A Cross-sectional, Observational Study to Characterise the Transition to Dolutegravir-based Regimens in South Africa in Terms of the Emergence of Obesity, Viral Re-suppression and Integration Into Routine Programme Care
Conditions: Dolutegravir
Sponsor: University of Witwatersrand, South Africa

                                           
 
 
 
 
 
 
 
EZ-FV-030 
 
 
A cross-sectional, observational study to characterise the transition to dolutegravir-based 
regimens in South Africa in terms of the emergence of obesity, viral re-suppression and integration 
into routine programme care 
 
 
Short Title: 
CHARACTERISE 
Protocol Version and Approval Date: 
Version 1.2, 06 April 2022 
Sponsor: 
Ezintsha, Faculty of Health Sciences 
University of the Witwatersrand  
Building C, Sunnyside Office Park 
32 Princess of Wales Terrance 
Parktown, Johannesburg 2193 
Funder: 
Unitaid 
Principal Investigator: 
Dr Bronwyn Bosch 
Ezintsha, Faculty of Health Sciences  
University of the Witwatersrand 
Building C, Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg, 2193 
 
 
 
CONFIDENTIAL 
Property of Ezintsha, University of the Witwatersrand  
May not be used, divulged, published, or otherwise disclosed without consent 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 2 of 35 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
A cross-sectional, observational study to characterise the transition to dolutegravir-based 
regimens in South Africa in terms of the emergence of obesity, viral re-suppression and integration 
into routine programme care 
 
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that: 
• 
I agree to personally conduct or supervise the study. 
• 
I have read the protocol and agree that it contains all necessary details for carrying out the study 
as described. I will conduct this protocol as outlined therein, as per any approved protocol 
amendments, as per ICH Good Clinical Practice (GCP) and all applicable national requirements and 
laws. 
• 
I will not deviate from the protocol without prior review and written approval from the 
Institutional Review Board or Ethics Committee, except where necessary to prevent immediate 
danger to the participant. 
• 
I will ensure that the requirements related to obtaining informed consent are in accordance with 
ICH Guidelines for GCP Section and local requirements. 
• 
I agree to document adverse events that occur during the study, to maintain adequate and 
accurate records and make those records available, in accordance with ICH Guidelines for GCP, 
South African GCP and other local requirements. I agree to promptly report to the Ethics 
Committee all changes in the research activity and all unanticipated problems involving risk to the 
participants. 
• 
I have sufficient time to properly conduct and complete the trial within the agreed trial period, 
and I will ensure that any qualified staff at my site(s) who are involved in the trial conduct are 
adequately trained regarding the protocol, and their responsibilities for the foreseen duration of 
the trial to conduct the trial properly and safely. If I delegate any of my trial activities, I will 
document this on a Delegation of Activities Form. I agree to ensure that all associates, colleagues, 
and employees assisting in the conduct of the study are informed about their obligations in 
meeting the above commitments. 
• 
I understand that the study may be terminated, or enrolment suspended at any time by me if it 
becomes necessary to protect the best interest of the participants. 
 
 
 
 
 
 
 
 
 
 
 
07 Apr 2022 
 
Dr Bronwyn Bosch 
 
 
 
 
Date 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 3 of 35 
 
SPONSOR SIGNATORY APPROVAL PAGE 
A cross-sectional, observational study to characterise the transition to dolutegravir-based 
regimens in South Africa in terms of the emergence of obesity, viral re-suppression and integration 
into routine programme care 
 
I, the undersigned have read this protocol and I approve the design of this trial: 
 
 
 
 
 
 
 
 
 
________________________________  
 
07 Apr 2022 
Nonkululeko Mashabane 
 
 
 
Date 
Head of Research Operations 
Ezintsha, University of the Witwatersrand  
 
  
 
 
 
 
 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 4 of 35 
 
TABLE OF CONTENTS 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................................................................ 2 
SPONSOR SIGNATORY APPROVAL PAGE ....................................................................................................... 3 
ABBREVIATIONS AND TERMS ........................................................................................................................ 6 
SYNOPSIS 
7 
1. 
SCHEDULE OF ASSESSMENTS ................................................................................................................ 16 
2. 
INTRODUCTION .................................................................................................................................... 17 
2.1 
Background ........................................................................................................................................... 17 
2.2 
Study Rationale ..................................................................................................................................... 19 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................................................... 20 
4. 
STUDY DESIGN ..................................................................................................................................... 21 
4.1 
Overall Design ....................................................................................................................................... 21 
4.2 
Study Treatments .................................................................................................................................. 22 
4.3 
Study Duration ...................................................................................................................................... 22 
4.4 
Individual Participant Withdrawal ........................................................................................................ 22 
5. 
STUDY POPULATION ............................................................................................................................ 23 
5.1 
Cohorts .................................................................................................................................................. 24 
5.2 
Recruitment .......................................................................................................................................... 24 
5.3 
Main Study Eligibility Criteria (Baseline Visit) ....................................................................................... 24 
5.3.1 
Inclusion criteria .......................................................................................................................... 24 
5.3.2 
Exclusion criteria .......................................................................................................................... 24 
5.4 
Sub-Study Eligibility Criteria (Subsequent Optional Visit(s)) ................................................................. 25 
5.4.1 
Inclusion criteria .......................................................................................................................... 25 
5.4.2 
Exclusion criteria .......................................................................................................................... 25 
5.5 
Participant Identification ...................................................................................................................... 25 
5.6 
Co-enrolment Guidelines ...................................................................................................................... 25 
6. 
STUDY VISITS ........................................................................................................................................ 25 
7. 
STUDY ASSESSMENTS, QUESTIONNAIRES, AND PROCEDURES .............................................................. 26 
7.1 
Main Study ............................................................................................................................................ 26 
7.1.1 
Enrolment (Visit 1) ....................................................................................................................... 26 
7.1.2 
Baseline assessments, questionnaires, and procedures (Visit 1) ................................................ 26 
7.2 
Viraemia confirmation visits (Visit 2) .................................................................................................... 27 
7.3 
Sub-Studies ........................................................................................................................................... 28 
7.3.1 
Screening and informed consent ................................................................................................. 28 
7.3.2 
Sub-study visit(s) ......................................................................................................................... 28 
7.3.3 
Telephonic follow-up ................................................................................................................... 28 
7.4 
Biohazard Containment ........................................................................................................................ 29 
8. 
SAFETY MONITORING .......................................................................................................................... 29 
8.1 
Responsibilities for Ensuring the Safety of Study Participants .............................................................. 29 
8.1.1 
Principal Investigator ................................................................................................................... 29 
8.1.2 
Study Sponsor .............................................................................................................................. 29 
8.2 
Adverse Events ...................................................................................................................................... 29 
8.2.1 
Definitions ................................................................................................................................... 29 
9. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 29 
9.1 
Sample Size Determination ................................................................................................................... 30 
9.2 
Analysis and Presentation of Data ........................................................................................................ 30 
9.2.1 
Disposition, demographic, and background data ........................................................................ 30 
9.2.2 
Primary and secondary endpoints ............................................................................................... 30 
9.2.3 
Safety data ................................................................................................................................... 30 
9.2.4 
Exploratory analyses .................................................................................................................... 30 
10. STUDY MONITORING ........................................................................................................................... 30 
11. ETHICAL CONSIDERATIONS................................................................................................................... 30 
11.1 Ethical Considerations ........................................................................................................................... 30 
11.2 Informed Consent Process .................................................................................................................... 31 
11.3 Blood Volume ........................................................................................................................................ 31 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 5 of 35 
 
11.4 Study Records and Confidentiality ........................................................................................................ 31 
11.5 Participant Remuneration ..................................................................................................................... 31 
12. ADMINISTRATIVE CONSIDERATIONS .................................................................................................... 32 
12.1 Protocol Amendments .......................................................................................................................... 32 
12.2 Clinical Data Records ............................................................................................................................. 32 
12.3 Record Retention .................................................................................................................................. 32 
12.4 Discontinuation of the Study ................................................................................................................ 32 
12.5 Publication Policy .................................................................................................................................. 32 
12.6 Study Audits .......................................................................................................................................... 33 
13. REFERENCES ......................................................................................................................................... 34 
APPENDICES 
35 
APPENDIX 1: 
STUDY GOVERNANCE ........................................................................................................ 35 
 
 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 6 of 35 
 
ABBREVIATIONS AND TERMS 
Term 
Definition 
AE 
BMI 
CVD 
DXA 
Adverse event 
Body mass index 
Cardiovascular disease 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
GCP 
Good Clinical Practice 
HbA1C 
HREC 
Glycosylated haemoglobin 
Human Research Ethics Committee 
ICF 
LMIC 
NCD 
Informed consent form 
Low- to middle-income countries 
Non communicable diseases 
OSA 
PLHIV 
POPIA 
Obstructive sleep apnoea 
People living with HIV 
Protection of Personal Information Act 
SAP 
TEE 
TLD 
TLE 
WBIS 
Statistical Analysis Plan 
Tenofovir disoproxil fumarate/emtricitabine/efavirenz 
Tenofovir disoproxil fumarate/lamivudine/dolutegravir 
Tenofovir disoproxil fumarate/lamivudine/emtricitabine 
Weight Bias Internalization Scale 
WHO 
World Health Organization 
Wits 
University of the Witwatersrand 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 7 of 35 
 
