Clinical trial NCT02384395
Conditions: HIV Acute HIV Infection
Keywords: Dolutegravir Abacavir Lamivudine acute HIV infection human leukocyte antigen latent HIV reservoir integrase-based regimen viremia antiretroviral therapy fixed dose combination
Sponsor: University of North Carolina, Chapel Hill
Start date: 2015-09-01; Completion date: 2021-09-17
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, single arm, 96-week open-label study of the safety and virologic efficacy of fixed dose combination Dolutegravir/Lamivudine/Abacavir (DTG/3TC/ABC FDC) initiated during acute HIV infection (AHI).

Detailed description:
The study will be conducted at the University of North Carolina in Chapel Hill, NC and Duke University in Durham, NC. The investigators plan to enroll up to 44 participants who will be enrolled for 96 weeks and will receive DTG/3TC/ABC FDC.

The investigators propose to evaluate the efficacy and time to viral suppression with DTG/3TC/ABC FDC as initial therapy for acute HIV infection (AHI), as well as the feasibility of prompt administration using a rapid human leukocyte antigen-B57 (HLA-B57) screening antibody assay. In addition to validating the restriction of resting cell infection (RCI) by antiretroviral therapy (ART) including a DTG-based regimen initiated during AHI, the investigators will seek correlations between low RCI, residual gastrointestinal associated lymphoid tissue (GALT) HIV expression, and measures of immune activation. The investigators hypothesize that rapid reduction in plasma viremia with this regimen will limit the area under the pre-ART viral load curve, and thus reduce the latent reservoir size as measured by a viral outgrowth assay one to two years following ART start, and as compared with the latent reservoir size in acutely infected individuals started on regimens without an integrase inhibitor based regimen. In addition, the investigators will examine the longitudinal impact of the proposed integrase-based regimen initiated during the acute period on immune activation through week 96. If residual viral expression and persistent immune dysfunction is related to the burden of the latent viral reservoir (and presumably its periodic activation) these abnormalities should be ameliorated by early ART with rapid viral suppression. The investigators hypothesize that earlier treatment coupled with more rapid ART-mediated virus suppression will be associated with better long-term T cell function, specifically better T cell function after 2 years of durable HIV suppression.

Arms: arm 1: Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily
Interventions: intervention 1: Dolutegravir 50 mg intervention 2: Lamivudine 300 mg intervention 3: Abacavir 600 mg
Intervention descriptions: intervention 1: Initial therapy for AHI intervention 2: Initial therapy for AHI intervention 3: Initial therapy for AHI

Protocol documents:
Prot_SAP_000.pdf: 
 
IGHID 11417 - The Safety and Efficacy of Fixed Dose Combination 
Dolutegravir/Abacavir/Lamivudine Initiated During Acute HIV 
Infection:  Impact on the Latent HIV Reservoir and Long-Term 
Immunologic Effect 
 
 
 
NCT number NCT02384395 
Document Date 07/26/2021 
 


Page 1 of 72 
 
 
IGHID 11417 - The Safety and Efficacy of Fixed Dose Combination 
Dolutegravir/Abacavir/Lamivudine Initiated During Acute HIV 
Infection:  Impact on the Latent HIV Reservoir and Long-Term 
Immunologic Effect  
 
 
 
Principal Investigator: Cynthia Gay, MD, MPH 
 
 
 
Co-Investigators: 
David Margolis, MD 
Joseph Eron, MD 
Mehri McKellar, MD 
JoAnn Kuruc, MSN, RN 
Kara McGee, MSPH, PA-C 
Nilu Goonetilleke, PhD 
 
 
 
 
 
Sponsor:  University of North Carolina at Chapel Hill  
Study# 201311 
 
 
 
 
Version 5.1 
July 26, 2021 
 
 
 
 
 
 
 
 
 
 
 
 


Page 2 of 72 
 
PROTOCOL TEAM ROSTER  
 
David Margolis, MD 
Professor of Medicine, Microbiology & Immunology, and Epidemiology 
University of North Carolina 
Division of Infectious Diseases 
120 Mason Farm Road, 2060 Genetic Medicine Building, CB #7042 
Chapel Hill, NC 27599-7042 
Phone:  (919) 966-6388 
Email: david_margolis@med.unc.edu 
 
Cynthia Gay, MD, MPH 
Associate Professor 
University of North Carolina 
Division of Infectious Diseases 
130 Mason Farm Road, 2nd Floor Bioinformatics Building, CB# 7030  
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 843-2726  
Fax: (919) 966-8928 
Email: cynthia_gay@med.unc.edu 
 
Joseph Eron, MD 
Professor of Medicine, School of Medicine, Director, Clinical Core, UNC Center for AIDS 
Research 
University of North Carolina  
Division of Infectious Diseases  
130 Mason Farm Road, 2nd Floor Bioinformatics, CB# 7030 
Chapel Hill, North Carolina 27599-7030 
Phone: (919) 843-2722  
Fax: (919) 966-8928 
Email: joseph_eron@med.unc.edu 
 
Mehri McKellar, MD,  
Assistant Professor 
Duke University  
Division of Infectious Diseases 
Box 3271 
Duke University Medical Center  
Durham, NC 27710 
Phone: (919) 613-6129 
Fax: (919) 681-8474 
Email: mehri.mckellar@duke.edu 
 
Kara McGee, MSPH, PA-C 
Duke University  
Division of Infectious Diseases 
Box 3284 
Duke University Medical Center  
Durham, NC 27710 
Phone: (919) 668-0242 
Fax: (919) 9681-8474 
Email: mcgee018@mc.duke.edu 
 
 


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JoAnn Kuruc, MSN, RN 
Clinical Program Director UNC HIV Cure Center  
University of North Carolina 
Division of Infectious Diseases 
130 Mason Farm Road, 2nd Floor Bioinformatics Building, CB# 7030  
Chapel Hill, North Carolina 27599-7030 
Phone:  (919) 966-8533 
Fax:  (919) 843-7625 
E-Mail:  joann_kuruc@med.unc.edu 
 
 
Nilu Goonetilleke, PhD 
Assistant Professor 
Depts Microbiology & Immunology / Medicine 
University of North Carolina 
120 Mason Farm Road, CB 7042 
2023 (Office 2017), Genetic Medicine Building 
Chapel Hill, NC 27599-7264 
Phone: (919) 962-3129 
Email: nilu_goonetilleke@med.unc.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ACRONYMS 
 
3TC 
 
= lamivudine 
ABC 
 
= abacavir 
AE 
 
= adverse event 
AHI 
 
= acute HIV infection 
ALT 
 
= alanine transaminase  
ANC   
= absolute neutrophil count 
ART 
 
= antiretroviral therapy 
AST 
 
= aspartate aminotransferase 
ATV 
 
= atazanavir 
β-HCG  
= β human chorionic gonadotropin 
BID 
 
= twice daily  
CHI 
 
= chronic HIV-1 infection 
COBI  
= cobicistat 
CrCL  
= creatinine clearance 
DTG 
 
= dolutegravir 
EAE  
 
= expedited adverse events 
EFV  
 
= efavirenz 
EVG 
 
= elvitegravir 
FCBP  
= females of child bearing potential 
FDA 
 
= Food and Drug Administration 
FDC 
 
= fixed dose combination 
FTC  
 
= emtricitabine 
HBcAB 
= hepatitis B core antibody 
HBsAg  
= hepatitis B surface antigen 
HBV 
 
= hepatitis B 
HCV 
 
= hepatitis C 
HLA 
 
= human leukocyte antigen 
HSR 
 
= hypersensitivity reactions 
IA 
 
= immunoassay 
IDS 
 
= Investigational Drug Services 
INI 
 
= integrase inhibitor 
IRB  
 
= institutional review board 
IRS 
 
= immune reconstitution syndrome 
IUD 
 
= intrauterine device 
LPV 
 
= lopinavir 
LFT 
 
= liver function test 
MI 
 
= myocardial infarction 
NAAT  
= nucleic acid amplification test 
NRTI  
= nucleoside/tide reverse transcriptase inhibitor 
NNRTI  
= nonnucleoside reverse transcriptase inhibitor 
NRTI/nRTI 
= nucleoside/nucleotide analogue reverse transcriptase inhibitor 
OHRP  
= Office for Human Research Protections 
PBMC  
= peripheral blood mononuclear cells 
PEP 
 
= post-exposure prophylaxis 
PI 
 
= protease inhibitor 
PT 
 
= prothrombin time 
PTT 
 
= partial thromboplastin time 
QD 
 
= once daily 
RCI 
 
= resting cell infection 
RTG 
 
= raltegravir 
RTV 
 
= ritonavir 
S/CO  
=signal to cut-off ratio 


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SCA 
 
= single copy assay 
SOE  
 
= schedule of events 
SMC   
= safety monitoring committee 
STAT  
= Screening and Tracing Active Transmission Program 
TDF 
 
= tenofovir disoproxil fumarate 
ULN   
= upper limit of normal 
UNC 
 
= University of North Carolina 
VOR 
 
= vorinostat 
VF 
 
= virologic failure 
ZDV 
 
= zidovudine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 6 of 72 
 
Table of Contents 
1.0 Protocol Schema .......................................................................................................................... 9 
1.1 Hypothesis  ................................................................................................................................ 9 
1.2 Primary Objective...................................................................................................................... 9 
1.3 Secondary Objectives ................................................................................................................ 9 
1,4 Other Objectives……………………………………………………………………………...10 
2.0 Introduction  .............................................................................................................................. 10 
2.1 Scientific Rationale ................................................................................................................. 10 
2.2 Study Treatment  ..................................................................................................................... 13 
2.3 Clinical and Safety Data  ......................................................................................................... 14 
3.0 Study Objectives ........................................................................................................................ 15 
3.1 Purpose .................................................................................................................................... 15 
3.2 Hypothesis ............................................................................................................................... 15 
3.3 Primary Objective.................................................................................................................... 15 
3.4 Secondary Objectives .............................................................................................................. 15 
3.5 Other Objectives……………………………………………………………………………...16 
4.0 Study Design  ............................................................................................................................. 16 
5.0 Study Population   ..................................................................................................................... 17 
5.1 Definitions ……………………………………………………….…………….…………….17 
5.2 Inclusion Criteria ..................................................................................................................... 18 
5.3 Exclusion Criteria .................................................................................................................... 19 
5.4 Recruitment……………………………...……….…………………………..………………20 
6.0 Study Treatment  ....................................................................................................................... 20 
6.1 Study Drug .............................................................................................................................. 20 
6.2 Product Information ................................................................................................................ 21 
 
6.2.1 
Dolutegravir …………………………………………………..………...………...21 
 
6.2.2 
Abacavir ……………………………………………..……………………………22 
 
6.2.3  Lamivudine………………………..………………………………………………23 
   6.3 Product Supply, Distribution, and Pharmacy ………………………………………….….....24 
   6.4 Concomitant Medications …………………………………………..……………………......24 
 
6.4.1 
Contraindications ………………………………..………………………………..24 
 
6.4.2 
Permitted Medications and Drug Interactions…………………..…………………24 
 
6.4.3  Prohibited Medications……………………………………………………………25 
 
6.4.4     Prohibited Medications During Longitudinal Phase of the Study ………………..25 
 
6.4.5  Hypersensitivity Reactions ………………………………………………...…......25 
   6.5 Potential Risks and Benefits ……………………………………….…………..…………….27 
7.0 Study Procedures ...................................................................................................................... 31 
7.1 Schedule of Events .................................................................................................................. 31 
7.1.1 Screening and Enrollment Visit .................................................................................. 32 
7.1.2 Weeks 2, 8, 16, 30, 60, and 84 .................................................................................... 34 


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7.1.3 Week 4  ....................................................................................................................... 35 
7.1.4 Weeks 12, 24, and 72 .................................................................................................. 35 
7.1.5 Weeks 48 and 96 ......................................................................................................... 36 
7.1.6 Weeks 120, 144, 192, 240 ........................................................................................... 36 
7.2 Optional Procedures ................................................................................................................ 37 
7.2.1 Leukapheresis .............................................................................................................. 37 
7.3 Screen Failures ........................................................................................................................ 37 
7.4 Study Treatment Stopping Rules ............................................................................................. 37 
7.5 Early Discontinuation or End of Study ................................................................................... 39 
    7.6 Withdrawal of a Participant from Study…………………………….…...……………….......39 
    7.7 Reimbursement …………………………………….…………………..…………………….40 
    7.8 Treatment at the End of the Study………………………………...………………………….40 
    7.9 Description of Evaluations…………………………………………………...………………40 
 
7.9.1 Clinical Evaluations and Procedures ………………………………………………..40 
 
7.9.2 Clinical Laboratory Evaluations …………………………………………………….43 
  7.10 Stored Samples ………………………………………….………………..………………....45 
8.0 Clinical Management Issues ..................................................................................................... 46 
8.1 Toxicity ................................................................................................................................... 46 
8.2 Toxicity Management.............................................................................................................. 46 
8.3 Pregnancy and Breastfeeding .................................................................................................. 55 
9.0 Criteria for Discontinuation …………………………………………………..……………...56 
   9.1 Permanent and Premature Treatment Discontinuation ……………………………………….56 
   9.2 Premature Study Discontinuation……………..……………………………..………………..56 
10.0 Statistical Considerations  ...................................................................................................... 56 
10.1 General Design Issues ........................................................................................................... 56 
    10.2 Primary Endpoint ………………………………………...……………………..……….....56 
    10.3 Secondary Endpoints ……………………………………………..………………………..57 
    10.4 Other Endpoints…………………………………………………………………………….57  
    10.5 Sample Size and Accrual ………………………………………………………..…………57 
    10.6 Monitoring ……………………………………….………………………………..……….57 
    10.7 Analyses …………………………………………………………….………………..........58 
11.0 Data Collection, Monitoring, and Adverse Event Reporting  ............................................. 59 
    11.1 Records to Be Kept …………………………………………………………….…………...59 
    11.2 Role of Data Management …………………………………………………………..…......59 
    11.3 Clinical Site Monitoring and Record Availability………………………………...………..59 
    11.4 Expedited Adverse Event Reporting to FDA……………………………………..……......60 
12.0 External Support/Collaboration/Funding ………………………………...………………60 
    12.1 National Cancer Institute…………………………….…………………..…………………60 
    12.2 ViiV Healthcare …………………………………............……………………..………….60 
13.0 Human Participants …………………………………………….………………….………61 
    13.1 IRB Review and Informed Consent…………………………...…………..………….…...61 


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    13.2 Participant Confidentiality ………………………………………………..………………61 
    13.3 Study Discontinuation …………………………………………….……….……………...61 
14.0 Publication of Research Findings ……………………………………………….………...61 
15.0 Biohazard Containment …………………………………………………………...………61 
16.0 References  ............................................................................................................................... 61 
Appendix 1  - List of Highly Effective Birth Control Methods ……………………………… 65 
Appendix 2 – List of Examples of Intrauterine Devices …………...………………………….66 
Appendix 3 – Essential Participant Information ………………………………………………67 
Appendix 4 – Study Drug Dispensing Options at Enrollment …………………………….….68 
Schedule of Events ………………………….……………………………………………………69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
PROTOCOL SCHEMA  
 
Title:  The safety and virologic efficacy of fixed dose combination (FDC) 
dolutegravir/abacavir/lamivudine initiated during acute HIV infection: impact on the latent HIV 
reservoir and long-term immunologic effect  
 
Purpose:  
 
To evaluate the safety and virologic efficacy of DTG/3TC/ABC FDC as initial therapy for 
acute HIV infection (AHI), as well as the feasibility of prompt administration using a rapid 
HLA-B57 screening antibody assay.  
 
To seek correlations between low RCI and measures of immune activation. 
 
Assess long term improvement in T-cell function following early initiation of ART 
accompanied by rapid vitral suppression.  
 
1.1 Hypotheses:  
 
The initiation of DTG/3TC/ABC FDC in individuals with AHI will be feasible, safe and 
will suppress viral replication more rapidly compared to initiation of a NNRTI-based 
regimen during AHI.  
 
Rapid reduction in plasma viremia with this integrase-based regimen will limit the area 
under the pre-ART viral load curve, and thus reduce the latent reservoir size one to two 
years following ART start. 
     Early intiaiton of ART coupled with the rapid reduction in plasma viremia will be associated 
with better long-term T cell function, specifically better T cell function after 2 years of 
durable HIV suppression. 
 
Design: This is a multicenter, single arm, open-label study of the safety and virologic efficacy of 
DTG/3TC/ABC FDC initiated during AHI.   
 
Study Sites:  The University of North Carolina, Chapel Hill, North Carolina, USA  and Duke 
University, Durham, North Carolina, USA. The study sites will be members of the Duke-UNC 
Acute HIV Infection Study Consortium. 
 
Study Population: Men and women >18 years of age newly diagnosed with AHI, and enrolled 
within 30 days of their AHI diagnosis.  
 
Sample Size and Study Duration: Projected sample size is 40 participants. These  participants 
will be enrolled in the treatment phase of the study for 96 weeks. The clinical care and HIV-1 
RNA and CD4 evaluations, along with the DTG/3TC/ABC FDC will be provided by the study 
for 96 weeks. After week 96, participants will be followed for longitudinatl assessment of 
immune cell function through week 240 (year 5), combined with CD4 count and HIV RNA 
measurements. 
 
Study Objectives:  
 
1.2 Primary Objective: To determine the virologic efficacy of DTG/3TC/ABC FDC given once 
daily to participants with AHI as determined by the proportion of treated participants with HIV-1 
RNA to <200 copies/mL at week 24. 
 
1.3 Secondary Objectives: 
- 
To evaluate the safety and tolerability of DTG/3TC/ABC FDC given once daily in 
acutely infected participants though 96 weeks of treatment. 
- 
To assess the feasibility of prompt administration of DTG/3TC/ABC FDC using a 
rapid HLA-B57 screening antibody assay. 


Page 10 of 72 
 
- 
To assess the virologic efficacy of DTG/3TC/ABC FDC given once daily to 
participants with AHI as determined by the proportion of treated participants with 
HIV-1 RNA to <50 copies/mL at week 48.   
- 
To compare virologic efficacy of DTG/3TC/ABC FDC to a historical control 
cohort treated with EFV/FTC/TDF FDC. 
- 
To measure the rate of virologic decline during the first 24 weeks of treatment 
compared to historical control cohort treated with EFV/FTC/TDF FDC. 
 
1.4 Other Objectives: 
- 
To evaluate immune activation as measured by the proportion CD8+ cells 
expressing HLA-DR and CD38+ at weeks 0, 24, 48, 96, 120, 144, 192, and 240. 
- 
To assess the effect of the treatment regimen on the latently infected reservoir as 
measured in PBMCs obtained via leukapheresis at week 48 in a subset of 
participants with HIV-1 RNA consistently <50 copies/mL (optional repeat at week 
96). 
- 
To assess the impact of the treatment regimen on detection of low level plasma 
viremia as measured by a single copy assay (SCA) at weeks 84 and 96. 
 
2. 
INTRODUCTION  
 
2.1 
Scientific Rationale 
Treatment of individuals diagnosed with acute HIV infection (AHI) has important public 
health implications for HIV transmission, and may result in clinical benefit to individuals.  
In  February of 2013, guidelines in the United States (US) were revised to recommend ART 
for all HIV-infected individuals, including those diagnosed with AHI [1].  ART treatment 
during the acute period preserves immune function [2], decreases the latent reservoir [3-5], 
and essentially halts viral diversification [6]. Accordingly, acutely infected patients 
suppressed on ART are most likely the population prone to enhanced control of viral 
replication (and functional cure), and thus, uniquely suited for eradication strategies or 
immune-based therapy. The Duke – University of North Carolina AHI Research 
Consortium has accepted AHI referrals from across North Carolina since 1998, allowing 
for prompt treatment.  
 
To evaluate the efficacy of ART initiated during the period of acute infection, we enrolled 
90 acutely infected patients on a treatment study with fixed-dose combination (FDC) 
efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF).  In interim analysis with 61 of 90 
participants, 92% achieved suppressed to <200 copies/mL by week 24 and 85% to <50 
copies/mL by week 48 [7].  In sum, virologic efficacy was similar to rates in large 
treatment trials with recommended first line ART regimens started in individuals with 
chronic HIV infection (CHI), and was well tolerated.  However, integrase inhibitor-based 
treatment in AHI is enticing given resistance concerns [8] (10% of AHI participants have 
been shown to have de novo NNRTI resistance [unpublished data, 2012]), fewer metabolic 
toxicities [9], less central nervous system side effects [10], and rapid viral suppression.  In 
unpublished data, individuals started on an elvitegravir-based regimen (n=16) during AHI 
suppressed more rapidly to <200 copies/mL at a median of 15 days (range 7-78) compared 
with 63 days (N=90; range 7-411) with FDC EFV/FTC/TDF.   
 
