Virologic Outcomes of Lamivudine/Dolutegravir in Virologically Suppressed Subjects With Expected or Confirmed Resistance to Lamivudine.
Phase: PHASE2
Conditions: HIV Infections
Sponsor: Fundacion SEIMC-GESIDA

 
 
CLINICAL STUDY PROTOCOL 
 
Virologic Outcomes of Lamivudine/Dolutegravir in 
Virologically suppressed subjects with Expected or 
confirmed Resistance to Lamivudine (VOLVER Study) 
 
 
Sponsor: Fundación SEIMC-GESIDA 
Protocol code: GESIDA 11820 
Nº EduraCT: 2021-000290-84 
Sponsor Contact:   C/ Agustín de Betancourt, 13-Entreplanta. 28003, Madrid (Spain) 
  
 
           Tel: +34 91 556 80 25 
       
Version of Protocol: 4.0 
Date of Protocol:  31. May. 2021 
 
 
 
Confidential information 
This protocol contains confidential information; therefore, it should be considered as confidential and limited to its intended use in 
this clinical trial. This protocol is only to be disclosed to the staff of Fundación SEIMC-GESIDA; Health Authorities; staff in charge of 
the review, authorisation, monitoring, auditing or inspection of the clinical trial; and also to the clinical staff in charge of 
conducting it. This material is not to be disclosed to individuals outside of this clinical trial without prior written authorisation from 
Fundación SEIMC-GESIDA. 
 

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PROTOCOL SIGNATURE PAGE 
 
Study Title: Virologic Outcomes of Lamivudine/Dolutegravir in Virologically suppressed 
subjects with Expected or confirmed Resistance to Lamivudine (VOLVER study). 
Protocol Code: GESIDA 11820 
EudraCT No.: 2021-000290-84 
Version: 4.0 of 31 May 2021 
Sponsor: Fundación SEIMC – GESIDA 
 
Signature of the Coordinating Investigators: 
Dr José Ramón Arribas - La Paz University Hospital 
 
 
Name  
 
Signature  
 
Date 
 
Dr Federico Pulido - 12 de Octubre Hospital  
 
 
Name  
 
Signature  
 
Date 
 
Signature of the sponsor: 
Dr Juan Julián Gonzalez García -  Chairperson of the Board of Directors 
 
 
Name  
 
Signature  
 
Date 
 
Signature of the Principal Investigator: 
Name:  
 
 
Site: 
 
 
Name 
 
Signature 
 
Date 

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1. SUMMARY
I. Sponsor:  Fundación SEIMC-GESIDA 
II. Clinical study title: Virologic Outcomes of Lamivudine/Dolutegravir in Virologically 
suppressed subjects with Expected or confirmed Resistance to Lamivudine (VOLVER 
study).  
III. Principal Investigators:  
Dr. José Ramón Arribas López 
La Paz University Hospital.  
Internal Medicine Department. Infectious Diseases Unit.  
Paseo de la Castellana, 261. CP 28046 – Madrid 
e-mail: joser.arribas@salud.madrid.org 
 
Dr. Federico Pulido 
12 de Octubre University Hospital.  
Internal Medicine Department. HIV Unit.  
Centro de Actividades Ambulatorias 2ª Planta Bloque D.  
Av. Cordoba s/n. 28041-Madrid 
e-mail: federico.pulido@salud.madrid.org 
IV. Clinical study phase: IIa.
V. Team participants:  
Multicentre study, to be conducted at 17 healthcare centres in Spain. The listing of all 
investigators and sites will be attached in a separate document. 
VI. Background:  
Dolutegravir (DTG) plus lamivudine (3TC) is a dual regimen combination recommended 
for both naïve and suppressed persons with HIV-1 infection1. However, data regarding 
the efficacy of this regimen in suppressed persons with history of past resistance or 
virologic failures is currently insufficient. In particular, it is important to determine if this 
combination is safe to use in persons with past resistance to 3TC. Limited data from 
retrospective cohorts, and a small number of participants from the DOLULAM and 
TANGO studies seem to point that DTG/3TC may be used without exposing individuals 

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to a significant risk of virologic failure, despite historical 3TC resistance or archived 
minority 3TC resistance-associated mutations 2–5. In our prospective pilot study ART-
PRO6 18/21 persons with past M184V/I mutations, not detected at baseline through 
proviral DNA Sanger sequencing, were switched to DTG/3TC and maintained virologic 
control for 96  weeks without any case of virologic failure7. In our study, archived 3TC-
resistance associated mutations were detected at baseline through next-generation 
sequencing (NGS) over the 5% threshold in more than half of participants with past 3TC 
resistance, without any detrimental effect on viral control. Although showing promising 
results, ART PRO study’s generalizability is limited due to the small size and the 
exclusion of participants exposed to integrase inhibitors, which call for a larger study. 
VOLVER study aims to enrol persons with confirmed or suspected history of 3TC 
resistance and demonstrate that, when proviral DNA population sequencing no longer 
detects 3TC resistance-associated mutations, DTG/3TC is sufficient to maintain virologic 
suppression. Based in our prior findings, we also want to confirm that the virological 
impact of 3TC-resistant archived minority variants prior to switching to DTG/3TC is 
negligible in this context.  
VII. Study design: 
Phase IIa, open-label, single arm, multicentric study. Follow up: 96 weeks.  
VIII. Study treatment:  
Dovato® (Dolutegravir 50 mg/Lamivudine 300 mg film-coated tablet): 
Route of administration: oral.  
Dose: Dolutegravir 50 mg/Lamivudine 300 mg/day. 
Posology: one 50 mg/300 mg film coated-tablet once daily.   
Intervention: change of current antiretroviral treatment to DTG 50 mg/3TC 300 mg QD. 
IX. Study Locations: 
This is a multicentre study, and it will be conducted at different healthcare centres in 
Spain. The listing of all investigators and sites where the clinical trial is going to be 
conducted is attached in a separate document 
X. Estimated sample size:  

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120 participants. A minimum of 30%-50% of the study population would be required to 
have historical RNA population genotype with confirmed M184V/I mutation.  
XI. Ethics Committee:  
The study will be evaluated by the Ethics Committee (Comité de Ética de la Investigación 
con medicamentos) of University Hospital La Paz which is authorized by the Ministry of 
Health 
and 
Consumer 
Affairs 
(https://www.aemps.gob.es/investigacionClinica/medicamentos/docs/listado -comites-
investigacion-clinica.pdf) and by the health authorities of the Autonomous Community of 
Madrid (Spain).  
XII. Hypothesis: 
Our hypothesis is that therapy with DTG/3TC would be able to maintain viral control in 
HIV infected participants with prior history of 3TC resistance but without evidence of 
M184V/I resistance mutation in proviral DNA population sequencing at baseline.  We 
also hypothesize that archived minority 3TC resistance associated mutations detected 
by next-generation (NGS) sequencing prior to the switch would not have a significant 
impact on the efficacy of DTG/3TC.  
XIII. Study Objectives and Endpoints: 
Primary objective 
Primary endpoint 
To assess the efficacy of a switch to DTG/3TC
for maintenance of virologic suppression at 48 
weeks in persons with past confirmed or 
suspected 3TC resistance, when proviral DNA 
population sequencing does not detect 3TC 
resistance-associated mutations at baseline. 
Proportion of virologic failure (VF) defined as 
HIV-1 RNA viral load (VL)  50 copies per mL 
at 48 weeks (in the intention-to-treat-exposed 
population (ITT-e) using the US Food and 
Drug 
Administration 
(FDA) 
snapshot 
algorithm). 
Secondary objectives 
Secondary endpoints 
To evaluate other estimations of virological 
control at weeks 48 and 96.  
- 
Proportion of VF ( 50 copies/mL) at week 
96, ITT-e, FDA snapshot.  
- 
Proportion of VF ( 50 copies/mL) at week 
48 and 96, per protocol population (PP), 
FDA snapshot.  
- 
Proportion of VF ( 200 copies/mL) at 
week 48 and 96, ITT-e and PP population, 

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FDA snapshot.
- 
Proportion 
of 
Confirmed 
Virologic 
Withdrawal ([CVW]: A VL  50 copies/mL 
followed by a VL  200 copies/mL in re-
test) at weeks 48 and 96, ITT-e and PP 
population, FDA snapshot. 
- 
Proportion of Precautionary Virologic 
Withdrawal ([PVW]: three consecutive VL 
between 50- 200 copies/mL) at weeks 48 
and 96, ITT-e and PP population, FDA 
snapshot. 
- 
Proportion of participants with VL<50 
copies/mL week 48 and 96, ITT-e and per 
protocol population, FDA snapshot. 
To assess viral resistance in persons 
experiencing VF. 
 
- 
Incidence of VF with drug resistance 
associated mutations. 
- 
Describe number and type of resistance-
associated mutations in VF 
To evaluate factors associated with VF. 
 
- 
Analysis of factors associated to VF (i.e 
time to VF). 
- 
Proportion 
of 
VF 
in 
pre-specified 
subgroups: 
- 
Confirmed historical M184V/I vs No 
resistance mutations 
- 
INSTI exposure vs No prior INSTI 
exposure 
- 
Time virologically suppressed  
- 
Time on 3TC/FTC 
To assess the impact of baseline archived 
minority 3TC resistance-associated mutations 
in viral control (in cases of VF and transient 
viral rebounds [VL 50copies/mL preceded 
and followed by VL<50 copies/mL]). 
- 
Proportion of participants with VF with 
baseline 
3TC 
or 
INSTI 
resistance- 
associated 
mutations 
detected 
at 
baseline by NGS with 1, 5, and 20% 
threshold. 
- 
Proportion of participants with transient 
viral rebounds with baseline 3TC or INSTI 

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resistance-
associated 
mutations 
detected at baseline by NGS with 1, 5, 
and 20% threshold. 
To evaluate the dynamics of archived minority 
3TC resistance-associated mutations after 
switching to DTG/3TC at 96 weeks. 
Type and frequency of resistance mutations 
(RT and integrase) in proviral DNA measured 
by NGS at baseline and week 96. 
To evaluate the immune effects of switch to 
DTG/3TC 
Change from Baseline in CD4+ cell count and 
in CD4+/CD8+ cell counts ratio at weeks 48 
and 96 
To evaluate the safety and tolerability of 
DTG/3TC in this study 
- 
Incidence and severity of AEs and 
laboratory abnormalities through week 48 
and 96. 
- 
Proportion of subjects who discontinue 
treatment due to AEs through weeks 48 
and 96. 
 
XIV. Disease under study: HIV-1 infection.  
XV. Study population:  
Persons receiving antiretroviral treatment, followed at study participating centres.  
Inclusion Criteria:   
a. Adults (  18 years old) with HIV-1 infection able to understand and give informed 
written consent. 
b. Stable ART in the 12 weeks prior to screening visit.  
- 
Only switch for tolerability/convenience/access reasons to generic drugs 
or switch from ritonavir to cobicistat or TDF to TAF would be allowed in 
the 12-week window and as long as the components of the regimen are 
unchanged.  
c. Viral load <50 copies/mL at screening and in the year prior to study entry. 
- 
A blip (50-500 copies/mL) would be allowed within 48 weeks prior to 
inclusion in the study, if preceded and followed by an undetectable VL 
determination.  
d. CD4+ count > 200 cells/µL at screening.  

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e. History of 3TC resistance: either confirmed historical 3TC resistance (historical 
RNA Sanger or RNA NGS>20% threshold genotype with M184V/I mutation) OR 
suspected historical 3TC resistance. 
- 
Suspicion of past 3TC resistance is defined as any of the following: 
i.
Previous treatment with only 2 NRTIs (1 of them being 
emtricitabine or 3TC [XTC]). 
ii. Two consecutive VL > 200 copies/mL while on treatment including 
XTC. 
iii. One VL > 200 copies/mL while on treatment including XTC PLUS 
change of ART as consequence of that elevated VL.  
Exclusion Criteria:  
a. Participants with M184V/I or K65R in screening visit proviral DNA Sanger 
genotype.  
b. Prior virologic failure (VF) under integrase inhibitor (INSTI)- based regimen. 
defined as two consecutive VL > 200 copies/mL while receiving INSTI regardless 
of genotypic test results 
c. INSTI resistance mutations in historical RNA genotype.  
d. Documented resistance to DRV defined as the presence of a combination of 
mutations scored with at least 15 points in the Stanford University HIV Drug 
Resistance Database. 
e. Positive Surface Hepatitis B Ag (HBAgS) OR negative HBAgS and negative 
hepatitis B surface antibody (anti-HBs) with positive anti-core antibody (anti-HBc) 
and positive HBV DNA.  
f. Pregnant, breastfeeding women, women with a positive pregnancy test at the 
time of screening, sexually active fertile women wishing to conceive or unwilling 
to commit to contraceptive methods (see Appendix 1 for the accepted list of the 
highly effective methods for avoiding pregnancy), for the duration of the study 
and until 4 weeks after the last dose of study medication. All women are 
considered fertile unless they have undergone a sterilizing surgery or are over 
the age of 50 with spontaneous amenorrhea for over 12 months prior to study 
entry. 

