Simplifying Treatment and Monitoring for HIV (STREAM HIV): Point-of-Care Urine Tenofovir Adherence and Viral Load Testing to Improve HIV Outcomes in South Africa
Phase: NA
Conditions: HIV/AIDS, HIV-1-infection
Sponsor: University of Washington

 
STREAM HIV Study 
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Protocol Signature Page 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization Guideline 
for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable requirements 
(e.g., US National Institutes of Health, Division of AIDS) and institutional policies. 
 
 
___
___________ 
 
 
 
October 5, 2020______ 
Signature of Investigator of Record 
 
 
 
Date 
 
 
___Paul K. Drain________________ 
Investigator of Record (Print Name) 
 
 
      
_______________ 
 
 
 
October 5, 2020______ 
Signature of Investigator of Record 
 
 
 
Date 
 
 
___Nigel J. Garrett______________ 
Investigator of Record (Print Name) 
 
 
 
Full Protocol Title: Simplifying Treatment and Monitoring for HIV (STREAM HIV): Point-of-Care 
Urine Tenofovir Adherence and Viral Load Testing to Improve HIV Outcomes in South Africa 
 
DAIDS Protocol Number: DAIDS-ES ID #38509 
DAIDS Protocol Version: 2.3 
Protocol Date: October 5, 2020 
 

 
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STUDY PROTOCOL 
 
Simplifying Treatment and Monitoring for HIV (STREAM HIV): 
Point-of-Care Urine Tenofovir Adherence and Viral Load Testing to Improve HIV 
Outcomes in South Africa 
 
“STREAM HIV Study” 
 
 
DAIDS Protocol Number: 
DAIDS-ES ID #38509 
 
Trial Registration:  
ClinicalTrials.gov NCT04341779  
IND: Non-Investigational New Drug Study 
IDE: Non-Significant Risk Medical Device 
 
Funded by: 
US National Institute of Allergy and Infectious Diseases 
#AI147752 
 
PROTOCOL VERSION 2.3 
October 5, 2020 
 
Principal Investigators: 
Dr. Paul Kevin Drain  
University of Washington, Seattle, USA 
Ninth and Jefferson Building, 908 Jefferson St., 12th floor, Seattle, WA 98104, USA 
Email: pkdrain@uw.edu Tel: 206-520-3820 Fax: 206-520-3831  
 
Dr. Nigel Joel Garrett  
CAPRISA/UKZN  
2nd Floor, Doris Duke Medical Research Institute (Private Bag X7), 719 Umbilo Road, Durban 4013, 
South Africa  
Email: nigel.garrett@caprisa.org Tel: +27 (0)31 260 4453 
 

 
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CONTENTS 
1. 
STUDY SUMMARY AND SCHEMA ...................................................................................... 7 
1.1 
Study Schema ................................................................................................................ 7 
1.2 
Study Summary .............................................................................................................. 8 
1.3 
Study Aims ..................................................................................................................... 9 
2. 
CONSORT DIAGRAM ......................................................................................................... 10 
3. 
STUDY PERSONNEL ......................................................................................................... 10 
3.1 
Leadership Team .......................................................................................................... 10 
3.2 
Co-Investigators (alphabetical order) ........................................................................... 11 
4. 
BACKGROUND .................................................................................................................. 11 
4.1 
Significance .................................................................................................................. 11 
4.2 
FDA/CDRH and Nonsignificant Risk Designation for the POC Urine Tenofovir 
Adherence Assay .................................................................................................................... 15 
5. 
STUDY OBJECTIVES ......................................................................................................... 16 
5.1 
Primary Objectives ....................................................................................................... 16 
5.2 
Secondary Objectives ................................................................................................... 16 
5.3 
Exploratory Objectives .................................................................................................. 16 
6. 
METHODS ........................................................................................................................... 17 
6.1 
Study Design ................................................................................................................ 17 
6.2 
Location and Setting ..................................................................................................... 18 
6.3 
Eligibility Criteria ........................................................................................................... 18 
6.4 
Recruitment, Consent, Screening, and Enrollment ...................................................... 19 
6.5 
Randomization .............................................................................................................. 19 
6.6 
Study Procedures and Interventions ............................................................................ 20 
6.6.1 
Baseline ................................................................................................................. 20 
6.6.2 
Follow-up ............................................................................................................... 20 
6.6.3 
Standard-of-care Arm Follow-up Procedures ........................................................ 21 
6.6.4 
Intervention Arm Follow-up Procedures ................................................................ 21 
6.6.5 
Procedures for Participants Switched to Non-TDF-containing Regimens ............. 22 
6.6.6 
Central Chronic Medicine Dispensing and Distribution Programme ..................... 22 
6.6.7 
Management of Viral Load Results – Standard of Care ........................................ 22 
6.6.8 
POC Tenofovir Adherence Testing and Management of Results ......................... 23 
6.7 
Retention Activities ....................................................................................................... 26 
6.8 
Targeted/Planned Enrollment ....................................................................................... 26 
6.9 
Schedule of Clinical Visits and Sample Collection ....................................................... 26 
6.10 
Additional Laboratory Testing for Aim 1 Objectives .................................................. 26 

 
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6.10.1 
Primary and secondary outcomes ......................................................................... 27 
6.10.2 
Exploratory outcomes ............................................................................................ 27 
6.11. 
Participant Withdrawal .............................................................................................. 28 
6.12. 
Study Duration .......................................................................................................... 28 
7. 
SAMPLE SIZE AND POWER ............................................................................................. 28 
8. 
ANALYSES FOR PRIMARY OUTCOMES ......................................................................... 28 
9. 
SECONDARY QUALITATIVE STUDY ................................................................................ 29 
9.1. 
Introduction and Rationale ............................................................................................ 29 
9.2. 
Justification and Feasibility ........................................................................................... 30 
9.3. 
Research Design .......................................................................................................... 31 
9.4. 
Outcomes and Analyses ............................................................................................... 32 
10. 
SECONDARY COST-EFFECTIVENESS ANALYSIS ..................................................... 33 
10.1. 
Introduction and Rationale ........................................................................................ 33 
10.2. 
Preliminary Cost-effectiveness Studies .................................................................... 33 
10.3. 
Research Design ...................................................................................................... 34 
10.4. 
Outcome Assessment and Reporting ....................................................................... 35 
11. 
PARTICIPANT REIMBURSEMENT ................................................................................ 35 
12. 
PROTECTION OF HUMAN SUBJECTS ......................................................................... 36 
12.1. 
Risks to Human Subjects .......................................................................................... 36 
12.2. 
Adequacy of Protection Against Risks ...................................................................... 37 
12.3. 
Potential Benefits of the Proposed Research ........................................................... 38 
12.4. 
Data Management and Safety Monitoring Plan ........................................................ 38 
13. 
TIMELINES ...................................................................................................................... 40 
14. 
POTENTIAL PROBLEMS AND ALTERNATIVE APPROACHES .................................. 40 
15. 
RESOURCE SHARING PLAN ........................................................................................ 41 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................... 42 
17. 
ETHICAL CONSIDERATIONS ........................................................................................ 42 
18. 
PROTOCOL REGISTRATION ......................................................................................... 43 
19. 
REFERENCES ................................................................................................................. 44 
20. 
APPENDIX I: 2019 SOUTH AFRICA HIV VIRAL LOAD MONITORING GUIDELINES . 56 
21. 
APPENDIX II: SCHEDULE OF EVALUATIONS ............................................................. 59 
 
 
 

 
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Abbreviations 
AIDS  
Acquired immune deficiency syndrome 
AE 
 
Adverse event 
ART 
 
Antiretroviral therapy 
ARC 
 
AIDS-related complex 
CAPRISA 
Centre for AIDS Programme of Research in South Africa 
CCMDD 
Central Chronic Medicine Dispensing and Distribution Programme 
CDC 
 
Centers for Disease Control and Prevention (US) 
DAIDS  
Division of AIDS (NIH) 
DALY  
Disability-adjusted life-year 
DBS 
 
Dried blood spots 
DTG 
 
Dolutegravir 
EC 
 
Ethics Committee 
EFV/3TC/TDF Efavirenz/emtricitabine/tenofovir diphosphate 
FDA 
 
Food and Drug Administration (US) 
FDC 
 
Fixed dose combination 
FTC 
 
Emtricitabine 
FTC-TP 
Emtricitabine-triphosphate  
GEE 
 
Generalized estimating equations  
HAL 
 
Hair Analytical Laboratory 
HIV 
 
Human Immunodeficiency Virus 
HIVDR  
HIV drug resistance 
HTTP  
Hypertext transfer protocol (presentation of web data) 
ICRC  
International Clinical Research Center 
IQR 
 
Interquartile range 
IPT 
 
Isoniazid preventive therapy 
IRB 
 
Institutional Review Board 
LMIC  
Low- and middle-income country 
LC-MS/MS 
Liquid chromatography/tandem mass spectrometry 
NACOSTI  
National Council of Science, Technology and Innovation  
NGS 
 
Next generation sequencing 
NIH 
 
National Institutes of Health (US) 
NNRTI  
Non-nucleoside reverse transcriptase inhibitor 
PLHIV  
People living with HIV 
POC 
 
Point-of-care 
PrEP  
Pre-exposure prophylaxis 
RDT 
 
Rapid diagnostic test 
REDCap 
Research Electronic Data Capture 
SAS 
 
Statistical Analysis Software 
SoC 
 
Standard-of-care 
STI 
 
Sexually transmitted infection 

 
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TDF 
 
Tenofovir disoproxil fumarate 
TFV 
 
Tenofovir 
TFV-DP 
Tenofovir diphosphate 
TLD 
 
Tenofovir/lamivudine/dolutegravir 
UCSF  
University of California, San Francisco 
UNAIDS 
Joint United Nations Program on HIV/AIDS 
US 
 
United States 
UW 
 
University of Washington 
VCT 
 
Voluntary counseling and testing 
VL 
 
Viral load 
WHO  
World Health Organization 
 

 
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1. 
STUDY SUMMARY AND SCHEMA 
1.1 
Study Schema 
Purpose: 
 
To determine the clinical efficacy, acceptability, and cost effectiveness of 
implementing an integrated model for HIV monitoring using point-of-care 
(POC) tenofovir (TFV) adherence testing with POC HIV viral load (VL) 
monitoring for improving adherence and outcomes among people living with 
HIV (PLHIV) who initiate first-line tenofovir disoproxil fumarate (TDF)-based 
ART in South Africa. 
Design: 
 
A Phase IIb open-label randomized controlled trial to assess routine POC 
TFV adherence testing with POC VL monitoring against the standard-of-care 
(SoC) with no objective TFV adherence testing and SoC VL monitoring. HIV-
positive individuals (≥16 years) will be randomized 1:1 to the intervention 
versus SoC. 
Central 
Hypotheses: 
Our central hypotheses are that POC TFV adherence testing combined with 
POC VL monitoring will improve adherence to ART, VL suppression rates, 
and retention in care, while being feasible, acceptable, and cost-effective. 
Primary 
Objectives: 
• To determine if implementing routine POC TFV adherence testing is 
superior to SoC (no adherence testing) in improving ART adherence at 24 
weeks after ART initiation among PLHIV receiving TDF-based ART in 
South Africa. 
• To determine if implementing routine POC TFV adherence testing in 
combination with routine POC VL monitoring is superior to SoC VL 
monitoring (with no adherence testing) in improving retention in care and 
VL suppression (<200 copies/mL) at 72 weeks after ART initiation among 
PLHIV initiated on first-line TDF-based ART in South Africa. 
Secondary 
Objectives: 
• To determine if implementing routine POC TFV adherence testing in 
combination with routine POC VL monitoring is superior to SoC VL 
monitoring (with no adherence testing) in improving retention in care and 
VL suppression (<200 copies/mL) at 24 weeks after ART initiation among 
PLHIV receiving TDF-based ART in South Africa. 
• To determine if implementing routine POC TFV adherence testing in 
combination with routine POC VL monitoring is superior to SoC VL testing 
(with no adherence testing) in improving ART adherence at 72 weeks after 
ART initiation among PLHIV initiated on first-line TDF-based ART in South 
Africa. 
• To assess the acceptability of POC VL and TFV adherence testing among 
PLHIV and providers. 
• To assess the cost-effectiveness of providing POC VL and TFV adherence 
testing to PLHIV as compared to SoC VL monitoring. 

