o mise d P h ase or i n t he C o nti n u ati o n P h ase are n ot affecte d b y t his I D M C 
rec o m me n d ati o n a n d P r ot oc ol A me n d me nt N o. 2 .
1. 3. 1.
Ris k Assess me nt
Ris k Assess me nt Ta ble, Ps y c hiatric dis or ders
Ps y c hiatric dis or ders i ncl u di n g s uici de i deati o n a n d be ha vi o urs are c o m m o n i n HI V -
i nfecte d patie nts. T he ps yc hiatric pr ofile f or D T G (i ncl u di n g s uici dalit y, de pressi o n, 
bi p olar a n d h y p o ma nia, a n xiet y a n d a b n or mal drea ms) was si milar t o R A L- or 
fa v o ura ble co m pare d wit h E F V -b ase d re gi me ns ot her A R T .   
P P D
P P D
P P D
P P D
P P D
P P D

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3.1.
Study Design
An IDMC has been will be instituted to perform periodic reviews of the accumulating 
data to ensure that subjects are not being sub-optimally treated (see Section 8.3.4.2).  The 
IDMC completed the first two of the three pre-planned analyses (see Section 
8.3.4.2).  Prior to the third interim analysis, the IDMC conducted an ad hoc review 
of trial data and the IDMC observed significant, clinically relevant differences 
between treatment arms in favour of DTG.  The IDMC recommended to the 
sponsor that the LPV/RTV treatment arm be discontinued and subjects currently 
receiving LPV/RTV in the study be switched to a regimen with DTG as the third 
drug, if considered appropriate by the Investigator.
Randomised Phase: Day 1 to Week 48 + 4-week treatment extension
Following the IDMC’s recommendation and as per Protocol Amendment No. 2, 
subjects randomised to the LPV/RTV arm will either (i) continue receiving 
LPV/RTV and complete the study after the 4-week treatment extension at Week 52, 
or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to 
have access to DTG in the Continuation Phase.
The primary efficacy endpoint corresponds to viral load measurements collected within a 
6 week  window around the Week 48 visit (including data from the Week 52 visit), as 
per the FDA’s Snapshot algorithm, and for this reason, the primary analysis is denoted as 
occurring at Week 48 with the understanding that data from the Week 52 visit may be 
included.
DTG Continuation Phase
Subjects randomised to receive DTG who successfully complete 52 weeks of treatment 
and subjects originally randomised to receive LPV/RTV but switched to DTG prior 
to Week 52 (as per Protocol Amendment No. 2) will continue to have access to DTG 
(Continuation Phase) until it is either locally approved and commercial supplies are 
available to patients (e.g. through public health services), the patient no longer derives 
clinical benefit, or the patient meets a protocol-defined reason for discontinuation.  
Investigative sites must make arrangements for provision of background NRTIs to all 
subjects to ensure continued access to these medications during the DTG Continuation 
Phase (unless provision by the sponsor is mandated by local regulation).
Subjects randomised to the LPV/RTV arm will receive LPV/RTV + two NRTIs through 
their Week 52 visit only, after which subjects will complete the study and will need to 
have alternate arrangements in place to access antiretroviral medication (unless mandated 
by local regulation).  Subjects randomised to the LPV/RTV arm, who switch to the 
DTG arm prior to study completion at Week 52, will continue to have access to DTG 
(Continuation Phase) as mentioned above.

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Study Completion
Subjects are considered to have completed the study if they satisfy one of the following:

Randomised to LPV/RTV + two NRTIs and completed the Randomised Phase 
including the Week 52 study visit;

Randomised to LPV/RTV + two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase including the Week 52 study visit, and did not 
enter the Continuation Phase;

Randomised to LPV/RTV+ two NRTIs, switched to DTG + two NRTIs and 
completed the Randomised Phase, including the Week 52 study visit, entered 
and completed the Continuation Phase (defined as remaining on study until 
commercial supplies of DTG become locally available to patients [e.g. through 
public health services]).