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g. Patients with active opportunistic infections or cancer requiring intravenous 
treatment and/or chemotherapy at screening.  
h. Any comorbidities or treatment with experimental drugs that according to the 
investigator could bias study results or entail additional risks for the participant.  
i. 
Participants receiving other medications that according to study drug label are 
contraindicated. 
j. 
Severe hepatic impairment (Class C) as determined by Child-Pugh classification. 
k. Alanine aminotransferase (ALT) over 5 times the upper limit of normal (ULN) or 
ALT over 3xULN and bilirubin over 1.5xULN.  
l. 
Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia or 
jaundice due to Gilbert's syndrome or asymptomatic gallstones); 
m. Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method. 
n. Any verified Grade 4 laboratory abnormality that to the investigators criteria would 
affect the safety of the participant if included in the study. 
o. History or presence of allergy to dolutegravir or lamivudine.  
XVI. Duration of the study:  
i. Duration of the participant selection period: 9 months. 
ii. Duration of the follow-up period: 96 weeks. 
iii. Data analysis and preparation of the final report: 6 months. 
 
 
 
 
 
 
 
 
 
 
 

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2. INDEX 
 
1. SUMMARY.......................................................................................................................................3
2. INDEX.............................................................................................................................................10
3. GENERAL INFORMATION .......................................................................................................... 14 
3.1 
Study identification ................................................................................................................. 14 
3.2       Type of clinical study ............................................................................................................. 14 
3.2
Study drug description...........................................................................................................14
3.3 
Principal investigators ............................................................................................................ 14 
3.4 
Collaborating centres ............................................................................................................. 14 
3.5 
Monitor identification .............................................................................................................. 15 
3.6 
Ethics committee of reference identification ....................................................................... 15 
3.7 
Expected duration .................................................................................................................. 15 
4. BACKGROUND AND JUSTIFICATION ..................................................................................... 15 
5. HYPOTHESIS AND OBJECTIVES ............................................................................................. 17 
5.1 Hypothesis ..................................................................................................................................... 17 
5.2 Objectives ......................................................................................................................................18
6. TYPE OF CLINICAL STUDY AND DESIGN...............................................................................20
6.1 Clinical study phase ..................................................................................................................... 20 
6.2 Study design .................................................................................................................................. 20 
7. PARTICIPANT SELECTION ......................................................................................................... 21 
7.1 Inclusion criteria ............................................................................................................................ 22 
7.2 Exclusion criteria ........................................................................................................................... 22 
7.3 Estimated sample size ................................................................................................................. 24 
7.4 Withdrawal criteria and loss to follow-up ................................................................................... 24 

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7.5. Security stop rules.......................................................................................................................25
7.6 Recruitment period .......................................................................................................................25
8. STUDY TREATMENT.................................................................................................................... 26 
8.1 Study treatment ............................................................................................................................. 26 
8.2 Dosage ...........................................................................................................................................26
8.3. Packaging and labelling..............................................................................................................26
8.4 Treatment compliance.................................................................................................................. 26 
8.5 Other treatments permitted and prohibited ............................................................................... 26 
9. STUDY DEVELOPMENT AND PROCEDURES .......................................................................... 28 
9.1 Study visits and procedures ........................................................................................................ 30 
9.2 Biological samples ........................................................................................................................ 34 
10. EVALUATION CRITERIA: STUDY VARIABLES .................................................................... 34 
10.1 
Primary endpoint .................................................................................................................... 34 
10.2 
Secondary endpoints ............................................................................................................. 34 
10.3 
Bias control and limitations ................................................................................................... 36 
11 STUDY SAFETY ..........................................................................................................................37
11.1 
Drug safety reference information ....................................................................................... 37 
11.2
Definitions................................................................................................................................37
11.3 
Casualty evaluation ................................................................................................................ 39 
11.4 
Intensity evaluation ................................................................................................................ 39 
11.5 
Safety variables and parameters ......................................................................................... 39 
11.6 
Adverse events information .................................................................................................. 39 
11.7 
Pregnancy ............................................................................................................................... 40 
11.8 
Notification procedure of SAEs ............................................................................................ 41 
11.9 
Notification procedure of severe and unexpected adverse events (SUSAR) ............... 42 

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12
ETHICAL ISSUES.................................................................................................................43
12.1
General and particular rules for investigators ....................................................................43
12.2 
Informed consent .................................................................................................................... 43 
12.3 
Safety and confidentiality procedures ................................................................................. 43 
12.4
Insurance.................................................................................................................................44
13
PRACTICAL CONSIDERATIONS.......................................................................................44
13.1 
Responsibilities of participants in the study ....................................................................... 44 
13.2 
Monitoring, auditing and inspection ..................................................................................... 45 
13.3 
Study documentation ............................................................................................................. 45 
13.4 
Data management .................................................................................................................. 45 
13.5 
Publication conditions ............................................................................................................ 46 
13.6 
Procedure for the modifications of the protocol ................................................................. 46 
13.7 
Ethics committee of research with medicines (CEIC) ....................................................... 46 
14 
STATISTICAL ANALYSIS .................................................................................................... 47 
14.1 
Sample size estimation ......................................................................................................... 47 
14.2
Statistical analysis..................................................................................................................47
15. REFERENCES ............................................................................................................................ 49 
APPENDIX 1. GUIDANCE ON PREGNANCY AND BREAST FEEDING .................................... 53 
APPENDIX 2: RISK ASSESSMENT AND TOXICITY MANAGEMENT ....................................... 56 
Risk Assessment ................................................................................................................................. 56 
Toxicity Management .......................................................................................................................... 61 
APPENDIX 3: Liver Safety – Checklist for Drug Restart Approval or Refusal ...................... 69 
APPENDIX 4: SERIOUS ADVERSE EVENT REPORT FORM .................................................... 70 
APPENDIX 5: PREGNANCY NOTIFICATION FORM ................................................................... 72 

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APPENDIX 6: PREGNANCY FOLLOW-UP FORM .......................................................................74
APPENDIX 7: LIVER EVENTS FORM............................................................................................76
APPENDIX 8: LIVER EVENTS BIOPSY FORM............................................................................. 84 
APPENDIX 9: POSSIBLE SUICIDALITY-RELATED ADVERSE EVENT FORM ....................... 91 
APPENDIX 10. LIVER IMAGING RECORD …...…………………………………………………………………………97
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. GENERAL INFORMATION 
3.1 Study identification 
Clinical study title: Virologic Outcomes of Lamivudine/Dolutegravir in Virologically 
suppressed subjects with Expected or confirmed Resistance to Lamivudine (VOLVER 
study).  
3.2 Type of clinical study 
Phase IIa, open-label, single arm, multicentric study. Follow up: 96 weeks.  
3.2 Study drug description 
Dovato® (Dolutegravir 50 mg/Lamivudine 300 mg film-coated tablet): 
Route of administration: oral.  
Dose: Dolutegravir 50 mg/Lamivudine 300 mg/day.  
Dosage: one 50 mg/300 mg film-coated tablet once daily.  
Intervention: change of current antiretroviral treatment to DTG 50 mg/3TC 300 mg QD. 
3.3 Principal investigators 
Dr. José Ramón Arribas López 
La Paz University Hospital.  
Internal Medicine Department. Infectious Diseases Unit.  
Paseo de la Castellana, 261. CP 28046 – Madrid 
e-mail: joser.arribas@salud.madrid.org 
 
Dr. Federico Pulido 
Centro de Actividades Ambulatorias 2ª Planta Bloque D.  
12 de Octubre University Hospital.  
Av. Cordoba s/n. 28041-Madrid 
e-mail: federico.pulido@salud.madrid.org 
3.4 Collaborating centres 
Multicentre study, to be conducted at 17 healthcare centres in Spain. The listing of all 
investigators and sites will be attached in a separate document. 

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3.5 Monitor identification 
Fundación SEIMC-GESIDA.  
C/ Agustín de Betancourt, 13-Entreplanta.  
Tel: +34 91 556 80 25 
Fax: +34 91 554 22 83 
email: secretaria@f-sg.org 
3.6 Ethics committee of reference identification
Hospital La Paz Research Ethics Committee (Comité Ético de Investigación Clínica, 
CEIC).  
Paseo de la Castellana, 261, 28046 Madrid. 
e-mail: ceic.hulp.@salud.madrid.org  
3.7 Expected duration 
After obtaining the approval of the study by La Paz Research Ethics Committee (Comité 
Ético de Investigación Clínica) and by the Spanish Agency for Medicines and Health 
Products (Agencia Española del Medicamento, AEMPS), it is intended to carry out the 
study according to the following work plan: 
i. 
Duration of the participant selection period: 9 months. 
ii. 
Duration of the follow-up period: 96 weeks. 
iii. 
Data analysis and preparation of the final report: 6 months. 
4. BACKGROUND AND JUSTIFICATION  
DTG/3TC is a dual regimen combination recommended for both naïve and suppressed 
persons with HIV-1 infection8. With the advent of DTG/3TC single tablet, a massive roll 
out of this antiretroviral therapy combination could be expected. Yet, data in treatment-
experienced persons with past VF or resistances is currently insufficient to guarantee 
the robust benefits that DTG/3TC has already proved in large multicentric studies 
including naïve and suppressed persons without past resistances2,9.  
3TC resistance-associated mutations are frequent in persons with past VF, with 
prevalence ranging from 34 to 96% depending on the setting, and the 2019 WHO HIV 
drug resistance report listing the M184V mutation as the most frequent mutation 

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associated with acquired NRTI drug resistance 10–12. A retrospective study analysing 
32,440 retrotranscriptase (RT) sequences of treatment-experienced persons found that 
about one third had codon 184 substitutions13. However, our group has demonstrated 
that 3TC resistance-associated mutations may not be detectable overtime as proviral 
DNA in suppressed persons detected only 26.9% of past M184V/I mutations14. At 
present, it is still unknown if proviral DNA genotyping in virologically suppressed patients 
can predict the efficacy of a given treatment, as this assay may not detect all previously 
existing drug-resistance mutations15–17. The importance of detecting minority resistant 
populations in proviral DNA is even more questionable since a high proportion of 
archived HIV is non replicating18,19. In addition, there is currently very little information on 
the relevance of those minority resistant populations detected by NGS, but not through 
proviral DNA population sequencing. To our knowledge, no study has prospectively 
investigated the dynamics of archived minority resistant variants in the presence of the 
drug to which they are theoretically resistant.  
Studies in virologically failing patients have shown that 3TC retains antiviral efficacy 
despite evidence of 3TC resistance-associated mutations20–22. The MOBIDIP study was 
the first trial evaluating a dual regimen including 3TC for maintenance of HIV suppression 
in persons with history of 3TC resistance-associated mutations. In said study, 265 
virologically suppressed participants- 96% of whom had a historical genotype detecting 
the M184V mutation- were randomized to either boosted protease inhibitor monotherapy 
or to 3TC plus boosted protease inhibitor. The study was prematurely discontinued after 
48 weeks because the proportion of VF with boosted protease inhibitor monotherapy 
was significantly higher compared to 3TC plus boosted protease inhibitor (difference 
between groups 21.8%)11. Considering these results and in the context of past 3TC 
resistance, it is reasonable to contemplate that combining 3TC to another drug with a 
high genetic barrier such as DTG would also succeed in maintaining virologic 
suppression. 
Reintroducing 3TC paired with DTG has shown promising results as maintenance 
therapy in persons with past 3TC resistance. The current scarce evidence for this 
strategy comes mostly from retrospective cohort analysis, a small number of participants 
from the DOLULAM study and four participants from the TANGO study who were found 

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to have the M184V mutation in proviral DNA at baseline and remained with virologic 
suppression through 48 weeks3–5,23. 
The only study prospectively evaluating the efficacy of DTG/3TC in suppressed persons 
with past 3TC resistance is our pilot study ART-PRO6, where we hypothesized that this 
combination would be effective in maintaining virologic control in integrase naïve persons 
if 3TC resistance-associated mutations were not detected on baseline proviral DNA 
Sanger sequencing. In our study, 18/21 persons with past M184V/I mutations, not 
detected at baseline through proviral DNA Sanger sequencing, were switched to 
DTG/3TC and have maintained virologic control for 96 weeks without any case of VF7. 
The three participants that did not reach week 96 were discontinued due to a DTG-
related insomnia and two protocol violations, where two participants included in the study 
had baseline M184V mutation and thus were prematurely removed from the study at 
week 12, despite sustaining undetectable VL (<50 copies/mL). Interestingly, archived 
3TC-resistance associated mutations were detected at baseline through NGS over the 
5% threshold in more than half of participants with past 3TC resistance, without any 
detrimental effect on viral control. Although showing promising results, ART-PRO study’s 
generalizability is limited due to the small size and the exclusion of participants exposed 
to integrase inhibitors.  
Reusing 3TC in persons with past resistance combined with DTG would not only open 
the possibility to recycle 3TC but would also allow access to a simplified regimen 
endorsed by guidelines in participants who, owing to previous VF, are frequently 
excluded from clinical studies and treated with complex antiretroviral combinations that 
may include high pill burden or risk of toxicity. Therefore, we believe it is reasonable to 
perform a fully powered study designed to confirm the initial favourable results of our 
pilot study ART-PRO.  
 