SYNOPSIS 
Title 
A cross-sectional, observational study to characterise the transition to 
dolutegravir-based regimens in South Africa in terms of the emergence of obesity, 
viral re-suppression and integration into routine programme care 
 
Short Title 
CHARACTERISE 
Background 
The ADVANCE clinical trial compared three recommended first-line regimens 
(two containing dolutegravir) head-to-head and demonstrated virological non-
inferiority at 48- and 96-weeks respectively1,2, paving the way for the mass- 
introduction of dolutegravir-containing regimens across low- and- middle-
income countries. 
The dolutegravir-containing regimens in ADVANCE were very well tolerated and 
demonstrated remarkable viral re-suppression in patients with viraemia when 
adherence measures were instituted, even in the presence of genotypically-
documented resistance1,2.   Across Africa, including South Africa, and in many 
other low- and middle-income countries (LMIC), the combination of tenofovir 
disoproxil fumarate/lamivudine (or emtricitabine) /dolutegravir (TLD) has been 
rolled out to millions of patients, much of this with Unitaid support to research, 
programmes and communities. Most ADVANCE patients have since transitioned 
out of the study and are on TLD in South African public sector clinics in central 
Johannesburg. 
One of the unanticipated findings of ADVANCE and the concomitant Unitaid-
supported NAMSAL3 study in Cameroon, as well as analyses of registration 
studies and observational studies, was the consistent finding that patients on 
dolutegravir experience significant weight gain and new-onset obesity4. It 
remains unclear whether this is a feature of the integrase inhibitor class (and 
aggravated by tenofovir alafenamide), or whether other factors are at play - it is 
possible that HIV infection itself may predispose to weight gain  in successfully 
treated patients, and other antiretrovirals may alter weight trajectories. The 
signal has  been met with alarm by the public health community, as many 
countries where TLD is being rolled out are experiencing a parallel obesity 
epidemic. Obesity is strongly associated with adverse   outcomes, including 
diabetes, cardio-vascular-disease (CVD), sleep apnoea, gastrointestinal and 
muscular-skeletal disorders, asthma, poor pregnancy outcomes, many cancers, 
mental health issues,  and poor COVID-19 outcomes. In many countries with 
large antiretroviral programmes, these concurrent epidemics have significant 
public health and financial implications, and clarification of the extent of the 
obesity signal is urgent. 
Weight gain on ADVANCE was greatest with more advanced HIV (low CD4, high 
viral load) and among women; other studies have confirmed this signal, as well 
as suggesting that Black patients are more predisposed. For South Africa, where 
the majority of those on TLD are Black women and many initiated with advanced 
disease, this has significant implications for future programme design. The study 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 8 of 35 
 
was extended to 192 weeks, utilizing Unitaid and ViiV funding, with continued 
drug donations from Gilead and ViiV. The study has been highly influential in 
regard to guidelines and is expected to yield in excess of 30 papers once 
complete. The 192-week manuscript is being written, but preliminary data 
suggest continued weight gain in all arms, even among men, but continued 
excellent suppression. 
Moreover, South African public health policy makers and academics have become 
increasingly aware  that attention needs to be paid to obesity (41% among 
adult women, and 11% among men in the general population), associated type-
2 diabetes (South Africa’s second-commonest cause of death after tuberculosis, 
and now the commonest cause of death among women), and cardiovascular 
risk,  all in the context of a background HIV epidemic. Almost a quarter of SA 
women, 80% of whom are Black, aged 15-49 had HIV in 2020 and one in five 
women had severe obesity (as opposed to 3% of  men), and almost half of 
women over 15 years were hypertensive, rising to 78% by age 55 years1. 
According to the South African Demographic and Health Survey (2016), type 2 
diabetes is also more  common in Black SA women than men, and in 2016 was the 
leading cause (7.2%) of death in women5.  There are reports from central Africa 
of high levels of diabetes experienced within those initiating or switched to TLD. 
Remarkably, women on ADVANCE had absolute baseline weights greater than 
men prior to ART initiation (evidence of a background obesity epidemic among 
women), and the majority were classified as being overweight or having obesity 
after 96 weeks of ART, irrespective of regimen. These overlapping common 
conditions are classic ‘’syndemics’’, a relatively new global health research 
priority. 
 
Rationale 
The introduction of dolutegravir has been one of the most significant and 
successful changes to HIV programmes in the last decade, affecting tens of 
millions of patients in low- and middle-income countries (LMIC). The remarkable 
tolerability and resistance profile that dolutegravir has conferred on modern 
antiretroviral combination regimens has significantly contributed to progress to 
the last ‘’90’’ of UNAIDS’ 90-90-90 targets6. Unitaid has been a major part of this, 
heavily investing in both facilitatory research, as well as community 
preparedness. 
The introduction has been accompanied by two unexpected observations – first, 
a positive indicator noting viral re-suppression rates (almost all patients with 
viral rebound on dolutegravir will re-suppress); and a second, less positive trend 
of treatment-emergent obesity (most women, and many  men, will develop 
obesity on dolutegravir). Both observations have raised important questions 
that require public health consideration, and for both observations, the 
ADVANCE study is in a unique position to add vital additional long-term African 
data to assist policy makers, planners, patients and health providers in 
understanding and designing future programmes. In addition, we have access to 
a further highly characterised cohort of patients initiated between 8-10 years 
previously, with similar baseline measurements, who were transitioned to TLD, 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 9 of 35 
 
allowing us to compare to the more recently initiated ADVANCE cohort, and 
allowing us to predict what will occur to the over 5 million South Africans and, 
indeed, the tens of millions of Southern Africans initiated on efavirenz and TDF-
containing antiretrovirals in the last 20 years, and now transitioning to TLD. 
Primary questions relating to safety, weight gain and viral suppression on 
treatment are: 
• 
Was the excellent tolerability and safety seen in ADVANCE over 4 years 
continued in the subsequent years? How does this compare to patients 
who had been on antiretroviral care for longer on efavirenz-based 
regimens within the state sector who then transitioned to TLD. 
• 
How much weight are people gaining on treatment, and what is the 
trajectory – is it more rapid over an initial period, or a continuous 
trajectory  over time? How does this compare to the long-term 
efavirenz-based patients on legacy regimens? 
• 
Is the weight gain leading to additional health problems, and if so, what 
are those problems? Does this differ from the patients on long-term 
therapy? 
• 
How significantly will the issues of treatment emergent weight gain, 
and the additional health problems associated with it, add to the public 
health burden, and how can we prepare and programme for this, 
particularly in LMIC countries, where there are already concurrent non 
communicable disease (NCD) epidemics? 
• 
It is encouraging that ADVANCE has been able to establish that it is now 
possible to achieve viral re-suppression routinely in a tightly regulated 
environment like a clinical trial. However, in a real world scenario like 
a resource-constrained government clinic, the development of 
resistance may be more likely as monitoring and adherence is less 
intense. In a real-world environment, are there opportunities to turn 
suppression failure trajectories around given the re-suppression 
opportunities this drug regimen provides? 
• 
What was the experience of patients movin from the clinical trial 
environment to a “real world” setting in the public sector clinics? 
To provide this data and answer the questions raised, we propose accessing the 
ADVANCE participants, as well as well-characterised patients who have 
previously  exited other studies, who were on tenofovir disoproxil 
fumarate/lamivudine or emtricitabine/efavirenz (TLE or TEE) and are now 
utilising the state dolutegravir antiretroviral programme. We will describe the 
general safety, long-term weight gain trajectory and associated obesity-related 
complications, as well as experience transitioning to the above state 
programmes in order to inform and guide future monitoring and screening 
programmes. We believe this is particularly important, as  it appears that the 
burden of these complications will be disproportionately borne by South African 
women, who already are experiencing an obesity epidemic, and in ADVANCE 
and other studies experienced the most  severe weight gain. Additionally, we 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 10 of 35 
 
propose to identify those with virological failure, the pattern of resistance, and 
the response to a routine adherence intervention. 
Finally, we want to describe the complex experience of these patients, their 
health providers, community members and advocates, and programme 
implementers, of dolutegravir introduction during the COVID-19 pandemic. 
Specifically, new regimens and long-acting antiretroviral agents are on the  
horizon, and it will be critical to be clear on lessons around mass regimen 
transition ahead of this change. 
 
