A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa
Phase: NA
Conditions: HIV, Hypertension, Alcohol Drinking, Maternal Child Health, Cost Effectiveness
Sponsor: University of California, San Francisco

 
A Multisectoral Strategy to Address Persistent Drivers of the 
HIV Epidemic in East Africa (SAPPHIRE) 
 
 
Sustainable East Africa Research in Community Health (SEARCH) 
Consortium 
 
Clinical Trial Phase:  IV 
 
Protocol Number: DAIDS-ES ID 38971 
 
Funded By:  National Institutes of Health 
 
 
Protocol Chair:  Diane Havlir, MD 
 
Protocol Co-Chairs:   Moses Kamya, MBChB, MPH, PhD 
 
Maya Petersen, MD, PhD 
 
Protocol Vice-Chair: Gabriel Chamie, MD, MPH 
 
Version Number: 7.0 
 
Version Date: 26-July-2023 
 
National Clinical Trial (NCT) Identified Number:  NCT04810650 
 

A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
Version 7.0 
Protocol number: DAIDS-ES ID 38971 
 
26-Jul-2023 
 
 
 
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Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Section 
7.3.2 
Updates to individual level inclusion criteria. 
To clarify minor changes to inclusion 
criteria. 
Section 
9.3.2 
Updated Intervention Procedures and 
Target Popluation table. 
Updates made to reflect incorporation of 
previously separated intervention into 
LEAP intervention. 
Appendix, 
section H 
Updates to CAB-LA extension timeframe  
and analyses. 
Minor updates to extend the timeline for 
participants in the CAB-LA extension arm 
in the event CAB-LA is not available in 
country, and to clarify the definition of 
covered time for participants on CAB-LA. 
Multiple 
sections 
Other minor clarifications and edits 
throughout protocol. 
To clarify and correct minor points. 
 
 

A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
Version 7.0 
Protocol number: DAIDS-ES ID 38971 
 
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TABLE OF CONTENTS 
 
1. KEY INVESTIGATOR ROLES ..................................................................................................... 6 
2. LIST OF ABBREVIATIONS ....................................................................................................... 10 
3. PROTOCOL SUMMARY ........................................................................................................... 12 
4. INTRODUCTION ....................................................................................................................... 15 
4.1. Background......................................................................................................................... 15 
4.2. Study Hypothesis for Primary Objective .............................................................................. 19 
5. OBJECTIVES ............................................................................................................................ 20 
5.1. Primary Objective................................................................................................................ 20 
5.2. Secondary Objectives ......................................................................................................... 20 
6. STUDY DESIGN ....................................................................................................................... 21 
7. STUDY POPULATION .............................................................................................................. 22 
7.1 Phase A ............................................................................................................................... 22 
7.1.1. Phase A Community Level Inclusion Criteria ................................................................ 22 
7.1.2. Phase A Community Level Exclusion Criteria ............................................................... 22 
7.2 Phase B ............................................................................................................................... 22 
7.2.1. Phase B Community Level Inclusion Criteria ................................................................ 22 
7.2.2. Phase B Community Level Exclusion Criteria ............................................................... 22 
7.3. Individual Level Inclusion Criteria for Component Interventions .......................................... 22 
7.3.1. Phase A Inclusion Criteria ............................................................................................ 22 
7.3.2. Phase B Individual Level Inclusion Criteria – Patient-Centered Delivery ....................... 24 
7.4. Recruitment Process ........................................................................................................... 25 
7.4.1. Phase A ........................................................................................................................ 25 
7.4.2. Phase B ........................................................................................................................ 25 
8. INTERVENTIONS ..................................................................................................................... 27 
9. STUDY PROCEDURES/EVALUATIONS .................................................................................. 29 
9.1. Randomization .................................................................................................................... 29 
9.1.1. Phase A Randomization ............................................................................................... 29 
9.1.2. Phase B Community Randomization ............................................................................ 29 
9.2. Phase A Dynamic Prevention and Dynamic Treatment Procedures .................................... 30 
9.2.1. Dynamic Prevention at Outpatient Clinics, Antenatal/Family Planning Clinics, 
Households, and Youth Multi-Sector Interventions ................................................................. 30 
9.2.2. Dynamic Treatment for Mobile Populations, Alcohol Users and Hypertension .............. 36 
9.2.3. Phase A Optimization ................................................................................................... 41 
9.3. Phase B Intervention ........................................................................................................... 41 
9.3.1 Community-Enhanced Reach ........................................................................................ 42 

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9.3.2 Person-Centered Delivery ............................................................................................. 45 
9.3.3 Overview: Data Enhanced Community Precision Health ............................................... 46 
9.4. Phase A Measurements ...................................................................................................... 47 
9.4.1. Dynamic Prevention ..................................................................................................... 47 
9.4.2. Dynamic Treatment ...................................................................................................... 48 
    9.4.3. Additional controls ........................................................................................................ 49 
9.5. Phase B Measurements ...................................................................................................... 50 
9.5.1 Phase B endpoint measures and evaluation .................................................................. 50 
9.5.2. RE-AIM Implementation Evaluation .............................................................................. 53 
9.6. Behavioral Measures .......................................................................................................... 56 
9.6.1. Procedures ................................................................................................................... 56 
9.7. Costing Evaluations ............................................................................................................ 58 
9.7.1. Overview ...................................................................................................................... 58 
9.7.2. Costing team procedures.............................................................................................. 58 
9.8. Mathematical Modeling ....................................................................................................... 59 
9.8.1. Procedures ................................................................................................................... 60 
9.9. Participant Discontinuation .................................................................................................. 60 
10. ASSESSMENT OF SAFETY ................................................................................................... 61 
10.1. Safety Assessment Overview............................................................................................ 61 
10.2. Adverse Event Procedures and Reporting Requirements ................................................. 61 
11. DATA HANDLING AND RECORDKEEPING ........................................................................... 62 
11.1. Data Management Responsibilities ................................................................................... 62 
11.2. Essential/Source Documents and Access to Source Data/Documents .............................. 62 
11.3. Quality Control and Quality Assurance .............................................................................. 62 
12. CLINICAL SITE MONITORING ............................................................................................... 63 
13. ADMINISTRATIVE PROCEDURES ........................................................................................ 63 
13.1. Regulatory Oversight ........................................................................................................ 63 
13.2. Study Implementation ....................................................................................................... 63 
13.3. ClinicalTrials.gov ............................................................................................................... 64 
14. HUMAN SUBJECTS PROTECTIONS ..................................................................................... 65 
14.1. Institutional Review Board/Ethics Committee .................................................................... 65 
14.2. Vulnerable Participants ..................................................................................................... 65 
14.2.1. Pregnant Women and Fetuses ................................................................................... 65 
14.2.2. Children ...................................................................................................................... 65 
14.2.3. Illiterate Participants ................................................................................................... 65 
14.3. Informed Consent ............................................................................................................. 66 
14.3.1. Informed Consent Process ......................................................................................... 66 
14.3.2. Assent Process .......................................................................................................... 70 

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14.3.3. Documentation of Informed Consent .......................................................................... 70 
14.3.4. Waiver of Informed Consent ....................................................................................... 70 
14.3.5. Stored Samples and Associated Data Considerations ................................................ 71 
14.4. Risks ................................................................................................................................. 71 
14.5. Social Impact Events ........................................................................................................ 71 
14.6. Benefits ............................................................................................................................. 72 
14.7. Compensation ................................................................................................................... 72 
14.8. Participant Privacy and Confidentiality .............................................................................. 72 
14.9. Study Discontinuation ....................................................................................................... 73 
14.10. Community Advisory Board and Other Relevant Stakeholders ........................................ 73 
15. STATISTICAL ANALYSIS ....................................................................................................... 74 
15.1 Overview ............................................................................................................................ 74 
15.2 Individually randomized trials in Phase A ........................................................................... 74 
15.2.1 Power calculations for individual-level trials ................................................................. 75 
15.3 Cluster randomized trials for Phase A ................................................................................ 77 
15.3.1 Power calculations for the cluster-level trial ................................................................. 78 
15.4 Additional analyses to optimize dynamic prevention and treatment .................................... 78 
15.5 Community randomized trial in Phase B ............................................................................ 79 
15.5.1 Power calculations for Phase B ................................................................................... 80 
15.6 Additional explanatory and descriptive analyses for Phase B ............................................. 80 
16. PUBLICATION POLICY .......................................................................................................... 81 
17. REFERENCES ........................................................................................................................ 82 
18. APPENDIX Extension of Dynamic Prevention Studies and Procedures for measuring 
implementation on Cabotegravir Injectable Suspension (CAB-LA) ................................................ 93 
 
 
 

A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
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1. KEY INVESTIGATOR ROLES 
Diane Havlir, MD 
Chair, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 ext. 424 
Email:  diane.havlir@ucsf.edu 
 
Moses R. Kamya, MBChB, MMed, PhD  
Co-Chair, Makerere University 
Address: Department of Medicine, P.O. Box 7072, Kampala, Uganda   
Phone Number: +256-414-533200 
Email: mkamya@infocom.co.ug 
 
Maya L. Petersen, MD, PhD 
Co-Chair, University of California, Berkeley 
Address: School of Public Health, 5402 Berkeley Way West, Berkeley, CA 94720-7358, U.S.A. 
Phone Number:  +1-510-642-0563 
Email: mayaliv@berkeley.edu 
 
Gabriel Chamie, MD, MPH 
Vice-Chair, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 ext. 445 
Email:  gabriel.chamie@ucsf.edu 
 
Laura Balzer, PhD 
Investigator and Protocol Statistician, University of California, Berkeley 
Address: School of Public Health, 5317 Berkeley Way West, Berkeley, CA 94720-7358, U.S.A. 
Phone Number:  +1-203-558-3804 
Email: laura.balzer@berkeley.edu 
 
Andrew Phillips, MSc, PhD 
Investigator, Modeling, University College London, London 
Address: Institute for Global Health, Glower Street, WC1 6BT, U.K. 
Phone Number:  +20-7830-2886 
Email: andrew.phillips@ucl.ac.uk  
 
Florence Mwangwa, MBChB, MPH 
Investigator, Adult and Adolescents Studies, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Phone Number: +256-779-386616 
Email:  fmwangwa@idrc-uganda.org  
 
Jane Kabami, PhDc, MPH 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 7475, Kampala, Uganda 
Phone Number: +256-706-315810 
Email: jkabami@idrc-uganda.org  
 
Elijah Kakande, MBChB 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 

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Phone Number: +256-779-386616 
Email:  rkakande@idrc-uganda.org   
 
Asiphas Owaraganise, MBChB 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Email:  asiphas@gmail.com 
 
Elizabeth Bukusi, MBChB, M.Med, MPH, PhD 
Investigator, Youth and Integration of HIV and Reproductive Health Services, Kenya Medical 
Research Institute 
Address:  Box 54840, Nairobi, Kenya 
Phone Number: +254-733-617503 
Email:  ebukusi@rctp.or.ke 
 
James Ayieko, MBChB, MPH, PhD 
Investigator, Adult and Adolescent Studies, Kenya Medical Research Institute 
Address: P.O. Box 517-20107, Njoro, Kenya 
Phone Number: +254-720-925262 
Email: jimayieko@gmail.com  
 
Norton Sang, MA 
Investigator, Kenya Medical Research Institute 
Address: P.O. Box 35-4132, Mega City, Kisumu, Kenya 
Phone Number: +254-715-778930 
Email: nortonsang@gmail.com  
 
Marilyn Nyabuti, MBChB 
Investigator, Kenya Medical Research Institute and the University of Washington, Seattle 
Address: P.O. Box 35-4132, Mega City, Kisumu, Kenya 
Phone Number: +254-715-778930 
Email: mnyanduko@gmail.com  
 
Judith Hahn, PhD, MA 
Investigator, Alcohol Use Studies, University of California, San Francisco 
Address:  UCSF Box 1224, San Francisco, CA 94158 
Phone:  +1-415-476-5815 
Email:  judy.hahn@ucsf.edu  
 
Carol Camlin, PhD, MPH 
Investigator, Social Sciences/Qualitative Studies, University of California, San Francisco 
Address:  Center for AIDS Prevention Studies, San Francisco, CA 94143, U.S.A. 
Phone Number:  +1-415-597-4998 
Email:  carol.camlin@ucsf.edu 
 
Matthew Hickey, MD 
Investigator, Hypertension Studies, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-628-206-8494 
Email:  matt.hickey@ucsf.edu 
 
 

A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
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Starley Shade, PhD 
Investigator, Cost Effectiveness, University of California, San Francisco 
Address:  Box 0886, San Francisco, CA 94143-0886, U.S.A. 
Phone Number:  +1-415-476-6362 
Email:  starley.shade@ucsf.edu 
 
Harsha Thirumurthy, PhD 
Investigator, Behavioral Economics Studies, University of Pennsylvania 
Address:  Department of Medical Ethics and Health Policy, Philadelphia, PA 19104 
Phone Number:  +1-215-746-0410 
Email:  hthirumu@upenn.edu 
 
Edwin Charlebois, PhD, MPH 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A 
Phone Number:  +1-415-476-6241 
Email:  edwin.charlebois@ucsf.edu 
 
Priscilla Hsue, MD 
Investigator, Cardiovascular Studies, University of California, San Francisco 
Address:  UCSF Box 0846, San Francisco, CA 94110 
Phone:  +1+415-206-8257 
Email:  Priscilla.hsue@ucsf.edu  
 
Theodore Ruel, MD 
Investigator, HIV Adolescent and Young Adult Studies, University of California, San Francisco 
Address:  UCSF Box 0434, San Francisco, CA 94143-0136, U.S.A. 
Phone Number:  +1-415-476-9197 
Email:  theodore.ruel@ucsf.edu 
 
Craig Cohen, MD, MPH 
Investigator, University of California, San Francisco 
Address:  Reproductive Sciences, Box 1224., San Francisco, CA 94158 - youth and integration 
of HIV and reproductive health services 
Phone Number:  +1-415-476-5874 
Email:  craig.cohen@ucsf.edu  
 
Eric Goosby, MD 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-5483 
Email:  eric.goosby@ucsf.edu  
 
Catherine Koss, MD 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 
Email: catherine.koss@ucsf.edu   
     
Urvi M Parikh, PhD 
Virologist, University of Pittsburgh, Pittsburgh 
     Address: S830 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261 

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     Phone Number: 412-648-3103 
     Email: ump3@pitt.edu 
 
Melanie Bacon, RN, MPH 
Investigator, National Institute of Allergy and Infectious Diseases, NIH 
Address: 5601 Fishers Lane 9G74, Bethesda, MD 20892, U.S.A. 
Phone Number: +1-240-627-3215 
Email:  mbacon@niaid.nih.gov  

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2. LIST OF ABBREVIATIONS  
 
AIDS: Acquired immunodeficiency syndrome 
ART: Antiretroviral therapy 
CAB-LA: Long-acting cabotegravir 
CE: Cost-effectiveness 
CHR: Committee on Human Research 
CHV: Community health volunteer 
CRF: Case report form 
CVD: Cardiovascular disease 
DALYs: Disability-adjusted life years 
DM: Diabetes mellitus 
DSMB: Date Safety Monitoring Board 
ELA: Empowerment and Livelihood for Adolescents 
FTE: Full-time equivalent 
FGD: Focus group discussion 
GPS: Global positioning system 
HIV: Human immunodeficiency virus 
HSV: Herpes simplex virus 
HTN: Hypertension 
IDI: In-depth interview 
IPV: Intimate partner violence 
IRB: Institutional Review Board 
KEMRI: Kenya Medical Research Institute 
MoH: Ministry of Health 
MTCT: Mother-to-child HIV Transmission 
NASCOP: National AIDS and STI Control Programme 
PEP: Post-exposure prophylaxis 
PEth: Phosphatidylethanol 
PRECEDE: Predisposing, Reinforcing, and Enabling Constructs in Educational Diagnosis and 
Evaluation 
PrEP: Pre-exposure prophylaxis 
SAP: Statistical analysis plan 
RE-AIM: Reach, Effectiveness, Adoption, Implementation and Maintenance 
SEARCH: Sustainable East Africa Research in Community Health 
SOMREC: Makerere University School of Medicine - Research and Ethics Committee 
SOPs: Standard Operating Procedures 
SSA: Sub-Saharan Africa 
STI: Sexually-transmitted infections 
TB: Tuberculosis 
TDF/FTC: Tenofovir disoproxil fumarate/Emtricitabine 
TMLE: Targeted maximum likelihood estimation 
TFV: Tenofovir analyte 
UCSF: University of California, San Francisco  
UNCST: Uganda National Council for Science and Technology 
VMMC: Voluntary medical male circumcision 
VHT: Village health team. This term (Uganda) used in protocol refers to equivalent CHV 
(community health volunteer)  

A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
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A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
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Protocol number: DAIDS-ES ID 38971 
 
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3. PROTOCOL SUMMARY  
Title: A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa 
(SAPPHIRE) 
Sample Size: 
Phase A Pilot Randomized Studies:  3,200 participants (2,200 HIV-negative participants, 650 
HIV-positive participants, 450 hypertensive participants  
Phase B Community Cluster Randomized trial: 16 communities of ~10,000 persons each 
Participating Sites for Phase B:  16 communities in rural western Kenya and rural western 
Uganda, that are geopolitical units (i.e. parish in Uganda, or sub-location in Kenya) of ~10,000 
persons each (5,000 ≥15 years) within the catchment area of government health clinics and are of 
sufficient distance from each other to avoid contamination. 
Overall Objective: Our overall objective is to determine to reduce HIV incidence and to improve 
community health with multi-sector, scalable interventions. 
Primary Objective: Reduce HIV incidence using innovative strategies for HIV prevention and 
treatment to simultaneously reach “persistent driver” populations. 
Secondary Objectives: 
1. Evaluate and optimize individual intervention component effects, alone (Phase A) and in 
combination (Phase B), versus control conditions on biomedical prevention coverage and 
HIV viral suppression 
2. Assess the effect of the intervention package on other health outcomes (mortality, 
tuberculosis, hypertension control, heavy alcohol use and mother-to-child HIV 
transmission, and pediatric immunization coverage) in Phase B 
3. Evaluate behavioral and other mechanistic pathways for intervention effects on proximal 
mediators of HIV incidence in Phase B 
4. Assess the reach, effectiveness, patient and provider adoption, fidelity and maintenance of 
intervention components in Phase B 
5. Use final study data to inform a strategic and sustainable investment model that maximally 
reduces HIV incidence and improves community health for the combination interventions 
tested in Phase B 
Study Design: This study will consist of 2 phases: 
• 
Phase A, in which randomized trials and pilot studies will assess effectiveness, fidelity and 
cost and improve context-specific “fit” of prevention and treatment interventions. Combining 
effectiveness with implementation and costing, Phase A will optimize intervention packages 
with context specific adaptations in structured consultation with stakeholders. 
• 
Phase B, which will evaluate the effects of these optimized dynamic prevention and 
treatment packages, on prevention coverage, population-level suppression, and HIV 
incidence, as well as other health outcomes, in a community randomized trial design. 
Interventions in Phase A:  
● Dynamic Prevention: We are evaluating ways to optimize dynamic prevention delivery with 
the following interventions: Provision of Dynamic Prevention intervention at 1) outpatient 
health centers, 2) antenatal/family planning clinics, 3) youth multisector events and 4) via 
village health workers interacting at households. 

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● Dynamic Treatment: We are evaluating services to improve HIV and hypertension care in 
difficult to reach populations: mobile population services; alcohol use intervention for heavy 
alcohol users, and hypertension interventions. 
 Study Schema   
  
 
Study Endpoints:   
Phase A: The primary endpoints in Phase A are: Prevention coverage (uptake and persistence of 
PrEP or PEP) and viral suppression (HIV RNA <400 c/mL).  For hypertension intervention, the 
primary endpoints are  linkage to care and hypertension control.  
Phase B: The primary and secondary endpoints in Phase B are: 
• 
HIV incidence  
• 
Prevention coverage (uptake and persistence of PrEP and PEP) 
• 
Viral suppression (HIV RNA <400 c/mL) 
• 
Mortality 
• 
Tuberculosis (annual incidence rate) 
• 
Hypertension control (<140/90 mmHg) 
• 
Heavy alcohol use  
• 
Mother-to-child HIV transmission (infant HIV free survival at) 
• 
Pediatric immunization coverage 
 
Sample Size and Power, Phase A 
 
Dynamic Prevention: Assuming a standard deviation in covered time of 35% (based on 
SEARCH), a two-sided hypothesis test (α=0.05), and conservatively ignoring precision gains from 
stratified randomization and covariate adjustment, a trial with 200 evaluable persons per arm will 
have 80% power to detect an approximately 10% absolute effect size (corresponding, for example, 
to an increase in covered time from 30% to 40%). For primary endpoint measurement for the trials 
at clinics, we will thus enroll up to 300 participants per arm meeting PrEP/PEP eligibility criteria 
(1,200 total).  We also enroll up to 300 participants per arm from 16 areas serviced by village 

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health workers (total N=600 HIV-negative persons).  For the youth intervention single arm pilots, 
we will enroll up to 100 persons/pilot-site to examine feasibility in primary analyses and prevention 
coverage in secondary analyses.  
 
Dynamic Treatment: Assuming approximately 40% suppression (or 50% linkage in the 
hypertension trial) in the control arm and a two-sided hypothesis test (α=0.05), a trial of 100 
persons per arm will be powered at 80% to detect a 20% increase in suppression (or linkage in the 
hypertension trial).  For the alcohol intervention trial, we will enroll up to 200 participants living with 
HIV per arm, for the mobility intervention trial we will enroll 125 participants living with HIV per arm, 
and for the hypertension linkage intervention we will enroll 125 participants per arm. For the 
hypertension treatment trial, we will enroll up to 200 participants (100/arm) based on assuming 
40% control in the non-intervention group for 80% power to detect an 20% or greater increase in 
control.    
 
Sample Size and Power, Phase B:  
With 16 communities (8/arm) each with ~5000 adults, 10% HIV prevalence, and 90% testing 
coverage, we anticipate being powered at 80% to detect a 40% relative reduction in annual HIV 
incidence (primary endpoint) from 0.5% in the standard-of-care (control) with a two-sided 
hypothesis test (α=0.05) and a design effect of 1.3. These power calculations were conducted with 
the inctools R package and under recency assay assumptions informed by recent validation 
studies: mean duration of recent infection (MDRI)=238 and false recent rate (FRR)=0%.1-3 
 
 
 

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4. INTRODUCTION 
4.1. Background 
HIV incidence in Sub-Saharan Africa (SSA) remains well above global elimination targets.4 
Despite an increasingly large, evidence-based toolkit to prevent HIV transmission, there were over 
1 million new HIV infections in SSA in 2018.4 We know from SEARCH5 and three other recent SSA 
population-level studies6-8 that reaching (and exceeding) the UNAIDS 2020 population-level viral 
suppression target of 73%9 is insufficient to achieve epidemic control (Table 1). We also know that 
key sub-populations, in particular youth,7, 10-13 men,5, 7, 13-15 mobile populations,16-18 and persons 
with heavy alcohol use19, 20 continue to fall short of viral suppression targets, putting them at higher 
risk for HIV complications, mortality, and onward HIV transmission. Finally, pre-exposure 
prophylaxis (PrEP), an intervention that has reduced incidence in affected populations in some 
areas where high rates of viral suppression were already present,21, 22 has not been effectively 
deployed in high risk populations (such as young women) in SSA.23, 24 To achieve control of the 
HIV epidemic and mitigate its consequences, we need new and scalable interventions to improve 
delivery of prevention and treatment to vital segments of the population that contribute to 
persistence of new infections.  We describe below why previous approaches that were effective 
for the majority of people in the ART roll-out do not work for subsets of these “persistent-driver” 
populations, our proposed solutions, and how a multi-component intervention trial can effectively 
inform stakeholders on programming and resource allocation to accelerate reductions in HIV 
incidence. 
Barriers to effective HIV prevention and treatment outcomes among key, persistent-driver 
populations fall into three major themes based on epidemiologic and qualitative data from 
SEARCH on seroconversions (N=704), PrEP utilization (3,489 starts25), viral suppression sub-
group analyses (N=13,5295, 13, 19), and other published literature. First, the majority of new 
infections are in youth, and in this growing, at-risk population, social and economic concerns often 
far outweigh health concerns on a day-to-day basis (individual barriers).26-29 There has been 
insufficient recognition that at any given moment in time, health is not a preeminent concern, 
particularly for youth. Indeed, poverty itself may increase “present bias” – the tendency  for short 
term considerations to outweigh long term ones – contributing to decision-making that harms 
health.30-33 Second and third, lack of flexibility in how prevention and treatment services, 
respectively, have been offered to people whose needs and behavior vary from mainstream 
community members (e.g. mobile populations, drinkers) and may be continually changing (systems 
barriers) have impeded uptake and impact of these services.34-38 
Modelling and phylogenetic studies suggest that further progress will require simultaneous 
and coordinated approaches in HIV treatment and prevention among persistent driver 
populations. Individual, “narrow” focused interventions (PrEP) for adolescent girls are important, 
but alone will not reach HIV elimination levels. Persistent driver populations are minority subsets of 
demographic populations of considerable size (e.g. while men are at elevated risk of non-
suppression, most HIV-infected men are suppressed); some of the barriers they face (e.g. inflexible 
health systems) are shared across the demographic groups and can be integrated into a 
personalized public health approach that combines i) foundational changes in health care delivery 
systems that are scalable and affordable (e.g., re-structuring treatment visits for youth to prioritize 
non-health concerns) with ii) the option to access more intensive services for the targeted group of 
persons for whom basic one-size-fits all approaches are insufficient (e.g. intensified alcohol 
counseling for heavy drinkers and “travel packs” for mobile populations). Assumptions that 
strategies to reach these populations will be prohibitively expensive or too complex for programs to 
implement are unsubstantiated, and stakeholders need well-designed studies incorporating 
multiple interventions for persistent driver populations, and integrating intensification based on 
choice, to understand what works and inform resource allocation as they move beyond the “90-90- 
90” era towards HIV elimination.     

A Multisectoral Strategy to Address Persistent Drivers of the HIV Epidemic in East Africa (SAPPHIRE) 
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Trial 
BCPP/Ya Tsie8 
HPTN 071 (PopART)7 
SEARCH5 
ANRS 12249 
(TasP)6 
Country 
Botswana 
South Africa/Zambia 
Kenya/Uganda 
South Africa 
Prevalence 
29% 
22% 
4-19% 
30% 
Arm 
C 
I 
C 
I 
Arm A 
I 
Arm B 
C 
I 
C 
I 
Universal 
testing 
— 
✓ 
— 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Home, 
mobile 
 
Home + 
field 
(men, 
youth) 
Home + 
field 
(men, 
youth) 
Multi-dz 
Fairs/ 
Home 
Multi-dz 
Fairs/ 
Home 
Home 
Home 
Testing 
frequency 
 
Baselin
e; 
ongoing 
targeted 
 
Ongoing 
Annual 
Ongoing 
~Annual 
Baseline 
Annual 
6 monthly 
6 
monthly 
Enhanced 
linkage 
 
 
✓ 
 
✓ 
✓ 
 
✓ 
 
✓ 
Rapid ART 
Start 
 
✓ 
 
 
 
 
✓ 
 
 
 
(from 
2016) 
 
 
 
 
 
 
 
Universal 
Treatment 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
(from 
2016) 
(from 
2016) 
(from 
2016) 
 
(from 
2016) 
(from 
2016) 
 
 
 
Differentiated 
ART Delivery 
 
 
 
✓ 
✓ 
 
✓‡ 
 
 
 
 
 
(Zambia†
) 
(Zambia†
) 
 
 
 
 
Population 
viral 
Suppression  
 
 
 
 
 
 
 
 
 
- at start 
75% 
70% 
54% 
57% 
56% 
42% 
42% 
26% 
24% 
- at end 
83% 
88% 
60% 
68% 
75% 
68% 
79% 
45% 
46% 
- difference 
+8 
+18 
+6 
+11% 
+16% 
+26 
+37 
+19 
+23 
HIV Incidence 
 
 
 
 
 
 
 
 
 
Annual 
Incidence for 
100 person-
years 
 
0.92 
0.59 
1.55 
 1.06            1.45 
0.27 
0.25 
2.27 
2.11 
Reduction 
(I vs C) 
31% reduction 
20% reduction 
not significant,  
but 32% reduction 
in intervention arm 
not significant 
Table 1. Comparison of population-level, Universal Test and Treat (UTT) Trials in Sub-Saharan Africa. 

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between years 1 & 
3 
 
To address these barriers for persistent driver populations to increase prevention coverage 
for HIV- persons and viral suppression for HIV-infected persons, we used the empirically-
validated PRECEDE model39 where health decision-making and health-seeking behaviors can be 
influenced via interventions that predispose, enable, and reinforce desired engagement with 
prevention and treatment services (see Section 8, below for comprehensive description of our 
PRECEDE intervention framework).   
Dynamic HIV prevention: Our 3 Dynamic 
Prevention components address 
barriers we identified in offering PrEP 
to >10,000 persons with risk factors 
for HIV acquisition in the region 
(Table 2). First, we will engage youth 
in HIV prevention and reproductive 
health services by generating 
demand for these services within 
existing life skills and vocational 
programs (BRAC youth development 
clubs in Uganda and micro-finance clubs in Kenya) via integration of key health and socio-
economic services. For youth, embedding HIV services within a broader, multi-sector strategy for 
individual and community empowerment via economic and social advancement can lead to better 
decision-making and also increase demand for and engagement with HIV services. Similar 
approaches have been used in diverse settings and may overcome present bias and other barriers 
faced by youth living in poverty by generating demand for services while improving future 
expectations and decision-making via increased opportunity.40-47 Despite a strong evidence base 
that these interventions can impact self-reported behaviors, and in some cases unintended 
pregnancies and STIs, and recent encouraging evidence from the DREAMS program (HIV 
incidence reduction in non-randomized longitudinal analyses48), there is little rigorous evidence that 
these interventions can reduce HIV incidence (as noted in a systematic review of income 
generation interventions for HIV prevention40) or impact biomedical prevention (e.g. PrEP, PEP, 
condom use) uptake or adherence from randomized studies.   
HIV prevention services that offer choice of delivery options (PrEP & PEP) and flexibility in 
their use and location of delivery over time allow for a dynamic, 
patient-centered model of prevention. This approach is responsive 
to the reality of an individual’s changing 
needs, thereby facilitating continued 
engagement. In SEARCH, PrEP use declined 
over time in spite of initial enthusiasm and uptake 
by early adopters.49 In multiple settings, poor 
adherence to PrEP remains its Achilles’ heel.50, 51 
Rather than presenting PrEP in a similar 
framework to ART (i.e. lifelong use with 100% 
adherence for efficacy with delivery at HIV clinic), 
approaches that incorporate flexibility in choice 
and delivery location, akin to contraception options 
for women in developed countries, may prove 
more successful. Indeed, over the past four decades, increased choice in contraception and 
flexibility in access have been directly associated with increased use.52, 53 Framing prevention in 
Figure 1. Adding the choice of PEP and flexible 
transitions to/from PEP/PrEP to increase long term 
prevention engagement & coverage. 
Table 2. Dynamic HIV Prevention: Problems and Solutions  
Figure 1 

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the context of healthy choices, rather than an assessment of risk, may also reduce the association 
of PrEP with “risky” behavior or promiscuity. Offering PEP – an event-driven option that does not 
require accurate prediction of risk before a potential HIV exposure (akin to a “morning after” pill), 
and which additionally provides protection for those with less sexual agency – is a critical 
innovation in flexible access to prevention services. PEP can also act as a “gateway” to PrEP and 
other prevention modalities (Figure 1), providing infrastructure to add new prevention options as 
they become available (e.g. the PrEP vaginal ring54, 55).   
Dynamic HIV Treatment: offering choice and flexibility in HIV clinical care and ART access 
that is tailored to the needs of key populations – including youth, men, mobile, and heavy alcohol-
using populations – may result in 
increased care engagement and 
viral suppression rates among 
these populations, compared to 
differentiated care models as 
currently conceptualized. We have 
identified key barriers and 
facilitators for engagement in 
treatment for each of these 
groups, obtained via quantitative 
surveys and focus group 
discussions among persons who 
have not engaged, dropped out of 
care or not achieved viral suppression in SEARCH and via existing literature (Table 4).36, 56-62 
Treatment outcomes are most likely to be effective when these barriers are overcome. For 
example in youth, using the PRECEDE framework we have piloted our proposed intervention that 
combines (i) a “life stage” assessment framework that addresses the many dynamic changes in 
relationships, school and employment present in youth (PREDISPOSING) (ii) flexible clinic access 
(ENABLING) and (iii) rapid viral load feedback (REINFORCING). Details on treatment interventions 
for other key driver populations are in the protocol (see Section 8, below).   
Community Precision Health uses data systems and analytics to extend the reach of the health 
care facility into the community more effectively and more efficiently. Currently, CHVs/VHTs collect 
a rich quantity of data using paper records. Under the current system, however, i) entry of 
CHV/VHT-collected data into facility-based data systems places substantial burden on CHVs/VHTs 
to travel to the facility for reporting; ii) data capture may be incomplete and occur after substantial 
time delay, undermining its utility to guide outreach activities; and, iii) no direct data flow exists from 
health facilities back to VHTs/CHWs, limiting their ability to provide defaulter and linkage support to 
persons in need.  Community Precision Health addresses these barriers by providing CHVs/VHTs 
and workers at outreach activities with a mobile device-based app to facilitate data capture and 
electronic reporting. This Community Precision Health system, which includes two-way data flow 
between existing country Electronic Medical Record (EMR) systems and the app, is designed to 
improve the ability of CHVs/VHTs to support the care cascade by providing enhanced and timely 
notification of persons failing to link to care or defaulting. The data system further generates a 
dynamic population-based database of community health outcomes, enabling the use of analytics 
(such as machine-learning based risk segmentation) to identify persons and local regions at higher 
risk of poor health outcomes (eg, risk of HIV infection, lack of viral suppression, or uncontrolled 
HTN) and thus providing the basis for tailoring of enhanced outreach, screening, and service 
referrals. 
 