Time to suppression may be relevant for HIV cure strategies, as our prior work 
demonstrated a correlation between the size of the latent reservoir and the under the pre-
ART HIV RNA curve [11], suggesting that more rapid viral suppression with an integrase-
based regimen in AHI could limit the size of the latent reservoir. Further, additional work 
has shown that ART initiation during AHI decreases, but does not normalize immune 
activation in all acutely infected patients [12, 13].  However, a shorter time to viral 


Page 11 of 72 
 
suppression has been associated with a reduction of CD8+ T cell activation 96 weeks 
following ART initiation in AHI [13].   
 
Based on this prior data, we propose to employ an integrase inhibitor, dolutegravir (DTG) 
in fixed dose combination (FDC) with abacavir/lamivudine (ABC/3TC, Epzicom) as initial 
therapy for AHI.  Integrase inhibitor-based treatment combinations have proven to be 
highly efficacious in the initial treatment of persons with chronic HIV infection (CHI) as 
demonstrated in STARTMRK (raltegravir) [14] and in ongoing elvitegravir treatment 
studies [10, 15], suggesting that integrase inhibitor-based regimens may be of value in 
individuals with AHI.  A barrier to prompt administration of this regimen in the setting of 
AHI includes the need to screen for HLA B*57:01 given the risk of hypersensitivity 
reactions (HSR) to ABC.  Accordingly, we will evaluate the feasibility of rapid screening 
for this allele using a human leukocyte antigen (HLA) B57 monoclonal antibody, to 
facilitate the earliest initiation of ART in AHI, given the possible benefit with earlier time 
to viral suppression. 
 
Effect of early ART on the frequency of RCI:  In most patients treated during chronic 
infection the frequency of RCI in circulating cells is 1000 per billion (1 per million) or 
greater [16]. We measured resting CD4+ T cell infection (RCI) in 20 AHI participants after 
stable suppression to <50 cps/ml, using a rigorous limiting-dilution outgrowth assay [17, 
18]. We find that immediate ART in AHI limits RCI to a frequency of <0.5 per million [11, 
18], in general agreement with work by Chun [19].  In the earlier study by Chun et al. of 7 
participants treated in acute or early infection, after 1-2 years of ART, RCI appeared to 
decay to frequencies similar to our cohort of participants treated in AHI. Whether these 
kinetics reflect rapid early decay of latently infected cells, or the early clearance of a less 
stable population of infected cells and persistence of a more rare population of stable cells 
is unclear. Nevertheless, these findings suggest if residual viral expression and persistent 
immune dysfunction are related to the burden of the latent viral reservoir (and presumably 
its periodic activation) these abnormalities should be ameliorated by early ART and rapid 
viral suppression in AHI.  Moreover, the rapid reduction in plasma viremia characteristic of 
integrase inhibitor-containing therapy may not only limit the latent reservoir size, but will 
almost certainly rapidly decrease infectiousness, an important issue during AHI [15]. 
 
Our painstaking method to reproducibly and accurately measure the frequency of infection 
within resting CD4+ T cells has been published [17], a modification of the methods 
originally published by Chun and Siliciano [20, 21]. Typically, 100 million resting CD4+ T 
cells are assayed, allowing detection of as few as 11 infected resting CD4+ T cells per 
billion (one of 48 macrocultures positive).  Given the low frequency of RCI, we have 
established that our assay can accurately measure infectious units per billion resting cells, 
estimated by a maximum likelihood method [22].  The method of statistical analysis has 
been established in our prior work [17, 23].  In the proposed study, the frequency of latent 
infection will be studies in participants at two occasions approximately 48 weeks apart. 
 
Effect of early and rapid HIV control on long-term immune cell function. 
Recent studies have demonstrated that a shorter window between HIV infection and durable 
viral suppression is associated with lower activation and possibly dysregulation of T cells, 
relative to non-HIV infected participants (Vinikoor 2013). However, measures of T cell 
activity suggesting residual T cell activation/ dysfunction were largely performed within 2 
years of starting antiretroviral therapy.  
In contrast, durable HIV suppression of > 2 years has been associated with restoration of 
most T cell functions including normal cellular activation (Rehr 2008) (Figure 1). We and 
others have, however, observed ongoing defects in long term suppressed individuals who 
began ART in the chronic stage of infection, most particularly, poorer T cell proliferation 


Page 12 of 72 
 
(Figure 2). Accordingly, we propose to assess immune cell function in participants for up to 
5 years following the onset of ART treatment.  
 
Figure 1 CD8 T 
cells from HIV+ 
ART participants 
on cART treated 
in 
chronic 
infection for > 2 
years are stable 
and by several 
measures exhibit 
normal function. 
A) HIV-specific CD8 T cell responses are stable over time. Interferon-gamma production in 
response to HIV CD8 T cell (optimal) peptides was quantified by ELISPOT. SFU spot-
forming units. T cell responses were measured in HIV+ ART-suppressed participants 
sampled yearly for up to 8 years. B) Antigen-specific (IFN-γ+) CD8 T cells from HIV+ ART 
participants can produce multiple cytokines (MIP-1β, TNFα) and degranulate (Perforinlow 
CD107a+). C) Similar expression of PD-1 on memory CD8 T cells from HIV+ and HIV-
participants.   
 
Figure 2 CD8+T cells in long-term ART treated HIV-infected individuals, first treated in 
chronic infection, exhibit some residual T cell phenotypic and functional dysregulation A) 
CD8 T cells from HIV-infected ART participants produce fewer daughter cells when they 
proliferate in response to antigen (replication index; ‘flu, EBV, CMV peptide pool) than those 
from HIV- participants. B) CD8 T cells from HIV+ ART participants display a more 
terminally-differentiated phenotype than CD8 T cells from HIV uninfected participants. 
TCM central memory TEM effector memory, TEMRA terminally differentiated. C) 
Representative plot showing T-bet and Eomes expression in memory CD8 T cells. D) 
Memory CD8 T cells from HIV-infected ART participants are skewed toward a T-bethigh 
effector-like phenotype.  
 
Vinikoor, M., et al., Antiretroviral therapy initiated during acute HIV infection fails to 
prevent persistent T cell activation J Acquir Immune Defic Syndr. 2013 April 15; 62(5): 505–
508. 
Rehr, M., et al., Emergence of polyfunctional CD8+ T cells after prolonged suppression of 
human immunodeficiency virus replication by antiretroviral therapy. J Virol, 2008. 82(7): p. 
3391-404. 
Clutton, G., et al., The differential short- and long-term effects of HIV-1 latency-reversing 
agents on T cell function. Sci Rep, 2016. 6: p. 30749. 
Henson, S.M., et al., p38 signaling inhibits mTORC1-independent autophagy in senescent 
human CD8(+) T cells. J Clin Invest, 2014. 124(9): p. 4004-16. 
Bengsch, B., et al., Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by 
the Inhibitory Receptor PD-1 Are an Early Driver of CD8+ T Cell Exhaustion. Immunity, 
2016. 


Page 13 of 72 
 
 
2.2        Study Treatment 
 
Integrase Inhibitors 
HIV integrase inhibitors (INIs) are a promising new class of ART drugs with reported 
potency and a favorable safety profile.  The first two approved integrase inhibitors, 
raltegravir (RTG) and elvitegravir (EVG) have been shown to be effective and well-
tolerated. In the STARTMRK study, RAL was shown to be non-inferior to an efavirenz 
(EFV) containing standard of care first-line regimen [24]. In the GS-US-236-0102 study, 
EVG co-formulated with the CYP3A4 inhibitor cobicistat (COBI), tenofovir (TDF), and 
emtricitabine (FTC) was non-inferior to the co-formulated standard of care regimen 
EFV/TDF/FTC (Atripla) as first-line treatment [25]. Further, an integrase-based regimen is 
now a recommended first line regimen for HIV-infected individuals [1].   
 
In the BENCHMRK study, patients with three-class antiretroviral resistance (naïve to INIs) 
received RAL or placebo plus optimized background therapy; 62% of RAL participants 
(versus 33% of placebo participants) had HIV RNA <50 c/mL at Week 48 [26]. In Study 
145 in INI naïve, treatment-experienced participants with at least two-class resistance, EVG 
once daily was non-inferior to RAL twice daily (BID), each administered with a 
background regimen that included a ritonavir (RTV)-boosted protease inhibitor (PI) and a 
second antiretroviral agent. At Week 48 of Study 145, 59% of the EVG group versus 58% 
of the RAL group achieved virologic response (<50 c/mL) [27]. 
 
In addition to providing high rates of virologic suppression in treatment-naïve and 
treatment experienced patients, INIs have been well-tolerated in clinical trials. In 
STARTMRK, there were fewer drug-related adverse events (AEs) reported for the RAL 
group compared with the EFV group, and fewer participants randomized to RAL 
discontinued from the study due to AEs [28]. In GS-US-236-0102, AEs were similar 
between the EVG and EFV groups, with the exception of higher rates of nausea in the EVG 
group; significantly higher rates of dizziness, abnormal dreams, and rash in the EFV group.  
In this study, a similar percentage of participants in the two groups discontinued treatment 
because of AEs (4% versus 5%, respectively) [25], and similar findings were observed 
through 96 weeks [29]. 
 
In sum, RAL and EVG are effective, but have some limitations.  Although well-tolerated, 
RAL requires twice-daily doses, has a low genetic barrier to resistance compared with 
ritonavir-boosted protease inhibitors (PIs) [30], and is currently not available in a FDC 
regimen.  EVG is only available as coformulated EVG/COBI/TDF/FTC (Stribild), and 
requires co-administration with a pharmacokinetic booster such as COBI [31], which 
introduces the potential for clinically significant drug-drug interactions with drugs that 
depend on CYP3A4 for clearance.  Further, EVG must be taken with food, and has a low 
genetic barrier to resistance compared with ritonavir-boosted PIs. EVG also carries a 
possible increased risk for proximal renal tubulopathy [32, 33], and Stribild is not 
recommended for patients with creatinine clearance (CrCl) under 70 mL/min. Both RTV 
and COBI (required in conjunction with EVG) boost TDF concentrations which may 
increase TDF proximal tubular toxicity [FDA, 2012].   
 
As above, RAL and EVG have relatively low thresholds for resistance development and 
share resistance pathways; accordingly, a patient who becomes resistant to one is likely 
resistant to the other. Clinical resistance to both RAL and EVG has been observed in Phase 
III studies in both treatment-experienced [27, 34] and treatment-naïve participants [24, 25, 
35]. In Study 145, comparing EVG- versus RAL-based therapy in treatment-experienced 
participants who failed therapy, 16/60 (27%) and 15/72 (21%) of patients with integrase 
genotype data available at the time of virologic failure developed integrase resistance 


Page 14 of 72 
 
mutations. Phenotypic cross-resistance to both drugs was typical, preventing sequencing 
from one drug to the other [27].  
 
Dolutegravir 
DTG is a next-generation integrase inhibitor with a plasma half-life of 14 hours, which 
allows for once-daily dosing without pharmacological boosting [36-38].  No relevant 
inhibition or induction of cytochrome P450 or food effect has been reported, suggesting 
low potential for interactions [37, 39].  Most HIV isolates with resistance to RAL and EVG 
remain susceptible to DTG, making DTG an important option for many treatment 
experienced patients with multi-class drug resistance and potentially preserving 
susceptibility to other integrase inhibitor drugs in the event of virologic failure on DTG. 
Based on in vitro and clinical data, DTG demonstrates excellent antiviral activity and 
tolerability typical of the integrase inhibitor class, but has a higher barrier to resistance. 
Dolutegravir is FDA-approved for the treatment of HIV-1 in the US for treatment.  
 
Dolutegravir is being developed as a single-tablet regimen in combination with abacavir-
lamivudine (DTG/ABC/3TC).  Such a regimen offers the advantage over other single-tablet 
ART regimens due to the lack of an effect on the cytochrome P450 enzyme CYP3A4, the 
absence of tenofovir DF (with the possible risk of renal or bone safety), and activity against 
transmitted viruses with NNRTI resistance.  Further, the bioequivalence of DTG/ABC/3TC 
FDC has been demonstrated without regard to food administration in 62 healthy HIV 
negative individuals [40].  
 
2.3 
Clinical and Safety Data 
DTG has been studied in several Phase III clinical trials (SPRING-2 [41], SINGLE [42], 
SAILING [43], VIKING-3 [44] AND FLAMINGO [45]) and found to be safe and 
effective. 
 
The SPRING-2 study was a randomized, double-blind trial which showed non-inferior 
efficacy of once-daily DTG to twice-daily RTG in ART-naïve participants over 96 weeks, 
with a similar safety profile and no evidence of emergent resistance to DTG in those with 
virologic failure [41]. DTG was also found to be superior to a PI-based regimen in the 
FLAMINGO study, in which ART-naïve participants were randomized to either DTG 
50mg once daily or darunavir (DRV) 800mg once daily plus ritonavir 100 mg once daily, 
with investigator-selected TDF-FTC or ABC-3TC.   No treatment-emergent resistance was 
detected in either group, but treatment discontinuation due to adverse events or stopping 
criteria were less frequent in the DTG versus DRV plus ritonavir group (2% versus 4%). 
 
The SINGLE study of dolutegravir was a blinded comparison of the single-tablet 
combination of dolutegravir combined with ABC/3TC versus the FDC EFV/TDF/FTC 
[46]. In this study, 833 ART-naïve participants were randomized to a FDC of dolutegravir 
at a dose of 50mg plus ABC and 3TC (DTG/ABC/3TC) or EFV/TDF/FTC, a recommended 
first line regimen [46].  The proportion of participants with HIV RNA levels <50 
copies/mL was higher in the DTG/ABC/3TC versus the EFV/TDF/FTC group (88% vs. 
81%, p=0.003) and participants receiving DTG/ABC/3TC suppressed more rapidly than 
those on EFV/TDF/FTC, 28 versus 84 days (p<0.0001), respectively.  The safety profile of 
DTG/ABC/3TC was also better, with fewer discontinuations related to adverse events, and 
no detectable resistance through 48 weeks.  In sum, in each of the 3 large studies (SINGLE 
[42] and SPRING 2  [41] and FLAMINGO [45]) of DTG in ART naïve patients, no 
participants developed either integrase or NRTI resistance.  
 
Additional safety data derives from the VIKING study in which twice daily DTG (50mg) in 
highly treatment-experienced patients was effective in decreasing HIV RNA levels, and 
only 3% of participants discontinued treatment due to adverse events.  


Page 15 of 72 
 
 
Summary 
We propose to evaluate the efficacy and time to viral suppression with DTG/3TC/ABC FDC 
as initial therapy for AHI, as well as the feasibility of prompt administration using a rapid 
HLA-B57 screening antibody assay. In addition to validating the restriction of RCI by ART 
including a DTG-based regimen initiated during AHI, we will seek correlations between low 
RCI, and measures of immune activation. We hypothesize that rapid reduction in plasma 
viremia with this regimen will limit the area under the pre-ART viral load curve, and thus 
reduce the latent reservoir size as measured by a viral outgrowth assay one to two years 
following ART start, [11] and as compared with the latent reservoir size in acutely infected 
individuals started on regimens without an integrase inhibitor based regimen.  In addition, 
we will examine the longitudinal impact of the proposed integrase-based regimen initiated 
during the acute period on immune activation through week 96. If residual viral expression 
and persistent immune dysfunction is related to the burden of the latent viral reservoir (and 
presumably its periodic activation) these abnormalities should be ameliorated by early ART 
with rapid viral suppression. We hypothesize that earlier treatment coupled with more rapid 
ART-mediated virus suppression will be associated with better long-term T cell function, 
specifically better T cell function after 2 years of durable HIV suppression. 
 
3. 
STUDY OBJECTIVES  
 
3.1 
Purpose 
 
 
To evaluate the safety and efficacy of DTG/3TC/ABC FDC as initial therapy for AHI, 
as well as the feasibility of prompt administration using a rapid HLA-B57 screening 
antibody assay.  
 
To seek correlations between low RCI, and measures of immune activation 
 
Assess long term improvement in T-cell function following early initiation of ART 
accompanied by rapid viral suppression.  
 
3.2 
Hypothesis 
 
 
The initiation of DTG/3TC/ABC FDC in individuals with AHI will be feasible, safe 
and will suppress viral replication more rapidly compared to initiation of a NNRTI-
based regimen during AHI.  
 
Rapid reduction in plasma viremia with this integrase-based regimen will limit the area 
under the pre-ART viral load curve, and thus reduce the latent reservoir size one to two 
years following ART start. 
 
Early initiation of ART coupled with the rapid reduction in plasma viremia will be 
associated with better long-term T cell function, specifically better T cell function after 
2 years of durable HIV suppression 
 
3.3 
Primary Objective  
 
3.3.1 
To determine the virologic efficacy of DTG/3TC/ABC FDC given once daily to 
participants with AHI as determined by the proportion of treated participants with 
HIV-1 RNA to <200 copies/mL at week 24. 
 
3.4 
Secondary Objectives  
 
3.4.1 
To evaluate the safety and tolerability of DTG/3TC/ABC FDC given once daily in 
acutely infected participants though 96 weeks of treatment. 
3.4.2 
To assess the feasibility of prompt administration of DTG/3TC/ABC FDC using a 
rapid HLA-B57 screening antibody assay. 


Page 16 of 72 
 
3.4.3 
To assess the virologic efficacy of DTG/3TC/ABC FDC given once daily to 
participants with AHI as determined by the proportion of treated participants with 
HIV-1 RNA to <50 copies/mL at week 48.   
3.4.4 
To compare virologic efficacy of DTG/3TC/ABC FDC to a historical control 
cohort treated with FDC EFV/FTC/TDF at weeks 24 and 48. 
3.4.5 
To measure the rate of virologic decline during the first 24 weeks of treatment 
compared to historical control cohort treated with DTG/3TC/ABC FDC. 
 
3.5 
Other Objectives 
3.5.1 
To evaluate immune activation as measured by the proportion CD8+ cells 
expressing HLA-DR and CD38+ at weeks 0, 24, 48, 96, 120, 144, 192, and 240. 
3.5.2 
To assess the effect of the treatment regimen on the latently infected reservoir as 
measured in PBMC’s obtained via leukapheresis at week 48 in a subset of 
participants with HIV-1 RNA consistently <50 copies/mL (optional repeat at week 
96). 
3.5.3 
To assess the impact of the treatment regimen on detection of low level plasma 
viremia as measured  by a single copy assay (SCA) at weeks 84 and 96. 
 
4. STUDY DESIGN   
 
This is a multicenter, single arm, 96-week open-label study of DTG/3TC/ABC FDC in AHI.  
The study will be conducted at the University of North Carolina in Chapel Hill, NC and Duke 
University in Durham, NC. Both sites are members of the Duke-UNC Acute HIV Infection 
Study Consortium. All Forty (40) participants will be enrolled in the treatment phase of the 
study for 96 weeks and will receive DTG/3TC/ABC FDC. The clinical care and HIV-1 RNA 
and CD4 evaluations, along with the DTG/3TC/ABC FDC will be provided by the study for 96 
weeks. After week 96, participants will be followed to allow longitudinal assessment of 
immune cell function, combined with CD4 count and HIV RNA measurement. 
 
If baseline resistance is detected after treatment begins (e.g. evidence of pre-existing baseline 
resistance (genotypic or phenotypic) that may adversely affect the efficacy of the study 
regimen), the study participant will be required to change their treatment regimen as per best 
clinical practice. The new regimen will not be provided by the study. The participant will obtain 
new medications via their medical insurance or through available clinical resources.  
 
After individuals are identified with AHI, they will be offered the opportunity to participate in 
the study.  The study consent form(s) will be signed for study participation and these include 
the screening and main study informed consent  as well as the consent for specimen storage.   
 