Proposal 
We propose an observational study to address: 
o Long term trajectory and consequences of weight gain and obesity on 
patients initiating and transitioning to TLD. The ADVANCE cohort is 
unique in this regard – it represents a cohort of diverse African patients 
who have been on dolutegravir on the continent the longest. In addition, 
our second cohort of patients were similarly characterised at baseline, and 
drawn from the same community, re-entering the same health system at 
study exit, while moving from TEE to TLD at approximately the same time 
as the ADVANCE patients. The  extensive characterisation of both men 
and women, as well as important predictors of weight  trajectory 
(baseline weight, CD4 and viral load), allow us to start modelling what 
the current roll-out of dolutegravir will look like in several years from 
now. Importantly, it will inform which,  if any, metabolic and other 
complications should be monitored, and potentially at which 
thresholds. 
o Levels of viral suppression, and prevalence of resistance in those 
without suppression, in patients that have transitioned to TLD. There is 
significant interest at the prospect of the programme simplicity of ‘’TLD 
to TLD’’ – of focusing on adherence challenges in viraemic patients, 
rather than changing drug regimens. Current WHO recommendations 
recommend a switch ‘to appropriate regimen’’ with prolonged 
viraemia, but there is considerable doubt whether this is necessary, as 
genotype testing in ADVANCE and other studies suggest no resistance 
occurring to dolutegravir, and additional data accruing from studies 
such as NADIA3, VISEND7  and ARTIST8 suggest that nucleoside 
backbones can be recycled successfully in most cases. The ADVANCE 
patients again represent patients who have been on dolutegravir the 
longest– and hence have had the most time to develop resistance – and 
screening them for viraemia,  resistance, and then re-suppression with 
an intensive adherence intervention, will again provide invaluable data 
on whether a ‘’TLD to TLD’’ approach is appropriate. 
o Patient, nurse, civil society and programme manager perceptions of the 
TLD expansion, against the backdrop of safety concerns about neural 
tube defects and weight gain. The mass  transition to TLD was supposed 
to be done alongside a community, patient and healthcare education 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 11 of 35 
 
programme, that emphasized viral suppression at the point of 
transition (to avoid switching viraemic patients with possible functional 
dual- or mono-therapy), informed consent around the issue of the 
neural tube defect risk, and finally, counselling about weight gain and 
emergent obesity, and mitigation strategies. In the end, the rollout 
coincided partly with the onset of the initial COVID-19 wave in South 
Africa, and one of the world’s most severe lockdowns, meaning that 
the impact on both education, the speed, experience and fidelity of the 
rollout, and monitoring has been very difficult to assess. 
 
We will utilise the ADVANCE cohort, as well as a similarly well-described cohort of 
patients previously  on tenofovir disoproxil fumarate/lamivudine (or 
emtricitabine)/efavirenz (TLE or TEE)2, who have transitioned to routine care on 
TLD, with whom we have continued contact. This will allow us to compare 
medium (5 year in the ADVANCE cohort) and longer (9 year in the other cohort) 
metabolic and virologic data of those on long-term antiretrovirals, and their 
experience in the transition to TLD. In addition, these patients, as well as the 
health care workers providing them care, the activists and community members 
involved in advocacy and education, and the programme managers coordinating 
care, can give us their experience with the transition, in focus group and 
individual discussions as part of a sub-study. As we are anticipating future moves 
to other regimens, including long-acting agents that may be far more complex 
than the transition to TLD, these lessons may prove invaluable. 
 
Design  
This is a single centre, follow-up, observational, cross-sectional study reviewing 
two cohorts of patients who have transitioned to routine care on tenofovir 
disoproxil fumarate/lamivudine/dolutegravir (TLD). The first cohort will include 
ADVANCE patients, in which participants were randomised to one of three arms 
including either DTG+TAF/FTC, DTG+TDF/FTC or EFV/TDF/FTC. The second cohort 
will include patients previously on TLE or TEE who have since transitioned to 
routine care on TLD. 
 
The medium (5-year data in the ADVANCE cohort) and longer (9-year data in the 
other cohort) metabolic and virologic consequences of those on long-term 
antiretrovirals will be described and compared in the above cohorts. 
 
After obtaining informed consent from potential participants, a single cross-
sectional, baseline visit will be conducted for each participant. Demographic data, 
clinical history, and details of previous and concomitant medications will be 
collected. Questionnaires including a food diary, Weight Bias Internalization Scale 
(WBIS) and Berlin questionnaire will be administered. Bone density and weight 
distribution will be assessed through use of a dual-energy X-ray absorptiometry 
(DXA) scan, and cardiac function assessed by conduction of a baseline 
electrocardiogram (ECG). 
 
Laboratory evaluations will include a renal function test, urea and electrolytes, 
liver function test, glycated haemoglobin (HbA1C), plasma HIV-1 RNA (viral load), 
lipid panel, serum glucose, and DNA extraction for genotyping in those with 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 12 of 35 
 
unsuppressed viral loads above 1000 copies/mL. Plasma samples will be stored 
locally for possible future analysis.  
 
After the baseline visit, participants who are suitable for one, or more, sub-study 
will be identified. A randomly selected sub-group for each of the following sub-
studies and additional investigations will be drawn from eligible participants 
within each cohort: 
• Sleep evaluation: actigraphy and polysomnography 
• Glucose metabolism evaluation: oral glucose tolerance test (OGTT) including 
assessment of glucose, insulin, and C-peptide to estimate insulin sensitivity 
and beta cell function 
• Experiences of users and providers in the roll out of TLD in South Africa. 
 
Abnormalities detected in the assessments will be managed by on-study medical 
personnel with referral as appropriate. 
Population 
Observational Cohort Population 
Adults of at least 18 years of age with HIV-1 infection who are currently on the 
TLD state programme who satisfy the below eligibility criteria. 
 
The following eligibility criteria will be used to select study participants for the 
main study (baseline visit only): 
• Inclusion criteria (baseline visit/main study): 
1. Able and willing to provide written or electronic informed 
consent for the baseline visit prior to any study-specific 
assessment or procedure. 
2. Age at least 18 years at the time of signing the informed 
consent form. 
3. Previously enrolled in the ADVANCE trial and have been on the 
TLD state programme for more than one year [Cohort 1] 
or, 
part of an existing cohort of patients initiating TLE (and 
switched to TEE) more than 9 years ago, who have been 
transitioned to TLD within the state programme for more than 
one year [Cohort 2]. 
4. Access to a reliable telephone or other device permitting 
information transfer. 
 
• Exclusion criteria (baseline visit/main study): 
1. Personnel (e.g., investigator, sub-investigator, research 
assistant, pharmacist, study coordinator or anyone mentioned 
in the delegation log) directly involved in the conduct of the 
study. 
2. Any physical, mental, or social condition, that, in the 
Investigator’s judgment, might interfere with the completion of 
the baseline assessments and evaluations. The Investigator 
should make this determination in consideration of the 
volunteer’s medical history. 
3. Participant is judged by the Investigator to be at significant risk 
of failing to comply with the provisions of the protocol as to 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 13 of 35 
 
cause harm to self or seriously interfere with the validity of the 
study results. 
 
Additional eligibility criteria will be used to identify study participants who are 
eligible for random selection for any of the sub-studies: 
• Inclusion criteria (sub-studies): 
1. Enrolled into main study and completed baseline visit. 
2. Able and willing to provide written or electronic informed 
consent for the relevant sub-study. 
3. Identified as high risk for development of OSA based on the 
Berlin Questionnaire responses [Sleep sub study only]. 
 
1. Exclusion criteria (sub-studies): Self-reported diabetic or on 
treatment for diabetes mellitus (Type 1 or 2) [Glucose metabolism 
sub-study only]. 
2. Serum glucose and/or HbA1C assessment at baseline consistent with 
a diagnosis of diabetes mellitus [Glucose metabolism sub-study 
only]. 
 
Participants may be enrolled into more than one sub-study. 
 
Treatment 
No treatment will be administered during this observational study. 
Objectives and 
Endpoints 
Primary Objective 
Primary Endpoint 
Characterisation of weight gain and 
metabolic consequences associated 
with long-term TLD use 
• Weight measurement with body 
mass index (BMI) calculation 
• Blood pressure (BP) 
• Plasma glucose, oral glucose 
tolerance test and C-peptide 
measurements 
• Lipid panel 
• Liver function tests 
• DXA 
• ECG 
 
 
Secondary Objectives 
Secondary Endpoints 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 14 of 35 
 
 
• Assessment of factors 
contributing to, and induvial 
perception on weight gain 
 
 
• Description of the presence of 
viraemia 
 
 
• Description of the presence 
and patterns of HIV-1 
resistance mutations in 
participants with viral loads > 
1000 copies/mL 
 
• Description and occurrence of 
associated sleep quality and 
disorders 
 
 
• Food diary questionnaire 
• Weight Bias Internalization 
Scale (WBIS) 
 
 
• Plasma HIV-1 RNA levels 
 
 
 
• HIV-1 genotyping 
 
 
 
 
 
 
• Berlin Questionnaire for risk of 
sleep apnoea 
• Polysomnography (PSG) in 
randomly selected 20% of 
participants at high risk of 
developing obstructive sleep 
apnoea (OSA) based on the 
Berlin Questionnaire 
 
Exploratory Objectives 
 
• 
The association between various specialised sleep and glucose metabolism 
parameters, as well as patient experiences with the transition to TLD, will be 
explored through the sub-studies detailed below. 
 
Sample Size 
Observational Cohort: 
375 participants in total. 
 
Enrolled participants will be assessed for their suitability for various sub-studies. 
From the eligible participants, up to 120 will be randomly selected to participate 
in each sub-study. The same participant may participate in more than one sub-
study. 
 
No formal sample size calculation was performed for this observational study. 
Duration 
The duration of participation for each participant will either be a single visit (of 
approximately 5 hours), or two or more visits depending on the presence of 
baseline viraemia and whether they are enrolled into any sub-studies. 
 