 
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Population: 
HIV-positive individuals (≥16 years) initiating a first-line, TDF-based ART 
regimen. 
Study Site: 
HIV clinic at the Prince Cyril Zulu Communicable Disease Centre, which is 
located adjacent to the CAPRISA eThekwini Clinical Research Site and near 
the transport hub for public commuters in central Durban. 
Study Size: 
270 in each arm, for 540 total participants. 
POC Testing: 
GeneXpert® by Cepheid with the Xpert® HIV-1 VL cartridge. 
Abbott POC urine TFV adherence assay. 
Primary 
Outcome 
Measurements: 
• Tenofovir diphosphate concentrations in dried blood spots (continuous) at 
the 24 week visit (target visit window: weeks 22-28) after ART initiation and 
study enrollment. 
• Composite measure of requiring both HIV VL suppression and retention in 
care (binary) at study clinic at study exit (72 weeks after ART initiation; 
target visit window for retention: weeks 68-80; target visit window for VL: 
weeks 68-84). Participants who are either retained but not virally 
suppressed, or who are virally suppressed but not retained, do not achieve 
the endpoint. 
- Retention in care at study clinic (binary): collecting ART from the study 
clinic (or from community pick-up point under supervision of the study 
clinic) at study completion (72 weeks). 
- HIV VL suppression (binary): HIV VL <200 copies/mL by a lab-based 
reference assay at the study exit visit (72 weeks) 
Study 
Duration: 
4 years, including enrollment period and 72 weeks of follow-up per 
participant. 
 
1.2 
Study Summary 
For millions of people living with HIV (PLHIV) receiving antiretroviral therapy (ART), adequate 
ART adherence and routine HIV viral load (VL) monitoring are critical to ensure viral suppression 
and good health outcomes. Initiation and management of life-long ART in low- and middle-income 
countries (LMICs) is challenging for both PLHIV and providers in part due to the reliance on self-
reported adherence and delays with lab-based VL testing, which are part of the usual care. Drs 
Drain and Garrett (co-principal investigators) recently completed a pilot study in South Africa 
demonstrating that point-of-care (POC) VL monitoring for PLHIV receiving efavirenz-based ART 
increased VL suppression and retention in care by 14% (95% CI 6 - 21%) over a 12-month period 
compared to standard lab testing. However, the applicability of these findings to the context of 
newer, more robust dolutegravir-based ART regimens being introduced in several LMICs, 
including South Africa, is not known. To complement POC VL monitoring, we have recently 
completed the development and initial evaluation of a novel POC urine TFV assay which can 
monitor ART adherence in clinic-based settings in real-time. 
 

 
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Our objective in this study is to determine the clinical efficacy and cost effectiveness of 
implementing an integrated model for HIV monitoring using POC TFV adherence testing and POC 
VL monitoring in improving ART adherence, maintaining durable VL suppression, and improving 
retention in care among PLHIV initiating first-line tenofovir disoproxil fumarate (TDF)-based ART 
in South Africa. We will randomize 540 participants (1:1) at ART initiation into routine POC TFV 
adherence testing with POC VL monitoring (Arm 1) or standard-of-care (SoC) with no objective 
TFV adherence testing and SoC VL monitoring (Arm 2). Participants will be followed to compare 
two primary outcomes: mean plasma TFV concentrations between study arms at 24 weeks after 
ART initiation and a composite outcome of VL suppression and retention in care between the 
study arms at 72 weeks after ART initiation. We will use process evaluation data, interviews and 
focus groups with patients and process evaluation data and interviews with staff to assess 
implementation of the POC assays. We will conduct detailed micro-costing to estimate 
intervention costs. We will parameterize an agent-based network transmission model with costs 
and effectiveness data collected during the trial to project the clinical outcomes and economic 
impact of POC testing on HIV-related outcomes and disability-adjusted life-years (DALYs). 
 
1.3 
Study Aims 
Aim #1:  
To determine if an integrated model for HIV monitoring using a POC TFV 
adherence assay and a POC VL test will improve adherence, VL suppression, and 
retention in care. 
 
Aim #2:  
To monitor implementation and assess patient and provider perspectives of real-
time POC TFV adherence testing and POC VL monitoring in South Africa. 
 
Aim #3: 
To estimate the costs and cost-effectiveness of implementing POC TFV adherence 
testing with POC VL monitoring, compared to no objective adherence testing and 
SoC VL monitoring. 
 
 
 

 
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2. 
CONSORT DIAGRAM 
 
 
3. 
STUDY PERSONNEL 
3.1 
Leadership Team 
Seattle-based Principal Investigator: 
Paul Drain 
 
 
USA cell phone: 
 
1-206-306-3066 
 
 
Email  
 
 
pkdrain@uw.edu  
 
 
Skype  
 
 
pkdrain 
Durban-based Principal Investigator: 
Randomize
(N=540)
Intervention was Superior to Standard-of-Care
Week 72
Intervention Arm
Urine POC tenofovir
adherence testing;
POC viral load testing
(N = 270)
Retention in care with 
suppressed viral load
Ensure Eligibility
HIV-infected adults initiating 
TDF-based ART
Analysis
Standard-of-Care 
Arm
No adherence testing;
Lab viral load testing
(N = 270)
Retention in care with 
suppressed viral load
ART adherence
ART adherence
Week 24
Analysis
Week 0

 
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Nigel Garrett 
 
 
Durban Cell phone:   
(076) 330-8300 
 
 
Email  
 
 
nigel.garrett@caprisa.org 
 
 
Skype  
 
 
nigegarrett 
 
3.2 
Co-Investigators (alphabetical order) 
• 
Salim Abdool Karim, CAPRISA 
• 
Anna Bershteyn, NYU 
• 
Connie Celum, UW 
• 
Tim Cressey, Chiang Mai (for TFV-DP adherence testing) 
• 
Deborah Donnell, UW 
• 
Jienchi Dorward, CAPRISA/U. of Oxford 
• 
Lisa Frenkel, UW 
• 
Geoff Gottlieb, UW 
• 
Monica Gandhi, UCSF 
• 
Richard Lessells, KRISP (for HIV resistance testing) 
• 
Koleka Mlisana, NHLS 
• 
Pravi Moodley, NHLS 
• 
Kogie Naidoo, CAPRISA 
• 
Hope Ngobese, eThekwini Municipality Health Unit  
• 
Monisha Sharma, UW (for CEA aim) 
• 
Jane Simoni, UW (for qualitative aim) 
 
4. 
BACKGROUND 
4.1 
Significance 
Over 20 million PLHIV, mostly in LMICs, are receiving ART.1,2 In South Africa, which has the 
world’s largest HIV treatment program,3,4 delivery of ART has led to a 15-year increase in life 
expectancy and a significant reduction in HIV-associated deaths.5,6 Despite these gains, the 
requirements for PLHIV to maintain high levels of ART adherence to achieve VL suppression and 
prevent emergence of drug-resistant HIV remains a major challenge. ART adherence is crucial to 
achieving treatment success and reaching the 90-90-90 UNAIDS targets7 and ending the HIV/AIDS 
epidemic.8,9 With the rapid increase of PLHIV initiating ART globally, there is an urgent need to 
redesign models of ART monitoring and management in LMICs, while not increasing the burden 
to HIV providers, laboratories, and health systems.10-13  
 
Poor HIV clinical outcomes in South Africa.  Many countries, including South Africa, have 
adopted a universal test-and-treat policy to provide ART regardless of CD4 count.14 Despite this, 
South Africa is far from reaching the UNAIDS 90-90-90 goals.15 In 2017, only 52% of the 7.9 
million PLHIV had achieved VL suppression.15,16 Global estimates are similar, with UNAIDS 

 
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reporting that in 2017, 47% of the 36.9 million PLHIV worldwide had achieved VL suppression.17 
Three major contributors to this shortfall are (1) overburdened health clinics and laboratories, (2) 
emergence of HIV drug resistance (HIVDR), and (3) poor ART adherence. First, an overburdened 
health system impacts health care outcomes in South Africa - only 39% of PLHIV initiated ART 
within a year of diagnosis,18 25% of PLHIV who initiated ART are lost to follow-up within one year, 
and <50% had a recorded VL within one year.3 This strain on HIV clinicians and laboratories has 
detracted resources from identifying new patients, initiating PLHIV on ART, and appropriately 
switching patients with treatment failure to another ART regimen. Second, to combat rising levels 
of HIVDR and reduce costs,19-22 the World Health Organization (WHO) now recommends dolutegravir 
(DTG), an integrase strand transfer inhibitor, in first- and second-line ART in LMICs.14,23-27 By the end 
of 2019, the South African DoH is planning to introduce tenofovir/lamivudine/DTG, known as “TLD”, 
in a fixed dose combination as the country’s first-line ART regimen. Since DTG-based therapy has 
a higher genetic barrier to resistance and a better tolerability than efavirenz-based therapy,14,28-32 
the role of VL testing may then shift towards identifying viremia related to poor ART adherence. 
With the roll-out of DTG-based ART, determining the role of emerging POC technologies, 
including a novel TFV adherence assay for treatment monitoring, will increasingly become a 
priority for LMICs. 
 
The challenge of HIV VL testing for PLHIV in LMICs.  The WHO recommends routine VL testing 
for monitoring ART,33 but current expansion rates of VL coverage have not met the needs of 
PLHIV and ART programs (Figure 1).34 High quality HIV reference labs are scarce in many 
LMICs.35 Significant challenges to scaling up capacity for VL testing include poor infrastructure, 
human resource shortages, delays with specimen transport, and incomplete results management 
- all of which impede the prompt detection and management of HIV viremia.35,36 In KwaZulu-Natal, 
the province with the highest HIV prevalence in South Africa, just five laboratories are processing 
and resulting over 100,000 VL tests every month (5.6 million VL tests annually in all South 
Africa).37 With optimized systems, most PLHIV do not receive their VL result until their next clinical 
visit in 2-3 months.38 In a cluster randomized trial evaluating the national adherence guidelines, 
<20% of PLHIV with a VL >1000 copies/mL received a follow-up VL test within three months (and 
of 
those 
who 
did, 
only 
15% 
suppressed to <400 copies/mL).155,156 
In a cohort study from four provinces, 
the median time from first VL >1000 
copies/mL to confirmation of viral 
failure was 30 weeks (IQR 17-
535,124).157 
To 
combat 
this 
challenge, the WHO has called for 
operational research on the cost, 
impact, and sustainability of models of 
POC VL testing for decentralized 
care.33 
 
Figure 1. Rising global demand for VL tests.34 

 
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POC HIV VL monitoring improves retention and VL suppression.  Diagnostic POC tests have 
rapidly emerged in LMICs.39-43 Three POC HIV VL assays have recently become available, and 
more are in development.44,45 The Xpert® HIV-1 VL test (Cepheid, Sunnyvale, US) requires 1 mL 
of blood to provide a quantitative result (40-10 million copies/mL) in <2 hours (Figure 2).46 This 
assay uses the fully automated molecular GeneXpert® platform, which is widely used in LMICs 
for diagnosing tuberculosis.47,48 In 2017, an estimated 9,449 GeneXpert® instruments had been 
procured in 130 countries.49 We conducted the first clinic-based feasibility and validation study of 
the Xpert® HIV-1 VL test, and found a strong correlation between the Xpert® and Roche Taqman 
v2.0 (Roche Diagnostics) across the HIV VL spectrum (Spearman ρ=0.94, p<0.001)115 when 
performed in the CAPRISA eThekwini clinic.50 A recent systematic review of subsequent studies 
confirmed high diagnostic accuracy when compared to laboratory reference VL assays (R2=0.94-
0.96).51 While other POC VL assays are available (SAMBA I/II semi-Q [Diagnostics for the Real 
World Ltd., Cambridge, UK];52 and m-PIMA, formerly Alere Q 
NAT [Alere, Waltham, MA, US]53), the Xpert® HIV-1 VL has the 
advantage of utilizing a multiplex, multi-cartridge platform 
widely available in LMICs, and is the first quantitative assay to 
receive both European and WHO regulatory approvals.54 We 
recently completed the pilot STREAM POC VL study, in which 
we randomized (1:1) 390 PLHIV (≥18 years) who were 
receiving ART for 6 months to receive POC HIV VL monitoring 
by an enrolled nurse (Arm 1) versus standard lab-based HIV 
VL monitoring by a professional nurse or physician (Arm 2). 
The primary outcome was a composite measure of HIV VL 
suppression (<200 copies/mL) and retention in care (collecting 
ART during a defined window period at study exit). After 12 months follow-up, those assigned to 
the POC arm had statistically significant higher VL suppression and retention by 13.9% (95% CI 
6.4—21.2%), as compared to the SoC arm.38 In secondary analyses, 99% of POC testing 
participants received their VL result nearly all on the same day, whereas only 77% of SoC 
participants received their VL result a median of 41 (IQR 28-69) days after blood draw. However, 
while VL monitoring will be critical to identify PLHIV with viremia, we do not know if these important 
findings will be similar for DTG-based ART, or how POC VL monitoring should be integrated with 
POC adherence testing.56  
 
Needing better solutions to improve ART adherence.  The barriers to maintaining adequate 
ART adherence are a complex mix of medical, behavioral, social and structural factors.57,58 
Studies of adherence interventions, including mHealth interventions, community-based 
supporters, and economic assistance, have shown mixed results in improving VL suppression in 
LMICs. Effective interventions in high-income settings (e.g. cognitive behavioral therapy) have 
shown little effect in LMICs.59-62 A primary challenge has been accurately measuring ART 
adherence in real-time at the clinical point-of-care. Clinicians rely on self-reported measures and 
 
Figure 2. GeneXpert® System and 
Xpert® HIV viral load cartridge. 