Randomised to DTG + two NRTIs, completed the Randomised Phase including the 
Week 52 study visit, and did not enter the Continuation Phase;

Randomised to DTG + two NRTIs, completed the Randomised Phase, including the 
Week 52 study visit, entered and completed the Continuation Phase (defined as 
remaining on study until commercial supplies of DTG become locally available to 
patients [e.g. through public health services]).
Figure 1
Study Schematic
The figure was updated to indicate that a switch from LPV/RTV arm to DTG arm may 
occur prior to study completion at Week 52, based on Investigator judgement.
4.5.
Withdrawal Criteria
Subjects must be discontinued from the study for any of the following reasons:

Confirmed virologic withdrawal criteria as described in Section 4.6.1 are met;

Subject requires substitution or dose modification of DTG, or substitution of 
LPV/RTV (a switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice 
daily or the opposite switch is allowed; as per Protocol Amendment No. 2, a 
switch from LPV/RTV to DTG will also be allowed);
…
4.6.
Virologic Criteria for Subject Management and Viral Resistance Testing
Following Day 1, no changes, or intensification of ART will be permitted prior to 
meeting confirmed virologic withdrawal criteria or Week 52, with the exception of a 

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switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily or the opposite 
switch, a switch from LPV/RTV to DTG as per Protocol Amendment No. 2, and one 
allowed background NRTI change for management of drug toxicity as described in 
Section 6.4.4., “Specific Toxicities/Adverse Event Management”.  Any NRTI change 
must ensure a fully active NRTI is still present based on Screening resistance testing.  A 
switch from 3TC to FTC (or vice versa) will not be considered a background NRTI 
change and is permitted.  Subjects unable to manage drug toxicity or tolerate IP (DTG or 
LPV/RTV) must be discontinued from the study as described in Section 6.4.
5.1.5. Protocol-Permitted Substitutions
A switch of DTG or LPV/RTV is not allowed except for a switch from LPV/RTV 
800/200 mg once daily to LPV/RTV 400/100 mg twice daily or the opposite switch.  As 
per Protocol Amendment No. 2, a switch from LPV/RTV to DTG will be allowed.
5.3.
Blinding
As this is an open-label study, blinding is not required.  No summaries of the study data 
according to actual randomised treatment groups will be available to sponsor staff prior 
to the planned Week 24 interim analysis.  According to the IDMC Charter, ViiV 
Healthcare/GSK personnel having direct responsibility for the conduct of the study 
and its analysis may however review summaries of data by treatment group if the 
IDMC recommends to the sponsor the termination of a treatment arm or the entire 
study.
5.6.4. Prohibited medications for subjects randomised to LPV/RTV
Avanafil added to list of prohibited medications for subjects randomised to LPV/RTV.
5.8.
Treatment after the End of the Study
The following text has been added:
Subjects originally randomised to receive LPV/RTV but switched to the DTG arm 
prior to Week 52 (as per Protocol Amendment No. 2) will continue to have access to 
DTG (Continuation Phase) until it is either locally approved and commercial 
supplies are available to patients (e.g. through public health services), the patient no 
longer derives clinical benefit, or the patient meets a protocol-defined reason for 
discontinuation.  Investigative sites must make arrangements for provision of 
background NRTIs to all subjects to ensure continued access to these medications 

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during the DTG Continuation Phase (unless provision by the sponsor is mandated 
by local regulation).
6.1.
Time and Events Schedule
The following footnote has been added:
j. Health outcomes assessments will only be conducted at Withdrawal if the 
Withdrawal visit occurs at or prior to Week 48.
6.4.10.
Suicidality Monitoring
Patients with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour). In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in patients with 
a pre-existing history of depression or psychiatric illness) in some patients being 
treated with INIs, including DTG.  Therefore, it is appropriate to monitor subjects for 
suicidality before and during treatment.
Subjects should be monitored appropriately and observed closely for suicidal 
ideation and behaviour or any other unusual changes in behaviour.  It is 
recommended that the Investigator consider mental health consultation or referral for 
subjects who experience signs of suicidal ideation or behaviour.  Subjects presenting 
with new onset/treatment-emergent depression should be advised to contact the 
investigator immediately if symptoms of severe acute depression (including suicidal 
ideation/attempts) develop, because medical intervention and discontinuation of the 
study medication may be required.
6.6.2. HIV-1 Pol Viral Genotyping and Phenotyping
Subjects meeting a ‘confirmed virologic withdrawal criterion’ (see Section 4.6.3) will 
have plasma samples tested for HIV-1 PRO and RT genotype and phenotype and HIV-1 
integrase genotype and phenotype from both Baseline samples and from samples 
collected at the time of meeting a ‘suspected virologic withdrawal criterion’; these results 
will be reported to the Investigator as soon as available to provide guidance for election 
of an alternative 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 analysed by Monogram Biosciences, Baseline isolate resistance 
testing may be performed at location(s) to be described in the SPM.  
8.3.4.2.
IDMC interim analyses