All participants considered potentially eligible for enrollment and who have signed the 
screening consent form will have screening lab tests drawn to determine eligibility per lab 
results.  
 
Completion of all remaining screening evaluations to further determine eligibility will be done 
after the participant reviews and signs the main study consent.  Screening and enrollment will 
occur on the same day, provided the participant meets the inclusion/exclusion criteria (Section 
5.2 and 5.3).  Due to the next business day turn around for hepatitis B surface antigen, and the 
molecular HLA B57 assay (when indicated), potential participants meeting all other 
inclusion/exclusion criteria but pending these 2 results and who sign the main informed consent 
will be given 7 days of study treatment, but instructed NOT to begin taking until notified by the 
study team after confirming HLA B*57:01 status and excluding active hepatitis B infection 
(Reference Appendix 4). Should the person have Hepatitis B or test positive for HLA B57, they 
will be instructed NOT to take study medication and to return to UNC for another ART 


Page 17 of 72 
 
regimen. This regimen WILL NOT be provided by the study and the person will be terminated 
from the study at this time. These people will be replaced on the study.  
 
Participants required to change their regimen due to resistance, adverse events or meeting 
criteria for virologic failure will be offered the opportunity to switch to the best available 
regimen as selected by their HIV provider and will be able to remain on study for clinical care 
and evaluations through week 96. The new regimen will not be provided by the study but 
obtained via their medical insurance or available clinical resources 
 
5. 
STUDY POPULATION  
 
5.1 
Definitions 
5.1.1 
For the purpose of this study and to facilitate rapid initation of ART, we will permit 
inconclusive HIV testing results that are predictive of AHI in the presence of HIV 
IA laboratory signal to cut-off (S/CO) ratios predictive of AHI.  
 
Acute HIV infection is defined as:  
 
 
A negative 4th generation HIV Ag/Ab Combination Assay or any HIV antibody 
IA test and a detectable HIV-1 RNA (NAAT or Viral load)  
 
OR 
 
 
A positive 4th generation HIV Ag/Ab Combination Assay with a S/CO ≥ 1 and 
a negative or indeterminate HIV confirmatory/differentiating antibody test 
result with an HIV-1 RNA (qualitative or quantitative) test pending. 
a. Note: Pending HIV RNA test result should be available within 7 
working days of study enrollment.  
 
      
OR 
 
 
A positive 4th generation HIV Ag/Ab Combination Assay and a negative or 
indeterminate HIV confirmatory/differentiating test with a detectable HIV-1 
RNA (qualitative or quantitative) test.  
 
OR 
 
 
Two different rapid HIV tests with discordant results with HIV serum antibody 
and/or HIV-1 RNA tests pending.  
 
      
OR 
 
 
A positive HIV antibody test according to standard criteria obtained within 30 
days after an initial negative or indeterminate HIV antibody, antigen, or nucleic 
acid amplification.  
 
5.1.2 
Date of HIV diagnosis is defined as: 
 
Date of blood collection with the first positive HIV test result (standard HIV 
antibody, rapid HIV antibody or qualitative or quantitative HIV RNA assay). 
 
5.1.3 
Virologic Failure is defined as:  
a.  Failure to achieve HIV-1 RNA <200 copies/mL by wk 24  
 
or  


Page 18 of 72 
 
b.  2 consecutive HIV-1 RNA levels >200 copies/mL at least 1 week apart after 
week 24. 
 
5.2 
Inclusion Criteria  
5.2.1 
Documentation of Acute HIV infection at or within 30 days of study entry.  
5.2.2 
Men and women age ≥18 years. 
5.2.3 
ART naïve, defined as ≤14 days of antiretroviral treatment at any time prior to 
entry.  The only exceptions are:  
 
Pre-exposure prophylaxis (PrEP) and documented as HIV-1 negative at least 1 
month prior to AHI diagnosis during PrEP, and  
 
Post-exposure prophylaxis (PEP) provided the participant was documented as 
HIV-1 negative at least 3-6 months following completion of PEP treatment. 
5.2.4 
Lab values obtained within 30 days prior to study entry:  
 
Absolute neutrophil count >500/mm3 
 
Hemoglobin > 8.5 g/dL for men and > 8.0 g/dL for women 
 
Platelet count >50,000/mm3 
 
Lipase ≤ 3 X upper limit of normal (ULN), single repeat test is allowed to 
determine eligibility 
 
Calculated creatinine clearance (Cockcroft-Gault formula) ≥ 50mL/min: 
o CrCl =  (140-age) x body weight (kg)  (x 0.85 if female) 
                                         Serum creatinine [mg/dL] x (72) 
5.2.5 
Testing for HBsAg is pending. 
Note: Participants who test positive for HBsAg will be terminated from the 
study prior to starting study treatment. 
5.2.6 
Testing for HLA-B57 and/or HLA-B*5701 is pending. 
Note: Participants who test positive for HLA-B*5701 will be terminated from 
the study prior to starting study treatment. 
5.2.7 
A female is eligible to enter and participate in the study if she:  
 
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, 
 
Is of child-bearing potential, with a negative pregnancy test at screening and at 
enrollment, who agrees to use one of the highly effective methods of 
contraception listed below.  
- 
Complete abstinence from intercourse from 2 weeks prior to 
administration of study medication, throughout the study, and for at least 
2 weeks after discontinuation of all study medication; 
- 
Approved hormonal contraception -  used alone is not considered a 
sufficient form of contraception for the study - see Appendix 1 for a 
listing of examples of approved hormonal contraception; 
- 
Any intrauterine device (IUD) or intrauterine system with published data 
showing that the expected failure rate is <1% per year; see Appendix 2 
for a listing of IUDs meeting this criterion; 
- 
Male partner sterilization with documentation of azoospermia confirmed 
prior to the female participant’s entry into the study, and this male is the 
sole partner for that female participant. The documentation on male 
sterility can come from the site personnel’s review of participant’s 


Page 19 of 72 
 
medical records, medical examination, and/or semen analysis, or medical 
history interview provided by her or her partner.; 
- 
Any other method with published data showing that the expected failure 
rate is <1% per year; 
- 
Any contraception method must be used consistently, in accordance with 
the approved product label and for at least 2 weeks after discontinuation 
of the study medication.  
5.2.8 Females who meet the post-menopausal definition, noted in 5.2.7, will have a 
follicle stimulation hormone (FSH) test to verify menopause,  
5.2.9 Ability and willingness of participant to give written informed consent. 
 
5.3 
 Exclusion Criteria 
5.3.1 ALT ≥5 times Upper Limit of Normal (≥5xULN)  
5.3.2 AST ≥3x ULN  
5.3.3 Bilirubin ≥1.5x ULN (with >35% direct bilirubin) 
5.3.4 Weight < 40 kg 
5.3.5 Women who are breast-feeding. 
5.3.6 Women with a positive pregnancy test on enrollment or prior to study drug 
administration. 
5.3.7 
Women and men of child bearing potential unwilling to agree to use an effective 
method of contraception required by the study.  
5.3.8 History or presence of allergy to the study drugs or their components. 
5.3.9 
Requires or is anticipated to require any of the prohibited concomitant therapy: 
barbiturates, dofetilide, fampridine (dalfampridine), modafinil, oxcarbazepine, 
pioglitazone, pilsicainide, pimozide, rifampin, rifapentine, phenytoin, 
phenobarbital, carbamazepine, and St. John’s wort. 
 
Dofetilide, fampridine, and pilsicainide are prohibited, as DTG may inhibit its 
renal tubular secretion resulting in increased dofetilide concentrations and 
potential for toxicity. 
5.3.10 Unable to discontinue any current medications that are excluded during study 
treatment. 
5.3.11 Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), radiation 
therapy, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy 
within 30 days prior to study entry.  
 
Prednisone at a daily dose of 10 mg or less (physiologic replacement dose) is 
permitted. 
5.3.12 Treatment with radiation therapy or cytotoxic chemotherapeutics agents within 28 
days prior to screening or has an anticipated need for these agents during the study. 
5.3.13 Administration of an HIV-1 immunotherapeutic vaccine within 90 days prior to 
screening. 
5.3.14 Prior treatment with any other experimental drug for any indication (within 30 days 
of initiating study treatment).  
5.3.15 Difficulty swallowing capsules/tablets. 
5.3.16 Inability to communicate effectively with study personnel. 
5.3.17 Incarceration; prisoner recruitment and participation are not permitted. 
5.3.18 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements or confound the 
analysis of study endpoints. 


Page 20 of 72 
 
5.3.19 Any condition (including but not limited to alcohol and drug use) or any active 
clinically significant disease or findings during screening of medical history or 
physical examination, which, in the opinion of the Investigator would interfere with 
patient safety or compliance. 
5.3.20 Serious illness requiring systemic treatment and/or hospitalization until patient 
either completes therapy or is clinically stable on therapy, in the opinion of the site 
investigator, for at least 7 days prior to study entry.  
 
NOTE: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, 
and other minor illnesses (as judged by the site investigator) have no 
restriction.  
5.3.21 A life expectancy less than twelve months. 
5.3.22 Acute viral hepatitis, including, but not limited to, hepatitis A, B, or C. 
5.3.23 History of myocardial infarction or diagnosis of coronary artery disease. 
5.3.24 History of ongoing or clinically relevant pancreatitis within the previous 6 months. 
5.3.25 Chronic hepatitis C infection with an anticipated need for treatment during the 
study period (through week 96). 
5.3.26 Chronic hepatitis B infection (see inclusion criteria 5.2.5). 
5.3.27 Evidence for moderate to severe hepatic impairment (as defined by the presence of 
cirrhosis, ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or 
gastric varices, persistent jaundice or Child-Pugh class B or greater hepatic 
impairment). 
5.3.28 Evidence of biliary abnormalities (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones). 
5.3.29 Any verified grade 4 laboratory abnormality with exception of ALT as defined in 
exclusion criteria 5.3.1  
 
5.4 
Recruitment 
Participants for this study are recruited from suspected or confirmed cases of AHI referred 
to UNC and Duke University ID clinics. Referrals are generated from the North Carolina 
(NC) Screening and Tracing Active Transmission (STAT) Program [47] and from clinical 
diagnoses made by both internal and external health care clinics. 
 
The risks and benefits of initiating ART during AHI are discussed with each AHI 
individual referred to the participating sites as a part of routine evaluation of a new AHI 
diagnosis. The discussion of initiating ART during AHI is considered an ethical obligation 
to allow each person to consider all options, and this occurs prior to the discussion of any 
study participation. Initiation of ART is at the discretion of each person and is entirely 
voluntary. If AHI individuals are interested in starting treatment, they are offered 
consideration of participation on a treatment study for acute HIV infected persons. 
 
6. 
STUDY TREATMENT 
 
6.1. 
Study Drug 
 
All participants will receive Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) 
and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) 
(DTG/ABC/3TC, GSK2619619), administered orally, once daily, with no food or fluid 
restrictions or requirements. 
 


Page 21 of 72 
 
The medication will be supplied by the study for the 96 weeks. Participants who have 
evidence of resistance to any of the study medications or develop a hypersensitivity 
reaction will need to obtain alternative ART medications via their own medical insurance or 
through available clinical resources, and will be assisted in doing so. 
 
The DTG/ABC/3TC FDC single tablet was approved by the U.S. Food and Drug 
Administration (FDA) on August 22, 2014 as a fixed dose combination tablet (FDC) for the 
treatment of HIV-infected adult participants, without clinically suspected resistance to any 
of the components. 
 
Therapy will be initiated with all drugs simultaneously since co-formulated in a single 
tablet. Drugs will be given in recommended doses. The timing of doses of study treatment 
will be left to the individual participants, but should be taken at the same time each day. 
Study drug will be dispensed in quantities sufficient to last until the next clinic visit with a 
small excess to accommodate the possibility of a delay in return to scheduled appointments. 
Study participants will be asked to bring their pill bottles to each visit to assess compliance. 
 
Duration 
Participants will participate in the treatment phase of the study for approximately 96 weeks 
following enrollment.  
 
There will be no study medication administered as part of the study in the  long-term 
longitudinal follow up phase. All participants will access their ART via standard means 
such as insurance, or medication assistance programs.  
 
Administration and Dispensing 
All participants will receive the Alert card for abacavir.  As each participant is enrolled, the 
study site must ensure that:   
1) the participant receives the wallet-size warning card;  
2) the designated health care provider (e.g., physician, study nurse coordinator, or 
pharmacist) reviews the signs and symptoms of a HSR with the participant; and  
3) the participant verbalizes an understanding of the steps to take in the event of a 
suspected HSR, including when and how to contact the study site. 
 
6.2. 
Product Information  
Dolutegravir/Abacavir/Lamivudine Tablets, 50 mg/600 mg/300 mg are purple, oval, film-
coated, biconvex tablets debossed with ‘572 Trı’ on one side and plain on the other side. 
The tablets contain 52.62 mg dolutegravir sodium which is equivalent to 50 mg 
dolutegravir free acid, 702 mg abacavir sulfate, which is equivalent to 600 mg abacavir free 
base, and 300 mg lamivudine. The tablets are packaged into HDPE bottles with child-
resistant closures that include induction seals. The bottles contain a desiccant.  
 
Plasma exposures of DTG, ABC, and 3TC following single-dose administration of this 
FDC tablet formulation were bioequivalent to those following co-administration of the 
separate tablet formulations of DTG 50 mg plus EPZICOM (ABC 600 mg/3TC 300 mg) 
under fasted conditions. 
 
Product Information on the individual components of 
Dolutegravir/Abacavir/Lamivudine FDC is provided below: 
 
6.2.1. Dolutegravir (DTG) - TIVICAY 
In ART-naïve, HIV-infected adult participants, DTG 50 mg once daily was shown 
to be an efficacious dose, and non-inferior to RAL in combination with a 
background regimen with dual NRTIs. When used in combination with ABC/3TC, 


Page 22 of 72 
 
DTG was shown to be superior to Atripla (EFV/TDF/FTC), a result driven by 
better tolerability of the DTG-based regimen. DTG was found superior in an open-
label, randomized and active-controlled study in which antiretroviral-naïve 
participants were randomized and received either DTG 50 mg or DRV 800 mg + 
RTV 100 mg once daily, both administered with dual NRTI therapy (either 
ABC/3TC or TDF/FTC). The results were largely driven by difference in 
withdrawals due to adverse events, and withdrawals due to other reasons. 
 
DTG 50 mg once daily has a higher barrier to resistance in INI-naïve patients, as 
demonstrated in the treatment-experienced (INI-naïve) SAILING study where 
significantly fewer virologic failures and significantly fewer participants with INI 
resistance were observed when compared with RAL [43]. Data from three 
treatment-naïve studies [41, 42, 45] are also supportive of DTG’s higher barrier to 
resistance, given that no participants on the DTG regimen developed resistance to 
either DTG or the background NRTIs, whereas resistance to both the third agent 
and the background NRTIs was observed in both the RAL-, EFV-, and DRV+RTV-
based comparator arms. 
 
Increases in CD4+ cell counts were observed for participants receiving DTG-
containing regimens across all patient populations that were evaluated in the Phase 
II and III program. These CD4+ cell count increases were similar in comparison 
with RAL in treatment-naïve and treatment-experienced participants, similar to 
DRV+RTV in treatment naïve participants, and were greater than those observed 
with EFV-containing regimens in treatment-naïve participants.  
 
There was no evidence of a diminished response to DTG in specific patient 
subgroups, such as gender, age (≤ 50 years), race, level of immunosuppression (low 
CD4+ cell counts or CDC Category C). However, there are limited data in 
participants aged ≥65 (n=27). 
 
DTG demonstrated a nonpathological effect of increasing creatinine levels due to 
inhibition of secretion by OCT2 transporter with no effect on GFR and effective 
renal plasma flow. 
 
6.2.2. Abacavir (Ziagen®, ABC)  
ABC is a potent NRTI which has been shown to result in similar (non-inferior) 
virological responses to zidovudine (ZDV) and better CD4+ T-cell responses, when 
used in combination with 3TC and EFV in antiretroviral-naïve patients.  Although 
ABC has been dosed twice a day, data about the prolonged intracellular half-life of 
its active moiety (carbovir triphosphate) and from clinical studies suggest once 
daily dosing is as effective as twice daily dosing when given with 3TC and EFV. 
This led to the Food and Drug Administration (FDA) approval of a combination 
tablet of ABC and 3TC given as a single tablet once-daily.   
 
ABC is generally well tolerated. Most clinical adverse events (AEs) are mild to 
moderate in severity and generally self-limiting. The most frequently reported 
clinical AEs across phase III studies were nausea/vomiting, headache, malaise or 
fatigue, and diarrhea. Elevated triglycerides and anorexia have also been reported. 
Clinical AEs and clinical laboratory abnormalities common to some nucleoside 
ARV agents (i.e., pancreatitis, peripheral neuropathy, anemia, and neutropenia) 
have not been commonly seen with ABC therapy. Lactic acidosis and severe 
hepatomegaly with steatosis, including fatal cases have been reported with the use 
of nucleoside analogues alone or in combination, including ABC, and other ARVs.  
Exclusive of ABC hypersensitivity reaction (HSR) (see next paragraph), no 


Page 23 of 72 
 
differences in the safety profile of ABC based on gender, race, or age are apparent; 
however, safety in selected populations (i.e., moderate to severe hepatic 
impairment) has not been evaluated.  
 
In clinical studies, approximately 5% of patients receiving ABC develop a HSR 
that in rare cases has proved fatal. HSR is characterized by the appearance of 
symptoms indicating multiorgan/body system involvement. Symptoms usually 
appear within the first 6 weeks of starting treatment with ABC (median time to 
onset is 9 days), but may occur at any time while on therapy, and most often 
include fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, or 
abdominal pain), and lethargy or malaise. Other signs and symptoms may include 
musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia), headache, 
paresthesia, and edema. Respiratory tract symptoms have been observed in 
approximately 20% of patients who experience HSR. Some patients with HSR 
were initially thought to have respiratory tract disease (pneumonia, bronchitis, 
pharyngitis) or a flu-like illness. The multisystem nature of the HSR has led to 
misdiagnosis of the HSR as an intercurrent medical illness or as being related to 
another medication. Participants who have had an HSR must be advised that they 
should never take ABC again or any product that contains ABC, such as Trizivir®, 
as a life-threatening second HSR can occur.  Diagnosis and management of HSR is 
discussed further in sections 6.4.4 and 8.2.1.   
 
Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 
patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 
screening was not performed. The incidence of suspected abacavir hypersensitivity 
reactions in clinical trials was 1% when participants carrying the HLA-B*5701 
allele were excluded. 
 
ABC is designated as FDA pregnancy Category C.   
 
6.2.3. Lamivudine (Epivir®, 3TC) 
 
3TC is a potent NRTI that is widely used in the management of HIV-1-infected 
participants.  Although 3TC is an effective antiviral NRTI, a resistance mutation at 
codon 184 emerges within weeks of monotherapy and is also seen when 3TC is 
used as part of any regimen that does not reduce HIV-1 RNA to levels below the 
assay limit of quantification. 
 
3TC is one of the best-tolerated NRTIs with AEs occurring in less than 5% of 
participants. Toxicities include headache, nausea and vomiting, malaise, fatigue 
and sleeplessness, anorexia, dizziness, rash, depression, anemia, neutropenia, and 
hyperamylasemia.  Lactic acidosis and severe hepatomegaly with steatosis, 
including fatal cases have been reported with the use of nucleoside analogues alone 
or in combination, including 3TC, and other ARVs.   
 
Participants who are co-infected with hepatitis B virus (HBV) may experience 
increased liver function tests and exacerbation of hepatitis symptoms when 3TC is 
stopped. Usually these symptoms are self-limiting; however, death has been 
reported. The causal relationship to 3TC discontinuation is unknown. HBV-
infected participants should be followed closely for the first several months 
following 3TC discontinuation. 
 
3TC is designated as FDA pregnancy Category C.   
 


Page 24 of 72 
 
6.3. 
Product Supply, Distribution, and Pharmacy 
 
6.3.1. Acquisition 
DTG/ABC/3TC single tablet FDC will be provided by ViiV Healthcare Limited.  
Study product will be available from the UNC Investigational Drug Services (IDS). 
 
6.3.2. Accountability 
The IDS will maintain complete records of all study products received from the 
ViiV and subsequently dispensed. 
 