 
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pill counts, but these are susceptible to social desirability bias and are poor measures of ART 
adherence.63,64 Clinicians in LMICs often lack access to HIVDR testing, making it difficult to 
distinguish whether viremia is caused by poor adherence or HIVDR.65 The WHO recommends VL 
testing after 6 months on ART, so healthcare workers may not detect early problems with 
adherence.33 This may be particularly problematic as adherence patterns are established early in 
the course of treatment and early attrition in ART programs remains high.66 The current 
techniques to detect antiretrovirals, including tenofovir, in various biological matrices all require 
liquid chromatography/tandem mass spectrometry (LC-MS/MS) or other spectrometry machines, 
all of which are expensive, laborious, and require trained personnel. Therefore, a simple, 
inexpensive, and objective test to accurately identify poor ART adherence is a high priority for 
LMICs. 
 
A POC urine tenofovir adherence test. After 
several years of research, we have recently 
developed and validated the first POC urine-based 
TFV adherence test as a simple antibody-based 
immunoassay.68-70 First, Dr. Drain et al completed 
a 
randomized 
controlled 
directly-observed 
pharmacokinetic 
study 
of 
HIV-negative 
participants taking TDF/emtricitabine (FTC) at 2, 4 
and 7 doses per week to establish the correlation 
between urine and plasma tenofovir levels, and to 
establish a threshold for POC detection (Figure 
3).67 
Subsequently, 
there 
were 
further 
collaborations with the University of California-San 
Francisco (UCSF) Hair Analytical Laboratory 
(HAL), who were working with Abbott/Alere™ Rapid 
Diagnostics, to develop an immunoassay to 
quantify urine tenofovir levels. A complex 
antibody selection process, involving the 
inoculation of rabbits, was used to isolate 
antibodies specific to tenofovir. These have 
now been purified and incorporated into an 
immunoassay, which has demonstrated high 
sensitivity (94%) and specificity (99%) for 
detecting tenofovir levels in urine, when 
compared to LC-MS/MS, from participants in 
the TARGET study (Figure 4).68 The 
correlation between tenofovir levels was high 
(0.92 in all samples, p<0.00001; 0.89 in 
samples positive for tenofovir, p<0.00001).68 
 
Figure 3.  Plasma, urine tenofovir levels by low 
(2 doses/wk), moderate (4 doses/wk), and perfect 
(7 doses/wk) adherence.67 
 
Figure 4.  Urine tenofovir by immunoassay vs. mass 
spectrometry from TARGET samples. Gandhi M, Drain 
PK. J AIDS. 2019. 

 
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The immunoassay has been translated into a corresponding lateral flow assay (LFA) for POC 
tenofovir-based ART adherence testing and has been validated in urine.158 The threshold of the 
assay has been designed to distinguish between people who have taken at least one fixed dose 
of TDF within the prior four days (corresponding with a TFV urine concentration of ≥1500 ng/mL) 
versus those who have taken no doses of TDF within the prior four days (corresponding with a 
TFV urine concentration of <1500 ng/mL).85 The sensitivity of the LFA using the TFV urine 
concentration threshold of 1500 ng/mL compared to the gold standard for TFV concentration 
detection, LC-MS/MS, was 97% (95% CI: 95-99%). Similarly, the LFA indicated a 97% specificity 
(95% CI: 93-99%) when compared to LC-MS/MS.85  
 
The POC urine TFV adherence assay is accurate, low cost (<$2/test), enables qualitative 
tenofovir detection within 10 minutes, and can be easily performed by clinical personnel at the 
point-of-care. When combined with POC VL monitoring, the POC TFV assay directly measures 
the presence (or absence) of tenofovir and has the potential to shift the paradigm for monitoring 
ART in LMICs. Currently, there are no studies of the clinical and cost-effectiveness of utilizing a 
POC adherence assay with VL testing to improve VL suppression in LMICs. 
 
Redesigning integrated models of HIV care and ART monitoring in LMICs.  As the number 
of PLHIV receiving ART continues to rise, developing and evaluating clinic-based strategies to 
improve ART adherence and maintain VL suppression will be paramount to reach the ambitious 
UNAIDS 90-90-90 targets.7 Existing models of HIV monitoring were designed for CD4-guided 
ART initiation of efavirenz-based ART, and new models of HIV care are needed using an 
integrated approach with early ART adherence testing and more efficient HIV VL testing.71-73 
Combining an objective POC adherence test with efficient POC VL monitoring could enable 
healthcare providers to rapidly categorize patients into non-adherent viral failures versus drug-
resistant viral failures, triggering expensive genotypic testing and switches to 2nd or 3rd line 
treatment only when appropriate (e.g., high adherence with viral failure).74-76 Furthermore, the 
mechanism by which a POC adherence test could improve ART monitoring for PLHIV and health 
care workers needs further investigation. Our proposed study will determine whether a novel POC 
urine TFV adherence test, combined with POC VL monitoring, could be a cost-effective 
intervention to support PLHIV in achieving VL suppression in LMICs.29 
 
4.2 
FDA/CDRH and Nonsignificant Risk Designation for the POC Urine Tenofovir 
Adherence Assay 
We obtained pre-trial consultation advice from the U.S. Food and Drug Administration’s (FDA) 
Center for Devices and Radiological Health (CDRH) regarding the use of the POC urine tenofovir 
adherence assay that will be used in this study. The FDA verified that the POC tenofovir 
adherence assay is not Investigational Device Exempt (IDE) since the assay results will be 
returned to participants and may be used to guide clinical care decisions. Per FDA regulations 

 
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(21 CFR 812), the alternative device determinations applicable to this study are either 
Nonsignificant Risk (NSR) or Significant Risk (SR). The adherence assay meets the criteria for a 
NSR Medical Device study since the device does not pose any serious risks to the health, safety, 
or welfare of participants in this study. The CDRH and the University of Washington Institutional 
Review Board (IRB) has agreed that this device meets the criteria for a NSR Medical Device 
study, and we will seek approval from the relevant IRBs to conduct this study with the POC 
tenofovir adherence assay as a NSR Medical Device.  
 
5. 
STUDY OBJECTIVES 
5.1 
Primary Objectives 
• 
To determine if implementing routine POC TFV adherence testing is superior to SoC 
(no adherence testing) in improving ART adherence at 24 weeks after ART initiation 
(target visit window: weeks 22-28) among PLHIV initiated on first-line TDF-based ART 
in South Africa. 
• 
To determine if implementing routine POC TFV adherence testing in combination with 
routine POC VL monitoring is superior to SoC VL monitoring (with no adherence 
testing) in improving retention in care and VL suppression (<200 copies/mL) at 72 
weeks after ART initiation (target visit window for retention: weeks 68-80; target visit 
window for VL: weeks 68-84) among PLHIV receiving TDF-based ART in South Africa. 
 
5.2 
Secondary Objectives 
• 
To determine if implementing routine POC TFV adherence testing in combination with 
routine POC VL monitoring is superior to SoC VL monitoring (with no adherence 
testing) in improving retention in care and VL suppression (<200 copies/mL) at 24 
weeks after ART initiation (target visit window: weeks 22-28) among PLHIV receiving 
TDF-based ART in South Africa. 
• 
To determine if implementing routine POC TFV adherence testing in combination with 
routine POC VL monitoring is superior to SoC (with no adherence testing) in improving 
ART adherence at 72 weeks after ART initiation (target visit window: weeks 68-84) 
among PLHIV receiving TDF-based ART in South African clinics. 
• 
To assess the acceptability of POC VL and TFV adherence testing among PLHIV and 
providers. 
• 
To assess the cost-effectiveness of providing POC VL and TFV adherence testing to 
PLHIV as compared to SoC VL monitoring. 
 
5.3 
Exploratory Objectives 
Exploratory objectives may be evaluated: 
• 
To assess the costs, both incurred and averted, of implementing the proposed model 
in Aim #1, and the cost per participant virally suppressed and retained in care. 

 
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• 
To determine the HIV genotype resistance pattern among PLHIV who develop viremia 
on dolutegravir-based ART. 
• 
To determine risk factors for poor retention in care or virological failure. 
• 
To determine the incidence of viremia and virological failure (≥50 copies/mL and ≥1000 
copies/mL) among PLHIV receiving ART at the clinical site. 
• 
To compare duration of viremia (i.e., time spent at VL ≥200 copies/mL) between the 
intervention and SoC arms. 
• 
To compare the time to participants’ receipt of VL results in the intervention versus 
SoC arms. 
• 
To compare the number of participants in the intervention versus SoC arms who are 
appropriately entered into the Central Chronic Medicine Dispensing and Distribution 
Programme (CCMDD) at 12 months. 
• 
To compare among participants in the intervention versus SoC arms the time to 
appropriate entry into the CCMDD.  
• 
To compare the number of clinic visits for participants in each study arm. 
• 
To further validate the POC TFV adherence assay against a gold-standard measure 
of tenofovir by tandem liquid chromatography mass spectrometry. 
• 
To further validate novel POC VL assays against a laboratory-based gold standard. 
• 
To compare time to appropriate ART regimen switch between the intervention and 
SoC arms. 
• 
To compare the number of unnecessary ART regimen switches between the 
intervention and SoC arms. 
• 
To assess TFV level in hair samples at 24 and 72 weeks after enrollment. 
• 
To compare VL results of whole blood, plasma, and dried blood spot on the Cepheid 
GeneXpert machine. 
• 
To characterize patients’ HIV infection and treatment history at ART initiation using a 
novel HIV recency test at baseline, National Health Laboratory Service data, HIV drug 
resistance testing and ART blood levels. 
• 
To assess and evaluate other relevant POC assays for PLHIV on ART, including the 
GeneXpert human papillomavirus (HPV) assay, if they become available. 
 
6. 
METHODS 
6.1 
Study Design 
This study will be a two-arm, open-label, randomized controlled superiority trial at an HIV clinic in 
Durban. HIV-positive individuals aged ≥16 years who are initiating a TDF-based, first-line ART 
will be randomized 1:1 to receive POC VL testing and POC TFV adherence testing, versus SoC 
viral load testing. VL testing will follow South African guidelines for HIV VL testing after ART 
initiation. The primary outcomes will include: (1) concentration of tenofovir diphosphate (TFV-DP) 
in dried blood spots (DBS) 24 weeks after ART initiation and study enrollment as a surrogate 
measure for adherence to first-line ART regimen and (2) a composite measure of retention in care 

 
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with suppressed VL (<200 copies/mL) 72 weeks after ART initiation and study enrollment. 
 
6.2 
Location and Setting 
The study will be conducted at the Prince Cyril Zulu Communicable Disease Centre (“CDC 
Clinic”) and the adjacent CAPRISA eThekwini Clinical Research Site (ECRS). The CDC Clinic 
and ECRS are located near the transport hub for public commuters in central Durban. The CDC 
Clinic initiates approximately 2,000 PLHIV on ART annually. Current South African Guidelines 
recommend a fixed-dose combination (FDC) drug of tenofovir diphosphate, lamivudine, and 
dolutegravir (TLD) for first-line ART for adolescents and adults. For women who are pregnant or 
may become pregnant, efavirenz, emtricitabine, tenofovir diphosphate (EFV/3TC/TDF) is offered 
as an alternative to TLD due to potential risks to fetal development involved with taking TLD during 
pregnancy. ART initiation is recommended on the same day as a patient receives an HIV-positive 
test unless there are symptoms or signs of opportunistic infections such as tuberculosis or 
meningitis. VL testing is recommended at six and 12 months after ART initiation, and then 
annually thereafter. If the VL is suppressed after 12 months, patients may be referred into the 
CCMDD, where they collect ART every two months from community pharmacies and other 
community pick-up points and are seen only every six months at the clinic for clinical and 
laboratory monitoring. 
 