5. HYPOTHESIS AND OBJECTIVES 
5.1 Hypothesis  
Our hypothesis is that therapy with DTG/3TC would be able to maintain viral control in 
HIV infected participants with prior history of 3TC resistance but without evidence of 
M184V/I resistance mutation in proviral DNA population sequencing at baseline.  We 

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also hypothesize that archived minority 3TC resistance associated mutations detected 
by next-generation (NGS) sequencing prior to the switch would not have a significant 
impact on the efficacy of DTG/3TC.  
5.2 Objectives  
Primary objective 
Primary endpoint 
To assess the efficacy of a switch to DTG/3TC
for maintenance of virologic suppression at 48 
weeks in persons with past confirmed or 
suspected 3TC resistance, when proviral DNA 
population sequencing does not detect 3TC 
resistance-associated mutations at baseline. 
 
Proportion of virologic failure (VF) defined as 
HIV-1 RNA viral load (VL) 50 copies per mL 
at 48 weeks (in the intention-to-treat-exposed 
population (ITT-e) using the US Food and 
Drug 
Administration 
(FDA) 
snapshot 
algorithm). 
 
Secondary objectives 
Secondary endpoints 
To evaluate other estimations of virological 
control at weeks 48 and 96.  
- 
Proportion of VF ( 50 copies/mL) at week 
96, ITT-e, FDA snapshot.  
- 
Proportion of VF ( 50 copies/mL) at week 
48 and 96, per protocol population (PP), 
FDA snapshot.  
- 
Proportion of VF ( 200 copies/mL) at 
week 48 and 96, ITT-e and PP population, 
FDA snapshot. 
-
Proportion 
of 
Confirmed 
Virologic 
Withdrawal ([CVW]: A VL  50 copies/mL 
followed by a VL  200 copies/mL in re-
test) at weeks 48 and 96, ITT-e and PP 
population, FDA snapshot. 
- 
Proportion of Precautionary Virologic 
Withdrawal ([PVW]: three consecutive VL 
between 50- 200 copies/mL) at weeks 48 
and 96, ITT-e and PP population, FDA 
snapshot. 
- 
Proportion of participants with VL<50 
copies/mL week 48 and 96, ITT-e and per 

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protocol population, FDA snapshot.
To assess viral resistance in persons 
experiencing VF. 
 
-
Incidence of VF with drug resistance 
associated mutations. 
-
Describe number and type of resistance-
associated mutations in VF 
To evaluate factors associated with VF.
 
-
Analysis of factors associated to VF (i.e 
time to VF). 
- 
Proportion 
of 
VF 
in 
pre-specified 
subgroups: 
- 
Confirmed historical M184V/I vs No 
resistance mutations
- 
INSTI exposure vs No prior INSTI 
exposure 
- 
Time virologically suppressed  
- 
Time on 3TC/FTC 
To assess the impact of baseline archived 
minority 3TC resistance-associated mutations 
in viral control (in cases of VF and transient 
viral rebounds [VL 50copies/mL preceded 
and followed by VL<50 copies/mL]). 
- 
Proportion of participants with VF with 
baseline 
3TC 
or 
INSTI 
resistance- 
associated 
mutations 
detected 
at 
baseline by NGS with 1, 5, and 20% 
threshold. 
- 
Proportion of participants with transient 
viral rebounds with baseline 3TC or INSTI 
resistance- 
associated 
mutations 
detected at baseline by NGS with 1, 5, 
and 20% threshold. 
To evaluate the dynamics of archived minority 
3TC resistance-associated mutations after 
switching to DTG/3TC at 96 weeks.  
Type and frequency of resistance mutations 
(RT and integrase) in proviral DNA measured 
by NGS at baseline and week 96. 
To evaluate the immune effects of switch to 
DTG/3TC 
Change from Baseline in CD4+ cell count and 
in CD4+/CD8+ cell counts ratio at weeks 48 
and 96  
To evaluate the safety and tolerability of 
DTG/3TC in this study 
- 
Incidence and severity of AEs and 
laboratory abnormalities through week 48 
and 96. 

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-
Proportion of subjects who discontinue 
treatment due to AEs through weeks 48 
and 96. 
*Intention- to -treat-exposed (ITT-e) includes all participants receiving at least one dose 
of DTG/3TC. 
**Per protocol (PP) analysis excludes participants with protocol violations, lost to follow-
up and those with low adherence (adherence at or below the 2.5th percentile of those in 
the study).  
6. TYPE OF CLINICAL STUDY AND DESIGN  
6.1 Clinical study phase 
Phase IIa study.  
6.2 Study design 
Open, single-arm, multicentric study evaluating the efficacy and safety of DTG/3TC as 
maintenance therapy for HIV-1 virologic suppression in persons with historical 3TC 
resistance.  
The study consists of a Screening phase (maximum 60 days prior to day 1), and a Switch 
phase (day 1).  
The study will screen for adult participants with HIV infection with history of confirmed or 
suspected resistance to 3TC receiving stable ART for at least 12 weeks and virologically 
supressed for at least one year prior to the study entry. Participants who provide informed 
consent and meet inclusion criteria will be screened in order to enrol 120 subjects.  
On day 1 all participants who meet study entry criteria will be switched to DTG/3TC. 
There will be two groups: one group with confirmed historical 3TC resistance mutation, 
that is, with the M184V/I in an historical RNA Sanger genotype (minimum 30%-50% of 
the study population), and another group with suspicion of 3TC resistance based on 
clinical and virological history. No participant with M184V/I or K65R detected in screening 
proviral DNA population sequencing will be allowed to enter the study. Participants will 
attend study centres at screening, baseline, weeks 4, 12, 24, 36, 48 (primary efficacy 
endpoint), 72 and 96 (secondary efficacy endpoint, end-of-study visit). Primary endpoint 
is proportion of virologic failure at 48 weeks, following the FDA snapshot algorithm, ITT-

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21
e analysis. There will be a safety analysis at week 24 and also a “stopping rule”
throughout the study, whereby if two cases of confirmed (CVW) or precautionary
virologic withdrawal (PVW) occur with INSTI resistance at any timepoint, the study will 
be terminated (see section 7.4 for definitions for CVW and PVW). Procedures described 
in this protocol will be performed at each visit, including blood sampling for hemogram, 
biochemistry, HIV viral load and CD4 count. At screening and week 96, proviral DNA 
NGS will be performed. RNA sanger genotype and proviral DNA NGS will be performed 
in all cases of CVW and PVW.
Overall study design: 
This study will be conducted in compliance with the protocol, Good Clinical Practice, and 
all applicable regulatory requirements.
7. PARTICIPANT SELECTION
Subjects will be offered to participate in the study on the basis of the following eligibility 
criteria.

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7.1 Inclusion criteria 
a. Adults (  18 years old) with HIV-1 infection able to understand and give informed 
written consent. 
b. Stable ART in the 12 weeks prior to study entry.  
- 
Only switch for tolerability/convenience/access reasons to generic drugs 
or switch from ritonavir to cobicistat or TDF to TAF would be allowed in 
the 12-week window and as long as the components of the regimen are 
unchanged.  
c. Viral load <50 copies/mL at screening and in the year prior to study entry. 
- 
A blip (50-500 copies/mL) would be allowed within 48 weeks prior to 
inclusion in the study, if preceded and followed by an undetectable VL 
determination (HIV-RNA <50 copies/mL).  
d. CD4+ count > 200 cells/µL at screening.  
e. History of 3TC resistance: either confirmed historical 3TC resistance (historical 
RNA Sanger or RNA NGS>20% threshold genotype with M184V/I mutation) OR 
suspected historical 3TC resistance. 
- 
Suspicion of past 3TC resistance is defined as any of the following: 
i. Previous treatment with only 2 NRTIs (1 of them being 
emtricitabine or 3TC [XTC]). 
ii. Two consecutive VL > 200 copies/mL while on treatment including 
XTC. 
iii. One VL > 200 copies/mL while on treatment including XTC PLUS 
change of ART as consequence of that elevated VL.  
7.2 Exclusion criteria 
a. Participants with M184V/I or K65R in screening visit proviral DNA Sanger 
genotype.  
b. Prior virologic failure (VF) under integrase inhibitor (INSTI)- based regimen. 
defined as two consecutive VL > 200 copies/mL while receiving INSTI regardless 
of genotypic test results  
c. INSTI resistance mutations in historical RNA genotype 

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d. Documented resistance to DRV defined as the presence of a combination of 
mutations scored with at least 15 points in the Stanford University HIV Drug 
Resistance Database. 
e. Positive Surface Hepatitis B Ag (HBAgS) OR negative HBAgS and negative 
hepatitis B surface antibody (anti-HBs) with positive anti-core antibody (anti-HBc) 
and positive HBV DNA.  
f. Pregnant, breastfeeding women, women with a positive pregnancy test at the 
time of screening, sexually active fertile women wishing to conceive or unwilling 
to commit to contraceptive methods (see Appendix 1 for the accepted list of the 
highly effective methods for avoiding pregnancy), for the duration of the study 
and until 4 weeks after the last dose of study medication. All women are 
considered fertile unless they have undergone a sterilizing surgery or are over 
the age of 50 with spontaneous amenorrhea for over 12 months prior to study 
entry. 
g. Patients with active opportunistic infections or cancer requiring intravenous 
treatment and/or chemotherapy at screening.  
h. Any comorbidities or treatment with experimental drugs that according to the 
investigator could bias study results or entail additional risks for the participant.  
i. 
Participants receiving other medications that according to study drug label are 
contraindicated. 
j. 
Severe hepatic impairment (Class C) as determined by Child-Pugh classification. 
k. Alanine aminotransferase (ALT) over 5 times the upper limit of normal (ULN) or 
ALT over 3xULN and bilirubin over 1.5xULN.  
l. 
Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (apart from hyperbilirubinemia or 
jaundice due to Gilbert's syndrome or asymptomatic gallstones); 
m. Creatinine clearance of <30 mL/min/1.73m2 via CKD-EPI method. 
n. Any verified Grade 4 laboratory abnormality that to the investigators criteria would 
affect the safety of the participant if included in the study. 
o. History or presence of allergy to dolutegravir or lamivudine.  

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7.3 Estimated sample size 
In previous studies of switch to DTG/3TC the rate of VF at week 48 has been 0.7%24. 
With 120 participants recruited, and considering the same proportion of VF, we could 
rule out differences in the proportion of VF > 4% with a binomial estimation of the 95% 
confidence interval (power 80%, alpha 5% bilateral). 
There will be two groups of participants: one with confirmed history of 3TC resistance 
based on historical RNA genotype and another one with suspected 3TC resistance 
based on clinical and virologic history. The group with confirmed 3TC resistance will 
comprise at least between 30-50% of the estimated sample size.  
7.4 Withdrawal criteria and loss to follow-up 
In accordance with the current revision of the Declaration of Helsinki (Fortaleza, Brazil 
October 2013)25 and with the applicable regulations, a participant has the right to 
withdraw from the study at any time and for any reason, without prejudice to the medical 
care provided by his doctor and /or referral centre in the future. A participant may be 
withdrawn from the study in the following scenarios: 
- 
Participant withdraws consent.  
- 
For safety reasons. In particular, subjects will be withdrawn from the study if any 
of the following occur:  
i. 
If adverse events (AEs) appear and, due to their type or severity, 
cause the participant not to remain in the study. See Appendix 
2: Toxicity Management. 
ii. 
Pregnancy. 
iii. 
Subject is incorrectly included in the study based on 
exclusionary screening proviral DNA lamivudine resistance or 
any other protocol exclusion criteria.  
iv. 
Subject meets criteria for Confirmed Virologic Withdrawal or 
Precautionary Virologic Withdrawal.  
 
 Confirmed Virologic Withdrawal (CVW):  
o A VL  50 copies/mL followed by a VL  200 
copies/mL in re-test 2-4 weeks apart. 
 