6.4. 
Concomitant Medications 
 
6.4.1. Contraindications 
 The DTG/ABC/3TC single tablet FDC is contraindicated in patients with 
known hypersensitivity to DTG, ABC or 3TC, or to any of the excipients. 
 The DTG/ABC/3TC single tablet FDC must not be administered to participants 
in combination with the antiarrthymic agents dofetilide (Tikosyn®) or 
pilsicainide 
- 
Dofetilide is prohibited as DTG may inhibit its renal tubular secretion 
resulting in increased dofetilide concentrations and potential for 
toxicity 
 The DTG/ABC/3TC single tablet FDC must not be administered to participant 
in combination with fampridine (dalfampridine); a potassium channel blocker. 
 
6.4.2. Permitted Medications and Drug Interactions 
Caution should be given to co-administering medications (prescription and 
nonprescription) that may change the exposure of DTG, ABC, 3TC or medications 
that may have their exposure changed by the DTG/ABC/3TC single tablet FDC. 
 
 
DTG should not be given with etravirine (ETR) without the coadministration of 
atazanavir+ritonavir (ATV+RTV), lopinavir/ritonavir (LPV/RTV) or darunavir 
+ ritonavir (DRV+RTV).   
 
The following drugs when co-administrated with DTG will cause a decrease in 
the plasma concentration of DTG and require an increase in dosing frequency 
to DTG 50mg twice daily: Efavirenz (EFV), Fosamprenavir + ritonavir 
(FPV+RTV), Tipranavir  + ritonavir (TPV+RTV) and rifampin. 
 
The following drugs when co-administrated of DTG will cause an increase in 
the plasma concentration of DTG: atazanavir (ATV), atazanavir & ritonavir 
(ATV & RTV); however, no dosage adjustment to DTG is required. 
 
Co-administration of DTG/ABC/3TC FDC with nucleoside analogs has the 
potential to cause lactic acidosis and severe hepatomegaly with steatosis, 
including fatal cases.  
 
Co-administration of DTG has the potential to decrease plasma concentrations 
of Neviripine (NPV), oxcarbazepine, phenytoin, phenobarbital, carbamazepine, 
and St. John’s wort. 
 
DTG should not be co-administered with antacids containing polyvalent 
cations (i.e. magnesium or aluminum). DTG is recommended to be 
administered 2 hours before or 6 hours after these agents. 
 
DTG/ABC/3TC FDC is recommended to be administered 2 hours before or 6 
hours after taking calcium or iron supplements, or alternatively, administered 
with food. Alternatively, DTG/ABC/3TC FDC and calcium or iron containing 
supplements can be taken together with food. 


Page 25 of 72 
 
 
Antacids containing polyvalent cations (e.g. Mg, Al) decrease DTG plasma 
concdentrations. Dolutegravir is recommended to be administered 2 hours 
before or 6 hours after taking antacid products containing polyvalent cations. 
 
Metformin concentrations may be increased by DTG/ABC/3TC FDC. Lower 
metformin doses may be considered for patients treated with DTG and 
metformin. 
  Potential drug-drug interaction between the ABC component of  
 DTG/ABC/3TC and riociguat 
 
6.4.3. Prohibited Medications 
The following medications or their equivalents may cause decreased concentrations 
of DTG. Therefore, the following medications must not be administered 
concurrently with DTG. 
 Fampridine (see 6.4.1) 
 Dofetilide (see 6.4.1) 
 Pilsicainide (see 6.4.1) 
 Barbiturates 
 Carbamazepine 
 Cytotoxic chemotherapy 
 Hepatitic C treatment 
 HIV immunotherapeutic vaccines 
 Interferon 
 Modafinil 
 Oxcarbamazepine 
 Phenobarbital 
 Phenytoin 
 Pioglitazone 
 Pimozide 
 Radiation therapy 
 Ribavirin 
 Rifampin 
 Rifapentine 
 St. John’s wort 
 Systemically administered immunomodulators 
 Troglitazone 
 Other experimental agents and antiretroviral drugs not otherwise specified in the 
protocol 
 
The following medications or their equivalents may cause decreased concentrations 
of ABC. Therefore, the following medications must not be administered 
concurrently with ABC. 
 
Riociguat 
 
Chronic use of oral glucocorticoids must be avoided; however, short treatment 
courses (for example, 10 days or less) and topical, inhaled, or intranasal use of 
glucocorticosteroids will be allowed. 
 
6.4.4. Prohibited Medications During the Longitudinal Phase of the Study  
Participants will not receive any ART via the study while in the longitudinal phase 
of the study. There is no concomitant medication which would preclude a 
participant from participating in the study after Week 96.  
 
6.4.5. Hypersensitivity Reactions 
 


Page 26 of 72 
 
Abacavir 
The HLA-B*5701 allele is associated with a significantly increased risk of a 
hypersensitivity reaction to abacavir. The PREDICT-1 study demonstrated that 
prospective HLA-B*5701 screening decreased the incidence of ABC-related HSR 
from 7.8% to 3.4% [48].  Screening for carriage of the HLA-B*5701 allele is 
recommended prior to initiating treatment with ABC, and for those testing positive, 
initiating an ABC-containing regimen is not recommended.  
 
Almost all patients developing a hypersensitivity reaction will have fever and/or 
rash (usually maculopapular or urticarial) as part of the syndrome, however 
reactions have occurred without rash or fever.  
 
Symptoms can occur at any time while being treated with abacavir, but usually 
appear within the first six weeks of initiation of treatment (median time to onset 11 
days).  
 
The signs and symptoms of this hypersensitivity reaction are listed below.  
 
Symptoms reported in at least 10% of patients with a hypersensitivity reaction 
are in bold text. 
     Skin 
 
     Gastrointestinal  
 
   
     Respiratory Tract 
 
 
     Miscellaneous: 
 
 
   
Neurological/Psychiatry: 
 
     Hematological: 
 
     Liver/pancreas: 
 
    Musculoskeletal: 
 
   
     Urology: 
rash (usually maculopapular or urticarial)  
 
nausea, vomiting, diarrhea, abdominal pain, mouth 
ulceration 
 
dyspnea, cough, sore throat, adult respiratory distress 
syndrome, respiratory failure 
 
fever, fatigue, malaise, edema, lymphadenopathy, 
hypotension, conjunctivitis, anaphylaxis 
 
 
headache, paresthesia 
 
Lymphopenia 
 
elevated liver function tests, hepatic failure 
 
myalgia, rarely myolysis, arthralgia, elevated creatine 
phosphokinase 
 
elevated creatinine, renal failure 
 
Some patients with hypersensitivity presented symptoms associated with a flu-like 
illness, gastroenteritis or reactions to other medications. Delaying diagnosis of 
hypersensitivity resulted in abacavir being continued or re-introduced, leading to a 
more severe hypersensitivity reaction or death. Therefore, the diagnosis of 
hypersensitivity reaction should be carefully considered for participants presenting 
with symptoms of these diseases and is a clinical diagnosis. If hypersensitivity 
reaction cannot be ruled out, the DTG/ABC/3TC single tablet FDC, or any other 
medicinal product containing abacavir (e.g. ZIAGEN, EPZICOM, KIVEXA, 
TRIZIVIR) should not be restarted. 
 
The symptoms related to this hypersensitivity reaction worsen with continued 
therapy, and usually resolve upon discontinuation of abacavir. 
 


Page 27 of 72 
 
Restarting abacavir following a hypersensitivity reaction results in a prompt return 
of symptoms within hours. This recurrence of the hypersensitivity reaction may 
be more severe than on initial presentation, and may include life-threatening 
hypotension and death. Regardless of their HLA-B*5701 status, participants 
who develop this hypersensitivity reaction must discontinue the 
DTG/ABC/3TC single tablet FDC and must never be re-challenged with the 
DTG/ABC/3TC single tablet FDC, or any other medicinal product containing 
abacavir (e.g. ZIAGEN, EPZICOM, KIVEXA,TRIZIVIR). 
 
There have been infrequent reports of hypersensitivity reactions following 
reintroduction of abacavir, where the interruption was preceded by a single key 
symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal or a 
respiratory symptom). 
 
On very rare occasions hypersensitivity reactions have been reported in patients 
who have restarted therapy, and who had no preceding symptoms of a 
hypersensitivity reaction. 
 
An Alert Card with information for the participant about this hypersensitivity 
reaction will be provided to the participant at enrollment on the study. 
 
See Appendix 3 for Essential Patient Information that will be reviewed and then 
provided to each participant at the screening and enrollment visits. 
 
Dolutegravir 
Hypersensitivity reactions have been reported with integrase inhibitors, including 
DTG, and were characterized by rash, constitutional findings, and sometimes, 
organ dysfunction, including liver injury. Mild to moderate rash is an expected 
adverse reaction for DTG-containing antiretroviral therapy. 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. The 
index case of a hypersensitivity reaction with DTG involved a profuse, purpuric,  
and coalescing leukocytoclastic vasculitis as well as clinically significant liver 
chemistry elevations. Other than this case, no other instances of serious skin 
reaction, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and 
erythema multiforme have been reported for DTG in clinical trials. 
 
DTG/ABC/3TC single tablet FDC and any other suspect agent should be 
discontinued immediately if signs or symptoms of hypersensitivity reactions 
develop (including, but not limited to, severe rash or rash accompanied by fever, 
general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, 
facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver 
aminotransferases should be monitored and appropriate therapy initiated.  
Delay in stopping treatment with the DTG/ABC/3TC single tablet FDC or other 
suspect agents after the onset of hypersensitivity may result in a life-threatening 
reaction. 
 
6.5. 
Potential Risks and Benefits 
 
 
Immune Reconstitution Syndrome (IRS) 
In HIV-infected patients with severe immune deficiency at the time of 
initiation of antiretroviral therapy (ART), an inflammatory reaction to 
asymptomatic or residual opportunistic infections may arise and cause serious 


Page 28 of 72 
 
clinical conditions, or aggravation of symptoms. Typically, such reactions have 
been observed within the first few weeks or months of initiation of ART.  
 
Liver chemistry elevations consistent with immune reconstitution syndrome 
were observed in some hepatitis B and/or C co-infected patients at the start of 
DTG therapy. Monitoring of liver chemistries is recommended in participants 
with hepatitis B and/or C coinfection 
 
 
Lactic Acidosis and Severe Hepatomegaly with Steatosis  
Treatment with the DTG/ABC/3TC single tablet FDC should be suspended in 
any participant who develops clinical or laboratory findings suggestive of lactic 
acidosis or pronounced hepatotoxicity, with or without hepatitis, which may 
include hepatomegaly and steatosis even in the absence of marked 
transaminase elevations. Symptoms associated with lactic acidosis include: 
generalized weakness, anorexia and sudden unexplained weight loss, 
gastrointestinal and respiratory symptoms. Female sex and obesity may be risk 
factors for the development of lactic acidosis and severe hepatomegaly.  
 
 
Acute Hepatic Failure 
Hepatotoxicity may develop in participants receiving dolutegravir-containing 
regimens. Participants with underlying hepatitis B or C may be at increased 
risk for worsening or development of transaminase elevations. Participants with 
an acute diagnosis of hepatitis A, B, or C as well as those with a chronic 
diagnosis of hepatitis B or C are excluded from study participation. Liver 
function is monitored regularly throughout the study. 
 
 
Pregnancy and Lactation 
The safe use of the DTG/ABC/3TC single tablet FDC in human pregnancy has 
not been established. DTG, ABC and 3TC have been shown to cross the 
placenta in reproductive toxicity studies in animals. 3TC and ABC, but not 
DTG, have been associated with findings in animal reproductive toxicity 
studies. In one study, approximately 0.9% of women taking DTG when they 
became pregnant had babies with serious brain and spine defects. These defects 
happened early in pregnancy, before many women knew they were pregnant. 
For this reason, females of childbearing age should avoid getting pregnant 
while in the study and if this is not an option, an alternative treatment should be 
considered. Therefore, administration of DTG/ABC/3TC FDC in pregnancy 
should be considered only if the benefit to the mother outweighs the possible 
risk to the fetus. 
 
There is no requirement to exclude females of child bearing potential (FCBP) 
from this study based on reproductive toxicity findings for DTG, ABC and 
3TC available to date. FCBP will be required to have a negative pregnancy test 
(serum β human chorionic gonadotropin [β-hCG]) at screen and a negative 
pregnancy test at enrollment (section 5.3.6). FCBP must agree to use one of the 
highly effective methods of contraception listed in the inclusion and exclusion 
criteria for this study (sections 5.2.7 and 5.3.7) In addition, FCBP will be 
assessed for pregnancy and their current birth control methods at each study 
visit and a urine pregnancy test will be performed at each visit. A serum 
pregnancy test will be performed at any visit when pregnancy is suspected 
based on participant report or reported date of LMP. The investigator or study 
coordinator will check and confirm at every visit that FCBP are avoiding 
pregnancy. (Reference SOE.) 
 


Page 29 of 72 
 
Women, who met the definition of menopause, per inclusion criteria 5.2.7 and 
5.2.8, will have an FSH Level done to confirm menopause.  
 
Health experts recommend that where possible HIV infected women do not 
breast feed their infants in order to avoid transmission of HIV. It is expected 
that dolutegravir will be secreted into human milk based on animal data, 
although this has not been confirmed in humans. Lamivudine is present in 
human milk. There is no information on the effects of lamivudine on the 
breastfed infant or the effects of the drugs on milk production. Because of the 
potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing 
viral resistance (in 3 HIV-positive infants), and (3) adverse reactions in a 
breastfed infant, mothers should be instructed not to breastfeed if they are 
receiving EPIVIR. For these reasons, women who are breastfeeding will be 
excluded from participating in this study (section 5.3.5).  
 
 
Embryo-fetal Toxicity 
Embryo-fetal toxicity may occur when dolutegravir is used at the time of 
conception and in early pregnancy. Dolutegravir should be used 
during pregnancy only if the expected benefit justifies 
the potential risk to the fetus. FCBP should be informed 
about the potential risk of neural tube defects with DTG 
and counselled about the use of effective contraception. 
It is recommended that pregnancy testing is conducted 
prior to initiation of DTG. If there are plans to become 
pregnant, or if pregnancy is confirmed within the first 
trimester while on DTG, the risks and benefits of 
continuing DTG versus switching to another antiretroviral 
regimen should be discussed. Factors to consider should 
include feasibility of switching, tolerability, ability to 
maintain viral suppression, actual gestational age, risk 
of transmission to the infant, and the available data 
around the potential risk of neural tube defects and other 
pregnancy outcomes for dolutegravir and alternative 
antiretroviral drugs. 
 
A causal relationship of these events to the use of DTG has not been 
established. The incidence of neural tube defects in the general population 
ranges from 0.5-1 case per 1,000 live births. As most neural tube defects occur 
within the first 4 weeks of fetal development (approximately 6 weeks after the 
last menstrual period), this potential risk would concern women exposed to 
DTG at the time of conception and in early pregnancy. 
 
Dolutegravir use during pregnancy has been evaluated in the Antiretroviral 
Pregnancy Registry (APR) in over 800 pregnancies (as of January 2020). 
Available human data from the APR do not show an increased risk of major 
birth defects for DTG compared to the background rate. 
 
 
Hypersensitivity reactions 
See Section 6.4.5 above. 
 


Page 30 of 72 
 
 
Hepatitis B  
In clinical trials of non-HIV-1-infected patients treated with 3TC for chronic 
hepatitis B virus (HBV), clinical and laboratory evidence of exacerbations of 
hepatitis have occurred after discontinuation of 3TC.  Exacerbations have been 
detected primarily by serum ALT elevations in addition to re-emergence of 
HBV DNA.  Although most events were self-limited, fatalities have been 
reported in some cases.  Post-marketing data also describes similar events after 
changes from 3TC-contining HIV regimens to regimens without 3TC in 
patients co-infected with HIV and HBV. Accordingly, patients co-infected with 
hepatitis B are excluded from participation in this study. 
 
 
Psychiatric Diagnosis 
Depression, Suicidal Thoughts/Behaviors, and Anxiety  
DTG demonstrated that some patients, mostly those who had mental health 
problems before taking dolutegravir, experienced feelings of deep sadness and 
unworthiness (depression), suicidal thoughts, and suicidal behaviors.  
 
The adverse drug reaction of anxiety has been added to the company Global 
Data Sheet (GDS) and clinical trial reference safety Information for DTG, 
Triumeq (DTG,/ABC/3TC FDC), and DTG + RPV.  
 
 
Myocardial Infarction 
In a prospective, observational study designed to evaluate the rate of 
myocardial infarction (MI) in patients on ART, the use of ABC within the prior 
6 months was correlated with an increased risk of MI [49]. In a sponsor-
conducted pooled analysis of clinical trials, no excess risk of MI was observed 
in ABC-treated participants as compared with control participants.  Altogether, 
10 studies have evaluated the association between abacavir and the risk of MI; 
among the five larger studies, three conclude there is an association and two 
reports the association is not robust [50]. In totality, the available data from the 
observational studies and from controlled clinical trials show inconsistency; 
therefore, evidence for a causal relationship between abacavir and the risk of 
MI is inconclusive.. 
 
 
Elevations in serum lipids and blood glucose 
Serum lipid and blood glucose levels may increase during antiretroviral   
therapy. Disease control and life style changes may also be contributing factors.  
 
 
Adverse Reactions or Events and associated Sign and Symptoms  
The DTG/ABC/3TC single tablet FDC contains DTG, ABC and 3TC; therefore 
the adverse events associated with these may be expected. For many of the 
adverse events listed it is unclear whether they are related to the active 
substance, the wide range of other medicinal products used in the management 
of HIV infection, or whether they are a result of the underlying disease process. 
 
 
Other potential adverse events 
Many of the adverse events listed occur commonly (nausea, vomiting, diarrhea, 
fever, lethargy, rash) in patients with ABC hypersensitivity. Therefore, 
participants with any of these symptoms should be carefully evaluated for the 
presence of this hypersensitivity reaction. If the DTG/ABC/3TC single tablet 
FDC has been discontinued in participants due to experiencing any one of these 
symptoms and a decision is made to restart ABC, this must be done only under 
direct medical supervision. 
 


Page 31 of 72 
 
Clinical safety data with DTG/ABC/3TC FDC are limited. The adverse 
reactions observed for the combination of DTG + ABC/3TC were generally 
consistent with the adverse reaction profiles for the individual components 
dolutegravir, abacavir and lamivudine. 
 
 
Summary of adverse reactions associated with the combination DTG+ABC/3TC  
Gastrointestinal disorders 
Common: abdominal distension, gastroesophageal reflux disease, 
dyspepsia 
Nervous System disorders 
Common: somnolence 
Musculoskeltal and connective tissue 
disorders  
Uncommon: arthralgia and myalgia  
Psychiatric disorders 
Common: depression, nightmare and sleep disorder 
Very Common: Insomnia  
Metabolism and nutrition disorders 
Common: hypertriglyceridemia and hyperglycemia 
General disorders  
Very Common: fatigue 
Note: Frequencies are defined by MedDRA system organ class as very common (≥1/10), common (≥1/100 and <1/10), 
uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000) and very rare (<1/10,000), including isolated reports. 
 
 
Summary of adverse reactions associated with the individual components of the 
DTG+ABC/3TC 
System Organ Class  
DTG 
ABC 
3TC 
Blood and lymphatic system 
disorders  
 
 
Uncommon: 
neutropenia, anemia, 
thrombocytopenia 
Immune System Disorders 
Uncommon: 
hypersensitivity, IRS 
Common: drug 
hypersensitivity 
 
Metabolism and nutrition 
disorders 
 
Common: anorexia 
 
Psychiatric disorders 
Common: Insomnia1, 
abnormal dreams  
 
 
Nervous System disorders  
Very Common: headache 
Common: dizziness 
 
 
Gastrointestinal disorders  
Very Common: nausea, 
diarrhea 
 
Common: vomiting, 
flatulence, abdominal pain, 
upper abdominal pain, 
abdominal discomfort 
 
 
Hepatobiliary disorders 
Uncommon: hepatitis 
 
Uncommon: 
transient elevations 
in AST and ALT 
Skin and subcutaneous 
tissue disorders 
Common: rash, pruritus 
 
Common: rash 
General disorders and 
administration site 
conditions 
Common: fatigue2 
Common: fever, 
lethargy, fatigue2 
Common: fatigue2, 
malaise, fever 
Laboratory  
Uncommon: elevations in 
CPK2, creatinine and total 
bilirubin  
 
 
Note: Frequencies are defined by MedDRA system organ class as very common (≥1/10), common (≥1/100 and <1/10), 
uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000) and very rare (<1/10,000), including isolated reports. 
 