6.3 
Eligibility Criteria 
Eligibility criteria are meant to be representative of PLHIV who are eligible to initiate ART in South 
Africa. We will enroll HIV-positive individuals (≥16 years old) who are initiating a TDF-based ART 
regimen, which is included in current and anticipated first-line ART regimens. The study involves 
collection of clinical data and biological specimens, so all participants must be willing and able to 
provide written informed consent in English or isiZulu, the local languages. 
 
Study eligibility criteria include the following: 
• 
HIV-positive  
• 
≥16 years old 
• 
Initiating a TDF-based, first-line ART regimen  
• 
Do not self-report being on an ART regimen in the prior month 
• 
Willing/able to provide written informed consent 
 
The exclusion criteria are the following: 
• 
Does not meet the study inclusion criteria above 
• 
Does not plan to continue receiving HIV care at the CDC Clinic 
• 
Per the decision or opinion of the PI or designee (for example, a clinically significant 
acute or chronic medical condition or circumstances that would make the patient 
unsuitable for participation or jeopardize the safety or rights of the participant 
 

 
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Of note, pregnancy is not a study exclusion criterion. 
 
6.4 
Recruitment, Consent, Screening, and Enrollment 
A Research Assistant or designee dedicated to this study will approach individuals who are being 
initiated on ART within the HIV clinic at the CDC Clinic. The Research Assistant/designee will 
describe the study and ask for voluntary participation. Individuals who want to voluntarily 
participate will be taken to a private area of the clinic and will be provided with a detailed 
explanation of the purpose and procedures of the study. The Research Assistant/designee will 
address any questions about study participation. HIV-positive individuals (≥16 years) interested 
in participating in the study will undergo the informed consent procedure as per standard 
operating procedures and thereafter if they are willing to participate, will sign the informed consent 
form for screening and possible enrollment into the study. Those who are not willing to participate 
in the study will experience no detrimental impact on their routine care at the CDC Clinic. A 
Research Nurse/designee will review the study inclusion/exclusion criteria, assess the potential 
participant’s eligibility, and complete the following evaluations: 
• 
Socio-demographics questionnaire 
• 
Locator information 
 
If eligibility is confirmed, the participant will be enrolled, and the Research Nurse/designee will 
complete the following evaluations with the participant: 
• 
HIV and ART assessment 
• 
Medical history 
• 
WHO staging 
• 
TB symptom screen 
• 
Substance use questions 
• 
WHO intimate partner violence tool 
• 
Mental health assessment tool (PHQ-9) 
• 
IPT assessment 
• 
ART adherence and counseling 
 
6.5 
Randomization 
The study statistician will generate an allocation sequence with variable sized blocks of random 
numbers using SAS 9.4 (SAS Institute Inc., Cary, NC). Randomization will be in a 1:1 ratio to the 
standard of care or intervention arm. Study arm allocation for each participant will be programmed 
within the electronic data collection tool (iDataFax) by the Data Manager, and no other members 
of the research team will be able to look up the random allocation sequence throughout the 
enrollment period. This will prevent any biases in study arm assignment from occurring. At 
enrollment, the participant will be randomized to either the control arm or the intervention arm in 
a 1:1 fashion, using the pre-programmed randomization tool within iDataFax. 
 

 
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6.6 
Study Procedures and Interventions 
6.6.1 Baseline 
Once written informed consent is obtained, but before randomization, a Research Assistant, 
Nurse, or designee will administer demographic, health related and locator information 
questionnaires. A Nurse/designee will also administer a brief clinical questionnaire, conduct a 
clinical examination, and determine the WHO HIV Stage. In order to minimize the number of blood 
draws required, if and where possible, the attending nurse will coordinate the standard ART 
initiation blood draws and study-specific blood draws for the participant. Blood will be drawn for 
haemoglobin (Hb) analysis, creatinine, CD4 count and Hepatitis B as per schedule of evaluation. 
Blood will also be drawn for storage of blood in the biorepository for VL testing and possible future 
genotype and/or tenofovir drug-level testing for ART adherence. Once all procedures are 
completed, participants will be randomised and assigned to a study arm via randomization 
procedures outlined above (Section 6.5). Participants will be provided with ART and scheduled 
for a follow-up visit as per South African guidelines, which typically occurs after one month. 
 
6.6.2 Follow-up  
When participants return to the clinic for routine care visits, they will be asked to present directly 
to the study team. The Research Assistant/designee will determine the assigned study group of 
the participant and direct them accordingly to either  the SoC arm procedures (Section 6.6.3) or 
the Intervention arm procedures (Section 6.6.4). Apart from POC VL and POC TDF adherence 
testing in the intervention arm (as outlined in Sections 6.6.7 and 6.6.8), the schedule of follow-up 
visits, clinical care, and laboratory monitoring will follow standard South African guidelines. All 
participants will have creatinine testing at month three; VL and creatinine at month six; and VL, 
creatinine, and CD4 testing at month 12 as per schedule of evaluation. Participants will be 
scheduled for visits at an average of once a month for the first six months, then every two months 
between months 6-12. Participants in both arms will be assessed for CCMDD eligibility around 12 
months and referred into CCMDD as appropriate. At each clinic visit, participants will see a nurse 
or physician, who will perform a clinical assessment, including symptoms/signs of tuberculosis, 
other opportunistic infections, and ART side effects. They will prescribe ART and additional 
medications and adherence counseling as appropriate, in accordance with South African 
guidelines. At each follow-up visit, all participants will complete the following evaluations with the 
Research Assistant, Nurse, or designee: 
• 
Locator information 
• 
TB symptom screen 
• 
ART adherence and counseling 
• 
ART side effect assessment 
• 
Vital signs assessment 
• 
Symptom directed physical exam (except for week 72) 
 

 
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In addition to those listed above, all participants will complete the following evaluations at weeks 
24 and 72: 
• 
Substance use questions 
• 
WHO intimate partner violence tool 
• 
Mental health assessment tool (PHQ-9) 
 
6.6.3 Standard-of-care Arm Follow-up Procedures 
In the SoC arm, routine CD4, creatinine, and VL testing will be performed according to the above 
schedule by the National Health Laboratory Services (NHLS) which provide all laboratory testing 
offsite for the CDC Clinic. The NHLS currently uses the Abbott Alinity m Analyser or Alinity m HIV-
1 assays for laboratory VL testing.  
 
6.6.4 Intervention Arm Follow-up Procedures 
Participants in the intervention arm will have urine TFV measurements conducted during each 
clinical encounter for the first five months after ART initiation. This will be tested by utilizing a rapid 
urine dipstick test. As per standard operating procedures, participants will be given a urine 
container, shown a private place to provide a urine sample, and the testing will be conducted at 
the clinical point-of-care. The threshold of the assay was designed to distinguish between PLHIV 
who have (“adherent”) taken TDF versus those who have not (“non-adherent”) taken TDF within 
the prior four days. Participants who are considered “adherent” by the assay will be informed of 
the result and encouraged to continue with good adherence. The PLHIV who are considered “non-
adherent” by the assay will also be informed of the result and receive standard enhanced 
adherence counseling. 
 
Participants in the intervention arm will have all routine ART monitoring tests performed according 
to the schedule described in the SoC arm follow-up procedures, however the POC VL assays will 
be utilized instead of lab-based VL testing. POC VL testing will be performed using Cepheid’s 
GeneXpert® HIV-1 VL assay performed at the beginning of the clinical encounter, so the clinical 
examination can be performed during the 90 minutes required to run a GeneXpert HIV VL test. If 
the participant is not able to wait for the results, then the study team will allow the participant to 
leave the study clinic but will ask them to remain in the vicinity and return to the clinic for their VL 
results. Prior to consent and enrollment, all potential participants will be counseled on the study 
procedures to ensure participants are able to comply with Intervention Arm study procedures, 
including potentially spending more time in clinic to receive VL results than they normally would 
as part of SoC clinic procedures. The GeneXpert testing will be conducted in the adjacent 
CAPRISA clinic site laboratory. Results will be managed according to SoC South African 
guidelines. However, all patients with a POC VL >200 copies/mL will have reflex POC urine TFV 
adherence testing performed within the same clinical visit.   
 

 
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In addition, participants in the Intervention arm may also be asked to provide a fingerprick of blood 
for HIV VL testing if this assay becomes available during the study period. This would be a 
validation sub-study against a reference assay VL results only, and therefore, these results would 
not be used to guide the intervention.  
 
6.6.5 Procedures for Participants Switched to Non-TDF-containing Regimens 
Following South Africa guidelines, all participants in this study who are initiated on a TDF-
containing regimen but are later found to have insufficient renal function (eGFR <50 
mL/min/1.73m2) will be switched to a non-TDF based regimen. SoC arm participants who are 
switched to a non-TDF based regimen will continue to be followed for the duration of the study. 
Intervention arm participants who are switched to a non-TDF based regimen will continue to be 
followed for the duration of the study and will continue to receive POC VL monitoring but will not 
receive POC TFV adherence monitoring. 
 
6.6.6 Central Chronic Medicine Dispensing and Distribution Programme 
From 12 months after ART initiation (study enrollment), eligible participants will be referred into 
CCMDD. Eligibility criteria for CCMDD as per South African guidelines are the following: 
 
a) Clinically stable and adherent on same first-line ART regimen for ≥12 months  
b) No current opportunistic infections (e.g., tuberculosis) or uncontrolled chronic illness, 
including hypertension, in previous six months  
c) Most recent viral load results show VL <50 copies/mL 
d) Not a caregiver for a child on ART, particularly for those with scheduled pick-up points on 
the same schedule as the child 
 
Eligible participants will be offered to voluntarily opt in to the program. In CCMDD, they will be 
prescribed a six-month supply of ART, which they collect in two-month installments from a 
community pick-up point including community-based organizations, churches and private 
pharmacies. They will be seen again in the clinic every six months. Those who are not in CCMDD 
will continue to see a nurse or physician in the study clinic until the end of the study.  
 
6.6.7 Management of Viral Load Results – Standard of Care 
The clinical decisions from the SoC VL testing will adhere to the South African guidelines. The 
algorithm for the 2019 VL monitoring guidelines can be found in Appendix I and is summarized 
below: 
• 
HIV VL <50 copies/mL – Reinforce the importance of good ART adherence and continue 

 
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routine VL monitoring 
• 
HIV VL 50-999 copies/mL – Provide enhanced ART adherence counseling, provide ART, 
and ask participant to return to the clinic in six months for repeat VL testing. If the VL 
remains high (50-999 copies/mL) upon repeat testing, then the participant should continue 
receiving enhanced adherence counseling and repeat VL testing every six months until 
viral suppression (<50 copies/mL) is achieved. 
• 
HIV VL ≥1,000 copies/mL – Provide enhanced ART adherence counseling; provide ART, 
and ask participant to return to the clinic in three months for repeat VL testing. If the VL 
remains high (≥1,000 copies/mL) after repeat testing, then participants on an NNRTI (non-
nucleoside reverse transcriptase inhibitor)-based regimen will be considered for switching 
to a new ART regimen by a physician. Participants on a TLD regimen will only be 
considered for resistance testing or a regimen switch after at least three VL ≥1000 
copies/mL over at least two years. 
 
Figure 6: Participant flow through study 
 
6.6.8 POC Tenofovir Adherence Testing and Management of Results 
POC TFV adherence testing will be conducted among only Intervention arm participants using an 
Abbott urine TFV adherence test per the testing schedule shown in Figure 6 (above). In months 
1-5, Intervention Arm participants will undergo POC TFV adherence testing at each monthly 
clinical check-up. Participants who are found to be “adherent” will have the importance of good 
adherence reinforced and will proceed with intervention monitoring procedures. Participants who 
are found to be “non-adherent” will be provided with enhanced adherence counseling until their 
next clinical check-up.  
 
