Genotype-Informed Versus Empiric Management of VirEmia (GIVE MOVE) in HIV-Infected Children and Adolescents on Antiretroviral Therapy: An Open-Label Randomised Clinical Trial
Phase: NA
Conditions: HIV-1-infection
Sponsor: Swiss Tropical & Public Health Institute

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Confidential 
 
Genotype-Informed Versus Empiric Management Of VirEmia (GIVE MOVE):  
An Open-Label Randomised Clinical Trial 
 
 
Study Type: 
Other Clinical Trial according to the Swiss Human Research Act (HRA) 
2014, Ordinance on Clinical Trials in Human Research (ClinO), Chapter 4 
 
Risk Categorisation: 
Risk Category A (lowest risk category; according to HRA, ClinO, 
Chapter 4) 
 
Study Registration: 
ClinicalTrials.gov: NCT04233242 
 
Sponsor: 
Prof. Niklaus Labhardt 
Socinstrasse 55, 4051 Basel, Switzerland 
+41 79 870 18 59 
n.labhardt@swisstph.ch 
 
Chief Investigator: 
Same as sponsor (investigator-initiated trial) 
 
Principal Investigator: 
Jennifer Brown 
 
Socinstrasse 55, 4051 Basel, Switzerland 
 
+41 79 512 97 16 
 
jennifer.brown@swisstph.ch 
 
Investigated Intervention: Genotype-informed management of unsuppressed viremia in children 
and adolescents living with HIV 
 
Protocol ID  
Lesotho: 
National Health Research Ethics Committee: ID 229-2019 
Tanzania: 
Ifakara Health Institute Institutional Review Board: IHI/IRB/No. 12-
2020; IHI/IRB/EXT/No. 10-2021 
National Institute for Medical Research: NIMR/HQ/R.8a/Vol 
IX/3442; NIMR/HQ/R.8a/Vol I/1768 
Tanzania Medicines and Medical Devices Authority: 
TMDA0020/CTR/0003/03 
Switzerland: 
Ethikkommission Nordwest- und Zentralschweiz: Req-2019-01275 
 
Version and Date: 
Version 1.4 (23.08.2021) 
 
 
 
 

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CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of the Sponsor/Chief 
Investigator. The information may not - in full or in part - be transmitted, reproduced, published, 
or disclosed to others than the applicable Competent Ethics Committee(s) and Regulatory 
Authority(ies) without prior written authorisation from the Sponsor/Chief Investigator except to the 
extent necessary to obtain informed consent from those who will participate in the study. 
 
 

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PROTOCOL SIGNATURE FORM    
 
The following persons have approved the GIVE MOVE protocol version 1.4 (23.08.2021) and 
confirm hereby to conduct the study according to the protocol, the current version of the World 
Medical Association Declaration of Helsinki, and ICH GCP E6R2 guidelines as well as the local 
legally applicable requirements. 
 
STEERING COMMITTEE MEMBERS 
Sponsor and Chief Investigator: 
Prof. Dr Niklaus Labhardt 
Date: _______________ 
Signature: _______________ 
 
Principal Investigator: 
Jennifer Brown 
Date: _______________ 
Signature: _______________ 
 
Expert Virology and Diagnostics: 
Prof. Dr Thomas Klimkait 
Date: _______________ 
Signature: _______________ 
 
Clinical Advisor: 
Dr Josephine Muhairwe 
Date: _______________ 
Signature: _______________ 
 
Clinical Coordinator Baylor, Lesotho (1): 
Dr Buntshi Paulin Kayembe 
Date: _______________ 
Signature: _______________ 
 
Clinical Coordinator Baylor, Lesotho (2): 
Dr Mosa Molapo Hlasoa 
Date: _______________ 
Signature: _______________ 
 
Lesotho Principal Investigator / Study Manager: 
Isaac Ringera 
Date: _______________ 
Signature: _______________ 
 
Clinical Coordinator CDCI, Tanzania: 
Prof. Dr Maja Weisser 
Date: _______________ 
Signature: _______________ 
25-Aug-2021 | 13:24:10 CEST
23-Aug-2021 | 09:27:25 CEST
23-Aug-2021 | 09:08:54 CEST
24-Aug-2021 | 09:18:59 CEST
23-Aug-2021 | 18:53:46 MESZ
24-Aug-2021 | 06:06:06 CEST
23-Aug-2021 | 13:53:57 CEST
25-Aug-2021 | 12:14:30 CEST

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Tanzania Principal Investigator / Local Principal Investigator Ifakara: 
Dr Ezekiel Luoga 
Date: _______________ 
Signature: _______________ 
 
Trial Statistician: 
PD Dr Tracy Glass 
Date: _______________ 
Signature: _______________ 
 
 
24-Aug-2021 | 19:39:21 CEST
23-Aug-2021 | 09:28:24 CEST

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TABLE OF CONTENTS 
GLOSSARY OF ABBREVATIONS 
7 
1 STUDY SYNOPSIS 
9 
2 BACKGROUND AND RATIONALE 
15 
2.1 
Scientific background and knowledge gaps 
15 
2.2 
Research question and intervention 
15 
2.3 
Rationale for study design 
16 
3 STUDY OBJECTIVES AND DESIGN 
16 
3.1 
Hypothesis and objectives 
16 
Hypothesis 
16 
Objectives 
16 
3.2 
Primary and secondary endpoints 
17 
Primary endpoint 
17 
Secondary endpoints 
17 
Exploratory endpoints 
17 
3.3 
Randomisation considerations 
18 
Potential effect modifiers 
18 
Randomisation procedure 
18 
3.4 
Study design 
18 
Setting 18 
3.5 
Study intervention 
20 
3.6 
Nested Study on Cost-Effectiveness 
21 
3.7 
Nested Study on Other Drivers of Viremia 
21 
4 STUDY POPULATION AND STUDY PROCEDURES 
21 
4.1 
Inclusion and exclusion criteria, justification of study population 
21 
Inclusion and exclusion criteria 
21 
Participant number and participant replacement 
21 
Rationale for including vulnerable participants (i.e. minors, pregnant/breastfeeding 
participants) in the study: 
21 
4.2 
Recruitment, screening and informed consent procedure 
22 
4.3 
Study procedures 
23 
Study duration 
23 
Study procedures 
23 
Stopping criteria 
25 
Sample storage 
25 
Data Management and Confidentiality 
25 
4.4 
Withdrawal of consent 
26 
5 STATISTICS AND METHODOLOGY 
26 
5.1 
Statistical analysis plan and sample size calculation 
26 
Null hypothesis 
26 
Determination of sample size 
26 
Planned analysis 
26 
Subgroup analysis 
27 
Datasets to be analysed, analysis populations 
27 

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Interim analysis 
27 
5.2 
Handling of missing data, withdrawals, and loss to follow-up 
27 
6 REGULATORY ASPECTS AND SAFETY 
28 
6.1 
Local regulations / Declaration of Helsinki 
28 
Reporting of SAEs 
28 
Follow up of SAEs 
29 
6.2 
(Periodic) safety reporting 
30 
6.3 
Pregnancy 
30 
6.4 
Amendments 
30 
6.5 
(Premature) termination of study 
30 
6.6 
Insurance 
31 
7 FURTHER ASPECTS 
31 
7.1 
Risk-benefit assessment 
31 
7.2 
Overall ethical considerations 
31 
8 QUALITY CONTROL AND DATA PROTECTION 
31 
8.1 
Quality measures 
31 
8.2 
Data recording and source data 
32 
8.3 
Confidentiality and coding 
32 
8.4 
Retention and destruction of study data and biological material 
32 
9 MONITORING AND REGISTRATION 
33 
10 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
33 
11 REFERENCES 
33 
12 APPENDIX 
38 
12.1 Appendix 1: Schedule of study procedures 
38 
12.2 Appendix 2: Electronic Case Report Forms (eCRF) 
40 
12.3 Appendix 3: Informed Consent Forms 
41 
Forms Lesotho 
41 
Forms Tanzania 
41 
12.4 Appendix 4: Staff List 
42 
12.5 Appendix 5: CVs of Main Investigators 
43 
12.6 Appendix 6: Monitoring Plan 
44 
 
 

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GLOSSARY OF ABBREVATIONS 
 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ASR 
Annual Safety Repot 
BASEC 
Business Administration System for Ethical Committees 
CALHIV 
Children and Adolescents Living with HIV; defined as ≥6 months and <19 
yearsCDCI 
Chronic Diseases Clinic Ifakara (at St. Francis Referral Hospital; affiliated with IHI) 
ClinO 
Ordinance on Clinical Trials in Human Research 
CRF 
Case Report Form 
FBC 
Full Blood Count 
EAC 
Enhanced Adherence Counselling 
eCRF 
electronic Case Report Form 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
EVAg 
European Virus Archive global 
FAS 
Full Analysis Set 
FPFV 
First Participant First Visit 
FPLV 
First Participant Last Visit 
GCP 
Good Clinical Practice 
GIVE MOVE Genotype-Informed Versus Empiric Management of Viremia 
GRT 
Genotypic Resistance Testing 
HBV 
Hepatitis B Virus 
HIV 
Human Immunodeficiency Virus 
HRA 
Swiss Human Research Act 
IAF 
Informed Assent Form 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IHI 
Ifakara Health Institute 
INSTI 
Integrase Strand Transfer Inhibitor 
IRB 
Institutional Review Board 
LPFV 
Last Participant First Visit 
LPLV 
Last Participant Last Visit 
MDH 
Management and Development for Health (Tanzania) 
NIMR 
National Institute for Medical Research (Tanzania) 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
PI 
Protease Inhibitor 
RCT 
Randomised Clinical Trial 
SAE 
Serious Adverse Event 
Swiss TPH 
Swiss Tropical and Public Health Institute 
UNAIDS 
United Nations Programme on HIV/AIDS 
USB 
University Hospital Basel (Universitätsspital Basel) 
VL 
Viral Load 
WHO 
World Health Organisation 
 