The HIV epidemic will unnecessarily claim and continue to adversely affect millions of lives 
unless we deploy innovative strategies that extend the gains beyond those of universal 
testing and ART. Universal ART must be followed by dynamic prevention and treatment 
Table 3. Dynamic HIV Treatment: Barriers and Solutions  

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paradigms that allow for heterogeneity in patient need and preference, as well as changing 
preferences over time – while targeting interventions to those at greatest risk of incident and 
uncontrolled HIV. Furthermore, HIV cannot be addressed in a vacuum and must be coupled 
with health services that are seen by community members as a priority - including evaluation 
and treatment for diseases such as hypertension,63-65 diabetes,66 and heavy alcohol use67, 
delivered in an environment that harnesses human capital among youth (the largest segment of 
the population in SSA68). In our proposal, we postulate that within this broader framework, we can 
successfully reduce HIV incidence, population viral load and mortality, while improving community 
health outcomes. We will rigorously evaluate these effects and their costs using a 2-stage 
optimization and factorial cluster randomized design.  
 
4.2. Study Hypothesis for Primary Objective  
Each of the Phase A studies will test a hypothesis related to the intervention: 
• 
Dynamic Choice Prevention delivered to women seen at antenatal clinics (ANC) will 
improve biomedical covered time, defined as the proportion of follow-up time that a 
participant is protected from HIV with either PrEP or PEP. 
• 
Dynamic Choice Prevention delivered to men and women seen at the outpatient 
department (OPD) will improve biomedical covered time, defined as above. 
• 
Dynamic Choice Prevention delivered to men and women seen in the community by village 
health teams (VHTs) will improve biomedical covered time, defined as above. 
• 
Dynamic Choice Treatment delivered to mobile persons with HIV will improve HIV viral 
suppression at 48 weeks. 
• 
The Healthy Living Intervention delivered to persons with HIV and heavy alcohol use will 
improve HIV viral suppression at 24 weeks.     
• 
A one-time transport voucher will increase linkage to hypertension care following 
community-based diagnosis. 
• 
Community-based hypertension care will improve hypertension control among persons with 
severe hypertension.  
 
The study hypothesis for the Phase B population level study is: A Precision Community Health 
Model leveraging existing facility-based outreach and community health workers, enabled by 
dynamic choice prevention/treatment multi-disease approaches and interactive data systems –will 
reduce HIV infections, deaths and improve health.  
 
 
 

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5. OBJECTIVES 
5.1. Primary Objective 
To reduce HIV incidence using innovative strategies for HIV prevention and treatment to 
simultaneously reach “persistent driver” populations. 
5.2. Secondary Objectives 
1. Evaluate and optimize individual intervention component effects, alone (Phase A) and in 
combination (Phase B), versus control conditions on biomedical prevention coverage and 
HIV viral suppression. 
2. Assess the effect of the intervention package on other health outcomes (mortality, 
tuberculosis, hypertension control, heavy alcohol use, mother-to-child HIV transmission and 
pediatric immunization coverage) in Phase B. 
3. Evaluate behavioral and other mechanistic pathways for intervention effects on proximal 
mediators of HIV incidence in Phase B. 
4. Assess the reach, effectiveness, patient and provider adoption, fidelity and maintenance of 
intervention components in Phase B. 
5. Use final study data to inform a strategic and sustainable investment model that maximally 
reduces HIV incidence and improves community health for the combination interventions 
tested in Phase B. 
 
 

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6. STUDY DESIGN 
In the “optimization” Phase A, the study will conduct randomized trials and pilot studies to assess 
effectiveness, fidelity and cost and improve context-specific “fit” of prevention and treatment 
interventions. Combining effectiveness with implementation, costing and modelling outcomes, the 
study will optimize intervention packages with context-specific adaptations in structured 
consultation with stakeholders. In the “evaluation” Phase B, the study will evaluate the effects of 
Dynamic Prevention and Dynamic Treatment intervention packages based on data from Phase A 
and new advances from outside the study, alone and in combination, on HIV incidence, biomedical 
prevention coverage and other health outcomes, in a pair-matched community randomized design. 
Study Schema  
 
 
We will evaluate population-level intervention implementation outcomes guided by the RE-AIM 
framework,69 elucidate mechanisms of action and component intervention effects using mixed 
methods and multi-level mediation analyses, and estimate incremental costs and gains using 
micro-costing and time-and-motion studies. Finally, the study will use the HIV Synthesis Model to 
model outcomes and costs of Phase B results over a period of decades to inform policy and 
stakeholder decisions to adopt successful strategies to achieve and sustain HIV epidemic control.    
Structured stakeholder consultations are formally incorporated in the study design and leverage 
regular and ongoing collaborations the study team has with the HIV, non-communicable disease 
and general health leads in Kenya and Uganda Ministries of Health and PEPFAR implementing 
partners at the national and the regional level. 
 
 

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7. STUDY POPULATION  
7.1 Phase A 
The study will take place in rural Kenya and Uganda in 12 geographically dispersed communities.   
 
7.1.1. Phase A Community Level Inclusion Criteria 
1. Non-adjacent geopolitical units in western Uganda and western Kenya. 
  
2. Most recent census population between 9,000 and 11,000 individuals. 
 
3. Served by an ART/PrEP/PEP providing health center with antenatal and family planning 
services.  
 
4. Community leader commitment for study participation and implementation.  
 
7.1.2. Phase A Community Level Exclusion Criteria 
1. Presence of ongoing community-based interventions that provide HIV prevention or 
treatment outside of the current in-country treatment guidelines. 
  
2. An urban setting defined as a city with a population of 100,000 or more inhabitants.  
 
3. Absence of a health center able to provide ART, PrEP and PEP. 
 
7.2 Phase B 
The study will take place in rural Kenya and Uganda in 16 geographically dispersed communities 
different from Phase A of ~10,000 persons each (5,000 persons ≥15 years). 
 
7.2.1. Phase B Community Level Inclusion Criteria 
1. Non-adjacent geopolitical units in western Uganda and western Kenya. 
  
2. Most recent census population between 9,000 and 11,000 individuals. 
 
3. Served by an ART/PrEP/PEP providing health center with antenatal and family planning 
services.  
 
4. Community leader commitment for study participation and implementation. 
 
7.2.2. Phase B Community Level Exclusion Criteria 
1. Presence of ongoing community-based interventions that provide HIV prevention or 
treatment outside of the current in-country treatment guidelines. 
 
2. An urban setting defined as a city with a population of 100,000 or more inhabitants. 
 
3. Absence of a health center able to provide ART, PrEP and PEP. 
 
4. Community that took part in Phase A. 
 
 
7.3. Individual Level Inclusion Criteria for Component Interventions 
7.3.1. Phase A Inclusion Criteria 

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Study Population 
Inclusion Criteria 
Exclusion Criteria 
Dynamic 
Prevention 
Outpatient and antenatal/FP clinics 
1. Age ≥15 years 
2. HIV-negative 
3. Current or anticipated sexual activity with 
partner(s) with known HIV-infection or 
unknown HIV status 
 
VHT households  
1. Age >15 years 
2. HIV-negative 
3. Current or anticipated sexual activity with 
partner(s) with known HIV-infection or 
unknown HIV status 
 
 
Youth multi-sector interventions  
1. Age ≥15 to ≤25 years 
2. HIV-negative 
3. Current or anticipated sexual activity with 
partner(s) with known HIV-infection or 
unknown HIV status 
4. At least one of the following risk factors: 
School drop-out, prior pregnancy, 
transactional sex, orphanhood, work in 
sector associated with higher HIV risk 
(e.g. boda boda driver), drink alcohol or 
STI history 
Outpatient and antenatal/FP clinics 
1. <15 years of age 
2. Unable to provide consent or parental 
co-consent as per country guidelines 
3. Participation in another Phase A RCT 
intervention component 
 
VHT households  
1 
 <15 years of age 
2 
Unable to provide consent or parental 
co-consent as per country guidelines 
3 
Participation in another Phase A RCT 
intervention component 
 
 
Youth multi-sector interventions   
1. <15 or >25 years of age 
2. Unable to provide consent or parental 
co-consent as per country guidelines 
3. Participation in another Phase A RCT 
intervention component 
 
Dynamic 
Treatment 
  
Mobile Travel Pack intervention 
1. Age ≥15 years 
2. HIV-positive 
3. HIV RNA non-suppression (>400 c/mL in 
the prior 12 months) or missed 2 visits in 
past 12 months or no VL measured in 
past 12 months 
4. Travel outside the community ≥2 times in 
past 12 months 
5. Enrolled or new to care in a study clinic 
 
Alcohol intervention 
1. Age ≥18 years 
2. HIV-positive 
3. HIV RNA non-suppression (>400 c/mL in 
the prior 12 months) or missed clinic visits 
(>2 weeks or <=90 days from last 
scheduled clinic visit) within past 6 
months, or out of care without return to 
care (>90 days from last scheduled clinic 
visit) within past 6 months 
4. Heavy alcohol use per AUDIT-C tool 
(scores of ≥4 for men, and ≥3 for women) 
5. Enrolled or new to care in a study clinic 
 
Hypertension Linkage and Treatment  
Interventions 
Mobile Travel Pack intervention 
1. <15 years of age 
2. Participation in another Phase A RCT 
intervention component 
 
 
 
 
 
 
 
Alcohol intervention 
1. <18 years of age 
2. Participation in another Phase A RCT 
intervention component 
3. No access to mobile phone 
 
 
 
 
 
 
 
 
 
Hypertension Linkage and Treatment 
Interventions 

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1. Age ≥25 years (linkage); age >40 years 
(treatment)  
2. Blood pressure ≥140/90 mmHg on three 
repeated measurements during 
community-based hypertension screening 
for linkage study and ≥160/100 mmHg for 
the treatment study   
3. Resident (by self-report) within catchment 
area of referral health center 
1. <25 years (linkage); age <40 years 
(treatment) 
2. Plan to out-migrate from the catchment 
area of referral health center within 30 
days of screening visit 
3. Already engaged in hypertensive care 
(by self-report) (linkage only) 
4. Blood pressure measure of ≥180/110 
mmHg during screening and symptoms of 
hypertensive emergency (linkage only) 
5. Pregnant (treatment) 
6. Co-morbidities that preclude home 
monitoring (treatment)  
 
7.3.2. Phase B Individual Level Inclusion Criteria – Patient-Centered Delivery   
Study Population 
Inclusion Criteria 
Exclusion Criteria 
Dynamic 
Prevention 
Antenatal clinics, outpatient clinics and other 
community locations (such as bars and youth 
events) 
1. Age ≥15 years 
2. HIV-negative 
3. Current or anticipated risk of HIV-infection  
Antenatal clinics, outpatient clinics and 
other community locations (such as bars 
and youth events) 
1. <15 years of age 
2. Unable to provide consent or parental 
co-consent as per country guidelines 
 
Other Patient-
Centered Delivery  
Interventions 
(Dynamic 
Treatment) 
  
Life Events Assessment and Plan (LEAP) 
Intervention 
1. HIV-positive 
2. One or more of the following: 
• 
Age ≥15 to ≤24 years 
• 
Pregnant 
• 
Breast-feeding 
• 
HIV RNA non-suppression (≥400 
c/mL in the prior 12 months, no HIV 
RNA in the last year, or diagnosed 
with HIV in last 4 weeks) at initiation 
or time of treatment failure 
 
Youth defaulters re-engagement by 
VHT/CHVs 
1. Age ≥15 to ≤24 years 
2. Missed ≥ 2 ART treatment or HIV 
prevention visits 
 
Severe Hypertension Treatment/Telehealth 
Intervention 
1. Age >40 years 
2. Blood pressure ≥160/100 mmHg 
3. Resident (by self-report) within catchment 
area of referral health center 
 
 
 
 
 
 
Life Events Assessment and Plan (LEAP) 
Intervention 
1. Unable to provide consent as per 
country guidelines 
 
 
 
 
 
 
 
 
 
Youth defaulters re-engagement by 
VHT/CHVs 
1. <15 or >24 years of age 
2. Unable to provide consent as per 
country guidelines 
 
Severe Hypertension 
Treatment/Telehealth Intervention 
1. Age <40 years 
2. Pregnancy 
3. Plan to out-migrate from the 
catchment area of referral health 
center within 30 days of 
screening visit 
4. Current hypertensive emergency 
(BP >180/110 mmHg AND signs 
or symptoms of hypertension 
emergency). Note: participants 
are eligible once they receive 

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VHT/CHV Child TB Prevention Intervention 
1. Age ≤5 years/ 
2. At least one member of participant’s 
household diagnosed with TB 
 
emergency treatment and are 
clinically stable. 
5. Co-morbidities that preclude 
home monitoring 
6. Unable to provide consent as per 
country guidelines 
 
VHT/CHV Child TB Prevention 
Intervention 
1. Age >5 years 
 
 
 
7.4. Recruitment Process 
7.4.1. Phase A 
Dynamic Prevention 
Outpatient, Antenatal/Family Planning Clinics, Households, and Youth Multi-Sector Interventions:  
The study will enroll persons currently active in, or willing to receive care or take part, in 1) 
outpatient clinics, 2) antenatal/family planning clinics, 3) community households (VHT study) and 4) 
Youth multi-sector interventions. The youth multisector interventions are tailored to respond to 
COVID pandemic restrictions. Study leadership will meet with clinic, VHTs, and  community leaders 
to explain the study purpose and goals.  In collaboration, study staff will approach consecutive 
potential participants for participation in the study. 
Dynamic Treatment 
Heavy alcohol drinkers, mobile populations and those with untreated or severe hypertension:  The 
study will offer Dynamic Treatment intervention components to 2 different populations with 
unsuppressed viral loads and/or missed visits:  1) mobile populations (travel outside community at 
least twice in past 12 months), 2) heavy alcohol users (AUDIT-C screening tool scores of ≥4 for 
men, and ≥3 for women70, 71). For the alcohol trial, staff will recruit from the clinic, and use bar-
based mobilization, in which staff will reach out to persons attending bars in study communities 
and offer referral for multi-disease (e.g., hypertension, diabetes and HIV) screening at each 
community clinic, with additional screening for trial eligibility among adults identified with HIV. The 
study will also examine one intervention to promote linkage to hypertension care among persons 
(age ≥25), regardless of HIV status, who have elevated blood pressure (≥140/90 mmHg) identified 
during community-based hypertension screening and a second study to evaluate an intensive 
community-based hypertension treatment intervention vs standard clinic monitoring for those with 
severe hypertension (≥160/100)  Study leadership will meet with clinic directors in the communities 
to explain the study purpose and goals.  In collaboration with study clinic leadership, study staff will 
approach consecutive potential participants for participation in the study. 
7.4.2. Phase B  
Dynamic Prevention   
HIV, Outpatient, Antenatal Health Clinics.  The study will offer Dynamic Prevention to persons 
currently enrolled, or willing to enroll, in study community settings including HIV/PrEP clinics, family 
planning clinics, antenatal clinics and youth clinics. Participants will be referred to these programs 
from Community Mobilization activities described in Section 9.3.1, and persons who self-present to 

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community clinics for HIV prevention services (i.e. testing, VMMC, PrEP, PEP, condom use) or STI 
screening.  The study will further expand uptake by including referrals from mobile outreach 
events, social network contacts of newly diagnosed PLHIV, PrEP and PEP users, and at youth 
multi-sector locations. Baseline and ongoing community sensitization for PrEP/PEP availability will 
be conducted.   
Dynamic Treatment 
Youth, Mobile Populations, Heavy Alcohol Users and Severe HTN :. A multi-faceted approach will 
be used to recruit participants. HIV-positive youth may be referred from youth multi-sector 
activities, community mobilization activities, or through recruitment at the study clinic.  HIV-positive 
persons  may be referred from community mobilization activities and social network contacts of 
persons already in care, as well as directly from the clinic. HIV-positive men and women over 18 
years of age enrolled in care in the study clinics will be screened for alcohol use via the AUDIT-C 
screening tool.70, 71  Persons with severe HTN will be referred from clinic, mobilization community 
events  and from VHT routine HTN screening.  
 
 

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8. INTERVENTIONS 
Prior to the implementation of intervention activities in Phase A and Phase B, the study will utilize 
stakeholder consultation to advise on community selection and intervention design, and, during the 
optimization period of Phase A, determination of which interventions piloted in the initial clinics will 
be implemented and expanded in Phase B. 
 
The study’s intervention components follow the PRECEDE model, based on social, cognitive and 
network theory that predispose, enable, and reinforce desired engagement with prevention and 
treatment services via their effect on health decision-making and health-seeking behaviors.39  A 
description of each intervention component as it relates to the PRECEDE framework is provided in 
Table 4. 
 
Table 4.  PRECEDE Framework for Intervention Components 
Intervention 
Component 
PRECEDE Framework Description 
 Published & Unpublished Evidence supporting/  
 informing intervention components in PRECEDE 
 Framework 
Dynamic 
Prevention 
  
  
  
Dynamic Prevention in Youth Multi-
Sector Interventions  
·       Youth Mobilization (Predisposing) 
·       Empowerment via Vocational & Life 
Skills Training (Uganda) & Micro-
finance (Kenya) (Enabling) 
·       Integrated HIV, Reproductive Health 
and Alcohol Use Education 
(Predisposing) 
·       On-site HIV testing & expedited 
ART/PrEP/PEP referral (Enabling) 
·       Social environment with local mentor 
(Reinforcing) 
·       Income-generating activities 
(Reinforcing) 
Dynamic Prevention at Youth Multi-Sector 
Interventions 
·       SEARCH with prior success with population-
wide adolescent & young adult mobilization72 
·       Ongoing pilot study of Youth Hubs for young 
women and men with integrated HIV and 
reproductive health services (SEARCH/BRAC). 
·       Prior evidence that vocational/life-skills 
training,44, 73 micro-finance74, 75 and social 
support43, 76 can have positive impacts on 
sexual risk behavior and decreased teen 
pregnancy, early marriage and non-consensual 
sex in youth 
·       Feasibility of Youth Hub testing & mobile 
testing77 with referral to ART, PrEP and PEP in 
SEARCH 
Dynamic Prevention at Clinics 
·        Community Mobilization 
(Predisposing) 
·        Flexible access to PrEP/PEP with 
mobile phone access line (Enabling) 
·        Structured Assessment of barriers to 
PrEP/PEP start and adherence, with 
personalized plans developed in 
response (Enabling) 
·        Dynamic transitions to/from PEP & 
PrEP (Reinforcing) 
·        Psychologic support for traumatic 
experiences (Enabling) 
·        Social Network Outreach 
(Predisposing) with multi-disease  
      screening and transport refund  
      vouchers (Enabling) 
Dynamic Prevention at Clinics 
·      Prior experience with community mobilization for 
population-level offer of PrEP25 
·     Distance from clinic a barrier to PrEP in 
SEARCH78 and community delivery associated 
with increased PrEP retention79 
·       SEARCH with prior experience assessing 
individual level barriers to PrEP during 
population-wide offer of PrEP,80-82 with potential 
for actionable, personalized plans 
·     In a survey of 48 PrEP recipients in SEARCH, 
80% felt that adding PEP would enhance 
prevention “coverage.” 
·     Choice in & flexible access to contraception has 
been associated with increased use;52, 53 and 
our SEARCH PEP pilot demonstrated high 
uptake and adherence to PEP and feasibility 
referral to PrEP 
·       SEARCH has pilot tested feasibility of Social  

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      Network Outreach with multi-disease health   
      checks among key populations, using HIV- and  
      HIV+ index cases: 87% (133/155) of social  
      contacts redeemed vouchers, including new  
      HIV+ patients who started same-day ART; all  
      HIV- contacts referred to PrEP 
Dynamic 
Treatment 
  
  
   Community Mobilization (Predisposing) 
Community Mobilization: Demonstrated impact of 
SEARCH universal testing and treatment 
intervention on social mobilization of PLHIV as 
advocates for other PLHIV83, 84 
Tailored Differentiated Care 
(Enabling/Reinforcing) for:  
 
Men: Integration of sexual health, multi-
disease chronic care, provider 
training on U=U messaging, flexible 
hours, welcoming environment and 
social events 
 
Mobile Populations: Queries about travel 
plans at each visit, assist with in-
/out-transfers, mobile phone access 
to clinics and mobile minutes for 
unexpected travel, non-standard refill 
schedules and out-of-facility refills, 
mobile population seasonal 
outreach;  
 
Heavy Drinkers: Alcohol screening 
(Predisposing); two in-person 
counseling sessions at times of 
regular clinic visits (Enabling); 
monthly booster phone calls 
between in-person sessions 
(Reinforcing) 
 
Tailored Differentiated Care 
 
Men: SEARCH has experience integrating sexual 
health into HIV testing fairs to generate 
demand (>30,000 fair visits) and integrating 
HIV and multi-disease chronic care.5 Strong 
evidence base identifying barriers to men’s 
engagement in HIV clinic.61, 85-88 Evidence of 
low knowledge re: U=U.89 Prior evaluation of 
facilitators to retaining men in care (with high 
retention).62  
 
Mobile Pops: SEARCH has experience eliciting 
heterogenous forms of mobility from PLHIV,90 
identifying barriers faced by mobile 
populations,61 and identifying new residents 
during peak periods of mobility.77 Mobile PLHIV 
identified mobile phone access to providers and 
“travel packs” for ART to cope with 
unanticipated travel. 
 
Heavy Drinkers: Multi-session brief alcohol 
interventions can significantly reduce alcohol 
consumption91 and increase viral suppression 
in PLHIV.92 Co-I Hahn (R01 AA0240990) 
conducted extensive research to adapt an 
efficacious brief alcohol intervention,93 similar to 
one associated with decreased alcohol use in 
India,94, 95 to the East African context. 
 
 
 

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9. STUDY PROCEDURES/EVALUATIONS  
9.1. Randomization 
9.1.1. Phase A Randomization 
We will randomize individuals to the active prevention or treatment intervention or to standard-of-
care as shown below.  
 
Table 5:  Randomizations in Phase A 
 
Participants will take part in only one of the eight interventions. After screening for eligibility for one 
of the above intervention components, participants will be randomized at the time of enrollment via 
computer-generated random assignment for all of the randomized trials except for the dynamic 
prevention household trial. For this  trial, we will randomize 16 villages (with their accompanying 
household reach of ~ 600 at risk persons) to intervention or control (cluster randomization). The 
youth multi-sector interventions will be non-randomized, single-arm pilots. 
 
The communities which will take part in the Phase A will be located in rural western Uganda and 
western Kenya.  These are primarily farming and fishing  communities and are geographically 
dispersed.   
 
9.1.2. Phase B Community Randomization 
The study will randomize the 16 communities (8 Ugandan and 8 Kenyan) as detailed in the Study 
Schema. Randomization will be stratified by country. The communities selected for randomization 
will not include health facilities that took part in Phase A activities. 
 
We will utilize an established randomization strategy that is both scientifically valid and transparent 
to the community stakeholders and uses local idioms to make the concept of randomization easily 
understood by traditional leaders and community members,96 as conducted in the SEARCH trial.5 
Community randomization will be conceptualized as an ongoing part of the community 
preparedness process in partnership with the community leaders and community individuals.  
 
Intervention 
Total number of 
participants  
Dynamic Prevention –Individual randomization  at 
outpatient health center 
600 
Dynamic Prevention – Individual randomization at 
antenatal clinic 
600 
Dynamic Prevention –Community cluster randomization of 
VHTs  
16 communities up to 
600 persons 
Dynamic Prevention- No randomization, single arm pilot of 
youth multi-sector intervention 
Up to 400  
Dynamic Treatment – Individual randomization Mobile 
Travel Pack 
200 
Dynamic Treatment – Individual randomization Alcohol 
Intervention 
400 
Hypertension Linkage- Individual randomization linkage to 
care 
200 
Hypertension Treatment – Individual randomizations- clinic 
vs community/home monitoring  
200 
Total 
3200 

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For the random assignment of each community, we will employ a public lottery to achieve 
maximum public acceptance of the randomization results by enhancing transparency and 
spreading ownership of the process. For each country separately, the randomization allocation will 
be written on separate pieces of paper or card and folded in half to obscure the label from view. 
The number of cards for each level will correspond with the randomization probabilities. These 
cards will then be placed in a sealed box with a hand hole cut out of the top of the box. For each 
country separately, a computer will randomly designate ordering of community sites. Then the 
lottery will be conducted as a series of draws according to the computer-generated ordering. The 
leader with the last draw will be responsible for holding and shaking the selection box. After the 
drawing is complete, the host country leader will announce the interventions corresponding to each 
allocation. The lottery will be a public event with members of the Community Advisory Board and 
local leadership present along with guests from other community-based organizations and the 
general public to witness the lottery conducted by local chiefs or leaders. This process assures 
equal chance of being randomized to each level of the intervention and eliminates any residual 
fears of bias or rigging. 
 
 
9.2. Phase A Dynamic Prevention and Dynamic Treatment Procedures 
9.2.1. Dynamic Prevention at Outpatient Clinics, Antenatal/Family Planning Clinics, 
Households, and Youth Multi-Sector Interventions  
The Dynamic Prevention intervention will include integrated PrEP and PEP services at outpatient 
clinics, antenatal/family planning clinics, youth multi-sector interventions and via VHT workers in 
community households. The procedures for each trial will include counseling on and services of 
PrEP/PEP, choice of service location (e.g. clinic, household, community, phone), HIV testing 
options (including rapid or self-test provision), option for longer (e.g. 3 month) supply of PrEP, 
provision of a clinical officer’s or nurse’s mobile telephone number for immediate PEP starts any 
day of the week, routine assessment of barriers to initiation or adherence to PrEP/PEP, including 
the offer of personalized potential solutions such as choice of in-clinic or offsite service delivery, 
psychologic supports for traumatic experiences, and offer of concurrent, additional health or 
prevention related services. These services will be integrated into Uganda and Kenya Ministry of 
Health (MoH) guidelines driven services for PrEP/PEP, augmenting local standard care procedures 
for the prevention of HIV. If additional prevention modalities, such as long-acting cabotegravir 
(CAB-LA) or the dapivirine vaginal ring, become available, they will be incorporated into the 
Dynamic Prevention intervention. In both arms, participants will have access to standard 
prevention offerings and will have study visits every 24 weeks for up to 3 years for HIV testing and 
outcomes measurement (including PrEP/PEP adherence assessment via small hair sample). For 
convenience, standard PrEP/PEP procedures are described in Section 9.2.1.5.  Table 6 describes 
the Dynamic Prevention intervention components.  
 
Table 6. Dynamic Prevention Intervention Components 
Component 
Description 
Approach 
PrEP/PEP counseling and 
services 
PrEP and PEP services 
delivered by clinical officer, 
nurse, VHT, with ability to cycle 
between PrEP and PEP as 
needed. The option of a longer 
supply of PrEP (e.g. 3 months) 
will be offered. 
Participants will enroll in the 
prevention program, which 
includes standard VMMC, STI 
screening, and reproductive 
health linkage. Participants can 
use any of the PrEP, PEP and 
HIV testing-only options and 
switch options as needed. 

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Choice of service location 
Services for PrEP/PEP/HIV 
testing will be delivered at clinic, 
home, or community site, with 
option for phone/virtual visits 
Participants will have a choice of 
service location for prevention 
visits 
HIV testing options 
Rapid HIV tests will be provided 
as standard of care; HIV self-
testing will be offered as an 
alternative 
Rapid HIV testing will be the 
primary testing modality used. 
Participants will have the option 
of using HIV self-tests kits (with 
instructions from provider) as an 
alternative testing modality 
during follow-up. 
Mobile phone access 
Provision of clinician mobile 
phone number for immediate 
PEP initiation 
Participants will be able to call 
clinical officer or nurse trackers 
7 days a week, including 
holidays, for immediate initiation 
of PEP after potential HIV 
exposure.  They may also have 
access to clinicians in case of 
questions, side effects or other 
concerns. 
Assessment of PrEP/PEP 
barriers and personalized 
actions 
Assessment of barriers to 
initiation or adherence to 
PrEP/PEP at each visit with 
personalized solutions offered 
After identification of barrier to 
initiation of PrEP/PEP, or to 
adherence among those already 
enrolled in PrEP/PEP, clinicians 
will be trained to offer 
personalized solutions, including 
but not limited to flexibility of 
service delivery location (clinic 
or an offsite location of 
participants’ choosing) and the 
integration of additional services 
into PrEP/PEP services such as 
reproductive health 
interventions. Clinicians will also 
have access to a data 
dashboard to monitor follow-up 
visits for HIV testing, PrEP/PEP 
provision. 
Psychologic support for 
traumatic experiences 
Clinical officer/nurse/counselor-
provided support for traumatic 
experiences, in consultation with 
regional psychologist, among 
PrEP/PEP participants 
Participants reporting traumatic 
experiences (e.g. non-
consensual sex or IPV) will be 
able to receive additional 
counseling provided by clinical 
officers, nurses or counselors by 
phone or at health centers. 
Clinic staff will provide such 
counseling in consultation with 
regional study psychologist. 
 
 
9.2.1.1. Clinician Training 
Prior to recruitment and enrollment of participants, staff offering PrEP/PEP in the Dynamic 
Prevention intervention locations will receive training that will include, but will not be limited to, the 
following components: 

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• 
Counseling for PrEP and PEP, including assessment of appropriateness of the prevention 
method and delivery of service with respect and without judgement. 
• 
Counseling clients on performing HIV self-testing 
• 
Successful identification of current or anticipated barriers to PrEP/PEP initiation to new 
participants, or adherence among participants currently receiving PrEP or PEP, and the 
development of personalized plans to address these barriers.  Solutions to commonly 
encountered barriers will be reviewed, and test cases and/or role-playing exercises may be 
employed to reinforce means by which positive plans and solutions can be employed. 
• 
Possible side effects of commonly prescribed PrEP and PEP medications, tailored to 
regimens recommended by country MoH guidelines, will be reviewed with staff, along with 
counseling and support mechanisms to encourage adherence as appropriate. 
• 
Counseling to provide psychologic support and additional community resources for 
participants reporting traumatic experiences. 
 
9.2.1.2. Youth Multi-Sector Interventions   
The youth multi-sector interventions will consist of single arm pilot studies (N=400 total) that aim to 
engage youth in HIV prevention in the context of existing community organizations offering life, 
financial and income generating skills. All youth will be offered dynamic prevention as outlined in 
the protocol in the context of settings either heavily attended by or that are youth focused.  The 
settings in which the single pilots will be conducted may include existing microfinance clubs, boda-
boda (i.e. motorcycle taxi) community welfare groups, and at small business kiosks (e.g. partnered 
with Community Volunteer Initiative for Development). These groups have continued during the 
COVID pandemic, are community-based, are attended by youth, and are models that could be 
generalized to interventions in Phase B.   
9.2.1.3. Informed Consent and Enrollment 
Prior to consent, participants will be screened to determine eligibility in the intervention.  A waiver 
of consent will be obtained to confirm eligibility during the screening process. Written informed 
consent to participate in the study will be obtained from all participants.  Consent forms will be 
translated from the original English to the language(s) spoken in the community.  The consent form 
will be read to participants in their local language.  Participants who agree to take part and sign the 
consent form will be enrolled in the study. Participants aged 15-17 years old who meet the 
definition of ‘mature or emancipated minors’ as set by the Uganda National Council for Science 
and Technology and the Kenya MOH can participate in these studies and will be consented on the 
adult participant consent forms.  
 
9.2.1.4. Dynamic Prevention Procedures  
After consent is obtained, the following procedures will be performed among participants 
randomized to the intervention arm of the clinic-based and VHT trials or enrolled in the youth pilot 
study: 
• 
Study clinicians will assess the participant’s current HIV prevention methods, if any, and 
discuss with the participant his or her HIV prevention options and the services provided by 
the Dynamic Choice intervention 
• 
PrEP/PEP counseling and services: 
i. 
Participants who have been referred or self-referred to the clinic for PEP, or those 
who indicate an HIV exposure in the past 72 hours, will be assessed immediately 

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for eligibility and appropriateness of initiation. Their ability to obtain PEP will be 
assessed, and  eligible persons will be started the same day. 
ii. 
Participants who do not report a recent exposure to HIV but are considered at high 
risk and not on PrEP will be introduced to the PrEP prevention method, with a 
discussion of its benefits and whether it meets the needs of the participant.  If the 
participant is interested and eligible, he or she will be initiated on PrEP according 
to standard care guidelines. 
iii. 
Participants who are already on PrEP or PEP will be introduced to the integrated 
clinic services of Dynamic Prevention intervention and their options for HIV 
prevention methods in the future will be discussed. 
iv. 
At each visit, study clinicians will assess participant’s needs and discuss HIV 
prevention methods available.  Participants will be offered a clinic provider phone 
number for immediate contact and initiation of PEP in the event of exposure, with 
access to the provider 7 days a week, including holidays.  Participants may switch 
between PrEP, PEP and HIV testing-only options as needed and according to 
their choice, in consultation with the provider. HIV self-testing will be offered as an 
alternative testing method. Participants who are at high risk but decline PrEP may 
opt for HIV testing every 3 months, with continual discussions with clinician of HIV 
risk and their options.  
v. 
Choice of service location: Participants will have the option to receive PrEP/PEP 
services at any of the designated locations, including any of the clinic settings and 
at youth multi-sector interventions.  
vi. 
For men, staff will ask about circumcision status, and discuss the benefits of 
VMMC, with referral to VMMC services for those interested. 
vii. 
At each visit, study clinicians will assess the need for specialized counseling to 
provide psychological support for traumatic experiences (e.g. domestic violence 
and rape). 
• 
Assessment of PrEP/PEP barriers and personalized actions: 
i. 
At the time of the first meeting and at subsequent visits thereafter, the study 
clinician will discuss with participants any potential barriers to PrEP/PEP initiation 
and adherence, such as distance to health facility, stigma, or work/school 
schedules. 
ii. 
If barriers are identified that may inhibit study participation or adherence to 
medications, the clinician will work with participants to develop solutions. These 
solutions may include offsite visits or flexible clinic hours or additional services, 
such as reproductive health care, at home visits. 
iii. 
If solutions to barriers to PrEP/PEP use involve offsite delivery, study staff 
providers will facilitate routine delivery of PrEP or PEP.  Nurse trackers will deliver 
medications and perform standard prevention procedures at participants’ homes 
or other desired offsite location.  Participants may change the location of the 
offsite delivery throughout the program. 
• 
Mobile phone access:  Participants will be provided access to one clinician’s mobile phone 
number at each facility taking part in the Dynamic Prevention intervention.  Participants will 
be told they can call the clinician any day of the week, including holidays, in the even they 
would like to start PEP immediately due to possible HIV exposure.  The phone number may 
also be used for other possible issues such as questions, concerns about side effects, and 
for general support of the participant’s adherence of PrEP/PEP. 