For months six and beyond, Intervention arm participants who receive a POC VL result of <50 
copies/mL will proceed with routine monitoring as outlined in Section 6.6.7. Participants who 
receive a POC VL result of 50-199 copies/mL will proceed with enhanced adherence monitoring 
Months
0      1      2      3      4      5      6
12
18
No objective adherence testing
ART 
initiation
Intervention Arm
Standard of care Arm
540 PLHIV 
initiating 
TDF-based 
ART
= POC TFV adherence test
= POC HIV VL test
Primary 
Outcome
Measures
ART Adherence (DBS)
SoC HIV
VL test
SoC HIV
VL test
Retention in care + 
HIV viral load
if viremia
if viremia
SoC HIV
VL test
SoC HIV
VL test

 
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and will be scheduled to receive another POC VL test in three months as described in the 2019 
VL monitoring guidelines in Section 6.6.7 for those with a VL of 50-999 copies/mL. Participants 
who receive a POC VL result of ≥200 copies/mL will be asked to provide a urine sample for POC 
TFV adherence testing.  
6.6.8.1 
Adherence Testing Procedures 
At scheduled and interim visits in which 
a POC TFV adherence test is required, 
the Research Assistant/designee will 
remind the Intervention arm participant 
about the purpose of adherence testing 
and the experimental nature of the 
adherence test. Participants will then be 
asked to provide a urine sample 
collected at the beginning of the 
participant’s 
visit. 
The 
Research 
Assistant/designee will perform the test 
using standard operating procedures 
provided by Abbott. The test results will 
appear 
within 
approximately 
3-5 
minutes. As shown in Figure 7, the test 
results 
will 
indicate 
either 
an 
indeterminate result (no control line appears), a positive result (only the control line appears), or 
a negative result (both the control line and the tenofovir test line appear). A positive result will 
indicate that the assay detected tenofovir in the participant’s urine and that the participant is 
“adherent”, and a negative result will indicate that the assay was unable to detect tenofovir in the 
participant’s urine and that the participant is “non-adherent”. If an indeterminate result appears, a 
new test will be conducted. 
6.6.8.2 
Management of Adherence Test Results and Communicating Results with Participants 
If a participant is found to be “non-adherent”, they will be informed of their test results and provided 
with enhanced adherence counseling and will be asked to return to the clinic in three months for 
repeat POC VL testing. More details on enhanced adherence counseling for “non-adherent” 
participants can be found below in Section 6.6.8.3. If a participant is found to be “adherent”, they 
will be asked to provide a blood sample for resistance testing, the importance of good adherence 
all the time will be reinforced, and they will be asked to return to the clinic in three months for 
repeat POC VL testing. If no drug resistance is found, then participants will not be contacted about 
their results and will proceed with routine care. If presence of drug resistance is found, then the 
Research Assistant will contact the participant and ask them to return to the clinic promptly to be 
switched to an appropriate second-line regimen. The full algorithm for management of POC VL 
and tenofovir results for Intervention arm participants can be found in Figure 8. 
Figure 7: Abbott Urine TFV Adherence Assay 

 
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Figure 8: Algorithm for management of POC VL and TFV results after six months 
6.6.8.3 
Enhanced Adherence Counseling for “Non-Adherent” Participants 
Intervention arm participants who are found to be “non-adherent” by the POC TFV adherence 
test will receive additional enhanced adherence counseling at the end of the visit in which their 
TFV adherence test results were received. The counseling session will begin by the Research 
Assistant/designee informing the participant that their test results indicated that they have not 
taken any of their ART pills within the prior 4 days. Participants will be reminded again of the 
experimental nature of the POC TFV adherence test and that diagnostic tests may sometimes, 
though rarely, produce inaccurate results. They will also be reminded of the importance in taking 
their ART every day as prescribed. The remainder of the counseling session will include a 
discussion with the participant about their barriers to adherence and ways to improve.  
 
The enhanced adherence counseling for Intervention arm participants is a novel area for clinical 
care delivery and will be guided by a formative qualitative assessment that will be conducted 
POC VL test
<200 copies/mL
SoC procedures
≥200 copies/mL
POC TFV test
"Non-adherent" TFV 
test result
Enhanced adherence 
counseling & return to 
clinic in 3 months for 
repeat POC VL test
"Adherent" TFV test 
result
Resistance test
No drug resistance
Enhanced adherence 
counseling & return to 
clinic in 3 months for 
repeat POC VL test
Drug resistance
Participant contacted & 
asked to promptly 
return to clinic to be 
switched to second-line 
regimen

 
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prior to commencing the study. The formative qualitative assessment will assess perspectives 
from providers and PLHIV on ART on the POC TFV adherence test and will help inform 
development of standard operating procedures for delivering POC TFV test results and 
subsequent adherence counseling to “non-adherent” participants in a way that will minimize any 
potential adverse effects such as stigmatization. After standard operating procedures for 
enhanced adherence counseling are developed, all research team members will be sufficiently 
trained to deliver POC TFV test results in a non-judgmental, supportive manner. 
 
6.7 
Retention Activities 
The clinical and research teams at the CDC Clinic have long-established retention strategies to 
ensure high rates of retention among participants. Standard retention strategies, in line with 
South African guidelines, include providing clinic cards with appointment dates, and contacting 
participants who are at least two weeks late for a scheduled clinic visit via an SMS or phone call 
to remind them about their missed appointment. Towards the end of follow-up, if a participant 
has not attended during the retention in care window (68-80 weeks), they will be defined as not 
retained in care. The research team will then attempt to trace the participant within the exit VL 
window (up to 84 weeks). Tracing will involve contacting participants via SMS or phone call, and 
visiting participants in their home or place of work, when given permission, to offer them a free 
ride to the research clinic. Intervention and SoC arm participants will receive identical retention 
strategies from the CDC Clinic throughout the duration of the study. 
 
6.8 
Targeted/Planned Enrollment 
We will enroll a total of 540 participants, 270 participants in each study arm. Considering the HIV 
epidemic is disproportionally affecting women in our setting, we expect to enroll slightly more 
women than men in our study. Based on historical performance, 75% of adults in the existing care 
model will meet our primary composite outcome. 
 
 
Standard of Care Arm 
Intervention Arm 
Total 
Total 
270 
270 
540 
 
6.9 
Schedule of Clinical Visits and Sample Collection 
The study schedule of evaluations is outlined in Appendix II. 
 
6.10 Additional Laboratory Testing for Aim 1 Objectives 
At enrollment, weeks 24 and 72, participants will be asked to provide a blood sample for plasma 
storage for retrospective HIVDR testing. All participants will have urine and DBS collected at 
weeks 12, 24, 48, and 72 and hair collected at weeks 24 and 72 to measure long-term and short-
term ART adherence. 
 

 
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6.10.1 Primary and secondary outcomes 
Tenofovir-diphosphate levels in DBS and tenofovir levels in urine. We will measure 
tenofovir diphosphate (TFV-DP) in whole blood-based DBS and TFV in urine in the Program 
for HIV Prevention and Treatment (PHPT) laboratory at Chiang Mai University (ISO:15189 
certified), led by Dr. Tim Cressey (Co-Investigator),67,113 which has been approved by the 
Division of AIDS (DAIDS) to perform antiretroviral drug level measurements by LC-MS/MS. 
The PHPT lab participates in the Clinical Pharmacology Quality Assurance and Quality 
Control Program (CPQA), which includes regular proficiency testing, external SOP review, 
and external audits. Dr. Drain has two NIH-supported projects with Dr. Cressey (#AI136648; 
#AI127200). 
 
6.10.2 Exploratory outcomes 
HIV genotypic resistance testing. Dr. Richard Lessells (Co-Investigator) and Dr. Tulio de 
Oliveira established KRISP as a next-generation genomics and bioinformatics laboratory at 
the University of KwaZulu-Natal in Durban.118,119 KRISP has the equipment for next-
generation sequencing (NGS) using the Illumina MiSeq platform, including PCR 
amplification and library preparation, and de novo viral genome assemblage.120 The KRISP 
lab will perform retrospective resistance testing for all baseline, follow-up, and exit samples 
from participants with a VL ≥200 copies/mL during the study follow-up period. For all 
samples with VL ≥200 copies/ml, they may perform next-generation sequencing (NGS) 
using the Illumina MiSeq platform using Primer ID. This NGS method will allow for detection 
of low-frequency drug resistance mutations (minority variants), which may be present at 
baseline and/or at time of virological failure. In addition, samples with a VL ≥200 copies/mL 
may also be tested by the PacBio method that is available either in Johannesburg or at the 
University of Washington. Sequences will be analyzed for HIV drug resistance mutations 
using the Stanford HIV drug resistance database (HIVdb) genotypic resistance interpretation 
system, and drug resistance mutations will be reported at detection thresholds of 1%, 2%, 
5% and 20%. Genotypic resistance testing for minority variants will also be performed at the 
Seattle Children’s Research Institute by Dr. Lisa Frenkel’s laboratory. 
 
HIV phenotypic resistance testing. Dr. Geoff Gottlieb (Co-Investigator) has agreed to 
perform phenotypic resistance testing in his lab at the UW. His lab requires two 2-mL 
cryovials of plasma, which will be collected from participants at baseline, at study exit (72 
weeks), and for each participant with a VL ≥200 copies/mL during the study follow-up period. 
 
Tenofovir levels in hair. Dr. Gandhi and the Hair Analytical Laboratory (HAL) lab at 
University of California-San Francisco (UCSF) will measure tenofovir levels in hair through 
independent funding. Hair collection procedures will be further described in detail in the 
standard operating procedures. Cumulative and recent adherence to ART will be measured 
by concentrations of TFV and 3TC in hair. TFV and 3TC are measured in hair samples at the 

 
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HAL at UCSF using validated methods. The trial will assess whether TFV levels in hair 
increase over time when providing results of the urine TFV assay back to participants. ART 
refills will be measured using routine pharmacy refill data. 
 
6.11. Participant Withdrawal 
Participants may voluntarily withdraw from the study for any reason, at any time. The site 
Investigator also may withdraw participants from the study as per clinical discretion, e.g. in order 
to protect their safety and/or if they are unwilling or unable to comply with required study 
procedures. Participants may also be involuntarily withdrawn from the study if the study is stopped 
or cancelled by the sponsor or ethics committees. Reasons for withdrawal will be recorded. 
 
6.12. Study Duration 
All participants enrolled in this study will be followed for a total of 72 weeks (18 months) from the 
date of study enrollment. The total study duration will be 4 years. 
 
7. 
SAMPLE SIZE AND POWER 
The sample size and power calculation are based on determining superiority of the intervention 
arm compared to the SoC arm (Table 2). Based on clinical data and our recently completed pilot 
study, we expect that 75% of adults will be virally suppressed and retained in care after 72 weeks. 
In order to detect a 10% improvement in the intervention (75% vs 85%), we need to enroll 270 
people per study arm (assuming two-sided alpha=0.05; beta=0.2). Therefore, we plan to enroll 
540 total participants over a 12-month period. 
 
 
 
 
 
 
 
 
 
 
8. 
ANALYSES FOR PRIMARY OUTCOMES 
Primary Outcome A: Tenofovir-diphosphate concentrations in DBS at 24 weeks (target visit 
window: weeks 22-28) after ART initiation and study enrollment. See also Study Schema, Primary 
Outcome Measures. 
 
Table 2.  Sample Size and Power Estimates. 
Outcome for 
 SoC arm 
Outcome for 
Intervention arm 
Power 
(beta) 
Sample size 
per arm 
Total 
sample size 
75% 
82.5% 
80% 
493 
986 
75% 
83.0% 
80% 
431 
862 
75% 
83.8% 
80% 
353 
706 
75% 
85.0% 
80% 
270 
540 
75% 
87.0% 
80% 
183 
366 
75% 
89.0% 
80% 
131 
262 
Power calculated for Fisher’s Exact test. 

 
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To assess Primary Outcome A, we will compare mean tenofovir-diphosphate concentrations 
measured by a lab-based assay between the Intervention and SoC study arms. We will present 
mean concentrations and standard deviation by study arm and compare the means using a two-
sample t-test assuming equal variances. 
 
Primary Outcome B: Composite measure of HIV VL suppression (<200 copies/mL) and retention 
in care at the study clinic at study exit (72 weeks from enrollment; target visit window for retention: 
weeks 68-80; target visit window for VL: weeks 68-84). See also Study Schema, Primary Outcome 
Measures. HIV VL suppression will be defined as achieving a VL <200 copies/mL, as measured 
by a lab-based reference assay at the study exit visit (72 weeks). The same lab-based reference 
assay will be used to measure HIV VL for both Intervention Arm and Control Arm participants. 
Retention in care will be defined as collecting ART from the study clinic (or from community pick-
up point under supervision of the study clinic) at study completion (72 weeks). Participants who 
have met the definition for both HIV VL suppression and retention in care at the study exit visit 
will be classified as having met the criteria for Primary Outcome B. All others will be classified as 
not meeting the criteria for Primary Outcome B. 
 