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 4 1
A n I D M C will be h as bee n i nstit ute d t o pr o vi de i n de pe n de nt re vie w of t he acc u m ulati n g 
data, pri maril y t o e ns ure s u bjects are n ot bei n g s u b -o pti mall y  treate d i n eit her ar m. 
T hree f or mal i nteri m a nal y ses are were pla n ne d f or re vie w b y t he I D M C ( Ta ble 5).
…
T he I D M C c o m plete d i nteri m a n al yses # 1 a n d # 2.  Pri or t o i nteri m a n al ysis # 3, t he 
I D M C c o n d ucte d a n a d h oc re vie w of tri al d at a a n d o bser ve d si g nific a nt, cli nic all y 
rele v a nt differe nces bet wee n tre at me nt ar ms i n f a v o ur of D T G.  T he I D M C 
rec o m me n de d t o t he s p o ns or t h at t he L P V/ R T V tre at me nt ar m be disc o nti n ue d a n d 
s u bjects c urre ntl y recei vi n g L P V/ R T V i n t he st u d y be s witc he d t o a re gi me n wit h 
D T G as t he t hir d dr u g, if c o nsi dere d a p pr o pri ate b y t he I n vesti g at or.  I nteri m 
a n al ysis # 3 will n o l o n ger t a ke pl ace.
8. 3. 5. 1.
Effic ac y a n al yses
T he f oll o wi n g te xt has bee n a d de d:
F oll o wi n g t he I D M C rec o m me n d ati o n t o s witc h L P V/ R T V s u bjects t o D T G, 
a d diti o n al se nsiti vit y a n al yses will be c o n d ucte d f or t he pri m ar y e n d p oi nt.  F urt her 
det ails of t hese a n al yses a n d a n y ot her i m p acte d a n al yses will be i ncl u de d i n t he 
R A P.
8. 3. 5. 3. He alt h o utc o mes a n al yses
M M A S- 8
T he ori gi nal M oris k y Me dicati o n A d here nce Scale ( M M A S) was a f o ur ite m scale t hat 
was de vel o pe d t o assess me dicati o n a d here nce wit h c hr o nic c o n diti o ns, s uc h as 
a nti h yperte nsi ve a ge nts [ M oris k y , 1 9 8 6].  M ore rece ntl y, a n ei g ht-ite m self-re p orte d 
scale was de vel o pe d calle d t he M oris ky 8 -Ite m Me dicati o n A d here nce Scale ( M M A S-8) 
[M oris k y , 2 0 0 8].  Sc ores of 8 i n dicate 
, a n d sc ores of less 
t h a n 6 or less i n dicate 
 o n t he M M A S-8 scale.  
Sc ores will be s u m marise d a n d c o m pare d bet wee n t he treat me nt gr o u ps i n a n e x pl orat or y 
a nal ys is at eac h ti me p oi nt.
G S R S
T he Gastr oi ntesti nal S y m pt o m Rati n g Scale ( G S R S) has 1 5 ite ms a n d is di vi de d i nt o f o ur 
d o mai ns: a b d o mi nal pai n; d y s pe ptic sy n dr o me; i n di gesti o n s y n dr o me; a n d b o wel 
s yn dr o me.  T he scale ra n ges fr o m 
 (0 1 ) t o 
 ( 7). T he 
o verall sc ore is calc ulate d b y  a d di n g t he c o m plete d sc ores of i n di vi d ual ite ms i n eac h 
gr o u p, f or a p ossi ble t otal ra n gi n g fr o m 0 1 5 t o 1 0 5.  Hi g her sc ores s h o w greater se verity 
of s y m pt o ms [S ve dl u n d , 1 9 8 8].  T he G S R S has bee n use d a n d vali dated i n ot her 
C CI
C CI
C CI
C CI