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• 
Participant contact information will be collected, including home location and mobile phone 
number(s) if available. 
• 
Baseline information will be collected including but not limited to date of birth, sex, clinic ID, 
education, and occupation 
• 
Participants’ opinions regarding approaches to promote retesting for HIV among persons at 
increased risk for HIV will be assessed in a brief survey during a follow up visit prior to 
study completion  
• 
At each visit, signs and symptoms of acute HIV infection will be reviewed by study 
clinicians, including fever), diffuse rash, or swollen or enlarged lymph nodes.  For patients 
suspected of having acute HIV, clinics will have access, provided by the study, for rapid 
viral load (using the Cepheid GeneXpert platform) if not available by the MoH, in order to 
ensure treatment of presumed HIV infection until test results return. The study will work with 
the MoH for partner notification in these cases to ensure completion and may also do social 
network outreach in order to identify and treat potential acute infection chains of infection.   
• 
HIV seroconversion:  For participants who are diagnosed with HIV in the course of the 
study, blood and hair samples will be collected for confirmatory HIV testing, drug 
resistance, and adherence measurement if indicated at the seroconversion visit and at 6 
and 12 months. Patients will be referred to standard HIV care and treatment, including 
same-day ART start.  
 
9.2.1.5. Standard PrEP and PEP Evaluations and Procedures According to MoH Guidelines 
All participants (in both study arms) will follow standard in-country guidelines for the provision of 
PrEP or PEP.97, 98  PrEP and PEP evaluations and procedures per in-country standard care 
guidelines are described below. 
 
PrEP Standard of Care Procedures 
 
Screening for eligibility for PrEP 
Patients who are eligible for PrEP will be screened as follows: 
• 
HIV antibody testing per standard care algorithm to confirm HIV-negative status 
• 
Symptom screen to rule out possible acute HIV infection 
• 
Symptom screen and/or laboratory testing for hepatitis B virus 
• 
Assessment of contraindication to use of country-recommended PrEP regimen 
• 
Determined ready and willing to initiate PrEP 
 
For patients suspected of having acute HIV, clinics will have access, provided by the study, for 
rapid viral load (using the Cepheid GeneXpert platform) if not available by the MoH, in order to 
ensure treatment of presumed HIV infection until test results return. 
 
PrEP counselling and initiation 
At the time of enrolment into the PrEP program, providers will provide risk-reduction and 
medication adherence counselling.  Condoms, along with education on their use, will also be 
offered.  The possible side effects of the medications will be explained, and PrEP will be 
dispensed, per country guidelines.  Patients will be given a 1-month supply of PrEP (with option for 
longer supply, e.g. 3 months, in intervention arm) and will be evaluated in 1 month for a review of 
adherence and side effects. 
 
Follow-up on PrEP 

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After the initial and 1-month visit, subsequent visits will take place at least every 3 months.  HIV 
antibody testing will be performed as per Table 7.  Pregnancy testing will be offered for women of 
child-bearing potential.  Providers will review the patient’s understanding of PrEP, barriers to 
adherence, tolerance to the medication, and risk profile; risk reduction counselling will be done as 
needed.  Symptoms of STI will also be evaluated, with treatment provided as indicated. 
 
Table 7. PrEP Standard Care Schedule of Evaluations 
Procedure or Evaluation 
Baseline 
1 month 
Every 3 
months1 
HIV testing per country algorithm 
X 
X 
X 
Symptom screen for possible 
acute HIV infection 
X 
X 
X 
Symptom screen and/or 
laboratory testing for hepatitis B 
virus 
X 
 
 
Counseling and adherence plan 
X 
 
 
Prescribe and dispense PrEP 
X 
X 
X 
Adherence assessment and 
support 
 
X 
X 
Pregnancy testing offered 
(women only) 
X 
X 
X 
Review barriers and perform risk 
reduction counselling 
X 
X 
X 
Symptom screen and follow-up 
for STIs 
X 
X 
X 
Creatinine testing (as available)2 
X 
 
X2 
1Study visits among participants receiving the dynamic prevention intervention will occur at least every 3 
months (at baseline and weeks 4, 12, and every 12 weeks during follow-up). 
2Routine creatinine testing is currently recommended in Kenya only (at baseline and annually) and will be 
done if available by government health services  
 
PEP Standard of Care Procedures 
 
Screening for eligibility for PEP 
Patients will be screened as follows: 
• 
HIV antibody testing per standard care algorithm to confirm HIV-negative status 
• 
Confirmation exposure occurred within past 72 hours and source was a person of HIV-
positive or unknown HIV status 
• 
Determined ready and willing to initiate PEP 
 
PEP counselling and initiation 
At the time of enrolment into the PEP program, providers will provide medication counselling and 
the possible side effects of the medications will be explained.  Pregnancy testing will be offered for 
women of child-bearing potential.  A 28-day supply of PEP will be dispensed; per country 
guidelines. 
 
Follow-up on PEP 
Patients will be followed up by phone or in-person at 7 days, 14 days and 28 days after PEP 
initiation.  Counseling on side effects and adherence will be provided as per Table 8.  PEP will be 
discontinued after 28 days.  HIV antibody testing will be performed as per Table 8. 
 

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Table 8. PEP Standard Care Schedule of Evaluations 
Procedure or Evaluation 
Baseline 
Day 7 
Day 14 
Day 28 
Assessment of exposure and 
eligibility for PEP 
X 
 
 
 
HIV antibody testing per country 
algorithm 
X 
 
 
X 
Dispense medications 
X 
 
 
 
Counseling, adherence 
assessment and support1 
X 
X 
X 
X 
Creatinine testing (as available)2 
X 
 
 
 
Pregnancy testing offered 
(women only) 
X 
 
 
X 
1Including hair sample collection for adherence assessment, if indicated 
2For patients on a regimen containing TDF, as available; routine creatinine testing is optional 
 
9.2.2. Dynamic Treatment for Mobile Populations, Alcohol Users and Hypertension 
The study intervention is enhancements of service delivery for mobile populations and heavy 
alcohol users, an intervention to promote linkage to care among persons screening positive for 
hypertension during community-based screening, and provision of care in a multi-disease chronic 
care model that includes service for HIV, hypertension and diabetes. ART will be delivered and 
monitored according to country guidelines and not provided by the study. Country guidelines for 
unsupressed viral loads will be followed.  Diabetes and hypertension care will be provided using 
MoH standards. Table 9 describes the Dynamic Treatment intervention components.  
 
Table 9. Dynamic Treatment Intervention Components 
Component  
Description 
Mobile Travel Pack  
1) Access to a mobility coordinator who will assist 
with transfers (to and from out-of-community HIV 
clinics), rescheduling, and out-of-facility refills; 2) 
Provision of a “travel pack” with alternative ART 
packaging options (e.g. ziplock bags, envelopes, 
pill boxes), up to 14-day supply of emergency 
ARVs, a packing list and mobility coordinator 
phone contact for unplanned travel; 3) Screening 
at every clinic visit for planned mobility; 4) 
Provision of a Mobile Number (hotline) to reach 
Mobility coordinator, along with routine phone 
outreach and a welcoming environment for 
participants to call or text Mobility coordinators 
with issues; 5) Provision of longer refills (up to 6-
months) for planned travel; 6) HIV viral load 
counseling (review and explanation of meaning of 
viral load results) 
Alcohol intervention 
1) Two in-person alcohol counseling sessions with 
alcohol counselors with support from a clinical 
psychologist; 2) monthly booster phone calls; 3) 
HIV viral load counseling (review and explanation 
of meaning of viral load results); 4) Provision of a 
mobile number (hotline) to reach alcohol 
counselor, along with routine phone outreach and 
a welcoming environment for participants to call or 
text alcohol counselors with issues  

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Hypertension Linkage intervention 
1) Travel voucher (financial incentive) conditional 
on linkage to hypertensive care 
Hypertension Treatment intervention  
1) All participants screened with blood pressure 
≥160/100 mmHg will be referred to the 
nearest clinic for an initial clinicial evaluation. 
In Phase B, participants will be offered the 
option of ongoing follow-up at home facilitated 
by a VHT/CHV or in the clinic 
2) Participants who do not link to care at a clinic 
may still be followed at home with VHT/CHV 
supported telehealth and encouraged to 
present to clinic for at least one in-person 
evaluation by a clinician. 
3) VHT/CHV home visit frequency determined 
based on severity of hypertension 
4) Hypertension care conducted at home with 
VHT/CHV measuring blood pressure and 
phone-based clinician consultation; referral for 
clinic visits if clinician concerned about 
symptoms or based on preference 
5) Clinician conducts telemedicine visit with 
patient to ask/answer questions, review blood 
pressure, prescribe medications 
6) VHT/CHV delivers medication from the clinic 
to the patient  
7) VHT/CHV-entered blood pressure and 
medication data populates dashboard to 
facilitate population management and CHV 
supervision by clinician 
8) Patients maintain the option of clinic visits for 
hypertension care if desired 
 
 
9.2.2.1. Informed Consent 
Prior to consent, participants will be screened to determine eligibility for the Dynamic Treatment 
intervention trials.  A waiver of consent will be obtained to confirm eligibility during the screening 
process. Written informed consent to participate in the study will be obtained from all participants.  
Consent forms will be translated from the original English to the language(s) spoken in the 
community.  The consent form will be read to participants in their local language.  Participants who 
agree to take part and sign the consent form will be enrolled in the study. 
 
9.2.2.2. Mobile Travel Pack 
 
The Dynamic Treatment intervention for mobile services will include: 1) Access to a Mobility 
Coordinator who will assist with out-transfers (for out-migrants to transfer HIV care to or receive 
ARV refills from outside locations), rescheduling and easy entry to clinic for in-migrants to establish 
care, and out-of-facility refills, as needed; 2) Provision of a “travel pack” with alternative ART 
packaging options (e.g. ziplock bags, envelopes, pill boxes), up to 14-day supply of emergency 
ARVs, a packing list, and either mobile minutes (airtime) and/or Mobility Coordinator phone contact 
(“hotline”) for unplanned/unexpected travel; 3) Routine phone outreach and a welcoming 
environment for participants to call or text Mobility coordinators with issues; 4) A standard 
screening form for each clinical encounter at ART visits to assess plans for mobility out of the 

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community; 5) Provision of longer refills (up to 6-months) for planned travel; and 6) HIV viral load 
counseling (review and explanation of meaning of viral load results). 
 
Clinic Services 
At each clinic, eligible persons will be randomized either to standard care (control) or to meet with 
the study Mobility Coordinator at each visit (intervention). The mobility coordinator official duties for 
intervention group participants include assessing travel plans, offering assistance to patients on 
ART with in/out transfers, providing travel packs that include alternate ART packaging emergency 
ARV supplies, and mobile numbers and/or mobile airtime to facilitate unexpected travel needs, 
assisting with scheduling and re-scheduling visits, coordinating unanticipated transfers and refills at 
out-of-facility locales as well as non-standard refill schedules to match anticipated mobility patterns. 
 
Procedures 
• 
Staff will screen potentially mobile individuals who have traveled outside the community 2 
or more times in the past year for trial eligibility. Staff will assess mobility of the patient 
using a standard screening form at the start of each visit.  
• 
Staff will provide intervention group participants a mobile phone number from a local carrier 
to reach the Mobility Coordinator as needed, and/or a minimum number of minutes, for 
patients to use in the event of unexpected travel and the need for assistance with 
medication refills, transfers, or rescheduling of visits.  At each clinic visit, the Mobility 
Coordinator with review with patients their mobile phone availability to ensure they have 
maintained the mobile number and have sufficient minutes for such immediate 
communication needs. 
• 
Intervention participants will also receive HIV viral load counseling (review and explanation 
of meaning of baseline and any follow up viral load results), routine phone outreach and a 
welcoming environment for participants to call or text the Mobility Coordinator with issues. 
• 
For intervention group participants who are mobile, the mobility coordinator will work with 
each participants’ clinician to prepare HIV, hypertension or diabetes medications for the 
time in which participants will be away from the community.  If needed, these medications 
can be delivered to the participant’s home. 
• 
Staff will maintain clinic documentation of mobile status of each HIV-positive participant to 
help track current clinic attendance status, specific needs for medications, transfers or other 
services, and future plans of travel or movement from the community.  Each intervention 
group participant will be provided with phone access to the Mobility Coordinator who will 
assist with their immediate needs related to travel or transfers to and from the study 
community. 
 
9.2.2.3. Alcohol Screening and Counseling 
Men and women who self-report alcohol use and meet study eligibility criteria will be invited to take 
part in an alcohol counseling program (Healthy Living) that is based on the Information, Motivation, 
and Behavioral skills (IMB) model and whose goal will be to reduce drinking, adapted for East 
Africa from efficacious alcohol counselling programs.93, 99  The program will include 2 in-person 
counselling sessions with “booster” phone counselling performed between the sessions at 3, 6 and 
9-weeks post-randomization.  The in-person counselling sessions will be workbook guided and 
include components designed to provide feedback on the consequences of alcohol use, 
emphasize individual responsibility, provide advice, offer empathy and help set goals.93-95  Prior to 

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implementation, staff will be trained on the principals of alcohol counseling using the Motivational 
Interviewing style and use of the workbook (minimum 2-days training plus refreshers). 
 
Procedures 
We will randomize eligible patients 1:1 either to the alcohol counseling intervention (led by an 
alcohol counselor) or to standard care (routine HIV care control). Patients who agree to take part in 
the alcohol counseling trial will provide informed written consent prior to screening and 
randomization.  Consent forms will be translated into local languages and a copy will be provided 
to participants.  The components of the alcohol counseling intervention include the following: 
• 
After consent is obtained, staff will inquire about the participant’s general health, assess 
their ART use, and administer the standardized 3-question AUDIT-C tool to assess their 
alcohol use.  A score of ≥4 for men and ≥3 for women will be considered positive for heavy 
alcohol use and render them eligible for randomization either to the alcohol counseling 
intervention or standard care.  For participants who score <4 (men) or <3 (women), staff will 
provide appropriate counseling and refer them to resources, as needed, but inform them 
they are not eligible for the specific alcohol counseling trial discussed. Participants scoring 
8 and above will be invited to participate, but will also be referred to their physician for a 
higher level of care for potential alcohol use disorder. Participants will also complete the full 
AUDIT assessment. Participants scoring 20 and above will also be offered a referral to their 
physician for a higher level of care for potential alcohol use disorder. 
• 
Intervention participants will then take part in the first sessions of the 2-session alcohol 
counseling program.  A trained alcohol counselor will administer the alcohol counseling 
workbook that describes the harmful effects of heavy alcohol use, elicits reasons to 
discontinue or reduce alcohol intake, elicits and records ways in which the participant could 
handle risky situations, and encourages the participant to make an agreement to alter their 
drinking habits.  A drinking diary will be provided for participants to record their daily alcohol 
intake. 
• 
Intervention participants will also receive HIV viral load counseling (review and explanation 
of meaning of baseline and any follow up viral load results), and baseline provision of a 
mobile number (hotline) to reach the alcohol counselor between sessions, as well as 
routine phone outreach and a welcoming environment for participants to call or text alcohol 
counselors with issues. 
• 
Staff will obtain intervention participant’s phone numbers (or a phone number of a close 
contact) and remind them they will receive a call every 3-4 weeks until his or her next health 
facility visit for a “booster” counseling session.  This counseling session will assess current 
drinking, compare this assessment to the participant’s drinking agreement recorded in prior 
counseling session, trouble-shoot problems and solutions, and discuss formulating a new 
drinking agreement for those who did not meet the goals of their previous agreement. The 
goals of the booster sessions are to reinforce motivation and behavioral skills, via reviewing 
drinking levels, ART adherence and reinforcing progress toward goals and discussing 
barriers or facilitators to achieving those goals. 
• 
At the participant’s next health facility visit, staff will administer the second and final part of 
the in-person counseling program, which will review the participant’s prior agreement on 
alcohol use, reaffirm reasons to reduce or discontinue drinking, and create an action plan 
for the future. 
• 
Following the primary endpoint measure (viral load at 24-weeks), all intervention arm 
participants will receive an additional “booster” counseling sessions (at 6- and 9-months 
post-randomization), to reinforce the alcohol counseling intervention. 

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9.2.2.4. Hypertension Linkage to Care and Treatment  
Linkage to care: Following community mobilization, study staff will offer community-based 
screening for hypertension to persons ≥25 years old during mobile outreach to community venues.  
Persons screened who have blood pressure measurements ≥140/90 mmHg after three repeated 
measurements at a single community-based screening will be eligible for enrollment into the 
hypertension linkage to care trial. Eligible adults who consent to participate will then choose a 
scratch card that reveals whether they have been randomized to receive a transport voucher that is 
reimbursed upon linkage to hypertension care (intervention) or randomized to read a message 
thanking them for screening and encouraging them to link to care for their hypertension clinic 
appointment (control). All participants will be provided information about hypertension and where to 
access hypertension care and scheduled for a clinic appointment within 14 days of 
screening/enrollment. Participants with blood pressure ≥160/100 will be scheduled for a clinic 
appointment within 3 days of screening/enrollment. 
 
Clinic Services: 
• 
All community members who screen positive for hypertension during community-based 
screening and link to the local government-run clinic (regardless of participation in the trial) 
will be offered repeat measurement of blood pressure, enrollment into the hypertension 
clinic and evaluation for anti-hypertensive treatment. 
 
Study staff will provide transport reimbursement (up to US$10) to Hypertension Linkage trial 
intervention participants who link to care within 30 days of screening.  
 
Treatment: Following community mobilization, study staff will offer community-based screening for 
hypertension to persons ≥40 years old during mobile outreach to community venues.  Persons 
screened who have blood pressure measurements ≥160/100 mmHg after three repeated 
measurements at a single community-based screening will be eligible for enrollment into the 
hypertension treatment trial. All persons will have immediate evaluation at clinical center for the 
hypertension. For follow-up, eligible adults who consent to participate will be randomized to receive 
follow-up hypertension care at home (intervention) or at the clinic (control) in Phase A.  In Phase B, 
participants will be offered the choice of care at home via VHT/CHV and telehealth, or at the clinic.. 
All participants will have the option of accessing hypertension care at the clinic if desired, 
regardless of randomization arm. Hypertension visit frequency (home or clinic-based) will be 
determined based on severity of hypertension and clinician judgement, with recommended 
frequency of every 4 weeks if blood pressure is uncontrolled (≥140/90 mmHg) and every 12 weeks 
if blood pressure is controlled (<140/90 mmHg). Table 14 describes the schedule of study 
evaluations. 
 
As per the standard of care, participants with co-morbid diabetes and/or HIV will have the option to 
receive VHT/CHV medication delivery for these conditions together with their hypertension 
medications. Medications will be prescribed by the clinician using standard treatment guidelines 
after completion of phone consultation for standard clinical evaluation. For participants with 
diabetes, the clinician will order a point-of-care random blood glucose when indicated to guide 
treatment decisions (to be performed by trained VHT/CHV or self-administered by participant). The 
clinician will advise the participant to come to the clinic for additional evaluation at any point they 
feel is clinically indicated.  
 

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Table 10. Hypertension Treatment Schedule of Evaluations* 
Procedure or Evaluation 
Week 
0 (Baseline) 
2 
4 
8 
12 
16 
24 
36 
48 
Clinical screening for signs/symptoms 
of secondary hypertension 
X 
 
 
 
 
 
 
 
 
Creatinine and urinalysis testing* 
X 
 
 
 
 
 
 
 
 
Clinic visit (intervention) 
X 
 
 
 
 
 
 
 
 
Clinic visit (control)
a 
X 
(X) 
X 
X 
X 
X 
X 
X 
X 
Home/Community visit (Intervention)a 
 
(X) 
X 
X 
X 
X 
X 
X 
X 
Assessment of adherence, barriers to 
care, preferences for care site 
X 
 
 
 
 
 
X 
 
X 
*In Phase B, creatinine and urinalysis will be done through standard of care 
aBoth Intervention and Control arms (Phase A) or home and clinic visits (Phase B) will be scheduled every 4 weeks when 
blood pressure is uncontrolled and every 12 weeks when blood pressure is controlled (shorter intervals of 2 week follow-
up should be considered for hypertensive urgency/emergency or at provider discretion in the setting of other clinical 
concerns). All participants (regardless of care engagement) should have visits by study staff for study measures at week 
24 (+/-4 weeks) and week 48 (+/-4 weeks). 
 
9.2.2.5. Social Network Referral Cards for HIV testing.  
To better understand strategies to reach persons at risk for HIV and with undiagnosed HIV, and to 
leverage social networks among persons enrolling in our Phase A studies, we may offer referral 
cards for HIV testing and multi-disease standard screening (e.g. hypertension) to participants in the 
study to distribute to their friends or family. This will be done during screening and at out-of-facility 
outreach testing offerings.  
 
9.2.3. Phase A Optimization 
The results of phase A will be used to finalize Dynamic Treatment and Dynamic Prevention 
packages for evaluation in Phase B via the following steps: 1) evaluation of short term (48 week) 
effects on primary and secondary outcomes to eliminate setting and subpopulation components 
unlikely to contribute substantially to population-level effects; 2) evaluation of implementation 
outcomesand, 3) structured stakeholder consultation, in which the above data are reviewed, 
together with a systematic review of external data on concurrent advances in HIV treatment and 
prevention. With the many new prevention modalities in development, we expect that some of 
those may be integrated into phase B study design.  
 
9.3. Phase B Intervention  
The Phase B intervention will consist of a three part intervention: 1) Community-enhanced reach 
activities 2) Person-centered care delivery; and, 3) Data-enhancement to improve precision 
of interventions (Figure 2)  
 
 
 
 
 
 
 
 
 

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Figure 2 
  
*CAB-LA will be included among Dynamic choice HIV prevention options if it is approved and available 
through in-country Ministry of Health programs. 
 
Procedures 
9.3.1 Community-Enhanced Reach 
We will conduct a series of community engagement activities in the intervention arms designed to 
reach persons at risk for HIV, undiagnosed with HIV or diagnosed and fallen out of care working 
closely with community health system, leveraging existing mobile outreaches in the community. 
The aim will be to reach all residents to offer health education, referral to study intervention 
components, and HIV and multi-disease screening. We will partner with ongoing MOH activities to 
leverage existing activities.   
 
Community Engagement 
 
The community engagement process will entail the multiple meetings with community leaders, 
health care leaders, members of the target population and other key stakeholders discuss the 
study and optimal approaches to community participation and mobilization, built on the approach 
used in the SEARCH study. 
 
These meetings with key leaders and stakeholders will be held in each region to introduce the 
study, answer questions and engage members in advising on topics that include: 
• 
Recruitment strategies 
• 
Identification of potential challenges and solutions to implementation 
• 
Optimum dates, times and locations of the activities 
• 
Populations or communities that could require special consideration 
• 
Other issues tailored to individual regions 

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In preparation for Community Mobilization activities, additional meetings with village leaders 
throughout each community will be held.  Advertising for the events may include poster, leaflet and 
radio advertising, with the enlistment of community-based volunteers to describe the events and 
encourage participation.  These efforts will incorporate the principles of a study community 
engagement plan which may include incentives at the Community Mobilization event, such as a 
raffle for prizes, supported by the community. 
 
Community Mobilization Activities 
 
Venues: Activity venues will be driven by existing health center outreaches and target populations.  
The number of venues and days in operation will be adapted to the needs of the individual 
participating communities.  The venues will generally be open to receive participants during 
business hours, and may include evening or early morning hours as well to reach specific 
populations (such as fisherfolk, transport workers, or barmaids).   
 
Target Populations: Mobilization activities aim to engage adult men and women and adolescents 
living in each community who do not regularly access health care at local clinics, in order to 
provide health education and screening, and introduce health study interventions. Participants will 
meet with staff to review the services offered and provide informed verbal consent to take part.  
The verbal consent form will be read to them in the local language. Information will be collected 
from each community member, including name, village of residence, age, gender, and fingerprint 
biometric. 
 
Pre-Test Counseling:  After verbal consent, pre-test counseling will take place to describe to 
participants, in detail, the diagnostic services offered and answer questions.  Education on the 
diseases for which community members are being screened will be provided, either in a group 
setting or on an individual basis. 
 
Multi-Disease Screening:  Multiple diagnostic services will be offered.  HIV Antibody testing will 
be offered for all participants and additional measures and testing below may be offered and 
tailored to the population age and demographic.  
 
• 
HIV testing will be performed according to country guidelines for those who do not self-
report as HIV-positive according to country policy:   
i. 
Initial rapid HIV test 
ii. 
Participants with a negative result will be informed that they are HIV-negative 
iii. 
Participants with an initial positive result will undergo a second rapid HIV test. If the 
result is positive, participants will be informed of their HIV-positive status. 
iv. 
Participants with discordant rapid test results (first test positive, second test 
negative) will undergo a third “tie-breaker” HIV test.  Participants with a positive “tie-
breaker” test will be informed that they are HIV positive. Participants with a negative 
“tie-breaker” test will be informed that they are HIV-negative.  
• 
Blood pressure:  Blood pressure measurement for all ≥18 years 
• 
Finger-stick blood random plasma glucose measure  
• 
TB Screening: Symptom screening with referral to clinic for further evaluation via chest x-
ray, sputum microscopy, and/or Xpert MTB/RIF assay64, 100 
• 
Malaria rapid diagnostic test (RDT) for participants with a temperature of >38oC 

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• 
STI testing, including syphilis and gonorrhea testing 
Post-test Counselling: All participants, regardless of test results, will receive standard post-test 
counselling per country guidelines, including participants newly diagnosed with HIV. For known 
HIV-positive participants already engaged in care, counselling will be adapted to meet their needs.  
 
Linkage: Study staff will refer individual participants with a positive screening test (i.e. HIV, 
hypertension for same or next day clinic appointments via a mobile phone call from the clinician to 
the client will be made at time of diagnosis to facilitate linkage.   
HIV:  All HIV-positive participants will be referred to the local health facility for care.  
Participants who are known or self-reported HIV-positive may be provided with specialized 
counselling, including targeted information on the benefits of linking to care and addressing 
participants’ specific fears. To increase outreach to persistent driver populations not yet in care, the 
study may coordinate with partner notification programs to embed free multi-disease “health 
checks” for sexual and social contacts of newly-identified HIV-positive individuals. HIV-negative 
participants will be offered PrEP referral if they consider themselves at high risk of infection.  
 Hypertension and diabetes:  Participants who screen positive for hypertension or diabetes 
will be referred to the local health facility for follow-up.  Other diseases:  Referrals to health facilities 
for hypertension, TB and malaria and STIs will be made as with other referrals, and staff will 
provide a “warm handoff” to clinicians from local health facilities present at the venue, as available 
and appropriate. 
 
Other services offered at Community Mobilization events will include sexual health education, 
referral to reproductive health services, and, in the event of a recent HIV exposure, referral to PEP 
services. 
 
Table 11.  Mobilization activities that may be performed, tailored to HIV epidemic and region  
 
Target Population  Location  
Frequency  
Service menu 
Adults with heavy 
alcohol use & 
female sex 
workers (FSWs) 
Drinking venues 
Every 3 months 
(weekend & night 
per venue) 
HIV, multi-disease testing w/ 
transport vouchers  
Adolescent girls 
and young women 
(AGYW - ages 
≥15-  ≤24), 
especially out of 
school 
Community venues 
(pop-up tents) 
Every 6 months 
HIV and STI testing, menstrual 
hygiene support, pregnancy testing, 
life-skills training, solar access 
Breastfeeding 
women 
Immunization 
outreach venues 
Every month  
Infant/early childhood 
immunizations, HIV self-testing & 
on-site rapid test, early infant 
diagnosis, nutrition support, on-site 
PrEP/PEP and ART linkage & 
education, ART start for breast-
freeding/pregnant women plus 
urgent referral  

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Pregnant women 
Immunization 
outreach venues 
Every month  
Referrals to ANC, HIV self-testing, 
nutrition support, HTN 
measurements, on-site PrEP, ART 
start for breast-freeding/pregnant 
women plus urgent referral 
Migrant workers  
Outreach venues  
Every 6 months 
HIV and multi-disease testing, 
linkage to OPD, solar access 
Fisherfolk 
Beaches/fish 
markets 
Every 3 months 
HIV testing, HTN measurements, 
sexual health education, alcohol 
education, solar lanterns 
Young men in 
transport 
Truck/boda stages 
Every 6 months 
HIV testing, HTN measurements, 
alcohol education, STIs screening, 
life-skills and IT training, solar 
access 
 
9.3.2 Person-Centered Delivery 
HIV care delivery has advanced significantly incorporating more patient-centered approaches and 
differentiated care. In SEARCH SAPPHIRE Phase B, our intervention communities will add 
additional interventions aimed to achieve the following outcomes, including: Increase biomedical 
prevention  coverage of those at highest risk, increase viral suppression, improve HTN control, 
reduce heavy alcohol use, strengthen MTCT cascade, and expand TB preventive therapy for 
children.  The intervention procedures are described in sections 9.2.1 and 9.2.2 and in Table 12 
below.  
 
Table 12.  Intervention Procedures and Target Population 
 
Intervention  
Procedures  
Target Population 
Dynamic Choice 
Prevention  
Structured approach to provide patient-centered 
biomedical options for prevention.  See section 9.2.1. 
CAB-LA will be incorporated into PrEP offerings when it 
becomes available in-country. 
Persons at risk for 
HIV, age ≥15 years  
Life events 
assessment and 
plan (LEAP) for 
youth, pregnant 
and breast-
feeding women, 
and 
unsuppressed 
persons 
receiving 
treatment  
We will conduct trainings with all providers to incorporte 
a life-stage assessment and plan (LEAP form) adapted 
from a randomized study showing that addressing life 
issues before delving into medical check-ins can 
improve viral suppression  
 
LEAP forms will be utilized for youth, pregnant women, 
and persons without viral suppression 
Persons with HIV 
and ≥15 to ≤24 
years, or pregnant/ 
breastfeeding, or 
unsuppressed viral 
load (≥400 c/mL) at 
initiation or at 
treatment failure  
Youth VHT to re-
engage 
defaulters  
New youth VHT will be trained to facilite re-engagment 
of youth who have defaulted from ART treatment or 
CAB-LA  
Youth (ages ≥15 to 
≤24 years) 
defaulters for ART 

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treatment or CAB-
LA 
Severe 
Hypertension 
Treatment 
Telehealth  
Persons with severe hypertension will have the option 
to participate in our telehealth model or standard care. 
Clinicians direct HTN management and VHT facilitate 
through telehealth – see section 9.2.2.4, Treatment 
section. 
Persons ≥ 40 with 
severe uncontrolled 
hypertension (BP ≥ 
160/100) 
VHT Child TB 
Prevention 
Intervention  
VHTs will be notified of children ≤ 5 years in need of TB 
prevention due to diagnosis of TB in the household; 
they will facilitate referral and engagement for TB 
prevention as per country guidelines  
Children ≤ 5 where 
TB diagnosed in the 
household  
 
 
9.3.3 Overview: Data Enhanced Community Precision Health  
Both community-enhanced reach and person-centered delivery will be strengthened through the 
strategic collection and use of data. A mobile device-based app will enable VHT/CHVs and  
persons working at mobile outreaches to electronically record key participant measures made 
during home visits and at mobile outreaches (as described in prior sections), including (depending 
on context) HIV test results, blood pressure measurements,  self-reported HIV risk, childhood 
vaccine coverage, and HIV care, HTN care, and biomedical prevention status. The app will be 
developed in partnership with country data teams charged by the Ministries of Health with 
implementation of country electronic medical record (EMR) systems and will be designed to 
harmonize with  these systems, including harmonization with current country data collection 
instruments. Information from the EMR will further be used to enhance capability of the VHT/CHV 
to support linkage of persons with HIV or HTN not in care or at risk for HIV and not in prevention 
program and defaulters from care by providing data back to VHTs/CHVs via the app about persons 
failing to link or defaulting from care. Building on existing country efforts, the app will also allow for 
electronic data capture of existing CHV/VHT ongoing household census activities, including 
capture of GPS coordinates for each household. Finally, data collected during mobile outreach and 
VHT/CHV home visits will provide a population-based database, which will be analyzed to enhance 
the effectiveness of ongoing outreach activities by identifying high yield venues and locations and 
local regions and persons who would benefit form more frequent or intensive outreach or services 
due to, eg,  elevated risk of HIV infection, unsuppressed viral load, and uncontrolled HTN. 
 