Participants selected for the sleep study will have an overnight admission at the 
Wits Faculty of Health Sciences sleep laboratory. 
 
Enrolment to the study is expected to complete within 6 months. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 15 of 35 
 
Statistical 
Analysis 
Participants enrolled in the main, and various sub-studies, will be summarised. 
Demographic data and other baseline characteristics will be summarised overall 
and per cohort, using simple descriptive statistics. 
 
All primary and secondary endpoints will be summarised descriptively overall, per 
cohort and for various risk factors as deemed appropriate in this exploratory 
study. Associations between weight gain, metabolic risk and presence of 
sustained viral re-suppression may be explored. Additionally, any HIV-1 resistance 
mutations noted on genotyping will be described in detail. 
 
 
 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 16 of 35 
 
1. 
SCHEDULE OF ASSESSMENTS 
All participant enrolled will form part of the main study. Main study assessments, questionnaires, and 
procedures may be performed or administered in any order. 
Specific sub-study questionnaires and assessments are detailed in Sections 7.2 and in the sub-study-
specific plans. 
Procedure / assessment / questionnaire 
Visit 1 
 
Visit 2 
If viraemic 
VL ≥ 1000 
Visit 2 
If viraemic 
VL < 1000 
Month(s) 
May – Jun 22 
Jul – Aug 22 
Jul – Aug 22 
Informed consent1 
X 
 
 
Demographic data 
X 
 
 
Medical and surgical history 
X 
 
 
Previous and concomitant medications 
X 
 
 
Height measurement 
X 
 
 
Weight measurement 
X 
 
 
Blood pressure, heart rate, temperature 
X 
 
 
Symptom-led physical examination (per investigator discretion) 
X 
X 
X 
Creatinine clearance (Cockcroft-Gault formula); UECr 
X 
 
 
Liver function test (total and indirect bilirubin, ALT, AST, GGT, ALP, 
albumin, and total protein) 
X 
 
 
HbA1C (glycated haemoglobin) 
X 
 
 
Plasma HIV-1 RNA 
X 
X 
X 
Plasma glucose 
X 
 
 
Lipid panel (total cholesterol, triglycerides, HDL, and LDL) 
X 
 
 
Oral Glucose Tolerance Test (OGTT) / Glucose Loading2 
X---------------------------------------------------------X 
C-peptide, insulin2 
X---------------------------------------------------------X 
Plasma for storage3 
X 
 
 
HIV-1 genotyping 
 
X 
 
DXA 
X 
 
 
ECG4 
X 
 
 
Polysomnography (PSG) in randomly selected 20% of patients5 
X---------------------------------------------------------X 
Adherence intervention 
 
X 
X 
Questionnaires: 
Food diary, Weight Bias Internalization Scale (WBIS), Berlin 
questionnaire 
 
 
 
Selection of participants for sub-study(ies)6 
X---------------------------------------------------------X 
ECG = electrocardiogram 
1 Written or electronic informed consent to be provide prior to any screening or study-specific assessments, 
questionnaires or procedures are conducted. 
2 Glucose metabolism assessed as part of the relevant sub-study in eligible patients (described in Section 7.3.2.2 below) 
3 Optional plasma storage 
4 A standard 12-lead ECG will be conducted after the participant has rested in the supine position for 10 minutes. 
5 This will be based on those identified as high risk for development of obstructive sleep apnoea (OSA) from the Berlin 
Questionnaire 
6 Study team personnel will review each participant’s baseline data and identify participants who are eligible for 
participation in one, or more, sub-study. Invited participants will be randomly selected from the set of eligible 
participants for each sub-study. Participants who decline the invitation to participate in one, or more, sub-study, will be 
replaced by a randomly selected, matched-cohort participant. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 17 of 35 
 
2. 
INTRODUCTION 
2.1 
Background 
 The introduction of dolutegravir has been one of the most significant and successful changes to HIV 
programmes in the last decade, affecting tens of millions of patients in low- and middle-income 
countries (LMIC). The remarkable tolerability and resistance profile that dolutegravir has conferred on 
modern antiretroviral combination regimens has significantly contributed to progress to the last ‘’90’’ 
of UNAIDS’ 90-90-90 targets6. Unitaid has been a major part of this, heavily investing in both 
facilitatory research, as well as community preparedness.The introduction has been accompanied by 
two unexpected observations – first, a positive indicator noting viral re-suppression rates (almost all 
patients with viral rebound on dolutegravir will re-suppress); and a second, less positive trend of 
treatment-emergent obesity (most women, and many men, will develop obesity on dolutegravir). 
Both observations have raised important questions that require public health consideration, and for 
both observations, the ADVANCE study is in a unique position to add vital additional long-term 
African data to assist policy makers, planners, patients and health providers in understanding and 
designing future programmes. In addition, we have access to a further highly characterised cohort of 
patients initiated between 8-10 years previously, with similar baseline measurements, who were 
transitioned to TLD, allowing us to compare to the more recently initiated ADVANCE cohort, and 
allowing us to predict what will occur to the over 5 million South Africans and, indeed, the tens of 
millions of Southern Africans initiated on efavirenz and TDF-containing antiretrovirals in the last 20 
years, and now transitioning to TLD. 
 
The ADVANCE clinical trial compared three recommended first-line regimens (two containing 
dolutegravir) head-to-head and demonstrated virological non-inferiority at 48- and 96-weeks 
respectively, paving the way for the mass- introduction of dolutegravir-containing regimens across 
low- and middle-income countries (LMIC)1,2. 
The dolutegravir-containing regimens in ADVANCE were very well tolerated and demonstrated 
remarkable viral re-suppression in patients with viraemia when adherence measures were instituted, 
even in the presence of genotypically-documented resistance1,2.  Across Africa, including South Africa, 
and in many other low- and middle-income countries (LMIC), the combination of tenofovir disoproxil 
fumarate/lamivudine (or emtricitabine) /dolutegravir (TLD) has been rolled out to millions of patients, 
much of this with Unitaid support to research, programmes and communities. Most ADVANCE 
patients have since transitioned out of the study and are on TLD in South African public sector clinics 
in central Johannesburg. 
One of the unanticipated findings of ADVANCE and the concomitant Unitaid-supported NAMSAL3 
study in Cameroon, as well as analyses of registration studies and observational studies, was the 
consistent finding that patients on dolutegravir experience significant weight gain and new-onset 
obesity4. It remains unclear whether this is a feature of the integrase inhibitor class (and aggravated 
by tenofovir alafenamide), or whether other factors are at play - it is possible that HIV infection itself 
may predispose to weight gain  in successfully treated patients, and other antiretrovirals may alter 
weight trajectories. The signal has  been met with alarm by the public health community, as many 
countries where TLD is being rolled out are experiencing a parallel obesity epidemic. Obesity is 
strongly associated with adverse outcomes, including diabetes, cardio-vascular-disease (CVD), sleep 
apnoea, gastrointestinal and muscular-skeletal disorders, asthma, poor pregnancy outcomes, many 
cancers, mental health issues,  and poor COVID-19 outcomes. In many countries with large 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 18 of 35 
 
antiretroviral programmes, these concurrent epidemics have significant public health and financial 
implications, and clarification of the extent of the obesity signal is urgent. 
Weight gain on ADVANCE was greatest with more advanced HIV (low CD4, high viral load) and among 
women; other studies have confirmed this signal, as well as suggesting that Black patients are more 
predisposed. For South Africa, where the majority of those on TLD arelack women and many initiated 
with advanced disease, this has significant implications for future programme design. The study was 
extended to 192 weeks, utilizing Unitaid and ViiV funding, with continued drug donations from Gilead 
and ViiV. The study has been highly influential in regard to guidelines and is expected to yield in 
excess of 30 papers once complete. The 192-week manuscript is being written, but preliminary data 
suggest continued weight gain in all arms, even among men, but continued excellent suppression. 
Moreover, South African public health policy makers and academics have become increasingly aware  
that attention needs to be paid to obesity (41% among adult women, and 11% among men in the 
general population), associated type-2 diabetes (South Africa’s second-commonest cause of death 
after tuberculosis, and now the commonest cause of death among women), and cardiovascular risk,  
all in the context of a background HIV epidemic. Almost a quarter of SA women, 80% of whom are 
Black, aged 15-49 had HIV in 2020 and one in five women had severe obesity (as opposed to 3% of  
men), and almost half of women over 15 years were hypertensive, rising to 78% by age 55 years1. 
According to the South African Demographic and Health Survey (2016), type 2 diabetes is also more  
common in Black SA women than men, and in 2016 was the leading cause (7.2%) of death in women5.  
There are reports from central Africa of high levels of diabetes experienced within those initiating or 
switched to TLD. Remarkably, women on ADVANCE had absolute baseline weights greater than men 
prior to ART initiation (evidence of a background obesity epidemic among women), and the majority 
were classified as being overweight or having obesity after 96 weeks of ART, irrespective of regimen. 
These overlapping common conditions are classic ‘’syndemics’’, a relatively new global health 
research priority. 
Primary questions relating to safety, weight gain and viral suppression on treatment are: 
• 
Was the excellent tolerability and safety seen in ADVANCE over 4 years continued in the 
subsequent years? How does this compare to patients who had been on antiretroviral care 
for longer on efavirenz-based regimens within the state sector who then transitioned to 
TLD. 
• 
How much weight are people gaining on treatment, and what is the trajectory – is it more 
rapid over an initial period, or a continuous trajectory  over time? How does this compare 
to the long-term efavirenz-based patients on legacy regimens? 
• 
Is the weight gain leading to additional health problems, and if so, what are those problems? 
Does this differ from the patients on long-term therapy? 
• 
How significantly will the issues of treatment emergent weight gain, and the additional 
health problems associated with it, add to the public health burden, and how can we 
prepare and programme for this, particularly in LMIC countries, where there are already 
concurrent non communicable disease (NCD) epidemics? 
• 
It is encouraging that ADVANCE has been able to establish that it is now possible to achieve 
viral re-suppression routinely in a tightly regulated environment like a clinical trial. 
However, in a real world scenario like a resource-constrained government clinic, the 
development of resistance may be more likely as monitoring and adherence is less intense. 
In a real-world environment, are there opportunities to turn suppression failure trajectories 
around given the re-suppression opportunities this drug regimen provides? 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 19 of 35 
 
• 
What was the experience of patients movin from the clinical trial environment to a “real 
world” setting in the public sector clinics? 
 