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1 
STUDY SYNOPSIS 
Sponsor / Chief 
Investigator 
Prof. Niklaus Labhardt 
Clinical Research Unit, Department of Medicine, Swiss Tropical and Public Health Institute 
Socinstrasse 55, 4051 Basel, Switzerland 
+41 79 870 18 59; n.labhardt@swisstph.ch 
Study Title 
Genotype-Informed Versus Empiric Management Of VirEmia (GIVE-MOVE): An Open-Label 
Randomised Clinical Trial 
Short 
Title 
/ 
Study ID 
GIVE MOVE 
Protocol Version 
and Date 
Version 1.4 (23.08.2021) 
Study 
Registration 
ClinicalTrials.gov: NCT04233242 
Study 
Category 
and Rationale 
Category A (lowest risk category according to the Swiss Human Research Act (HRA) 2014, 
Ordinance on Clinical Trials in Human Research (ClinO), Chapter 4). 
Rationale for risk categorisation: The trial’s intervention, Genotypic Resistance Testing (GRT) 
and GRT-informed treatment, is part of standard care for people living with HIV in most high-
income countries. The intervention is not expected to pose any risks beyond those present in 
standard care. Additional blood collection required by the study will be limited to age-
appropriate volumes. Data collection and questionnaires are expected to pose only minimal 
risks. All study participants will be treated with antiretroviral drugs licenced in Lesotho and 
Tanzania, using indications and dosages as defined in WHO guidelines as well as Tanzania 
and Lesotho guidelines. 
Background and 
Rationale  
Children and adolescents are highly vulnerable to adverse health consequences (including 
impaired growth and neurocognitive development) caused by HIV. Unlike adults, children and 
adolescents living with HIV (CALHIV) and receiving antiretroviral therapy (ART) in sub-
Saharan Africa suffer high rates of treatment failure (approx. 25-40%). Treatment failure may 
be caused by non-adherence to therapy, incorrect drug dosing, or viral drug resistance. GRT 
is a diagnostic test to detect drug resistance, allowing for an informed selection of drugs that 
will be effective in the respective patient. GRT-informed patient management is routine in high-
income countries but rarely available in sub-Saharan Africa. We intend to assess the effect of 
GRT-informed management of unsuppressed viremia on subsequent health outcomes in 
CALHIV. 
Risk 
/ 
Benefit 
Assessment 
Risks to study participants are minimal (see “Study Category and Rationale” above). 
Participants in the intervention group will receive and are expected to benefit from GRT-
informed onward therapy (optimized drug regimen based on testing the drug resistance profile) 
already during the study period. In case this study shows that GRT-informed management is 
superior to standard care, at study closure all participants with an elevated viral load (VL) will 
receive GRT and GRT-informed onward therapy. 
Objective(s) 
Primary objective: To assess if GRT-based management of viremia in CALHIV on ART in 
resource-limited settings improves overall health outcomes. The results of this trial are 
intended to inform future WHO and national guidelines on the use of GRT in CALHIV. 
Secondary objectives: To assess the impact of GRT-based management of viremia in 
CALHIV on various individual health outcomes including mortality, morbidity, and virologic 
status. 
Exploratory objectives: To assess the dynamics of viral resuppression and the viral 
development of drug resistance without vs with GRT-based management of viremia. 
Endpoint(s) 
Primary endpoint: The composite primary endpoint is the occurrence of any one or more of 
the events i) death due to any cause during the follow-up period (36 weeks), ii) HIV- or ART-
related hospital admission of ≥24 hours duration (possibly, probably or definitely related to HIV 
or ART, judged by the endpoint committee blinded to the study arm) during the follow-up period 
(36 weeks), iii) new clinical WHO stage IV event (excluding lymph node tuberculosis, stunting, 
oral or genital herpes simplex infection and oesophageal candidiasis; judged by the endpoint 
committee blinded to the study arm) during the follow-up period (36 weeks), and iv) no 
documentation of a suppressed VL (<50 c/mL) at 9 months follow-up (window: 32-44 weeks). 
The primary endpoint will be assessed as an event ratio of participants reaching one or more 
of the composite endpoints. 

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Secondary endpoints: 
1. 
Separate analyses of the four components of the primary endpoint, namely: 
a. 
Death due to any cause 
b. 
HIV- or ART-related hospital admission of ≥24 hours duration (possibly, 
probably or definitely related to HIV or ART, judged by the endpoint 
committee blinded to the study arm) 
c. 
New clinical WHO stage IV event (excluding lymph node tuberculosis, 
stunting, oral or genital herpes simplex infection and oesophageal 
candidiasis, judged by the endpoint committee blinded to the study arm) 
d. 
No documentation of a suppressed VL (<50 c/mL) at 9 months follow-up 
(window: 32-44 weeks) 
2. 
Loss to follow-up, defined as no documented clinic visit in the window period (32-44 
weeks) of the 9-month study visit 
3. 
Observed virologic failure, defined as a VL ≥50 c/mL, at the 9-month study visit 
(window: 32-44 weeks) among participants who had a viral load result at the 9-month 
study visit 
4. 
Composite endpoint (see primary endpoint above) assessed at 6 months (window: 
20-28 weeks) after the decision on the regimen for onward treatment (i.e. after the 
availability of a follow-up VL result in the control arm or after the availability of a GRT 
result in the intervention arm) 
Exploratory endpoints: 
1. 
Time to viral resuppression (<50 c/mL; considering VL testing done with samples from 
the 3-, 6- and 9-month study visit in both arms) 
2. 
Drug regimen switches in the absence of major drug resistance mutations and non-
switches in the presence of major drug resistance mutations (as identified by Sanger 
sequencing, according to the Stanford HIV drug resistance database) 
3. 
Emergence of new drug resistance mutations within the study period (i.e. measured 
drug resistance at the 9-month visit vs at the baseline visit) 
Study Design 
Open-label two-arm randomised clinical trial  
Statistical 
Considerations 
Analyses will follow CONSORT guidelines and intention-to-treat principles.  
Outcomes will be described by arm using summary statistics. The primary outcome, the 
proportion of individuals not having experienced the primary endpoint, will be assessed using 
a logistic regression model, reporting odds ratios. Binary secondary outcomes will be 
evaluated in the same way. Continuous secondary outcomes will be assessed using linear 
regression models, reporting adjusted mean differences between arms. Time to event 
outcomes will be assessed using appropriate methods, such as Kaplan-Meier estimation and 
Cox proportional hazards models. All estimates will be reported with 95% confidence intervals 
(CI). All models will be adjusted for the stratification factors of country, age, and ART regimen 
at enrolment. Subgroup analyses are planned by country, age, sex, and ART regimen at 
enrolment.  
An interim analysis is planned once 50% of the study participants have completed the 9-month 
study visit and/or reached the primary endpoint, and stopping criteria for success or futility 
have been defined. 
Inclusion- 
/ 
Exclusion 
Criteria 
Inclusion criteria: 
- 
In care in a study site 
- 
Age ≥6 months and <19 years 
- 
Latest HIV VL result ≥400 c/mL 
- 
On an unchanged ART regimen for ≥6 months 
- 
Phlebotomy for latest VL test <4 months before screening 
- 
Consent given 
Exclusion criteria: 
- 
Indication for treatment switch according to WHO guidelines at screening 
- 
1st enhanced adherence counselling (EAC) session initiated >2 weeks prior to 
screening 
- 
Intention to transfer out of the study site (and not into a different study site) within 3 
months after randomisation 
- 
Already enrolled in another study if judged as non-compatible by the (Local) Principal 
Investigator 

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- 
Pregnant or breastfeeding at screening (no exclusion based on pregnancy or 
breastfeeding after enrolment) 
- 
Acute illness requiring hospitalisation at screening (no exclusion based on 
hospitalisation after enrolment) 
- 
Received a resistance test within the last 12 months 
Members of vulnerable populations, specifically children and adolescents, will be enrolled in 
this study. This is justified by i) the minimal risk of the study, ii) the potential benefits through 
participation in this study, and iii) the fact that there is a shortage of research assessing ways 
to improve HIV treatment for these age groups. While pregnant and breastfeeding adolescents 
will not be enrolled, becoming pregnant during the study period will not lead to exclusion given 
the low risk and potential benefits through participation. 
Number 
of 
Participants with 
Rationale 
276 participants (138 participants per arm). 
Taking into account the best available data from the study sites and the literature, we 
considered various realistic and clinically relevant scenarios. A rate of 20% vs 35% of 
participants reaching the primary endpoint in the intervention vs control arm necessitates a 
sample size of 276 participants to reach 80% power. 
Intervention arm 
The VL ≥400 c/mL before enrolment triggers genotypic resistance testing (GRT), followed by 
GRT-informed patient management and counselling. Onward treatment is informed by this 
GRT result. 
Control arm 
Standard of care according to national guidelines (though using a more conservative cut-off 
for viral suppression, and enforcing 3 sessions of EAC): The VL ≥400 c/mL before enrolment 
is followed by 3 sessions of EAC and a follow-up VL test. Onward treatment is informed by this 
follow-up VL result. 
Study 
procedures 
Baseline study visit (window: 0-12 weeks after VL test date): 
- 
Both arms: 
o 
Consent procedure (can be completed before the baseline study visit) 
o 
Screening, enrolment and randomisation 
o 
Demographic data, medical history 
o 
EAC session 1 (if not already completed) 
o 
Laboratory: CD4 testing; hepatitis B virus (HBV) testing (if not already known 
to be HBV-positive), full blood count (FBC) or haemoglobin, serum 
creatinine 
o 
Blood samples taken for storage 
- 
Control arm: no further action 
- 
Intervention arm: blood draw for GRT 
EAC 2 study visit (window: 3-5 weeks after baseline study visit) 
- 
Control arm: EAC session 2 
- 
Intervention arm: GRT-informed EAC session 2; GRT-informed decision on onward 
therapy 
Control arm EAC 3 and follow-up VL study visit (window: 6-10 weeks after baseline study 
visit) 
- 
Control arm: EAC session 3; blood draw for follow-up VL test 
- 
Intervention arm: no visit 
3-month study visit (window: 10-14 weeks after baseline study visit): 
- 
Both arms: blood samples taken for storage 
- 
Control arm: VL-informed decision on onward therapy 
- 
Intervention arm: EAC session 3 
6-month study visit (window: 20-28 weeks after baseline study visit): 
- 
Both arms: blood samples taken for storage 
9-month study visit (window: 32-44 weeks after baseline study visit): 
- 
Both arms: blood samples taken for storage; CD4 testing; VL testing (part of 
composite primary endpoint) 
Decision follow-up visit (window: 20-28 weeks after decision, i.e. after availability of the 
follow-up VL result in the control arm or after availability of the GRT result in the intervention 
arm): 
- 
Both arms: blood samples taken for storage and VL testing 
- 
Notes: 