Page 32 of 72 
 
1 Insomnia was observed at a greater frequency with the combination DTG + ABC/3TC (i.e., very common) when 
compared to the individual component DTG 
2 These were asymptomatic and mainly in association with exercise 
 
 
 
 
7. 
Study Procedures 
 
7.1. 
Schedule of Events 
 
A detailed Schedule of Events (SOE) is provided at the end of the protocol. 
 
The SOE represents all possible study visits through End of Study (EOS).  Exceptions to 
specific events are noted. 
 
After enrollment, study windows will span half the time between visits.  
Examples: 1) Week 2 visit is + or – 1 week of enrollment and Week 4 visit 
 
     2) Week 8 visit is + or – 2 weeks of Week 4 visit and Week 12 visit 
 
     3) Week 36 visit is + or – 6 weeks of Week 24 visit and Week 48 visit  
 
     4) Week 120 visit is + or – 3 months of Week 96 and Week 144 visit 
 
 
7.1.1. Screening and Enrollment Visit 
 
All participants considered potentially eligible for enrollment will complete the main study 
consent and when applicable, a screening consent prior to the main consent to facilitate the 
ascertainment of eligibility labs required for study entry.  All participants who signed a 
screening consent will undergo screening evaluations to determine eligibility.  Screening 
and enrollment can occur on the same day, provided the participant meets the 
inclusion/exclusion criteria (Section 5.2 and 5.3).  
 
Screening labs that are standard of care may be obtained after signing the screening consent 
and prior to signing the study’s main informed consent. These tests, although part of study 
screening, are standard of care for clinical evaluation of newly diagnosed patients.  
Obtaining these labs immediately following the clinical evaluation and after signing the 
study screening ICF will facilitate the ability to prescribe medication sooner, including on 
the same day as the visit, should the participant decide against study participation or fail to 
meet eligibility.  
 
The following study screening labs will be obtained after the screening consent is obtained.  
CBC with differential 
Lymphocyte markers 
Chemistries: 
(sodium, potassium, chloride, 
bicarbonate, glucose, BUN, creatinine,  
creatinine clearance)  
Hepatic function tests:  
(ALT, AST, alk phos, total bilirubin, direct 
bilirubin and lipase)  
HIV antibody test 
HIV-1 RNA 
Serum pregnancy test (females)  
Follicle stimulating hormone level 
(optional - to confirm menopause only)  
Hepatitis B surface antigen   
Hepatitis C antibody/refex RNA  
STD screening (RPR, CT, GC)  
HLA B*57:01 screening 
Genotype and integrase genotype  
Immunology samples for study  
 
Enrollment can occur pending the HLA B57 and hepatitis B surface antigen test results. 
Due to the next business day turn around for hepatitis B surface antigen, and the molecular 


Page 33 of 72 
 
HLA assay (when indicated), potential participants meeting all other inclusion/exclusion 
criteria but pending these 2 results and who sign informed consent will be given 7 days of 
study treatment, but instructed NOT to begin taking until notified by the study team after 
confirming HLA B57 or HLA B*57:01 status (when indicated) and excluding active 
hepatitis B infection (Reference Appendix 4). Should the person have Hepatitis B or test 
positive for HLA B*57:01, they will be instructed NOT to take study medication and to 
return to UNC or Duke for another ART regimen. This regimen WILL NOT be provided by 
the study and the person will be terminated from the study at this time. These people will be 
replaced on the study. The PID and SID will not be re-assigned.  
 
The screening/enrollment visit must occur within 30 days of the date of AHI diagnosis 
(Section 5.1.) 
 
During the main study consent process, all participants will be offered the opportunity to 
participate in the leukapheresis sub-study. Participants may elect to participate in the sub-
study at screening/enrollment in the main consent  or they may choose to participate later in 
the study and resign a new consent at that time.   
 
Enrollment occurs on the same day as screening. Participants with AHI who are eligible, 
have had the study explained to them and have signed the main study consent will be 
enrolled if therapy is initiated within 30 days of their diagnosis with AHI. Efforts will be 
made to initiate therapy as soon as possible.  
 
The study drug and study commitment will be reviewed at the time of enrollment.  
 
Prior to enrollment the following will be completed: 
 
Depression Assessment (PHQ-9)  
 
Screening Informed consent (completed prior to screening laboratory 
assessments) 
 
Main study Informed Consent  
 
Inclusion/exclusion criteria  
- 
Clinical laboratory evaluations within acceptable parameters 
 
Pending confirmation of HLA and hepatitis B status  
 
Adherence counseling 
 
The date that participants start therapy will be considered study day 0. The participant will 
be considered enrolled on the study the day he/she screens and is sent home with the study 
medications. Should participant test HLA B*57:01 positive, he/she will be terminated from 
the study.  
 
The following procedures and laboratory tests will be completed during the 
screening/enrollment evaluation after the participant has signed all applicable (screening 
and main) informed consents. 
 
 Medical history – inclusive of all concomitant meds within last 30 days. 
 Complete physical examination - inclusive of Vital Signs, height, & weight  
 Acute HIV assessment – questionnaire administered by study coordinator which explores 
HIV and STI testing history, drug and alcohol use and HIV acquisition risk.  
 Depression Assessment (PHQ-9 questionnaire)  
Note: Most participants will have a depression  assessment done as part of the standard initial 
ID clinical evaluation done on the same day as their consent, screening/enrollment.  These 
assessments, done by ID clinic social workers, will be used as the baseline assessment and may 
be obtained prior to the study consent.  
 Females: Serum Pregnancy test 
Note: Pregnancy test must be verified as negative within 72 hours of study entry. 


Page 34 of 72 
 
 Females: FSH level to document menopause  
 Clinical laboratory evaluation or documentation of below within prior 30 days: 
- 
Chemistries – sodium, potassium, chloride, bicarb, gluc, BUN, creatine and creatinine 
clearance 
- 
Hepatic Function Test (or LFTs) – AST, ALT, Alk phos, T. Bili 
- 
Direct bilirubin – obtained at screening only  
- 
Lipase  
- 
CBC with differential 
- 
Lipid, preferred fasting and can be obtained at visit 2 if not fasting at blood draw.  
 Urine Testing  
- 
Urinalysis macro 
- 
GC and CT testing (not required if done within 30 days of visit and documentation 
of results (and treatment, if applicable) available) 
 HIV-1 RNA PCR 
 Lymphocyte Markers (CD4/CD8) 
 HIV-1 Combo Ag/Ab with confirmatory/differential test (if the test is not 
positive, meaning the differential test results are negative or indeterminate, the 
test will be repeated at week 12) 
- 
AHI testing results based on SCO values will be obtained from the 
testing lab at the time of the indeterminate differentiating test result 
and prior to the HIV RNA confirmation test availability.  
- 
AHI criteria based on the use of SCO with 4th generation HIV test 
and/or Geenius HIV-1/HIV-2 Supplemental Assay banding patterns 
can be found in study specific standard operating procedures.  
 HIV Genotype and Integrase Resistance Genotype testing 
 RPR serology (not required if done within 30 days of visit and documentation of results (and 
treatment, if applicable) available) 
 Hepatitis B antibody and surface antigen (HBsAg) 
- 
Results available next business day. 
- 
Refence Appendix 4 - participants given a 7 day starter pack of study 
treatment at enrollment, will be instructed NOT to begin until 
contacted by study staff and notified of a negative result.   
 Hepatitis C antibody test – if positive, reflex to HCV RNA test 
 HLA B57/58 flow cytometry antibody assay  
- 
If the HLA B57/58 flow cytometry assay is negative, the participant 
can be enrolled and immediately start study treatment. 
- 
A positive result on the HLA B57/58 flow cytometry assay will be 
reflexed to a molecular HLA test to specifically detect B*57:01, with 
results anticipated the next business day.  Reference Appendix 4 for 
dispensing study medications. Participants will be given a 7 day starter 
pack of study treatment at enrollment, but instructed NOT to begin 
until contacted by study staff and notified of a negative result.   
 
Research Assay Collections  
- 
HIV-1 T lymphocyte studies and plasma and serum for storage 
 
All participants will be counseled on the signs and symptoms of hypersensitivity associated 
with Abacavir and given the “Alert Card” containing information about this 
hypersensitivity reaction (see Attachment 3). 
 
All persons agreeing to participate in the study and having signed the study consent, will be 
counseled on the practice of safer sexual practices including the use of effective barrier 
methods.  
 
7.1.2. Weeks 2, 8, 16, 36, 60, and 84  
 


Page 35 of 72 
 
The following evaluations will be performed:  
 
Targeted physical exam  
 
For females of child bearing potential (FCBP) – urine pregnancy test and assess 
date of LMP1 and birth control measures2 
 
ART adherence reviewed  
 
Concomitant medications reviewed 
 
Adverse Event Assessment  
 
Research Assay Collections  
- 
HIV-1 T lymphocyte studies & plasma and serum for storage (week 2 
only)  
- 
Single copy assay (week 84 only) 
 
Clinical Laboratory Evaluations  
- 
Serum pregnancy test1 (if >35 days since first day of last menstrual period in 
women pre-menopause) 
- 
HIV-1 RNA PCR 
- 
APTT/PT & INR (at week 36 and week 84 if plan to do leukapheresis optional 
procedures) 
 
¹Females of child-bearing potential will have serum pregnancy testing as 
clinically indicated at any time point during the course of the study through 
Week 96. 
2Females of child-bearing potential (FCBP) will be terminated or withdrawn 
from study if inadequate birth controls measures are assessed or the female 
participant indicates that she changed her mind and would like to be pregnant 
at any time point during the course of the study through Week 96. 
 
7.1.3. Week 4 
 
The following evaluations will be performed: 
 
Targeted clinical exam and physical  
 
ART adherence reviewed  
 
Concomitant medications reviewed 
 
Adverse Event Assessment  
 
Clinical Laboratory Evaluations 
- 
Urine pregnancy test (all FCBP) 
- 
Assess date of LMP and Birth Control Measures  
o 
Serum pregnancy test (if >35 days since first day of last menstrual 
period in women pre-menopause) 
- 
HIV-1 RNA PCR 
- 
Chemistries (sodium, potassium, chloride, bicarb, gluc, BUN and creatinine and creatinine 
clearance) 
- 
LFTs (AST, ALT, Alk phos, T. Bili) 
- 
CBC with diff 
 
7.1.4. Weeks 12, 24, and 72 
 
The following evaluations will be performed: 
 
Targeted clinical exam and physical  
 
ART adherence reviewed  
 
Concomitant medications reviewed 
 
Adverse Event Assessment  
 
Clinical Laboratory Evaluations 
- 
Urine pregnancy test (all FCBP) 
- 
Assess date of LMP and Birth Control Measures  


Page 36 of 72 
 
o Serum pregnancy test (if >35 days since first day of last 
menstrual period in women pre-menopause) 
- 
HIV-1 RNA PCR 
- 
Chemistries (sodium, potassium, chloride, bicarb, gluc, BUN &  creatinine and 
creatinine clearance) 
- 
LFTs (AST, ALT, Alk phos, T. Bili) 
- 
CBC with diff 
- 
Lymphocyte Markers (CD4/CD8) 
 
 
Week 12 only: 
HIV-1 Combo Ag/Ab with confirmatory/differentiating test (only obtained on 
participants who had a negative or indeterminate confirmatory/differentiating 
test at enrollment). The study can perform the HIV1/2 
confirmatory/differentiating without the HIV-1 Comb Ag/Ab test if the Combo 
test was positive at baseline.  
 
 
Weeks 12 and 24 only:  
Research Assay Collections  
- 
HIV-1 T lymphocyte studies, serum and plasma storage 
 
 
Weeks 24 and 72 
Depression Assessment (PHQ-9) 
 
7.1.5. Weeks 48 and 96 
 
The following evaluations will be performed: 
 
Targeted clinical exam and physical  
 
ART adherence reviewed  
 
Concomitant medications reviewed 
 
Depression Assessment (PHQ-9) 
 
Adverse Event Assessment  
 
Clinical Laboratory Evaluations 
- 
Urine pregnancy test (all FCBP)  
- 
Assess date of LMP and Birth Control Measures  
o Serum pregnancy test (if >35 days since first day of last menstrual 
period in women pre-menopause) 
- 
HIV-1 RNA PCR 
- 
Chemistries (sodium, potassium, chloride, bicarb, gluc, BUN & creatinine and creatinine 
clearance and Lipase) 
- 
LFTs (AST, ALT, Alk phos, T. Bili) 
- 
Fasting Lipids  
- 
CBC with diff 
- 
CD4/CD8 
 
Research Assay Collections  
- 
HIV-1 T lymphocyte studies, serum and plasma storage 
- 
Single copy assay (week 96 only) 
 
Optional Procedures:  
- 
Leukapheresis 
 
7.1.6. Weeks 120, 144, 192, 240 
Once participants complete Week 96, they will be followed for up to 3 years. 
Subsequent visits will occur at Weeks 120, 144, 192 and 240. At each visit, 
participants will have research samples collected and the following evaluations will 
be obtained from chart abstraction of the clinical provider’s evaluations done 
during the window period of the visit:  


Page 37 of 72 
 
 
Update medical history documenting new diagnosis since the last clinical 
appointment.  
 
Update concomitant medications to include all meds taken at the time of the 
office visit or within the last 30 days, if available.  
 
Update ART medication Note all ART changes along with the date and reason 
for the change.  
 
Adverse Event Assessment per longitudinal follow-up (see protocol section 
8.2.13.1)  
 
Obtain medical release, as necessary, for participants who have medical care 
provided outside the UNC or Duke Hospital Centers. 
 
Clinical Laboratory Evaluations - collect as part of study to supplement clinical 
assessment. If already drawn as part of the provider visit, do not repeat. Use the 
values obtained at the clinical visit.  
- 
HIV-1 RNA PCR 
- 
CBC with diff 
- 
CD4/CD8 
 
Research Assay Collections  
- 
HIV-1 T lymphocyte studies, serum and plasma storage 
 
 
7.2. 
Optional Procedures   
 
Due to practical considerations, leukapheresis procedures to collect specimens will be 
optional for enrollees, and performed as agreed upon by each individual participant. Efforts 
will be made to obtain consent for both leukapheresis procedures as possible, and to 
perform both on at least 10 participants. Once optional leukapheresis procedure have been 
completed on at least 10 participants, each additional participant (above the initial 10) who 
agrees to these optional procedures will be explained that some or all of the procedures may 
not be performed since collection of the samplemay not provide information to change or 
impact the study and thus justify them undergoing the risk of the procedure. 
 
Participants will be asked to participate in the following optional sub-study: 
 
7.2.1. Leukapheresis 
The first leukapheresis sample will be obtained between weeks 36-48, preferably as 
close to week 48 as possible and the participant must have an undetectable HIV-
RNA. The second time point will occur between weeks 84-96, preferably as close 
to week 96 as possible. For the second time point, participants must have an 
undetectable HIV-1 RNA.  
 
 
Additional criteria for leukapheresis: 
- 
Prothombin time (PT): < 1.2 x ULN 
- 
Partial thromboplastin time (APTT): < 1.5 x ULN 
- 
Platelets: > 100,000/mm3 
- 
Adequate venous access 
 
7.3. 
Screen Failures 
 
Participants can have abnormal labs repeated once to be eligible for study participation.  
 
Participant with a positive HLA B*57:01 PCR-SSP or Hepatitis B test will be terminated 
from study. These participants would not be considered screen failures as they were 
enrolled pending these results.  
 


Page 38 of 72 
 
7.4. 
Study Treatment Stopping Rules 
 
7.4.1. HLA B*57:01 or Hepatitis B surface antigen positive  
Any enrolled participant found to be positive for the HLA B*57:01 allele or for 
Hep B sAg will be terminated from the study prior to starting study treatment, and 
will be prescribed another ART regimen. This regimen would not be covered by 
the study and would be the responsibility of the participant. This participant would 
not be allowed to continue on the study and would be replaced. This participant 
would be asked to return the 7 day supply of study treatment administered while 
confirmation of HLA B*57:01 and hepatitis B status was pending and would be 
referred for initiation of ART per routine clinic procedures. 
 
7.4.2. Baseline Resistance 
Any enrolled acutely infected participant with evidence of baseline resistance will 
be continued on study and ART optimized using genotype results. Descriptive 
results will be reported but will not be included in the efficacy portion of the data 
analysis. 
 
7.4.3. Potential Hepatotoxicity 
Stopping criteria for elevated transaminases are delineated below. 
 
 
ALT ≥3XULN and bilirubin ≥2xULN (>35% direct bilirubin; bilirubin 
fractionation required) 
 
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 with symptoms or worsening of acute hepatitis or 
hypersensitivity such a 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; 
Participants with ALT ≥5xULN should be followed weekly until resolution or 
stabilization (ALT <5xULN on 2 consecutive evaluations). 
When liver chemistry stopping criteria above is met, do the following: 
- 
Immediately discontinue DTG and withdraw the participant from the study. 
Participants should not restart DTG due to the risk of a recurrent reaction. 
Report the event to the study sponsor within 24 hours of learning its 
occurrence.  
- 
Make every reasonable attempt to have the participants return for evaluation 
within 24 hours for repeat chemistries and evaluation; 
- 
Consider a hepatology consultation 
- 
Monitor participants twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline value 
In the event that liver stopping criteria are met, the PI will consider the 
following additional tests to further evaluate the liver event. However any 


Page 39 of 72 
 
additional evaluations will be charged to the participant or the participants 
health care insurance: 
- 
Viral hepatitis serology including: 
a) 
Hepatitis A IgM antibody; 
b) 
HBsAg and Hepatitis B Core antibody (IgM) 
c) 
Hepatitis C RNA; 
d) 
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) 
- 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
- 
Fractionate bilirubin, if total bilirubin is > 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 computerized 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, or 
other over the counter medications or putative hepatotoxins at every study visit 
to monitor elevated ALT/AST. 
 
7.4.4. Virologic Failure  
For the purpose of clinical management in this study, virologic failure must be 
confirmed by a repeat and consecutive plasma HIV-1 RNA measurement between 
one to four weeks after the initial suspected virologic failure sample. 
 
Individual participants who meet the VF definition will be continued on study 
follow-up as per protocol, will have therapy optimized or discontinued per best 
clinical practice, and may continue on study therapy if clinically indicated. ART-
adherent participant is defined as a participant that has ≥ 95% adherence by pill 
counts. 
 
The following guidelines will be followed for scheduling confirmatory HIV-1 RNA 
testing in the setting of concurrent illness, immunization within the prior 4 weeks 
or ART interruption (per below) in an effort to avoid false-positive results: 
 
Confirmatory testing should be scheduled 2-4 weeks following resolution of 
any intercurrent illness. 
 
Confirmatory testing should be scheduled at least 4 weeks following any 
immunization. 


Page 40 of 72 
 
 
If therapy is interrupted due to toxicity management, non-compliance, or other 
reasons, confirmatory testing should be scheduled 2-4 weeks following 
resumption of full dose of study medication. 
 
7.5. 
Early Discontinuation or End of Study 
Participants who do not complete at least the first 12 weeks of the study will be replaced.  
 
Participants who elect to terminate the study at any time after 12 weeks of therapy, but 
before the week 96 visit, will have a study termination visit completed which will be 
identical to the week 96 visit as outlined in the SOE. 
 
Participants will be terminated from the study if they are positive for HLA B57/58 or 
Hepatitis B.  
 
7.6. 
Withdrawal of a Participant from Study  
Participants will be withdrawn from further study evaluations for any of the following 
reasons: 
 
Withdrawal of informed consent (participant’s decision to withdraw for any 
reason) 
 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in 
the opinion of the investigator, indicates that continued study treatment and 
participation in the trial is not in the best interest of the participant. 
 
Participants who become prisoners or become involuntarily incarcerated for 
treatment of either a psychiatric or physical (e.g. infectious disease) illness. 
 
Pregnancy or females of reproductive potential who changed their minds and 
desire to be pregnant  
 
Requires the use of long-term, unacceptable concomitant medications. 
 