2.2 
Study Rationale 
 To provide this data and answer the questions raised, we propose accessing the ADVANCE 
participants, as well as well-characterised patientswho have previously  exited other studies, who 
were on tenofovir disoproxil fumarate/emtricitabine/efavirenz (TEE) and are now utilising the state 
dolutegravir antiretroviral programme. We will describe the general safety, long-term weight gain 
trajectory and associated obesity-related complications, as well as experience transitioning to the 
above state programmes in order to inform and guide future monitoring and screening programmes. 
We believe this is particularly important, as  it appears that the burden of these complications will be 
disproportionately borne by South African women, who already are experiencing an obesity 
epidemic, and in ADVANCE and other studies experienced the most  severe weight gain. Additionally, 
we propose to identify those with virological failure, the pattern of resistance, and the response to 
a routine adherence intervention. 
Finally, we want to describe the complex experience of these patients, their health providers, 
community members and advocates, and programme implementers, of dolutegravir introduction 
during the COVID-19 pandemic. Specifically, new regimens and long-acting antiretroviral agents are 
on the  horizon, and it will be critical to be clear on lessons around mass regimen transition ahead of 
this change. 
We propose an observational study to address: 
o Long term trajectory and consequences of weight gain and obesity on patients initiating and 
transitioning to TLD. The ADVANCE cohort is unique in this regard – it represents a cohort 
of diverse African patients who have been on dolutegravir on the continent the longest. In 
addition, our second cohort of patients were similarly characterised at baseline, and drawn from 
the same community, re-entering the same health system at study exit, while moving from TEE 
to TLD at approximately the same time as the ADVANCE patients. The  extensive 
characterisation of both men and women, as well as important predictors of weight  
trajectory (baseline weight, CD4 and viral load), allow us to start modelling what the current 
roll-out of dolutegravir will look like in several years from now. Importantly, it will inform 
which, if any, metabolic and other complications should be monitored, and potentially at 
which thresholds. 
o Levels of viral suppression, and prevalence of resistance in those without suppression, in 
patients that have transitioned to TLD. There is significant interest at the prospect of the 
programme simplicity of ‘’TLD to TLD’’ – of focusing on adherence challenges in viraemic 
patients, rather than changing drug regimens. Current WHO recommendations recommend 
a switch ‘to appropriate regimen’’ with prolonged viraemia, but there is considerable doubt 
whether this is necessary, as genotype testing in ADVANCE and other studies suggest no 
resistance occurring to dolutegravir, and additional data accruing from studies such as 
NADIA3, VISEND7  and ARTIST8 suggest that nucleoside backbones can be recycled 
successfully in most cases. The ADVANCE patients again represent patients who have been 
on dolutegravir the longest– and hence have had the most time to develop resistance – and 
screening them for viraemia,  resistance, and then re-suppression with an intensive 
adherence intervention, will again provide invaluable data on whether a ‘’TLD to TLD’’ 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 20 of 35 
 
approach is appropriate. 
o Patient, nurse, civil society and programme manager perceptions of the TLD expansion, 
against the backdrop of safety concerns about neural tube defects and weight gain. The mass  
transition to TLD was supposed to be done alongside a community, patient and healthcare 
education programme, that emphasized viral suppression at the point of transition (to avoid 
switching viraemic patients with possible functional dual- or mono-therapy), informed 
consent  around the issue of the neural tube defect risk, and finally, counselling about 
weight gain and emergent obesity, and mitigation strategies. In the end, the rollout 
coincided partly with the onset of the initial COVID-19 wave in South Africa, and one of the 
world’s most severe lockdowns, meaning that the impact on both education, the speed, 
experience and fidelity of the rollout, and monitoring has been very difficult to assess. 
 
We will utilise the ADVANCE cohort, as well as a similarly well-described cohort of patients previously  
on tenofovir disoproxil fumarate/lamivudine (or emtricitabine)/efavirenz (TLE or TEE)2, who have 
transitioned to routine care on TLD, with whom we have continued contact. This will allow us to 
compare medium (5 year in the ADVANCE cohort) and longer (9 year in the other cohort) metabolic 
and virologic data of those on long-term antiretrovirals, and their experience in the transition to TLD. 
In addition, these patients, as well as the health care workers providing them care, the activists and 
community members involved in advocacy and education, and the programme managers 
coordinating care, can give us their experience with the transition, in focus group and individual 
discussions as part of a sub-study. As we are anticipating future  moves to other regimens, including 
long-acting agents that may be far more complex than the transition to TLD, these lessons may prove 
invaluable. 
3. 
OBJECTIVES AND ENDPOINTS 
Primary 
Objectives 
Endpoints 
Characterisation of weight gain and metabolic 
consequences associated with long-term TLD use 
• Weight measurement with BMI calculation 
• Blood pressure (BP) 
• Plasma glucose, HbA1C 
• Lipid panel 
• Liver function tests 
• DXA 
• ECG 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 21 of 35 
 
Secondary 
Objectives 
Endpoints 
• Assessment of factors contributing to, 
and induvial perception on weight gain 
 
 
• Description of the presence of viraemia 
 
 
• Description of the presence and patterns 
of HIV-1 resistance mutations in 
participants with viral loads > 1000 
copies/mL 
 
• Description and occurrence of associated 
sleep quality and disorders 
 
 
• Food diary questionnaire 
• Weight Bias Internalization Scale 
 
 
• Plasma HIV-1 RNA levels 
 
 
 
• HIV-1 genotyping 
 
 
 
 
• Berlin Questionnaire for risk of sleep 
apnoea 
• Polysomnography (PSG) in randomly 
selected 20% of participants at high risk 
of developing OSA based on the Berlin 
Questionnaire 
Exploratory Objectives 
• 
The association between various specialised sleep and glucose metabolism parameters, as well as 
patient experiences with the transition to TLD, will be explored through the sub-studies detailed 
below. 
 
4. 
STUDY DESIGN 
4.1 
Overall Design 
 This is a single centre, follow-up, observational, cross-sectional study reviewing two cohorts of 
patients 
who 
have 
transitioned 
to 
routine 
care 
on 
tenofovir 
disoproxil 
fumarate/lamivudine/dolutegravir (TLD). The first cohort will include ADVANCE patients, in which 
participants were randomised to one of three arms including either DTG+TAF/FTC, DTG+TDF/FTC or 
EFV/TDF/FTC. The second cohort will include patients previously on TLE or TEE who have since 
transitioned to routine care on TLD. 
 
The medium (5-year data in the ADVANCE cohort) and longer (9-year data in the other cohort) 
metabolic and virologic consequences of those on long-term antiretrovirals will be described and 
compared in the above cohorts. 
 
After obtaining informed consent from potential participants, a single cross-sectional, baseline visit 
will be conducted for each participant. Demographic data, clinical history, and details of previous and 
concomitant medications will be collected. Questionnaires including a food diary, Weight Bias 
Internalization Scale (WBIS) and Berlin questionnaire will be administered. Bone density and weight 
distribution will be assessed through use of a dual-energy X-ray absorptiometry (DXA) scan, and 
cardiac function assessed by conduction of a baseline electrocardiogram (ECG). 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 22 of 35 
 
 
Laboratory evaluations will include a liver function test, glycated haemoglobin (HbA1C), plasma HIV-1 
RNA (viral load), lipid panel, C-peptide, both serum glucose and oral glucose tolerance test, and DNA 
extraction for genotyping in those with unsuppressed viral loads above 1000 copies/mL. Plasma 
samples will be stored locally for possible future analysis.  
 
After the baseline visit, participants who are suitable for one, or more, sub-study will be identified. A 
randomly selected sub-group for each of the following sub-studies and additional investigations will 
be drawn from eligible participants within each cohort: 
• Sleep evaluation: actigraphy and polysomnography 
• Glucose metabolism evaluation: oral glucose tolerance test (OGTT) including assessment of 
glucose, insulin, and C-peptide to estimate insulin sensitivity and beta cell function 
• Experiences of users and providers in the roll out of TLD in South Africa. 
 