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o 
Where possible, this study visit may be combined with a study visit described 
above 
o 
If required (i.e., if delays occur in the real-life study setting), this visit may 
also take place after the window period of the 9-month study period 
Clinical assessments, documentation of ART and co-medication, and adherence assessments 
will take place at each visit. Additional visits may take place according to standard care (e.g. 
additional visits after switching drug regimen, depending on the drug regimen selected; 
clinically indicated visits; etc.) and will be documented. Participants may be asked to return for 
additional visits if the purpose of a study visit was not fulfilled, e.g. if laboratory results were 
not ready or phlebotomy was not possible. Missing participants will be traced, contacted and 
encouraged to return back to care. Serious Adverse Events (SAEs) will be documented, 
reported, and followed up. 
Study 
Duration 
and Schedule 
29 months: 18-month enrolment period plus up to 11-month follow-up (follow-up window: 32-
44 weeks). 
Planned first participant first visit (FPFV): 03.03.2020 (actual) 
Planned first participant last visit (FPLV): 10.11.2020 (actual) 
Planned last participant first visit (LPFV): 03.05.2022  
Planned last participant last visit (LPLV): 02.04.2023 
Steering 
Committee 
 
Sponsor and Chief Investigator: 
Prof. Dr Niklaus Labhardt, MD, MIH 
+41 79 870 18 59 
n.labhardt@swisstph.ch 
 
Principal Investigator: 
Jennifer Brown, MSc, MAS 
+41 79 512 97 16 
jennifer.brown@unibas.ch 
 
Expert Virology and Diagnostics: 
Prof. Dr Thomas Klimkait, PhD 
+41 61 207 32 72 
thomas.klimkait@unibas.ch 
 
Clinical Advisor: 
Dr Josephine Muhairwe, MD, MPH 
+266 5325 9839 
j.muhairwe@solidarmed.ch 
 
Clinical Coordinator Baylor (1), Lesotho: 
Dr Buntshi Paulin Kayembe, MD 
+266 5977 5684 
bkayembe@baylorlesotho.org  
 
Clinical Coordinator Baylor (2), Lesotho: 
Dr Mosa Molapo Hlasoa, MD  
+266 5896 2045 
mmolapohlasoa@baylorlesotho.org 
 
Lesotho Principal Investigator / Study Manager: 
Isaac Ringera, MPH, RN 
+266 5677 1018 
i.ringera@solidarmed.ch 
 
Clinical Coordinator CDCI, Tanzania: 
Prof. Dr Maja Weisser, MD 
+41 61 328 67 42 
maja.weisser@usb.ch 
 
Tanzania Principal Investigator / Local Principal Investigator, Ifakara Tanzania: 
Dr Ezekiel Luoga, MD 
+255 768 351 248 

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eluoga@ihi.or.tz 
 
Trial Statistician: 
PD Dr Tracy Glass, PhD 
+41 61 284 87 14 
tracy.glass@swisstph.ch 
Study Centres 
Countries: Lesotho and Tanzania 
 
Number of centres: 10  
 
Centres: 
One-Stop Clinic and Chronic Diseases Clinic Ifakara (CDCI) at St. Francis Referral Hospital 
(affiliated with the Ifakara Health Institute (IHI)) 
Address: Off Mlabani Passage, P.O. Box 53, Ifakara, Tanzania 
 
Temeke Regional Referral Hospital 
Address: Box 45232, Dar es Salaam, Tanzania 
 
Mbagala Rangi Tatu Hospital 
Address: Box 45232, Dar es Salaam, Tanzania 
 
Upendano Dispensary 
Address: Box 70225, Dar es Salaam, Tanzania 
 
Baylor Clinic Butha-Buthe 
Address: Butha-Buthe Government Hospital Compound, Butha-Buthe 400, Lesotho 
 
Baylor Clinic Mokhotlong 
Address: Mokhotlong Government Hospital Compound, Main Road, Mokhotlong, Lesotho 
 
Baylor Clinic Leribe 
Address: Motebang Hospital Compound, Hlotse, Leribe, Lesotho 
Seboche Mission Hospital 
Address: P.O. Box 304, Butha-Buthe, Lesotho 
 
Baylor Clinic Maseru 
Address: Baylor COE Maseru, Maseru, Lesotho 
 
Baylor Clinic Mohale’s Hoek 
Address: Ntsekhe Hospital Compound, P.O. Box 29, Mohale’s Hoek, Lesotho 
Data privacy 
Data will be captured with the MACRO electronic data capture software (Elsevier), which 
creates an audit trail. The relevant study team members have received and/or will receive GCP 
training as well as training on using the MACRO software. Paper-based CRFs may be used 
as a back-up, in which case data will be transferred to MACRO.. 
All data and biological samples will be coded and stored securely, and only key authorised 
study team members as well as authorised auditors and monitors may be granted full access 
to source data and to all study-related files and samples. All involved parties will keep the 
patient data strictly confidential. Study data will be archived for at least 10 years after study 
termination. Biological material will be labelled with a unique identifier. Biological material and 
data may be used for further research. Transfer agreements will be requested from the 
respective IRBs / ethics committees in each project country.  
After publication of the study findings, a dataset from which all identifying information has been 
removed will be made publicly available using a public data repository platform. 
For quality assurance, monitoring is planned at key stages in the study. Sites in Lesotho will 
be monitored by the Clinical Operations Unit at the Swiss Tropical and Public Health Institute 
(Swiss TPH); the site in Tanzania will be monitored by the IHI. 
Ethical 
considerations 
GIVE MOVE attempts to answer clinically relevant questions relating to populations for whom 
targeted research is lacking. This trial entails minimal risks and may benefit participants’ health 

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through providing access to diagnostic tests (GRT) that can play an important role in clinical 
decision-making but are not routinely available at the study sites. Participation is voluntary, 
and consent/assent can be withdrawn at any time without affecting the patient’s clinical care. 
Measures to ensure confidentiality and protect patient rights include the use data capture 
software that creates an audit trail, GCP training for key study team members, and monitoring 
activities at key stages in the study in order to ensure quality and ICH GCP E6R2 adherence. 
GCP Statement 
This study will be conducted in compliance with the protocol, the current version of the 
Declaration of Helsinki, the ICH GCP E6R2, the Swiss Human Research Act (HRA) 2014, as 
well as other locally relevant legal and regulatory requirements. 
 
 
 

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2 
BACKGROUND AND RATIONALE  
2.1 
Scientific background and knowledge gaps 
Three million children and adolescents worldwide are living with HIV, and over 350 die from 
HIV/AIDS-related causes every day (2017)1,2. Sub-Saharan Africa remains the most heavily 
affected region, accounting for almost 90% of children and adolescents living with HIV (CALHIV)2. 
However, paediatric HIV is vastly understudied3–5 and is listed as a neglected disease6. 
Substantial progress has been made towards providing life-saving antiretroviral therapy (ART) to 
all people living with HIV. ART can suppress viral replication and prevent HIV transmission to 
sexual partners and own children7–9, and early, successful ART is key to child development as it 
reduces mortality and morbidity, improves neurocognitive and growth outcomes10,11, lowers the 
risk of drug resistance, and preserves future therapy options. However, unlike adults, CALHIV 
suffer high treatment failure rates of 25—40%3,12–21, with adolescents having the poorest 
outcomes of all age groups3,15,22. Treatment failure can result in AIDS, death and further 
transmission of HIV at the onset of sexual activity. 
Most ART failure is caused by non-adherence to therapy and/or HIV drug resistance, though the 
underlying factors differ by age group. In younger children, main drivers include: transmitted drug 
resistance from mothers; acquired drug resistance from previous or ongoing incomplete viral 
suppression23–26, ongoing poor adherence27, the lack of child-friendly medication, and the need 
for regular drug dose adjustments with increasing weight13. In adolescents, psychological and 
stigma-related issues further contribute to poor adherence28,29. 
Despite increasing monitoring of treatment success through viral load testing, most diagnosed 
treatment failures do not trigger a timely and suitable response17. Without resistance testing, 
healthcare providers cannot determine if treatment failure is caused by drug resistance, 
necessitating an urgent switch of therapy regimen, or by poor adherence to therapy, in which 
case unnecessary switching must be avoided to preserve limited treatment options.  
Genotypic resistance testing (GRT) provides reliable information on whether unsuppressed 
viremia is caused by ongoing poor adherence or HIV drug resistance. With increasing levels of 
HIV drug resistance to first-line ART30, GRT is likely to become increasingly important in the 
provision of optimised HIV care. However, since GRT remains unavailable in many low- and lower 
middle income settings31, little is known on the clinical value and cost-effectiveness of GRT in 
these settings. Previous modelling studies32–34 on the cost-effectiveness of GRT in various 
countries in sub-Saharan Africa have had discrepant conclusions, and focused only on adults. 
Likewise, one ongoing randomised clinical trial in South Africa and Uganda, the REVAMP trial, is 
only enrolling adults35. Furthermore, the trial includes only participants on a non-nucleoside 
reverse transcriptase inhibitor (NNRTI)-based first-line drug regimen, rapidly becoming 
outdated36. Finally, one registered trial in Tanzania employs GRT only upon sustained viremia 
after counselling37, potentially missing the opportunity to reduce time to clinical action. 
2.2 
Research question and intervention 
CALHIV on ART in sub-Saharan Africa face high rates of treatment failure, yet evidence on the 
causes and optimal management of treatment failure in resource-limited settings is lacking. The 
Genotype-Informed Versus Empiric Management Of VirEmia (GIVE MOVE) study attempts to 
address this gap by assessing the clinical value of GRT-informed management in CALHIV with 
viremia while on ART. Participants will be randomized to an intervention or a control arm. 
Participants in the intervention arm will receive GRT-informed clinical management, whereas 
those in the control arm will receive standard care as per current guidelines of the World Health 
Organization38,39. 
The primary research question is whether GRT improves clinical management and results in 
improved clinical outcomes – i.e. a higher proportion of participants who are alive, have no new 