To assess Primary Outcome B, we will estimate the relative risk (RR)  achieving our primary 
outcome in the intervention relative to standard of care study arms using Poisson regression, 
which provides unbiased estimates of the log relative risks, with generalized estimating equations 
(GEE) to adjust standard errors for the choice of Poisson distribution. RRs will be provided with 
two-sided 95% confidence interval (CI) and p-value.  
 
P-values will not be adjusted for multiple testing and p<0.05 will be interpreted as statistically 
significant. The full statistical analysis plan, including planned analyses for secondary and 
exploratory outcomes, is detailed in the study’s Statistical Analysis Plan. 
 
9. 
SECONDARY QUALITATIVE STUDY 
9.1. 
Introduction and Rationale 
The objective of this aim is to evaluate the implementation of POC TFV and viral load testing at 
the South African clinic and to assess the perspectives of patients and providers regarding 
acceptability of POC testing. This will be achieved through a mixed-methods approach: process 
evaluations, focus group discussions, and semi-structured interviews among the study 
participants as well as process evaluations and semi-structured interviews among the health care 
workers at the study clinic. Understanding the logistical barriers to implementation at the clinic as 
well as patient and provider perspectives is critical to developing feasible, acceptable, and 
effective clinic-based monitoring protocols. In current practice, delayed recognition of adherence 
challenges has compromised the ability of providers to assist patients in achieving durable VL 
suppression. Objective data provided at regular intervals and in real-time on recent medication 
adherence may open the window for more accurate and strategic provider-patient communication 

 
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about medication-taking during routine visits. 
 
9.2. 
Justification and Feasibility 
Poor adherence to ART has been the Achilles’ heel of HIV management, in part due to the 
difficulties in identifying PLHIV who poorly adhere to ART. Patient reports often overestimate 
adherence and provider estimates are notoriously inaccurate.121 Until now, the lack of an objective 
assessment of adherence has hindered the ability of providers to offer, or refer patients to, 
supplemental adherence counseling. POC tests are minimally intrusive for patients and not time 
or labor intensive. They may improve clinical decision-making, patient-provider communication, 
and patient outcomes by the provision of real-time objective adherence data. To our knowledge, 
no published studies have evaluated the barriers and facilitators for POC adherence and VL 
testing in South Africa, particularly not with the urine-based POC TFV adherence test that we have 
only recently developed. 
 
Rapid diagnostic tests (RDTs) have been widely implemented for several infectious diseases, 
including HIV, tuberculosis, malaria, and syphilis.78 Feasibility studies have shown that 
appropriately trained nurses and/or community health workers can implement POC testing with 
low error rates.122-124 However, results from POC tests or RDTs may not necessarily change 
prescribing practices or improve patient outcomes, if patients are unwilling to undergo testing or 
if clinicians are unwilling to act upon results. One clear example has been the reluctance of 
clinicians to prescribe isoniazid preventive therapy (IPT) to PLHIV who do not have tuberculosis-
related symptoms, even when data are rather clear that IPT is both safe and effective for 
preventing active tuberculosis disease.125,126 Similarly, we aim to change the longstanding 
problem of assessing and addressing non-adherence in the clinical encounter, but we first need 
to determine if such routine POC testing can be implemented within a busy clinic setting and if 
patients and providers will engage with the process. 
 
Dr. Jane M. Simoni (Co-Investigator), who will lead this study Aim, leads an acceptability research 
programs on new long-acting ART at UW (#AI120176)127 and on Cell and Gene Therapy for HIV 
Cure (#AI126623)128. She co-chairs the NIAID HIV/AIDS Network Coordination’s Behavioral 
Science Consultative Group, which advises all the NIAID networks on behavioral science aspects 
of their research. She and Dr. Drain are colleagues at the UW Center for AIDS Research (CFAR) 
and have been collaborating on a pilot study of acceptability for POC adherence testing among 
key patient and provider populations in Seattle, US. Her ongoing work involves focus group 
discussions and key informant interviews for ART adherence and clinical studies to overcoming 
barriers to HIV care and ART initiation in several LMICs.  
 
As part of preliminary qualitative work in the STREAM study, participants who received POC VL 
testing reported practical benefits of the intervention, including reducing the number of visits to 
the clinic and less need to take days off work. Healthcare workers also highlighted practical 
benefits for patients, but also expressed concerns about implementation of POC VL testing in 

 
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public sector clinics. We aim to further investigate barriers and facilitators to POC VL testing, and 
conduct a qualitative assessment of POC adherence testing. 
 
9.3. 
Research Design 
We will conduct a mixed-methods study based on the Theory of Change model (Figure 9). We 
will use a mix of process evaluations, semi-structured interviews and focus group discussions to 
collect information from PLHIV and use process evaluations and semi- structured interviews to 
collect information from health care workers on the implementation of a POC TFV adherence test 
and POC VL test and perspectives on appropriate use. At the clinic, we will collect detailed 
process evaluation information regarding number and timing of per-protocol POC tests requested 
from patients, urine samples provided, tests processed, results made available to providers, and 
results relayed to patients. These data will be collected by study personnel working on-site 
throughout the study duration. The team will scrutinize participant records and medical records 
and confer with providers to ensure accuracy of data. With a subset of study participants (PLHIV 
enrolled in Aim #1 in the intervention arm), we will complete a semi-structured interview after their 
six-month study visit and at/after their final (exit) visit administered by an interviewer who was not 
part of the clinical team. Two to four focus group discussions will also be conducted at these time 
points. For each healthcare worker, we will conduct two private in-depth interviews to explore key 
topics. These interviews will occur once all participants have completed the six-month study visit, 
as well as at the end of the trial, after the final results from the clinical trial are unblinded. 
 
 
 
Study Populations:  We will randomly select and recruit approximately 20 participants enrolled in 
the intervention arm of the main trial. The participants will be randomly selected and stratified by 
sex (1:1 female: male), age (1:1 ≤25 years: >25 years), and VL outcomes (1:1 suppressed: 
detectable) to ensure equal representation. For the healthcare workers, we will aim to enroll  
approximately 5-10 health care workers who provide care for participants in the main trial. 
 
Figure 9.  Theory of Change model, as adopted for the STREAM-HIV study. 

 
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Qualitative Domains and Topics:  We will assess patient perspectives on their experience of POC 
testing with semi-structured interviews and focus group discussions at two time points (Table 3). 
Open-ended items will query their comprehension of the clinic’s routine testing and monitoring 
procedures, their understanding of the POC testing specifically, their experiences with providing 
samples and receiving test results, their perspective of the impact of the testing on their 
encounters with providers - including any related communication around adherence, and what, if 
any, impact the POC testing had on their self-report of adherence to their providers. We will also 
be asking questions about whether POC results motivated increased adherence. The in-depth 
interviews with providers at two time points will cover the domains of understanding of the POC 
testing procedures and protocols, barriers to and facilitators of POC test implementation, 
approach to explaining POC test results and methods for requesting samples, how results were 
typically relayed, impact of results (if any) on timing and content of patient encounters. 
 
Data Collection and Management: All semi-structured interviews and focus group discussions will 
be conducted in participants’ language of choice and will be audio recorded. Each audio recording 
will be transcribed verbatim by a certified transcription service and will be verified by the research 
team to ensure accuracy. Transcripts that are completed in isiZulu will be translated to English 
and back-translated to isiZulu to verify accuracy of each translation. All audio recordings, original 
transcripts, and translated transcripts will be retained by the study team in accordance with the 
applicable record retention requirements. 
 
9.4. 
Outcomes and Analyses 
Data from the process evaluation will be summarized descriptively using counts and ranges. 
Notes from the semi-structured interviews as well as focus group discussion transcripts will be 
translated into English for analysis. The data will be analyzed with content analysis, using 
‘Framework’129 and ‘Interpretive description’.130 Framework analysis involves indexing all verbatim 
text, charting information from each transcript onto a series of thematic matrices. Choice of 
thematic headings will be guided by core concepts emerging out of the data using an open coding 
approach and by theoretical concepts from the design.131 Specific topics will be designated as 
Table 3.  Interview domains for PLHIV & providers. 
Participant domains 
• comprehension of the clinic’s routine testing and monitoring procedures 
• understanding of the POC testing 
• experiences with providing samples and receiving test results 
• perspective of the impact of the testing on their encounters with providers—
including any related communication around adherence 
• impact the POC had on their self-report of adherence to their providers 
Provider domains 
• understanding of the POC procedures and protocols 
• barriers to and facilitators of POC implementation 
• approach to explaining POC and methods for requesting samples 
• how results were typically relayed 

 
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core categories; axial coding and constant comparison will explore the relationships between 
emerging data and contextual situation.130 Particular attention will be paid to documenting how 
latent or interpreted meanings are derived from text considering translation and context issues. 
Preliminary findings will be discussed with the research team, participants, and healthcare 
workers to validate our interpretations and enhance our understanding of the data. 
 
10. SECONDARY COST-EFFECTIVENESS ANALYSIS 
10.1. Introduction and Rationale 
Our objectives are to estimate the costs of POC adherence testing and POC VL testing, and to 
project the budget impact and cost-effectiveness of implementing this intervention in South Africa. 
If our clinical intervention improves clinical outcomes at reasonable costs compared to the 
standard-of-care, then our conceptual model may be an efficient method of delivering HIV care in 
LMICs. 
 
10.2. Preliminary Cost-effectiveness Studies 
We have conducted micro-costing and cost-effectiveness analyses (CEAs) of several HIV 
prevention strategies in Africa, including HIV testing, linkage to ART, and PrEP.133-138 Using cost 
and clinical effectiveness data from our home-based HIV testing and linkage to care trials in 
KwaZulu-Natal,139-142 we developed and parameterized an individual-based, stochastic HIV model 
that incorporates sexual behavior, concurrency, migration, sexually transmitted co-infections, and 
the HIV treatment cascade (including HIV testing and ART initiation/dropout). We utilized the 
model to simulate intervention health and economic outcomes. Incremental cost-effectiveness 
ratios (ICERs) were calculated by comparing the projected intervention impact relative to HIV 
services. Implementing home HIV testing in KwaZulu-Natal was projected to be cost effective by 
WHO standards across all ART initiation thresholds: US$985 per disability adjusted life year 
(DALY) averted with ART initiation at CD4 count of ≤500 cells/µL.136 Our research team has 
completed a preliminary micro-costing exercise as part of the pilot STREAM study and found the 
cost of POC VL testing was lower than 
centralized 
laboratory 
testing 
when 
assuming a clinic volume of at least 50 
patients initiated on ART per month (Table 
4).143,144 
These 
collective 
analyses 
demonstrate our capacity to conduct 
rigorous evaluation of HIV treatment 
interventions, and to utilize mathematical 
models to calculate the economic impact 
for HIV programs. 
 
Table 4. Per patient cost of VL testing in South Africa (US$) 
Test Costs 
POC 
Centralized Lab 
  Public 
Private 
HIV Viral Load 
 
 
 
Clinic Medical 
Consumables 
0.41 
0.48 
0.48 
Lab Consumables 
0.11 
24.72 
33.41 
Cartridge/Test 
18.82 
Lab Staff Costs 
0.33 
Equipment Costs 
0.18 
Clinic Staff costs 
0.44 
1.55 
1.55 
Total Per Test 
20.29 
26.75 
35.44 

 
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10.3. Research Design 
Costing: We will use activity-based micro-costing, staff interviews, and time and motion studies, 
to estimate the costs incurred and averted, along with the primary study outcomes to estimate the 
cost per PLHIV virally suppressed and retained in care in the Intervention and SoC arms. An 
experienced research assistant will conduct time and motion studies to estimate the nurse and 
clinician times necessary to complete the clinic visits for both the SoC and intervention arms, and 
to estimate average number of patients seen in the clinic each day. We will conduct time and 
motion studies during study initiation and again when the intervention is running at full capacity to 
explore the range of costs incurred during start up and at full efficiency. We will assess the time 
required to complete each step of the HIV care visit (adherence testing, VL testing, clinical 
assessment, counseling). Preliminary results will be shared with the teams to implement 
strategies for improved efficiency. Observing multiple visits by various staff members will allow 
estimation of the average time taken for each step; time needed for research activities (e.g. 
administering informed consent) will be removed from intervention time to provide an estimate of 
the intervention, if implemented as a government program. 
 