Abnormalities detected in the assessments will be managed by on-study medical personnel with 
referral as appropriate. 
4.2 
Study Treatments 
No treatment will be administered during this observational study. Participants taking medication(s) 
at the time of screening and enrolment, will continue to take this throughout their participation in the 
study. 
4.3 
Study Duration 
The duration of participation for each participant will either be a single visit (of approximately 5 hours), 
or two or more visits depending on whether they are enrolled into any sub-studies. 
Total duration will be from 1 to 60 days. 
Participants selected for the sleep study will have an overnight admission at the University of the 
Witwatersrand (Wits) Faculty of Health Sciences sleep laboratory. 
4.4 
Individual Participant Withdrawal 
A participant may be withdrawn from the study for any of the following reasons: 
• 
At the request of the participant (withdrawal of informed consent), irrespective of the reason for 
this 
• 
At the request of the primary care provider if he or she thinks the study is not in the best interest 
of the participant 
• 
At the discretion of the Investigator if he or she believes that continuation in the study would be 
detrimental to the participant’s well-being in any way, or 
• 
At the discretion of the Institutional Review Board/Ethics Committee if they believe that 
continuation in the study would be detrimental to the participant’s well-being in any way. 
Participants will be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or are lost to follow-up for any other reason. For participants who are lost to follow-up, the 
Investigator will attempt to trace the participant, and will demonstrate "due diligence" by 
documenting all steps taken to contact the participant (e.g., dates of telephone calls, home visit, etc.) 
in the source documents. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 23 of 35 
 
If a participant withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
If a participant withdraws from the study, he or she may request destruction of any samples taken 
and not tested. This must be documented by the Investigator in the site study records. 
Participants who withdraw or are withdrawn will not be replaced. 
5. 
STUDY POPULATION 
Adults of at least 18 years of age with HIV-1 infection who are currently on the TLD state programme 
who satisfy the below eligibility criteria. 
 
The following eligibility criteria will be used to select study participants for the main study (baseline 
visit only): 
• Inclusion criteria (baseline visit/main study): 
1. Able and willing to provide written or electronic informed consent for the baseline 
visit prior to any study-specific assessment or procedure. 
2. Age at least 18 years at the time of signing the informed consent form. 
3. Previously enrolled in the ADVANCE trial and have been on the TLD state 
programme for more than one year [Cohort 1] 
or, 
part of an existing cohort of patients initiating TLE (and switched to TEE) more than 
9 years ago, who have been transitioned to TLD within the state programme for 
more than one year [Cohort 2]. 
4. Access to a reliable telephone or other device permitting information transfer. 
 
• Exclusion criteria (baseline visit/main study): 
1. Personnel (e.g., investigator, sub-investigator, research assistant, pharmacist, study 
coordinator or anyone mentioned in the delegation log) directly involved in the 
conduct of the study. 
2. Any physical, mental, or social condition, that, in the Investigator’s judgment, might 
interfere with the completion of the baseline assessments and evaluations. The 
Investigator should make this determination in consideration of the volunteer’s 
medical history. 
3. Participant is judged by the Investigator to be at significant risk of failing to comply 
with the provisions of the protocol as to cause harm to self or seriously interfere 
with the validity of the study results. 
 
Additional eligibility criteria will be used to identify study participants who are eligible for random 
selection for any of the sub-studies: 
• Inclusion criteria (sub-studies): 
1. Enrolled into main study and completed baseline visit. 
2. Able and willing to provide written or electronic informed consent for the relevant 
sub-study. 
3. Identified as high risk for development of OSA based on the Berlin Questionnaire 
responses [Sleep sub study only]. 
 
• Exclusion criteria (sub-studies): 
1. Self-reported diabetic or on treatment for diabetes mellitus (Type 1 or 2) [Glucose 
metabolism sub-study only]. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 24 of 35 
 
2. Serum glucose and/or HbA1C assessment at baseline consistent with a diagnosis of 
diabetes mellitus [Glucose metabolism sub-study only]. 
 
 
Participants may be enrolled into more than one sub-study. 
5.1 
Cohorts 
The following well-described cohorts of participants will be enrolled (375 participants in total): 
• 
Cohort 1: ADVANCE patient cohort, who have been on the TLD state programme for more than 
one year. 
• 
Cohort 2: existing cohorts of patients initiating TLE (and subsequently switched to TEE) more than 
9 years ago and who have since transitioned to TLD within the state programme for more than 
one year. 
5.2 
Recruitment 
Potential participants may volunteer in response to advertised clinical trial information or will be 
contacted in compliance with POPIA regulations and invited to participate in the informed consent 
process (Section 11.2) and attend the baseline visit. Written informed consent will be obtained prior 
to any screening, and study-specific assessments and procedures. 
The full recruitment strategy will be outlined in the relevant SOP. 
5.3 
Main Study Eligibility Criteria (Baseline Visit) 
The following eligibility criteria will be used to select study participants for the main study (baseline 
visit only). 
5.3.1 
Inclusion criteria 
1. Able and willing to provide written or electronic informed consent for the baseline visit prior to 
any study-specific assessment or procedure. 
2. Age at least 18 years at the time of signing the informed consent form. 
3. Previously enrolled in the ADVANCE trial and have been on the TLD state programme for more 
than one year [Cohort 1] 
or, 
part of an existing cohort of patients initiating TLE (and switched to TEE) more than 9 years ago, 
who have been transitioned to TLD within the state programme for more than one year [Cohort 
2]. 
4. Access to a reliable telephone or other device permitting information transfer. 
5.3.2 
Exclusion criteria 
1. Personnel (e.g., investigator, sub-investigator, research assistant, pharmacist, study coordinator 
or anyone mentioned in the delegation log) directly involved in the conduct of the study. 
2. Any physical, mental, or social condition, that, in the Investigator’s judgment, might interfere with 
the completion of the baseline assessments and evaluations. The Investigator should make this 
determination in consideration of the volunteer’s medical history. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 25 of 35 
 
3. Participant is judged by the Investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of the 
study results. 
5.4 
Sub-Study Eligibility Criteria (Subsequent Optional Visit(s)) 
The following additional eligibility criteria will be used to identify study participants who are eligible 
for random selection for any of the sub-studies. Participants may be enrolled into more than one sub-
study. 
5.4.1 
Inclusion criteria 
1. Enrolled into main study and completed baseline visit. 
2. Willing to provide written or electronic information consent for the relevant sub-study. 
3. Identified as high risk for development of OSA based on the Berlin Questionnaire responses [Sleep 
sub study only]. 
 
5.4.2 
Exclusion criteria 
1. Self-reported diabetic or on treatment for diabetes mellitus (Type 1 or 2) [Glucose metabolism 
sub-study only]. 
2. Serum glucose and/or HbA1C assessment at baseline consistent with a diagnosis of diabetes 
mellitus [Glucose metabolism sub-study only]. 
5.5 
Participant Identification 
All volunteers who provide informed consent to participate in the study will be allocated a unique 
sequential screening number which will be used as the primary identifier for the duration of the study 
for enrolled participants. 
5.6 
Co-enrolment Guidelines 
Participants may be co-enrolled in other research studies if these are observational in nature or 
include behavioural interventions only. Other co-enrolments require approval by the Principal 
Investigator after consideration of possible confounding effects and participant safety and well-being 
regarding blood draw volumes and exposure to multiple assessments. 
6. 
STUDY VISITS 
A brief screening assessment will be conducted for all study participants who provide informed 
consent for participation in the study. Those who are eligible for enrolment will continue into a 
baseline visit where all main study questionnaires will be administered, and assessments and 
procedures conducted. 
Participants who are eligible for various sub-studies will be identified by the study team after review 
of their baseline visit results. Sub-study participants (up to 120 participants) will be randomly selected 
from these eligible participants and will be invited to provide separate informed consent for each sub-
study. An additional visit or visits will be conducted for each sub-study. The number of study visits for 
each participant will depend on the number of sub-studies in which they participate. All study visits 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 26 of 35 
 
(including the screening/baseline visits) will be completed for each participant within a maximum of 
60 days. 
Questionnaires to be administered, and assessments and procedures to be conducted at each study 
visit (main and sub-studies) are detailed in Section 1. Details regarding each questionnaire, assessment 
and procedure are described in Section 7. 
7. 
STUDY ASSESSMENTS, QUESTIONNAIRES, AND PROCEDURES 
No study-specific assessments will be performed, or information gathered, until the potential 
participant has given written, informed consent (Section 11.2) for screening assessments and (if found 
to be eligible) for study participation. 
The timing of all assessments and procedures is detailed in the Schedule of Assessments (Section 
Error! Reference source not found.). 
7.1 
Main Study 
Screening and baseline assessments are expected to be performed on the same day but may be spread 
over two or more separate days given the expected duration of the visit (approximately 5 hours). 
7.1.1 
Enrolment (Visit 1) 
Review of the main study eligibility criteria will be performed for all participants providing informed 
consent for the main study (baseline visit).  
7.1.2 
Baseline assessments, questionnaires, and procedures (Visit 1) 
The following main study (baseline) evaluations will be performed. These may be performed in any 
sequential order during the baseline visit. All questionnaires, surveys and rating scales will be 
administered in accordance with the specific guidelines associated with validated versions of the tools 
and will be included in the Study Assessments Manual. 
Participants will be required to fast for 8 hours (water permitted ad libitum) prior to the drawing of 
blood for serum glucose assessments and lipid panel. If additional baseline assessments are scheduled 
for the same day as the blood draw, this will be performed as one of the first procedures of the visit 
and participants will be given a meal at the research unit before proceeding with the remaining 
assessments. 
7.1.2.1 
Demographics, and social background and habits data 
The following will be collected: 
• 
Sex, age, race, and country of origin 
• 
Town of residence 
• 
Use of tobacco products, alcohol, and illicit/street drugs. 
7.1.2.2 
Medical and surgical history 
General information related to past and current relevant medical conditions and surgical procedures 
will be collected, as well as pregnancy and lactation status (for female participants only). 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 27 of 35 
 