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antiretroviral studies, which examine the GI symptoms associated with boosted PIs [Sáez 
de la Fuente; 2009; Mtambo, 2013].
9.8.
Independent Data Monitoring Committee (IDMC)
The following text has been added:
The IDMC completed pre-planned interim analyses #1 and #2 and following an ad 
hoc review of trial data prior to interim analysis #3, the IDMC observed significant, 
clinically relevant differences between treatment arms in favour of DTG.  The 
IDMC recommended that the LPV/RTV treatment arm be discontinued and 
subjects currently receiving LPV/RTV in the study be switched to a regimen with 
DTG as the third drug, if considered appropriate by the Investigator.  Interim 
analysis #3 will no longer take place.
10. REFERENCES
The following reference has been added:
WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and 
preventing HIV infection: Recommendations for a public health approach. Second 
edition 2016. Available at: http://www.who.int/hiv/pub/arv/arv-2016/en/ (accessed 
29 March 2017).
The following references have been updated:
GlaxoSmithKline Document Number RM2007/00683/07RM2007/00683/10: 
GSK1349572 Clinical Investigator's Brochure. February 2014October 2016.
Kaletra EU Summary of Product Characteristics, February 20142017.
Kaletra US Product Information, November 20132016.
TIVICAY Summary of Product Characteristics, January 2014February 2017.
TIVICAY US Product Information, August 2013March 2017.
11.7.3.
Protocol Amendment 03
Protocol changes for Amendment 03, from protocol changes to Amendment 02 (19-
Apr-2017)
This protocol amendment applies to all participating sites.
Amendment 03 Summary and Rationale:

2 0 1 3 N 1 7 2 6 7 2 _ 0 3
C O N FI D E N TI A L
2 0 0 3 0 4
1 4 3
C ha n ges were ma de t o t he pr ot oc ol t o ma na ge a n d miti gate ris ks f oll o wi n g i de ntificati o n 
of a p ote ntial safet y  iss ue related t o ne ural t u be defect i n i nfa nts b or n t o w o me n wit h 
e x p os ure t o d ol ute gra vir at t he ti me of c o nce pti o n.

Refere nces t o t he m ost rece nt versi o n of t he D T G i n vesti gat or’s br oc h ure a n d 
s u p ple me nts were i ncl u de d.

T he Ris k Assess me nt ta ble ( Secti o n 1. 3. 1) was u p date d t o i ncl u de la n g ua ge re gar di n g 
ris k a n d miti gati o n of ne ural t u be defects .

I ncl usi o n criteri o n 2 ( Secti o n 4. 2) was u p date d t o e xcl u de t he d o u ble barrier met h o d 
of c o ntrace pti o n, w hic h d oes n ot meet u p date d G S K/ Vii V Healt hcare criteria f or a 
hi g hl y e ffecti ve met h o d.  Acce pta ble met h o ds of c o ntrace pti o n were clarifie d a n d 
pr o vi de d wit hi n t he pr ot oc ol; details of t hese are n o l o n ger pr o vi de d i n t he S P M .

T he Wit h dra wal Criteria ( Secti o n 4. 5) were u p date d t o i ncl u de a re mi n der t hat 
fe males of c hil d beari n g p ote ntial w h o c ha n ge t heir mi n ds a n d desire t o be pre g na nt
s h o ul d als o be wit h dra w n fr o m t he st u d y.

T he Ti me a n d E ve nts Ta ble ( Secti o n 6. 1). was u p date d t o i ncl u de a re mi n der f or 
i n vesti gat ors t o c hec k at e ver y visit t hat fe males of c hil d beari n g p ote ntial are a v oi di n g 
pre g na nc y .