Gross noncompliance with administration of the study medication(s) or with 
completion of protocol procedures such that reliable safety assessments (clinical 
and laboratory) are jeopardized. 
 
Confirmed virologic failure (VF) as defined in section 5.1.3 
 
Confirmed creatinine clearance (Cockcroft-Gault formula) below 50 mL/min 
while on treatment. 
- 
Due to required dose reduction of 3TC due to decreased clearance. 
 
7.7. 
Reimbursement  
For each study visit, participants will receive a stipend to help cover travel costs.  For 
participants co-enrolled on other studies with study visits occurring at the same time as this 
study, the participant will receive compensation once for travel. If the participants receive 
their travel reimbursement from the other study, they will receive a stipend at the visits that 
immunology labs are collected specifically for analysis on this study (weeks 0, 12, 24, 48,  
and 96). 
 
Participants will receive an additional stipend when they participate in the optional 
leukapheresis procedure. 
 
7.8. 
Treatment at the End of the Study 
Following Week 96 all participants will need to make alternative arrangements for 
independent access to all other antiretroviral therapy. 
 
7.9. 
Description of Evaluations 
 
7.9.1. Clinical Evaluations and Procedures 


Page 41 of 72 
 
Participants will be evaluated by physical examinations, medical history, clinical 
laboratory tests, vital sign measurements, and AE evaluations.  Safety assessments 
will include grading of the frequency and severity of AEs associated with the 
treatment including clinical laboratory values. Participants and/or their primary 
care provider will be informed of any clinically significant laboratory test result or 
clinical event that occurs throughout the study.  Participants will be referred for 
care where appropriate. Clinical labs will be collected and processed at UNC 
McLendon Lab, UNC CFAR HIV/STD Laboratory Core (CHSLC), Duke Hospital 
Lab, or Lab Corp.  
 
 
 
Informed Consent  
Prior to performing any study-related procedure or assessments, the study 
coordinator will discuss the study with the potential participant and obtain 
signed informed consent.  This communication should be documented. 
 
 
Completed medical histories 
Medical histories will be obtained at screening and should include demographic 
information (date of birth, gender, race, ethnicity), participant’s medical 
history, and medication history. 
 
 
Updates to medical histories at all clinical visits 
 
 
Complete Physical Exams 
A complete physical examination (PE) is done at the following visits:  
- 
Screening  
- 
Early Termination 
- 
Week 96 or End of Study (EOS)  
The PE will include a complete review of systems, vital signs, and weight.  
Height will be measured at the Screening Visit only.  The complete physical 
exam also includes signs and symptoms, and diagnoses. 
 
 
Directed or targeted medical histories and physical exams 
A targeted physical examination is done at all other designated visits and 
includes vital signs and is to be driven by any previously identified or new 
event that the participant has experienced since the last study visit or any 
unresolved signs or symptoms experienced previously.  This assessment will 
include weight, vital signs, a signs and symptoms update, and clinical 
assessment of HIV disease. 
 
 
Vital Signs - Temperature, respiration, pulse, and blood pressure and weight at 
each study visit.  
 
 
Height - Required at study screening visit only 
 
 
Concomitant Medication History 
- 
Include all current medications and any PRN medications used within 
the past 30 days.  
- 
All medication, over the counter (OTC) and herbal supplements taken 
within 30 days of study entry  
- 
After study entry, only new and discontinued prescription medications 
will be recorded.  
 
 
Signs, symptoms and diagnosis of illnesses and disease 


Page 42 of 72 
 
- 
At entry, record all grades of signs and symptoms that occurred 30 
days prior to study entry.  
- 
After study entry, grade ≥3 signs and symptoms must be recorded. 
- 
Record all signs and symptoms that lead to a change in treatment, 
regardless of grade. 
 
 
Blood Collection - Please reference SOE. 
 
 
Acute HIV Assessment.  
The study coordinator will administer this IRB approved assessment to 
participants at the enrollment visit and/or Week 2 visit (if unable to complete at 
enrollment). This assessment will be completed as close as possible to 
enrollment and will assess participant demographics, risk associated with HIV 
acquisition, and sexual, alcohol and drug preferences and usage in relation to 
date of HIV acquisition.  
 
 
Depression Assessment  
Participants will be assessed every 6 months for depression as well as suicidal 
thoughts or ideation. The PHQ-9 form will be used to document the 
assessment. This form is completed at the initial clinical evaluation by the ID 
clinic social worker. The study coordinator will administer this form every 6 
months while a participant is on study. The PHQ-9 form will be reviewed by 
the study PI. Any changes in the PHI-9 assessment that indicate the 
development of depression, increased severity of depression or suicidal 
thoughts will be addressed immediately with the study PI and the participant’s 
primary ID provider in collaboration with other necessary psycho-social 
counselors per established protocol for management of suicidality/severe 
depression in the UNC ID Clinic.  
 
 
Assessment of Adverse Events - Please reference protocol section 8.2. 
 
 
Assessment of Pregnancy Status which includes the date of last menstrual 
period (LMP) and birth control measures. Women with > 35 days since the 
LMP will have a serum pregnancy test done to confirm negative status.  
 
POCT urine pregnancy test will be completed at all study visits.  
 
Female participants indicating that they changed their mind and desire to 
become pregnant will be withdrawn from the study.  
 
 
HLA B57/58 flow cytometry assay 
In order to allow prompt initiation of DTG/3TC/ABC FDC, we will employ a 
flow cytometry assay using an HLA-B57/58 reactive monoclonal antibody as a 
screening test.  This assay has been validated for this study in the UNC Center 
for AIDS Research (CFAR) HIV/STD Laboratory Core (CHSLC). 
  
A negative result will be reported negative for HLA-B57, and the individual 
may enroll on study and start treatment. 
  
A positive HLA-B57 result will be reflexed to a molecular HLA test to 
specifically detect B*57:01, with results available same day or next business 
day (if received in lab after 11:00am).  The confirmatory molecular HLA test 
will confirm if reactivity in the flow cytometry assays is due to the presence of 
HLA-B*57:01 or to other cross-reactive HLA alleles.  Studies have reported a 


Page 43 of 72 
 
prevalence of the HLA-B*57:01 allele of 5-6% among HIV-infected 
patients [40, 41].  Because of cross-reactivity, confirmatory testing will be 
required in a few more individuals than the expected 1-3 B*57:01 positive 
participants during the study. 
 
 
Longitudinal follow-up will include an extended study schedule:  
 
Study research sample collection and abstracted medical record updates for 
PHI 05 participants will be extended to 5 years in accordance with the 
following schedule: 
 
 
Week 120 
(2.5 years) 
Week 144 
(3 years) 
Week 192 
(4 years) 
Week 240 
(5 years) 
Clinical Updates  
Blood collection for: 
X 
X 
X 
X 
 - CD4 count 
X 
X 
X 
X 
 - HIV viral load 
X 
X 
X 
X 
 - Immune Assays 
X 
X 
X 
X 
Note: The clinical labs for CD4 and HIV RNA PCR values can be obtained 
from medical record if clinical appointment is done separately from the 
research collection. The clinical labs need to be obtained within the study 
visit window. 
 
 
Leukapheresis  
This is an optional sub-study. Participants can undergo 2 resting cell 
assessment leukaphereses at one of the following locations: 1) the UNC’s 
Apheresis Lab located on the 1st floor of UNC Hospitals, or 2) the American 
Red Cross (ARC) Apheresis Lab located in Durham, NC. Participant’s enrolled 
at Duke University will have the procedure completed in the Apheresis Lab 
located at Duke University.   
 
These optional leukapheresis products will be transported on the day of 
collection to the Margolis Laboratory on the UNC campus.   
 
Leukapheresis is a procedure in which white blood cells are donated for 
research. Only white blood cells are removed in this process, and red blood 
cells and blood plasma (liquid) is not removed. During leukapheresis, the 
blood is removed through a needle inserted in a vein in one arm and it will 
pass through sterile disposable centrifuge tubing to a leukapheresis 
machine, which separates blood into plasma, red blood cells, platelets and 
white blood cells. The red cells and most of the plasma will be returned 
through a needle in the other arm or to the same arm, a total loss of red blood 
cells of only 15 mL. White cells, some platelets and a small amount of 
plasma will be retained for use in research. Each donation takes between 2 
to 4 hours. The mild reduction in white blood cell and platelet counts is 
only temporary and is not hazardous to the participant’s health. No sedation 
is required with this procedure 
 
Note: Refer to the UNC Apheresis or the ARC SOPs and Study Specific Lab 
Manual for procedures specific to this study.  
 
Participants who experience a Grade 3 or higher toxicity related to the first 
leukapheresis procedure at Week 48, will not be asked to complete the 2nd 
procedure at Week 96 of the study. The exception would be in the case of ≥ 


Page 44 of 72 
 
Grade 3 blood pressures (BP). Elevated BP observed during the leukapheresis 
procedure will be monitored via Apheresis Lab policies. These will be noted and 
documented but Grade 3 or higher BPs will not be used to discontinue study 
participation from a future leukapheresis as Grade 2 and 3 BPs are frequently 
observed during this procedure secondary to the BP cuff placement and 
nervousness of the participant.   
 
7.9.2. Clinical Laboratory Evaluations 
Labs utilized for the clinical evaluations will be UNC McLendon Lab or LabCorp 
with HLA testing conducted in the UNC CFAR HIV/STD Laboratory Core 
(CHSLC). Details of specimen collection are found in the Lab Procedures Manual 
for this study.  
 
The results of clinical laboratory tests will be assessed by the investigator to 
determine the participant’s continuing eligibility at specified visits. If values are 
outside the normal reference range, the investigator will determine whether or not 
the abnormal value is clinically significant. All confirmed abnormal laboratory 
values that the investigator deems clinically significant must be reported as AEs. 
Participants and/or their primary care provider will be informed of any clinically 
significant laboratory test result or clinical event that occurs throughout the study. 
Participants will be referred for care where appropriate. 
 
 
Clinical Chemistries 
Includes sodium, potassium, chloride, bicarb, glucose, BUN, creatinine, 
and creatinine clearance.  Lipase will be done a screening and weeks 48 
and 96. 
 
 
Hepatic Function Tests  
Includes ALT, AST, alkaline phosphatase and total bilirubin. A direct 
bilirubin will be done at screening only.  
 
 
Hematology 
CBC with WBC differential 
 
 
Fasting Lipids  
 
 
Prothrombin time (PT) and PTT, and INR 
Evaluation based on selection of optional procedure(s) and performed at or 
around the Week 36 and 84 Visit. 
 
 
HIV EIA Combo Ag/Ab Testing with differentiating/confirmatory test 
This testing will be repeated at Week 12 if the differentiating/confirmatory 
test is not positive at enrollment visit. It is not required to repeat the HIV 
EIA Ag/Ab test if positive at enrollment. 
 
 
HLA B57 Assays 
Peripheral blood samples collected in EDTA will be screened for HLA-
B*57:01 using a flow cytometry assay with a HLA-B17 specific 
monoclonal antibody.  In this assay, cells are stained with monoclonal 
antibodies to CD3-APC and HLA-B17-biotin.  After incubation and lysis 
of red blood cells, streptavidin –PE is added.  After an additional wash and 
paraformaldehyde fixation, CD3 positive T cells are assessed for 
expression of HLA-B17 related HLA antigens.   
 


Page 45 of 72 
 
HLA-B*57:01 (a B17 related HLA molecule) is excluded if no B17 
staining is observed.  Samples that demonstrate HLA-B17 antibody 
binding will be reflexed for further testing on the same day with an HLA-
B*57:01 PCR-SSP assay to determine if HLA-B*57:01 is present or if 
positive staining is due to a cross-reactive (related) HLA antigen (such as 
B58 or B*57:03).  Results from the HLA-B*57:01 PCR-SSP assay would 
be available same day if samples are received early in the day, or on the 
next business day. 
 
 
HIV RNA 
Performed at all study visits.  
 
 
CD4+ T cell differential panel 
 
 
FSH Level – follicle stimulating hormone level will be done on all women 
at screening who indicate menopause per definition in 5.2.7. 
  
 
Serum pregnancy test 
For females of child bearing potential, ascertainment of a negative result 
will be required for study enrollment and at any visit if pregnancy is 
suspected. Documentation of the date of last menstrual period (LMP) 
required at all study visits through Week 96 to rule out suspicion of 
pregnancy. Additionally, review and documentation of birth control 
methods will be done at each study visit through Week 96. 
 
 
POCT urine pregnancy  
For FCBP, this test will be performed at each study visit. Serum pregnancy 
test will be performed at any visit where pregnancy is suspected.  
 
 
Hepatitis B antibody and surface antigen (HBsAg) at screening 
 
 
Hepatitis C antibody test – reflex HCV RNA if positive at screening 
 
Labs that are abnormal and meet grading standards per DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014, will be 
reassessed.  
 
Labs utilized for the clinical evaluations will be performed at the Duke University Lab, 
UNC McLendon Lab or LabCorp. 
 
Blood collected for research will be studied primarily at one of the following 
laboratories: Margolis Lab, Goonetilleke Lab,  and UNC CFAR HIV/STD Laboratory 
Core (CHSLC). 
 
These research laboratory evaluations include:   
 
HIV-1 infection of resting CD4+ T cells, VIA, and Latency Clearance 
Assay; 
 
CD4/CD8 Immunology Processing; 
 
Single Copy HIV RNA Assay; 
 
HIV-1 T-Cell Lymphocyte Studies. 
 
7.10. 
Stored Samples 
 


Page 46 of 72 
 
A separate IRB application will be submitted for future analysis involving these blood 
samples.  These stored samples will only be used for research including genetic studies of 
the stored samples, after specific further review and approval by the UNC IRB. 
 
Stored Specimens  
Any remaining specimens that will be stored for future research will be stored safely and 
securely in a research specimen storage laboratory at the University of North Carolina at 
Chapel Hill (UNC-CH).  No protected health information (PHI) is included with the 
samples.  The samples will be identified by coded number to maintain participant 
confidentiality.  The link between Participant Identifier Code (PID) on the samples and PHI 
is maintained in a secured file on a secured server in the control of the principal investigator 
at UNC-CH.  Future researchers would not have access to this link.  Only study personnel, 
people who work at the research specimen storage laboratory at UNC-CH and IRB 
approved researchers will have access to the participants’ samples.  Since all the stored 
specimens are de-identified, the people who work at the research specimen storage 
laboratory will not have any personally identifying information that would link to a 
participant.  The researchers who receive the specimens may receive   information 
pertaining to lab assay values, age, and sex of the specimen donor, but will not be given the 
name or any other information that identifies the participant.  These samples will be stored 
indefinitely. 
 
 
8. CLINICAL MANAGEMENT ISSUES 
 
8.1. 
Toxicity 
 
Only toxicities considered to be possibly, probably or definitely related to DTG/ABC/3TC 
FDC will be managed directly by this protocol.  
 
8.2. 
Toxicity Management  
Adverse events that occur during the trial should be evaluated by the Investigator or their 
designee.  The grading system for drug toxicities is located in the U.S. Department of 
Health and Human Services, National Institutes of Health, National Institute of Allergy and 
Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.0. [November 2014], which can 
be found on the DAIDS RSC Web site:  
http://rsc.tech-res.com/safetyandpharmacovigilance/.   
 
Additional information regarding detecting, documenting and reporting AEs and SAEs 
are available in Section 8.2.2. 
 
NOTE: In the event of a discontinuation of DTG/ABC/3TC FDC for any reason, re- 
initiation of this drug should be undertaken with caution. The investigator or their designee 
must obtain a complete history of the events surrounding the discontinuation of 
DTG/ABC/3TC FDC, evaluate for the possibility of a clinically suspected hypersensitivity 
reaction (HSR), and initiate participant management as outlined below, regardless of a 
participant’s HLA-B*5701 status. 
 
8.2.1  Grade 1 or Grade 2 Toxicity/Adverse Event 
 
Participants who develop a Grade 1 or Grade 2 AE or toxicity may continue study 
medication at the discretion of the Investigator or their designee. (NOTE: see Section 
6.4.5 “Specific Toxicities/Adverse Event Management” for exceptions to this 


Page 47 of 72 
 
guideline). Participants who choose to withdraw from study due to a Grade 1 or 2 AE 
should have study withdrawal and follow-up evaluations completed. 
 
8.2.2   Grade 3 Toxicity/Adverse Event 
 
Participants who develop a Grade 3 AE or toxicity should be managed as follows: 
 
If the Investigator or their designee has compelling evidence that the Grade 3 AE or 
toxicity has not been caused by the study medication, dosing may continue after 
discussion with the study management team.  
 
Participants who develop a Grade 3 AE or toxicity, which the Investigator or their 
designee considers related or possibly related to the study medication, the 
medication should be withheld and be rechecked each week until the AE returns to 
Grade 2. Once the AE is Grade ≤2, study drug  may be re-started, with the exception 
of suspected HSR due to abacavir. 
 
Should the same Grade 3 AE recur within 28 days in the same participant, the study 
drug should be permanently discontinued and the participant withdrawn from study. 
Participants experiencing Grade 3 AEs requiring permanent discontinuation of the 
study drug 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 the study medication. 
 
Participants with Grade 3 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion with 
the study management team, may continue the study drug if the Investigator or their 
designee has compelling evidence that the toxicity is not related to the study 
medication. 
 
Exceptions are noted below for lipid abnormalities. 
 
8.2.3 Grade 4 Toxicity/Adverse Event 
 
Participants who develop a Grade 4 AE or toxicity should have the study drug 
permanently discontinued. However, if the Investigator has compelling evidence 
that the AE is not causally related to the study drug, dosing may continue after 
discussion with and agreement from the study management team. Participants 
should be rechecked each week until the AE returns to Grade 2. 
 
Participants experiencing Grade 4 AEs requiring permanent discontinuation of study 
drug should be followed weekly until resolution of the AE and encouraged to 
complete the withdrawal and follow-up study evaluations as noted above. 
 
Participants with Grade 4 asymptomatic laboratory abnormalities should be 
investigated for all potential non-drug related causes, and, following discussion with 
the study management team, may continue therapy if the Investigator has 
compelling evidence that the toxicity is not related to the study drug. Exceptions are 
noted below for lipid abnormalities.  
 
A follow-up visit should be performed 4 weeks after the last dose of study 
medication if AEs or laboratory abnormalities are ongoing. 
 
8.2.4 Specific Toxicities/Adverse Event Management 


Page 48 of 72 
 
 
General guidelines for the management of specific toxicities that are considered to 
be related or possibly related to IP are provided below. Toxicities that the 
Investigator considers related or possibly related to one of the background ART 
medications may be addressed by substitution of the medication for another 
approved HIV medication. 
 
The DTG/ABC/3TC single tablet FDC contains DTG, ABC and 3TC; therefore the 
adverse events associated with these individual components may be expected. For 
many of the adverse events listed it is unclear whether they are related to the active 
substance, the wide range of other medicinal products used in the management of 
HIV infection, or whether they are a result of the underlying disease process. 
 
Participants who permanently discontinue study medications for reasons of toxicity 
should be followed weekly until resolution of the AE and encouraged to complete 
the withdrawal and Follow-Up study evaluations. 
 
8.2.5 
Hypertriglyceridemia/Hypercholesterolemia 
 
Participants who experience asymptomatic triglyceride or cholesterol elevations 
may continue to receive study medications. A confirmatory fasting triglyceride 
and/or cholesterol level should be obtained prior to the institution of medical 
therapy for hyperlipidemia. 
 
8.2.6 
Lipase Elevations and Pancreatitis 
 
Participants with asymptomatic Grade 1 or 2 elevations in lipase may be followed 
closely for the development of symptoms.  
 
Participants with asymptomatic Grade ≥3 elevations in lipase that are considered 
possibly or probably related to the study drug should have the study drug 
interrupted until serum lipase returns to Grade ≤2. Repeat lipase testing within 2 
weeks of any Grade ≥3 result. Participants with persistence of Grade ≥3 lipase in 
the absence of other diagnoses or reoccurrence of lipase elevation (at Grade ≥2) 
following reintroduction of the study drug should permanently discontinue the 
study drug. 
 