Precautionary Virologic Withdrawal (PVW) 

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25
o Three consecutive VL 50-200 copies/mL (each VL 
separated 2-4 weeks). 
- 
At investigator discretion based on good clinical practice guidelines and clinical 
judgement deeming the participant ineligible to continue the study. 
- 
Transfer to another hospital that is not a participating centre in the study.  
- 
Loss to follow-up. 
- 
The participant is not willing to comply with the procedures required in the 
protocol.  
The causes leading to withdrawal from the study will be clearly recorded in the Clinical 
Research Document (CRD). A specific Withdrawal Visit will be scheduled to detail the 
participant’s evolution, date of treatment discontinuation and new prescribed therapy (if 
applicable). If any ongoing AE is present at the time of Withdrawal Visit, the participant 
will be followed until its resolution or stabilization.  
Participants discharged from the study will return to usual care according to the local 
guidelines and clinical practice. 
Withdrawn participants may be replaced to achieve the estimated sample size, provided 
the stopping rule does not apply.  
7.5. Security stop rules 
Study will be terminated at any timepoint if two cases of CVW or PVW with development 
of INSTI resistance occur. 
A security analysis will take place at week 24. Study will be prematurely discontinued if 
less than 80% participants in the per protocol population have VL<50 copies/mL (FDA-
Snapshot algorithm).  
7.6 Recruitment period 
Study recruitment period is estimated in nine months, alternatively, until sample size is 
achieved.  
A 60-day window is established between screening visit and day 1 visit.  
If CD4+ count or VL inclusion criteria are not met on first screening visit, one re-screening 
visit within 4 weeks would be allowed per participant. Re-screening visit will only be 

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performed if deemed appropriate by Medical Monitor and the investigator after detailed 
review of clinical history and mitigating factors. 
8. STUDY TREATMENT 
8.1 Study treatment 
DTG/3TC (Dovato®).  
8.2 Dosage 
Dovato® (Dolutegravir 50 mg/Lamivudine 300 mg film-coated tablet): 
Route of administration: oral.  
Dose: Dolutegravir 50 mg/Lamivudine 300 mg/day.  
Dosage: one 50 mg/300 mg film coated-tablet once daily.   
Intervention: change of current antiretroviral treatment by DTG 50 mg/3TC 300 mg QD. 
8.3. Packaging and labelling 
Dovato® will be supplied by the hospital Pharmacy Department of each participating site 
for the treatment of their respective patients, dispensed in a controlled fashion and 
according to hospital directives. 
The containers of Dovato® will be provided by the study Sponsor and the labelling for 
the study will be done by an outside agent in accordance with current national legislation.  
8.4 Treatment compliance 
Treatment adherence will be assessed by active questioning at study visit plus pill count, 
every visit from week 4 through week 96/end of study. Study drug will be labelled 
according to subject identification code, visit number and date. At every visit, the 
remaining medication will be returned by the participant to be counted and collected, and 
new medication will be assigned.  
8.5 Other treatments permitted and prohibited 
At study initiation, all concomitant medications will be recorded in the CRD and checked 
for potential drug-drug interactions at “https://www.hiv-druginteractions.org/checker". 

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Thereafter, all changes in medication will be detailed in the CRD. Additionally, all 
diagnostic, therapeutic or surgical procedures performed during the study period will be 
recorded, including date, indication, description of the procedure and clinical findings. 
Prohibited drugs 
The following medications or their equivalents can cause a decrease in the concentration 
of DTG and therefore should not be administered simultaneously with DTG. 
 
Carbamazepine 
 
Oxcarbamazepine 
 
Phenobarbital 
 
Phenytoin 
 
Rifampin or rifapentine 
 
St. John’s wort 
DTG/3TC is contraindicated with co-administration of medicinal products with narrow 
therapeutic windows, that are substrates of organic cation transporter (OCT2), including 
but not limited to fampridine (also known as dalfampridine). Co-administration has the 
potential to cause seizures due to increased fampridine plasma concentration.  
NOTE: DTG should be administered 2 hours before or 6 hours after medicines with 
divalent cations (Ca++, Fe++), multiple vitamin supplements or antacids containing 
aluminium or magnesium salts.  
All treatments considered experimental will be prohibited during the study. 

 
 
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9. STUDY DEVELOPMENT AND PROCEDURES 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
 
V9 
Week 
Screening 
D1  
(Basal 
visit) 
W4 
 (±2 
days) 
W12  
(± 4 
days) 
W24  
(± 6 
days) 
W36  
(±6 
days) 
W48  
(± 6 
weeks)  
W72  
(±8 
days) 
W96 
 (±6 
weeks) 
Follow 
up 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
x 
x 
 
 
 
 
 
 
 
 
Screening visit 
assessments 
x 
 
 
 
 
 
 
 
 
 
Physical Exam† 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital signs and BMI 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Laboratory assessment 
(hemogram, chemistry 
including renal and hepatic 
function tests)
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Pregnancy test (if 
applicable), blood or urine 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Quantitative plasma HIV-1 
RNA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
CD4+ and CD8+ count 
cells/µL 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
PBMC proviral DNA RT 
Sanger sequencing  
 
x 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 1. Evaluation calendar per visit. 
† Physical exam will be performed symptom-orientated from day 1 (V1) onwards.  
A 60-day window is allowed between screening visit and day 1. Re-screening would only be allowed under special circumstances and 
careful evaluation by Medical Monitor and investigator (see section 7.6) 
For the endpoint visits (week 48 and 96) a ±6-week window is allowed.  
Withdrawal visit will be performed if any subject prematurely discontinues the study, see specific assessments in section 9.1  
All serious adverse events will be reported from the moment the written informed consent is signed (see section 11 [Study safety]).  
A Follow-up visit will be scheduled 28 days after the last dose of study medication to monitor and report any ongoing adverse event or 
laboratory abnormality considered to be potentially harmful for the participant. 
PMBC Proviral DNA RT, 
PR and INSTI NGS  
x 
 
 
 
 
 
 
 
x 
 
Dispense study treatment 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Study treatment pill count 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Concomitant Medication 
review 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

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9.1 Study visits and procedures
The study will be offered to participants that meet all the inclusion criteria and none of 
the exclusion criteria. There will be a total of 10 visits (screening, day 1, week 4, week 
12, week 24, week 36, week 48, week 72, week 96 and a follow-up visit).
Screening visit: 
Participants will receive the information relative to proceedings and study visits. If they 
agree to participate in the study, written informed consent should be signed before any 
procedure is performed. Screening assessments include: 
- 
Review of inclusion and exclusion criteria. 
- 
Demographic data: age, sex, race, country of origin 
- 
HIV infection data: HIV subtype, mode of transmission, HIV + diagnosis date, 
nadir CD4+, CDC stage, presence of previous AIDS diagnosis, HIV associated 
conditions, ART duration, time with VL <50 copies/ mL (excluding one blip [50-
500 copies/mL preceded and followed by a VL<50 copies/mL] in the year prior 
to study entry) , previous antiretroviral treatments (number, type, reasons for 
change, date of change),  resistance studies (resistance mutations detected in 
historical genotypic population studies, date of the genotypic study, viral load 
detected during the genotypic study).  
-
General medical history: previous illnesses, active diseases, active treatments, 
tobacco, alcohol and drug habits.  
- 
Physical exam including weight, height, BMI, blood pressure and heart rate.  
- 
Adverse events. 
- 
Laboratory assessments will include:  
o Hemogram 
o Chemistry: liver function tests, renal function tests, fasting lipids, 
glucose. 
o Pregnancy test in women of childbearing potential (blood or urine 

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sample) 
o AgHBs, antiHBc, antiHBs and HBV DNA in those with isolated antiHBc 
(if not performed in the 12 months prior to screening visit).  
o CD4+ and CD8+ count. 
o Viral load (quantitative plasma HIV-1 RNA) 
o PBMC DNA Sanger sequencing (RT): using Big Dye Terminator 
(Applied Biosystem), and the Stanford HIVDB algorithm to interpret 
resistance mutations  
o PBMC proviral DNA NGS sequencing (integrase, protease and RT) – 
sample will be saved to be performed retrospectively if participant 
continues to switch phase. For NGS, HIV-1 DNA will be extracted from 
PBMCs using the QIAamp® DNA blood minikit (Qiagen, Hiden, 
Germany) and a 3385 bp pol gene fragment will be amplified by nested 
PCR as described elsewhere26. NGS will be performed with Illumina in 
a Miseq instrument (Illumina, San Diego, CA, USA). Sequences wil be 
preprocessed with Prinseq-lite (http://prinseq.sourceforge.net/) and 
FLASH (http://www.cbcb.umd.edu/software/flash) programs27,28. The 
resulting aligned reads will be analyzed for HIV-1 drug resistance 
testing with PaSeq software (https://paseq.org/). The 1% threshold is 
for resistance interpretation. Baseline samples with 3TC or integrase 
resistance-associated mutations detected through NGS will undergo 
hypermutation 
analysis 
with 
Hypermut 
2.0 
software 
(https://www.hiv.lanl.gov/content/sequence/hypermut/hypermut.html).  
Day 1: 
- 
Review of inclusion and exclusion criteria. 
- 
Concomitant medication. 
- 
Adverse events. 
- 
Physical exam including weight, height, BMI, blood pressure and heart rate. 

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- 
Switch to study treatment: DTG/3TC 50/300 mg once daily. 
- 
Laboratory assessments will include:  
o
Hemogram.
o Chemistry: liver function tests, renal function tests, fasting lipids, 
glucose. 
o CD4+ and CD8+ count. 
o Viral load (quantitative plasma HIV-1 RNA). 
o Pregnancy test if women of childbearing potential (blood or urine 
sample) 
Visits week 4 to week 96: 
- 
Concomitant medication. 
- 
Adverse events. 
- 
Physical exam including weight, height, BMI, blood pressure and heart rate. 
- 
The remaining study medication will be counted and collected, and new 
medication will be dispensed. 
- 
Laboratory assessments will include:  
o Hemogram. 
o Chemistry: liver function tests, renal function tests, fasting lipids, 
glucose. 
o CD4+ and CD8+ count. 
o Viral load (quantitative plasma HIV-1 RNA). 
o Pregnancy test if women of childbearing potential (blood or urine 
sample). 
- 
Week 96 additional assessments:  
o PBMC proviral DNA NGS sequencing (integrase, PR and RT) 

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In the event of a VL  50 copies/mL at any time point between day 1 and week 96, a 
visit will be scheduled within 2-4 weeks to perform a VL re-test.  
A Follow-up visit will be scheduled 28 days after the last dose of study medication to 
monitor and report any ongoing adverse event and concomitant medication or 
laboratory abnormality considered to be potentially harmful for the participant.  
Investigators are allowed to perform additional assessments and procedures following 
local guidelines and clinical criteria (i.e vaccination, sexually transmitted infection 
screening), as long as they are not judged to interfere with study proceedings and are 
registered with detail in the medical history.  
After week 96 study visit, the investigator is responsible for ensuring that the 
participants have continued access to antiretroviral treatment.  
Withdrawal Study Visit: 
If at any given point the participant is prematurely discontinued from the study, for any 
of the specified reasons in section 7.4 a Withdrawal Study Visit will be performed and 
registered in the CRD. This visit will include:  
- 
Concomitant medication. 
- 
Adverse events. 
- 
Physical exam including weight, height, BMI, blood pressure and heart rate. 
-
Pregnancy test if women of childbearing potential (blood or urine sample).
- 
The remaining study medication will be counted and collected. 
- 
Laboratory assessments will include:  
o Hemogram. 
o Chemistry: liver function tests, renal function tests, fasting lipids, 
glucose. 
o CD4+ and CD8+ count. 
o Viral load (quantitative plasma HIV-1 RNA). 