T he Refere nces ( Secti o n 1 0) was u p date d t o i ncl u de a refere nce citi n g met h o ds of 
hi g hl y effecti ve c o ntrace pti o n a n d u p date t he refere nce t o t he c urre nt D T G 
I n vesti gat or’s Br oc h ure.
A list of s pecific c ha n ges is pr o vi de d bel o w.  U n less state d ot her wise, ne w te xt is 
re prese nte d i n b ol d f o nt, a n d delete d te xt i n stri ket hr o u g h f o nt.
List of S pecific C h a n ges
A ut h ors
A ut h or(s):
Refere nces t o I n vesti g at or’s Br oc h ure a n d S u p ple me nts
T he D T G i n vesti gat or br oc h ure versi o n n u m ber was u p date d i n Secti o n 1. 1, Secti o n 1. 3, 
a n d 6. 4. 4. 7, a n d refere nces t o I B s u p ple me nts were a d de d.
Secti o n 1. 3. 1   Ris k Assess me nt
A n a d diti o nal ris k a n d miti gati o n strate g y  was a d de d t o t he ta ble i n t his secti o n as s h o w n 
bel o w.  
P P D
P P D
P P D
P P D

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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy1
Investigational Product (IP) [DTG]
Refer to IB for additional information on 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, and, if she is a female 
of childbearing potential, agrees to follow 
one of the options for prevention of 
pregnancy listed in the Inclusion Criterion 2 
(see Section 4.2) during treatment with 
study drug and until at least 2 weeks after 
the last dose of study medication.
2. Women who become pregnant, or who 
desire to be pregnant while in the study will 
have study treatment discontinued and be 
withdrawn from the study.
3. Females of childbearing potential are 
reminded re: pregnancy avoidance and 
adherence to contraception requirements at 
every study visit.
4. Pregnancy status is monitored at every 
study visit.
Section 4.2 Inclusion Criteria, inclusion criterion 2
2.     A female subject may be eligible to enter and participate in the study if she:
a.
is of non-childbearing potential defined as either post-menopausal (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 child-bearing 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 2 weeks after discontinuation 
of all study medication:

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 for subjects randomised to the DTG arm
(see the SPM for a listing of examples of approved hormonal contraception),
including:
o
Combined oestrogen and progestogen oral contraceptive 
[Hatcher, 2011])
o
Contraceptive subdermal implant
o
Injectable progestogen [Hatcher, 2011]

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o
Contraceptive vaginal ring [Hatcher, 2011]
o
Percutaneous contraceptive patches [Hatcher, 2011]

Approved hormonal contraception (as for subjects randomised to the DTG 
arm; see above) and a barrier method for subjects randomised to the 
LPV/RTV arm (see the SPM for a listing of examples of approved hormonal 
contraception).

Intrauterine device or intrauterine system. 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). 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 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.

Any other method with published data showing that the expected failure rate
is <1% per year.
Any contraception method must be used consistently and in accordance with the 
approved product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 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/Stopping Criteria, last bullet

Pregnancy (intrauterine), regardless of termination status of pregnancy (Section 
6.4.11).  As a reminder, females of childbearing potential who changed their 
minds and desire to become pregnant, or who state they are no longer willing 
to comply with the approved pregnancy avoidance methods, should also be 
withdrawn from the study.
Section 6.1 Time and Events Table
Table 1
Footnote ‘o’ was revised as shown below:
o. Pregnancy testing will be conducted (women of child bearing potential only) on serum 
(S) samples with the exception of Day 1, which must be a urine (U) test to confirm status 
prior to administration of IP. Remind females of childbearing potential of the need to 

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avoid pregnancy while on study and adherence to the study’s contraception 
requirements.
Section 10 References
The following reference has been updated:
GlaxoSmithKline Document Number RM2007/00683/1011: GSK1349572 Clinical 
Investigator's Brochure, Version 11. October 20162017.
The following additional references were included:
GlaxoSmithKline Document Number 2017N352880_00: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 01. December 2017.
GlaxoSmithKline Document Number 2017N352880_01: GSK1349572 Clinical 
Investigator's Brochure, Version 11, Supplement 02. June 2018.
Hatcher RA, Trussell J, Nelson AL, et al, editors. Contraceptive Technology. 20th
edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. Table 3-2.