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clinical WHO stage 4 events (few WHO stage 4 conditions excluded) or HIV-related hospital 
admission, and are in care with a suppressed viral load – 9 months after randomisation. 
The intervention is described in detail in Chapters 3.4 (Study design) and 3.5 (Study intervention); 
the objectives, research questions, and endpoints are described in Chapters 3.1 (Hypothesis and 
objectives) and 3.2 (Primary and secondary endpoints). 
2.3 
Rationale for study design 
We plan an open-label randomised clinical trial for the following two reasons: First, a randomised 
design will provide the highest level of evidence on the value of GRT in the population studied. 
Second, the study will be open-label due to the nature of the intervention (GRT results provided 
to the health care providers) which cannot be blinded. However, laboratory technologists 
performing viral load (VL) testing and endpoint committee members deciding if a WHO stage 4 
event or HIV- or ART-related hospitalisation fulfils the criteria to be considered an endpoint will 
be blinded. 
Lesotho and Tanzania differ greatly along many parameters, including their burden of HIV (adult 
HIV prevalence: 24.4% in Lesotho40 vs 4.5% in Tanzania41) and their other dominant infectious 
diseases (high tuberculosis burden in Lesotho vs malaria, tuberculosis and other tropical diseases 
in Tanzania). Thus, inclusion of both settings will imply external validity of findings for similar 
resource-limited African settings. 
We plan to conduct this study in CALHIV (age range ≥6 months to <19 years) since these 
population groups are particularly vulnerable to treatment failure and especially children and 
adolescents have often been neglected in previous HIV research3–6. 
3 
STUDY OBJECTIVES AND DESIGN  
3.1 
Hypothesis and objectives 
Hypothesis 
We hypothesise that providing resistance information will allow for care to be customised 
according to the individual child/adolescent’s health situation and needs, i.e. targeted adherence 
support for those without drug resistance and a rapid switch to an optimised ART regimen (with 
differentiated adherence support) for those with drug-resistant HIV, and thus lead to better clinical 
and virologic outcomes. 
Based on our available data from the study sites as well as published literature17,18,42–47, we 
considered various realistic scenarios for the ratio of participants in either arm that might reach 
the primary endpoint (i.e., reach one or more of the composites to the primary endpoint) described 
in Chapter 3.2 (Primary and secondary endpoints). In order to avoid missing a true and clinically 
relevant effect, we selected a scenario in which 20% vs 35% of participants in the intervention vs 
control arm reach the primary endpoint as the hypothesis on which we based our calculation of 
the required sample size. 
Objectives 
Primary Objective: To assess if GRT-based management of viremia in CALHIV on ART in 
resource-limited settings improves overall health outcomes. The results of this trial are intended 
to inform future WHO and national guidelines on the use of GRT in CALHIV. 
Secondary Objectives: To assess the impact of GRT-based management of viremia in CALHIV 
on various individual health outcomes including mortality, morbidity, and virologic status. 
Exploratory Objectives: To assess the dynamics of viral resuppression and the viral development 
of drug resistance without vs with GRT-based management of viremia. 

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3.2 
Primary and secondary endpoints 
Primary endpoint 
The composite primary endpoint is the occurrence of any one or more of the events i) death due 
to any cause during the follow-up period (36 weeks), ii) HIV- or ART-related hospital admission 
of ≥24 hours duration (possibly, probably or definitely related to HIV or ART, judged by the 
endpoint committee blinded to the study arm) during the follow-up period (36 weeks), iii) new 
clinical WHO stage IV event (excluding lymph node tuberculosis, stunting, oral or genital herpes 
simplex infection and oesophageal candidiasis; judged by the endpoint committee blinded to the 
study arm) during the follow-up period (36 weeks), and iv) no documentation of a suppressed VL 
(<50 c/mL) at 9 months follow-up (window: 32-44 weeks). The primary endpoint will be assessed 
as an event ratio of participants reaching one or more of the composite endpoints. 
An endpoint committee whose members are unaware of study arm assignments will review all 
reported WHO stage IV events and hospitalisations and determine if the events in question qualify 
as endpoints. 
Participants who experience a WHO stage IV event (with the noted exceptions) or hospitalisation 
of ≥24 hours duration (possibly, probably or definitely related to HIV or ART) before 9 months of 
follow-up may then, if judged beneficial by the clinician in charge and the endpoint committee, 
receive GRT for the benefit of their health even if they are randomised to the control arm. 
Secondary endpoints 
1. Separate analyses of the four components of the primary endpoint, namely: 
a. Death due to any cause 
b. HIV- or ART-related hospital admission of ≥24 hours duration (possibly, probably 
or definitely related to HIV or ART, judged by the endpoint committee blinded to 
the study arm) 
c. New clinical WHO stage IV event (excluding lymph node tuberculosis, stunting, 
oral or genital herpes simplex infection and oesophageal candidiasis, judged by 
the endpoint committee blinded to the study arm) 
d. No documentation of a suppressed VL (<50 c/mL) at 9 months follow-up (window: 
32-44 weeks) 
2. Loss to follow-up, defined as no documented clinic visit in the window period (32-44 
weeks) of the 9-month study visit 
3. Observed virologic failure, defined as a VL ≥50 c/mL, at the 9-month study visit (window: 
32-44 weeks) among participants who had a viral load result at the 9-month study visit 
4. Composite endpoint (see primary endpoint above) assessed at 6 months (window: 20-28 
weeks) after the decision on the regimen for onward treatment (i.e. after the availability of 
a follow-up VL result in the control arm or after the availability of a GRT result in the 
intervention arm) 
Exploratory endpoints 
1. Time to viral resuppression (<50 c/mL; considering VL testing done with samples from the 
3-, 6- and 9-month study visit in both arms) 
2. Drug regimen switches in the absence of major drug resistance mutations and non-
switches in the presence of major drug resistance mutations (as identified by Sanger 
sequencing, according to the Stanford HIV drug resistance database) 
3. Emergence of new drug resistance mutations within the study period (i.e. measured drug 
resistance at the 9-month visit vs at the baseline visit) 

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3.3 
Randomisation considerations 
Potential effect modifiers 
Certain baseline factors may have an effect on the primary and secondary endpoints, including 
the site, age, sex, and the participant’s ART regimen at enrolment. In order to minimise bias, 
randomisation will be stratified by:  
- 
Country (Lesotho or Tanzania) 
- 
Age ([≥ 6 months to <12 years] vs [≥12 years to <19 years]) 
- 
ART regimen at enrolment (NNRTI-based, protease inhibitor (PI)-based, or integrase 
strand transfer inhibitor (INSTI)-based regimen) 
In children, sex is unlikely to have a major impact on outcomes. Given the sample size and the 
relatively even sex distribution (expected female:male ratio approx.3:2), a strong clustering effect 
is unlikely. However, sex will be considered in the planned subgroup analysis. 
Randomisation procedure 
Eligible and consented patients will be consecutively enrolled and randomised in a 1:1 ratio to the 
intervention and control arms. Randomisation will be stratified by country (Lesotho or Tanzania), 
age ([≥ 6 months to <12 years] vs [≥12 years to <19 years]), and ART regimen at enrolment 
(NNRTI-, PI-, or INSTI-based regimen), using permuted blocks with varying block size. 
Randomisation will be automated using the MACRO electronic data capture software (Elsevier; 
see chapters 4.3 Study procedures, and 8.2 Data recording and source data). Randomisation of 
a participant will be performed once eligibility and consent have been confirmed and entered into 
the database, thereby maintaining concealment of allocation. 
3.4 
Study design 
GIVE-MOVE is an open-label, two-arm, multicentre, superiority randomised clinical trial. 
Participants will be randomized in a 1:1 ratio to the intervention or the control arm. In the 
intervention arm, GRT (Sanger sequencing) will be performed and the decision on whether a 
treatment switch or optimisation of the ART backbone is indicated, as well as the choice of the 
new regimen (if applicable), will be based on GRT results. Participants in the control arm will be 
managed according to the standard of care based on the current WHO recommendations38,39, 
with minor changes: there will be 3, rather than 2-3, sessions of enhanced adherence counselling 
(EAC); and the viral load cut-off will be set to 400 c/mL, rather than 1000 c/mL. Participants in the 
control arm will receive 3 EAC sessions at monthly intervals, with a follow-up VL test at the 3rd 
EAC session. In line with the national guidelines48,49, the follow-up VL test can be delayed if there 
is clear evidence of poor adherence to therapy, defined here as i) a pill count of <90%, and/or ii) 
a self-reported period of no drug intake of ≥2 days in the last 4 weeks. Onward treatment will be 
informed by the follow-up VL in line with standard care. The composite primary endpoint will be 
assessed latest 9 months (window: 32-44 weeks) after randomization (see Figure 1). 
Although participants and treating healthcare professionals will not be blinded, laboratory 
technologists measuring the viral load (a key component of the primary and some secondary 
endpoints) will be blinded, as will the endpoint committee assessing if hospitalisations and 
potential WHO stage 4 events constitute an endpoint. 
Setting 
The sites of enrolment are: 
- 
Baylor Clinic Leribe, Leribe, Lesotho 
- 
Baylor Clinic Butha-Buthe, Butha-Buthe, Lesotho 
- 
Baylor Clinic Mokhotlong, Mokhotlong, Lesotho 
- 
Baylor Clinic Maseru, Maseru, Lesotho 
- 
Baylor Clinic Mohale’s Hoek, Mohale’s Hoek, Lesotho 

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- 
Seboche Mission Hospital, Butha-Buthe, Lesotho 
- 
One-Stop Clinic, Chronic Diseases Clinic Ifakara at St Frances Referral Hospital, Ifakara, 
Tanzania 
- 
Temeke Regional Referral Hospital, Dar es Salaam, Tanzania 
- 
Mbagala Rangi Tatu Hospital, Dar es Salaam, Tanzania 
- 
Upendano Dispensary, Dar es Salaam, Tanzania 
 
GRT will take place at Seboche Mission Hospital Laboratory, Butha-Buthe, Lesotho; Ifakara 
Health Institute (IHI) Laboratory, Ifakara, Tanzania. Other laboratory diagnostics will take place 
at the routine laboratories for the respective sites. If required, sample referral to other laboratories 
will be acceptable (notably: Pathcare laboratory, South Africa; Lancet laboratory, Tanzania with 
referral to South Africa; Temeke referral laboratory, Tanzania; others possible if required). 
Participants give consent for the further use of the provided biological samples for any other 
biomedical analysis that has been approved by the respective Institutional Review Boards (IRBs) 
/ ethics committees (samples from Lesotho: National Health Research and Ethics Committee 
(NH-REC); samples from Tanzania: IHI IRB and National Institute for Medical Research (NIMR)). 
For this purpose, samples labelled with a unique identifier may be transferred to Switzerland if 
the respective analyses cannot be performed in the GIVE MOVE GRT laboratory in the respective 
project country (Seboche Mission Hospital Laboratory, Butha-Buthe, Lesotho / IHI Laboratory, 
Ifakara, Tanzania). 
 
 

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Figure 1: Overview of GIVE MOVE treatment algorithm and study visits. The decision follow-up visit is not shown. 
Further visits may be indicated, e.g. for follow-up testing upon drug regimen switches (dependent on the choice of new 
drug regimen) or in the case of pregnancy/breastfeeding, and will be documented. EAC: enhanced adherence 
counselling; GRT: genotypic resistance testing; VL: viral load. For detailed procedures at each study visit, see Table 3. 
3.5 
Study intervention 
The study intervention will consist of the following components: 
1. Genotypic resistance testing (GRT); 
2. Secure forwarding of GRT results to an expert committee for review; 
3. Secure forwarding of GRT results with the expert committee’s treatment recommendation 
to the healthcare provider, ensuring GRT triggers rapid clinical action; 
4. GRT-based decision on further therapy (switch or maintain current ART regimen; choice 
of regimen); and 
5. GRT-informed adherence support. 
 