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- 
If CVW or PVW occur, resistance test (RNA Sanger sequencing, integrase, PR 
and RT, ViroSeq HIV-1 Genotyping System (Abbott Molecular, Spain) and 
PBMC proviral DNA NGS sequencing (integrase, PR and RT) will be 
performed.  
9.2 Biological samples  
All genotyping analysis will be centralized in 12 de Octubre University Hospital:  
a. Proviral DNA population sequencing (Sanger, RT) and NGS (RT, PR, integrase) 
i. Sample: PBMC (10 mL blood, CPT tube). 
ii. Screening visit and also week 96 for NGS. 
b.  RNA population sequencing (Sanger, RT, PR, integrase) and PBMC proviral DNA 
NGS sequencing (integrase, PR and RT) in the event of CVW or PVW: 
i. Samples: Peripheral blood (10 mL blood, CPT tube) and PBMC (10 mL blood, 
EDTA tube). 
ii. Any timepoint throughout the study.  
10. EVALUATION CRITERIA: STUDY VARIABLES  
10.1 
Primary endpoint 
Proportion of virologic failure defined as HIV-1 RNA viral load 50 copies per mL at 48 
weeks, ITT-e population, using the US Food and Drug Administration (FDA) snapshot 
algorithm).  
ITT-e includes all participants receiving at least one dose of DTG/3TC.  
10.2 
Secondary endpoints 
a. Proportion of VF ( 50 copies/mL) at week 96, ITT-e, FDA snapshot.  
b. Proportion of VF ( 50 copies/mL) at week 48 and 96, per protocol population, FDA 
snapshot. Per protocol population excludes participants with protocol violations, lost 
to follow-up and those with low adherence (adherence at or below the 2.5th 
percentile of those in the study).  
c. Proportion of VF ( 200 copies/mL) at week 48 and 96, ITT-e and PP population, FDA 

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35
snapshot. 
d. Proportion of CVW at weeks 48 and 96, ITT-e and PP population, FDA snapshot. 
e. Proportion of PVW at weeks 48 and 96, ITT-e and PP population, FDA snapshot. 
f. Proportion of participants with VL<50 copies/mL week 48 and 96, ITT-e and PP, FDA 
snapshot. 
g. Incidence of VF with drug resistance associated mutations. 
h. Description of number and type of resistance-associated mutations in VF. 
i. 
Analysis of factors associated to VF (i.e time to VF). 
j. 
Proportion of VF in pre-specified subgroups: 
- 
Confirmed historical M184V/I vs No documented resistance mutations. 
- 
INSTI exposure vs No prior INSTI exposure. 
- 
Time virologically suppressed  
- 
Time on 3TC/FTC. 
k. Proportion of participants with VF with baseline 3TC or INSTI resistance- associated 
mutations detected at baseline by NGS with 1, 5, and 20% threshold. 
l. 
Proportion of participants with transient viral rebounds with baseline 3TC or INSTI 
resistance- associated mutations detected at baseline by NGS with 1, 5, and 20% 
threshold. 
m. Type and frequency of resistance mutations (RT and integrase) in proviral DNA 
measured by NGS at baseline and week 96. 
n. Change from Baseline in CD4+ cell count and in CD4+/CD8+ cell counts ratio at weeks 
48 and 96. 
o. Incidence and severity of AEs and laboratory abnormalities through week 48 and 96. 
p. Proportion of subjects who discontinue treatment due to AEs through weeks 48 and 
96. 
q. Descriptive demographic and clinical variables: 
- 
Demographic data: age, sex, race, country of origin 
- 
HIV infection data: HIV subtype, mode of transmission, HIV + diagnosis date, 
nadir CD4+, CDC stage, presence of previous AIDS diagnosis, HIV associated 
conditions, ART duration, time with viral load <50 copies/mL (excluding one blip 
[50-500 copies/mL preceded and followed by a VL<50 copies/mL] in the year 
prior to study entry) , previous antiretroviral treatments (number, type, reasons 

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for change, date of change), resistance studies (resistance mutations detected 
in historical genotypic population studies, date of the genotypic study, viral load 
detected during the genotypic study, time since the virological failure or 
interruption of antiretroviral treatment and the completion of the genotypic study. 
-
General medical history: previous illnesses, active diseases, active treatments, 
tobacco, alcohol and drug habits. 
- 
Physical exam including weight, height, BMI, blood pressure and heart rate.  
- 
Laboratory assessment variables: Haemoglobin, leukocytes, lymphocytes, 
neutrophils, CD4+ and CD8+, GOT, GPT, GGT, Bilirubin, Creatinine, Ions, total 
cholesterol, HDL, LDL, triglycerides, glucose.  
10.3 
Bias control and limitations 
The absence of 3TC resistance mutations in the population genotype of proviral DNA 
Sanger does not guarantee the success of DTG/3TC treatment. However, based on the 
results from our pilot study ART-PRO29, we believe that this is a reasonable working 
hypothesis. If any case of VF occurred, proviral DNA RT+ INSTI NGS for retrospective 
analysis will allow to detect if any archived resistance minority variants were present at 
baseline and could therefore be the cause of failure.  
Proviral HIV analysis could be limited by the number of latently infected CD4 
lymphocytes present in the sample, so PBMCs will be used to ensure maximum 
resistance detection capacity. 
Objective primary and secondary endpoints will allow to reduce the potential bias 
associated with the open label design of the study. 
 
 
 
 
 
 

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11 STUDY SAFETY 
11.1 
Drug safety reference information 
In this study, the reference safety information will be the European Medicine Agency 
Dovato® product information30. 
11.2 
Definitions 
Adverse event (AE): 
Any medical event presented by a clinical research subject to whom a pharmaceutical 
product has been administered and does not necessarily have to have a causal 
relationship with said treatment.  
The following will be registered as an AE: 
- 
Significant or unexpected worsening of the condition to be treated during the 
study. 
- 
Exacerbation of pre-existing chronic, intermittent or episodic diseases, including 
an increase in frequency and /or severity. 
- 
A new condition detected or diagnosed after the administration of the product 
under investigation, even if it could have been present before study initiation.  
- 
Suspicious clinical signs, symptoms or sequelae. 
-
Clinical signs, symptoms or sequelae of a suspected overdose of the medicinal 
product under investigation or concomitant medication. 
- 
Obvious failure of the expected biological or pharmacological effect. 
- 
Any medical reaction before, during or after the treatment resulting from the 
procedures specified in the protocol, such as those derived from sampling. 
- 
Grade III-IV laboratory events, as classified by DAIDS toxicity scales31. 
It will not be considered, and therefore not recorded as an AE: 
- 
Medical or surgical procedures due to the course of the disease allowed in the 
clinical study. 
- 
Situations leading to hospital admission for social or convenience reasons, 

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without any medical underlying reasons.  
-
Clinical signs, symptoms or sequelae of the study disease or its expected 
progression. 
Serious adverse event (SAE): 
Any medical event leading to:  
-
Death
- 
Life endangerment 
- 
Hospital admission, prolongation of existing hospital admission  
- 
Persisting or significant disability / incapacity, or results in a congenital 
anomaly or defect. 
- 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or 
ALT  3xULN and INR>1.5 (if INR measured) which may indicate severe liver 
injury must be reported as a serious adverse event (excluding studies of 
hepatic impairment or cirrhosis). 
- 
Events not included in the preceding paragraphs but that may endanger the 
participant or require intervention to prevent any of the abovementioned 
results. Examples of such events are intensive treatment in an emergency 
department or at home for an allergic bronchospasm; blood dyscrasias or 
seizures that do not lead to hospital admission, or the development of 
dependence or drug abuse. 
For notification purposes, suspicions of AEs that are considered medically important will 
be treated as serious, even if they do not meet the above criteria, such as those that put 
the participant at risk or require intervention to prevent any of the abovementioned 
outcomes.  
Unexpected Serious Adverse Reaction (SUSAR):  
Any serious adverse event which nature, severity or consequences are not consistent 
with the available product information. 

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11.3 
Casualty evaluation 
Investigators will assess casualty of the AE with the study medication according to the 
following definitions: 
 
Relatedness Rating
Definition
 
 
Related 
An adverse event in which there is a reasonable possibility of a causal relationship to 
the use of the study drug. ‘A reasonable possibility’ is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship. Facts/evidence or 
arguments that may support ‘a reasonable possibility’ include, e.g. a temporal 
relationship, a pharmacologically-predicted event, or positive dechallenge or 
rechallenge. Confounding factors, such as concomitant medication, a concurrent 
illness, or relevant medical history, should also be considered. 
Not Related 
An adverse event which is not related to the use of the drug. 
11.4 
Intensity evaluation 
The intensity of the AE will be graded following the DAIDS grading table for Severity of 
AEs31.  
11.5 
Safety variables and parameters 
To investigate AEs, investigators will enquiry at every visit for AEs. To avoid bias and to 
promote spontaneous report of AEs, questions addressed to participants will be open 
and are not to have a leading nature. Questions may be as:  
- 
How are you? 
- 
Have you presented any symptoms since the last visit?  
- 
Have you needed evaluation by another healthcare professional?  
- 
Have you visited any emergency department? 
- 
Have you taken any other medications besides antiretroviral treatment since the 
last visit? If so, why? 
11.6 
Adverse events information 
All SAEs and AEs will be collected from the signing of the ICF until the follow-up visit.  

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All AEs occurring during the study, until the end of the follow-up period, whether or not 
they are attributed to the study medication, will be evaluated by the investigator and 
recorded in detail in the CRD. Data on the description of the AE, start and end date, 
severity/intensity, causality with the investigational drug product, evolution, outcome of 
the AE and measures adopted (treatments, additional complementary examinations) will 
be recorded, including those related to the investigational medication (eg, suspension). 
Regardless of the causal relationship with the study drug, all AE will be followed until 
resolution or until considered stable. The investigator is authorized to judge if the severity 
of the AE requires discontinuation of the treatment or participant withdrawal from the 
study. Participants may also voluntarily withdraw if they perceive an AE as not tolerable. 
A Follow-up visit will be scheduled 28 days after the last dose of study medication to 
monitor and report any ongoing adverse event or laboratory abnormality considered to 
be potentially harmful for the participant.  
The outcome of the AE will be evaluated as follows: 
- Resolved. 
- Improved 
- Unchanged. 
- Worsening. 
- Death. 
Action taken by the investigators with regards to the study medication: 
- None. 
- Discontinuation.  
- Interruption. 
- Dose reduction. 
- Delay in the beginning of treatment. 
 
11.7 
Pregnancy 
Female participants will be instructed to notify the investigator if they become pregnant 
at any time during the study.  

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Women of childbearing potential should be informed about the potential risk of neural 
tube disorders with DTG (see Appendix 1 ). These defects happen early in pregnancy, 
before women may know they are pregnant. 
Women of childbearing age should use an appropriate contraceptive method for the 
duration of the study and up to 4 weeks after completion (see Appendix 1, Guidance on 
Pregnancy and Breast Feeding). The chosen contraceptive method will be documented 
in the subject’s medical records. Women of childbearing potential will be informed of the 
potential risk of neural tube defects and will be counselled on avoiding pregnancy, safer 
sexual practices and the proper use of their chosen contraceptive methods.  
A pregnancy test (blood or urine) will be performed at every study visit. Any pregnancy 
occuring within the study will result in immediate withdrawal from the study and 
discontinuation of study drug treatment. 
Each pregnancy will be notified to the Medical Monitor as soon as it is known to the 
investigator. Information will be recorded on the appropriate form (see Appendix 5 and 
6) and submitted to the Sponsor within 24 hours of of learning of a subject's pregnancy. 
All pregnancies should also be reported to ViiV Healthcare within 1 week, regardless of 
causality. Additionaly, pregnancies will be registered in the AntiretroviralPregnancy 
Registry (www.apregistry.com).  
Pregnancy should be followed to determine the outcome, including spontaneous or 
voluntary termination, birth details, and the presence or absence of any defect such as 
congenital anomaly or complications for the mother and / or newborn. Pregnancy results 
should also be recorded for female partners of a male participant who is participating in 
the study. If the outcome of pregnancy meets SAE criteria or if the newborn has a SAE, 
the procedures described for the notification of SAE will be followed. Spontaneus 
abortions must be reported as a SAE. 
11.8 
Notification procedure of SAEs 
Investigators should notify the sponsor or whoever assumes the tasks delegated by the 
sponsor within a maximum period of 24 hours after learning of the existence of a SAE, 
with an accompanying SAE notification form.  
The investigator shall complete and sign the SAE report form (Appendix 6) and send it 
by fax: 
 

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915542283 
Fundación SEIMC-GESIDA 
C/ Agustín de Betancourt nº 13, entreplanta 
Madrid 28003 
 
and/or email to: pharmacovigilance@f-sg.org 
 
SAEs associated with DTG/3TC should also be reported to ViiV Healthcare within 24 
hours, regardless of casualty. The sponsor or whoever assumes the tasks delegated by 
the sponsor may request additional information from the investigator. The investigator 
will provide information to the sponsor or to those who assume the tasks delegated by 
the sponsor whenever requested and, in any case, when their initial evaluation changes 
in terms of severity or causality. The sponsor or whoever assumes the tasks delegated 
by the sponsor will keep a detailed record of all the SAEs communicated to them by the 
researchers. 
11.9 
Notification procedure of severe and unexpected adverse events (SUSAR) 
The sponsor or whoever assumes the tasks delegated by the sponsor, will notify all the 
suspicions of SUSAR according to the current regulations on clinical trials to the Spanish 
Agency of Medicine and Health Products (AEMPS), to the ethical committees (CEIC) 
and to the authorities of the Autonomous Community of Madrid within a maximum period 
of fifteen calendar days from the moment they are aware of their existence. When the 
SUSAR has caused the death of the participant or endangered his life, the notification 
will be made within a maximum period of seven calendar days from the moment in which 
it is known. The relevant information regarding subsequent events will be supplemented 
within eight days. 
The minimum initial information for the notification of an adverse event must include the 
following: 
- Adverse event and starting date. 
- Initials, sex and age (or date of birth) of the participant. 
- Information about the treatment received. 