We will collect intervention costs, as well as treatment costs averted as a result of the intervention. 
We will use standardized cost menus to collect site costs, including start-up costs, human 
resources, supplies, VL test costs, and other expenses. When data are not available from our 
cohort, we will utilize data from population-based South African studies. Additional cost data may 
be obtained from health facilities, published government information on labor costs, and health 
economics literature. Analyses will follow the guidelines for costing HIV interventions,145 and will 
reflect the provider perspective. We will collect data on patient costs incurred in the intervention 
and control arms to explore the societal perspective; to demonstrate whether POC VL testing 
saves patients, and therefore society, time and expense. 
 
Mathematical model: We will adapt a previously validated mathematical model of HIV 
transmission to project long-term intervention outcomes. We will use EMOD-HIV, an open-source 
agent-based network transmission model to project the cost and clinical impact of implementing 
this intervention in South Africa.146,147 We will work closely with Dr. Anna Bershteyn, who led the 
model’s scientific development. EMOD includes geographic patterns of (1) age-specific 
demographics (fertility, mortality, migration); (2) a sexual network that reproduces age/sex specific 
patterns for different sexual relationships (marital, informal, transitory) (3) a detailed, user-
configurable care continuum for HIV treatment interventions, including age, sex, heterogeneity in 
risky sexual behavior, and heterogeneities in access and retention in care (e.g., age and sex 
differences in diagnosis and linkage) (Figure 10).148,149 EMOD includes a detailed within-host 
model of HIV progression and treatment, allowing for modeling of the health and transmission 
benefits associated with ART.150,151 EMOD has been calibrated to predict health outcomes of HIV 
interventions in South Africa. EMOD has been shown to successfully predict HIV incidence found 
in the SEARCH trial and phylogenetic findings of HIV transmission in South Africa prior to 
availability of study results.152,153 The EMOD model is ideally suited to investigating the cost-

 
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effectiveness of POC adherence and resistance testing, because of the flexible framework that 
allows for highly configurable interventions. We will program a novel POC testing intervention by 
adapting the current care cascade to allow for TFV adherence and VL testing. In addition, the 
EMOD model tracks costs associated with the intervention and SoC scenarios and projects HIV 
infections, HIV-related deaths, and DALYs. We will parameterize the model with empiric cost and 
effectiveness data from the proposed clinical trial. 
 
Cost-effectiveness: We will calculate the ICERs as the ratio of the difference in mean costs divided 
by the difference in mean effects across simulations for the intervention compared to the 
standard-of-care over a 10-year time horizon. Consistent with guidelines for economic analyses, 
we will discount costs and health benefits at 3% annually, and consider ICERs that fall below 
South Africa’s per capita GDP to be cost-effective, in line with WHO guidelines for CEAs.145,154 
 
10.4. Outcome Assessment and Reporting 
The micro-costing data, time and motion studies, and clinical outcomes will be used to estimate 
the average cost per HIV-positive patient achieving VL suppression and retained in care in the 
integrated model for HIV monitoring, as compared to the SoC arm. Budget impact analysis will 
assess the overall costs incurred and averted by adding an intervention. The mathematical 
modeling will project clinical outcomes and estimate the cost-effectiveness of the intervention. 
These data are key to informing decision makers considering implementation of HIV adherence 
interventions. 
 
11. PARTICIPANT REIMBURSEMENT  
Study participants will be reimbursed as per CAPRISA Policy on Study Participant Compensation 
guidance, which adhere to the Department of Health and SAPHRA guidelines, and will consider 
Figure 10.  Structure of the EMOD model calibrated for HIV CEAs in South Africa. 

 
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time of visits, inconvenience of study procedures, and transport expenses. The reimbursement 
will be stipulated in the consent form and will be collected after the participant has completed their 
study visit. 
 
12. PROTECTION OF HUMAN SUBJECTS 
12.1. Risks to Human Subjects 
The proposed research project involves an intervention aimed to improve ART adherence among 
HIV-positive individuals. The intervention includes two POC tests that are not currently being 
used in South Africa as standard of care. The GeneXpert® by Cepheid HIV-1 VL test being used 
in this intervention was previously used in the STREAM pilot study and found no study-related 
adverse effects from the intervention. The Abbott POC urine TFV adherence assay has not yet 
been used as part of an intervention but is expected to be nonsignificant risk, as designated by the 
U.S. Food and Drug Administration (FDA). More details on the designation of the device’s risk can 
be found in Section 4.2.  
 
For the purposes of this study, only serious adverse events (SAEs), and adverse events perceived 
to be related to ART adherence testing will be documented. The severity of clinical symptoms will 
be scored using the DAIDS Table (July 2017 2.1 Version; https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables) for Grading the Severity of Adult and 
Pediatric AEs. Reporting on adverse events to the medical officer and relevant Institutional 
Review Boards will comply with relevant regulations. 
 
This study also involves the collection of personal and clinical data, as well as biological 
specimens from human participants. The primary risk to the participants in this study will be from 
the collection of blood samples. Venipuncture and finger-prick have small risks of discomfort, 
persistent bleeding and/or bruising, and introducing an infection. Answering demographic and 
health-related questions have minimal risks to consenting participants. Participants in this setting 
have a high risk of being lost to follow-up with a known life-threatening infection. We will minimize 
this risk by having the research assistant contact the participants with any actionable test results. 
Furthermore, to assess mortality, we will obtain consent from participants to cross match the 
South African ID number with the South African death registry, and to search for the participants’ 
laboratory results in the National Health Laboratory Service TrakCare system. Additional risks 
may be anxiety experienced due to TFV and VL testing and potential breach of participant 
confidentiality. 
 
All participants will be ≥16 years of age, English or isiZulu speaking, and able to provide written, 
signed informed consent. Most of the participants in this study may be considered part of a 
vulnerable population. First, the vast majority of participants will be Zulu, which is one of 12 
nationally recognized ethnic groups and an historically disadvantaged group in South Africa. 
Second, this project will be conducted in a low-income area of KwaZulu-Natal, where most people 

 
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live in dense, government-subsidized housing. All participants will be HIV-positive and may 
experience stigma if confidentiality around their HIV status is not maintained. Focus group 
participants may be at additional risk for a breach of confidentiality and social harm. Participation 
in the focus groups will be completely voluntary, and those who are asked to participate will be 
informed of the potential risks and counseled on these potential risks prior to enrollment in a focus 
group. Maintaining the protection of the data in this vulnerable population will be paramount to 
this project.  
 
12.2. Adequacy of Protection Against Risks 
The study related material will be approved by the University of KwaZulu-Natal Biomedical 
Research Ethics Committee in Durban and University of Washington’s Institutional Review Board 
in Seattle. All consent forms and participant education materials will be available in both English 
and isiZulu. To develop the isiZulu consent form, the English document was translated into 
isiZulu, and then back-translated by a different person. This process of back-translation of the 
isiZulu consent form helped ensure a satisfactory translation. 
 
The Research Assistant/designee will approach adults and/or adolescents waiting for ART 
initiation in the clinics to explain the study and discuss the eligibility criteria. If the individual 
agrees to participate, the research assistant will read and review the consent form in English or 
isiZulu and ask the individual to summarize the study components. If the individual agrees to 
participate, he/she will be asked to sign a copy of the English or isiZulu consent form. Throughout 
this process, ethical norms that are standard to the study setting will be adhered to. 
 
During the course of the study, confidentiality will be preserved, and the data will be maintained 
securely in the research office. The logbook containing the study identification numbers, 
completed consent forms, and completed data forms will remain on the premises and stored in 
locked cabinets. The online data will be stored in iDataFax, a password-protected data 
management service. All computers with access to the data will be password protected. All data 
will be analyzed using the participant’s study identification number and not their identifiable 
information. The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC), 
the University of Washington Institutional Review Board, study monitors, or study sponsors will 
retain the right to review participant records, excluding personal identifiers, to ensure the study 
is following the study protocol and international and local guidelines for human subjects research. 
Other local, U.S., and international regulatory entities may also review participants’ study records. 
 
There will be several mechanisms in place to minimize risk and ensure participant confidentiality 
and safety. First, research assistants will emphasize the voluntary nature of study participation 
and that any participant is free to withdraw from the study at any time and without impact to their 
routine medical care. Second, the study protocol, consent forms, and project materials will be 
reviewed and approved by the University of KwaZulu-Natal Medical Research Ethics Committee 
in Durban and the University of Washington Institutional Review Board in Seattle prior to 

 
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commencing the study or recruiting participants. Both ethics boards have a Federal-Wide 
Assurance number. In addition, the consent forms will be translated to isiZulu and back-translated 
to ensure accuracy. Third, data will be reviewed on a regular basis to make certain that the 
proposed research projects are not causing harm or adverse events. The Institutional Review 
Boards will be notified of any breaches in confidentiality, study protocol violations, or severe 
adverse events attributable to this study within 10 days of the event. Fourth, extensive training 
will be provided to both the research assistants and nurses regarding the study protocol, the 
consent form, the importance of maintaining participant confidentiality and safety. All study 
consent forms will be maintained in secure, locked cabinets at the study sites. Fifth, there will be 
regular communication between the study team and the clinic team in Durban, to ensure that we 
are not disrupting patient flow or treatment. Sixth, any potential breach of confidentiality will be 
minimized by conducting participant interviews in a private space, maintaining study data in a 
locked office, entering data onto a secure website, and ensuring that all research computers are 
password protected. 
 
Several steps will be taken to minimize the clinical risks in the proposed research project. First, 
to minimize risks of discomfort, bleeding, and infection during blood draws, we will always use 
sterile needles and syringes, practicing good technique, and conducting the procedures in a 
designated space. Second, to mitigate the risks of anxiety related to receiving or coping with an 
HIV diagnosis, we have counselors at site, and are able to refer participants to social workers, if 
required. 
 
12.3. Potential Benefits of the Proposed Research 
This study will evaluate two novel POC tests that may improve HIV care for patients and 
healthcare workers in South Africa through real-time knowledge of ART adherence levels and VL. 
Participants in this study may benefit from learning their VL and recent ART adherence levels and 
receiving enhanced adherence counseling when needed during the same clinic visit in which their 
test is conducted. Healthcare workers may also benefit from receiving TFV and VL test results in 
real-time. 
 
More broadly, the knowledge gained from the participants in this study will help inform medical 
practices and public health policies in other resource-limited settings. If the research findings 
support our hypotheses, then the relevant interventions could be a cost-effective method of 
monitoring HIV care and treatment. 
 
12.4. Data Management and Safety Monitoring Plan 
The data collection method that will be used is Electronic Data Capture (EDC) using DFdiscover 
(5.1.0, DF/Net, Seattle, USA). DFdiscover is a validated clinical database management system 
which is FDA CFR Part 11 compliant. Electronic Case Report Form (eCRF) data will reside on 
the DFdiscover server housed at CAPRISA Doris Duke Medical Research Institute and is backed 

 
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up at regular intervals by CAPRISA and securely stored at two locations, one at CAPRISA Doris 
Duke Medical Research Institute and the other at the UKZN Data Centre, Howard College, 
University of KwaZulu-Natal. 
 
The electronic-CRF design will be guided by the study protocol with final approval by the study 
team. All study staff will be allocated user roles, specific to their function in the study. Database 
access will be restricted by passwords and validation levels. The study staff and statistician can 
access the database in “read-only” mode once data has been entered. The CAPRISA data 
management team will have write-access. All external electronic lab data must be password 
protected and will be imported into DFdiscover. 
 
In the event of internet downtime, power outages, or any situation that makes the system 
inaccessible, one-ply paper CRFs will be used to collect the data, which will be scanned through 
to the CAPRISA data centre once the internet is active again. DFdiscover has optical character 
recognition (OCR) which will read the check boxes and numerical fields on the CRFs and store 
them in the study database. Any fields not recognized by the OCR system will be entered 
manually by data encoders. Data encoders will verify all data by cross-checking the scanned 
version to what is captured by OCR.  
 
All queries and/or reasons for data changes will be generated electronically and will form part of 
the weekly QC Report that will be distributed to the appropriate study team members. Study staff 
also have the option of addressing any query at any time. Queries arising during validation of the 
data will be recorded in quality control (QC) reports sent to the sites on a regular basis. Any 
queries from scanned CRFs resulting in a change to the database must be documented on the 
original CRF and rescanned. QC rates will be communicated to the site on a monthly basis. 
Scheduled monthly downloads will be sent to the University of Washington study data manager 
in the SAS format. These downloads will also be made available on request. 
 