 

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3.6 
Nested Study on Cost-Effectiveness 
In a nested study, we intend to assess the cost and cost-effectiveness of GRT for CALHIV with 
viremia while on ART if superiority of the intervention arm is shown. Costs to the healthcare 
facilities will be documented (cost of GRT, cost of ART, estimated average number and cost of 
visits, and hospitalisation costs) and used to estimate the average costs in each arm and the 
difference in costs per additional virally suppressed CALHIV. 
 
3.7 
Nested Study on Other Drivers of Viremia 
In a mixed methods analysis, we intend to assess further drivers of viremia beyond viral resistance 
from a patient-centred perspective. GIVE MOVE participants who have completed the study, as 
well as their caregivers, will be invited to participate in interviews that will address their individual 
situation as well as any structural, treatment-related, social, or other barriers that have prevented 
them from adhering to ART as prescribed. An interview guide will be submitted to the relevant 
ethics committees before the start of this study. 
4 
STUDY POPULATION AND STUDY PROCEDURES 
4.1 
Inclusion and exclusion criteria, justification of study population 
Inclusion and exclusion criteria 
The study population will consist of CALHIV receiving ART in one of the study sites. 
Inclusion criteria: 
- 
In care in a study site 
- 
Age ≥6 months and <19 years 
- 
Latest HIV VL result ≥400 c/mL 
- 
On an unchanged ART regimen for ≥6 months 
- 
Phlebotomy for latest VL test <4 months before screening 
- 
Consent given (see Chapter 4.2 Recruitment, screening and informed consent procedure) 
Exclusion criteria: 
- 
Indication for treatment switch according to WHO guidelines at screening 
- 
1st enhanced adherence counselling session initiated >2 weeks prior to screening 
- 
Intention to transfer out of the study site (and not into a different study site) within 3 months 
after randomisation 
- 
Already enrolled in another study if judged as non-compatible by the (Local) Principal 
Investigator 
- 
Pregnant or breastfeeding at screening (no exclusion based on pregnancy or 
breastfeeding after enrolment) 
- 
Acute illness requiring hospitalisation at screening (no exclusion based on hospitalisation 
after enrolment) 
- 
Received a resistance test within the last 12 months 
Participant number and participant replacement 
The study will enrol 276 participants (138 per arm) in a 1:1 allocation. Participants prematurely 
leaving the study will not be replaced. 
Rationale for including vulnerable participants (i.e. minors, pregnant/breastfeeding 
participants) in the study: 
Minors are included in the study for the following reasons: 

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- 
The risk to participants is minimal 
- 
There are high potential health benefits: participants in the intervention arm will receive 
GRT-informed care shortly after randomisation; in case this study shows that GRT-
informed management is superior to standard care, at study closure participants in both 
study arms with an elevated VL will receive GRT-informed care. 
- 
There is a need for HIV research in children: paediatric HIV is classified as a neglected 
disease6 since most research is conducted on adults, and there is a lack of data on 
optimising HIV care for CALHIV in low- and lower middle income countries. 
- 
Children and adolescents have a greater need (compared to adults) for rapid management 
of therapy failure: 
o Unmanaged HIV infection can negatively impact growth and neurocognitive 
development in children and adolescents 
o Children and adolescents have a longer prospective lifetime on ART, necessitating 
an optimised choice of drug regimen 
- 
In children and adolescents, there is a greater potential (compared to adults) to improve 
treatment outcomes: 
o Treatment success is poorer in children and adolescents, necessitating action and 
leaving a wider margin for improvement 
o Treatment failure caused by incorrect drug dosing and/or suboptimal adherence is 
more common in children and adolescents, meaning that there is a greater 
potential for GRT to prevent unnecessary treatment switches 
Patients who are known to be pregnant or breastfeeding will not be enrolled. However, if 
pregnancy or breastfeeding occurs or becomes known after enrolment, no exclusion will take 
place. Pregnant or breastfeeding participants in either study arm will receive additional follow-up 
visits and additional viral load tests in accordance with national guidelines. These additional visits 
will be recorded. 
4.2 
Recruitment, screening and informed consent procedure 
CALHIV fulfilling the inclusion criteria and/or their caregivers will be informed about the study, 
complete the consent procedure (see below), and will be screened, enrolled, and randomised. All 
these processes will generally take place at the routine visit one month after phlebotomy for viral 
load testing. This will be considered the baseline visit. In cases where caregiver consent is 
required (see below), the caregiver may be asked to accompany the eligible patient to the clinic. 
If required, consent can take place before the baseline visit, either in an additional clinic visit or 
outside the clinic (e.g. in a home visit). 
Informed consent will be obtained with the following algorithm: 
- 
Adult participants (Lesotho: ≥16 years; Tanzania: ≥18 years): 
o Study information read to or by the participant 
o Participant Informed Consent Form (ICF) signed by the participant 
- 
Adolescent participants (Lesotho: ≥12 and <16 years; Tanzania: ≥12 and <18 years): 
o Study information read to or by the caregiver and the participant 
o Caregiver ICF signed by the caregiver 
o Adolescent Informed Assent Form (IAF) signed by the participant 
- 
Older child participants (≥6 years and <12 years): 
o Study information read to or by the caregiver 
o Simplified study information with no disclosure of HIV status read to or by the 
participant (note: more detailed information than included in the Child IAF may be 
given depending on the child’s level of understanding and HIV disclosure) 
o Caregiver ICF signed by the caregiver 
o Child IAF signed or name written by the participant 
- 
Younger child participants (<6 years): 
o Study information read to or by the caregiver 
o Caregiver ICF signed by the caregiver 

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For both countries, for the purpose of this study a caregiver is defined as a parent, a legal guardian, 
or an adult aged ≥18 years and living in the same household as the participant. 
In the case of illiteracy, the signature can be replaced by a thumb print and a witness must co-
sign the form. The witness must be a literate adult aged ≥18 years who is not part of the study 
team and who, where possible, should be chosen by the participant/caregiver giving 
consent/assent. 
The investigators will explain to each participant and/or caregiver (see algorithm above) the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential 
risks and benefits and any discomfort it may entail. Each participant/caregiver will be informed 
that participation in the study is voluntary and that he or she may withdraw from the study at any 
time and that withdrawal of consent will not affect his or her subsequent medical assistance and 
treatment. The participant/caregiver will be informed that the participant’s medical records may 
be examined by authorised individuals other than their treating physician, either at the study site 
or remotely after a confidential transfer of the data. 
All participants and/or caregivers will be given an ICF (and IAF where applicable; see above) 
describing the study and providing sufficient information to make an informed decision about 
participation in the study. 
It is foreseen that most participants will be enrolled in a single joint screening, enrolment and 
baseline visit. If the potential participant/caregiver needs more time to decide about participation, 
they can take as much time as needed so long as the time windows for eligibility are not exceeded; 
thereafter, they will no longer be able to participate. 
The formal consent of a participant/caregiver will be obtained according to the algorithm above 
before the participant is submitted to any study procedure and before recording any patient data 
in the electronic data capture tool. 
The ICF (and IAF where applicable) will be signed and dated by an authorised study team 
member at the same time as the participant/caregiver signs. A copy of the signed ICF/IAF will be 
given to the study participant or their caregiver. The ICF/IAF will be retained as part of the study 
records. The informed consent process will be documented in the patient file and any discrepancy 
to the described process described in the study protocol will be documented and explained.  
Participants will not be reimbursed for their participation in the study. However, transport costs 
for any study-related visits will be compensated. Compensation includes the cost of transport for 
the participant and, if the participant is a minor, for up to one caregiver. A snack or meal can be 
provided at study visits. 
4.3 
Study procedures 
Study duration 
The trial was launched at the first site (Baylor Clinic Leribe) on 20.02.2020 and is expected to 
continue until early/mid-2023 (excluding preparation and analysis). The expected total duration is 
37 months, consisting of an 26-month enrolment period and up to 11-month follow-up (window 
for 9-month follow-up: 32-44 weeks corresponding to 8-11 months). 
The following visit dates are foreseen / have occurred: 
First patient first visit (FPFV; actual date): 03.03.2020 
First patient last visit (FPLV; actual date): 10.11.2022 
Last patient first visit (LPFV): 03.05.2022 
Last patient last visit (LPLV): 02.04.2023 
Study procedures 
An overview of study procedures is shown in Figure 1. Detailed procedures at each study visit 
are shown in Chapter 12.1 (Appendix 1: Schedule of study procedures). 

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Baseline study visit (window: 0-12 weeks after VL test date): 
- 
Both arms: 
o Consent procedure (can be completed before the baseline study visit) 
o Screening, enrolment and randomisation 
o Demographic data, medical history 
o EAC session 1 (if not already completed) 
o Laboratory: CD4 testing; hepatitis B virus (HBV) testing (if not already known to be 
HBV-positive); full blood count (FBC) or haemoglobin; serum creatinine 
o Blood samples taken for storage 
- 
Control arm: no further action 
- 
Intervention arm: blood draw for GRT 
EAC 2 study visit (window: 3-5 weeks after baseline study visit): 
- 
Control arm: EAC session 2 
- 
Intervention arm: GRT-informed EAC session 2; GRT-informed decision on onward 
therapy 
Control arm EAC 3 and follow-up VL study visit (window: 6-10 weeks after baseline study visit): 
- 
Control arm: EAC session 3; blood draw for follow-up VL test 
- 
Intervention arm: no visit 
3-month study visit (window: 10-14 weeks after baseline study visit): 
- 
Both arms: blood samples taken for storage 
- 
Control arm: VL-informed decision on onward therapy 
- 
Intervention arm: EAC session 3 
6-month study visit (window: 20-28 weeks after baseline study visit): 
- 
Both arms: blood samples taken for storage 
9-month study visit (window: 32-44 weeks after baseline study visit): 
- 
Both arms: blood samples taken for storage; CD4 testing; VL testing (part of composite 
primary endpoint) 
Decision follow-up visit (window: 20-28 weeks after decision, i.e. after availability of the follow-up 
VL result in the control arm or after availability of the GRT result in the intervention arm): 
- 
Both arms: blood samples taken for storage and VL testing 
- 
Notes: 
o Where possible, this study visit may be combined with a study visit described 
above 
o If required (i.e., if delays occur in the real-life study setting), this visit may also take 
place after the window period of the 9-month study period 
Clinical assessments (including: WHO stage, co-morbidities, symptoms and side-effects; at the 
baseline and 9-month visit: height, middle upper arm circumference in children <5 years, 
nutritional status and supplementation; at baseline, decision and 9-month visit: weight), 
documentation of ART and co-medication, and adherence assessments will take place at each 
visit. Additional visits may take place according to standard care (e.g. additional visits after 
switching drug regimen, depending on the drug regimen selected; clinically indicated visits; etc.) 
and will be documented. Participants may be asked to return for additional visits if the purpose of 
a study visit was not fulfilled, e.g. if laboratory results were not ready or phlebotomy was not 