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- Name and address of the doctor notifying the AE. 
- Causality relationship with the medication under study. 
12 ETHICAL ISSUES 
12.1 
 General and particular rules for investigators 
Investigators will strictly adhere to the provisions of this protocol, fully completing the 
data collection notebook sheets. 
The study will follow the prevailing recommendations for medical research involving 
human subjects, as reflected in the latest version of the Declaration of Helsinki and the 
current the applicable Spanish Legislation on Clinical Studies (RD 1090/2015, of 
December 4, which regulates clinical trials with medications). 
12.2 
Informed consent 
All participants will be informed before starting the study of the objectives, procedures, 
potential related inconveniences derived from said procedures, and the risks of the 
study. All subjects will receive a participant information sheet, along with the written 
informed consent that must be signed at screening visit before any procedure relating to 
the study is performed.  
12.3 
Safety and confidentiality procedures 
All information obtained from this study is considered confidential. The confidentiality of 
the personal and genetic data obtained will be protected, respecting at all times the basic 
ethical principles of research with biological samples, and as established by the 
applicable legislation (Regulation 2016/679 of the European Parliament and of the 
Council of 27 April 2016 on the protection of natural persons with regard to the 
processing of personal data and on the free movement of such data). 
Participants may at any time exercise their right to access and modify their information, 
as established by the Spanish Organic Law for Personal Data Protection 3/2018 and the 
European General Data Protection Regulation 2016/679. 

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In case of considering the participation in a new study, with a different objective to that 
indicated in the information sheet, the participant will be informed and new consent and 
permission to use the samples will be requested. Biological samples will not be used for 
other studies without the explicit permission of the participant and the approval of the 
CEIC. 
12.4 
Insurance 
There will be civil liability insurance policy for the trial as established in article 8 of RD 
1090/2015, of December 4. 
13 PRACTICAL CONSIDERATIONS 
13.1 
Responsibilities of participants in the study 
Rules for participants 
Participating subjects must follow the indications of the investigators and communicate 
any eventuality to them. 
Participants will be duly informed of the prohibitions or restrictions to which they must be 
adherent throughout the study. Failure to comply with these recommendations will imply 
abandoning the study. 
All subjects participating in the study have the right to leave the study at any time, 
withdrawing their consent, without having to justify this decision and without causing any 
detriment effect in their clinical follow-up. If this occurs, the investigator will try to ensure 
that the subject performs all the necessary evaluations to ensure that no adverse events 
occur and to ensure appropriate follow-up. 
Rules for investigators 
Investigators are obliged to comply with the norms established in the current legislation 
regarding clinical trials. 
Protocol compliance 
Protocol deviations should be avoided. If these occur, the investigator must inform the 

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monitor and the implications of such deviations will be reviewed and discussed among 
the investigation team. Deviations from the protocol will be documented specifying the 
reasons, date, action taken, and the impact on the participant and the trial. 
Documentation regarding deviations from the protocol will be stored in the Investigator's 
Archive. 
13.2 
Monitoring, auditing and inspection 
The study will be monitored by a monitor of SEIMC-GESIDA Foundation, who will 
prepare an appropriate monitoring plan for the study. Regular visits and phone calls will 
be made to investigators. During visits, the monitor should review participant and study 
drug records and documents, and the preservation of said documents. In addition, the 
monitor should evaluate the study procedures and discuss any problems with the 
investigator. During the course of the study, audit visits may be carried out in the 
participating centres. The investigators will allow direct access to the source data / 
documents for monitoring, auditing or review by the La Paz Research Ethics Commitee 
(Comité Ético de Investigación Clínica, CEIC) and inspection by the Health Authorities. 
13.3 
Study documentation 
All documentation related to the study (protocol, CRD, informed consent, 
authorizations...) will be archived during the study in a safe place and easily accessible 
by the research team. All information contained in clinical, histological, biochemical and 
molecular reports, observations or other activities are necessary for the reconstruction 
and evaluation of the study. Examples of these documents are hospital records, 
laboratory notes, memorandums, participant diary, evaluation checklists, medication 
dispensing record or other pharmacy documents, recording of data obtained from 
automated devices, digitized photo files, X-rays, etc. 
13.4 
Data management 
Processing, communication and transfer of personal data of all participating subjects will 
comply with the provisions of Organic Law 03/2018, on the protection of personal data. 
At the time of registration, a Participant Number will be assigned to each participant. This 
information will be registered in the CRD. The investigator will be responsible for keeping 
the appropriate information about each participant so that health authorities can have 

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access to such information if necessary. These records must be kept confidential for the 
period of time legally mandated by current regulations. 
13.5 
Publication conditions 
All information from the study will be considered confidential. The Principal Investigator 
assumes the set of responsibilities linked to this function, and the exclusive ownership 
of the results of the study, which may be freely exploited. Principal Investigator commits 
to publish the results of the study in a scientific journal or to make them available to the 
public as established by the Declaration of Helsinki, item 36: “Researchers, authors, 
sponsors, editors and publishers all have ethical obligations with regard to the publication 
and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results 
must be published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be accepted 
for publication”. 
13.6 
Procedure for the modifications of the protocol 
Any protocol modifications must be documented with a protocol amendment. 
Amendments will be duly identified by their chronological order number, dated and 
signed by the sponsor and the investigator. If the modifications are relevant, the sponsor 
must request authorization from the Reference CEIC and the AEMPS, as established by 
current regulations. 
13.7 
Ethics committee of research with medicines (CEIC) 
The protocol and the informed consent documents will be evaluated by the CEIC of La 
Paz University Hospital whose composition is already known and accredited by the 
health 
authorities 
of 
the 
Autonomous 
Community 
of 
Madrid 
(http://www.msssi.gob.es/profesionales/ pharmacy / ceic / pdf / ceicsacreditadoses.pdf). 
The decision of the CEIC regarding the development of the study will be provided in 
writing to the investigator. A copy of that decision must be sent to the sponsor. 

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The sponsor will present the required progress reports of the study to the CEIC and will 
communicate the suspicions of serious and unexpected adverse reactions. Upon 
completion of the study, the sponsor must inform the CEIC. 
14  STATISTICAL ANALYSIS 
14.1 
Sample size estimation 
In previous studies of switch to DTG/3TC the rate of virologic failure at week 48 has been 
0.7%24. With 120 participants recruited, and considering the same proportion of virologic 
failures, we could discard differences in the proportion of virologic failures >4% with a 
binomial estimation of the 95 confidence interval. 
14.2 
Statistical analysis  
In addition to main analysis, a security analysis will take place at week 24, to determine 
if study is to be continued (section 7.5). 
To compare two means we will use Student’s t test (if normal distribution) or non-
parametric Wilcoxon rank-sum (Mann-Whitney) test. If needed, an adjusted analysis 
would be performed. Proportions will be compared with x2 test.  
Endpoints will be analysed including the intention-to-treat exposed population, that is, all 
participants who received at least one dose study drug.  
Main Analysis – Primary endpoint: 
The main primary endpoint will be the proportion of virological failure HIV-1 RNA VL 50 
copies/mL, at 48 weeks, following FDA snapshot algorithm in the population “by intention 
to treat -exposed”. This result will be expressed as a percentage and 95% confidence 
interval. 
Secondary planned analysis -Secondary endpoints:  
a. Proportion of VF ( 50 copies/mL) at week 96, ITT-e, FDA snapshot. This result will 
be expressed as a percentage and 95% confidence interval. 
b. Proportion of VF ( 50 copies/mL) at week 48 and 96, PP population, FDA snapshot.  
c. Proportion of VF ( 200 copies/mL) at week 48 and 96, ITT-e and PP population, FDA 
snapshot. This result will be expressed as a percentage and 95% confidence interval. 

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d. Proportion of CVW at weeks 48 and 96, ITT-e and PP population, FDA snapshot. 
This result will be expressed as a percentage and 95% confidence interval. 
e. Proportion of PVW at weeks 48 and 96 ITT-e and PP population, FDA snapshot. This 
result will be expressed as a percentage and 95% confidence interval. 
f. Proportion of participants with VL<50 copies/mL week 48 and 96, ITT-e and PP 
population, FDA snapshot. This result will be expressed as a percentage and 95% 
confidence interval. 
g. Incidence of VF with drug resistance associated mutations. Descriptive analysis of 
number and type of resistance mutations.  
h. Univariant and multivariant logistic regression analysis of factors associated to 
virological failure (time to VF). 
i. 
Proportion of VF in pre-specified subgroups: 
- 
Confirmed historical M184V/I vs No resistance mutations. 
- 
INSTI exposure vs No prior INSTI exposure. 
- 
Time virologically suppressed. 
- 
Time on 3TC/FTC. 
j. 
Proportion of participants with VF with baseline 3TC or INSTI resistance- associated 
mutations detected at baseline by NGS with 1, 5, and 20% threshold. 
k. Proportion of participants with transient viral rebounds with baseline 3TC or INSTI 
resistance- associated mutations detected at baseline by NGS with 1, 5, and 20% 
threshold. 
l. 
Univariant and multivariant logistic regression model analysis of the association 
between 3TC or integrase resistance-associated mutations by NGS and potentially 
confounding variables reaching signification below 0.1 in the different univariant 
models.  
m. Logistic regression model analysis of the impact in virological response of mutations 
detected by NGS. 
n. Type and frequency of resistance mutations (RT and integrase) in proviral DNA by 
NGS at baseline and week 96. Hypermutation analysis of mutations detected through 
NGS.   
o. Univariant and multivariant logistic regression analysis of factors associated to 
change on frequency of resistance mutations detected by NGS at baseline and week 
96.  

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p. Incidence and severity of AEs and laboratory abnormalities grade III-IV through week 
48 and 96. 
q. Proportion of subjects who discontinue treatment due to AEs through weeks 48 and 
96. 
r. Change from Baseline in CD4+ cell count (W48 minus baseline and W96 minus W48) 
and in CD4+/CD8+ cell counts ratio at weeks 48 and 96.  
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research involving human subjects. World Med Assoc. 2013. 
26.  
Perrier M, Visseaux B, Landman R, et al. No impact of HIV-1 protease minority 
resistant variants on the virological response to a first-line PI-based regimen 
containing darunavir or atazanavir. J Antimicrob Chemother. 2018;73(1):173-176. 
doi:10.1093/jac/dkx366 
27.  
Schmieder R, Edwards R. Quality control and preprocessing of metagenomic 
datasets. Bioinformatics. 2011;27(6):863-864. doi:10.1093/bioinformatics/btr026 
28.  
genome 
assemblies. 
Bioinformatics. 
2011;27(21):2957-2963. 
doi:10.1093/bioinformatics/btr507 
29.  
De Miguel Buckley R, Rial-Crestelo D, Dominguez-Dominguez L, et al. 
Dolutegravir ( DTG ) and Lamivudine ( 3TC ) for Maintenance of HIV Viral 
- 
- Week Results of a Pilot Clinical Trial (ART-PRO). In: European AIDS 
Conference. 
30.  
Dovato. Summary of product characteristics. Eur Med Agency. 2019. 
doi:10.2307/j.ctvdf0dxq.12 
31.  
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, Corrected Version 2.1. [July 2017]. Natl Inst Allergy Infect Dis. 2017. 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf. 
 
 
 

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APPENDIX 1. GUIDANCE ON PREGNANCY AND BREAST FEEDING 
Preliminary results from an observational study revealed an increased risk of neural 
tube defects in infants born to women who took dolutegravir at the time of 
conception. Later data from the study has shown a numerically higher rate of neural tube 
defects with exposure to dolutegravir compared to non-dolutegravir-containing 
antiretroviral regimens at the time of conception, however, the difference was not 
statistically significant. A causal relationship of these events to the use of dolutegravir 
has not been established. No increased risk was reported in infants born to women who 
started dolutegravir later during pregnancy. 
Reproductive toxicology studies have not shown any relevant findings. Likewise, other 
data on the use of dolutegravir in pregnancy, including data from the Antiretroviral 
Pregnancy Registry (APR), clinical trials and post-marketing use have not indicated an 
increased risk of neural tube defects, although the extent of exposure from these other 
data sources is currently insufficient to confirm or rule out an increased risk of neural 
tube defects with DTG-containing regimens taken at the time of conception and in early 
pregnancy. 
Further information about this potential risk is provided in the Investigator Brochure for 
DTG-containing products and, where applicable, the approved Local Prescribing 
Information). 
Reproductive toxicity data for 3TC and DTG guidance on the use of these active principle 
in pregnancy, is given in the relevant approved Local Prescribing Information. 
A female, may be eligible to enter and participate in the study if she:  
 
a. 
is of non-child-bearing potential defined as either post-menopausal (12 months of 
pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or, 
b. 
is of child-bearing potential with a negative pregnancy test at both Screening and Visit 
1 and agrees to use one of the highly effective methods to avoid pregnancy documented 
below. 
 