Study staff who have access to the data on their computer systems will be trained on how to use 
the system and the importance of system security. Support will always be available from the data 
manager and IT department at CAPRISA, if any issues arise.  
 
All CRFs and source documents are to be securely stored in the participant study file in a secure 
double-locked, fire resistant unit with restricted access in accordance with GCP requirements. 
Upon completion of the study, the close-out site monitoring visit and finalization of the database 
for analysis, any original forms will be bound and kept for long term storage. Study documentation 
and CRFs will not be destroyed without written permission from the sponsor.  
 
Please note that after discussions with the NIH Program Officers, the establishment of a Data 
Safety Monitoring Board (DSMB) was not considered to be necessary for this proposed study; 
however, a Safety Monitoring Committee (SMC) will be established to monitor the study’s 

 
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progress and participants’ safety. The full Safety Monitoring Plan (SMP) is detailed elsewhere 
and will follow the guidelines established by the NIAID Division of AIDS (DAIDS) Safety Monitoring 
Committee Guidelines. NIAID will be responsible for the formation of the SMC, unless otherwise 
specified by the NIAID Program Officer, and the SMP will be approved by NIAID in writing before 
the study may be initiated. 
 
13. TIMELINES 
The proposed timeline for study-related activities and manuscripts can be found below. Of note, 
the actual timeline for research activities may deviate from the proposed timeline. 
 
14. POTENTIAL PROBLEMS AND ALTERNATIVE APPROACHES 
Study feasibility. In the pilot STREAM study, participants were recruited six months after ART 
initiation, and ~20 PLHIV were enrolled per week. In this proposed study, the aim is to enroll an 
average of 10.4 participants per week (10.4 PLHIV x 52 weeks = 540 participants), which may 
seem ambitious. However, from past experience at this high-volume clinic, enrolling and 
managing 2-3 PLHIV/day will be fully achievable with the requested resources. 
 
Recruitment of HIV-infected participants. The CDC Clinic initiates around 2000 PLHIV on ART 
each year. However, if necessary, participants can be recruited from another HIV clinic or from 
CAPRISA’s clinical research site in Vulindlela. 
 
Burden for patients. POC Xpert® VL testing will be expedited upon participant arrival. If 
Proposed Timeline for Research Activities and Manuscripts. 
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Aim 1. Randomized Controlled Trial 
Training & Preparation 
  
 
Cohort Enrollment Period 
 
 
 
Cohort Follow-up Period 
 
 
 
Lab Testing 
 
 
 
 
 
 
Statistical Analyses 
 
 
 
Manuscripts 
 
M1 
M2 
M3 
M4 
Aim 2. Qualitative Research 
 
Data Collection 
 
 
 
 
 
 
Analyses 
 
 
 
 
 
 
 
 
 
 
Manuscripts 
 
M5 
M6 
M7 
Aim 3. Cost-effectiveness Analyses 
 
 
Data Collection 
 
 
 
Statistical Analyses 
 
 
 
Manuscripts 
 
M8 
M9 
M10 

 
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participants are unable to wait two hours for their VL result, their permission will be sought to 
disclose the result over the phone. 
 
Costing may not capture the true costs. Time and motion studies may distinguish research costs 
from programmatic costs, but efficiencies in a research study might differ from that achieved in 
public programs. 
 
Mathematical modelling is subject to uncertainty. A well-calibrated and validated model will be 
utilized, and extensive uncertainty analyses will be performed to identify influential parameters. 
 
15. RESOURCE SHARING PLAN 
For all data generated during the course of this project, the prevailing standards and guidelines 
in documenting and depositing data sets will be followed. 
 
Quality-controlled raw data, as well as processed data used in publications will be made available. 
As described in the grant application, protocols and workflows will be implemented exactly as 
described and documented such that other groups will be able to precisely reproduce results from 
the raw data. 
 
The PIs, as well as other personnel assigned to the study, will disseminate results from this 
research through presentations at public lectures, scientific institutions and meetings, and/or 
publication in major journals. The institutions and PIs will adhere to the NIH Grants Policy on 
Sharing of Unique Research Resources including the Sharing of Biomedical Research 
Resources: Guidelines for Recipients of NIH Grants and Contracts on Obtaining and 
Disseminating Biomedical Research Resources. 
 
Data Sharing Plan 
Intellectual property and data generated under this project will be administered in accordance with 
University of Washington, CAPRISA, and NIH policies, including the NIH Data Sharing Policy and 
Implementation Guidance of March 5, 2003. Materials generated under the project will be 
disseminated in accordance with University of Washington, CAPRISA and NIH policies. 
Depending on such policies, materials may be transferred to others under the terms of a material 
transfer agreement. Access to databases and associated software tools generated under the 
project will be available for educational, research, and non-profit purposes. Such access will be 
provided using web-based applications, as appropriate. Publication of data shall occur during the 
project, if appropriate, or at the end of the project, consistent with normal scientific practices. 
Research data that documents, supports, and validates research findings will be made available 
after the main findings from the final research data set have been accepted for publication. Such 
research data will be modified to prevent the disclosure of personal identifiers to remain in 
compliance with the Protection of Human Subjects guidelines. 

 
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Publications 
We will disseminate the results from this research as broadly as possible. First, we will publish 
our results in Open Access journals, if appropriate. Second, we will post author PDFs of our 
manuscripts on our respective websites in accordance with the copyright rules of the journals. 
Third, we will practice posting our manuscripts on Internet archives (such as arxiv.org) when 
possible. 
 
Presentations 
We expect that the research personnel will attend national conferences periodically and present 
the results from this research to the scientific community. Because of the multidisciplinary nature 
of the work, different group members will present at various conferences, such as the Conference 
on Retrovirus and Opportunistic Infections, International AIDS Society, and South African HIV 
Clinicians conferences, which focus on the appropriate aspects of our research.  
 
16. QUALITY CONTROL AND QUALITY ASSURANCE 
The University of Washington’s International Clinical Research Center and CAPRISA have a long 
track record of conducting quality research. This study will be monitored by the CAPRISA Quality 
Assurance Team, which will include six-monthly reports on study conduct findings. Particular 
attention will be placed on consent forms, adherence to the protocol, completion of source 
documents and CRFs, and appropriate and timely communication with the ethics committee, 
especially in the case of any protocol deviation. In addition, the study team will have weekly 
meetings to monitor study progress. CAPRISA routinely measures QC and retention rates on all 
studies. 
 
17. ETHICAL CONSIDERATIONS 
The study has been approved (IRB# STUDY00007544) by the University of Washington 
Institutional Review Board (FWA00006878). Ethical approval will also be sought from the 
University of KwaZulu-Natal’s Biomedical Research Ethics Committee (BREC). 
 
Collection and analyses of socio-demographic information and biological samples taken for 
clinical purposes will be covered by ethics approval. No investigational products will be utilized in 
this study and hence there is no requirement for regulatory approval from the South African Health 
Products Regulatory Authority. Informed consent will be obtained from potential participants to 
participate in the study and to store blood samples. A waiver for requiring parental consent for 
potential participants under age 18 was approved by the University of Washington Institutional 
Review Board and will be sought from University of KwaZulu-Natal’s Biomedical Research Ethics 
Committee. Thus, potential participants aged 16-17 years will provide independent informed 
consent, and we will not require these participants to re-consent to the study at age 18. These 

 
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biological specimens will be handled by trained staff and labeled with a unique identifier for each 
participant. The results will be transmitted to the clinics in an electronic format but only accessed 
by authorized and trained clinic staff. Only key members of the data team will have access to the 
electronic data, which will be password protected. Once enrolled into the study, participants will 
be able to withdraw at any point. 
 
18. 
PROTOCOL REGISTRATION 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol informed consent form(s) approved, as appropriate, by 
their local institutional review board (IRB)/ethics committee (EC) and any other applicable 
regulatory entity (RE). Upon receiving final approval, sites will submit all required protocol 
registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory 
Support Center (RSC).  The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all of the required documents have been received. 
 
Site-specific informed consent forms (ICFs) WILL NOT be reviewed or approved by the DAIDS 
PRO, and sites will receive an Initial Registration Notification when the DAIDS PRO receives a 
complete registration packet.  Receipt of an Initial Registration Notification indicates successful 
completion of the protocol registration process. Sites will not receive any additional notifications 
from the DAIDS PRO for the initial protocol registration.  A copy of the Initial Registration 
Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites 
should implement the amendment immediately.  Sites are required to submit an amendment 
registration packet to the DAIDS PRO at the RSC.  The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all the required documents have been received. Site-
specific ICF(s) WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a complete registration 
packet. A copy of the Amendment Registration Notification should be retained in the site's 
regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual. 
 
 

 
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Fox MP, Pascoe SJS, Huber AN, et al. Effectiveness of interventions for unstable patients on 

 
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antiretroviral therapy in South Africa: results of a cluster-randomised evaluation. Trop Med Int 
Health 2018; 23(12): 1314-1325. 
157. 
Hermans LE, Tempelman HA, Carmona S, et al. High rates of viral resuppression on first-line 
ART after initial virological failure. CROI 2018 [abstract 1118]. 
 

 
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20. APPENDIX I: 2019 SOUTH AFRICA HIV VIRAL LOAD MONITORING GUIDELINES 
 

 
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21. APPENDIX II: SCHEDULE OF EVALUATIONS  
 
2
3
4
5
6
7
8
9
10
11
12
13
Screening 
Enrollment
W4
W8
W12
W16
W20
W24
W32
W40
W48
W56
W64
W72
W3-6
W7-10
W11-14
W15-18
W19-22
W22-28
W30-34 W38-42 W46-50 W54-58 W62-66
W68-84
Informed consent
x
Locator information
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Socio-demographics questionnaire
x
x
Eligibility assessment 
x
Baseline HIV and ART assessment
x
Medical history 
x
WHO Staging 
x
TB symptom screen
x
x
x
x
x
x
x
x
x
x
x
x
x
Substance use questions
x
x
x
WHO Intimate partner violence tool$
x
x
x
Mental health assessment tool (PHQ-9)
x
x
x
IPT assessment
x
ART adherence and counselling
x
x
x
x
x
x
x
x
x
x
x
x
x
ART side effect assessment
x
x
x
x
x
x
x
x
x
x
x
x
CCMDD assessment
x
x
x
x
Semi-structured interview~
x
x
Focus group discussion~
x
x
Vital signs assessment
x
x
x
x
x
x
x
x
x
x
x
x
x
Comprehensive physical exam
x
x
Symptom directed physical exam
x
x
x
x
x
x
x
x
x
x
x
Haemoglobin
EDTA (4mls) 
x
Creatinine 
SST (5mls)
x
x
x
x
CD4 count# 
EDTA (4mls) 
x
x
Hep B surface antigen
SST (5mls) 
x
Pregnancy Test$
Urine
x
Cervical smear$
Cytobrush/smear
x
Laboratory Viral load (SOC arm)
EDTA (4mls)
x
x
POC Viral load (intervention arm)
EDTA (4mls) 
x
x
Tenofovir Adherence Test (Intervention arm)
Urine
x
x
x
x
x
x*
x*
HIV Incidence Test (Sedia)%
Whole blood
x
Genexpert HPV testing$
Vaginal swab
x
ART resistance testing (intervention arm)
EDTA (4mls) 
x^
x^
VL and resistance testing* &
x
x
x
Plasma HIV incidence test (plasma)
x
Tenofovir diphosphate levels (dry blood spots)
EDTA (4mls) 
x
x
x
x
Short-term tenofovir adherence testing
Urine
x
x
x
x
Longterm tenofovir adherence testing
Hair
x
x
Total blood volume (mls)
28
9
27
21
14
Key: 
$ female participants only
# can be POC in intervention arm
* only if viraemic >200 copies/ml
% test not used for clinical management, and not provided to participant
^ only if viraemic >200 copies/ml and detectable tenofovir levels
~ only for subset of participants
& VL will be retrospectively tested on stored specimens for primary outcome measure for all participants
EDTA (10mls)
STREAM HIV Schedule of Evaluations (Version 2.3 14 September 2020) 
Storage
Department of Health Routine Testing
Study specific Testing
Clinical 
Visit
Evaluations
Target Visit Window
Sample
1
0