7.1.2.3 
Previous and concomitant medications 
Details of previous and ongoing medications will be collected. 
7.1.2.4 
Physical examination and vital signs 
Height and weight (as measured in light indoor clothing or underwear only, but without shoes) will be 
measured, and body mass index (BMI) derived. Only blood pressure will be necessary to collect as part 
of vital signs. 
A symptom-directed physical examination will be performed by the investigator where necessary. 
7.1.2.5 
Factors contributing to weight and perception of weight gain 
• 
Food diary 
• 
Weight Bias Internalization Scale (WBIS)9 
7.1.2.6 
Sleep evaluation 
Sleep quality and associated disorders will be evaluated using the: 
• 
Berlin Questionnaire: a self-administered questionnaire designed to identify subjects at high risk 
for obstructive sleep apnoea10. 
• 
Polysomnography in a randomly selected 20% of patients in those identified to be at high risk of 
development of OSA 
7.1.2.7 
Laboratory assessments 
Blood sampling will be performed to collect samples for the following laboratory assessments: 
• 
Serum chemistry: serum sodium, potassium, chloride, bicarbonate 
• 
Liver function: total protein, albumin, total bilirubin, direct bilirubin, alkaline phosphatase (ALP), 
gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), lactate dehydrogenase (LDH) 
• 
Renal function: urea, creatinine, estimated creatinine clearance (Cockcroft-Gault method) 
• 
Lipid panel: total cholesterol, triglycerides, HDL, and LDL cholesterol 
• 
Glucose metabolism: plasma glucose, HbA1C 
• 
HIV virological suppression: plasma HIV-1 RNA 
An additional plasma (50 mL) sample will be stored for possible future analysis. 
Details regarding blood sample collection, handling and processing, and the assays (where applicable) 
will be documented in the Laboratory Manual. 
7.2 
Viraemia confirmation visits (Visit 2) 
These visits will only be conducted for participants with unsuppressed viral loads at baseline. In 
instances where a single baseline HIV-1 RNA level is ≥ 1000 copies/mL, a repeat viral load and HIV 
genotyping will be done, and an assessment of adherence and intensive adherence counselling done. 
Once genotyping results are available, the participant may be recalled for review of results and referral 
back into the state ART programme for ongoing care. In instances where a single baseline HIV-1 RNA 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 28 of 35 
 
level is < 1000 copies/mL, adherence counselling will be done, and the participant recalled for a repeat 
viral load to assess re-suppression. 
7.3 
Sub-Studies 
Participants may be invited to take part in more than one sub-study, or none. Up to 120 participants 
will be enrolled into each sub-study. 
7.3.1 
Screening and informed consent 
Separate informed consent will be obtained for each sub-study for participants invited to take part in 
these. 
7.3.2 
Sub-study visit(s) 
7.3.2.1 
Sleep evaluation 
Participants who are selected and provide consent for participation in the sleep sub-study, will have 
the following additional assessments: 
• 
Actigraphy 
• 
Overnight polysomnography (PSN) at the Wits Faculty of Health Sciences Sleep Laboratory. 
Further details can be found in the Sleep Sub-Study Plan. 
7.3.2.2 
Glucose metabolism evaluation 
Participants with normal serum glucose and HbA1C at the baseline visit, and who are not on treatment 
for diabetes mellitus (Type 1 or 2), will be randomly selected for participation in the glucose 
metabolism sub-study. Those who provide consent for participation will attend a single visit where an 
OGTT, including measures of glucose, insulin, and c-peptide to estimate insulin sensitivity and beta-
cell function, will be performed. 
Further details can be found in Glucose Metabolism Sub-Study Plan. 
7.3.2.3 
Review of experiences of users and providers in the roll out of TLD in South Africa 
This qualitative sub-study seeks to understand the roll out of TLD in South Africa since its introduction 
in 2019. To achieve this, we will perform in-depth interviews and focus group discussions with various 
key informants and stakeholders. The purpose of in-depth interviews will be to understand the roll 
out from a guideline’s perspective and how some of that has been put into practice. The focus group 
discussions will seek to ascertain how the target population of the programme (people living with HIV) 
have reacted to the transition, their perceptions, and practical constraints. 
Further details can be found in the Qualitative Assessment of User and Provider Experiences in the 
Roll-out of TLD in South Africa Sub-Study Plan. 
7.3.3 
Telephonic follow-up 
Participants taking part in sub-studies will be contacted telephonically within 28 days of completion 
of their last sub-study visit to inform them of the results of their assessments and conduct adherence 
counselling where necessary. Abnormalities detected in assessments (suggesting undiagnosed 
medical issues) will be managed by on-study medical personnel with referral as appropriate. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 29 of 35 
 
7.4 
Biohazard Containment 
Precautions will be employed by all personnel in the handling of blood and urine specimens collected 
during this study. 
All biological specimens will be transported using packaging mandated by national and regional 
regulations. Details of these procedures will be described in the Laboratory Manual and will comply 
with relevant IATA Dangerous Goods Regulations. 
8. 
SAFETY MONITORING 
8.1 
Responsibilities for Ensuring the Safety of Study Participants 
8.1.1 
Principal Investigator 
The Principal Investigator has a personal responsibility to closely monitor study participants and an 
inherent authority to take whatever measures necessary to ensure their safety, including ensuring 
that procedures and expertise are available to cope with medical emergencies during the study. 
8.1.2 
Study Sponsor 
The Sponsor has an institutional responsibility to ensure participant safety and undertakes to 
promptly notify the Wits Human Research Ethics Committee (HREC) of findings that could adversely 
affect the safety of participants included in the study, impact the conduct of the study, or alter the 
HREC’s approval of, or favourable opinion to continue, the study.  
8.2 
Adverse Events 
8.2.1 
Definitions 
Some of the assessments and procedures used in this study may be associated with rare discomfort 
or adverse events (AEs), e.g., blood sampling, six-minute walk test, injection of contrast media, skin 
irritation from electrodes used in polysomnography. 
For this study, AEs associated with study assessments or procedures will be recorded in the eCRF for 
each participant. The following information be recorded for each AE: 
• 
a description of the AE 
• 
the dates of onset and resolution of the event 
• 
the characteristics of the event (seriousness, severity in accordance with the DAIDS Grading Table 
Version 2.1, Jul 2017)11 
• 
the action taken in response to the event (including treatment required) 
• 
the outcome of the event. 
9. 
STATISTICAL CONSIDERATIONS 
Details of the statistical analyses and their presentation will be documented in the Statistical Analysis 
Plan (SAP). 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 30 of 35 
 
9.1 
Sample Size Determination 
No formal sample size was calculated for this exploratory study. On-study findings may suggest that 
larger sample sizes are required to further analyse endpoints in specific groups, and further planning 
for this may be performed. 
9.2 
Analysis and Presentation of Data 
9.2.1 
Disposition, demographic, and background data 
Participants enrolled in the main, and various sub-studies, will be summarised. Demographic data and 
other baseline characteristics will be summarised overall and per cohort.  
9.2.2 
Primary and secondary endpoints 
All primary and secondary endpoints will be summarised descriptively overall, per cohort and for 
various risk factors as deemed appropriate in this exploratory study. Associations between weight 
gain, metabolic risk and presence of sustained viral re-suppression may be explored. Additionally, any 
HIV-1 resistance mutations noted on genotyping will be described in detail. 
9.2.3 
Safety data 
All AEs will be listed. 
9.2.4 
Exploratory analyses 
Details of exploratory endpoints and analyses to be performed will be included in the SAP. 
10. 
STUDY MONITORING 
Study conduct will be monitored by a research site monitor. Review of individual participant records, 
including consent forms, electronic case report forms (eCRFs), supporting data, questionnaire 
responses, and laboratory specimen records will be performed as detailed in the Clinical Monitoring 
Plan, to ensure protection of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect the site files to ensure that good clinical 
practice requirements are being followed. 
The Clinical Monitoring Plan will describe these activities and will take into consideration necessary 
adaptations to be made if physical access to the site is limited at any stage due to pandemic 
restrictions. 
11. 
ETHICAL CONSIDERATIONS 
11.1 
Ethical Considerations 
The study will be conducted according to GCP (including South African GCP Guidelines [Error! 
Reference source not found.]), the Belmont Report, the Declaration of Helsinki, and South Africa legal 
requirements regarding clinical research. The study protocol and relevant supporting documents will 
be submitted for review and approval by the Wits HREC responsible for oversight of research 
conducted at the study site. The study protocol will be registered with the South African National 
Clinical Trial Registry (www.sanctr.gov.za), National Human Research Ethics Committee 
(www.ethicsapp.co.za) and www.ClinicalTrial.gov. Six-monthly progress reports will be submitted to 
the HREC for the duration of the study, and as requested. Upon completion or premature termination 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 31 of 35 
 