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possible. Missing participants will be traced, contacted and encouraged to return back to care. 
Serious Adverse Events (SAEs) will be documented, reported, and followed up. 
The sites will receive written guidance defining the prioritisation of tests/blood use in the event 
that insufficient blood is available, the use of paediatric vials where appropriate, as well as safe 
blood volumes in paediatric patients. Study-related phlebotomy will be limited to age-appropriate 
volumes per blood draw50, defined here as: ≤5 mL for participants <5 years; ≤10 mL for 
participants ≥5 and <10 years; ≤15 mL for participants ≥10 and <15 years; and ≤25 mL for 
participants ≥15 years. 
Stopping criteria 
Criteria for the Sponsor/Chief Investigator to prematurely terminate the study are listed in Chapter 
4.4 (Withdrawal). 
An interim analysis will be conducted and allow for premature termination of the study in the case 
of clear futility or success. The criteria for premature study termination are detailed in Chapter 5.1 
(Statistical analysis plan and sample size calculation). 
Sample storage 
Biological samples will be stored at -80 °C. Further use of remaining biological samples will be 
possible if approved by the respective IRBs / ethics committees (samples from Lesotho: NH-REC; 
samples from Tanzania: IHI IRB and NIMR), including but not limited to: genetic sequencing of 
other HIV-1 genetic sequences; drug level testing; testing for other viral infections; etc. Samples 
may be transported to Switzerland (Molecular Virology group, Department of Biomedicine, 
University of Basel) for further analyses if the respective analyses cannot be performed in the 
GIVE MOVE GRT laboratory in the respective project country (Seboche Mission Hospital 
Laboratory, Butha-Buthe, Lesotho / IHI Laboratory, Ifakara, Tanzania). Material Transfer 
Agreements will be requested from the respective IRBs / ethics committees in both project 
countries; a Data Transfer Agreement will additionally be requested in Tanzania. 
Data Management and Confidentiality 
A study specific Data Management Plan will be in place before the start of data collection that 
describes all data management products and procedures in detail. This includes but is not limited 
to software details and procedures specific to data collection, management and review. All study 
team members that are responsible for data entry will receive training for data capture and 
management. The Principal Investigator is responsible for data quality and will take reasonable 
measures to ensure complete and accurate data. Study data will be reviewed regularly by 
monitors and data managers and queries will be raised within the electronic data capture system 
to clarify inconsistencies, incoherencies and missing data for the purpose of data cleaning. A 
computer-generated time stamped audit trail will keep track of all user-specific data processing 
operations such as creation, modification and deletion. 
All data will be stored securely in a way that allows future access for the research team. Only 
study team members (as listed in the delegation log/study team log), as well as the data manager, 
monitors and IRBs / ethics committees / regulatory authorities, will be given access to the study 
data. All data will be owned by the Sponsor/Chief Investigator. Data will be kept in compliance 
with local legal requirements, for a minimum of ten years. All relevant recorded data will be 
encrypted and password secured, using the MACRO electronic data capture software, which 
generates an audit trail. A master list linking the participant unique identifier and the participant 
details such as name will be kept at the respective study site under lock and key. 
Swiss TPH servers are located in Basel with a defined policy in place for server set-up, 
maintenance and security. This includes processes regarding server qualification, back-ups, 
disaster recovery and restricted server access.  

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The study database in MACRO allows for database freeze and database lock for either interim or 
final statistical analyses. Database lock will prevent any further changes after final data entry and 
query resolution and will be implemented according to agreed timelines.  
After the end of the study and once trial results have been published, a dataset from which all 
identifying information has been removed will be made publicly available using a public data 
repository platform. 
4.4 
Withdrawal of consent 
Enrolled participants will only be removed from the study upon withdrawal of consent, and will 
then continue to receive standard care for onward therapy, with the responsibility for further 
follow-up and management lying with the clinic in which the patient is in care. Participants 
withdrawing consent will not be replaced. In the case of withdrawal of consent, data and materials 
collected up to that point may still be used but no further data or sample collection will be permitted. 
5 
STATISTICS AND METHODOLOGY 
5.1 
Statistical analysis plan and sample size calculation 
Null hypothesis 
The null hypothesis is that patients in the intervention have the same odds ratio for the composite 
primary endpoint as patients in the control arm. 
Determination of sample size 
The sample size was estimated with the aim of showing a significant reduction of the composite 
primary endpoint in the intervention arm compared to the control arm. The significance level was 
chosen to be 5%, while the power was chosen to be at least (1-β) = 80%.  
Based on the available literature17,18,42–47 and own experience at the study sites, we compared 
various realistic scenarios of what ratio of participants would reach the primary endpoint in each 
study arm (see Table 1). 
Table 1: Sample size for different scenarios with 80% power and α = 0.05. 
Differencea  
PInt 
PC 
n (per arm) 
20% 
 
0.25 
0.45 
89 
 
0.20 
0.40 
82 
 
0.15 
0.35 
73 
15% 
 
0.25 
0.40 
152 
 
0.20 
0.35 
138 
 
0.15 
0.30 
121 
a Reduction of the event rate for the treatment group compared to the 
control group. PInt: Probability of event in the intervention group; PC: 
Probability of event in the control group. 
As our hypothesis for the sample size calculation, we selected the scenario in which 20% vs 35% 
of participants reach the primary endpoint in the intervention vs the control arm. Using a Pearson’s 
chi-squared test with a significance level of 5% and a power of 80%, a required sample size of 
276 was calculated (see Table 1). 
Planned analysis 

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Statistical analysis will be performed by the trial statistician using Stata. Analyses will follow 
CONSORT guidelines51–53 and intention-to-treat principles. A flowchart will describe the inclusion 
and follow-up of participants by study arm. Baseline characteristics will be described by study arm 
with summary statistics such as median and interquartile range or number and percentage; no 
formal testing between arms will be performed54. Outcomes will be described by arm using 
summary statistics. The primary outcome, the proportion of individuals having experienced the 
primary endpoint, will be assessed using a logistic regression model, reporting odds ratios. Binary 
secondary outcomes will be evaluated in the same way. Continuous secondary outcomes will be 
assessed using linear regression models, reporting adjusted mean differences between arms. 
Time to event outcomes will be assessed using appropriate methods, such as Kaplan-Meier 
estimation and Cox proportional hazards models. All estimates will be reported with 95% 
confidence intervals (CI). All models will be adjusted for the stratification factors of country, age, 
and ART regimen at enrolment55. We will compare each endpoint between the intervention and 
control arms. Further details will be provided in the statistical analysis plan. 
Subgroup analysis 
Effect modification of the primary outcome by country (Lesotho or Tanzania), sex (male or female) 
age ([≥6 months to <12 years] or [≥12 years to <19 years]), and ART regimen at enrolment 
(NNRTI-, PI-, or INSTI-based regimen) will be assessed by incorporating an interaction between 
arm and the effect modifier acknowledging that power will be low. 
Datasets to be analysed, analysis populations 
The full analysis set (FAS) will include all participants as randomised. All statistical analyses will 
be performed on the FAS according to the intention-to-treat principle (i.e. all participants will be 
analysed on the basis of the intervention to which they were randomly allocated). 
A per-protocol analysis set will include all randomised participants who completed the study 
without a protocol violation. The primary endpoint will be performed on the per-protocol analysis 
set. 
Interim analysis 
One formal interim analysis is planned. The cut-off for this interim analysis is planned when 138 
participants (50% of the intended sample size) have completed the 9-month study visit and/or 
reached the primary endpoint. The same analysis as planned for the final analysis will be 
performed for the composite primary endpoint. 
The trial may be concluded early for success if a significant difference between the two trial arms 
for the composite primary endpoint is achieved. Also, premature stopping due to futility will be 
considered if obtaining a difference of ≥10 percentage points between the study arms is unlikely 
to be demonstrated. 
The interim analysis will be performed by an external independent statistician at an external data 
analysis centre, who will not be involved in the study conduct and will be blinded for the treatment 
allocation. The results will be reviewed by a Data Safety Monitoring Board, who will issue a 
recommendation to continue or stop the trial to the Steering Committee. The Steering Committee 
will vote on and thereby determine the continuation or termination of the trial. In the event of a tie, 
the Sponsor/Chief Investigator will cast the deciding vote. 
5.2 
Handling of missing data, withdrawals, and loss to follow-up 
Missing baseline and outcome data will be summarised by study arm. As outlined above, the 
primary analyses will be the intention-to-treat population. In the case of missing data or drop-outs, 
we may adjust for further baseline variables which are associated with missing outcome data 
(which is analogous to performing multiple imputation in the case of a single endpoint)56. We may 

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consider multiple imputation as sensitivity analyses if necessary. Details will be provided in the 
statistical analysis plan. 
6 
REGULATORY ASPECTS AND SAFETY 
6.1 
Local regulations / Declaration of Helsinki 
This study is conducted in compliance with the protocol, the current version of the Declaration of 
Helsinki, the ICH GCP E6R2, the HRA as well as other locally relevant legal and regulatory 
requirements.  
 