The study drug should be held in all participants with a confirmed diagnosis of 
clinical pancreatitis that is considered possibly or probably related to the study 
medication. After complete resolution of the episode, participants may be re-
challenged with the study drug, only if the Investigator has compelling evidence 
that the event was not caused by study drug. Upon rechallenge, 
lipase determinations should be performed every 2 weeks for at least 6 weeks 
after re-initiation of treatment. With any elevation of lipase of Grade ≥2 or any 
recurrence of symptoms, the participant should discontinue study drug and be 
withdrawn from study. 
 
8.2.7 
Decreased Renal Function 
 
Participants who have a decline in creatinine clearance of >50% must return for a 
confirmatory assessment as soon as possible.  
 


Page 49 of 72 
 
If development of a creatinine clearance measuring <50 mL/min via Cockroft-
Gault method, participant must return for a confirmatory assessment as soon as 
possible.  
 
8.2.8 
Allergic Reaction 
 
Participants may continue study drug for Grade 1 or 2 allergic reactions at the 
discretion of the Investigator. The participant should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further 
systemic signs or symptoms develop. Antihistamines, topical corticosteroids, or 
antipruritic agents may be prescribed. 
 
Participants with Grade ≥3 allergic reactions that are considered to be possibly or 
probably related to the study drug should permanently discontinue the medication 
regimen and the participant may continue on study off study drug. Participants 
should be treated as clinically appropriate and followed until resolution of the AE. 
 
Participants should be managed in terms of a clinically suspected ABC 
Hypersensitivity.  
 
8.2.9 
Abacavir Hypersensitivity Reaction (HSR) 
 
The most significant toxicity associated with ABC is the well-characterized drug-
related hypersensitivity.  
 
The diagnosis of HSR to ABC remains a clinical diagnosis. There is no 
pathognomonic clinical sign or laboratory finding that renders the diagnosis.  In 
clinical studies, approximately 5-6% of participants receiving ABC develop an 
HSR that in rare cases has proved fatal. HSR is characterized by the appearance of 
symptoms indicating multiorgan/body system involvement.  
 
Symptoms usually appear within the first 6 weeks of starting treatment with ABC 
(median time to onset is 9 days), but may occur at any time while on therapy. 
 
Symptoms most often include fever, rash, gastrointestinal symptoms (nausea, 
vomiting, diarrhea, or abdominal pain), respiratory symptoms (dyspnea, sore throat, 
cough), and lethargy or malaise.  Other signs and symptoms may include 
musculoskeletal symptoms (myalgia, rarely myolysis, arthralgia), headache, 
paresthesia, and edema. Respiratory tract symptoms (dyspnea, sore throat, cough) 
have been observed in approximately 20% of participants who experience HSR. 
Some participants with HSRs were initially thought to have respiratory tract disease 
(pneumonia, bronchitis, pharyngitis) or a flu-like illness.  
 
Physical findings may include lymphadenopathy and, occasionally, mucous 
membrane lesions (conjunctivitis and/or mouth ulceration). The rash is variable and 
may be absent, but often appears maculopapular or urticarial. Laboratory 
abnormalities that may accompany ABC hypersensitivity include elevated 
transaminases, CK, or creatinine or lymphopenia. 
 
The misattribution of the symptoms of HSR to another medical condition or delay 
in diagnosis of hypersensitivity has resulted in ABC being continued or 
reintroduced, leading to more severe presentation or rapid (within hours) onset of 
HSR or death. Therefore, the diagnosis of HSR should be carefully considered for 
participants presenting with symptoms of these diseases, even if another medical 


Page 50 of 72 
 
diagnosis seems likely. Reintroduction of ABC in participants after treatment 
interruption, with no preceding symptoms of HSR, has rarely resulted in HSR. 
 
Symptoms related to HSR worsen with continued therapy and usually resolve upon 
discontinuation of ABC. Restarting ABC following an HSR results in a prompt 
return of symptoms within hours. This recurrence of the HSR may be more severe 
than on initial presentation and may include life-threatening anaphylaxis; 
hypotension; liver, renal and respiratory failure; and death. Participants who 
develop an HSR must discontinue ABC and MUST NOT be rechallenged with 
ABC. 
 
Management of HSR 
 
In any participant treated with ABC, the clinical diagnosis of suspected HSR (as 
detailed in the Local Country Prescribing Information) must remain the basis of 
clinical decision making. Regardless of HLA-B*5701 status, it is important to 
permanently discontinue ABC and not re-challenge with ABC (i.e., 
DTG/ABC/3TC, ZIAGEN™, EPZICOM/KIVEXA™ or TRIZIVIR™) if a HSR 
cannot be ruled out on clinical grounds, due to the potential for a severe or even 
fatal reaction. 
 
Symptoms usually start to resolve (within 24 hours) after stopping therapy. 
Symptomatic support, such as intravenous fluids for those who develop 
hypotension, is advised. There are no clinical data demonstrating the benefit of 
antihistamines or corticosteroids in the management of hypersensitivity. 
Nevertheless, symptomatic and/or supportive treatment may be reasonable.  
Laboratory and other investigations which may be useful in the evaluation and 
treatment of ABC HSR include, but may not be limited to, measurement of ALT, 
AST, creatinine phosphokinase, serum creatinine, white blood cell differential 
count, and chest x-ray, if respiratory symptoms are present.   
 
In order to avoid restarting the ABC-containing product, participants who have 
experienced an HSR reaction should be asked to return the remaining tablets to the 
pharmacy.   
 
Participants who have had an HSR must be advised to never take an ABC-
containing product (Ziagen®, Trizivir®, or the ABC/3TC fixed-dose combination).  
ABC therapy SHOULD NOT be restarted following a HSR, because more severe 
symptoms will occur within hours and may include life-threatening hypotension 
and death. Fatal HSRs have been associated with re-initiation of ABC therapy.  
Participants who develop signs or symptoms of HSR, MUST contact their doctor 
immediately for advice.  The site investigator must be notified and provide sign-off 
for those participants who discontinue ABC due to HSR.   
 
Study Drug will be held for all incidences of suspected ABC HSR. 
  
 
8.2.10 Skin reactions without other symptoms typical of ABC HSR 
 
Participants should be instructed to contact the Investigator or study coordinator as 
soon as possible if they develop a rash while on study. 
 
Participants who develop rash of any grade should be evaluated for the possibility 
of an ABC HSR or a serious skin reaction such as Stevens-Johnson Syndrome 
(SJS), Toxic Epidermal Necrolysis (TEN) or Erythema Multiforme. SJS, TEN and 


Page 51 of 72 
 
Erythema Multiforme have been reported very rarely in patients taking ABC-
containing products. These patients generally do not have the cluster of additional 
symptoms (e.g., gastrointestinal and respiratory) that characterize the ABC HSR, 
but they do have features typical of these serious skin reactions. 
 
If a serious skin reaction develops, the study drug (and / or all other concurrent 
medication(s) suspected in the Investigators causality assessment) should be 
discontinued, and the participant should not be re-challenged with any ABC-
containing medicinal product (i.e. ZIAGEN, TRIZIVIR, EPZICOM or KIVEXA). 
 
The following guidance is provided for clinical management of participants who 
experience rash alone in the absence of accompanying diagnosis of ABC HSR, 
systemic or allergic symptoms or signs of mucosal or target lesions. 
 
 
Participants with an isolated Grade 1 rash may continue the study drug at 
the Investigator’s discretion. The participant should be advised to contact 
the Investigator immediately if there is any worsening of the rash, if any 
systemic signs or symptoms worsen, or if mucosal involvement develops. 
 
Participants may continue study drug for an isolated Grade 2 rash. 
However, the study drug (and all other concurrent medication(s) suspected) 
should be permanently discontinued for any Grade ≥2 rash that is 
associated with an increase in ALT. The participant should be advised to 
contact the physician immediately if rash fails to resolve (after more than 
two weeks), if there is any worsening of the rash, if any systemic signs or 
allergic symptoms develop, or if mucosal involvement develops. 
 
Participants should permanently discontinue the study drug (and all other 
concurrent medication(s) suspected) for an isolated Grade 3 or 4 rash, and 
the participant should be withdrawn from the study. Participant 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 8.2.2) and appropriate toxicity ratings should be used to grade the events. 
 
If the etiology of the rash can be definitely diagnosed as being unrelated to  the 
study drug and due to a specific medical event or a concomitant non-study 
medication, routine management should be performed and documentation of the 
diagnosis provided. 
 
8.2.11 Adverse Events (AEs) 
 
Reports of AEs will be elicited by verbally questioning the participant at all visits.  
The study coordinator will also telephone the participant approximately 2 to 3 days 
after initiation of medications.  The participant will be instructed to contact the 
study coordinator or investigator if such events occur at any point during the study. 
 
Any events spontaneously reported by the participant or observed by the study 
team will be recorded.  
 
If an AE occurs, the study coordinator, in collaboration with the investigator or 
their designee, will evaluate the severity and seriousness of the AE and the 
relationship to the study product, and will document the findings as outlined in 
section 8.2.5.  Appropriate countermeasures, including medical intervention or 
procedures, must be instituted if indicated clinically. 
 


Page 52 of 72 
 
All reactions will be graded according to the U.S. Department of Health and 
Human Services, National Institutes of Health, National Institute of Allergy and 
Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0. 
[November 2014]. Available from: 
http://rsc.techres.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRAD
ING_TABLE_v2_NOV2014.pdf    
 
 
 
8.2.12 Definition of an Adverse Event 
 
An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product that does not necessarily have a causal relationship with the 
treatment. 
 
An AE can therefore be any unfavorable or unintended sign (including an abnormal 
lab finding, for example), symptom, or disease temporally associated with the use 
of a study drug, whether or not considered related to the study drug. 
 
1. An AE does include a/an 
 
Exacerbation of a pre-existing illness; 
 
Increase in frequency or intensity of a pre-existing episodic event 
or condition; 
 
Condition detected or diagnosed after study product administration 
even though it may have been present prior to the start of the study; 
and  
 
Continuous persistent diseases or symptoms present at Baseline 
that worsen following the start of the study  
 
2. An AE does not include a/an: 
 
Medical or surgical procedure (e.g., surgery, endoscopy, tooth 
extraction, transfusion); however, the condition that led to the 
procedure is an AE; 
 
Pre-existing diseases or conditions present or detected at the start 
of the study that do not worsen; 
 
Situations where an untoward medical occurrence has not occurred 
(e.g., hospitalizations for cosmetic elective surgery, social or 
convenience admissions); 
 
The disease or disorder being studied or sign or symptom 
associated with the disease or disorder unless more severe than 
expected for the participant’s condition; and 
 
Overdose of either the study medication or concurrent medications 
without any signs or symptoms. 
 
3. Recording the AE 
In general, abnormal laboratory findings (e.g., clinical chemistries, 
hematology, urinalysis) or abnormal assessments (e.g., vital signs, EKGs) 
are not recorded as AEs unless they are considered clinically significant by 
the investigator.  If an abnormal lab finding is considered clinically 
significant, it must be recorded in the AE log as: 
 
If it contributes to a clinical diagnosis, the diagnosis must be 
recorded as the AE (e.g., a clinically significant elevation in blood 


Page 53 of 72 
 
glucose must be recorded as “diabetes” if a clinical diagnosis is 
made); OR 
 
If an abnormal finding does not indicate a clinical diagnosis, the 
abnormality itself must be recorded. 
 
8.2.13 Adverse Event Reporting Period 
The AE reporting period for each participant begins from the time of signing the 
informed consent and lasts until the final treatment visit (Week 96) for each 
participant. 
 
AEs leading to discontinuation, AEs of ≥Grade 3 severity, related adverse events, 
and lab abnormalities as well as safety concerns will be communicated in a timely 
manner to ViiV Healthcare, and the UNC IRB.  The Sponsor of this study is ViiV 
Healthcare. The principal investigator (Cynthia Gay, MD, MPH) or her designee at 
UNC-CH will be responsible for reporting to the UNC IRB and ViiV Healthcare.  
 
8.2.13.1 Adverse Event Reporting after Week 96 (Longitudinal Phase)  
This is the longitudinal phase of the study. The study will no longer provide 
medication. Adverse events reporting will be restricted to the following: 
• 
Any adverse event occurring as a consequence of procedures required 
by the longitudinal follow-up will be followed and documented in 
accordance with provisions outlined below. 
 
For the purpose of this follow-up phase - an AE is any untoward medical 
occurrence in a participant associated with procedures required for the follow 
up. An AE can therefore be an unfavorable and unintended sign, symptom, or 
disease temporarily associated with procedures required in the longitudinal 
phase (i.e., hematoma following venipuncture). 
 
An AE does not include the following for the Longitudinal phase  
• 
Any medical condition or clinically significant laboratory abnormality 
with an onset date after week 96 is not an AE. 
• 
Any medical condition or clinically significant laboratory abnormality 
occuring after week 96 and which is attributed to the initial treatment 
phase of the protocol by the PI will be followed according to the 
treatment AE guidelines. 
 
New medical diagnosis occurring after Week 96 and not related to the initial 
treatment phase will be captured as part of the medical history but will not be 
reported as an AE.  
 
8.2.14 Documentation of Adverse Events 
Throughout the trial, the study coordinator will monitor closely for the 
development of AEs and the investigator or their designee will determine clinical 
significance of AEs, and medical interventions will be initiated if required.  
 
1. Chart documentation will include: 
 
Concise diagnosis 
 
Onset date 
 
Criterion for regarding as an AE; 
 
Setting; 
 
Resolution date; 
 
Severity (per DAIDS toxicity grading table) 


Page 54 of 72 
 
2. Relation to the study product (unrelated, unlikely, possibly, probably, 
definitely); an AE may be considered related if it follows a reasonable 
temporal sequence from administration of the study drug product, 
confirmed by improvement when the product is stopped and re-appears on 
repeated exposure.  
3. Study drug product change (interrupted or discontinued); and  
4. Seriousness (not serious, fatal, life threatening, leads to or prolongs 
hospitalization, results in persistent or significant disability or incapacity, 
congenital anomaly or birth defect, important medical event). 
 
 
8.2.15 Definition of a Serious Adverse Event 
 
As provided in Title 21 CFR part 312, an SAE is an AE occurring at any dose that 
results in any of the following outcomes; 
 
1. Death; 
2. A life-threatening AE; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability or incapacity;  
5. A congenital anomaly or birth defect; and  
 
Important medical event that may not result in death, be life-threating, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, it may jeopardize the participant and may require medical and surgical 
intervention to prevent one of the outcomes.  
 
 
8.2.15.1 Definition of a Serious Adverse Event after Week 96  (Longitudinal 
Phase) 
Any SAE occurring during the initial treatment phase will be followed, 
documented and reported under the treatment phase of the protocol. Similarly 
any new SAEs occurring before week 96 and considered related to the study 
drug administered or procedure completed in the treatment phase will be 
followed, documented and reported per protocol.  
 
The only SAE which will be reported after Week 96 are events considered to 
be related to the procedures required in the follow up visits after week 96. 
The definition of SAE is in section 8.2.15.  
 
The relationship to the study procedures (e.g., invasive procedures such as 
venipuncture) should be assessed using the following consideration  
• 
NO: Evidence exists that the AE has an etiology other than the study 
procedure  
• 
YES: the AE occurred as a result of a protocol-required procedure 
such as venipuncture.  
 
8.2.16 Definition of a Serious Unexpected Adverse Event 
 
A serious unexpected adverse event is defined as an SAE that is not identified in 
the IB. 
 
8.2.17 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs 


Page 55 of 72 
 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the medical and 
scientific judgment of the investigator or their designee 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 or their designee to be more 
severe than expected for the participant’s condition, are not to be reported as AEs 
or SAEs. 
 
8.2.18 Reporting of Serious Adverse Events 
 
All SAEs occurring during the study will be reported to the UNC IRB per the UNC 
IRB reporting requirements and ViiV Healthcare within 24 hours of knowledge of 
the occurrence.  A written report (Serious Adverse Event Report Form) will be 
faxed or sent within 72 hours.  Additional information will be supplied upon as 
requested.  The Sponsor of this study is ViiV Healthcare. The principal investigator 
(Cynthia Gay, MD, MPH) or her designee at UNC-CH will be responsible for 
reporting to the UNC IRB and ViiV Healthcare.  
 
8.2.18.1 
Any SAE deemed by the investigator or their designee to be related to a 
protocol related procedure after Week 96 should be collected and reported 
using the ViiV Healthcare SAE report form.  
 
 
8.2.19 Follow-Up of AEs and SAEs 
 
All AEs and SAEs must be followed until resolution, become chronic, or stable.  
The resolution status of such an event must be documented.  In addition, the 
investigator should report all follow-up for reportable SAEs to the IRB. 
 
8.3 
Pregnancy and Breastfeeding 
8.3.3 
Screening  
If the pregnancy test is positive at screening, the potential participant will not be 
allowed to enroll on the study and start study treatment.  No further evaluations are 
necessary.  
 
Females and males of reproductive potential will be required to use effective 
contraception while on study. Men or women refusing to use study-required 
contraception will not be allowed to enroll on the study or continue on the study. 
No study medication will be provided.  
 
Breastfeeding excludes a woman from participation due to the potential for HIV-1 
transmission.  
 
8.3.4 
Pregnancy during study participation  
The study will assess women for the date of their last menstrual period and perform 
a POCT urine pregnancy test at each study visit. A serum pregnancy test will be 
done for any suspected pregnancy based on clinical assessment or date of LMP. If 
the participant becomes pregnant during the study then study medication must be 
changed immediately to a regimen that would be safe and effectively control viral 
replication in a pregnant woman. The participant may continue in the study in an 


Page 56 of 72 
 
off study treatment/on study status.  The participant will be followed until the 
pregnancy outcome.   
 
Participants who become pregnant will be seen monthly until week 12/16 of 
pregnancy and every 3 months thereafter.  
 
8.3.5 
Reporting Requirements 
Although not considered an adverse experience, it is the responsibility of 
investigators or their designees to report any pregnancy in a participant or a 
participant’s partner (spontaneously reported to them) that occurs during the study.  
 
Any pregnancy that occurs in a female participant or a partner of a male participant 
during study participation will be reported using a clinical trial pregnancy form. 
The participant will be informed that there is an antiretroviral pregnancy registry to 
monitor fetal outcomes in those exposed to dolutegravir during pregnancy. The 
pregnancy will be followed up to determine outcome (including premature 
termination) and status of mother and child(ren). Pregnancy complications and 
elective terminations for medical reasons must be reported as an AE or SAE. 
Spontaneous abortions must be reported as an SAE. 
 
If the pregnancy continues to term, the outcome (health of infant) must also be 
reported the UNC IRB and ViiV Healthcare.  
 
8.3.6 
The Sponsor of this study is the University of North Carolina at Chapel Hill. The 
principal investigator (Cynthia Gay, MD, MPH) at UNC-CH will be responsible 
for reporting to the UNC IRB and ViiV Healthcare.  
 
8.3.7 
We will obtain a medical release or separate consent granting permission to follow 
the health of both the pregnant partner and her unborn child.  We will conduct a 
post-delivery interview and complete a CRF to collect the data related to the 
pregnancy outcome.   
 
9 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
Study treatment should be discontinued if: 
 
A Grade 3 or 4 reaction occurs that is definitely, probably or possibly related to 
study treatment. 
 
Hypersensitive reaction to Abacavir cannot be ruled out. 
 
Completion of treatment as defined in the protocol. 
 
Request by participant to terminate treatment. 
 
Pregnancy 
 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
 
9.2 
Premature Study Discontinuation 
 
 
Every effort should be made to retain participants on study to assess safety outcomes.  
Participants should discontinue study if:  
 
Request by the participant to withdraw. 
 
Request of the primary care provider if s/he thinks the study is no longer in the best 
interest of the participant. 


Page 57 of 72 
 
 
Participant judged by the investigator to be at significant risk of failing to comply 
with the provisions of the protocol as to cause harm to self or seriously interfere 
with the validity of the study results. 
 
At the discretion of the IRB, Office for Human Research Protections (OHRP), 
other government agencies as part of their duties, investigator, or industry 
supporter.  
 
10 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
This is a multicenter, single arm, open-label study of the safety, virologic efficacy, 
feasibility, and impact of DTG/3TC/ABC FDC initiated during the period of AHI on 
resting cell infection, and immune activation.  Participants will be followed for 96 weeks.  
The primary objective is virologic efficacy as determined by the measurement of plasma 
HIV-1 RNA levels at Week 24. 
 