 
 
 
 
 
 
 
 
 
 
Figure 3 
 

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9.4. Phase A Measurements 
9.4.1. Dynamic Prevention 
The primary outcome will be PrEP/PEP “prevention coverage” defined as the proportion of follow 
up that an individual is protected from HIV infection with either PrEP or PEP, as assessed by self-
report (with secondary analyses integrating drug levels from hair samples101 and prescription 
refills). These data will be collected from surveys, Ministry of Health medical records and pharmacy 
records.  
 
Process and implementation measures will be obtained from clinic-based records and logs. 
Examples of measures which may be obtained are in  Table 13.  Additional information on 
mediators will be determined by surveys, focus groups and in-depth interviews (Table 14). 
Table 13. Phase A Dynamic Prevention Process Measures 
Setting 
Intervention Fidelity 
Patient-level Intervention Adoption & 
Process Outcomes 
Outpatient clinic  
Proportion of patients who receive: 
• Counseling & education about 
PrEP/PEP options upon enrollment 
• 3-month HIV testing offered 
• Mobile PEP/sexual health hotline 
• Offer of delivery site options 
 
Proportion of visits with: 
• Structured barrier & plan 
assessment completed 
• On time offsite delivery completed if 
requested 
• Delivery of reproduction health 
services if requested 
Adoption 
• Number of calls to hotline and topics of calls 
• Proportion of patients who select offsite 
delivery option 
• HIV tests performed at 3-month intervals 
and results provided 
 
Process 
• Proportion of patients who initiate PrEP 
• Proportion of patients who initiate PEP 
Family 
planning/antenatal  
clinic 
Core PrEP/PEP Fidelity Measures 
(defined for PrEP/PEP clinic above) 
 
Core PrEP/PEP Adoption & Process 
Outcomes 
(defined for PrEP/PEP clinic above) 

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Additional setting-specific measures 
• Proportion of patients who receive 
offer of offsite delivery of 
reproductive health services 
• Proportion of visits with delivery of 
reproductive health services if 
requested 
 
Additional setting – specific measures 
• Proportion of patients who select offsite 
delivery of reproductive health services 
Youth Multi-
Sector 
Interventions  
Core PrEP/PEP Fidelity Measures 
(defined for PrEP/PEP clinic above) 
 
Additional setting – specific measures 
• Proportion of persons attending 
youth multi-sector events who 
received health information on 
dynamic prevention   
Core PrEP/PEP Adoption & Process 
Outcomes 
(defined for PrEP/PEP clinic above) 
 
Additional setting – specific measures 
• Proportion (self-report) of youth who refer 
social network contacts for HIV prevention 
services.  
 
Social and behavioral research using quantitative, qualitative and mixed methods will be 
embedded within each trial to measure pathways of intervention action and implementation factors 
that affect outcomes. 
 
Pathways of intervention action. We posit individual-level, interpersonal and structural 
determinants of uptake of DCP, a selected number of which will be the focus of this research. 
These will be explored in the study population of DCP trial participants using in-depth interviews in 
sub-samples of participants in the trials, and in a sample of DCP providers. Key constructs to be 
measured, and domains that may be explored in qualitative inquiry are outlined in Table 14:  
 
Table 14. Phase A Pathways of Intervention Action 
Mediator 
• 
Health knowledge, beliefs, and 
behaviors (including sexual risk behavior 
and alcohol use) 
• 
Sexual and reproductive health 
empowerment 
• 
Mental health and social support 
• 
Structural barriers to care and prevention 
(including mobility, transport costs, and 
food insecurity) 
• 
Perceived quality of care and trust in 
health care providers 
  
9.4.2. Dynamic Treatment 
• 
The primary outcome for the Mobile Travel Pack and Alcohol Counseling interventions will 
be viral suppression (HIV RNA<400 cps/ml) at 48 weeks for the mobility trial and 24 weeks 
for the alcohol trial. Secondary outcomes for the Mobility (“travel pack”) intervention trial 
may include time retained in care (non-retention defined as the period of time following >2 
weeks from a missed clinic visit until return to clinical care) and ART-covered time over 48 
weeks.  Secondary outcomes for the Alcohol Counseling intervention trial may include viral 
suppression at 48 weeks, heavy alcohol use at 24 and 48 weeks (measured by self-report 
and corroborated by phosphatidylethanol [PEth], a valid biomarker of prior 2-3 weeks’ 
alcohol consumption102,102), and time retained in care (non-retention defined as the period of 

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time following >2 weeks from a missed clinic visit until return to clinical care) over 24 
weeks. The primary outcome for the Hypertensive Linkage Intervention will be linkage to 
hypertension care at the local government clinic within 30 days of screening positive for 
high blood pressure during community screening. Secondary outcomes for the 
Hypertension Linkage intervention trial will include linking to hypertension care on the date 
of their scheduled appointment and blood pressure control (defined as systolic blood 
pressure <140 mmHg and diastolic blood pressure <90 mmHg) at 3, 6 and 12 -months 
post-enrollment. The primary outcome for the hypertension treatment trial will be HTN 
control at 24 weeks (blood pressure <140/90 mmHg). Secondary outcomes will include time 
to attaining hypertension control, HTN control at 12 months, proportion retained in care at 
24 and 48 weeks.  
 
Process and implementation measures for the Dynamic Treatment measures will be obtained from 
clinic-based records and logs. Examples that may be evaluated are shown in  Table 15.   
Additional information on mediators will be determined as described in Table 14, with the addition 
of a sexual behavior and mobility survey. 
Table 15. Phase A Dynamic Treatment Process Measures 
Setting 
Intervention Fidelity 
Patient-level Intervention Adoption & Process 
Outcomes 
Mobile Travel 
Pack 
Proportion of intervention participants 
who receive: 
• Education about support for travel by 
the Mobility Coordinator 
• Hotline for unplanned travel & mobile 
minutes 
• Screening for travel at each visit  
• Offer of travel pack, including 
alternative medication packaging 
• Offer of longer refills 
• Assistance with entry to clinic (in-
migrants) or transfer to out-of-
community clinics (out-migrants) 
 
Adoption (intervention) 
• Number of calls to hotline and topics 
• Proportion of patients selecting travel pack, 
including alternative packaging 
• Proportion of patients selecting longer refills 
• Facilitated planned and unplanned transfers 
completed 
• Out-of-facility refills attempted and filled 
Process Outcomes (intervention & control) 
• ART covered time (Medication Possession 
Ratio) 
• Number of missed visits 
Alcohol 
Intervention 
Proportion of intervention participants 
who receive: 
• Initial counseling session, follow-up 
counseling session 
• Booster phone calls attempted 
Adoption (intervention) 
• 
Engagement on counseling sessions & 
booster phone calls 
Process Outcomes (intervention & control) 
• 
ART covered time (Medication Possession 
Ratio) 
• 
Number of missed visits 
Hypertension 
Linkage 
Intervention 
Proportion of intervention participants 
who receive transport reimbursement 
upon linkage to care 
Process Outcomes 
• 
Linkage to scheduled appointment 
Hypertension 
Treatment  
Proportion of intervention participants 
who receive the home/community follow-
up visits.  
Process Outcomes 
• 
Home/community follow-up visits 
• 
Clinical officer participation in off-site visit 
via mobile phone 
 
 
9.4.3. Additional controls 
To quantify the potential spillover between randomized arms and to understand secular trends, we 
may take 2 approaches. We may review retrospective records for primary outcomes among 

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participants (pre and post intervention, internal control). We may also enroll external controls for 
outcome comparisons with the clinic-based intervention trials for Dynamic Prevention (outpatient 
department and antenatal/family planning clinic) and for Dynamic Treatment (mobile populations 
and heavy drinkers). In communities otherwise not participating in Phase A, we will select clinics 
meeting the inclusion/exclusion criteria of each of the respective trials. In each site, individual 
participants will be recruited, consented, enrolled, and measured using analogous procedures of 
each of the respective trials. Outcomes will be compared between each trial’s intervention arm, 
each trial’s control arm, and the external controls using difference-in-differences. 
 
9.5. Phase B Measurements 
Baseline and interim measures (Intervention only): 
Through community-enhanced outreach, described above (Section 9.3.1), we aim to obtain 
baseline measures on all community residents (N=~80,000 persons; ~40,000 adults) in the 
intervention arm at the start of Phase B. Specific measures include multidisease screening (e.g., 
HIV, hypertension, TB) and corresponding care status. During the course of person-centered 
delivery, described above (Section 9.3.2), we will also collect and utilize data to improve 
intervention delivery. For example, providers will utilize life events assessment and plan (LEAP) 
forms to identify and address barriers to HIV viral suppression. Likewise, through the data-
enhanced community precision health model, described above (Section 9.3.3), we will also use 
data collected in both the community and at clinics to inform targeted interventions for screening, 
linkage, and re-engagement. As detailed below (Section 9.6.2), we will also measure and assess 
intervention implementation. 
There will be no study-specific measures prior to endline in control communities. We may obtain 
community-level data at baseline from existing MoH records. 
9.5.1 Phase B endpoint measures and evaluation 
At month 30, we aim to obtain the following measures on all residents in both intervention and 
control communities (N=~160,000 persons; ~80,000 adults) to assess the primary and secondary 
endpoints of Phase B. The following Table provides an overview of endpoint definition, target 
population, and key metrics. 
 
 
 

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Table 16. Phase B Study Outcomes  
 
CAB-LA will be included in PrEP/PEP coverage measurements if it is approved and available 
through in-country Ministry of Health programs by the month-30 evaluations. Prior to the start of 
month-30 measures, a households will be enumerated via remote GPS and through community 
health workers. 
 
Month 30 Evaluation 
At the time of the first visit to a household, all adult members present will be approached by study 
staff who will describe the measurement cohort activities and offer participation in the study.  
Households will be visited up to 3 times to identify all eligible adults (≥15 years) for participation.  
Written consent will be obtained from each individual participating, using a private area of the 
home for the consent discussion.  Consent forms will be translated into local languages and a copy 
will be provided to participants.  Identifying information will be collected from each household 
member, including name, age, sex, and digital fingerprint biometrics. 
 
Demographic, Health and Economic Data Collection 
During visits to each household, study staff will enumerate household members, identify 
relationships between household members and the head of household (as well as identify 
couples/partners within household members), and obtain demographic information (i.e. age, sex, 
occupation, highest level of education attained, school attendance, and marital status), health 
information (including self-reported HIV status, ART use, circumcision status (men only), any prior 
diagnosis and treatment for hypertension or diabetes and household economic data on workforce 
participation (i.e. income-generating activities) and income.  
   
Testing 
Pre-Test Counseling:  After obtaining consent, pre-test counseling will take place to describe to 
participants in detail the diagnostic services offered and answer questions.  Education on the 
diseases being screened will be provided. 
 

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Multi-Disease Screening:  The following tests will be performed: 
• 
HIV antibody testing will be performed on adults who do not self-report being HIV-positive 
according to country policy:   
i. 
Initial rapid HIV test 
ii. 
Participants with a negative result will be informed that they are HIV-negative 
iii. 
Participants with an initial positive result will undergo a second rapid HIV test.  If 
the result is positive, participants will be informed of their HIV-positive status. 
iv. 
Participants with discordant rapid test results (first test positive, second test 
negative) will undergo a third “tie-breaker” HIV test.  Participants with a positive 
“tie-breaker” test will be informed that they are HIV positive. Participants with a 
negative “tie-breaker” test will be informed that they are HIV-negative. 
v. 
Participants who test HIV-positive by antibody measurement will have a sample 
collected for future Geenius testing for study endpoint confirmation only. 
• 
All adult community members will be assessed for recent HIV infection using a multi-assay 
algorithm (MAA).  
• 
All adult participants who are self-reported HIV-positive or who test HIV-positive will have a 
sample collected for HIV RNA measurement and be assessed for alcohol use via AUDIT-C 
if aged ≥18 years. On a subset of participicants, we may also obtain dried blood spot 
samples for phosphatidylethanol (Peth) testing. 
• 
All adult participants will be administered a questionnaire to assess HIV risk and use of oral 
PrEP or PEP. This will be the same questionnaire used to succesfuly assess HIV 
prevention coverage in the Phase A Dynamic Choice Prevention trials. Staff will also review 
clinical records for CAB-LA dispensing (if CAB-LA is approved and available through in-
country Ministry of Health programs), and a subset of participants reporting recent 
PrEP/PEP use may be selected for hair sample collection to assess tenofovir levels. Hair 
tenofovir level testing: Hair samples collected from members of HIV-negative cohort who 
are active PrEP users (as determined by clinical records)  
• 
Blood pressure measurements will be performed on all community members age ≥30 
years.  
Post-test Counselling: All participants, regardless of test results, will receive standard post-test 
counselling per country guidelines for point-of-care measurements, including participants newly 
diagnosed with HIV. For known HIV-positive participants already engaged in care, counselling will 
be adapted to meet their needs. 
HIV RNA test results will be delivered to the participant’s local health centre, if already receiving 
care, or the health centre they were referred to (see below) if recently diagnosed or out of care.  
PEth test and hair sample results, if obtained, will not be provided to participants. 
 
Linkage: Study staff will refer individual participants with a positive screening test (i.e. HIV, 
hypertension) with facilitated linkage, as described previously (Section 9.3.1).  
 
Mortality, TB, MTCT and Immunization Surveillance 
Surveillance for mortality, TB, MTCT and childhood immunization coverage will be performed as 
follows: 
• 
Mortality:  A Vital Status Survey will be administered to the head of each household to 
collect information on any deaths that occurred among household members. We will use a 

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Vital Status survey previously utilized in the SEARCH “test and treat” trial,103 which 
ascertained vital status on over 90% of participants and collected data on date of death 
(month/year) and cause of death within four categories (illness, accident/trauma, 
pregnancy/childbirth, or suicide). We will also collect data on location (if known) at time of 
death. This survey will also capture births into the household and migrations (i.e., persons 
moving in and out of the household). 
• 
TB:  Study staff will review local Ministry of Health (MoH) TB registries for information on 
incident cases of TB disease.  Study staff will name-match TB cases (documented in MoH 
TB registries) to study participants (all ages). The government is the sole supplier of anti-
tuberculosis antibiotics in Uganda and Kenya, and therefore TB therapy is only available 
through government-run or associated clinics and hospitals. All TB clinic dispensaries keep 
government registries with diagnostic and treatment-related outcomes (including death) for 
every case, as well as name, age, HIV status, date of TB diagnosis, date of TB treatment 
initiation, and residence (detailed to the village level). Staff may also review registries for 
data on TB prevention and treatment among study participants.  
• 
Mother-to-child HIV Transmission: In the Vital Status Survey (see mortality, above), we will 
ask about any infants/children born over the study period. All children <3 years of age born 
to women with HIV or unknown HIV status will be assessed for vital status and undergo 
appropriate pediatric HIV testing.  
 
9.5.2. RE-AIM Implementation Evaluation  
RE-AIM-based implementation basic descriptive metrics (Table 17) will be calculated leveraging 
available medical record and pharmacy stock data, and study CRFs (to capture, for example use of 
the life stage assessment tool in youth clinics, frequency of mobile population outreach) at health 
centers and other locations. 
 
Table 17. RE-AIM Dynamic Prevention Metrics, Phase B 
 
Target Populations 
Evaluation Metrics 
Measures & Data 
Sources 
Reach  
"The absolute 
number, 
proportion, and 
representativeness 
of individuals who 
are willing to 
participate in a 
given initiative" 
1. All persons who are HIV-
negative and community 
residents aged > 15 years at 
study baseline 
2. Subset of HIV-negative 
persons who are "at risk" for 
HIV transmission defined by 
self-report 
Proportion of target population 
screened for Dynamic Prevention 
 
Proportion of target population ever 
enrolled in Dynamic Prevention 
Screening and 
enrollment study 
CRFs over 3-year 
study period 
 
Socio-demographics 
(including mobility) 
and HIV rapid tests  
Effectiveness  
"The impact of an 
intervention on 
important 
outcomes, 
including potential 
negative effects, 
quality of life, and 
economic 
outcomes." 
1. Baseline HIV-negative 
residents 
2. Month 30 HIV-negative 
residents 
3. Subset of HIV-negative 
residents “at risk” for HIV 
infection (defined as above) 
 
 
Prevention coverage: proportion of 
target population with follow-up time 
covered by either PrEP or PEP 
 
See section 4 of SAP for additional 
details and secondary effectiveness 
outcomes 
Primary: Pharmacy 
refill data, clinical 
records over 30 
month study period 
 
Secondary: self-
reported  
adherence; 
Tenofovir hair levels 
in subsample  of 
HIV-measurement 
cohort at month 30 

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Adoption  
"The absolute 
number, 
proportion, and 
representativeness 
of settings and 
intervention 
agents who are 
willing to initiate a 
program." 
Patients: Persons enrolling in 
Dynamic Prevention 
 
Providers:  PrEP/PEP providers 
at each of the delivery settings 
(HIV clinic, ANC clinic 
 
Clinics: All PrEP/PEP delivery 
sites in communities randomized 
to Dynamic Prevention 
Patient: Proportion of target population 
making use of each of the choice-
based options provided (e.g. mobile 
phone visits, self-test, etc...) 
• See Table 13 for additional detail on 
subpopulation-specific patient-level 
adoption measures, which will also 
be implemented in Phase B 
 
Provider: Proportion of providers with 
a)  knowledge of the core components 
of the Dynamic Prevention package; 
and,  b) who have enrolled persons in 
Dynamic Prevention; and, c) who have 
made use of each of the components 
of dynamic treatment for their patients 
(provider level summaries of the 
individual adoption measures above) 
 
Clinic: Proportion of HIV clinics sites 
that have initiated Dynamic 
Prevention; clinic- level summaries of 
the individual-level adoption measures 
above  
 
All: Provider, Staff and Patient 
perceptions of the importance and 
utility of Dynamic Prevention and its 
components. 
Screening and 
enrollment study 
CRFs over 30 month 
study period 
 
Provider, staff, and 
patient surveys 
conducted at study 
baseline and month 
30 
Implementation 
"At the setting 
level, 
implementation 
refers to the 
intervention 
agents’ fidelity to 
the various 
elements of an 
intervention’s 
protocol. This 
includes 
consistency of 
delivery as 
intended and the 
time and cost of 
the intervention.” 
Patients: Persons enrolling in 
Dynamic Prevention 
 
Providers:  PrEP/PEP providers 
at each of the delivery settings 
(HIV clinic, ANC clinic 
 
Clinics: All PrEP/PEP delivery 
sites in communities randomized 
to Dynamic Prevention 
Fidelity of intervention delivery 
 
Patient: Proportion of target population 
who receive each setting-specific core 
intervention component as scheduled 
(e.g. PEP hotline provided, offsite after 
hour visits offered)   
• See Table 13 for additional detail on 
patient level fidelity measures, 
which will also be implemented in 
Phase B  
 
Provider: Proportion of providers and 
staff who complete scheduled 
trainings;  provider-level summaries of 
the individual fidelity measures above   
 
Clinic: Timing and coverage with 
which clinics implement core 
intervention components;  clinic-level 
summaries of the individual fidelity 
measures above  
 
Cost: 
• Component-specific costs of 
intervention (e.g., costs of PEP 
hotline, offsite visits) 
Fidelity: 
implementation 
CRFs throughout 
study period, direct 
observation of 
intervention 
activities in clinic 
 
Cost: direct 
observation, time in 
motion, clinic & 
administrative 
records, patient 
surveys, conducted 
during Phase B 

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• Patient opportunity and 
transportation costs to access 
intervention/ prevention services 
• Health systems costs (including 
drugs and clinical monitoring) 
• See Protocol Section 8 for 
additional details 
Maintenance  
"The extent to 
which a program 
or policy becomes 
institutionalized or 
part of the routine 
organizational 
practices and 
policies. 
Maintenance in 
the RE-AIM 
framework also 
has referents at 
the individual level. 
At the individual 
level, maintenance 
has been defined 
as the long-term 
effects of a 
program on 
outcomes after 6 
or more months 
after the most 
recent intervention 
contact." 
Communities randomized to 
Dynamic Prevention 
Core components of each setting 
specific intervention in place 6 months 
after completion of the 30 month study 
Brief clinic-level 
assessment via 
direct observation 
and review of clinic 
records. 
 
Staggered initiation 
of follow up for 
communities in 
Phase B will allow 
for 6-month 
evaluation in 6 sites. 
For longer-term 
maintenance 
evaluation of 
interventions 
adapted, we will 
seek supplementary 
funding 
 
 
 

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9.6. Behavioral Measures  
Phase A:  We will use longitudinal mixed methods to understand behavioral mediators of the study 
outcomes in Phase A. We will conduct surveys, in-depth interviews (IDI), and/or focus group 
discussions (FGD) with participants and health care providers in the trials. .   
 
Phase B: We will conduct qualitative research in SAPPHIRE Phase B to understand 
implementation processes and contexts and their potential influence on trial outcomes. This will 
include: 
1) eliciting perceptions and understanding experiences of interventions among a) selected 
target populations and b) community-based practitioners (VHTs/peers) engaged in 
intervention delivery to evaluate facilitators and barriers to uptake of services; 
2) observing out-of-clinic mobile outreach and service delivery strategies across diverse 
venues to understand social dynamics, spatial and environmental contexts, and any 
unforeseen aspects of implementation that may affect success of the strategies.  
A focus on key features of Phase B not yet studied in Phase A. Our approach in Phase B is to 
focus qualitative inquiry on key design features and components of Phase B not previously 
explored in depth in our prior work in Phase A. These include: 
1) an expansion of the cadre and role of VHT/CHVs and youth peers in  
• 
identifying persons with HIV or HTN not in care or at risk for HIV and not in prevention 
program and (re)linking them to services 
• 
supporting outreach to high risk persons to strengthen care cascades (VHT-based linkage 
and defaulter support) and support hybrid delivery (HTN telehealth, VHT DCP, alcohol 
intervention, other services) 
 
2) an expansion of entry points to services, including not VHT/peer home visits but also mobile 
facility services, and venue-based outreach targeting specific target populations, including  
• 
adults w/ heavy alcohol intake and FSWs at drinking venues  
• 
AGYW (esp out of school) at community ‘pop up’ canopies 
• 
young men in transport at trucking/boda boda stages 
• 
pregnant and breastfeeding women at immunization clinics 
3) A new prevention technology, CAB-LA, that has not before been rolled out at population-level. If 
CAB-LA is not approved and available through in-country Ministry of Health programs during 
Phase B, it will not be included. 
 
9.6.1. Procedures 
9.6.1.1. Mixed Methods Research Staff  
Quantitative surveys and qualitative interviews, FGDs and participant observation will be 
administered by study staff trained in qualitative research methods and fluent in the local 
languages of each community.  
 
9.6.1.2. Sampling for Mixed Methods Measures  
In Phase A, quantitative surveys will be conducted, and FGDs and IDIs will be conducted in 
randomized controlled trials between 23 and 36 weeks of Phase A and among 45 HIV-uninfected 
young adults and 10 health care providers. Additionally, we will conduct qualitative interviews (IDIs) 

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with participants in Phase A treatment trials who are identified with HIV non-viral suppression at 
trial endpoint measurement. 
 
 In Phase B, Table 19 summarizes target populations and evaluations. 
 
We will conduct in-depth interviews among purposive samples of participants and community-
based practitioners, and conduct observations at venues, to pursue our research objectives as 
show in the tables below: 
Table 18. In-depth interviews 
Behavior / Research 
domain 
Study 
population 
Purposive sampling category  
Timing  
PrEP/PEP uptake 
a) Perceptions of 
mobilization strategies  
b) Barriers/facilitators of 
biomedical HIV prevention 
uptake 
HIV- adults 
recruited from 
community 
venues who are 
eligible for 
PrEP/PEP 
(N=60) 
1. Sex: male/female (including 
patrons and female sex workers) 
2. Uptake: initiated or declined 
PrEP/PEP 
3. multi-disease or HIV-focused 
recruitment 
Following clinic-
based screening 
for HIV and offer 
of PrEP/PEP 
PrEP/PEP uptake 
a) Perceptions of 
mobilization strategies  
b) Barriers/facilitators of 
biomedical HIV prevention 
uptake 
HIV- youth who 
are eligible for 
PrEP/PEP 
(N=20-30) 
1.Sex: male/female 
2.Age band: 15-19, 20-24  
2. Uptake: initiated or declined 
PrEP/PEP 
3. Outreach modality (peer home 
visit, community pop-up canopy 
outreach) 
Following clinic-
based screening 
for HIV and offer 
of PrEP/PEP 
Linkage and retention in 
HIV treatment 
a) Perceptions of 
intervention, outreach 
strategy 
b) Barriers and facilitators 
to retention and 
adherence 
HIV+ adults 
undiagnosed or 
out of care 
(n=20-30) 
1. Sex: male / female 
2. interim outcome: linked to care 
and suppressed, not linked, linked 
but not virally suppressed 
3. Outreach modality (CHV/VHT 
home visit, mobile facility-based 
outreach) 
2-12 weeks after 
linkage referral 
Linkage and retention in 
HIV treatment 
a) Perceptions of 
intervention, outreach 
strategy 
b) Barriers and facilitators 
to retention and 
adherence 
HIV+ youth 
undiagnosed or 
out of care 
(n=20-30)  
1. Sex: male / female 
2. interim outcome: linked to care 
and suppressed, not linked, linked 
but not virally suppressed 
3. Outreach modality (peer home 
visit, community pop-up canopy 
outreach) 
2-12 weeks after 
linkage referral 
Perceptions of social role, 
motivations and 
intervention experiences 
for HIV and HTN of CHVs 
and Peers  
CHVs (n=10-20) 
Peers (n=10-20) 
1. Sex: male / female 
2. Worker type 
Weeks 24-72 of 
study 
 

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Table 19. Observation during implementation  
Research domain 
Target population 
Venue type 
• 
Physical attributes of space 
and setting 
• 
Appearances and 
behaviors of individuals in 
venues 
• 
Social interactions 
(implementation team, 
patrons, and both) 
• 
Public reactions to 
implementation strategies 
• 
Informal public 
conversations related to 
strategies 
 
• 
Adults with unhealthy alcohol 
use 
• 
Bar maids/female sex 
workers 
Bars 
 
• 
Migrant workers 
• 
Young men in transport (truck 
driver, boda boda) 
Truck/ Boda boda stands 
 
• 
Pregnant & Breastfeeding 
women 
• 
Out of school youth 
Mobile facility-based 
outreaches / immunization 
campaigns / pop-up canopies 
 
 
9.6.1.3. Consent 
Study staff will obtain written consent for participation in quantitative surveys, IDIs and FGDs.  
 
9.6.1.4. Quantitative Survey Measures 
Survey measures will include instruments that evaluate the following: 
• 
Health Knowledge, Beliefs, and Practices Survey: Administered to a subset of the 
HIV+ and HIV- Cohorts, collecting information on health knowledge, preferences 
and behaviors. 
• 
Sexual and Reproductive Empowerment Survey for Adolescents and Young Adults: 
Administered to a subset of the HIV+ and HIV- Cohorts under age 25, measuring 
perceived psychological empowerment. 
• 
Felt Stigma Survey: Administered to a subset of the HIV+ and HIV- Cohorts, the HIV 
Felt Stigma survey collecting information on HIV-related stigma. 
• 
In-Depth Interview (IDI) & Focus Group Discussions (FGDs):  Administered to a subset of 
members of the HIV-negative and HIV-positive cohorts by staff trained in qualitative 
interview practices, with topics including barriers to care, engagement in HIV prevention 
and/or care services, stigma, sexual risk-taking, and other subjects 
 
9.7. Costing Evaluations  
9.7.1. Overview 
We will use standard micro- costing techniques and time-and-motion studies to measure the cost 
of each intervention in Phase A (between weeks 12 and 36 of Phase A) and the combination 
packages in Phase B (week 24 and week 120 of Phase B). Data will be collected from care 
providers, patient medical records, clinic and study administrative and financial records. Patient 
questionnaires will be used to elicit expenditures for transportation to participate in the intervention 
and receive care, expenditures for additional health services received (e.g. hospitalization), and the 
value of the time lost to participate in the intervention and access care.  
 
9.7.2. Costing team procedures  

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Costing team composition and training: Cost data collection will be conducted by two teams, one in 
Uganda and one in Kenya.  Each Cost Data Team will consist of a medically-trained person, a 
person trained in finance, economic or accounting and a Costing Officer, who has prior experience 
conducting costing data collection under the SEARCH trial.  The study’s Costing Co-Investigator 
will train the team on the tools and procedures to collect costing data and do time in motion 
studies. After training, the costing team will schedule visits to all 4 sites (Phase A) and 8 
intervention and 8 control communities (Phase B). Upon completion of cost data collection, in-
country teams will enter and submit data to the Costing Co-Investigator for review to clarify any 
aspects of data collection. The Costing Co-Investigator will complete costing data report will be 
generated.  
 
Costing data collection. At the site visits, the costing team will collect information on expenditures 
for each of the study interventions in Phase A and for each of the packages (Dynamic Prevention, 
Dynamic Treatment ) in Phase B classified in one of four categories; (i) personnel (including fringe 
benefits); (ii) recurring supplies and services; (iii) capital and equipment; and (iv) facility space (as 
appropriate). We will also collect retrospective expenditure data to document program start-up 
costs. The costs of each program activity will be identified through interviews with administrative, 
finance and human resources officers, supplemented by direct observation in a limited number of 
formal time-and-motion studies. The costing approach will emphasize resources utilized, rather 
than out-of-pocket costs. For example, where expenditures do not fully reflect the opportunity cost 
of the resources used (e.g., donations or transfer payments), we will adjust the valuations 
accordingly. Costs for capital items will be amortized on a straight-line basis over their expected 
useful life, and assuming no salvage value. Facility space required by the interventions will be 
valued at the market rental rate. Following assignment of expenditures to these four broad 
categories, we will further allocate each expenditure item across three areas, (i) service delivery; 
(ii) staff training directly related to service delivery; (iii) indirect costs consisting of intervention 
overhead and administration.  
 
Personnel Costs and the Allocation of Overhead Across Activities: Overhead and administrative 
costs will be allocated to the programs in proportion to the full-time equivalent staff (FTEs) that 
study intervention service providers constitute of all service provider FTEs at the study sites. We 
expect that the preponderance of intervention costs will be personnel time. The appropriate 
approach to measuring personnel time will depend upon the way services are organized at the 
study sites. For example, if dedicated staff is hired specifically for these interventions, costs can be 
obtained directly from compensation data. In the more likely case that service providers have 
multiple responsibilities, the time dedicated to these interventions can be obtained via interviews 
supplemented by direct “time and motion” observations, including completion by staff of logs 
recording major activities, for one-week periods during each assessment period.  
Measuring Unit Costs: Outputs (denominator of the unit cost) include the numbers of participants 
receiving each type of study-supported services. Unit costs are defined as the relevant program 
costs divided by each of these outputs, respectively. To supplement this information, we will also 
collect information on participant-level contact hours, to allow us to examine the importance of 
participant and intervention-level factors related to variation in unit cost. We will also assess the 
variation in unit costs across the study sites and identify the major determinants of that variation. 
These findings are intended to provide program managers with insights into costs structures that 
may be used to enhance program efficiency.  
 
9.8. Mathematical Modeling 

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The study will adapt an existing, individual-based simulation model of HIV sexual transmission, 
progression and effects of prevention and treatment (HIV Synthesis Model) to model the effects 
(and costs) of the Phase A interventions in order to inform the interventions to move into the Phase 
B trial and, after Phase B, to inform an Investment Case.  
 
9.8.1. Procedures 
The HIV Synthesis Model updates in 3-month periods and simulates age, gender, number of 
condomless sex partners, HIV testing and HIV acquisition risk and occurrence (dependent on viral 
load in condomless sex partnerships had by people of the opposite sex, considering alternative 
age-sex mixing patterns).  Health impact is conveyed in terms of viral suppression, morbidity and 
mortality, and also brought together as DALYs in the whole adult population. TB risk in HIV 
infected and uninfected persons will be included in the model.  The model has previously been 
used to evaluate the potential long-term effectiveness and cost effectiveness of several treatment 
and prevention interventions, including HIV testing initiatives, oral TDF/FTC PrEP, VMMC, choice 
of specific ART, and adherence and monitoring strategies for ART.  For the purposes of this study, 
the model will be calibrated to local historic epidemic data.  The study will add in to the structure a 
risk of hypertension with its effect on cardiovascular disease risk, and the beneficial effects of 
antihypertensive medication on hypertension.  Effects of interventions to modify alcohol use will be 
modelled as the effect of those interventions on ART adherence (and PrEP and PEP adherence).   
 
After Phase B the study will build on this first phase of the modelling to inform an investment case 
for a final intervention package shown to be beneficial in Phase B. The underlying modelling 
approach to the Investment Case will be as used above when modelling the potential effects and 
cost effectiveness of intervention packages but will be additionally informed by effectiveness data 
from Phase B.  If our intervention proves to be sufficiently impactful on HIV incidence we will put 
together an Investment Case to reduce incidence sustainably below 1 / 1000 person years. This 
will likely be arguing the case for additional resources to achieve this.  We will additionally use the 
results to inform the current breakdown of HIV program resources from the current budget 
envelope.  We will convey long term health impacts in terms of morbidity and mortality from AIDS 
and non-AIDS conditions and DALYs, projecting over several decades. 
 