Serious Adverse Events (SAEs) 
An SAE (ClinO, Art. 63 / ICH GCP E6R2) is any untoward medical occurrence that 
- 
Results in death or is life-threatening, 
- 
Requires in-patient hospitalisation or prolongation of existing hospitalisation, 
- 
Results in persistent or significant disability or incapacity, or 
- 
Causes a congenital anomaly or birth defect  
The Sponsor/Chief Investigator will consult with the Principal Investigator and/or Local Principal 
Investigator as well as with the respective Study Physician and will make i) an assessment of 
causality of the intervention, and ii) a severity assessment according to the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (2017; see 
Table 2)57. 
Table 2: Grading of (Serious) Adverse Events. 
Grading 
Description 
Relationship of the SAE with the trial intervention 
(Possible) relationship 
Causal relationship cannot be ruled out 
No relationship 
Causal relationship can be ruled out 
Severity of the SAE (assessed using the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1, 2017)57 
Grade 1 
Mild event 
Grade 2 
Moderate event 
Grade 3 
Severe event 
Grade 4 
Potentially life-threatening event 
Grade 5 
Death 
Reporting of SAEs 
In the case of an SAE, any study personnel must inform the Local Principal Investigator within 72 
hours of his/her awareness of the SAE. The Local Principal Investigator must document and 
report to SAE to the Sponsor/Chief Investigator and the Principal Investigator immediately (within 
a maximum of 24 hours). The Sponsor/Chief Investigator is responsible for reporting of the SAE 
to the respective IRBs / ethics committees within 72 hours (for authorities relevant to the country 
in which the SAE took place) or 15 days (for all other authorities relevant to the trial): 
SAEs in Lesotho:  
- 
Will be reported to the NH-REC Lesotho within 72 hours of reporting to the Sponsor/Chief 
Investigator 
- 
Will be reported to NIMR Tanzania and the IHI IRB within 15 days of reporting to the 
Sponsor/Chief Investigator 
SAEs in Tanzania:  
- 
Will be reported to NIMR Tanzania and the IHI IRB within 72 hours of reporting to the 
Sponsor/Chief Investigator 

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- 
Will be reported to the NH-REC Lesotho within 15 days of reporting to the Sponsor/Chief 
Investigator 
The Sponsor/Chief Investigator may delegate reporting of SAEs to IRBs / ethics committees to 
the Principal Investigator. 
Follow up of SAEs 
SAEs will be documented in a separate form within the eCRF. Further details relating to SAEs 
will be captured separately from the eCRF. SAEs (excluding death) will be followed up in one or 
more visits until resolution or stabilisation takes place, even if this exceeds the study period. 
 
 

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6.2 
(Periodic) safety reporting 
An annual safety report (ASR) will be submitted once a year to the local Ethics Committee by the 
Sponsor/Chief Investigator or a (Local) Principal Investigator (ClinO, Art. 43 Abs). 
The ASR contains information from all sites. The Sponsor/Chief Investigator distributes the ASR 
to all the participating Investigators. 
6.3 
Pregnancy 
Participants who are pregnant (pregnancy test) or breastfeeding at screening will not be enrolled; 
however, pregnancy after the baseline study visit will not lead to exclusion. Female participants 
who become pregnant during the study period will receive standard care (including more frequent 
clinic visits) according to the national guidelines48,49. Additional visits due to pregnancy will be 
recorded as such. If births occur within the study period, the HIV status and health of the new-
born will be recorded. 
6.4 
Amendments 
Substantial changes to the study setup, study organisation, study protocol or relevant study 
documents will be submitted to the relevant IRBs / ethics committees for approval before 
implementation. Under emergency circumstances, deviations from the protocol to protect the 
rights, safety and well-being of human subjects may proceed without prior approval of the relevant 
IRBs / ethics committees. Such deviations will be documented and reported to the relevant IRBs 
/ ethics committees as soon as possible. The definition of substantial amendments includes: 
changes that affect the safety, health, rights and obligations of participants; changes in the study 
protocol that affect the study’s objectives or central research topic; changes of study sites 
(excluding those already mentioned in this document as potential additional study sites); and 
changes of the Sponsor/Chief Investigator or Principal Investigator (ClinO, Art. 29). 
A list of all non-substantial amendments will be submitted once a year to the relevant IRBs / ethics 
committees, together with the ASR. 
6.5 
 (Premature) termination of study 
The Sponsor/Chief Investigator may prematurely terminate the study. Reasons for premature 
termination may include: 
1) Ethical concerns 
2) Insufficient participant recruitment 
3) Risks to participant safety or doubtful participant safety 
4) Alterations in accepted clinical practice that make the continuation of the trial unwise 
5) Criteria for success or futility reached in the interim analysis, as defined in Chapter 5.1 
(Statistical analysis plan and sample size calculation; only if decided by the Steering 
Committee) 
Upon regular study termination, the IRBs / ethics committees (Lesotho: NH-REC; Tanzania: IHI 
IRB and NIMR; Switzerland: EKNZ) will be notified within 90 days. Upon premature study 
termination or study interruption, the same IRBs / ethics committees will be notified within 15 
days. 
Participant data and samples will not be anonymised upon the end of data analysis (however, at 
no time point will they be directly associated with the participant’s name). Biological materials 
labelled with a unique identifier may be stored beyond the end of the study for further use. 
ICFs/IAFs will be stored under lock and key for at least 10 years. Participant data marked with a 
unique identifier will be stored digitally for further use. 
 
 

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6.6 
Insurance 
In the event of study-related damage or injuries, the liability of the Swiss TPH provides 
compensation, except for claims that arise from misconduct or gross negligence. Given the low 
risk of the study, no additional insurance is required. 
7 
FURTHER ASPECTS 
7.1 
Risk-benefit assessment  
The risk to participants is minimal and is limited to risks related to phlebotomy, which are rare 
(pain or bruising at the site of puncture; in very rare cases, risks may include fainting, nerve 
damage, bacterial infection and haematoma). All healthcare-related procedures (notably, 
phlebotomy, diagnostic testing, interpretation of GRT results) will be conducted by experienced 
personnel. The eCRFs and patient samples will be labelled with a unique identifier and will not 
contain the participant’s name, ensuring confidentiality. 
Participants in the intervention arm will potentially benefit from GRT and GRT-informed onward 
therapy (ensuring an optimal drug regimen) at baseline, and all participants will receive GRT if 
they still have an elevated VL at study closure in case the intervention proves beneficial. 
The evidence generated in this trial is intended to inform future national and international clinical 
guidelines, potentially benefitting CALHIV in many resource-limited countries. Furthermore, 
additional evidence generated (e.g. on current local drug resistance profiles) may inform 
local/national policies. 
7.2 
Overall ethical considerations 
CALHIV suffer high rates of virologic failure despite ART, yet research to guide the management 
of viremia in these age groups is lacking 3–6. GIVE MOVE aims to inform national and international 
(WHO) clinical guidelines and policies to improve HIV care. In order to increase the 
generalisability of results (including feasibility and cost-effectiveness), this trial is conducted in 
two different African settings with very distinct features. 
This trial entails minimal risks and has potential health benefits for participants. Participation is 
entirely voluntary, and informed consent can be withdrawn at any time. 
All data and biological samples obtained in Lesotho will belong jointly to the Clinical Research 
Unit, Department of Medicine, Swiss TPH and to SolidarMed. All data and samples obtained in 
Tanzania will belong jointly to the Clinical Research Unit, Department of Medicine, Swiss TPH 
and to IHI. The Sponsor/Chief Investigator may make the data and samples available to GIVE 
MOVE study team members or external researchers for GCP-conform further use if approved by 
the relevant IRBs / ethics committees (Lesotho: NH-REC; Tanzania: IHI IRB and NIMR). 
8 
QUALITY CONTROL AND DATA PROTECTION 
8.1 
Quality measures  
Study personnel will be trained on all important study related aspects, including a trial-specific 
training, GCP training, training on data entry and handling and study interventions (e.g. laboratory 
technologists will receive further training on resistance testing; physicians, other healthcare 
professionals, and laboratory technologists will receive trainings on interpreting resistance 
results). Monitoring visits are planned in both countries at key stages of the trial. In addition to 
onsite monitoring, central monitoring checks will be built into the MACRO study database that flag 
inconsistent and erroneous data in real-time fashion. 
For quality assurance the Sponsor/Chief Investigator, representatives of the relevant IRBs / ethics 
committees / regulatory authorities, and trial monitors may visit the research sites. Direct access 

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to the source data and all study related files is granted on such occasions. All involved parties will 
keep the participant data strictly confidential. 
8.2 
Data recording and source data 
All data collected during the study period will be captured online in electronic case report forms 
(eCRFs) into the MACRO Electronic Data Capture (EDC) tool on tablets or computers at each 
study site. Paper-based CRFs may be used as a back-up, in which case data will be transferred 
to MACRO eCRFs. Source data includes the original records and copies of original records of 
information relating to the study and can be electronic or paper-based. The eCRF will be 
considered the source for some data, which will be identified accordingly in the monitoring plan. 
For laboratory tests, laboratory reports will be considered as source data. If MACRO cannot be 
used temporarily, e.g. if the internet is not working, data normally entered straight into MACRO 
will be captured on paper forms until electronic upload is possible, in which case the paper forms 
will be the source data. 
8.3 
Confidentiality and coding 
Trial and participant data will be handled with uttermost discretion and will only be accessible to 
authorised personnel who require the data to fulfil their duties within the scope of the study, as 
well as to authorised auditors and monitors. On the eCRF and other study specific documents, 
participants are only identified by a unique participant number. Since age is an important 
consideration in children and adolescents (e.g. to assess potential stunting), the date of birth will 
be recorded on the eCRF. 
The participant identification list will be securely stored at each site as described above. The 
ICFs/IAFs will be stored under lock as hard copies at the respective study sites. Traceability will 
be ensured by use of a unique study number, which will be linked to the participant’s ART number 
for participants in Lesotho and their Unique CTC ID Number for participants in Tanzania (in the 
participant identification list, the eCRFs and the ICFs/IAFs), date of birth (in the participant 
identification list, ICFs/IAFs and CRFs), and participant name (in the participant identification list 
and ICFs/IAFs only). Key study documentation will be stored on a shared folder only accessible 
to key study team members. An automatic safety back-up of the data on this shared folder will be 
made at least once per week. 
Biological material in this study is not identified by participant name but by a unique identifier. 
Biological material is appropriately coded and stored in a restricted area only accessible to the 
authorised personnel. After study closure, biological material may be further used for biomedical 
research, including genetic analyses, though only if approved by the respective IRBs / ethics 
committees (Lesotho: NH-REC; Tanzania: IHI IRB and NIMR). For analyses that cannot be 
performed by the GIVE MOVE GRT laboratories (Seboche Mission Hospital Laboratory, Butha-
Buthe, Lesotho / IHI Laboratory, Ifakara, Tanzania), samples may be transported to Switzerland. 
Material Transfer Agreements may be requested from the NH-REC (Lesotho) and NIMR 
(Tanzania) for the export of biological material, and biological material will only be transferred as 
outlined within these agreements. 
8.4 
Retention and destruction of study data and biological material 
All study data will be archived for at least 10 years after study termination (including in the event 
of premature termination of the study).  
Biological material will be labelled with a unique identifier and stored at i) the Butha-Buthe 
Government Hospital laboratory, Butha-Buthe, Lesotho; ii) the Seboche Mission Hospital 
laboratory, Butha-Buthe, Lesotho, iii) the Ifakara Health Institute laboratory, Ifakara, Tanzania; or 
iv) Haus Petersplatz, Department of Biomedicine, University of Basel, Basel, Switzerland. 
Biological material may be used for further biomedical research beyond the scope of the present 
study, so long as this use preserves the rights and safety of study participants, and if approved 