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Women of childbearing potential should be informed about the potential risk of neural tube 
disorders with DTG. These defects happen early in pregnancy, before many women even know 
they are pregnant. 
Women of childbearing potential should be counselled about the importance of pregnancy 
avoidance, safer sexual practices and adherence to contraception requirements throughout 
the study, and for at least 4 weeks after the last study visit.  
Women of childbearing potential must be using a highly effective method of contraception as 
detailed below, which should be documented in the eCRF. 
Females of childbearing potential should be reminded about the importance of pregnancy 
avoidance and of adherence to contraception requirements at every study visit. 
If pregnancy is confirmed while taking DTG/3TC, treatment should be discontinued and the 
subject should be switched to an alternative regimen 
Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive potential: 
 
 
Complete abstinence from penile-vaginal intercourse from 2 weeks prior to administration 
of Investigational Product, throughout the study, and for at least 4 weeks after 
discontinuation of all study medications; 
 
Any intrauterine device with published data showing that the expected failure rate is <1% 
per year:  
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS) 
bilateral tubal occlusion. 
 
 
Male partner sterilization confirmed prior to the female subject’s entry into the study, and 
this male is the sole partner for that subject; 
 
Approved hormonal contraception: 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation: oral intravaginal or transdermal. 

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Progestogen-only hormonal contraception associated with inhibition of ovulation: injectable.
 
 
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 4 weeks after discontinuation of study medication.   
 
Reporting of pregnancy information  
Any pregnancy that occurs during study participation must be reported (see Appendix 5 
and 6). To ensure subject safety, each pregnancy must be reported to Sponsor within 
24 hours of learning of its occurrence. All pregnancies should also be reported to ViiV 
Healthcare within 1 week, regardless of causality. The pregnancy must be followed up 
to determine outcome (including premature termination) and status of mother and child, 
which must also be reported to Sponsor. Pregnancy complications and elective 
terminations for medical reasons must be reported as an adverse event or serious 
adverse event. Spontaneous abortions must be reported as a serious adverse event. 
Any serious adverse event occurring in association with a pregnancy brought to the 
investigator’s attention after the subject has completed the study and considered by the 
investigator as possibly related to the investigational product, must be promptly reported 
to Sponsor. 
Investigators are also encouraged to report any pregnancy that occurs during study 
participation to the Antiretroviral Pregnancy Registry (APR) prospectively, and before the 
pregnancy outcome. More information including copies of applicable case report forms 
and fax numbers are available at www.apregistry.com. 
 
 
 
 
 
 
 
 

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APPENDIX 2: RISK ASSESSMENT AND TOXICITY MANAGEMENT 
Reference safety information for this study is the Investigator Brochure and/or approved 
Local Prescribing Information for the study treatments. 
Here we summarized some risk and toxicity information, especially of DTG. 
The current key risks associated with the use of the DTG single entity or other DTG-
containing products are presented below. Further information on these, and other known 
or theoretical risks associated with the use of these products, is included in the 
Investigator Brochure for the DTG-containing products, and, where applicable, in the 
approved Local Prescribing Information.  
Risk Assessment  
Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
 
 
Investigational Product: dolutegravir/lamivudine 
Refer to Investigator Brochure and/or approved Local Prescribing Information for 
additional information 
 
Hypersensitivity 
and rash 
 
Hypersensitivity reactions has been 
observed uncommonly with DTG. 
Rash, generally mild to moderate in 
intensity, was commonly reported in 
DTG Phase IIb/III clinical trials. No 
episodes of severe rash, such as 
Stevens-Johnson Syndrome, toxic 
epidermal necrolysis and erythema 
multiforme, were reported.  
 
 
Subjects 
with 
history 
or 
presence of allergy to any of the 
study drugs or their components 
are excluded. 
Specific/detailed 
toxicity 
management 
guidance 
is 
provided 
for 
hypersensitivity 
reactions and rash. 
The subject informed consent 
form includes information on this 
risk and the actions subjects 
should take in the event of a 
hypersensitivity 
reaction 
or 
associated 
signs 
and 
symptoms. 

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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk
Mitigation Strategy
 
 
Investigational Product: dolutegravir/lamivudine
Refer to Investigator Brochure and/or approved Local Prescribing Information for 
additional information 
Drug 
induced 
liver injury and 
other clinically 
significant liver 
chemistry 
elevations 
Non-clinical 
data 
suggested 
a 
possible, 
albeit 
low, 
risk 
for 
hepatobiliary toxicity with DTG. Drug-
related hepatitis is considered an 
uncommon 
risk 
for 
antiretroviral 
therapy containing DTG regardless of 
dose or treatment population. For 
subjects with hepatitis B virus and/or 
hepatitis 
C 
virus 
co-infection, 
improvements in immunosuppression 
because of human immunodeficiency 
virus (HIV) virologic and immunologic 
responses 
to 
DTG-containing 
antiretroviral 
therapy, 
along 
with 
inadequate therapy for hepatitis B 
virus 
co-infected 
subjects, 
likely 
contributed to significant elevations in 
liver chemistries.  
There have been rare post-marketing 
reports of acute hepatic failure in 
association 
with 
DTG-containing 
regimens. 
 
Current treatment guidelines do not 
recommend mono-therapy with 3TC 
for patients with hepatitis B virus 
infection, which is what subjects on 
DTG/3TC 
would 
be 
receiving. 
Emergence 
of 
HBV 
variants 
Subjects meeting any of the 
following criteria during the 
screening period are excluded 
from participating  
 
Alanine 
aminotransferase 
(ALT) 
5 times the upper 
limit of normal (ULN) or ALT 
3xULN 
and 
bilirubin 
1.5xULN (with >35% direct 
bilirubin) 
 
Unstable 
liver 
disease, 
cirrhosis 
and/or 
known 
biliary abnormalities (except 
for 
hyperbilirubinemia 
or 
jaundice due to Gilbert's 
syndrome or asymptomatic 
gallstones) 
 
Subjects with an anticipated 
need for hepatitis C virus 
therapy 
with 
interferon 
and/or ribavirin prior to the 
primary endpoint 
 
Positive Surface Hepatitis B 
Ag (HBAgS) OR negative 
HBAgS 
and 
negative 
hepatitis B surface antibody 
(anti-HBs) with positive anti-
core antibody (anti-HBc) and 
positive HBV DNA.  
 
Specific/detailed 
liver 
stopping criteria and toxicity 
management guidance is 
provided for suspected drug 
induced liver injury or other 
clinically 
significant 
liver 
chemistry elevations  

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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk
Mitigation Strategy
 
 
Investigational Product: dolutegravir/lamivudine
Refer to Investigator Brochure and/or approved Local Prescribing Information for 
additional information 
associated with resistance to 3TC has 
been 
reported 
in 
HIV-1-infected 
patients who have received 3TC-
containing antiretroviral regimens in 
the presence of concurrent infection 
with 
HBV. 
Additionally, 
discontinuation of 3TC in hepatitis B 
virus infected subjects can result in 
severe exacerbations of hepatitis B 
virus.  
 
For subjects co-infected with hepatitis 
C virus and HIV, [some] treatment 
guidelines 
recommend 
that 
the 
hepatitis C virus infection is treated 
first before starting treatment for the 
HIV. Additionally, interferon and/or 
ribavirin toxicity maybe frequent and 
difficult to differentiate causality from 
investigational product. 
Theoretical 
serious 
drug 
interaction with 
dofetilide 
and 
pilsicainide 
Dolutegravir must not be administered 
concurrently with medicinal products 
with narrow therapeutic windows, that 
are substrates of organic cation 
transporter 2 (OCT2), including but 
not limited to dofetilide, pilsicainide or 
fampridine 
(also 
known 
as 
dalfampridine. 
The 
co-administration 
of 
DTG/3TC 
with 
dofetilide 
or 
fampridine are prohibited in the 
study. 
Psychiatric 
disorders 
Psychiatric 
disorders 
including 
suicide ideation and behaviours are 
Due to the elevated risk in the 
HIV-infected 
population, 

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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk
Mitigation Strategy
 
 
Investigational Product: dolutegravir/lamivudine
Refer to Investigator Brochure and/or approved Local Prescribing Information for 
additional information 
common in HIV-infected patients. In 
clinical trials, the psychiatric profile for 
DTG 
(including 
suicidality, 
depression, bipolar and hypomania, 
anxiety and abnormal dreams) was 
generally 
similar 
or 
favourable 
compared with other antiretroviral 
therapy, although a higher incidence 
of depression and suicidal ideation 
/behaviours with DTG compared with 
darunavir/ritonavir was noted in the 
FLAMINGO 
clinical 
study. 
An 
evaluation 
of 
aggregate 
data, 
including 
post-marketing 
data 
concluded that a causal association 
between DTG and depression and 
suicidal behaviours could not be ruled 
out. These events occur primarily in 
patients with a prior history of 
psychiatric illness.
The reporting rate for insomnia was 
statistically 
higher 
for 
blinded 
DTG+ABC/3TC 
compared 
to 
efavirenz/tenofovir/emtricitabine in the 
SINGLE clinical study; however, this 
was not duplicated in other VH 
Sponsored Phase IIb/III studies with 
DTG or DTG/ABC/3TC. 
treatment emergent assessment 
of suicidality will be monitored 
during this study. Investigators 
are advised to consider mental 
health consultation or referral for 
subjects who experience signs 
of suicidal ideation or behaviour  

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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk
Mitigation Strategy
 
 
Investigational Product: dolutegravir/lamivudine
Refer to Investigator Brochure and/or approved Local Prescribing Information for 
additional information 
Renal function 
Lamivudine is eliminated by renal 
excretion and exposure increases in 
patients with renal dysfunction. 
Due to requirements for dose 
reduction of 3TC in patients with 
renal dysfunction, subjects with 
a 
creatinine 
clearance 
<30 
mL/min (CKD-EPI method) are 
excluded. 
Participants who develop a 
Grade 4 eGFR toxicity (per 
DAIDs criteria) should have 
study drug withdrawn.  
Neural tube 
defects 
In 
a 
birth 
surveillance 
study 
conducted in Botswana (the Tsepamo 
study), preliminary results showed 
that in babies born to women who 
were taking DTG when they became 
pregnant there was an increased risk 
of neural tube defects compared with 
the background rate. Later data from 
the study has shown a numerically 
higher rate of neural tube defects with 
exposure to DTG compared to non-
DTG-containing 
antiretroviral 
regimens at the time of conception, 
however, the difference was not 
statistically 
significant. 
A 
causal 
relationship of these events to the use 
of DTG has not been established. No 
increased risk of these defects was 
reported in babies born to mothers 
Pregnancy testing should be 
performed before initiation of 
DTG therapy in all women of 
childbearing potential (negative 
pregnancy test at screening and 
randomization). (Section 9) 
 
Women who are pregnant or 
who plan to become pregnant, 
are excluded.  
 
All 
women 
of 
reproductive 
potential should use a highly 
effective 
method 
of 
contraception – see Section11.7 
/Appendix 1  
 
Subject informed consent form 
provides information about this 
potential risk.  

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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk
Mitigation Strategy
 
 
Investigational Product: dolutegravir/lamivudine
Refer to Investigator Brochure and/or approved Local Prescribing Information for 
additional information 
who started DTG containing regimen 
later in pregnancy 
Dolutegravir was tested in a complete 
package of reproductive toxicology 
studies, 
including 
embryofoetal 
development studies. No adverse 
development 
outcomes, 
including 
neural tube defects, were identified. In 
reproductive 
toxicity 
studies 
in 
animals, DTG was shown to cross the 
placenta. 
Data analysed to date from other 
sources including the Antiretroviral 
Pregnancy Registry, clinical trials, and 
post-marketing data are insufficient to 
address the risk of neural tube defects 
with DTG. 
Toxicity Management 
In the event of a discontinuation of a DTG-containing product for suspected drug induced 
liver injury, other clinically significant liver chemistry elevations, severe skin reaction or 
hypersensitivity reaction, subjects should not be rechallenged with a DTG-containing 
product due to the risk of a recurrent reaction. These subjects should be withdrawn from 
study and seek/be reviewed for alternative antiretroviral therapy (but may continue on 
study, but off study drug). Further details on this are provided in this section as 
appropriate. 
 
Hypersensitivity and rash  

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Allergic Reaction 
Subjects may continue investigational product(s) for Grade 1 or 2 allergic reactions at 
the discretion of the Investigator. The subject should be advised to contact the 
Investigator immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents 
may be prescribed.  
 
related to the investigational product(s) should permanently discontinue the 
investigational product regimen and the subject should be withdrawn from the study. 
Subjects should be treated as clinically appropriate and followed until resolution of the 
adverse event. 
Rash 
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. 
Subjects with an isolated Grade 1 rash may continue investigational product at the 
Investigator’s discretion. The subject should be advised to contact the Investigator 
immediately if there is any worsening of the rash, if any systemic signs or symptoms 
worsen, or if mucosal involvement develops. 
Subjects may continue investigational product for an isolated Grade 2 rash. However, 
investigational product (and all other concurrent medication(s) suspected in the 
Investigators causality assessment) should be permanently discontinued for any Grade 
2 rash that is associated with an increase in ALT. The subject 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. 