9.9. Participant Discontinuation  
Participants are free to withdraw from active participation in the study at any time upon request.  
An investigator may discontinue a participant from the study for the following reasons: 
 
• 
The participant meets a previously unrecognized exclusion criterion 
• 
Significant non-compliance with the study 
• 
Any event or situation that occurs such that participation would not be in the best interest of 
the participant 
 
 
 

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10. ASSESSMENT OF SAFETY  
10.1. Safety Assessment Overview  
All medications provided in this study are standard care for the intervention described.  HIV testing 
and care will be performed according to MoH guidelines, including regular safety assessments 
such as VL for HIV-positive individuals in care, and other standard measurements. HIV RNA will be 
performed every 24 weeks in the Phase A dynamic prevention trials. 
 
Care will be taken to protect the privacy of participants in this study.  However, there is a risk that 
others may inadvertently see participants research or medical information, and thus privacy may be 
compromised. 
 
10.2. Adverse Event Procedures and Reporting Requirements  
As all intervention procedures in this study are standard care and prevention procedures 
recommended by the Uganda and Kenya MoH, and risks to participation in general are minimal, 
this study will not monitor or collect data on all adverse events.  In the unlikely event that a serious 
adverse event (SAE) is considered possibly, probably or definitely related to the study, or in the 
event of unexpected incidents or protocol violations, reporting to University of California-San 
Francisco CHR, Makerere University SOMREC, and Kenya Medical Research Institute SERU IRBs 
will be done as outlined in Table 20.  Investigators will be monitoring events  the intervention arms, 
and suspected events will be reviewed by study investigators prior to submission to the IRB. 
 
Table 20.  Event Reporting Timeline 
Institution 
Type of Events 
When to Report 
UCSF-Committee on 
Human Subjects 
Research (CHR) 
• 
External (off-site) adverse event that UCSF PI 
determines changes the study risks or benefits, OR 
necessitates modification to the CHR-approved 
consent document(s) and/or the CHR-approved 
application/ protocol 
• 
On-site protocol violations (events occurring at UCSF) 
• 
Within 10 working days 
of PI’s awareness 
Makerere University 
School of Medicine 
Research Ethics 
Council (SOMREC) 
• 
All Serious or Unexpected events considered 
possibly, probably or definitely related 
• 
Fatal or life-threatening 
events within 3 working 
days of awareness  
• 
All other SAEs within 7 
calendar days 
KEMRI Scientific and 
Ethics Review Unit 
(SERU) 
• 
All Serious or Unexpected events considered 
possibly, probably or definitely related 
• 
Notification within 24 
hours of awareness; 
report within 5 working 
days 
National Institute of 
Allergy and 
Infectious Diseases 
(NIAID) 
• 
All Serious or Unexpected events considered 
possibly, probably or definitely related 
• 
At the time of reporting 
to IRBs 
 

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11. DATA HANDLING AND RECORDKEEPING  
11.1. Data Management Responsibilities  
Data management for this study will be overseen by the Infectious Diseases Research 
Collaboration (IDRC) Data Management Center located in the main IDRC research complex in 
Nakasero, Kampala, Uganda.  The Data Management Center (DMC) is also responsible for 
providing IT support to all staff members. 
 
Data Management System 
For any study components using paper data collection, IDRC has designed and developed a 
custom Data Management System that is used to manage the data, using Microsoft SQL Server as 
the backend for all data storage.  MS Access is used for double data entry and SAS programs are 
used for comparing 1st and 2nd entry and generating discrepancy reports.  In addition, the DMC 
has developed custom Visual Basic programming for direct survey and data entry of data in the 
field. Data Transformation Services/ SQL Server Integration Services (DTS/SSIS) packages are 
used to automatically import/export any new data and stored procedures written in T-SQL are used 
to automatically generate new data queries on a daily basis.  There is a web interface to the whole 
system written in ASP.NET to allow users to view the data, view reports, and even modify the data 
they are authorized to access.  With regular backups and a full audit trail, the whole system is 
regulatory compliant (21 CFR Part 11). 
 
11.2. Essential/Source Documents and Access to Source Data/Documents  
Data is collected as a mixture of paper Case Report Forms (CRFs) and logs and electronic data 
capture from health facility databases and field data tablets.  Data is entered locally and uploaded 
to the DMC after quality assurance measures have taken place.  Only study investigators and staff 
affiliated with the study will have access to source data. 
 
External data sharing will be made through a data request proposal procedure coordinated by the 
PIs and the IDRC Data Department.  A standardized data request sheet will be completed by 
outside investigators and reviewed by the senior management and/or the Principal Investigator.  
Data and associated documentation will be available to users under a data-sharing agreement that 
provides for: (1) a commitment to using the data only for research purposes and not to identify any 
individual participant; (2) a commitment to securing the data using appropriate computer 
technology; and (3) a commitment to destroying or returning the data after analyses are completed.  
User registration is required to access or download files. As part of the registration process, users 
must agree to the conditions of use governing access to the public release data, including 
restrictions against attempting to identify study participants, destruction of the data after analyses 
are completed, reporting responsibilities, restrictions on redistribution of the data to third parties, 
and proper acknowledgement of the data resource. 
 
11.3. Quality Control and Quality Assurance 
The data management system is designed to collect, transfer and store data for Data Management 
Center studies. Data from any paper records will be 100% double entered into the system via 
Microsoft Access Databases or Web-based data entry screens. Locally collected data is 
compressed, password-protected, and then securely uploaded to a cloud based server (Network 
Solutions, Inc.) using secure-FTP via the FileZilla application.   Cloud-based uploads are downloaded 
daily to the Kampala DMC.  After the data has been input into the Data Management Center server, 
it is electronically verified and is then written to the SQL database. Edit checks or queries are run 

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nightly and the results are posted to a secure clinical trials website so that the sites can electronically 
address problems with the data the next day. The site corrects data via the website and the database 
is updated automatically. 
 
In order to ensure data security and integrity, the following measures will be implemented: 
• 
All members of the study team will be educated in the study protocol prior to the onset of 
the study.  
• 
Detailed Standard Operating Procedures (SOPs) will be written for all project activities and 
be provided to relevant team members.  
• 
Team members will be thoroughly trained on the SOP’s.  
• 
Where applicable, team members will receive additional training on the use of tablet 
computers.  
• 
All data transcribed from paper will be double data entered or verified.  
• 
All electronic data will be backed up regularly.  
• 
All data will be transferred to the main Data Center in Kampala to the secure server. This 
sever is backed up on a daily basis and a monthly backup is stored off-site.  
• 
All computers, including the tablets, will be password protected.  
• 
All computers, including tablets, will be locked in a secure room each night.  
• 
Any Log Books and CRF’s will be locked in a secure room each night. 
 
12. CLINICAL SITE MONITORING  
Site monitors under contract to the University of California, San Francisco will visit participating 
clinical research sites to review participants records, including consent forms, CRFs, and 
laboratory records to ensure protection of study participants, compliance with IRB approved 
protocol/amendments, and accuracy and completeness of records. The monitors will inspect sites’ 
regulatory files to ensure that local regulatory requirements, in addition to U.S. Federal regulations, 
are being followed. 
 
13. ADMINISTRATIVE PROCEDURES  
13.1. Regulatory Oversight 
The proposed research study will be reviewed and approved by the IRBs of all the participating 
institutions in the U.S., Uganda and Kenya. This includes the UCSF Committee on Human 
Research (CHR), the Makerere University School of Medicine - Research and Ethics Committee 
(SOMREC), the Uganda National Council of Science and Technology (UNCST), the Kenya Medical 
Research Institute (KEMRI).  As described in Section 15.10, this study will employ four levels of 
data and participant safety monitoring including Study Steering Committee oversight, US and host 
country Institutional Review Board (IRB) review, Data Safety Monitoring Board (DSMB) Review, 
and External Clinical Site Monitoring.  Section 10.2 describes event reporting guidelines to 
individual IRBs overseeing this study. 
 
13.2. Study Implementation 
No study activities will commence prior to approval of US and host country IRBs and all other 
required local and international institutions. This study is funded and supported by the National 
Institutes of Health. 
 
 

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13.3. ClinicalTrials.gov  
This protocol will be registered in ClinicalTrials.gov. 
 
 
 

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14. HUMAN SUBJECTS PROTECTIONS  
14.1. Institutional Review Board/Ethics Committee  
The proposed research study will be reviewed and approved by the IRBs of all the participating 
institutions in the U.S., Uganda and Kenya. This includes the UCSF Committee on Human 
Research (CHR), the Makerere University School of Medicine - Research and Ethics Committee 
(SOMREC), the Uganda National Council of Science and Technology (UNCST), the Kenya Medical 
Research Institute (KEMRI). 
 
14.2. Vulnerable Participants  
Many persons living in these regions of East Africa are economically or educationally 
disadvantaged, by American or African standards. The investigative team believes that the 
opportunity to participate in this study should be made available to people independent of 
economic and educational attainment. Participants in rural populations and those who are 
educationally disadvantaged are among those most at risk in their country for poor HIV care 
outcomes, and it is important to provide opportunities to participate in research to all people 
independent of their literacy. If a potential study participant is unable to read or write, his or her 
fingerprint will substitute for a signature, and a signature from a witness to the informed consent 
procedures will be obtained. Participants taking part in activities for which a verbal consent is 
required will have the consent text read to them in their language. None of the diagnostic tests or 
procedures provided in the study are more harmful to children or pregnant women as compared to 
others. All tests and treatments provided are standard of care.  Prisoners (incarcerated persons) 
will not be included in the research during incarceration.  
 
14.2.1. Pregnant Women and Fetuses  
Pregnant women may take part in the study and could benefit from their participation through 
testing or intervention activities.  None of the diagnostic tests or procedures provided in the study 
are more harmful to pregnant women and fetuses as compared to other groups. 
 
14.2.2. Children  
Youth aged 15 years and up are among the populations most in need of improved HIV outcomes 
and are a group targeted for participation this study.  The Uganda National Council for Science and 
Technology (UNCST) has determined that individuals aged ≥14 years are able to provide 
independent consent for research if they have a sexually transmitted infection, and the National 
AIDS and STI Control Programme (NASCOP) and Kenya Medical Research Institute (KEMRI) 
state that individuals aged ≥12 years are able to provide independent consent for research.  In 
both Uganda and Kenya, children of the age represented in this study can obtain HIV testing 
services and HIV care without parental consent, and including parental accompaniment could 
significantly inhibit youth from accessing these services.  As with adults, participants <18 years will 
be given sufficient time to read or be read the consent form in their language and to ask any 
questions.  None of the diagnostic tests or procedures provided in the study are more harmful to 
youth as compared to other groups. 
 
14.2.3. Illiterate Participants  
They study will enroll participants who may be economically or educationally disadvantaged.  
Participants in rural populations and those who are educationally disadvantaged are among those 

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most at risk in their country for poor HIV care outcomes, and it is important to provide opportunities 
to participate in research to all people independent of their literacy.  If a potential study participant 
is unable to read or write, his or her fingerprint will substitute for a signature, and a signature from 
a witness to the informed consent procedures will be obtained.  Participants taking part in activities 
for which a verbal consent is required will have the consent text read to them in their language.  As 
with other groups, illiterate participants will be provided sufficient time to be read the consent form 
or ask questions in order to understand study procedures. 
 
14.3. Informed Consent  
14.3.1. Informed Consent Process  
All written and verbal consent forms will be translated into the local language and back translated 
into English to ensure correct use of language. Consent forms will be read aloud to participants by 
trained staff. The informed consent will describe the purpose of the study, all the procedures 
involved, and the risks and benefits of participation. Interviewers will ask participants to summarize 
the study and explain the reasons why they want to participate. Either a signature or a thumbprint 
(for those who cannot read) will be acceptable to confirm informed consent for participation in the 
study, in the case of written consent forms.  Witnesses independent from the study will be required 
to be present for consent discussion and co-sign consent forms for participant who are illiterate. 
Affirmation of verbal consent will be obtained through recording to responses on verbal consent 
logs. Consent documentation may be tablet versus paper based to maintain optimal infection 
control.  
 
To minimize the likelihood of persons feeling pressured to participate in research we will 
emphasize the concepts of individual voluntary choice to participate in research and the need for 
research assistants to respect the voluntary choice of others during the process of obtaining 
informed consent. Study participants will also be informed that participation can be stopped at any 
point during the study at their request.  Descriptions of individual consent forms and procedures 
are below. 
 
Written consent for Phase A Dynamic Prevention Intervention components:  Participants taking 
part in the randomized controlled trials of PrEP/PEP activities in Phase A will meet with study staff 
to review the services offered and provide informed written consent to take part after being given 
adequate time to review the consent form have all questions answered.  Participants who are aged 
≥15 to ≤17 years and are not deemed mature or independent minors by the governments of 
Uganda and Kenya will require parental co-consent on the same written consent document in order 
to participate. 
 
Written consent for Phase A Dynamic Treatment Intervention components:  Participants taking part 
in the randomized controlled trials of the Mobile Travel Pack and Alcohol Use intervention activities 
in the Phase A clinics, or in the Hypertension Linkage or Treatment trials, will meet with study staff 
to review the services offered and provide written informed consent to take part after being given 
adequate time to review the consent form have all questions answered.  As described in Section 
15.2.2, both Uganda’s UNCST and Kenya’s NASCOP and KEMRI institutions state that individuals 
who are aged ≥15 to ≤17 years may consent independently if the research involves study of a 
sexually transmitted infections. 
 

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Verbal Consent for Hypertension Screening in Phase A:  Participants taking part in screening for 
the hypertension linkage or treatment studies will meet with study staff to review the services 
offered and provide informed verbal consent to take part.  The verbal consent form will be read to 
them in the local language, confirmation of consent will be documented as affirmation of their 
agreement to participate. 
 
Verbal Consent for HIV Screening and Referral for Alcohol Intervention in Phase A:  Participants 
who are candidates for the alcohol intervention study will be offered multi-disease screening 
including HIV testing and alcohol use-related questions at the health facility and will provide 
informed verbal consent to take part.  The verbal consent form will be read to them in the local 
language, confirmation of consent will be documented as affirmation of their agreement to 
participate. 
 
Written Consent for Surveys, In-Depth Interviews and Focus Group Discussions in Phase A and 
Phase B:  Written consent will be obtained from each youth and adult participating in: 1) stigma, 
mobility, sexual behavior, youth life-skills and behavior surveys, and each youth and adult selected 
for in-depth interviews and focus groups. Consent forms will be translated into local languages and 
a copy will be provided to participants. Participants who are aged ≥15 to ≤17 years and are not 
deemed mature or independent minors by the governments of Uganda and Kenya will require 
parental co-consent on the same written consent document in order to participate. 
 
Verbal Consent for Health Testing Activities in Phase B:  Participants taking part in the Community 
Mobilization and Mobile Outreach testing activities will meet with study staff to review the services 
offered and provide informed verbal consent to take part.  The verbal consent form will be read to 
them in the local language, confirmation of consent will be documented as affirmation of their 
agreement to participate. 
 
Written consent for the Dynamic Prevention Intervention in Phase B:  Participants taking part in the 
Dynamic Prevention intervention for PrEP (including CAB-LA if approved in-country), PEP, or HIV-
testing services with VHT/CHV re-engagemnet of youth defaulters will meet with staff to review the 
services offered and provide informed written consent to take part after being given adequate time 
to review the consent form have all questions answered.  Participants who are aged ≥15 to ≤17 
years and are not deemed mature or independent minors by the governments of Uganda and 
Kenya will require parental co-consent on the same written consent document in order to 
participate. 
 
Written consent for the Person-Centered Treatment Delivery (Dynamic Treatment Intervention) in 
Phase B – LEAP Form, Mobile Travel Pack, and Alcohol Use in Phase B: Youth and adults taking 
part in the LEAP form guided discussion, mobile services and/or alcohol counseling intervention for 
those who screen positive for heavy alcohol use, including VHT/CHV re-engagement of youth 
defaulters, will meet with staff or counselors to learn more about the research and provide informed 
written consent to take part in the specific study activities. As described in Section 15.2.2, both 
Uganda’s UNCST and Kenya’s NASCOP and KEMRI institutions state that individuals who are 
aged ≥15 to ≤17 years may consent independently if the research involves study of a sexually 
transmitted infections. 
 

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Written consent for Severe Hyptertension Treatment Telehealth in Phase B:  Eligible adults taking 
part in Severe Hypertension Treatment Telehealth will first meet with staff to learn more abou the 
research and provide informed written consent to take part. 
 
Verbal consent for Volunteer Health Team/Community Health Volunteer (VHT/CHV) staff:  Youth 
VHT/CHV members who are taking part in activities related to the engagement of defaulters of 
ARV treatment or HIV prevention therapies will be consented to have minimal demographic data 
and work history data about them collected. The verbal consent form will be read to them in the 
local language by the study coordinator or study staff, and confirmation of consent will be 
documented as affirmation of their agreement to participate.  
 
Verbal Consent for Measurement Outcomes at Month 30 in Phase B: At the time of the first visit to 
a selected Measurement Cohort household, all adult members present will be approached by study 
staff who will describe the Measurement Cohort activities and offer participation in the study.  
Households will be visited up to 3 times to identify all eligible adults (≥15 years) for participation in 
the measurement cohorts.  Consent forms will be translated into local languages and a copy will be 
provided to participants.  Identifying information will be collected from each household member, 
including name, age, and gender.  As described in Section 15.2.2, in both Uganda and Kenya 
children of the age represented in this study can obtain HIV testing services and HIV care without 
parental consent, and including parental accompaniment could significantly inhibit youth from 
accessing these services. The verbal consent form will be read to them in the local language, 
confirmation of consent will be documented as affirmation of their agreement to participate. 
 
Written Consent for Hair Sample Collection Phase B: For the subset of those participants 
encountered during Measurement Outcome activities who are HIV-negative and who are currently 
on ARV-based prevention (e.g. PrEP or PEP) and selected for hair sample collection and testing 
for ARV drug levels, study staff will review the purpose of the hair collection and testing, the 
procedures for the hair collection and that the testing will be done at a later date and that the 
results will not be shared with them. Participants who are aged ≥15 to ≤17 years and are not 
deemed mature or independent minors by the governments of Uganda and Kenya will require 
parental co-consent on the same written consent document in order to participate. Participants will 
also be consented upon enrollment in the Phase A prevention trials for blood and hair sample 
collection (for HIV diagnostics, resistance testing, and PK) in a subsection of the Phase A Dynamic 
Prevention Intervention ICF. 
 
Table 21. Consent Populations and Procedures 
Study Population 
Consent 
Number of participants  
Data Collection Tools 
Phase A Dynamic 
Prevention RCTs 
1. Written consents 
for PrEP/PEP RCTs 
in, antenatal/FP 
clinics, outpatient 
clinics, VHT 
households, and 
Youth multi-sector 
interventions  
Approximately 2200 
control/intervention 
participants 
. CRFs, PrEP/PEP MoH 
records and logs, 
surveys 

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Phase A Dynamic 
Treatment RCTs 
1. Written consent 
for Mobile Travel 
Pack RCT 
2. Verbal consent 
for health and 
alcohol screening; 
written consent for 
Alcohol use RCT 
1. Verbal consent 
for Hypertension 
screening; Written 
consent for 
Hypertension 
Linkage and 
treatment RCTs 
1.Mobile study: up to 250 
(control and intervention) 
participants 
2. Alcohol study: up to 400 
(control and intervention) 
participants 
3. Hypertension linkage: up 
to 250 (control and 
intervention) participants 
4. Hypertension treatment: 
Up to 200 (control and 
intervention) participants  
CRFs, MoH care 
records and logs, 
surveys 
Behavioral measures, 
Phase A 
1. Written consent 
for survey on 
stigma, mobility, 
sexual behavior, 
and socioeconomic 
topics 
2. Written consents 
for in-depth 
interviews and for 
focus group 
discussions  
1. A subset of participants 
taking part in Phase A RCTs 
2. A subset of participants 
and providers taking part in 
Phase A activities 
1. Survey containing 
modules on stigma, 
mobility, sexual 
behavior, and 
socioeconomic topics 
2. In-depth interview 
guides and focus 
group discussion 
guides  
 
Behavioral measures, 
Phase B 
Written consents for 
in-depth interviews 
1. HIV-negative adults from 
drinking venues:  80 
2. HIV-negative youth: 20-30 
3. Adults with heavy alcohol 
use at risk for HIV: 120 
4. HIV-positive adults 
undiagnosed/out of care: 20-
30 
5. HIV-positive youth 
undiagnosed/out of care: 20-
30 
6. VHTs: 8-12 
7. Peers: 8-12 
1. In-depth interview 
guides 
 
 
 
Community Mobilization 
(Community-Enhanced 
Reach) 
Verbal consent for 
testing activities 
All residents ≥15 years in 
intervention communities 
Testing data on tablets 
Dynamic Prevention 
Phase B – PrEP/PEP at 
HIV clinic , 
antenatal/family planning 
clinic and Youth Multi-
Sector Interventions 
1. Written consent 
for enrollment in 
Dynamic Prevention 
 
 
All participants enrolled 
PrEP/PEP/HIV-testing/CAB-
LA programs in intervention 
communities (8 
communities) who agree to 
take part 
PrEP MoH records, 
PEP MoH records, data 
on tablets 
Person-Centered 
Treatment Delivery for 
Youth, 
Pregnant/Breastfeeding 
Written consent for 
enrollment at the 
clinic or venue 
where activities are 
taking place 
Youth, pregnant/ 
breastfeeding women and/or 
unsuppressed/no VL in past 
year/newly HIV-diagnosed 
MoH care records and 
data on tablets 

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Women and 
Unsuppressed – Phase B 
  
 
who agree take part in LEAP 
activites 
Severe Hypertension 
Treatment Telehealth – 
Phase B 
Written consent for 
enrollment in 
Severe 
Hypertension 
Telehealth 
Eligible participants with 
severe hypertension who 
agree to take part 
MoH care records 
Measurement Outcomes 
1. Verbal consent 
for Measurement 
Outome testing and 
data collection 
activies 
2. Written consent 
for subset of 
PrEP/PEP 
recipients 
1. All community residents – 
approximately 40,000 adults, 
80,000 people total 
2. Subset of PrEP/PEP 
recipients 
 
Testing, survey, and 
MoH data 
 
14.3.2. Assent Process 
For participants aged ≥15 to ≤17 years taking part in youth-based surveys, interview guides and 
focus group discussions, and participants of this age who are taking PrEP or PEP and have agreed 
to hair sample collection for pharmacokinetic analysis, parental co-consent will be obtained on the 
same consent form that adults sign.  Separate assent forms will not be used in this study. The 
consent discussion will take place with both the participant and one parent or guardian present, 
and the informed consent process will follow the guidelines described in Section 15.3.1. 
 
As individuals over the age of 14 are allowed to independently consent for research in Kenya and 
Uganda, without the involvement of parents or guardians, if the research concerns the testing or 
treatment of a sexually transmitted disease. As noted above, the Uganda National Council for 
Science and Technology (UNCST) has determined that individuals aged ≥ 14 years are able to 
provide independent consent for research if they have a sexual transmitted infection, and the 
National AIDS and STI Control Programme (NASCOP) states that individuals aged ≥ 12 years are 
able to provide independent consent for HIV and STI screening and treatment while Kenya Medical 
Research Institute (KEMRI) allows mature minors to consent independently for research. 
 
14.3.3. Documentation of Informed Consent  
Documentation of written informed consent and verbal consent will be recorded on informed 
consent logs for all study activities.  The logs will contain the participant’s study ID, clinic ID, initials, 
name, language of consent used, and whether the individual signed the document or provided a 
fingerprint in the case of written consents, or verbally affirmed their consent in the case of verbal 
consents. 
 
14.3.4. Waiver of Informed Consent  
A waiver of consent will be obtained from all IRBs for the collection of data from medical records 
related HIV, prevention and other disease care and prevention records, from participants in both 
intervention and control communities, as shown in Table 21..  The waiver of consent will meet the 
following criteria:  (1) the research involves no more than minimal risk to the subjects; (2) the 
waiver of consent will not adversely affect the rights and welfare of the subjects; and (3) the 
research could not practicably be carried out without the waiver. 

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14.3.5. Stored Samples and Associated Data Considerations  
Hair samples collected from HIV-negative members on PrEP modalities (oral PrEP, CAB LA, or 
dapivirine ring if available in-country) or PEP in Phase A and at month 30 in Phase B will be 
collected and stored for later measurements of ARV drug levels (e.g. TFV, CAB, or DPV), which 
will be conducted at the UCSF Hair Analytical Lab in the United States.  Blood samples from 
persons who acquire HIV in Phase A prevention trials or Phase B HIV-negative members on PrEP 
modalities or PEP will be stored for additional testing for HIV diagnostics (if indicated), HIV drug 
resistance, and PrEP/PEP drug levels in-country or at the UCSF Hair Analytical Lab in the United 
States. Samples for PEth testing will be collected at Baseline and Year 3 in Phase B and stored 
until shipment to the United States Drug Testing Laboratory (USDTL) in the United States. All 
samples will labeled only with the participants’ study ID number, initials, and the date of collection.  
A database that links these samples to other identifiers will be accessed only by study investigators 
and personnel and will be password protected. 
 
All other biological samples collected during the study will be tested shortly after collection and any 
remaining specimen discarded. 
 
14.4. Risks  
Privacy: The primary risk to study participation is breach of privacy.  Care will be taken to protect 
the privacy of participants and parents/guardians, as described in Section 14.8. However, there is 
a risk that others may inadvertently see patients’ medical information, and thus their privacy may 
be compromised.  Further details on the social impact of such potential privacy breaches are 
described in section 14.5. 
Psychological Discomfort: There is the possibility of some psychological discomfort that may arise 
from questions and sensitive issues assessed in the stigma, sexual behavior, and youth life-skills 
and behaviors surveys and the in-depth qualitative interviews.  We will train all study staff involved 
with surveys and qualitative interviews to recognize signs and symptoms of psychological 
discomfort and in the use of strategies to minimize such discomfort.  This will include reminders 
that an individual may always choose to not answer any specific question that makes them 
uncomfortable or to stop surveys and interviews at any time.  Referral resources for significant 
issues will also be made available to study staff should subject referrals to care be desired. 
 
Venipuncture and fingerprick sample collection: Study sampling during testing activities will be 
done by venipuncture or fingerprick, depending on the assay. The total volume of blood taken per 
participant, including blood taken for standard health facility evaluations, is too small to for 
participants to experience any serious side-effects, although a mild and transient feeling of 
discomfort or bruising may occur at the site of sampling and bruising. 
 
Ensuring Necessary Medical or Professional Intervention in the Event of Adverse Effects: 
Procedures will be put in place for the referral and care, free of charge, for necessary medical or 
professional intervention in the event of the unlikely occurrence of severe adverse effects.  Care 
will be provided at local Ministry of Health care clinics or nearby referral hospitals as necessary. 
 
14.5. Social Impact Events  

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Individuals enrolled in this study may experience personal problems resulting from the study 
participation. Such problems are termed social impact events. Although study sites will make every 
effort to protect participant privacy and confidentiality, it is possible that participants' involvement in 
the study could become known to others, and that participants may experience stigmatization, 
discrimination or, in rare cases, intimate partner violence as a result of being perceived as being 
HIV-infected or at risk for HIV infection. For example, participants could be treated unfairly, could 
have problems being accepted by their families and/or communities, or could experience abuse by 
their partner. Problems may also occur in circumstances in which study participation is not 
disclosed, such as impact on employment related to time taken for study visits.  
 
In the event that a participant reports a social impact event, every effort will be made by study staff 
to provide appropriate assistance, and/or referrals to appropriate resources. Social impact events 
that are judged by the investigators to be serious, unexpected, or more severe or frequent than 
anticipated, will be reported to the relevant IRBs.  
 
14.6. Benefits  
Participants may receive no direct benefit to participation.  Some participants may learn of their HIV 
status or receive diagnoses of other diseases through testing activities implemented by the study 
sooner than they would otherwise, or link to appropriate facilities for the treatment or prevention of 
diseases which might not have been known to them. HIV-negative individuals may benefit from the 
enhanced services in the Dynamic Prevention intervention.  Youth, men and mobile populations 
may benefit from facilitated treatment options available in the Dynamic Treatment intervention, 
including increased or facilitated access to the clinic, counseling based on alcohol use or better 
outcomes for viral suppression related to the service delivery model.  From a societal perspective, 
knowledge gained from this study could improve strategies for reducing HIV incidence and 
improving community health. 
 
14.7. Compensation  
Participants will not receive compensation or payment in this study for taking part in research 
activities, except those randomized to the travel voucher intervention who link to care within 30 
days of screening for the Hypertension Linkage trial or those participating in in-depth interviews.  
For those individuals referred for social network health screening, transportation reimbursement 
will be provided upon linkage to the location of the health screening venue. 
 
14.8. Participant Privacy and Confidentiality  
Care will be taken to protect the privacy of participants and parents/guardians. Study participants 
will be identified only by their unique identification number on study documents except those 
maintained for contact information or consent documents.  Participant study documents will be kept 
in individual files in secure filing cabinets in the study facilities. Testing results and sample and 
results transport documentation will be maintained in the local labs but will likewise not contain 
participant identifiers and will be accessed by study personnel only. After the study is over, all files 
containing personal identifiers such as participants’ names, names of parents, guardians or 
relatives, and phone numbers and home locations will be destroyed. 
 
In order to ensure data security and integrity, the following measures will be implemented: 
• 
All members of the study team will be educated in the study protocol prior to the onset of 
the study.  

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• 
Detailed Standard Operating Procedures (SOPs) will be written for all project activities and 
be provided to relevant team members.  
• 
Team members will be thoroughly trained on the SOP’s.  
• 
Where applicable, team members will receive additional training on the use of tablet 
computers.  
• 
All data transcribed from paper will be double data entered or verified.  
• 
All electronic data will be backed up regularly.  
• 
All data will be transferred to the main Data Center in Kampala to the secure server. This 
sever is backed up on a daily basis and a monthly backup is stored off-site.  
• 
All computers, including the tablets, will be password protected.  
• 
All computers, including tablets, will be locked in a secure room each night.  
• 
Log books and CRF’s will be locked in a secure room each night. 
 
14.9. Study Discontinuation  
The study may be discontinued at any time by the IRB, NIAID, or other government entities as part 
of their duties to ensure that research participants are protected.  
 
14.10. Community Advisory Board and Other Relevant Stakeholders 
We will utilize a multilayered set of boards. These include: a) stakeholder advisory board 
consisting of representatives from the Uganda and Kenya Ministries of Health, IDRC and KEMRI 
research organizations, and PEPFAR implementing partners at the national and regional level, 
who will meet after Phase A is complete and prior to initiation of Phase B, and again at the 
conclusion of Phase B; b) formal external scientific advisory board meeting annually that 
includes experts in HIV prevention and treatment; experts in PrEP and youth in Uganda and 
Kenya; and experts in economics/development in East Africa; and c) in-country advisory board 
meeting annually with representation of MoH leads from HIV, non-communicable disease, the 
World Bank, PEPFAR implementing partners and HIV+ persons.  Finally, local community 
advisory boards will provide invaluable input and communication with biannual meetings.  We will 
have ongoing communication with the Kenya and Uganda National AIDS program, and with the 
PEPFAR implementing partners.   
 
 
 

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15. STATISTICAL ANALYSIS 
This section provides an overview of the statistical considerations. 
 
15.1 Overview  
This is a two-phase study designed to first optimize interventions and then evaluate the population-
level effects of combination intervention packages. In Phase A, we will conduct and analyze data 
from 6 individually randomized trials, one cluster randomized trial, and single arm pilot studies. We 
will evaluate Dynamic Prevention delivered in four settings (outpatient department, antenatal/family 
planning clinic, community (VHT) and youth multi-sector interventions) on prevention coverage 
among persons at risk of HIV acquisition. Two trials will evaluate Dynamic Treatment for two 
subpopulations (mobile persons and heavy drinkers) on viral suppression among HIV+ persons 
with or at risk of unsuppressed viral replication. Two trials will evaluate interventions (linkage and 
treatment) for adults with hypertension.  
 
In Phase B, we will evaluate the population-level effects of a precision community health model, 
including community-enhanced reach, person-centered delivery, and data-enhanced precision, on 
HIV outcomes (HIV incidence, PrEP/PEP coverage, viral suppression, MTCT) and community 
health (mortality, TB, hypertension control, alcohol use, and pediatric immunization coverage).  
 
Here, we describe the analytic approach for the primary outcomes in each trial. Analyses of 
secondary outcomes will be implemented analogously. 
 
15.2 Individually randomized trials in Phase A 
For all studies, the community-level inclusion/exclusion criteria, individual-level inclusion/exclusion 
criteria, recruitment process, study interventions, and study procedures have previously been 
described. Briefly in each trial, consenting participants will be randomized in a 1:1 ratio to the 
intervention or standard-of-care. Blocked randomization will be stratified on site and further 
stratified by sex for certain trials enrolling both sexes. All analyses of Dynamic Prevention in Phase 
A will restrict to participants enrolled before September 1, 2021.  
 
The primary outcome for the individual-level prevention trials will be biomedical covered 
time defined as the proportion of follow-up time that the participant is protected from HIV infection 
with either PrEP or PEP.  Follow-up time for the primary outcome will be over 48 weeks; follow-up 
time will be censored at HIV seroconversion, death, or withdrawal. Secondary and sensitivity 
analyses will examine alternative definitions of covered time, including restricting follow-up to 
periods of self-reported HIV risk.   
 