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by the relevant IRBs / ethics committees (Lesotho: NH-REC; Tanzania: IHI IRB and NIMR). 
9 
MONITORING AND REGISTRATION 
The trial will undergo monitoring to ensure compliance with the study protocol and good clinical 
practice (GCP) principles. Sites in Lesotho will be monitored by the Clinical Operations Unit of 
the Swiss TPH; sites in Tanzania will be monitored by IHI. Monitoring procedures are outlined in 
the Monitoring Plan (see Chapter 12.6 Appendix 6: Monitoring Plan). 
The Sponsor/Chief Investigator agrees to allow inspectors from IRBs / ethics committees / 
regulatory agencies to review study records and to assist them in their duties, if requested. 
Monitors and regulators will have access to source data as well as all study documentation, and 
the Sponsor/Chief Investigator, Principal Investigator, and/or other central members of the study 
team will assist them in all their queries. 
The trial is registered at ClinicalTrials.gov: NCT04233242. 
10 FUNDING / PUBLICATION / DECLARATION OF INTEREST 
The major funding for the study will come from a grant from Fondation Botnar (grant number 
REG-19-008; obtained by NDL). Further funding will come from the Swiss National Science 
Foundation (grant number PCEFP3_181355; obtained by NDL), the University Hospital of Basel 
(contribution to salaries of co-investigators; confirmed), and potentially the Federal Commission 
for Scholarships for Foreign Students (funding application planned for a PhD programme for a 
study team member from one of the project countries). The minor funding that has yet to be 
obtained according to the current budget is not critical to the completion of the study. The funding 
sources are/will not be not involved in the study design, data collection, data analysis, 
interpretation of the results, or writing the manuscript. 
The study will be embedded in the SolidarMed Lesotho country programme, the Baylor College 
of Medicine Children’s Foundation Lesotho (BCMCFL) country programme, and in operations of 
the Clinical Diseases Clinic Ifakara (CDCI) and Management and Development for Health (MDH) 
in Tanzania, and will thus benefit from logistics and human resources of these organisations. 
The listed co-investigators declare the following conflicts of interest: 
Thomas Klimkait reports advisory board membership fees from ViiV and Gilead for work outside 
this study. NDL reports having received travel grants to attend scientific conferences from Gilead 
Sciences Sarl. All other team members have no conflicts of interest to declare. 
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Antiretroviral Drugs for Treating and Preventing HIV Infection. Geneva; 2018. 
40.  Ministry of Health Lesotho. Lesotho Population-Based HIV Impact Assessment (LePHIA) 
2016-2017. 
Summary 
Sheet: 
Preliminary 
Findings.; 
2017. 
https://phia.icap.columbia.edu/wp-content/uploads/2018/02/Lesotho-Summary-
Sheet_A4.2.7.18.HR_.pdf. 
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Published 
2017. Accessed December 3, 2018. 
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therapeutic failure in children and adolescents in rural Tanzania: an emerging public health 
concern. AIDS. 2017;31(1):61-70. doi:10.1097/QAD.0000000000001273 
43.  Labhardt ND, Bader J, Lejone TI, et al. Should viral load thresholds be lowered?: Revisiting 
the WHO definition for virologic failure in patients on antiretroviral therapy in resource-limited 
settings. Medicine (Baltimore). 2016;95:e3985. doi:10.1097/MD.0000000000003985 
44.  Dow DE, Shayo AM, Cunningham CK, Reddy EA. Durability of antiretroviral therapy and 
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doi:10.1371/journal.pone.0116144 
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12 APPENDIX 
12.1 Appendix 1: Schedule of study procedures 
Table 3: Schedule of study procedures. 
 
 
 
 
Time 
- 1 month
0
(window: 0-
12 weeks 
after 
sample 
date for 
latest VL 
test) 
1 month 
(window: 3-
5 weeks 
after 
baseline 
study visit) 
2 months
(window: 6-
10 weeks 
after 
baseline 
study visit) 
3 months 
(window: 
10-14 
weeks after 
baseline 
study visit) 
6 months 
(window: 
20-28 
weeks after 
baseline 
study visit) 
9 months 
(window: 
32-44 
weeks after 
baseline 
study visit) 
6 months after 
decision on 
onward 
therapy 
(window: 20-28 
weeks after 
availability of 
follow-up VL 
(control) or GRT 
(intervention) 
result a 
Visit name 
Pre-study 
visit 
Baseline 
study visit 
EAC 2 
study visit 
Control arm 
EAC 3 and 
follow-up 
VL study 
visit 
3-month 
study visit  
6-month 
study visit 
9-month 
study visit 
Decision follow-
up visit 
Consent / assent 
b 
 
X c 
 
 
 
 
 
 
Screening and 
enrolment 
 
X 
 
 
 
 
 
 
Randomisation
 
X 
 
 
 
 
 
 
Collection of 
participant’s 
general and 
contact 
information 
 
X 
 
 
 
 
 
 
Collection of 
medical history d 
 
X  
 
 
 
 
 
 
Weight 
 
X 
Intervention 
arm (at 
decision) 
 
Control arm 
(at 
decision) 
 
X 
 
Assessment of 
height, MUAC (in 
children <5 
years), nutritional 
status, and of 
nutritional 
supplements 
 
X 
 
 
 
 
X 
 
Clinical 
assessment e 
 
X  
X 
Control arm 
X 
X 
X 
X a 
Documentation of 
ART and co-
medication 
 
X 
X 
Control arm 
X 
X 
X 
X a 
Adherence 
assessment f 
 
X 
X 
Control arm 
X 
X 
X 
X a 
EAC 
 
X c 
X g 
Control arm 
Intervention 
arm g 
 
 
 
Phlebotomy h
 
 
 
 
 
 
 
 
VL testing  
X i 
 
 
Control arm 
j 
 
 
X 
X a 
GRT 
 
Intervention 
arm 
 
 
 
 
 
 
CD4
 
X 
 
 
 
 
X 
 
FBC or 
haemoglobin 
 
X 
 
 
 
 
 
 
HBV k and 
serum 
creatinine 
 
X 
 
 
 
 
 
 
Post-hoc VL 
testing 
 
 
 
 
X 
X 
 
 
Post-hoc GRT
 
Control arm 
 
 
 
 
X l 
 
Storage for 
further use 
 
X 
 
 
X 
X 
X 
X a 
Pregnancy test m
 
X 
 
 
 
 
X 
 
Decision on 
onward therapy 
 
 
Intervention 
arm g 
 
Control arm 
j,n 
 
 
 

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Additional clinic 
visits and 
laboratory testing 
o 
As required by standard of care 
 
MUAC: middle upper arm circumference; VL: viral load; EAC: enhanced adherence counselling; FBC: full blood count; 
GRT: genotypic resistance testing; HBV: Hepatitis B virus 
 
a Where possible, will be planned to coincide with another study visit; will be collected even after the 9-month study 
visit 
b Oral and written participant and/or caregiver information; written informed consent (and assent if applicable) 
c If not previously completed 
d Clinical information at ART initiation; previous ART regimens/exposure; exposure to prevention to mother-to-child 
transmission strategies 
e WHO stage; co-morbidities; symptoms and side-effects  
f Contentedness with ART; pill count; self-reported adherence 
g In intervention arm: informed by GRT result 
h Written guidance will define prioritisation of tests/blood use in the event that insufficient blood is available, the use of 
paediatric vials where appropriate, as well as safe blood volumes in paediatric patients. Phlebotomy will be limited to 
age-appropriate volumes per blood draw, defined here as: ≤5 mL for participants <5 years; ≤10 mL for participants ≥5 
and <10 years; ≤15 mL for participants ≥10 and <15 years; and ≤25 mL for participants ≥15 years.  
i VL test before trial begin; result ≥400 c/mL is an inclusion criterion 
j If there is a clear indication of poor adherence (defined as a pill count of <90% and/or a self-reported period of no drug 
intake of ≥2 days in the last 4 weeks), monthly EAC can continue and VL testing and the decision on onward therapy 
can be delayed until there is no longer clear evidence of poor adherence 
k Except if already known to be HBV positive 
l If viral load permits (approx. ≥100 c/mL) 
m Female participants aged ≥12 years, unless already known to be pregnant  
n Based on empirical guidelines 
o Including (but not limited to) additional visits/tests due to: ART regimen substitutions or switches necessitating 
laboratory safety testing (e.g. alanine transaminase, full blood count, etc.); pregnancy/breastfeeding; clinical indication 
 
 

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12.2 Appendix 2: Electronic Case Report Forms (eCRF) 
 
 

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12.3 Appendix 3: Informed Consent Forms 
Forms Lesotho 
- 
English Informed Consent Form for participants aged ≥16 years, Lesotho 
- 
English Informed Consent Form for caregivers of participants aged <16 years, Lesotho 
- 
English Assent Form for participants aged ≥12 and <16 years, Lesotho 
- 
English Assent Form for participants aged ≥6 and <12 years, Lesotho 
- 
Sesotho Informed Consent Form for participants aged ≥16 years, Lesotho 
- 
Sesotho Informed Consent Form for caregivers of participants aged <16 years, Lesotho 
- 
Sesotho Assent Form for participants aged ≥12 and <16 years, Lesotho 
- 
Sesotho Assent Form for participants aged ≥6 and <12 years, Lesotho 
 
Forms Tanzania 
- 
English Informed Consent Form for participants aged ≥18 years, Tanzania 
- 
English Informed Consent Form for caregivers of participants aged <18 years, Tanzania 
- 
English Assent Form for participants aged ≥12 and <18 years, Tanzania 
- 
English Assent Form for participants aged ≥6 and <12 years, Tanzania 
- 
Swahili Informed Consent Form for participants aged ≥18 years, Tanzania 
- 
Swahili Informed Consent Form for caregivers of participants aged <18 years, Tanzania 
- 
Swahili Assent Form for participants aged ≥12 and <18 years, Tanzania 
- 
Swahili Assent Form for participants aged ≥6 and <12 years, Tanzania 
 
The above-mentioned forms are attached to this document. 
 

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12.4 Appendix 4: Staff List 
 
The staff list is attached to this document. 
 

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12.5 Appendix 5: CVs of Main Investigators 
 
 
 
The CVs of Steering Committee members, Site Co-Investigators, Clinical Co-Investigators, 
Statistics and Data Co-Investigators, and Diagnostic Co-Investigators (see Chapter 12.4 
Appendix 4: Staff List) are attached to this document. 
 

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12.6 Appendix 6: Monitoring Plan 
 
The monitoring plans for both countries are attached to this document.