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Subjects should permanently discontinue investigational product (and all other 
concurrent medication(s) suspected in the Investigators causality assessment) for an 
isolated Grade 3 or 4 rash, and the subject should be withdrawn from the study. Subjects 
should be treated as clinically appropriate and followed until resolution of the adverse 
event. 
The rash and any associated symptoms should be reported as adverse events (see 
(Section 11) and appropriate toxicity ratings should be used to grade the events (based 
on DAIDS [Division of ADS] toxicity gradings). 
If the etiology of the rash can be diagnosed as being unrelated to investigational product 
and due to a specific medical event or a concomitant non-study medication, routine 
management should be performed and documentation of the diagnosis provided. 
 
Liver Chemistry Stopping and Follow up Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject safety and evaluate liver event etiology during administration of study drug and 
the follow-up period (in alignment with the FDA premarketing clinical liver safety 
guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
For any participant meeting one of the criteria outlined in Table 1 or Table 2, or if the 
Investigator believes that it is in the best interest of the patients, the Investigator must 
follow the required actions and follow up assessments also outlined in these tables. 
Table 1 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
ALT absolute 
ALT  8xULN 
ALT increase 
ALT 
5xULN but <8xULN persists for 2 weeks (with bilirubin <2xULN and 
no signs or symptoms of acute hepatitis or hypersensitivity) 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and International normalised ratio (INR)>1.5, if INR measured 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for >2 weeks 

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(See Table 2 for actions where subjects CAN be monitored weekly for >2 
weeks) 
Symptomatic3 
ALT  3xULN (if baseline ALT is ULN) with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
ALT  3x baseline (if baseline ALT>ULN) with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
 
Immediately hold DTG.  
 
If a causal relationship between the liver 
event and DTG cannot be ruled out, then 
DTG must be permanently discontinued 
and the Subject not rechallenged due to the 
risk of a recurrent reaction.   
 
Report the event to the Sponsor by 
telephone within 24 hours. 
 
Events of possible drug-induced liver injury 
with hyperbilirubinemia2 will be reported to 
Sponsor as serious adverse events using 
the serious adverse event case report form. 
 
Complete the liver event case report form 
for all events meeting liver stopping criteria, 
and submit to Sponsor within one week of 
first becoming aware of the event 
Perform liver event follow up assessments. 
 
Monitor the subject until liver chemistries 
resolve, stabilise, or return to within 
baseline (see MONITORING below).
 
If the liver event has a clear underlying 
alternative cause, other than drug-induced 
liver injury, then Drug Restart may be 
considered by Sponsor (for exception see 
Liver 
Safety 
– 
Study 
Treatment 
Rechallenge and Restart) 
 
If restart is not allowed or not granted, 
permanently discontinue study treatment 
and may continue subject in the study for 
any 
protocol 
specified 
follow 
up 
assessments. 
MONITORING: 
 
Make every reasonable attempt to have 
subjects return to clinic within 24 hours for 
repeat liver chemistries (include ALT, 
 
Viral hepatitis serology, including: 
 
Hepatitis A immunoglobulin M 
(IgM) antibody;
 
HBsAg and hepatitis B core 
antibody; 
 
Hepatitis C RNA; 
 
Hepatitis E IgM antibody. 
 
Cytomegalovirus IgM antibody. 
 
Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain 
heterophile 
antibody 
or 
monospot 
testing). 
 
Syphilis screening. 
 
Drugs of abuse screen, including 
alcohol. Record alcohol use on the liver 
event case report form 
 
Serum acetaminophen adduct High 
Performance Liquid Chromatography 
assay 
(quantifies 
potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week (2) [FDA, 2009]).  The site must 
contact the medical monitor when this 
test is required. NOTE: not required in 
China 
 
Serum creatinine kinase and lactate 
dehydrogenase. 
 
Fractionate bilirubin, if total bilirubin 
1.5xULN. 
 
Obtain complete blood count with 
differential to assess eosinophilia. 

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aspartate 
aminotransferase, 
alkaline 
phosphatase, bilirubin) and perform liver 
event follow up assessments at the central 
laboratory as described to the right.  
 
A specialist or hepatology consultation is 
recommended.
Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline. 
 
Anti-nuclear 
antibody, 
anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G (or 
gamma globulins). 
 
Liver imaging (ultrasound, magnetic 
resonance, 
or 
computerised 
tomography) and /or liver biopsy to 
evaluate liver disease. Complete Liver 
Imaging and/or Liver Biopsy case report 
form. 
Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, 
other over 
the 
counter 
medications. 
 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that subject if 
ALT  3xULN and bilirubin  2xULN. Additionally, if serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury.  
 
2. 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN 
and INR>1.5, if INR measured which may indicate severe liver injury must be reported 
as a serious adverse event (excluding studies of hepatic impairment or cirrhosis); 
INR measurement is not required and the threshold value stated will not apply to subjects 
receiving anticoagulants 
 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to 
hypersensitivity (such as fever, rash or eosinophilia).  Record the appearance or worsening 
of any such clinical symptoms on the adverse event report form. 
Table 2 
Liver Chemistry Increased Monitoring Criteria 
Criteria 
Actions 
ALT 
5xULN and <8xULN and 
bilirubin 
<2xULN 
without 
symptoms believed to be related 
to liver injury or hypersensitivity, 
and who can be monitored weekly 
for >2 weeks. 
 
Notify the medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety.  
 
Subject can continue study treatment  
 
Subject 
must return weekly for repeat 
liver 
chemistries 
(ALT, 
aspartate 
aminotransferase, 
alkaline phosphatase, bilirubin) until resolution, 
stabilisation 
(ALT <5×ULN on 2 
consecutive 
evaluations) or return to within baseline 

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66
 
If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above 
Liver Safety – Study Treatment Rechallenge and Restart 
Rechallenge refers to resuming study treatment following drug induced liver injury.  
Following DILI, drug rechallenge is associated with a 13% mortality across all drugs in 
prospective studies (1) [Andrade et, 2009]. Clinical outcomes vary by drug, with nearly 
50% fatality with halothane readministered within one month of initial injury. However, 
some drugs seldom result in recurrent liver injury or fatality.   
In the event of a discontinuation of DTG/3TC for a Liver Stopping Event, subjects should 
not be rechallenged with DTG/3TC due to the risks associated with rechallenge. 
‘Drug restart’ refers to resuming study treatment following a Liver Stopping Event in 
which there is a clear underlying cause (other than drug induced liver injury) of the liver 
event (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis).  
If a causal relationship between the liver event and DTG/3TC cannot be ruled out, then 
DTG/3TC must be permanently discontinued and the subject not rechallenged.  
Drug restart with DTG/3TC in a patient who has a Liver Stopping Event is permitted 
providing the investigator follows the specific Drug Restart Criteria: 
Drug Restart Following Transient Resolving Liver Events Not Related to Study 
Drug 
Restart can be considered when liver chemistries improve to within 1.5x baseline and 
ALT<3xULN) where: 
 
Liver chemistries have a clear underlying cause other than drug-induced liver injury 
(e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis).  
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, 
and the drug should not be associated with HLA markers of liver injury. 
 
The subject is receiving compelling benefit and benefit of drug restart exceeds risk 
 
Approval from Study Team and Ethics Committee or Institutional Review Board for 
the drug restart has been obtained. 

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The subject has been provided with a clear description of the possible benefits and 
risks of drug restart, including the possibility of recurrent, more severe liver injury or 
death. 
 
The subject has also provided signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study file. 
 
Following drug restart, the Subject will return to the clinic once a week for liver 
chemistry tests for one month or for as long as clinically indicated and then 
laboratory monitoring may resume as per protocol.  If protocol defined stopping 
criteria for liver chemistry elevations are met, study drug must be stopped. 
See Appendix 3. Liver safety -Checklist for Drug Restart Approval or Refusal. 
Suicidal Risk Monitoring 
Subjects with HIV infection may occasionally present with symptoms of depression 
and/or suicidality (suicidal ideation or behaviour). In addition, there have been some 
reports of depression, suicidal ideation and behaviour (particularly in patients with a pre-
existing history of depression or psychiatric illness) in some patients being treated with 
integrase inhibitors, including DTG. Therefore, it is appropriate to monitor subjects for 
suicidality before and during treatment.  
Subjects should be monitored appropriately and observed closely for suicidal ideation 
and behaviour, or any other unusual changes in behaviour. It is recommended that the 
investigator consider mental health consultation or referral for subjects who experience 
signs of suicidal ideation or behaviour. 
If any subject experiences a possible suicidality-related adverse event (PSRAE) while 
participating in this study that is considered by the Investigator to meet ICH E2A (ICH 
E2A, 1994) definitions for seriousness, the Investigator will collect information using a 
PSRAE case report form (or agreed alternative) in addition to reporting the event on a 
serious adverse event case report form. A PSRAE may include, but is not limited to, an 
event that involves suicidal ideation, a preparatory act toward imminent suicidal 
behaviour, a suicide attempt, or a completed suicide.  The investigator will exercise his 
or her medical and scientific judgment in deciding whether an event is possibly suicide-

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related. PSRAE forms should be completed and reported to Sponsor within one week of 
the investigator diagnosing a possible suicidality-related serious adverse event. 
 
Decline in Renal Function 
Treatment with DTG/3TC must be discontinued in any Subject developing a grade 4 
decreased in creatinine clearance. 
A confirmatory creatinine clearance assessment should be conducted within 2 weeks.  
 
References: 
1. Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714. 
2. FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. 
July 
2009. 
Accessed 
07 
January 
2015 
at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022145s032,203045s010,2
05786s001lbl.pdf 
3. International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. 
Clinical safety data management: Definitions and standards for expedited reporting. ICH 
E2A. 1994 
 
 

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APPENDIX 3: Liver Safety – Checklist for Drug Restart Approval or Refusal 
“Drug restart” after discontinuation of Study Drug due to Liver Stopping Criteria (as 
defined in the protocol), can only be approved by the Study’s Governing Body (e.g., 
Protocol/Study Team or Study Chair) or Principal Investigator for transient, defined 
non-drug-induced liver injury with no evidence of: 
 
immunoallergic injury/HLA association with injury 
 
drug-induced liver injury 
 
alcoholic hepatitis 
Investigators MUST: 
1. Hold study drug while labs and evaluations are completed to assess diagnosis, and 
not restart until “Drug restart” has been approved by the Study’s Governing Body or 
Principal Investigator. 
2. Complete the table below and submit to the Study’s Governing Body or Principal 
Investigator. The Liver Event case report form should already have been submitted 
to the Study’s Governing Body or Principal Investigator, along with liver imaging 
and/or liver biopsy case report forms and/or SAE case report form where applicable. 
Where restart of TRIUMEQ or any other ABC-containing product is being considered, 
provide documentation verifying HLA-B*5701 status. 
Subject Number:
Yes
No
Have liver chemistries improved to within 1.5x baseline and ALT<3xULN?
Was subject’s HIV infection stable or improving on Study Drug?
Were any of the following high risk factors included in the initial liver injury event?
(Do not restart if ‘Yes’ for any one of the following high risk factors): 
 
fever, rash, eosinophilia, or hypersensitivity  
 
 
 
drug-induced liver injury  
 
 
 
alcoholic hepatitis (aspartate aminotransferase>ALT, typically <10xULN) 
 
 
 
Study Drug (other than ABC) has an HLA genetic marker associated with 
liver injury 
 
 
For restart of TRIUMEQ, or any other abacavir- containing Study Drug, the 
subject MUST be HLA-B*5701 negative1   
Specify HLA-B*5701 status2: 
 
1. In countries/regions where HLA-B*5701 pre-therapy screening is not considered standard of 
care, subjects stopping abacavir- containing study drug due to Liver Stopping Criteria MUST 
be tested and found to be negative for the HLA-B*5701 allele before abacavir- containing 
Study Drug can be re-started. 
2. If study drug does not containing ABC then record HLA-B*5701 status as “not applicable” 
 
 

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APPENDIX 4: SERIOUS ADVERSE EVENT REPORT FORM

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APPENDIX 5: PREGNANCY NOTIFICATION FORM

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APPENDIX 6: PREGNANCY FOLLOW-UP FORM

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APPENDIX 7: LIVER EVENTS FORM

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APPENDIX 8: LIVER EVENTS BIOPSY FORM

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APPENDIX 9: POSSIBLE SUICIDALITY-RELATED ADVERSE EVENT FORM

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APPENDIX 10: LIVER IMAGING RECORD

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