The primary outcome for the individual-level treatment trials is an indicator of viral 
suppression (HIV RNA<400 cps/mL). The primary outcome is viral suppression at 48 weeks 
for the mobility intervention trial and 24 weeks for the alcohol intervention trial. In both trials, 
the primary analysis will exclude individuals who die or withdraw during follow-up; the alcohol 
intervention study will additionally exclude participants who move out of the study region. In the 
primary analysis, participants who do not have a viral load measurement within the ascertainment 
window will be assumed to be unsuppressed; secondary analyses will adjust for incomplete 
ascertainment of viral loads. Additional sensitivity analyses will assess the robustness of these 
analytic choices. 
 
The primary outcome for the hypertension linkage trial is an indicator of linkage to 
hypertension care by 30 days. The primary definition will rely on clinical records; individuals 
without records will be assumed to never have linked. To assess the impact of the voucher, we will 

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examine, as a secondary outcome, linkage to the scheduled appointment. The primary outcome 
for the hypertension treatment trial is blood pressure control (<140/90 mmHg) at 24 weeks. 
The primary definition will rely on three repeated blood pressure measurements using standard 
procedures, with participants considered controlled if the average of the 2nd and 3rd 
measurements is <140/90 mmHg. In the primary analysis, participants who do not have their blood 
pressure measured within the ascertainment window will be assumed to be uncontrolled; 
secondary analyses will adjust for incomplete ascertainment of blood pressure measures.  
 
In these trials, we will evaluate the interventions using targeted maximum likelihood estimation 
(TMLE), which provides precision and power gains over an unadjusted approach (e.g., the 
Student’s t-test) by adjusting for stratification factors and for chance imbalance between 
randomized arms on additional baseline predictors of the outcome.104 In secondary analyses, we 
will also implement an unadjusted estimator, the contrast of arm-specific average outcomes. In the 
prevention trials, we will test the null hypothesis of no changes in covered time due to the 
intervention with a two-sided test at the 5% significance level. In the treatment and linkage trials, 
we will test the null hypothesis of no improvements in outcomes due to the intervention with a one-
sided test at the 5% significance level. We will also report point estimates and 95% confidence 
intervals for each effect measure and the arm-specific average outcomes.  
 
15.2.1 Power calculations for individual-level trials  
Power and sample size calculations for Phase A individual-level trials were based on standard 
formulas for a two-sample t-test (dynamic prevention) and two-sample test of proportions (dynamic 
treatment and linkage), using power.t.test and power.prop.test in R, respectively.105 All input 
parameters were informed by SEARCH data, when possible. We expect these calculations to be 
conservative, because of the precision gained through stratified randomization and through 
covariate adjustment during the analysis.104 
 
Since the prevention trials at antenatal clinics and outpatient departments have the same outcome 
(prevention coverage), we use the same sample size and power calculations for both. For each 
outcome, Figure 4 provides the effect size, on the absolute scale, detected with 80% power 
varying the number of participants per arm and outcome under the standard-of-care with a two-
sided hypothesis test at the 5% significance level.  

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Figure 4: Effect size (in percent improvement) detected with 80% power for a given sample size 
and outcome under the standard-of-care for the prevention trials at antenatal clinics and the 
outpatient department (top left), the mobility intervention trial (top right), alcohol intervention trial 
(middle left), the HTN linkage trial (middle right), and the HTN treatment trial (bottom). For 
example, an effect size of 10% corresponds with an increase in prevention coverage from 30% to 
40%.   
 
For the individually randomized prevention trials (delivered at the antenatal clinic and outpatient 
department), we anticipate having 80% power to detect at least a 9.8% absolute increase in 
prevention coverage with a standard deviation of 0.35 and 200 participants/arm. Even with 25% 
attrition (from 200 to 150 participants/arm) and higher than expected variability (e.g., standard 
deviation=0.40), these calculations suggest we would be well-powered to detect at least a 13% 

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absolute increase in prevention coverage. To ensure sufficient power, we will thus enroll at least 
400 participants per prevention trial for measurement of the primary endpoint.  
 
For the mobility trial, we anticipate having 80% power to detect at least a 19.7% absolute increase 
in viral suppression at 48 weeks from 40% under the standard-of-care and with 100 
participants/arm. Even with 25% attrition (from 100 to 75 participants/arm) and lower or higher 
suppression under the standard-of-care, these calculations suggest we would be well-powered to 
detect at least a 22.3% absolute increase in suppression. To ensure sufficient power, we will thus 
enroll at least 200 participants in the trial.  
 
For the alcohol trial, we anticipate having 80% power to detect at least a 14% absolute increase in 
viral suppression at 24 weeks from 40% under the standard-of-care and with 200 participants/arm. 
Even with 25% attrition (from 200 to 150 participants/arm) and lower or higher suppression under 
the standard-of-care, these calculations suggest we would be well-powered to detect at least a 
16% absolute increase in suppression. To ensure sufficient power, we will thus enroll at least 400 
participants in the trial.  
 
For the hypertension linkage trial, we anticipate having 80% power to detect at least a 19.3% 
absolute increase in linkage from 50% under the standard-of-care and with 100 participants/arm. 
Even with 25% fewer participants enrolled (from 100 to 75 participants/arm) and lower or higher 
linkage under the standard-of-care, these calculations suggest we would be well-powered to detect 
at least a 22.7% absolute increase in linkage. To ensure sufficient power, we will thus enroll at 
least 200 participants in the trial. For the hypertension treatment trial, we anticipate having 80% 
power to detect at least a 20% absolute increase in hypertension control from 40% under the 
standard-of-care (estimated based on SEARCH) with 100 participants/arm. Even with 20% fewer 
participants enrolled (from 100 to 80 participants/arm) and lower or higher control under the 
standard-of-care, these calculations suggest we would be well-powered to detect at least a 22% 
absolute increase in control. To ensure sufficient power, we will thus enroll at least 160 participants 
(and a maximum of 200 participants) in the trial.  
 
15.3 Cluster randomized trials for Phase A 
For the VHT cluster randomized trial (CRT), the community-level inclusion/exclusion criteria, 
individual-level inclusion/exclusion criteria, recruitment process, study interventions, and study 
procedures have previously been described. Briefly, N=16 villages (served by VHTs) will be 
randomized in a 1:1 ratio to the intervention or standard-of-care, after matching on country. Within 
each cluster, participants will be consented and enrolled in the measurement cohort if HIV-
uninfected and at risk of HIV acquisition. Analyses of the VHT trial will restrict to participants 
enrolled before September 1, 2021.  
 
The primary outcome for the cluster-level prevention trial will be biomedical covered time, 
defined as in the individually randomized prevention trials. As before, follow-up time for the primary 
outcome will be over 48 weeks; follow-up time will be censored at HIV seroconversion, death, or 
withdrawal. Secondary and sensitivity analyses will examine alternative definitions of covered time, 
including restricting follow-up to periods of self-reported HIV risk.   
 
Prevention coverage will be compared between arms using a TMLE, adapted to appropriately 
account for the dependence of outcomes within clusters.5, 106 107 Given the limited number of 
clusters, we will use Adaptive Pre-specification to optimally adjust for covariate imbalance between 
randomized arms, while preserving Type-I error control.108 In secondary analyses, we will 
implement the unadjusted estimator as the contrast of the average arm-specific outcomes. We will 

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test the null hypothesis that the Dynamic Prevention did not improve prevention coverage, as 
compared to standard-of-care, with a two-sided test at the 5% significance level.  
 
15.3.1 Power calculations for the cluster-level trial 
Figure 3 provides the sample size and power calculations for the VHT trial based on standard 
formulas for CRTs (Chapter 7 of Hayes and Moulton).107 All input parameters were informed by 
SEARCH data, when possible. We expect these calculations to be conservative, because of the 
precision gained through stratified randomization and through covariate adjustment during the 
analysis. 
 
For Dynamic Prevention delivered via VHTs, we anticipate an average (harmonic mean) 20 HIV-
uninfected cohort members per cluster. Assuming 10% coverage under the standard-of-care, a 
standard deviation of 0.35, and matched coefficient of variation of km=0.25, we anticipate 80% 
power to detect at least a 15% absolute increase in prevention coverage with N=16 clusters (N=8 
clusters/arm). Even with 20% fewer participants (from 20 to 16 participants/cluster), these 
calculations suggest we would be well-powered to detect at least a 16.5% absolute increase in 
prevention coverage. 
 
 
Figure 5: For the cluster-level prevention trial, the effect size (in percent improvement) detected 
with 80% power for a given cluster size N=16 villages total. Calculations assume a standard 
deviation of 0.35, a matched coefficient of variation of km=0.25 (informed by SEARCH data) and 
vary coverage under the standard-of-care. 
 
15.4 Additional analyses to optimize dynamic prevention and treatment 
For each trial, we will assess the fidelity to intervention implementation, intervention adoption, and 
process outcomes. We will also examine feasibility and prevention coverage in the youth 
multisectoral intervention pilot studies.  
 
To understand effect heterogeneity, we will repeat the analyses outlined above within the following 
pre-specified subgroups: country, sex (for trials enrolling both sexes), age group (for trials enrolling 
adults of all ages), and may include mobility (for trials enrolling both mobile and non-mobile adults). 
 
For each of the trials, we will provide descriptive statistics of populations and outcomes, overall as 
well as stratified by intervention arm and country. We will further evaluate predictors of sub-optimal 
outcomes using TMLE (primary) and with univariate associations (secondary). For interventions 
with suggested efficacy, we may examine pathways of intervention action using formal mediation 
analyses.109, 110 These analyses will be complemented with participant and provider qualitative data 
and mixed method approaches.  

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Finally, to quantify the potential spillover between randomized arms and to understand secular 
trends in the clinic-based intervention trials for Dynamic Prevention (outpatient department and 
antenatal/family planning clinic) and for Dynamic Treatment (mobile populations and heavy 
drinkers), we may conduct retrospective record review to obtain endpoint measures before the 
trials’ initiation and compare them with endpoints measured during the trials’ follow-up through a 
pre-post analysis. Additionally, we may use difference-in-differences to compare each trial’s 
intervention arm and each trial’s control arm to the external controls.111 
 
15.5 Community randomized trial in Phase B 
In Phase B, we will randomize the N=16 study communities pair-matched on predictors of the 
primary endpoint (HIV incidence) and stratified by country.  
 
We will assess population-level effects with Two-Stage TMLE, an approach appropriate for cluster 
randomized trials.5, 106 In Stage I, we estimate the outcome for each community. Then in Stage II, 
we use a cluster-level TMLE to estimate intervention effectiveness by comparing the community-
specific endpoints between randomized arms. Given the limited number of clusters, we will use 
Adaptive Pre-specification to optimally adjust for covariate imbalance between randomized arms, 
while preserving Type-I error control.108 In secondary analyses, we will implement the unadjusted 
estimator as the contrast of the arm-specific mean outcomes. For each endpoint, we will test the 
null hypothesis of no improvement from the intervention with a one-sided test at the 5% 
significance level. We will also report point estimates and two-sided 95% confidence intervals for 
each effect measure and the arm-specific mean outcomes.  
 
The primary study outcome is HIV incidence among adult community members and assessed at 
month 30 with a recency assay. Stage I estimates of HIV incidence (per 100 person-years) will 
account for assay characteristics, such as mean duration of recent infection (MDRI) and false 
recent rate (FRR). Stage II estimates will use leave-one-out cross-validation to select from the 
following community-level covariates the combination that maximizes empirical efficiency: baseline 
HIV prevalence, baseline proportion with HIV who are suppressing viral suppression (<400 c/mL), 
or nothing (unadjusted). 
 
The following secondary outcomes will be compared between arms using the analogous two-stage 
approach:  
• 
Biomedical prevention coverage: proportion of HIV-negative follow-up time during which 
the participant was protected from HIV by PrEP or PEP (inclusive of CAB-LA) 
• 
Population-level viral suppression: proportion of adults with HIV who are suppressinv 
viral suppression (HIV RNA level < 400 c/mL) at month 30 
• 
Mortality: the incidence (per 100 person-years) of death to illness and incidence of death 
due to all causes among adults  
• 
Annual incidence of active TB disease, overall and stratified by age group and HIV-
association 
• 
Hypertension control (BP<140/90 mmHg) among community members aged 30+ years at 
month 30 
• 
Prevalence of heavy alcohol use (AUDIT-C value of 3+ among women and 4+ among 
men) among persons with HIV and age 18+ years at month 30 
• 
Infant HIV-free survival: the proportion of infants boarn to women with HIV or HIV-
unknown status who are alive and without HIV at month 30 
Pediatric immunization coverage: the proportion of children (aged < 5 years) with up-to-
date vaccination at month 30 
 

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15.5.1 Power calculations for Phase B 
For primary endpoints of HIV incidence, we present the following power calculations based on 
inctools R package,1 which implements and extends the HIV incidence methods of Kassanjee et 
al.112 The R package is a more robust implementation of the prior ABIE (Assay Based Incidence 
Estimation) spreadsheet tool, developed by the CEPHIA (Consortium for the Evaluation and 
Performance of HIV Incidence Assays). When possible, we used prior data to inform key 
parameters, including (i)community size, (ii) HIV prevalence, (iii) expected testing coverage, (iv) 
expected outcome under the standard-of-care, and (v) recency assay characteristics.2, 3 We expect 
these calculations to be conservative, because of the precision gained through our pre-specified 
choice of a one-sided hypothesis test and through covariate adjustment during the analysis.5, 104, 106 
 
With 16 communities (8 per arm) each with ~5000 adults, 10% HIV prevalence, and 90% testing 
coverage, we anticipate being powered at 80% to detect a 40% relative reduction in annual HIV 
incidence from 0.5% in the standard-of-care (control) with a two-sided hypothesis test (α=0.05), a 
design effect of 1.3, mean duration of recent infection (MDRI) of 238, and false recent rate (FRR) 
of 0%. As shown in Figure 6, these calculations are fairly robust to the test coverage achieved and 
HIV incidence under the standard-of-care. 
 
 
Figure 6: For the Phase B cluster randomized trial, the effect size (in relative reduction in HIV 
incidence) detected with 80% power varying testing coverage and HIV incidence under the 
standard-of-care (control).  
 
15.6 Additional explanatory and descriptive analyses for Phase B 
For the 16 communities participating in Phase B, we will provide descriptive statistics of the 
baseline characteristics of study participants, overall and stratified by country. Characteristics 
reported will include sex, age, marital status (single, married, widowed, divorced/separated), 
education (no school, primary, secondary, post-secondary), occupation,  and mobility. For each 
study outcome compared between arms, we will also report formal consort diagrams as well as 
participant flow diagrams enumerating inclusions and exclusions for all clusters and individuals 
contributing to each analysis. 
 
Implementation evaluation will be based on the RE-AIM framework. We will also conduct 
multivariable analyses to evaluate risk factors for poor outcomes, including viral non-suppression, 
low prevention coverage among persons at risk of HIV, and HIV seroconversion. Variable 
importance measures will be estimated with a pooled individual-level TMLE with the community 

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treated as the independent unit.106  We will implement analogous predictor analyses for other 
community health outcomes.  
 
To inform our understanding of mechanisms of action, we may specify hierarchical causal models 
to represent the relationships between key study variables, including the community-level 
intervention, community-level mediators, individual-level mediators, and individual-level 
outcomes.104, 109, 110 We may assess mediation at the community-level, using methods analogous to 
the individual-level mediation analyses. We may augment these cluster-level analyses with multi-
level mediation analyses.  
 
16. PUBLICATION POLICY  
The findings from this study may be published in a medical journal. No individual identities will be 
used in any reports or publications resulting from the study. The researchers will publish results of 
the study in accordance with NIH, UCSF, UNCST, KEMRI and Makerere University guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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18. APPENDIX Extension of Dynamic Prevention Studies and Procedures for 
measuring implementation on Cabotegravir Injectable Suspension (CAB-LA) 
National Clinical Trial (NCT) Identified Number: NCT05549726 
 
This Appendix describes the continuation of the 3 Dynamic Prevention Randomized studies 
(refer to section 9.2.1 of protocol) for a 48 week follow up period following re-consent for this 
CAB-LA extension. Persons who are already enrolled in the trials and were randomized to the 
intervention arm will be eligible to receive CAB-LA as one of the options in the “Dynamic 
prevention” model.  Persons in the control arms will be eligible to receive CAB-LA if and when it 
is rolled out through in country programs.  If CAB-LA is not available in country at the 48-week 
endpoint, all participants in the intervention arm will have the opportunity to continue in the study 
until Week 96, and participants who are currently on CAB-LA may continue through the 
extension. The study will end at Week 96, and by that time participants will be transitioned to in 
country prevention care. At 96 weeks, persons on CAB-LA will be transitioned to in country 
CAB-LA or to other prevention options if CAB-LA is not available. Prior to this transition, 
available in country options will be assessed by the study team.  HIV prevention options will be 
discussed with each study participant by their Week 88 visit, with a plan established for the 
transition to the participant’s preferred prevention method in coordination with local health 
facilities to avoid interruption after their 96 weeks of study participation is completed.    
 
The overall purpose of this extension is to 1) Determine if adding the option of CAB-LA as a 
prevention choice using a patient-centered HIV prevention delivery model increases prevention 
coverage (i.e. proportion of time that is covered by a biomedical prevention option, such as 
PrEP or PEP) compared to the standard-of-care in 3 ongoing randomized trials of Dynamic 
Choice Prevention in rural Uganda and Kenya; and, 2) Conduct a hybrid implementation study 
(Primary Objective Clinical and Secondary Objective Implementation) focusing on initial 
implementation of a patient-centered model for CAB-LA using the RE-AIM evaluation framework 
among persons randomized to the intervention arms.     
 
A. Background and Rationale 
 
Background: SEARCH Sapphire is an ongoing, NIH-funded study that is testing multi-disease 
and multi-sector interventions aimed at reducing HIV burden and improving health in rural 
Uganda and Kenya. Phase A is a portfolio of randomized prevention and treatment 
implementation studies that will inform a population-level study in Phase B (refer to section 3.0 
of protocol).  
 
This appendix describes a 48-week extension of 3 ongoing randomized trials in Phase A 
studying a patient-centered “Dynamic Choice Prevention” (DCP) implementation strategy for 
delivering existing evidence-based biomedical prevention interventions vs. standard of care 
(SOC). The Dynamic prevention model offers participants choices on prevention modality on an 
ongoing basis: oral PrEP, or oral PEP, and the option to switch between products. The trials are 
being conducted in 3 settings: antenatal (ANC) clinics, the outpatient department (primary care 
clinics), and in rural community settings in Western Kenya and Uganda (refer to section 9.2.1 of 
protocol). All clinic and village health team staff (i.e., Clinical Officers, nurses, coordinators, 
health workers) are trained and equipped for HIV prevention care in the clinical setting, 
appropriate to their role (refer to section 9.2.1.1 of the protocol). 
 
In the CAB-LA extension, participants in the intervention and control arms are reconsented and 
remain in their initial randomized arm. Persons in the intervention arms who remain HIV 

  
94 
 
negative will be offered CAB-LA as an additional biomedical prevention option, if eligible.  CAB-
LA will be delivered at health clinics. The primary 48-week endpoint for this extension is 
proportion of time covered by a biomedical prevention product.  As of May 9, 2022, a total of 
1213 HIV-negative persons aged 15 years and older and at risk for HIV acquisition were 
enrolled in the studies. (Table 1). New participants are being enrolled at the present to time to 
replace those participants who have moved and have been unable to continue in the CAB-LA 
study. The total number of participants in the study eligible for CAB-LA will not exceed the 593 
listed in Table 1. 
 
 
Table 1. Enrollment in 3 SEARCH Sapphire Dynamic Prevention Trials as of May 9, 2022  
Dynamic 
Prevention 
Study  
Intervention 
and Control, 
(N) Uganda  
Intervention  
(N) Uganda  
Intervention 
and Control, 
(N) Kenya 
Intervention 
(N) Kenya  
Total 
Enrolled 
(N), 
Intervention 
and Control   
Total 
Enrolled 
Intervention 
(N) 
Antenatal/SRH 
Clinic  
200 
100 
201 
103 
401 
203 
Outpatient 
Department 
Clinics  
201 
100 
201 
97 
402 
197 
Household Study 
Community 
Village Health 
Team (VHT)  
200 
83 
210 
110 
410 
193 
All Trials 
Together  
601 
283 
612 
310 
1213 
593 
 
 
Population: The persons eligible for participation in the extension are those who were enrolled 
in the 3 ongoing trials. Persons for the ANC study are recruited and enrolled through offering 
study participation at ANC clinics at government sponsored health facilities. Persons for the 
Outpatient department are recruited and enrolled through offering study participation at 
Outpatient department clinics at government sponsored health facilities. Persons for the 
community study are recruited via home visits by village health teams/community health 
workers (refer to section 7.5.1 of protocol). 
 
Inclusion criteria for the Extension include:  
1) Enrollment in a SEARCH Sapphire Dynamic prevention study 
2) HIV negative at start of extension 
3) Residing in study region 
 
Additional inclusion criteria to access CAB-LA as a prevention option  
1) Not pregnant at time of initial CAB-LA injection 
2) Participant weighs at least 35kg 
 
Additional Exclusion Criteria to access CAB-LA as a prevention option 
1) Participant has Hepatitis B or chronic Hepatitis C Diagnosis  
2) Participant has ALT >=5x ULN 
3) Participant has clinical history of liver cirrhosis or current clinical evidence of cirrhosis or 
severe liver disease 
4) Previous hypersensitivity reaction to cabotegravir  

  
95 
 
5) Receiving the following co-administered drugs for which significant decreases in 
cabotegravir plasma concentrations may occur due to uridine diphosphate 
glucuronosyltransferase: 
i. Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin 
ii. Antimycobacterials: Rifampin, rifapentine 
6) Participants with a current or anticipated need for chronic systemic anticoagulation or a 
history of known or suspected bleeding disorder, including a history of prolonged 
bleeding, except for the use of anticoagulation for deep vein thrombosis (DVT) 
prophylaxis (e.g., postoperative DVT prophylaxis) or the use of low dose acetylsalicylic 
acid (≤325 mg). 
 
 
Study Intervention Clinic Locations: All participating ANC and OPD clinics in the DCP trial will 
offer CAB-LA. For VHT/CHV communities, the nearest health facility will offer CAB-LA for all 
participants 
1) In Uganda, the sites for each of the trials: 
a. OPD: Itojo Hospital, Kitagata Hospital 
b. ANC: Bwizibwera HCIV, Bushenyi HCIV 
c. VHT: Ndeija Health Center III 
2) In Kenya, the sites for each of the trials: 
a. OPD: Magunga Level IV Hospital, Oyani Hospital 
b. ANC: Oyani Hospital, Sena Health Centre 
c. CHV: Sibouche Health Centre, Ogongo Sub-District Hospital 
 
The demographic characteristics of the persons enrolled in the intervention arm as of May 9, 
2022 currently who will be eligible for CAB-LA patient-centered intervention are shown in Table 
2. 
 
Table 2. Demographics of persons in intervention arm eligible for CAB-LA in extension 
phase of trial as of May 9, 2022.  
ANC Clinic  
Outpatient 
Department  
Community   
Total Enrolled  
203  
197  
193  
Female Participants   
203 (100%)  
119 (60.4%)  
111 (57.2%)  
Age years number 
and %  
   
   
   
   15-25 years   
120 (56.9%)  
90 (44.1%)  
75 (38.9%)  
   26- 30  
47 (22.3%)  
33 (25.0%)  
29 (25.4%)  
   31-40  
35 (16.6%)  
51 (16.2%)  
49 (18.7%)  
   41-60   
9 (4.3%)  
26 (12.7%)  
36 (15.0%)  
   61+  
0 (0%)  
4 (2.0%)  
4 (2.1%) 
  
Rationale: HIV prevention services that offer choice of prevention products (PrEP & PEP) and 
flexibility in their use and location of delivery over time allow for a dynamic, patient-centered 
model of prevention. This approach is responsive to the reality of an individual’s changing 
needs, thereby facilitating continued engagement. CAB-LA is highly efficacious for HIV 
prevention that was recently approved by the US FDA based on two large, randomized trials 
HPTN 083 and HPTN 084. As CAB-LA is rolled out across rural sub-Saharan Africa, it is 

  
96 
 
important to determine how the addition of this option impacts prevention coverage in real-
world settings for women and men at risk for HIV. In addition, it is critical to design, evaluate, 
and improve patient-centered CAB-LA delivery strategies that maximize uptake and impact of 
this new product.    
 
Ethical Considerations: The HPTN 084 study that showed efficacy of CAB LA for prevention 
included sites in both Uganda and Kenya. Applications for approval of CAB LA are under review 
in each of these countries. Thus,  the information generated in this study on evaluating a 
dynamic prevention implementation strategy will be directly applicable.  During this proposed 
study extension, CAB LA is expected to become publicly available through Ministry of Health 
(“MoH”) sponsored programs (in both Kenya and Uganda). UCSF is developing an additional 
extension to 96 weeks, which will examine longer-term safety and implementation data of CAB-
LA. Should there be delay in rollout of the MoH programs, participants could continue in this 
additional extension phase. After the endpoint of the 96-week extension is reached, participants 
will be transitioned to a standard of care regimen, via local healthcare system, based on the 
investigator’s clinical judgment and local country guidelines  
 
B. Hypothesis and Objectives  
 
Hypotheses: A dynamic choice prevention model that includes a patient-entered CAB-LA 
delivery option will have higher levels of biomedical prevention coverage (assessed over 48 
weeks following re-consent for the CAB-LA extension study) compared to the standard of care.   
 
This hypothesis will be tested by comparing covered time between the intervention and 
control arms in the 3 ongoing randomized trials during the extension phase.  
 
The secondary hypothesis:  Addition of patient-centered CAB-LA into an ongoing dynamic 
choice prevention will improve biomedical prevention coverage (compared to dynamic choice 
prevention without CAB-LA).  
 
These hypotheses will be tested by comparing covered time during the extension with 
the CAB-LA option to covered time prior to the extension among intervention arm participants.  
 
We expect that incorporating the option of CAB-LA with patient-centered delivery for persons 
who self-identify at risk for HIV living in rural Uganda and Kenya will increase overall biomedical 
covered prevention time compared to the standard of care. In a population that has been offered 
-- and some of whom have taken up -- oral PrEP and PEP, we also expect to learn 
characteristics of who is most interested in CAB-LA, how our patient-centered CAB-LA delivery 
models work in different settings, and the cost of the delivery models in different settings.  
 
Primary Objective: To compare biomedical prevention coverage achieved using a Dynamic 
prevention model that includes a patient-centered CAB-LA delivery intervention to biomedical 
prevention coverage under the standard of care over 48 weeks.  
 
Secondary Objectives: To determine the reach, effectiveness, adoption, implementation and 
maintenance of a patient-centered CAB-LA program embedded in 3 ongoing trials in the setting 
of antenatal clinic, outpatient clinic, and community.  
 
Tertiary Objectives: To evaluate change in knowledge, awareness and 
acceptability/satisfaction at the staff and provider level with CAB-LA before and after provider 
and staff training and education in CAB-LA with patient-centered delivery model. 
 

  
97 
 
C. Study Design and Schema 
 
Study Design: This proposal is an extension of 3 ongoing randomized trials comparing a 
patient-centered “Dynamic Choice” implementation strategy for delivering biomedical 
prevention options compared to standard of care (Figure 1). Each trial is enrolling persons 
15 years of age and older who are HIV uninfected and at risk of acquiring HIV. The Dynamic 
Choice Prevention intervention allows choice of PEP/PrEP, refill schedule, service delivery 
location (e.g. clinic, community, home), and HIV testing (self or staff). Persons can move from 
PEP to PrEP as they prefer (refer to section 9.2.1.4 of protocol). 
 
 
 
 
Figure 1. Dynamic Choice Implementation Strategy  
 
 
 
Intervention: In the extension phase, participants will remain in their initial randomization arm. 
For persons in the intervention arm, CAB-LA will be integrated into the dynamic choice delivery 
model as an additional biomedical prevention option in a patient-centered delivery model based 
on the precede framework. 
 
The Dynamic Choice Delivery Model includes integrated PrEP and PEP services at outpatient 
clinics, antenatal clinics, and via VHT workers in community households. The procedures for 
each trial include PrEP/PEP counseling and services, choice of service location, HIV testing 
options, option for longer PrEP refills, provision of a clinical officer’s or nurse’s mobile telephone 
number for immediate PEP starts any day of the week, assessment of PrEP/PEP barriers and 
personalized actions, psychologic supports for traumatic experiences, and offer of concurrent, 
additional health or prevention related services (Table 10 of Main Protocol). For participants that 
chose CAB-LA as the biomedical prevention option, the patient-centered delivery model (Table 
3) will be implemented.  The standard of care differs according to country but does not routinely 
offer PEP or PrEP to clients seeking services, does not offer choice of service location, HIV 
testing option or access to medical provider mobile phone number. Clients are required to return 

  
98 
 
after one month for a refill for PREP, whereas in our model, there is an option from the start for 
3 month medication supply. 
 
 
Table 3. Patient-Centered Delivery Model 
Intervention  
Population and frequency 
Purpose 
Education, case studies and discussion on concept 
of  dynamic prevention and on the profile of each 
prevention option product  
Health center leadership and staff, 
provider, participants;  initial and 
ongoing  
Predisposing  
Integration into antenatal, OPD clinics, IPV/GBV 
support services, travel packs, 24 hour hotline for 
participants   
For oral PrEP/PEP only- HIV testing choice (self or staff) 
and home or clinic delivery 
Participants;  ongoing  
Enabling 
Provider text/check-in to participant one week after 
starting new option, data on biomedical prevention 
covered time (reinforcing)  
Participants and staff; ongoing data 
feedback  
Reinforcing 
 
Outcomes: The primary outcome for the extension is the proportion of time covered by a 
biomedical prevention option during the 48 week follow-up period of the CAB-LA Extension; 
follow-up time will be censored at HIV diagnosis, death, or withdrawal. Biomedical covered time 
is defined as the proportion of follow-up time that each participant is covered by either PrEP 
(TDF/3TC or CAB-LA) or PEP. For TDF/3TC, covered time is defined using self-reported use; in 
a subset of participants who report PrEP use we will measure tenofovir drug levels using small 
hair samples to allow for calibration of self-reported measures. For CAB-LA, coverage begins 3 
days after initial injection and continues 2 months + 7 days after last injectionFor PEP, covered 
time is defined using self-reported use; in a subset of participants who report PEP use we will 
measure drug levels using hair samples to allow for calibration of self-reported measures. A 
secondary outcome for the extension is “at-risk covered time”, defined as the proportion of time 
that a participant reports being at risk of HIV infection during which they are covered by a 
biomedical prevention option. Incident HIV infections, defined by a prespecified testing 
algorithm, will be an additional secondary outcome. 
 
Secondary outcomes of reach, effectiveness, adoption, implementation and maintenance will be 
evaluated using a mixed methods approach that includes surveys of participants, and health 
center providers and staff.  Tertiary outcomes of knowledge, awareness and 
acceptability/satisfaction at the staff and provider level will be measured by surveys at the 
baseline, midpoint and end of the study.  Measurement details delineated  in Table 4 . 
 
In addition to these surveys, trained staff will conduct in depth interviews (IDI) to provide insights 
into the intervention implementation and attitudes of participants and staff. These qualitative in-
depth interviews will be conducted among purposively-selected samples of study participants 
and providers, to ascertain the perceptions of and experiences with CAB-LA use and delivery. 
Participants who are clients will be asked about 1) Experiences with counseling, method/service 
preferences and decision-making to go on CAB-LA; 2) Method/services satisfaction, barriers 
and facilitators to uptake and maintenance, and social networks and support as a facilitator or 
hindrance; and 3) Recommendations to improve CAB-LA Delivery. Health care providers 
engaged in  CAB-LA service delivery will be asked about their 1) Professional identity and 
motivation, as a potential factor influencing implementation; 2) First impressions and knowledge 

  
99 
 
of CAB-LA; 3) Clinical training experiences relevant to CAB-LA provision; 4) Experiences with 
and acceptability of individual elements of CAB-LA; and 5) Recommendations for improving 
CAB-LA delivery.  
 
For all research activities related to qualitative evaluation of SEARCH SAPPHIRE, written 
informed consent will be obtained from all selected for recruitment to the study. 
 
Qualitative IDIs for CAB-LA will be conducted between 2-6 months from enrolment. The specific 
data collection activities to be conducted during the phase are listed below. For Seroconverts, 
IDIs are will continue until the maximum number of participants is reached or the study 
intervention ends, whichever comes first. 
i. CAB-LA Patient IDI cohort: We will systematically select ~n=30 patients per each 
region (South West Uganda and Kenya) (total 40 < ~n < 72), with samples within 
region to be balanced by original trials (Out- patient, ANC/PNC, VHT); further balance 
to be observed by gender and community, proportional to overall intervention 
enrolment. 
ii. CAB-LA Provider IDI cohort: We will select a sample of care providers who administer 
CAB-LA from the CAB-LA trial health facilities or who inform the community about that 
option (VHTs / CHVs per each region. I.e. n=2-3 OPD providers, n=2-3 ANC/PNC 
providers, n-1-2 VHTs per region (total 8 < ~n < 12 providers per region).  
iii. Seroconverts Patient IDI cohort: We aim to interview all participants in the intervention 
arm who received a diagnosis of HIV during the course of the DCP study and who are 
willing to be interviewed, up to a total of 36 per country. 
 
For this study, IDIs will be recorded using the TASCAM DR-05 digital recorder. This digital 
recording device was selected for use in this study because it has a high quality microphone that 
captures high quality sound even in settings with a lot of ambient background noise. 
 