10.2 
Primary Endpoint 
 
10.2.1 Efficacy – Virologic 
 
Virologic failure (VF) is defined as:  
 failure to achieve HIV-1 RNA <200 copies/mL by week 24, or  
 consecutive HIV-1 RNA levels >200 copies/mL at least 1 week apart after 
week 24 
 
10.3 
Secondary Endpoints 
 
10.3.1 Safety 
Occurrence of a Grade ≥ 3 AE, including sign/symptom, lab toxicity, or clinical 
event, or Grade ≥ 1 AE that is definitely, probably, or possibly related to study 
treatment any time from study treatment initiation through week 96. 
 
Safety data will include local and systemic signs and symptoms, laboratory measures 
of safety/toxicity, and all adverse and serious adverse events. Safety data will be 
routinely collected throughout the duration of the study. Relationship to study 
treatment will be judged by the protocol team. 
 
10.3.2 Feasibility of using a rapid HLA-B57 screening antibody assay 
Time from date of sample collection for testing with the HLA-B57 assay to date of 
result and date of initiation of study treatment. 
 
10.3.3 Time to HIV-1 RNA levels <200 and <50 copies/mL 
 
10.3.4 HIV-1 RNA level at week 48 
 
10.4 
Other Endpoints 
 
10.4.1 Detection of low level viremia as measured by single copy assay at weeks 84 and 
96 
 
10.4.2 Proportion CD8+ cells expressing HLA-DR and CD38+ at weeks 0, 24, 48, 96, 
120, 144, 192, and 240. 
 
10.4.3 Frequency of resting cell infection at week 48   


Page 58 of 72 
 
 
10.5 
Sample Size and Accrual 
 
The total sample size is 40 participants. The samples size for this pilot study is primarily 
determined by practical considerations.  Participants who do not start study treatment or 
discontinue study prior to week 12 will be replaced. Enrollment will continue until the 
proposed 40 participants have been enrolled.  Based on prior experience within the Duke-
UNC Acute HIV Consortium, the team expects that 1-2 participants will accrue into the 
study per month, inclusive of both sites.   
 
 
 
10.5.1 Efficacy 
 
The primary virologic assessment will be the proportion of participants with HIV 
RNA levels <200 copies/mL at week 24.  Assuming 10% of drop out of 
participants, the 95% confidence interval for the result of 28 of 36 (or 77.8%) 
completed participants suppressing viremia to < 200 copies/ml would be 64 to 
91.4%. 
 
10.6 
Monitoring 
 
Accrual, baseline characteristics, conduct of the study (including premature study 
discontinuations), any interruptions of ART, virologic failures, and all reported toxicities and 
AEs will be monitored during the study by the protocol team on a regular basis.  
 
It will be the responsibility of the protocol team to interpret the toxicity data, make decisions 
needed to protect participants from undue risk that may require enrollment suspension or 
study termination or possible modifications to the study for safety concerns, and determine 
whether or not participant replacements are needed.  
 
Study Wide Stopping Rules 
 
If the study experiences 3 failures, in the first 10 participants or 5 total 
virological failures that are not clearly due to non-adherence, the study will be 
stopped. 
 
10.7 
Analyses 
 
10.7.1 Primary Analyses 
 
As this is a pilot study, statistics for the primary analysis will be primarily 
descriptive.  The proportion and 95% confidence intervals of participants with 
plasma HIV-1 RNA < 200 copies/mL and <50 copies/mL at Weeks 24 and 48, 
respectively, will be tabulated and presented.   
 
10.7.2 Secondary Analyses 
 
10.7.2.1 
Safety and feasibility   
- 
Descriptive summary (proportions and 95% confidence intervals) of all 
adverse events (AEs), all drug-related AEs, and any grade 3/4 AEs will 
be generated.   
 
- 
The feasibility of using a rapid HLA B57 antibody test to allow prompt 
initiation of an ABC-containing regimen will be assessed by 


Page 59 of 72 
 
calculating the time (median and range in days) from the date of 
sample collection for testing to date of result and date of initiation of 
study treatment.   
 
10.7.2.2 
Virologic   
- 
Longitudinal presentation of median plasma HIV-1 RNA (log10 
copies/mL scale) and CD4 cell count will be presented by visit during 
the 96 weeks of follow-up.   
 
- 
Time-to-viral-suppression will be examined among enrolled patients in 
relation to baseline characteristics using the Kaplan Meier method and 
multivariate Cox proportional hazards regression. Time-to-viral-
suppression will be defined as the time to HIV RNA <200 copies/mL 
or <50 copies/mL after ART initiation. Potential exposures will include 
duration from estimated-date-of-infection until treatment, baseline 
CD4 count, baseline HIV RNA level, and age. The Kaplan Meier 
method and log-rank tests will be used to compare time-to-viral-
suppression between participants and our acute HIV cohort of 90 
individuals who initiated FDC EFV/FTC/TDF within 30 days of AHI 
diagnosis.  Multivariate proportional hazards regression will be used to 
estimate hazard ratios, controlling for baseline variables. The final 
model will be built using backwards elimination with a 10% change in 
estimate criteria for retaining confounding variables.  
 
- 
Differences in time-to-viral-suppression will be compared between 
enrollees on this study and our acute HIV cohort (n=90) who initiated 
FDC EFV/FTC/TDF within 30 days of AHI diagnosis to assess 
virologic efficacy at weeks 24 and 48 using log-rank tests and Kaplan-
Meier methods.  
 
- 
Virologic Failures will be presented and separated into two types, (A) 
VF without resistance (likely due to markedly inadequate adherence) 
and (B) VF with resistance.  The proportion and 95% confidence 
intervals of participants exhibiting each type of VF will be presented. 
 
10.7.2.3 
Other Analaysis  
- 
The frequency of CD8+ cells expressing HLA-DR and CD38+ will be 
compared with levels of immune activation in seronegative patients 
and those on the acute HIV cohort who initiated FDC EFV/FTC/TDF 
during AHI using one way analysis of variance tests at baseline, and 
weeks 24, 48, and 96. 
 
10.7.2.4 
Immune Cell Function 
- 
Longitudinal assessments of T cell phenotype and function will be 
performed. Data will be compared with cross-sectional data generated 
from sampling of HIV-1 seronegative individuals. 
 
- 
Standardized cellular assays will focus on i) measuring both CD4 and 
CD8 T cell proliferation to viral antigens (HIV, EBV, Influenza and 
CMV) and mitogenic stimulation (Figure 2A) ii) phenotypic and 
memory status of CD8 T cells, particularly expression of T-cell master 
regulators T-bet and Eomes (Figure 2B,C) iii) activation markers 
including PD-1, CD160, CD38 and HLA-DR (Figure 1C, Clutton 
2016) and iv) measurements of cellular metabolism, specifically 


Page 60 of 72 
 
measures of aerobic glycolysis and mitochondrial mass and 
polarization (Henson 2014, Bengsch 2016).  
 
- 
Statistical analysis of data will be performed in conjunction with the 
UNC CFAR Biostatistics Core. 
 
11. 
DATA COLLECTION, MONITORING, AND ADVERSE EVENT REPORTING 
 
11.1. 
Records to Be Kept 
 
Source documents will be provided for each participant.  Participants will be identified by 
name in the source documents but will not be identified by name in the database or on any 
report associated with the study.  Participants will be identified by the participant 
identification number (PID) and study identification number (SID) provided by the study 
database upon screening.  
 
11.2. 
Role of Data Management 
 
It is the responsibility of the study site to assure the quality of data for this study.  This role 
extends from protocol development to generation of the final study databases. 
 
11.3. 
Clinical Site Monitoring and Record Availability 
 
The site investigator or their designee will make study documents (e.g., consent forms, study 
drug product, distribution forms, source documents) and pertinent hospital or clinic records 
readily available for inspection by the local IRB, site monitors, the FDA, and the industry 
supporters or designee for confirmation of the study data. 
 
11.4. 
Expedited Adverse Event Reporting to FDA 
 
11.4.1. Adverse Event Reporting  
 
Adverse events involving investigational (study) drugs, such as those relating to 
Investigational New Drug (IND) applications, including those for cellular products 
administered under IND, should be reported as required in the study protocol and 
sent to the FDA.   
 
11.4.2 Reporting Requirements for this Study 
 
 The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used in this study. 
 
 The study product, for which expedited reporting is required, is:  DTG/3TC/ABC 
FDC.  
 
11.4.3 Grading Severity of Events 
 
U.S. Department of Health and Human Services, National Institutes of Health, 
National Institute of Allergy and Infectious Diseases, Division of AIDS. Division of 
AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0. [November 2014] , must be used and is available on the DAIDS 
RSC website: http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 


Page 61 of 72 
 
All confirmed ≥ grade 3 lab results and serious adverse events occurring during 
clinical studies must be reported to the appropriate ViiV healthcare Clinical contact 
person by the research staff within 24 hours of their knowledge of the event. AEs 
occurring after Week 96 will be reported as described in protocol sections 8.2.13.1 
and 8.2.15.1. 
 
11.4.4 Expedited AE Reporting Period 
 
 
The expedited AE reporting period for this protocol is the entire study duration 
for an individual participant (from study enrollment until study completion or 
discontinuation of the participant from study participation for any reason).  
 
After the protocol-defined AE reporting period, unless otherwise noted, only 
suspected, unexpected serious adverse reactions (SUSARs), as defined in 
Version 2.0 of the EAE Manual, will be reported to the FDA if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
 
12. 
EXTERNAL SUPPORT/COLLABORATION/FUNDING 
  
12.1.  National Cancer Institute, Frederick, MD 
12.1.1. Single Copy HIV RNA assay 
 
12.2. 
ViiV Healthcare 
 
 
13. 
HUMAN PARTICIPANTS 
 
13.1. 
Institutional Review Board (IRB) Review and Informed Consent 
 
 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB responsible for oversight of the study.  A signed consent 
form will be obtained from each participant.  The consent form will describe the purpose of 
the study, the procedures to be followed, and the risks and benefits of participation.  A copy 
of the consent form will be given to the participant, and this fact will be documented in the 
participant’s record. 
 
13.2. 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will 
be identified by coded number only to maintain participant confidentiality.  All records will 
be kept locked in a secure area accessibly only to research study personnel.  All computer 
entry and networking programs will be done with coded numbers only.  Clinical information 
will not be released without written permission of the participant, except as necessary for 
monitoring by IRB, or the industry supporters or designee.  
 
13.3. 
Study Discontinuation 
 
The study may be discontinued at any time by the IRB, the industry supporters or other 
government agencies as part of their duties to ensure that research participants are protected.  
 
14. 
PUBLICATION OF RESEARCH FINDINGS 
 


Page 62 of 72 
 
Any presentation, abstract, or manuscript will be made available for review by the industry 
supporters prior to submission.  
 
15. 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for Disease 
Control and Prevention and the National Institutes of Health. 
 
All dangerous goods materials, including diagnostic specimens and infectious substances, 
must be transported using packaging mandated by CFR 42 Part 72.  Please refer to 
instructions detailed in the International Air Transport Association (IATA) Dangerous Goods 
Regulations. 
 
16. 
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Page 66 of 72 
 
 
Appendix 1 
 
List of Highly Effective Birth Control Methods for Avoidance of Pregnancy in 
Females of Childbearing Potential  
• 
Abstinence 
• 
Contraceptive subdermal implant 
• 
Combined estrogen and progesterone oral contraceptive  
• 
Injectable progestogen 
• 
Implants of levonorgestrel 
• 
Contraceptive (Estrogenic) vaginal ring 
• 
Percutaneous contraceptive patches 
• 
Intrauterine device (IUD) or intrauterine system (IUS) with published data 
showing an expected failure rate of <1% per year 
• 
Male partner sterilization (vasectomy with documentation of azoospermia) prior 
to the female participant’s entry into the study, and this male is the sole partner for 
that participant. The documentation on male sterility can come from the site 
personnel’s review of participant’s medical records, medical examination, and/or 
semen analysis, or medical history interview provided by her or her partner. 


Page 67 of 72 
 
Appendix 2 
 
Examples of Intrauterine Devices (IUDs) with published data showing an expected 
failure rate of <1% per year 
This list is not all inclusive and IUDs not included on this list may meet this protocol-
required definition.  Check the product labeling carefully for any IUD. 
 
 Paragard T380A 
 Mirena 
 Flexigard 330 
 Ombrelle 380 
 Cu-Safe 300 
 Cu-Fix 390 
 TCu380Ag 
 TCu380S  
 
Supporting References 
Paragard T380A Prescribing Information (May 2006) 
 
Mirena Prescribing Information (Oct 2009) 
 
Kulier R, Helmerhorst FM, O’Brien P, et. al. Copper containing, framed intra-uterine devices 
for contraception. Cochrane Database Syst Rev 2006;CD005347 
 
Boateng J, Chi I-c and Jones DB. An evaluation of six new intrauterine devices. 
Advances in Contraception. 1994;10:57-70. 
 
 
 
 
 
 
 
 
 
 


Page 68 of 72 
 
Appendix 3 
Essential Participant Information 
 
1. Participants must be made aware of the possibility of a hypersensitivity reaction to 
abacavir that may result in a life-threatening reaction or death and that the risk of a 
hypersensitivity reaction is increased if they are HLA-B*5701 positive. 
 
2. Participants must also be informed that HLA-B*5701 negative individuals can also experience 
abacavir hypersensitivity reaction. Therefore, ANY participant who develops signs or symptoms 
consistent with a possible hypersensitivity reaction to abacavir MUST CONTACT their doctor 
IMMEDIATELY. 
 
3. Participants who are hypersensitive to abacavir should be reminded that they must never take the 
DTG/ABC/3TC single tablet FDC or any other medicinal product containing abacavir (e.g. 
ZIAGEN, EPZICOM, KIVEXA, TRIZIVIR) again, regardless of their HLA-B*5701 status. 
 
4. In order to avoid restarting the DTG/ABC/3TC single tablet FDC, participants who have 
experienced a hypersensitivity reaction should be asked to return the remaining DTG/ABC/3TC 
FDC tablets to the Investigator or site staff. 
 
5. Participants who have stopped the DTG/ABC/3TC single tablet FDC for any reason, and 
particularly due to possible adverse reactions or illness, must be advised to contact their doctor 
before restarting 
 
6. Each participant should be reminded to read the package leaflet included in the DTG/ABC/3TC 
single tablet FDC pack. They should be reminded of the importance of removing the Alert Card 
included in the pack, and keeping it with them at all times. 
 
 
 
 
 
 
 


Page 69 of 72 
 
Appendix 4  
Study Drug Dispensing Options at Enrollment 
 
1. Options for drug dispensing at the study sites: Duke University (Duke) and the University of 
North Carolina at Chapel Hill (UNC):  
a) Send the participant home with a 7 day supply of FDC dolutegravir/abacavir/lamivudine. The 
participant is instructed to start the medication ONLY after confirmation of the HLA and 
Hepatitis B testing results. The remainder of the 30 day supply of medication will be picked 
up by the participant or can be mailed to the participant after confirmation of negative testing 
results. (Offered only at UNC). 
b) Mail the participant 30 days of medications after the HLA and Hepatitis B testing results are 
confirmed (Duke and UNC) 
c) Bring the participant back after confirmation of HLA and Hepatitis B testing results to get 30 
days of the medication (Duke and UNC) 
 


Page 70 of 72 
 
Schedule of Events 
Combined 
Screen and 
Enrollment
 
 
 
Treatment Phase  
Early 
Discontinuatio
n or End-of-
Study 
Evaluations 
Study Weeks 
0 
2 
4 
8 
12 
16 
24 
36 
48 
60 
72 
84 
96 
Clinical Procedures  
Consent, Eligibility, Demographics,  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination1 (vital 
signs, height & weight) and medical history2 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted Clinical Assessments3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Acute HIV Assessment  
X* 
 
 
 
 
 
 
 
 
 
 
 
 
Depression Assessment (PHQ-9) 
X# 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
Assessment of Pregnancy and Birth Control  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ART & Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures 
Chemistries4 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Liver Function Labs5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC with differential 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy Test  
 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
 
Follicle Stimulating Hormone∞ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipids 
X7 
 
 
 
 
 
 
 
X 
 
 
 
X 
Lipase 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
HLA B57 Rapid test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 Combo Ag/Ab test 
X 
 
 
 
X8 
 
 
 
 
 
 
 
 
HBV AB, HBVsAg and HCV AB± 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RPR9  
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Genotype 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ T Cell Differential Panel 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine for GC and Chlamydia9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis macro 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte Activation Studies10, 12   
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Serum and PBMCs for storage10 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
Single Copy Assay13 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Optional Procedures  
PT and APTT  
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Resting Cell Infection Measurement11 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Leukapheresis11  
 
 
 
 
 
 
 
 
X 
 
 
 
X 


Page 71 of 72 
 
 
1 The Complete PE will include a complete review of systems, vital signs, and weight.  Height will be measured at the 
Screening Visit only.  The complete physical exam also includes signs and symptoms, and diagnoses. 
2 Medical histories will be obtained at screening and should include demographic information (date of birth, gender, 
race, ethnicity), participant’s medical history, and medication history. 
3 A targeted physical examination is done at all other visits and includes vital signs and is to be driven by any 
previously identified or new event that the participant has experienced since the last study visit or any unresolved 
signs or symptoms experienced previously.  This assessment will include weight, vital signs, a signs and symptoms 
update, and clinical assessment of HIV disease. 
* The acute HIV assessment will be initiated at screening/enrollment visit but may be completed at the Week 2 visit if 
required.  
# The baseline depression assessment (PHQ-9) may be completed prior to consent as this assessment is a standard of 
care assessment done on all new ID clinic patients.  
4 Chemistries includes sodium, potassium, chloride, bicarb, glucose, BUN,creatinine and calculation of creatinine 
clearance.   
5 Includes ALT, AST, alkaline phosphatase and total bilirubin. A direct bilirubin will be done at screening only. 
6 For females of child bearing potential, ascertainment of a negative POCT urine pregnancy test result will be required 
at all study visits. Suspicion of pregnancy based on clinical assessment or date of LMP will require a serum 
pregnancy test at the study visit. (reference protocol section 7.9.1.)  
∞Optional test – complete on any women who meet the definition of menopause as described in protocol section 5.2.7, 
to confirm menopause.  
7 Fasting and can be obtained at visit 2 if not fasting at screen/enrollment visit. 
8 Repeat HIV-1/2 confirmatory/differentiating testing at week 12 if the enrollment test is negative or indeterminate.  
Only repeat HIV -1 Combo Ab/Ab test with differentiating test if the Combo Ag/Ab test  was negative at enrollment. 
Completion of both test acceptable if exact testing results not available at enrollment.  
±  Reflex to HCV RNA test, if positive 
9 Testing not required if done within 30 days of visit and documentation of results (and treatment, if applicable) are 
available. 
10 Processed and stored at UNC CFAR HIV/STD Laboratory Core (CHSLC). Analysis to be completed in the 
Goonetilleke Lab at UNC. 
11 Processed in the Margolis Lab 
12 Includes serum, plasma and PBMCs for storage - (1) 3.5 mL SST and (4) 8.5 mL ACD 
13 Processed and stored at UNC CHSLC. Batched and shipped to National Cancer Institute (NCI) in Fredericksburg, 
MD 
14 In situations where the CBC with differential is not required to run the CD4 test, the CBC is optional. 
15 Abstract from clinical record. Clinical lab testing can be abstracted from clinical record if testing completed within 
visit window and separate from research samples collection. Complete clinical labs at UNC McLendon Lab for 
provider availability in UNC EMR.  
 
Schedule of Events 
 
 
Longitudinal Follow -Up Phase  
Study Weeks 
120 
144 
192 
240 
ClinicalAssessment per chart abstraction15  
Consent, Demographics, and/or Medical Release (as required)15  
X 
X 
X 
X 
Update medical history15 
X 
X 
X 
X 
Adverse Event Assessment15 
X 
X 
X 
X 
Update ART & Concomitant Medication15 
X 
X 
X 
X 
Clinical Laboratory Procedures or documentation per chart abstraction  
CBC with differential14, 15 
X 
X 
X 
X 


Page 72 of 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR15 
X 
X 
X 
X 
CD4+ T Cell Differential Panel15 
X 
X 
X 
X 
Research Assay  
Lymphocyte Activation Studies10,12   
X 
X 
X 
X