of the study, the Investigator will provide the HREC with a summary of the study’s outcome, and any 
reports required. 
11.2 
Informed Consent Process 
The principles of informed consent in the current edition of the Declaration of Helsinki will be 
implemented before any protocol-specified procedures or interventions are carried out. The consent 
form will describe the purpose of the study, the assessments, questionnaires, and procedures to be 
performed, and the risks and benefits of participation. Separate consent forms will be available for 
the main study and all sub-studies. Participation in the sub-studies is voluntary and consent will be 
sought for these after completion of the baseline visit of the main study for participants who are 
eligible for further enrolment into sub-studies. Separate consent will be required for each sub-study 
in which a participant is enrolled. 
Potential participants will have the opportunity to have any questions answered before and after 
signing the informed consent forms (ICFs). The informed consent process and all questions raised will 
be documented.  
The study staff who conduct the informed consent process will also sign the ICFs. A copy of the consent 
form(s) will be given to the participant, and this fact will be documented in the participant’s record. 
Any participant who is rescreened should be reconsented and eligibility for the study must be re-
checked prior to enrolment. 
11.3 
Blood Volume 
The volume of blood to be drawn from participants taking part in the main study is less than 100 mL. 
For a participant taking part in all additional sub-studies, the total blood volume across the entire 
study will not exceed 250 mL over 60 days. 
11.4 
Study Records and Confidentiality 
The study site will establish a standard operating procedure for confidentiality protection. The site will 
ensure that study records, including ICFs, locator forms, case report forms, notations of all contacts 
with the participant, and all other source documents are stored in a secure manner. 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain participant confidentiality. 
All records will be kept in a secure storage area with limited access. Clinical information will not be 
released without the written permission of the participant, except as necessary for monitoring, and 
auditing by the HREC. 
The Principal Investigator or designee and all employees and co-workers involved with this study may 
not disclose or use, for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to those individuals for the purpose of the study. 
All computers used during the study conduct will be password-protected, and records will only be 
accessible to authorised study staff. 
11.5 
Participant Remuneration 
For each day of protocol-related study procedures, the participants will receive compensation for 
travel costs to and from the clinic and inconvenience incurred, as per local regulating body 
recommendations. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 32 of 35 
 
12. 
ADMINISTRATIVE CONSIDERATIONS 
12.1 
Protocol Amendments 
Any protocol amendments will be prepared by the Sponsor and submitted to the HREC in accordance 
with their requirements. 
Approval must be obtained from the HREC before the implementation of any changes, except for 
changes necessary to eliminate an immediate hazard to participants, or changes that involve logistical 
or administrative aspects only (e.g., change in contact information). 
12.2 
Clinical Data Records 
A log of names, signatures and initials of all staff authorised to enter data into a participant’s clinic file 
and eCRF will be kept. 
The Investigator will maintain paper or electronic source documentation for all study participants. 
Protocol-specific participant information will be captured in an eCRF. The Clinical Data Management 
System will comply with guidelines and requirements for electronic systems used in clinical research. 
Data validation and quality control procedures will be detailed in the Data Management Plan. 
All deviations from this study protocol will be documented in the Trial Master File and included in the 
final study report. An assessment of the significance of each protocol deviation will be presented in 
the clinical study report. 
12.3 
Record Retention 
All source data, clinical records and laboratory data relating to the study will be archived for a 
minimum period after completion of the study in accordance with South African GCP guidelines, 
Sponsor and Funder requirements. Data will be available for retrospective review or audit by 
arrangement with the appropriate representative at the archiving organisation (e.g., Sponsor Head).  
12.4 
Discontinuation of the Study 
The Sponsor, the Funder, the Principal Investigator, and the HREC independently reserve the right to 
discontinue the study at any time for safety or other reasons. This will be done in consultation with 
the Funder, Sponsor and Principal Investigator where practical. In the event of premature termination 
or suspension of the study, the above-mentioned parties will be notified in writing by the 
terminator/suspender stating the reasons for early termination or suspension. Following such a 
decision, the Sponsor and the Investigator will ensure that adequate consideration is given to the 
protection of the participants’ interest and safety. Ongoing participants will be followed up 
telephonically to ensure that feedback related to the results of their assessments, questionnaires and 
procedures is provided. 
12.5 
Publication Policy 
A dissemination plan will be developed with all project partners prior to study completion. After study 
completion, results will be disseminated using the following strategies: written methods (i.e., 
publications in peer reviewed scientific journals), presentations at scientific conferences and 
workshops, in person dissemination of results to the research participants, and using electronic 
methods such as the project website and electronic media to publish results. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 33 of 35 
 
12.6 
Study Audits 
Audits may be carried out by the SAMRC, Sponsor, or HREC quality assurance representatives. All 
documents pertinent to this study must be made available for such inspections after adequate notice 
of the intention to audit is provided. 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 34 of 35 
 
13. 
REFERENCES 
1.  
Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus Two Different 
Prodrugs of Tenofovir to Treat HIV. N Engl J Med. 2019;381(9):803-815. 
doi:10.1056/NEJMoa1902824 
2.  
Venter WDF, Sokhela S, Simmons B, et al. Dolutegravir with emtricitabine and 
tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, 
emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 
infection (ADVANCE): week 96 results from a randomised, phase 3, n. Lancet HIV. 
2020;7(10):e666-e676. doi:10.1016/S2352-3018(20)30241-1 
3.  
Dolutegravir-Based or Low-Dose Efavirenz–Based Regimen for the Treatment of HIV-
1. N Engl J Med. 2019;381(9):816-826. doi:10.1056/NEJMoa1904340 
4.  
Hill A, Waters L, Pozniak A. Are new antiretroviral treatments increasing the risks of 
clinical obesity? J virus Erad. 2019;5(1):41-43. 
http://www.ncbi.nlm.nih.gov/pubmed/30800425 
5.  
South African Department of Health. South Africa Demographic and Health Survey 
2016.; 2016. https://www.samrc.ac.za/sites/default/files/attachments/2019-01-
29/SADHS2016.pdf 
6.  
UNAIDS. 90-90-90: An Ambitious Treatment Target to Help End the AIDS Epidemic.; 
2014. chrome-
extension://efaidnbmnnnibpcajpcglclefindmkaj/viewer.html?pdfurl=https%3A%2F%2
Fwww.unaids.org%2Fsites%2Fdefault%2Ffiles%2Fmedia_asset%2F90-90-
90_en.pdf&clen=984788&chunk=true 
7.  
Mulenga LB, Fwoloshi S, Mweemba A, et al. Dolutegravir with Recycled NRTIs is 
Noninferior to PI-based ART: Visend Trial. In: IAS-USA. ; 2022:Oral Abstract 135. 
https://www.croiconference.org/wp-
content/uploads/sites/2/resources/2022/croi2022-abstract-ebook.pdf 
8.  
Keene CM, Griesel R, Zhao Y, et al. Virologic efficacy of tenofovir, lamivudine and 
dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based 
first-line regimen. AIDS. 2021;35(9):1423-1432. doi:10.1097/QAD.0000000000002936 
9.  
Durso LE, Latner JD. Understanding Self-directed Stigma: Development of the Weight 
Bias Internalization Scale. Obesity. 2008;16(S2):S80-S86. doi:10.1038/oby.2008.448 
10.  
Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin Questionnaire 
To Identify Patients at Risk for the Sleep Apnea Syndrome. Ann Intern Med. 
1999;131(7):485. doi:10.7326/0003-4819-131-7-199910050-00002 
11.  
Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events. Published 2017. chrome-
extension://efaidnbmnnnibpcajpcglclefindmkaj/viewer.html?pdfurl=https%3A%2F%2
Frsc.niaid.nih.gov%2Fsites%2Fdefault%2Ffiles%2Fdaidsgradingcorrectedv21.pdf&clen
=507845&chunk=true 
 
 

Ezintsha, University of the Witwatersrand 
Confidential 
EZ-FV-030 
Clinical Study Protocol 
 
 
 
Version 1.2, 06 Apr 2022 
Page 35 of 35 
 
APPENDICES 
APPENDIX 1: 
STUDY GOVERNANCE 
The following Investigators and Institutional Affiliations are established. Designees may be provided, 
as appropriate. 
Name 
Role  
Institution 
Dr Bronwyn Bosch 
Principal 
Investigator 
Ezintsha, University of the Witwatersrand 
Building C 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
South Africa 
Prof Francois Venter 
Co-Principal 
Investigator 
Ezintsha, University of the Witwatersrand 
Building C 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
South Africa 
Dr Simiso Sokhela 
Co-Principal 
Investigator 
Ezintsha, University of the Witwatersrand 
Building C 
Sunnyside Office Park 
32 Princess of Wales Terrace 
Parktown, Johannesburg 
South Africa