For this study, the interviews will be conducted in the participant’s preferred language. The  
Qualitative study team will then transcribe and translate the audio recorded data into English for 
analysis within 14 days of the interview. Staff will use either Express Scribe or VideoLAN Client 
(VLC) software for this process. QRCs/QRAs will share responsibility for coding all 
transcriptions of recorded IDIs. Coding will be conducted in Dedoose using a codebook 
developed iteratively by the team. Analysis will follow a modified framework analysis of key code 
excerpts exported from Dedoose after coding. 
 
Costing of CAB-LA implementation will be conducted in each region (Kenya and Uganda) and 
location type (Antenatal Clinic, Outpatient Department, Community) at Baseline/Screening and 
at two injection visits during follow-up.  Costing exercises will employ an activity-based 
approach and include site visits and employ rigorous costing methods using standardized micro-
costing tools. We will also conduct time-and-motion activities using self-administered tools with 
on-site staff to estimate the amount of time spent implementing CAB-LA.  We will interview 
study staff to identify resources used to implement the intervention and estimate time spent 
providing oversight and management of implementation activities. 
 
Implementation Research Design: The secondary objective of the extension is an 
implementation evaluation of the intervention focused on the initial implementation of patient-
centered CAB-LA using the RE-AIM framework. The domains of interest and key outcomes are 
summarized in the table below. Throughout, study weeks are used to refer to weeks in CAB-LA 

  
100 
 
extension (eg, “week 0” is date of re-consent for the CAB-LA extension, “week 48” is 48 weeks 
after re-consent for the CAB-LA extension). 
 
Table 4. RE-AIM Evaluation Framework. 
 
As a tertiary objective, we will also assess provider and staff Knowledge, Acceptability and 
Awareness via provider and staff surveys (Likert scales) and IDI at weeks 0, 24, and 48.  
 
D. Schedule of Evaluations 
 
Domain 
/Outcome 
Definition  
Measurement  
Timing  
Reach 
(Participant level)  
Proportion of eligible participants 
who initiate CAB-LA weeks 0-48. 
Characteristics (including prior PrEP 
and PEP use) and attitudes 
(knowledge, acceptability and 
feasibility) of participants using CAB-
LA 
Demographics, CAB-LA 
dispensing logs 
Knowledge, 
Acceptability and 
Feasibility (Survey and 
IDI). Evaluation includes 
focus on equitable 
access by gender, 
education and SES.  
CAB LA dispensing 
throughout follow-up 
Surveys and IDI: 
Week 0, 24 and 
week 48  
Effectiveness 
(Participant level) 
Impact of adding CAB-LA to 
Dynamic choice prevention on 
biomedical covered time 
(comparison of follow-up during the 
CAB-LA extension vs. follow-up time 
in Phase A trials prior to CAB-LA 
extension). 
CAB-LA dispensing 
logs, PrEP and PEP use 
as defined for primary 
endpoint in extension. 
Throughout follow-up  
Adoption  
(Provider and 
staff level in 
different settings) 
% of staff and providers invited that 
participate in the interventions, 
where participation is defined as  
i) participation in CAB-LA trainings; 
and ii) offering CAB-LA to 
participants. We will further assess 
the characteristics of participant vs. 
non-participant staff.   
Training attendance 
rosters; CAB-LA 
dispensing logs  
Throughout follow-up 
Implementation 
(Provider and 
systems level)  
Fidelity: Proportion of providers 
offering CAB-LA on appropriate 
schedule, appropriate provision of 
oral bridging   
Costing: Incremental cost of adding 
CAB-LA to dynamic choice 
prevention  
Adaptations: Type, timing and 
reasons they were made 
CAB-LA and oral 
bridging dispensing logs 
Time in motion and 
program costing 
Adaptation logs  
Throughout follow-up 
Maintenance 
(adapted from 
standard RE-AIM 
to accommodate 
shorter follow-up) 
(Participant level)  
Persistence on CAB-LA among 
participants who initiate CAB-LA 
Reasons for discontinuation of 
biomedical prevention or switching to 
other biomedical prevention option 
CAB-LA dispensing logs 
Participant survey on 
reasons for 
discontinuation and 
switching  
Throughout follow up 

  
101 
 
For all participants, from the time of reconsenting at the start of study CAB-LA availability (Week 
0), there will be study visits every 24 weeks for the duration of their participation.  
 
At the time of writing of this protocol version, the standard of care for both Kenya and Uganda is 
to offer biomedical prevention as part of the HIV prevention package that includes provision of 
PrEP for persons at risk of HIV acquisition, such as persons with partners living with HIV or of 
unknown HIV status, or those with a history of exchange/transactional sex, recent STIs, or 
recurrent use of PEP (more than 3 times a year). PEP is offered primarily after occupational 
exposures or in cases of sexual assault.  For participants consenting in the extension, in the 
control arm, they will continue to be seen by government staff in the HIV clinic or other service 
location, like a drop-in centre, and receive prevention interventions according to standard of 
care guidelines recommended by the country’s Ministry of Health.  There will be no change to 
their HIV prevention healthcare (refer to section 9.2.1.5 of protocol) 
  
Control participants will be seen for a study visit every 24 weeks for HIV testing (RNA and 
rapid), weight, and a survey on which prevention method(s) they have been using and self-
reported risk. If control participants report using medications such as PrEP or PEP at the interim 
visits, they will be asked to provide hair, blood, or urine samples in order to measure HIV 
prevention medication levels. 
 
For intervention participants who do not choose CAB-LA, there will be study visits every 12 
weeks (refer to section 9.2.1 of the protocol); however, they can decide to begin CAB-LA at any 
time during the initial 48-week extension.  Participants will not be able to initiate or restart CAB-
LA in the additional extension period between Week 48 and Week 96; only those who are taking 
CAB-LA at the time of the Week 48 visit may continue. Intervention participants that choose 
CAB-LA will have study visits that align with their injection visits (every 4 weeks for the first two 
months and then every 8 weeks thereafter), but can return to an alternate DCP intervention if 
they decide to stop CAB-LA.  
 
 
For participants that select CAB-LA, the extension visits will also include (Table 6): 
• 
A separate qualitative interview (At time of CAB-LA start, Week 24 and Week 48)  
• 
Safety Labs: 
o HBsAg at baseline 
o ALT at Weeks 0 and 24; optionally at Weeks 8 and 48 
• 
Pregnancy tests  
• 
In addition to the Week 24 and 48 extension visits, injection visits will occur in clinic 
every 4 weeks for the first two months and then every 8 weeks thereafter 
• 
HIV-RNA Cepheid test at baseline, Week 24, Week 48, Week 72, Week 96 and 
reinduction 
• 
Plasma will be stored at each visit for future use to evaluate use of alternate HIV 
assays and cabotegravir PK. Small hair samples will be stored at visit weeks 8, 24, 
32, and 48 to assess cabotegravir PK.    
• 
Participants that stop CAB-LA prior to the end of the extension time period will 
continue to be followed in the study but not be actively followed beyond the 96 week 
followup time of the study.  
o Oral PrEP (TDF/3TC) will be recommended to cover tail 
o Participants will switch back to Q12 week follow-up  

 
 
102
Table 5. Schedule of Evaluations Dynamic Choice Prevention Extension – Baseline to Week 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Late visits for routine assessments will not be considered Protocol Violations, allowing flexibility during the COVID-19 pandemic 
2 This assessment will be done on all intervention participants at baseline 
3 See Figure 2 
4 Week 48 visits may occur between 40 and 56 weeks after Baseline 
 
 
 
 
Screening/ 
Baseline 
Week 12 
Week 24 
Week 36 
Week 484 
DCP Intervention (For persons not receiving CAB-
LA)1 
 
 
 
 
 
Study visit 
X 
X 
X 
X 
X 
DCP intervention, including: 
X 
X 
X 
X 
X 
- Offer PrEP, PEP, prevention options2 
X 
X 
X 
X 
X 
- HIV testing options 
X 
X 
X 
X 
X 
- Visit location choice 
X 
X 
X 
X 
X 
- Structured assessment of barriers 
X 
X 
X 
X 
X 
- GBV screening 
X 
 
X 
 
X 
HIV self-test (alternative to rapid) 
 
X 
X 
X 
 
Rapid (blood-based) HIV test 
X 
X 
X 
X 
X 
STI symptom screen 
X 
X 
X 
X 
X 
Pregnancy testing (optional) 
X 
X 
X 
X 
X 
DCP (including those persons on CAB-LA) and 
SOC 
 
 
 
 
 
Measure height (baseline only) and weight 
X 
 
X 
 
X 
Assess self-reported PrEP/PEP use and HIV risk over 
prior 6 months 
X 
 
X 
 
X 
Complete Week 24 or 48 Visit eCRF 
 
 
X 
 
X 
Hair sample collection if any PrEP or PEP doses taken 
in last 30 days 
 
 
X 
 
X 
HIV RNA 
 
 
X 
 
X 
SOC Only 
 
 
 
 
 
Study Visit 
X 
 
X 
 
X 
Referral to standard prevention options 
X 
 
X 
 
X 
Rapid (blood-based) HIV test 
X 
 
X 
 
X 
Suspected seroconversion3 

 
 
103
If CAB-LA is not available in country at the 48-week endpoint, all participants in the intervention arm will have the opportunity to conitinue 
on the study until week 96 or until CAB-LA is available in country, whichever occurs first, according to the schedules of evaluation 
described in Tables 5a and 6.  Participants who are currently on CAB-LA at the Week 48 visit may continue on CAB-LA through Week 96.  
CAB-LA may not be initiated or restarted during the additional 48 week extension to Week 96.  Prior to conducting procedures for visits 
after Week 48, participants in the intervention arm will be reconsented to extend their participation up to Week 96. 
Table 5a. Schedule of Evaluations for Extension of Intervention Arm – Week 60 to Week 96 
 
Week 60 
Week 72 
Week 84 
Week 963 
DCP Intervention (For persons not receiving CAB-
LA)1 
 
 
 
 
Study visit 
X 
X 
X 
X 
DCP intervention, including: 
X 
X 
X 
X 
- Offer PrEP, PEP, prevention options2,* 
X 
X 
X 
X 
- HIV testing options 
X 
X 
X 
X 
- Visit location choice 
X 
X 
X 
X 
- Structured assessment of barriers 
X 
X 
X 
X 
- GBV screening 
 
X 
 
X 
HIV self-test (alternative to rapid) 
X 
X 
X 
 
Rapid (blood-based) HIV test 
X 
X 
X 
X 
STI symptom screen 
X 
X 
X 
X 
Pregnancy testing (optional) 
X 
X 
X 
X 
Measure weight 
 
X 
 
X 
Assess self-reported PrEP/PEP use and HIV risk over 
prior 6 months 
 
X 
 
X 
Complete Week 72 or 96 Visit eCRF 
 
X 
 
X 
HIV RNA 
 
X 
 
X 
Suspected seroconversion2 
 
1Late visits for routine assessments will not be considered Protocol Violations, allowing flexibility during the COVID-19 pandemic or for other outbreaks. 
2 See Figure 2 
3 Week 96 visits may occur between 88 and 104 weeks after Baseline 
*Participants will not be given the option to initiate or restart CAB-LA after the Week 48 visit; only other prevention options will be available. 
 
 

 
 
104
Table 6. Schedule of Evaluations for CAB-LA users (weeks indexed by date of initial CAB LA injection) – Baseline to 
Week 96  
 
CAB 
Screening/ 
Baseline 
CAB 
Week  
4 
CAB 
Week 8 
CAB 
Week 
16 
CAB 
Week 
24 
CAB 
Week 
32 
CAB 
Week 40 
CAB 
Week 
487 
CAB 
Week  
56 
CAB 
Week 
64 
CAB 
Week 
72 
CAB 
Week  
80 
CAB 
Week 
88 
CAB 
Week  
967 
Measure weight 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CAB LA injection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
STI Symptom Screen 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
X 
Suspected 
Seroconversion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Rapid test (Country 
std. algorithm) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-HIV RNA6 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
-Stored plasma (2cc) 
for future HIV testing  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CAB PK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Hair sample (if CAB-
LA received in last 
120 days) 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
   -Stored plasma (from 
2 cc sample above) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Safety Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Pregnancy testing1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
-ALT Monitoring4, 5 
X 
 
X* 
 
X 
 
 
X* 
 
 
X* 
 
 
X* 
Adverse Event 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GBV Screening 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Survey and IDI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-Participant CAB-LA 
Survey and IDI2 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
-Provider and Clinic 
Staff DCP-LA Survey 
and IDI 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Costing3 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
For participants who stop CAB LA before end of extension study 
 
 
 
 
 
 
   -For 48 weeks from last injection: Recommend oral PrEP (TDF/3TC) to cover tail  
 
 
 
 
 
 
  -Switch back to Q12 week visits - HIV RNA and pregnancy testing Q12 weeks 
 
 
 
 
 
 
 
1For women who become pregnant, repeat pregnancy tests are not needed. Women who become pregnant during the study will be followed to delivery for assessment of mother and infant status  
2 Participant survey/IDI will be conducted at start of CAB-LA and Weeks 24 and 48 from time of CAB-LA start or discontinuation.  
3Costing will occur between weeks 24-48. 
4ALT Monitoring will occur at baseline, Week 24 for all participants. *Per provider discretion, ALT monitoring will occur at Weeks 8, 48, 72 and 96. 
5Bilirubin and additional labs indicated will be tested in the case of ALT increase. 
6HIV RNA will be drawn at CAB-LA reinduction, as described in Table 6. 
7 Week 48 visits may occur between 40 and 56 weeks after Baseline; Week 96 visits may occur between 88 and 104 weeks after Baseline; only participants on CAB-LA at the Week 48 visit may take CAB-LA between weeks 48 and 96. 

 
 
E. Extension Consent Process 
 
All participants in the DCP trials will be offered participation in the CAB-LA Extension. Consent 
forms will be translated from the original English to the language(s) spoken in the community. 
The consent form will be read to participants in their local language. Participants who agree to 
take part and sign the consent form will continue in the study. Participants aged 15-17 years old 
who meet the definition of ‘mature or emancipated minors’ as set by the Uganda National 
Council for Science and Technology and the Kenya MOH can participate in these studies and 
will be consented on the adult participant consent forms (refer to section 9.2.1.3 of the protocol). 
Participants aged 15-17 that do not meet the definition of ‘mature or emancipated minors’ may 
participate with parental co-signature. All participants will be asked to re-consent for the CAB-LA 
extension. In this consent, women will be informed about the risks and benefits of CAB-LA 
during pregnancy and breastfeeding  In the case that participants become pregnant while using 
CAB-LA, they will be asked for an additional re-consent to follow-up for ascertainment of 
pregnancy and infant outcomes.  
 
Participants will remain in the randomization arm they were assigned to at their initial DCP visit 
in Phase A (refer to section 9.1.1 of the protocol). Participants in the SOC arm will consent to 
return for two additional follow-up visits at weeks 24 and 48 following re-consent for the CAB-LA 
extension. Intervention participants that do not choose CAB-LA will consent to continue the 
quarterly study visits and Intervention participants that choose CAB-LA will have study visits that 
align with their injection visits (every 4 weeks for the first two months and then every 8-weeks 
thereafter). Intervention participants will have flexibility to switch between PrEP, PEP, and CAB-
LA. Unlimited switches between biomedical prevention options, including between CAB-LA and 
oral, will continue to be permitted during the extension, both to reflect participant choice and to 
bridge planned missed doses of CAB-LA. Clients and providers will discuss options for 
prevention and risk during regular visits and interim visits, in addition to continuous provider 
trainings on offering choice and refreshers for clients. Changes in prevention choices will be 
documented in study eCRF forms, which will include the CAB-LA option. DCP intervention 
participants that choose the CAB-LA option will be informed about the visit schedule, side 
effects, and risks and benefits, before consenting. If CAB-LA becomes available via the Ministry 
of Health during the trial, persons in the control arm will be eligible as per standard of care.  
 
Documentation of written informed consent and verbal consent will be recorded on informed 
consent logs for all study activities.  The logs will contain the participant’s study ID, clinic ID, 
initials, name, language of consent used, and whether the individual signed the document or 
provided a fingerprint in the case of written consents, or verbally affirmed their consent in the 
case of verbal consents. 
 
Stored Samples and Associated Data Considerations  
 
Plasma samples will be collected and stored for retrospective HIV testing and PK.  
 
Hair samples collected from participants on PrEP, CAB-LA or PEP in the extension will be 
collected and stored for later measurements of HIV-prevention drug levels, which will be 
conducted at the UCSF Hair Analytical Lab in the United States.   
 
Blood samples from persons who acquire HIV in Phase A prevention trials will be stored for 
additional testing for HIV diagnostics (if indicated0 and HIV drug resistance.  Testing will be 
performed in-country when available (e.g. standard genotyping for HIV drug resistance). 

 
 
 
106
Specialized research assays for diagnostic and resistance testing (e.g. next-generation 
sequencing) will be performed at the University of Pittsburgh Parikh Lab in the United States.  
Blood and urine samples will be stored for testing CAB-LA/PrEP/PEP drug levels performed at 
the UCSF Hair Analytic Lab in the United States. 
 
Specimens may be held up to five years in order to complete HIV diagnostics, resistance, or PK 
tests as outlined in this protocol. The study may hold specimens to test in batches at later time 
since these tests are being performed solely for research, not for clinical care, or for a biobank 
for future use. Specimens will be destroyed after tests are performed.  
 
All other biological samples collected during the study will be tested shortly after collection and 
any remaining specimen discarded. 
 
 
F. Cabotegravir (GSK1265744A) Injectable Suspension- for intramuscular use: 
Product information  
 
2. CAB-LA will be supplied by the ViiV Healthcare Limited Pharmaceutical Company 
3. Indications and Usage. CAB-LA is indicated in at-risk adults and adolescents weighing 
at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired 
HIV-1 infection. Individuals must have a negative HIV-1 test prior to initiating CAB-LA. 
CAB-LA will not be used as a supplement for PEP. 
4. Administration Overview.  
a. CAB-LA will be offered as direct to inject only (no oral lead-in) 
b. Injection: Single-dose vial containing 600 mg/3 mL (200 mg/mL) of cabotegravir 
is a white to light pink, free-flowing, extended-release injectable suspension 
c. CAB-LA will be administered by trained healthcare staff by gluteal intramuscular 
injection only. Body Mass Index will be considered to ensure appropriate needle 
length is sufficient to reach the gluteal muscle.  
d. Study participants will be tested for HIV infection prior to initiating CAB-LA, and 
with each subsequent injection of CAB-LA, including HIV RNA testing (Cepheid).   
e. Prior to starting CAB-LA, healthcare staff will counsel study participants about the 
importance of adherence to scheduled dosing visits to help reduce the risk of 
acquiring HIV infection and development of resistance. 
5. Pharmacy 
a. The study sponsor, UCSF, will receive CAB-LA directly from ViiV Healthcare and 
distribute to the country pharmacies per country study drug shipping procedures 
b. In-country pharmacists will receive and log the CAB-LA per country procedure 
and detailed in the CAB-LA Pharmacy SOPs  
c. As described in 6c below, CAB-LA will be stored at 2°C to 30°C (36°F to 86F) at 
clinic sites; proper storage and handling will be monitored by in-country 
pharmacy teams and validated by accountability logs and other source 

 
 
 
107
documents 
d. Details on these procedures are outlined in the Standard Operating Procedures.  
i. CABPHARM-01 Study Drug Ordering and Acquisition 
ii. CABPHARM-02 Study Drug Accountability 
iii. CABPHARM-03 Study Drug Storage 
iv. CABPHARM-04 Dispensing and Administration of Study Drug 
v. CABPHARM-05 Disposition and Destruction of Study Drug 
vi. CABPHARM-06 Communication and Dissemination of Information to the 
Study Pharmacist 
6. Injection Dosing 
a. The initial injection dose of CAB-LA is a single 600-mg (3-mL) intramuscular 
injection of CAB-LA given 4-weeks apart for 2 consecutive  times  
b. After the 2 initiation injection doses given consecutively 4-weeks apart, the 
continuation injection dose of CAB-LA will be a single 600-mg (3-mL) 
intramuscular injection of CAB-LA, every 8-weeks.  
c. There is a +/- 7 day window for before or after the date the participant is 
scheduled to receive their next injection 
7. Missed Doses. Study staff will provide adherence support to CAB-LA participants. 
When doses are missed, study staff will follow the applicable guidelines. Providers will 
work pro-actively and prospectively identify periods during which participants are likely to 
miss doses (eg travel).  Participants will be provided with oral bridging prevention 
medication (TDF-FTC) to cover these periods. Upon return to clinic for planned or 
unplanned missed doses, CAB-LA dosing will be as per protocol below.  
a. If a scheduled injection visit is missed or delayed by more than 7 days, the study 
clinician will determine when resumption is appropriate.  
b. Recommended Dosing after a missed visit is detailed in Table 7. 
 
Table 7. Missed Dosage Recommendations  
Time since Last Injection 
Recommendation 
If second injection is missed 
and 
time since first injection is: 
Less than or equal to 8-weeks 
Administer 600-mg (3-mL) gluteal intramuscular injection 
of CAB-LA as soon as possible, then continue to follow the 
every 8-weeks injection dosing schedule. 
Greater than 8-weeks 
Restart with 600-mg (3-mL) gluteal intramuscular 
injection of CAB-LA, followed by a second 600-mg (3-
mL) initiation injection 4-weeks later. Then continue to 
follow the every 8-weeks injection dosing 
schedule thereafter. 

 
 
 
108
If third or subsequent 
injection is missed and time 
since prior injection is: 
Less than or equal to 12 weeks 
Administer 600-mg (3-mL) intramuscular injection of CAB-
LA as soon as possible, then continue with the 
every 8-weeks injection dosing schedule. 
Greater than 12-weeks 
Restart with 600-mg (3-mL) gluteal intramuscular injection 
of CAB-LA, followed by the second 600-mg (3-mL) 
initiation injection dose 4-weeks later. Then continue with 
the every 8-weeks injection dosing schedule thereafter. 
4. Contraindications. CAB-LA is contraindicated in individuals: 
a. With unknown or positive HIV-1 status  
b. With previous hypersensitivity reaction to cabotegravir  
c. Receiving the following co-administered drugs for which significant decreases in 
cabotegravir plasma concentrations may occur due to uridine diphosphate 
glucuronosyltransferase: 
i. Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin 
ii. Antimycobacterials: Rifampin, rifapentine 
5. Drug Interactions 
i. Use of Other Antiretroviral Drugs after Discontinuation of CAB-LA. 
Residual concentrations of cabotegravir may remain in the systemic 
circulation of individuals for prolonged periods (up to 12 months or 
longer). These residual concentrations are not expected to affect the 
exposures of antiretroviral drugs that are initiated after discontinuation of 
CAB-LA  
ii. Potential for Other Drugs to Affect CAB-LA. Cabotegravir is primarily 
metabolized by UGT1A1 with some contribution from UGT1A9. Drugs 
that are strong inducers of UGT1A1 or 1A9 are expected to decrease 
cabotegravir plasma concentrations; therefore, coadministration of CAB-
LA with these drugs is contraindicated  
iii. Established and Other Potentially Significant Drug Interactions. 
Information regarding potential drug interactions with cabotegravir is 
provided in Table 8 below.  
 
Table 8. Drug Interactions with CAB-LA 
 
Concomitant Drug Class: 
Drug Name 
Effect on 
Concentration 
Clinical Comment 

 
 
 
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Anticonvulsants: 
Carbamazepine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Cabotegravir 
Coadministration is contraindicated with 
CAB-LA due to potential for significant 
decreases in plasma concentration of CAB-
LA. 
Antimycobacterials: 
Rifampin Rifapentine 
Cabotegravir 
Antimycobacterial: 
Rifabutin 
Cabotegravir 
When rifabutin is started before or 
concomitantly with the first initiation injection 
of CAB-LA, the recommended dosing of 
CAB-LA is one 600-mg 
(3-mL) injection, followed 2 weeks later by a 
second 600-mg (3-mL) initiation injection 
and monthly thereafter while on rifabutin. 
When rifabutin is started at the time of the 
second initiation injection or later, the 
recommended dosing schedule of CAB-LA 
is 600 mg (3 mL) monthly while on rifabutin. 
After stopping rifabutin, the recommended 
dosing schedule of CAB-LA is 600 mg (3 
mL) every 8-weeks. 
 
6. Drugs without Clinically Significant Interactions with Cabotegravir. The following 
drugs can be co-administered with cabotegravir (non-antiretrovirals) or given after 
discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose 
adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and 
ethinyl estradiol, and rilpivirine. 
a. Special Populations 
i. CAB-LA will be used during pregnancy if the expected benefit 
justifies the potential risk to the fetus. Factors to consider include 
the long acting nature of CAB-LA, the actual gestational age, 
adherence, the risk of seroconversion and available data around 
the safety of study drugs and alternative PrEP regimens in 
pregnancy and breastfeeding. 
ii. In the HPTN 084 trial evaluating cabotegravir long-acting (LA) 
for pre-exposure prophylaxis (PrEP) in women in sub–Saharan 
Africa, no birth defects were reported of the 63 women that 
became pregnant while taking CAB-LA. Given the need for more 

 
 
 
110
data on pregnancy and breastfeeding while taking CAB-LA, 
participants will be monitored closely for side effects during 
pregnancy and breastfeeding during the study and up to 8 
weeks post-partum.  
iii. Pregnant participants will sign a consent to be monitored for up 
to 8-weeks postpartum to ascertain the pregnancy and infant 
outcomes 
iv. Participants will be registered in the Antiretroviral Pregnancy 
Registry to contribute to the global scientific community’s 
understanding of CAB-LA use in pregnancy and breastfeeding  
v. It is recommended that participants of child bearing potential 
taking CAB LA should use an effective contraceptive method 
during the study, through any additional extension phase and for 
52 weeks after the last injection if transitioning off CAB-LA, to 
avoid pregnancy.  Participants that are currently on a 
contraceptive method at CAB-LA start will be informed of the 
risks and benefits of CAB-LA during pregnancy, if they chose to 
stop using contraceptives. Participants not on a contraceptive 
method when starting CAB-LA will be informed about the risks 
and benefits to CAB-LA during pregnancy if they become 
pregnant. CAB-LA will not be given to women who are pregnant 
at time of initial injection; women who become pregnant after 
starting CAB-LA will be allowed to remain on CAB-LA during 
pregnancy, as deemed appropriate by their provider, and will be 
re-consented for additional follow-up of pregnancy and infant 
outcomes. 
vi. It is not known if cabotegravir is present in human breast milk, 
affects human milk production, or has effects on the breastfed 
infant. Participants who are currently breastfeeding will be 
informed of the risks and benefits in the consenting process, and 
unknown effects on infants of exposure to CAB-LA through 
breastmilk.   
vii. No dosage adjustment of CAB-LA is necessary for participants 
with mild (creatinine clearance 60 to <90 mL/min) or moderate 
renal impairment (creatinine clearance 30 to <60 mL/min). In 
participants with severe renal impairment (creatinine clearance 
15 to <30 mL/min) or end-stage renal disease (creatinine 
clearance<15 mL/min), increased monitoring for adverse effects 
will be provided 
viii. No dosage adjustment of CAB-LA is necessary for participants with mild 
or moderate hepatic impairment 

 
 
 
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b. Overdosage. There is no known specific treatment for overdose with CAB-LA. If 
overdose occurs, the participant will be treated appropriately, and further CAB-LA 
continuation determined by the Investigator.  
c. Storage and Handling. 
i. CAB-LA will be stored at 2°C to 30°C (36°F to 86°F) in the original carton 
until ready to use. Exposure up to 30°C is permitted, but freezing is not. 
CAB-LA cannot be mixed with any other product or diluent. 
ii. If the pack has been stored in the refrigerator, the vial will be brought to 
room temperature prior to administration (not to exceed 30°C [86°F]). 
iii. Once the suspension has been drawn into the syringe, the injection will  be 
administered as soon as possible, but may remain in the syringe for up to 
2 hours. The filled syringes will not be placed in the refrigerator. If the 
medicine remains in the syringe for more than 2 hours, the filled syringe 
and needle will be discarded 
d. Possible Side effects: 
i. Allergic reactions: 
• 
generally ill feeling 
• 
blisters 
• 
tiredness 
 
• 
muscle or joint aches 
 
• 
trouble breathing 
• 
fever 
• 
blisters or sores in the mouth 
• 
redness or swelling of eves 
• 
swelling of the mouth, face lips or tongues 
ii. Liver problems 
iii. Depression or Mood Changes 
iv. Most Common Side Effects: 
• 
Pain, tenderness, hardened mass or lump, swelling, bruising, 
redness, itching, warmth, loss of sensation at the injection site, 
abscess, and discoloration  
• 
stomach pain 
• 
vomiting 
• 
diarrhea 
 
• 
muscle pain 
• 
headache 
• 
rash 
• 
fever 
• 
loss of appetite 
• 
tiredness 
• 
drowsiness 
• 
sleep problems 
• 
back pain 
• 
nausea 
• 
upper respiratory infection 
 

 
 
 
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G. Toxicity Management.  
CAB-LA was very well tolerated in the registration studies. For this extension, SAEs will be 
captured in the intervention arm and Grade 3 and 4 AEs, and non-serious ADRs leading to 
withdrawal will be captured for participants on CAB-LA. Grade 3 and 4 AEs will be graded and 
recorded using the NIAID Adverse Event Grading of Severity scale 
(https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables). Clinical 
Adverse Events not identified elsewhere are described in Table 10. The Clinical Management 
Team (CMT) will be notified of SAEs as soon as possible and will be reported per regulatory 
guidelines as stated in Table 9 below.  
 
Table 9. Reporting Guidelines 
 
Institution 
 
Contact information 
Type of Event 
  Reporting 
Timeframe 
Reporting 
Method 
UCSF IRB 
UCSF Committee for 
Human Research 
3333 California Street, 
Suite 315 
University of California 
San Francisco, CA 94118  
Campus Mailbox: 0962  
Facsimile: (415) 502-134 
SAEs/ Grade 3 or 
higher AEs that change 
the study risks or 
benefits, OR 
necessitates 
modification to the IRB-
approved consent 
document(s), and/or the 
IRB-approved 
application/protocol 
Within 10-
working days of 
awareness 
 
Via online 
reporting 
system 
NIAID 
Melanie Bacon, Program 
Officer, NIH 
SAEs or Harm 
determined to be 
possibly, probably or 
definitely related to 
study intervention 
 
Participants 
administered CAB-LA: 
 
All pregnancies  
 
At the time of 
reporting to IRBs 
 
 
 
One-week of 
awareness 
(Pregnancies) 
 
Email 
ViiV 
 
GSK Medical Information, 
Safety Services & Vendor 
Management Group 
 
oax37649@gsk.com 
Participants 
administered CAB-LA: 
 
All SAEs and 
Significant Safety 
Issues  
 
All pregnancies  
 
All Liver Events Grade 
3 and higher 
Within 72 hours 
of awareness 
(SAEs and 
Significant Safety 
Issues) 
 
One-week of 
awareness 
(Pregnancies and 
Liver Events) 
 All SAEs and 
Significant 
Safety Issues: 
Email 
notification with 
SEARCH 
SAPPHIRE AE 
CRF, Country-
specific SAE 
Reporting 
Forms, and 
attachment with 
supplemental 
information 
 
Pregnancies: 
Email 
notification with 

 
 
 
113
Pregnancy 
Reporting CRF  
 
Liver Events 
(Grade 3+): 
Email 
notification with 
Liver Reporting 
CRF  
  
KEMRI-SERU 
The Scientific and Ethics 
Review Unit 
Through The Deputy 
Director CMR  at 
seru@kemri.org. 
All reportable SAEs, 
SUSARs, and Harm 
Notify/ report to 
SERU secretariat 
within 48 hours 
upon learning of 
the event and 
submit the full 
report within 5 
working days of 
awareness 
Via online 
reporting 
system to 
SERU 
secretariat  
PPB 
Pharmacy and Poisons 
Board 
  
All reportable Grade 3 
or higher SAEs, 
SUSARs, and Harm 
Report to PPB 
within 7 working 
days of 
awareness 
Via online 
reporting 
system to PPB 
ECCT (Expert 
Committee on 
Clinical Trials) 
MU-SOMREC 
Executive Secretary 
Faculty of Medicine, 
Research and Ethics 
Committee 
P.O. Box 7072 
Kampala 
 
 
All serious and 
unexpected events 
irrespective of 
relationship 
Fatal and life 
threatening 
events within 3 
working days of 
awareness and 
all other SAEs 
within 7 calendar  
days  
Via Regulatory 
Manager 
NDA 
National Drug Authority 
All serious and 
unexpected events 
irrespective of 
relationship 
Within 7 days of 
awareness 
Via online 
reporting 
 
Grade 3  
Any grade 3 or higher clinical or laboratory AE observed prior to their first injection of active 
CAB will prompt consultation with the clinical officer (CO) prior to any injectable dosing.   
 
At any time, participants who develop a Grade 3 AE or toxicity that is not specifically 
addressed in the Table below and is judged to be related to CAB-LA by the Investigator, 
CAB-LA use will be temporarily discontinued. In general, the investigator will re-evaluate the 
participant until resolution of the toxicity. For Grade 3 AEs deemed related to CAB-LA, will 
be permanently discontinued if improvement to severity ≤Grade 2 cannot be documented 
within 4 weeks of awareness. If CAB-LA is resumed after holding for a Grade 3 AE and the 
same Grade 3 AE recurs without alternative explanation, CAB-LA will be permanently 
discontinued. For Grade 3 AEs deemed unrelated to CAB-LA, the participant may continue 
with appropriate clinical management by the site, per local standards of care.    
 
Grade 4  

 
 
 
114
Any grade 4 or higher clinical or laboratory AE observed prior to first injection will prompt 
evaluation and may requiring holding of dosage, as determined by the CO and CMT. 
Participants who develop a Grade 4 AE or toxicity that is not specifically addressed in Table 
11 (regardless of relationship to CAB-LA) will have the CAB-LA injections temporarily 
discontinued. CAB-LA  use will not be resumed if the Grade 4 AE is considered by the 
Investigator to be related to the injections. If CAB-LA use is resumed and the same Grade 4 
AE recurs at Grade 4 level at any time, CAB-LA will be permanently discontinued, unless an 
alternative explanation for the recurrence is clearly documented.  
 
Pregnancy 
 
Any pregnancy that occurs during study participation must be reported using the Pregnancy 
Reporting Case Report form to NIAID and ViiV Healthcare within one week of learning of its 
occurrence. Pregnancies that are associated with SAEs will be reported within 72 hours 
using the Adverse Event CRF, Country-specific SAE Reporting form, and supplemental 
information attached.   
 
   
The pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child(ren), which must also be reported to NIAID and ViiV 
Healthcare using the Pregnancy Outcomes case report form. The pregnancy outcome 
should also be reported to ViiV Healthcare in accordance with the terms of the contract.  
 
Pregnancy complications and elective terminations for medical reasons must be reported as 
an adverse event or serious adverse event.  Spontaneous abortions must be reported as a 
serious adverse event in accordance with SAE reporting timelines. 
 
Any serious adverse event occurring in association with a pregnancy brought to the 
investigator’s attention after the participant has completed the study and considered by the 
investigator as possibly related to the investigational product, must be promptly reported to 
NIAID and ViiV Healthcare. 
 
 
Table 10. DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
 
 
General Criteria for Discontinuation of CAB-LA 
Participants may voluntarily discontinue CAB-LA for any reason at any time. Investigators 
will permanently discontinue participants from CAB-LA per protocol for any of the specific 

 
 
 
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criteria below. Investigators also may permanently discontinue participants for reasons not 
shown here (e.g., to protect participants’ safety and/or if participants are unable or unwilling 
to comply with CAB-LA use procedures).  
 
 
The criteria for permanent discontinuation of CAB-LA use for an individual participant are:  
• 
CAB-LA -related toxicity requiring permanent discontinuation per the guidelines 
above and below  
• 
Request by participant to permanently terminate use of CAB-LA  
• 
Clinical reasons determined by the Investigator 
• 
Acquires HIV infection   
 
CAB-LA will be temporarily withheld from a participant for any of the following reasons:  
• 
Report of use of prohibited concomitant medications. CAB-LA injections may resume 
when the participant reports that he/she is no longer taking the prohibited 
medication, provided other reasons for temporary hold/permanent discontinuation do 
not apply.   
• 
The participant is unable or unwilling to comply with required study procedures such 
as HIV testing and routine laboratory assessments, or otherwise might be put at 
undue risk to their safety and well-being by continuing CAB-LA use, according to the 
judgment of the Investigator.   
• 
The participant has one or more reactive HIV test results or expresses a concern 
about having acute HIV infection.  
Guidance on Toxicity Management for Specified Toxicities:  
 
Table 11: Nausea, Vomiting, and Diarrhea 
CONDITION AND 
SEVERITY  
IMMEDIATE 
ACTION  
FOLLOW-UP AND MANAGEMENT  
 
Nausea, Vomiting, and Diarrhea  
Grade 1 and 2  
Continue CAB-LA 
Will be treated symptomatically with hydration, 
oral antiemetic therapies or antiemetic 
suppositories at the discretion of the Investigator. 
The Investigator will order any clinically relevant 
laboratory analyses (per judgment of the 
Investigator).  

 
 
 
116
Grade ≥ 3   
Discontinue CAB-
LA temporarily  
Participants with Grade 3 nausea, vomiting, or 
diarrhea, for which an alternative etiology is not 
established, will discontinue CAB-LA temporarily 
until Grade 2 or lower and be treated 
symptomatically. Should condition(s) not improve 
to Grade ≤ 2 within 7 days, the Investigator will 
consider temporary discontinuation or 
progressing to permanent discontinuation of 
CAB-LA.  
 
 
 
Liver chemistry monitoring 
 
Liver chemistry monitoring is at the discretion of the provider and will occur at baseline and 
Week 24. Additional ALT measurements will be taken and Weeks 8 and 48 per provider 
discretion.  Cabotegravir will be stopped if certain protocol specified liver event stopping criteria 
are met, or hepatotoxicity is suspected. 
 
Liver Event Stopping Criteria 
 
CAB must be stopped if any of the following Liver Event Stopping Criteria are met, or if the 
Investigator believes that it is in the best interests of the participant: 
• 
ALT >= 3xULN AND bilirubin >= 2xULN  
• 
ALT >=5xULN for more than 2 weeks 
• 
ALT >=8xULN 
• 
ALT >=3xULN (or >=3x baseline ALT) with symptoms of worsening of acute hepatitis or 
hypersensitivity such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia 
Consideration should also be given to stopping CAB in any participant with aminotransferase 
elevations > 3x ULN who cannot be monitored every 1-2 weeks. 
 
When a Liver Event Stopping Criterion is met, the treating physician must do the 
following: 
 
• 
   Immediately stop CAB-LA 
• 
If ALT >= 3xULN and bilirubin >=2xULN, report as a serious adverse event (SAE) within 
72 hours using the SAE case report form. 
• 
For all events meeting Liver Event Stopping Criteria, perform repeat liver chemistries and 
liver event follow up assessments (ideally within 24 hours of knowledge of the liver 
chemistry elevations) as described in the Follow-Up Assessment below and report to 
UCSF, NIAID, and ViiV Healthcare using the Liver Event Case Report form within one 
week of first becoming aware of the event.  
• 
A specialist or hepatology consultation is recommended if available. 

 
 
 
117
• 
Monitor participants 2 times a week until liver chemistries resolve, stabilise or return to 
within baseline values. 
 
Follow up Assessment following ANY Liver Stopping Event 
 
Make every attempt to carry out liver event follow-up assessments as described below for the 
laboratory tests that are available locally.  
 
• 
Viral hepatitis serology, including: 
• 
Hepatitis A immunoglobulin M (IgM) antibody; 
• 
HBsAg and hepatitis B core antibody; 
• 
Hepatitis C RNA; 
• 
Hepatitis E IgM antibody. 
• 
Cytomegalovirus IgM antibody. 
• 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing). 
• 
Syphilis screening. 
• 
Drugs of abuse screen, including alcohol. Record alcohol use on the liver event case 
report form if using.  
• 
Serum acetaminophen/paracetamol levels  
• 
Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin >=1.5xULN. 
• 
Obtain complete blood count with differential to assess eosinophilia. 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin G (or gamma globulins). 
• 
Gamma glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), and serum 
albumin 
• 
International normalised ratio (INR) 
• 
Liver imaging (ultrasound, magnetic resonance, or computerised tomography) and /or liver 
biopsy to evaluate liver disease. [A Liver Imaging and/or Liver Biopsy Case Report Form 
is available if required]. 
• 
Obtain history and record the appearance or worsening of clinical symptoms of liver injury, 
or hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever rash as relevant on the AE/SAE report form. 
• 
Obtain history and record use of concomitant medications including acetaminophen, 
herbal remedies, other over the counter medications or putative hepatotoxins. 
 
Liver-Safety- CAB-LA Restart 
 

 
 
 
118
“Drug restart” refers to resuming study treatment in which there is a clear cause other than Drug 
Induced Liver Injury (DILI). For long acting agents, a restart may actually be a continuation of 
therapy rather than a true restart due to the timeframe between dose administration relative to 
decision making on allowing a restart. 
 
Participants who meet Liver Event Stopping Criteria should NOT restart CAB-LA unless there is 
a compelling alternative cause for the liver chemistry abnormalities.  
 
“Drug restart” with CAB-LA in a participant who has a Liver Stopping Event may be permitted 
when liver chemistries improve to within 1.5x baseline and ALT < 3 xULN, provided the criteria 
set out in the Liver Safety Restart Guidelines are met. This should take into account when the 
next scheduled injection of CAB LA is due. If the restart criteria are not met by the time window 
for the next injection, consideration should be made to transitioning participants onto an 
alternative regimen. 
 
If restart is not allowed or not granted by the Study’s Governing Body or Principal Investigator, 
permanently discontinue study treatment. Participants may continue participation in the study for 
any protocol specified follow up assessments. 
 
Liver Safety Restart Guidelines 
 
If a causal relationship between the liver event and CAB-LA cannot be ruled out, then CAB-LA 
must be permanently discontinued and the participant not restarted.  
 
Note: Any decision regarding potential restart should take into account when the next scheduled 
injection of CAB LA is due. If the restart criteria below are not met by the time window for the 
next injection(s), consideration should be made to transitioning participants onto an alternative 
regimen. 
 
CAB-LA Restart Following Transient Resolving Liver Events Not Related to CAB-
LA 
Restart can be considered when liver chemistries improve to within 1.5x baseline and 
ALT<3xULN where: 
• 
Liver chemistries have a clear underlying cause other than drug-induced liver injury (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis).  Furthermore, 
there should be no evidence of alcoholic hepatitis or hypersensitivity, and the drug is not 
associated with HLA markers of liver injury. 
• 
The participant is receiving compelling benefit and the benefit of drug restart exceeds risk. 
The long acting nature of CAB LA should be taken into consideration. 
• 
Approval from the Principal Investigator and Ethics Committee or Institutional Review 
Board for the drug restart has been obtained. 
• 
The participant has been provided with a clear description of the possible benefits and 
risks of drug restart, including the possibility of recurrent, more severe liver injury or death 
and the long acting nature of CAB injections. 
• 
The participant has also provided signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study file. 

 
 
 
119
• 
Following drug restart, the participant will return to the clinic once a week for liver 
chemistry tests for one month or for as long as clinically indicated and then laboratory 
monitoring may resume as per protocol.  If protocol defined stopping criteria for liver 
chemistry elevations are met, study drug must be permanently stopped.  
 
Hypersensitivity 
 
Hypersensitivity reactions have been reported in association with other integrase inhibitors 
and were characterized by rash, constitutional findings and sometimes organ dysfunction, 
including liver injury. Administration of CAB oral lead-in was used in clinical studies to help 
identify patients who may be at risk of a hypersensitivity reaction. While there have been no 
confirmed occurrence of a severe hypersensitivity reactions attributable to cabotegravir in 
clinical trials to date, investigators should remain vigilant regarding their occurrence and 
should discontinue CAB-LA and other suspect agents immediately if signs or symptoms of 
hypersensitivity reactions develop (including, but not limited to, severe rash, or rash 
accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, 
conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema. Clinical status, including 
laboratory parameters with liver transaminases, should be monitored and appropriate therapy 
initiated. 
 
All rash and suspected hypersensitivity events should be assessed with special attention to 
systemic symptoms, laboratory abnormalities, or mucosal involvement.  Close clinical follow-
up, including follow-up of laboratory abnormalities, and appropriate medical intervention, 
including referral to dermatologist as appropriate, should be instituted for these events. The 
prolonged release characteristics of CAB LA should be taken into consideration when these 
products are discontinued. 
 
Participants should be instructed to contact the Investigator as soon as possible if they 
develop a rash or allergic symptoms on study. 
 
Suicidal Ideation 
 
There have been reports of depression and suicidal ideation and behaviours (particularly in 
patients with a pre-existing history of depression or psychiatric illness) in some people living 
with HIV being treated with integrase inhibitors. Depression has also been reported in 
individuals receiving cabotegravir for PrEP. 
 
Participants should be monitored appropriately for any unusual changes in behaviour, before 
and during the course of the study. Participants with depressive symptoms or suicidal ideation 
and behaviours on CAB-LA should be promptly evaluated.  It is recommended that the 
investigator consider mental health consultation or referral for participants who experience signs 
of suicidal ideation or behaviour. 
 
Confirmation of suspected HIV infection   
In cases of suspected HIV-infection, clinic staff are trained and use a seroconversion SOP for 
reference to proceed as depicted in Figure 2. For all cases, the clinical management team is 

 
 
 
120
notified immediately, as simultaneous confirmatory testing, additional sample collection 
(including stored samples for further HIV testing and PK), counseling, and linkage to ART care 
are initiated.  
 
 
 

 
 
 
121
Figure 2. HIV Seroconversion Algorithm and Sample Collection 
 
 
 
 
For persons receiving CAB-LA, the following approach will be used for guidance on testing and 
administration of CAB-LA injections (Figure 3). 
 
Figure 3. Algorithm for participants receiving CAB-LA Injections 
 
 
 
 

 
 
 
122
 
 
 
 
 
 
H. Analyses 
 
This section provides an overview of the stastical considerations. 
 
The primary study endpoint in this extension will be biomedical covered time defined as the 
proportion of follow-up time that the participant is protected from HIV infection by any PEP or 
PrEP (inclusive of CAB-LA). Follow-up will be over the 48 weeks following re-consent for the 
CAB-LA extension. At risk covered time will be a secondary outcome, defined as the proportion 
of at-risk follow-up time that the participant is protected from HIV infection by any PEP or PrEP 
(inclusive of CAB-LA). We will also conduct sensitivity analyses, varying the definitions of 
coverage and risk. For example, we will also examine covered time from CAB-LA only (i.e., 
exclusive of oral PrEP or PEP), and we will conduct a sensitivity analysis in which we treat time 
after loss to follow-up among persons not known to have moved out of the study region and 
time after study withdrawal as presumed to be non-covered.  
 
For our primary objective in this extension, we will compare covered time during the 48 week 
CAB-LA extension between the intervention and control arms. For improved efficiency, Targeted 
Maximum Likelihood Estimation (TMLE) will be used to adjust for differences in baseline 
participant characteristics between the two trial arms, accounting for the stratified randomization 
design. In secondary analyses, we will further use TMLE to i) adjust for measured differences 
between arms at time of start of the CAB-LA extension period; and, ii) adjust for baseline and 
time-varying factors that are predictive of the outcome and that differ between persons that do 
vs. do not have their follow-up time censored. The primary analysis will pool over the trials, 
accounting for clustering inherent in the community trial; secondary analyses will stratify by trial 
site. We will test the null hypothesis that covered time is the same between arms with a two-
sided test at the 5% significance level. 
 
Our secondary objective to evaluate implementation will follow the RE-AIM framework and 
corresponding measures (defined in Table 4). Analyses assessing the primary measures of 
Reach, Adoption, Implementation and Maintenance will be based on standard descriptive 
statistics. Analyses to evaluate Effectiveness will compare covered time over the 48 week CAB-
LA extension period to covered time prior to the CAB-LA extension among intervention 
participants. We will adjust for measured changes in participant characteristics between these 
two follow-up periods, using a TMLE designed for serial measures. Measures of control 
participants will also be used to adjust for temporal trends. We will test the null hypothesis that 
coverage of the DCP model with CAB-LA is the same as coverage of the DCP model without 
CAB-LA. We will again use a two-sided test at the 5% significance level. Primary analyses will 
again pool over trials, while secondary analyses will be stratified by trial. In addition, we will 
evaluate marginal and adjusted predictors of CAB-LA uptake and persistence. Our tertiary 
objective to evaluate changes in knowledge, awareness, and acceptability/satisfaction will be 
based on applying TMLE to survey data, accounting for repeated measures. 
 
These analyses will be complemented with costing evaluations as well as participant and 
provider qualitative data from IDI. 

 
 
 
123
 
All analyses of the community-based trial will account for clustering.  
 
Pharmacokinetic analyses: 
We will perform pharmacokinetic (PK) analyses of cabotegravir concentrations in plasma and 
small hair samples with two objectives. 1) To examine hair levels of CAB as predictors of 
effectiveness; 2) To examine factors associated with CAB PK variability and study correlations 
between CAB hair and plasma levels at the end of dosing intervals and during the PK tail. In the 
phase 3 trials of CAB LA, plasma concentrations of CAB did not fully explain CAB breakthrough 
infections (especially since failures occurred despite on-time injections) and therefore PK 
metrics, such as hair, that reflect longer-term exposure, may provide important insights 
regarding CAB exposure in addition to plasma. Drug concentrations of cabotegravir will be 
analyzed via liquid chromatography tandem mass spectrometry (LS-MS/MS) at the Hair 
Analytical Laboratory at UCSF. Plasma samples will be collected prior to each injection, while 
hair samples will be collected at weeks 8, 24, 32, and 48 after CAB LA start.  
 
First, we will analyze hair concentrations of cabotegravir in plasma and small hair samples as 
predictors of effectiveness. We will take the proximal 2 cm of hair from the scalp and segment 
the hair into two 1.0 cm segments (reflecting the prior two months of drug exposure in 1 month 
intervals), analyzing CAB levels in each segment. We will analyze hair levels from each 
collection visit from all participants who acquire HIV infection after starting CAB LA and three 
randomly selected controls who did not acquire HIV to compare exposure metrics from those for 
with and without HIV acquisition. We use sampling fraction weights to properly combine data 
from participants who acquire HIV (sampled with certainty) and controls in order to obtain 
accurate estimates for the entire study population.  
 
Second, to examine factors associated with PK variability, we will perform univariate linear 
mixed effects regression using hair levels of CAB assessed as continuous outcomes with 
candidate predictor variables that may influence exposure, such as age, sex and body mass 
index (BMI), as well as plasma levels, and delays in injection visits. We will then build 
multivariate models to assess how associations with hair levels change when controlled for 
other factors. We will examine scatterplots and Spearman correlation coefficients between hair 
and plasma concentrations of CAB, including at the end of the dosing interval (using the hair 
concentration in the proximal 0.5 cm of hair since hair is collected before injections) and during 
the PK tail for participants who elect to stop CAB LA or who acquire HIV and start an oral ART 
regimen.  
 
 
I. Analyses of In-Depth Interviews  
 
Qualitative in-depth interviews will be conducted among purposively-selected samples of study 
participants and providers, to ascertain the perceptions of and experiences with CAB-LA use 
and delivery. Data will analyzed using a framework analysis approach, wherein transcribed and 
translated data are inductively coded by a cross-regional team of trained qualitative 
researchers, the initial sets of findings are consolidated and grouped into conceptual categories, 
and a framework matrix is used to further condense findings tied most salient to the research 
questions.  
 
 
J. Costing  

 
 
 
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Costs will be estimated as the sum of the product of resources (e.g. staff minutes) times unit 
costs (e.g. compensation levels). “Economic” costs (the true value of resources consumed or 
“opportunity costs”) will be assessed by identifying the value of subsidized or donated resources 
with information from databases (e.g. wage rates) and donors. We will use prices prevailing at 
the time of study onset and will convert any locally incurred costs using the Kenya or Uganda 
Shilling / US dollar exchange rate at that time. Costs of CAB-LA implementation will be 
compared to the costs of oral PrEP implementation estimated during the primary trial to 
estimate the incremental cost of CAB-LA implementation.  
 
Power and Sample size considerations 
 
For each ongoing trial, we assume 90% of participants consent to the extension (reflecting the 
high retention in the ongoing trials seen to date). Of those, we assume 90% are retained 
through the extension. In the individually randomized ANC and OPD trials, we anticipate >80% 
power to detect a 11% or greater absolute increase in prevention coverage between arms with 
162 participants/arm (assuming 𝜎𝜎=0.35). In the cluster-randomized community-based trial, we 
anticipate >80% power to detect a 15% or greater absolute increase in prevention coverage 
between arms with ~20 participants in each of the 16 clusters (assuming mean prevention 
coverage in the standard of care arm of 10%, 𝜎𝜎=0.35, and a matched-pair coefficient of 
variation km=0.25). These calculations are expected to be conservative given the ongoing 
enrollment and primary approach to conduct a pooled analysis as well as the increased 
precision from stratified randomization and through covariate adjustment with TMLE. Minimum 
detectable effect sizes varying these assumptions (including allowing for lower retention in 
either the ongoing or extension studies) are shown in Figure 4.  
 
Figure 4. Minimum detectable effect sizes for the primary hypothesis  
 
 
Human participants and data protection. This is an implementation study; the primary risks for a 
client would be any loss of confidentiality, or risk from blood draw in measurement of the HIV 
outcome.  For risk mitigation, all participants undergo informed consent in their native language, 
staff are fully trained on confidentiality. The SEARCH Sapphire team has SOPs and procedures 
for data collection and security. Because CAB-LA is not yet approved in Uganda or Kenya, we 
will be recording Grade 3 and 4 AEs and reporting to these as required to regulatory authorities.  
 
 

 
 
 
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K. REFERENCES 
 
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N, Ntege PN, Nair G, Nakabiito C, Nuwagaba-Biribonwoha H, Panchia R, Singh N, 
Siziba B, Farrior J, Rose S, Anderson PL, Eshleman SH, Marzinke MA, Hendrix CW, 
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WR, Smith K, Hanscom B, Cohen MS, Hosseinipour MC; HPTN 084 study group. 
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2. Landovitz RJ, Li S, Eron JJ Jr, Grinsztejn B, Dawood H, Liu AY, Magnus M, 
Hosseinipour MC, Panchia R, Cottle L, Chau G, Richardson P, Marzinke MA, Eshleman 
SH, Kofron R, Adeyeye A, Burns D, Rinehart AR, Margolis D, Cohen MS, McCauley M, 
Hendrix CW. Tail-phase safety, tolerability, and pharmacokinetics of long-acting 
injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the 
HPTN 077 trial. Lancet HIV. 2020 Jul;7(7):e472-e481. doi: 10.1016/S2352-
3018(20)30106-5. Epub 2020 Jun 1. PMID: 32497491. 
 
3. Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, Cabello R, 
Chariyalertsak S, Dunne EF, Frank I, Gallardo-Cartagena JA, Gaur AH, Gonzales P, 
Tran HV, Hinojosa JC, Kallas EG, Kelley CF, Losso MH, Madruga JV, Middelkoop K, 
Phanuphak N, Santos B, Sued O, Valencia Huamaní J, Overton ET, Swaminathan S, 
Del Rio C, Gulick RM, Richardson P, Sullivan P, Piwowar-Manning E, Marzinke M, 
Hendrix C, Li M, Wang Z, Marrazzo J, Daar E, Asmelash A, Brown TT, Anderson P, 
Eshleman SH, Bryan M, Blanchette C, Lucas J, Psaros C, Safren S, Sugarman J, Scott 
H, Eron JJ, Fields SD, Sista ND, Gomez-Feliciano K, Jennings A, Kofron RM, Holtz TH, 
Shin K, Rooney JF, Smith KY, Spreen W, Margolis D, Rinehart A, Adeyeye A, Cohen 
MS, McCauley M, Grinsztejn B; HPTN 083 Study Team. Cabotegravir for HIV 
Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021 Aug 
12;385(7):595-608. PMID: 34379922. 
 
 
4. Eshleman SH, Fogel JM, Piwowar-Manning E, Chau G, Cummings V, Agyei Y, 
Richardson P, Sullivan P, Haines CD, Bushman LR, Petropoulos C, Persaud D, Kofron 
R, Hendrix CW, Anderson PL, Farrior J, Mellors J, Adeyeye A, Rinehart A, St Clair M, 
Ford S, Rooney JF, Mathew CA, Hunidzarira P, Spooner E, Mpendo J, Nair G, Cohen 
MS, Hughes JP, Hosseinipour M, Hanscom B, Delany-Moretlwe S, Marzinke MA. 
Characterization of Human Immunodeficiency Virus (HIV) Infections in Women 
Who Received Injectable Cabotegravir or Tenofovir Disoproxil 
Fumarate/Emtricitabine for HIV Prevention: HPTN 084. J Infect Dis. 2022 Mar 
18:jiab576. Epub ahead of print. PMID: 35301540. 
 
5. Marzinke MA, Grinsztejn B, Fogel JM, Piwowar-Manning E, Li M, Weng L, et al. 
Characterization of HIV infection in cisgender men and transgender women who 
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J Infect Dis. 2021 Nov 16;224(9):1581-1592. PMID: 33740057. 
 
6. Markowitz M, Frank I, Grant RM, Mayer KH, Elion R, Goldstein D, et al. Safety and 
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HIV. 2017 Aug;4(8):e331-e40. PMID: 28546090. 
7. Eshleman S, Fogel JM, Halvas EK, Mellors JW, Piwowar-Manning EM, Rinehart AR, et 
al. CAB-LA PrEP: Early Detection of HIV Infection May Reduce In STI Resistance 
Risk. Virtual Abstract presented at Retroviruses and Opportunistic Infections Confernce, 
February 12-16, 2022.  
8. Delany-Moretlwe S, Hughes J, Guo X, Hanscom B, Hendrix CW, Farrior J, et al. 
Evaluation of CAB-LA Safety and PK in Pregnant Women in the Blinded Phase of 
HPTN 084. Abstract 700.  Virtual Conference presented at Retroviruses and 
Opportunistic Infections Confernce, February 12-16, 2022. 
9. Blair CS, Li S, Chau G, Cottle L, Richardson P, Marzinke MA, Eshleman SH, Adeyeye A, 
Rinehart AR, Margolis D, McCauley M, Hendrix CW, Landovitz RJ; HPTN 077 Study 
Team. Brief Report: Hormonal Contraception Use and Cabotegravir 
Pharmacokinetics in HIV-Uninfected Women Enrolled in HPTN 077. J Acquir 
Immune Defic Syndr. 2020 Sep 1;85(1):93-97. PMID: 32452972. 
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11. Uganda National Council for Science and Technology. National Guidelines for 
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12. Delany-Moretlwe S, Hughes JP, Bock P, Dadabhai S, Hunidzarira P, Innes S, 
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Mgodi N, Nahira Ntege P, Nakabiito C, Nuwagaba-Biribonwoha H, Panchia R, 
Angria F, Singh N, Siziba B, Spooner E, Farrior J, Rose S, Berhanu R, Agyei Y, 
Eshleman SH, Marzinke MA, Piowar-Manning E, Beigel-Orme S, Hosek S, 
Adeyeye A, Rooney J, Rinehart A, Hanscom B, Cohen MS, Hosseinipour MC. 
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L. List of Investigators 
 
Diane Havlir, MD 
Chair, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 ext. 424 
Email:  diane.havlir@ucsf.edu 
 
Moses R. Kamya, MBChB, MMed, PhD  
Co-Chair, Makerere University 
Address: Department of Medicine, P.O. Box 7072, Kampala, Uganda   
Phone Number: +256-414-533200 
Email: mkamya@infocom.co.ug 
 
Maya L. Petersen, MD, PhD 
Co-Chair, University of California, Berkeley 
Address: School of Public Health, 5402 Berkeley Way West, Berkeley, CA 94720-7358, 
U.S.A. 
Phone Number:  +1-510-642-0563 
 
Gabriel Chamie, MD, MPH 
Vice-Chair, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 ext. 445 
Email:  gabriel.chamie@ucsf.edu 
 
Laura Balzer, PhD 
Investigator and Protocol Statistician, University of California, Berkeley 
Address:  School of Public Health, 5317 Berkeley Way West, Berkeley, CA 94720-7358, 
U.S.A. 
Phone Number:  +1-203-558-3804 
Email:  laura.balzer@berkeley.edu  
 
Andrew Phillips, MSc, PhD 
Investigator, Modeling, University College London, London 
Address: Institute for Global Health, Glower Street, WC1 6BT, U.K. 
Phone Number:  +20-7830-2886 
Email: andrew.phillips@ucl.ac.uk  
 
Florence Mwangwa, MBChB, MPH 
Investigator, Adult and Adolescents Studies, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Phone Number: +256-779-386616 
Email:  fmwangwa@idrc-uganda.org  
 
Jane Kabami, MPH 
Investigator, Infectious Diseases Research Collaboration 

 
 
 
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Address: P.O. Box 7475, Kampala, Uganda 
Phone Number: +256-706-315810 
Email: jkabami@idrc-uganda.org  
 
Elijah Kakande, MBChB 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Phone Number: +256-779-386616 
Email:  rkakande@idrc-uganda.org   
 
Asiphas Owaraganise, MBChB 
Investigator, Infectious Diseases Research Collaboration 
Address: P.O. Box 4745, Kampala, Uganda 
Email:  asiphas@gmail.com 
 
Elizabeth Bukusi, MBChB, M.Med, MPH, PhD 
Investigator, Youth and Integration of HIV and Reproductive Health Services, Kenya Medical 
Research Institute 
Address:  Box 54840, Nairobi, Kenya 
Phone Number: +254-733-617503 
Email:  ebukusi@rctp.or.ke 
 
James Ayieko, MBChB, MPH, PhD 
Investigator, Adult and Adolescent Studies, Kenya Medical Research Institute 
Address: P.O. Box 517-20107, Njoro, Kenya 
Phone Number: +254-720-925262 
Email: jimayieko@gmail.com  
 
Norton Sang, MA 
Investigator, Kenya Medical Research Institute 
Address: P.O. Box 35-4132, Mega City, Kisumu, Kenya 
Phone Number: +254-715-778930 
Email: nortonsang@gmail.com  
 
Marilyn Nyabuti, MBChB 
Investigator, Kenya Medical Research Institute and the University of Washington, Seattle 
Address: P.O. Box 35-4132, Mega City, Kisumu, Kenya 
Phone Number: +254-715-778930 
Email: mnyanduko@gmail.com  
 
Judith Hahn, PhD, MA 
Investigator, Alcohol Use Studies, University of California, San Francisco 
Address:  UCSF Box 1224, San Francisco, CA 94158 
Phone:  +1-415-476-5815 
Email:  judy.hahn@ucsf.edu  
 
Carol Camlin, PhD, MPH 
Investigator, Social Sciences/Qualitative Studies, University of California, San Francisco 
Address:  Center for AIDS Prevention Studies, San Francisco, CA 94143, U.S.A. 
Phone Number:  +1-415-597-4998 
Email:  carol.camlin@ucsf.edu 

 
 
 
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Matt Hickey, MD 
Investigator, Hypertension Studies, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-628-206-8494 
Email:  matt.hickey@ucsf.edu 
 
Starley Shade, PhD 
Investigator, Cost Effectiveness, University of California, San Francisco 
Address:  Box 0886, San Francisco, CA 94143-0886, U.S.A. 
Phone Number:  +1-415-476-6362 
Email:  starley.shade@ucsf.edu 
 
Harsha Thirumurthy, PhD 
Investigator, Behavioral Economics Studies, University of Pennsylvania 
Address:  Department of Medical Ethics and Health Policy, Philadelphia, PA 19104 
Phone Number:  +1-215-746-0410 
Email:  hthirumu@upenn.edu 
 
Edwin Charlebois, PhD, MPH 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A 
Phone Number:  +1-415-476-6241 
Email:  edwin.charlebois@ucsf.edu 
 
Priscilla Hsue 
Investigator, Cardiovascular Studies, University of California, San Francisco 
Address:  UCSF Box 0846, San Francisco, CA 94110 
Phone:  +1+415-206-8257 
Email:  Priscilla.hsue@ucsf.edu  
 
Theodore Ruel, MD 
Investigator, HIV Adolescent and Young Adult Studies, University of California, San Francisco 
Address:  UCSF Box 0434, San Francisco, CA 94143-0136, U.S.A. 
Phone Number:  +1-415-476-9197 
Email:  theodore.ruel@ucsf.edu 
 
Craig Cohen, MD, MPH 
Investigator, University of California, San Francisco 
Address:  Reproductive Sciences, Box 1224., San Francisco, CA 94158 - youth and 
integration of HIV and reproductive health services 
Phone Number:  +1-415-476-5874 
Email:  craig.cohen@ucsf.edu  
 
Eric Goosby, MD 
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-5483 
Email:  eric.goosby@ucsf.edu  
 
Catherine Koss, MD 

 
 
 
130
Investigator, University of California, San Francisco 
Address:  UCSF Box 0874, San Francisco, CA 94143-0874, U.S.A. 
Phone Number:  +1-415-476-4082 
Email: catherine.koss@ucsf.edu   
 
Urvi M Parikh, PhD 
  Virologist, University of Pittsburgh, Pittsburgh 
     Address: S830 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261 
     Phone Number: 412-648-3103 
     Email: ump3@pitt.edu 
 
Melanie Bacon, RN, MPH 
Medical Officer, National Institute of Allergy and Infectious Diseases, NIH 
Address: 5601 Fishers Lane 9G74, Bethesda, MD 20892, U.S.A. 
Phone Number: +1-240-627-3215 
Email:  mbacon@niaid.nih.gov 
 
Bishop Opira, Bpharm, MPH 
Pharmacist, Infectious Diseases Research Collaboration, Kampala, Uganda 
    Address: Plot 2C Nakasero Hill Road,P.O. Box 7475 Kampala, Uganda 
    Phone: +256 (0)312 281 479 
    Email: opibish@idrc-uganda.org 
 
Greshon Rota, Bpharm 
Pharmacist, Kenya Medical Research Institute 
   Address:P.O. Box 54840 00200 Off Raila Odinga Way. Nairobi, Kenya. 
   Phone: +254 722205901 
   Email: director@kemri.go.ke 
 
Alex Rinehart, PhD 
Medicine Development Leader, Prevention, ViiV Healthcare 
Address: Five Moore Drive, Research Triangle Park, North Carolina USA 
    Phone: 919-483-2085 
    Email: alex.r.rinehart@viivhealthcare.com 
 
Maggie Czarnogorski 
Head, Innovation and Implementation Science, ViiV Healthcare 
    Address: 1012 14th St Nw, Suite 700, Washington, District Of Columbia 
    Phone: 202-638-0750 
    Email: maggie.x.czarnogorski@viivhealthcare.com