Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART): A Cluster-randomized Trial of the Impact of a Combination Prevention Package on Population-level HIV Incidence in Zambia and South Africa
Phase: NA
Conditions: HIV
Sponsor: HIV Prevention Trials Network

 
HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
 
 
 
A Study of the HIV Prevention Trials Network 
 
 
DAIDS ID:  
11865 
 
 
Sponsored by: 
Division of AIDS, National Institute of Allergy and Infectious Diseases 
U.S. National Institutes of Health 
 
 
Funded by: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation 
U.S. National Institutes of Health 
 
 
 
Protocol Chair: 
Richard Hayes 
London School of Hygiene & Tropical Medicine 
London, United Kingdom 
 
Protocol Co-Chair: 
Sarah Fidler 
Imperial College 
London, United Kingdom 
 
 
 
Final Version 3.0 
16 November 2015 
 
 
 
Non-IND Study

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HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
 
 
TABLE OF CONTENTS 
 
LIST OF TABLES AND FIGURES ............................................................................................... 6 
LIST OF ABBREVIATIONS AND ACRONYMS ........................................................................ 7 
PROTOCOL TEAM ROSTER ....................................................................................................... 9 
INVESTIGATOR SIGNATURE PAGE....................................................................................... 15 
SCHEMA ...................................................................................................................................... 16 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME ................................ 19 
1.0 
INTRODUCTION ............................................................................................................. 20 
1.1 
Background and Prior Research ...................................................................................... 20 
1.2 
Rationale .......................................................................................................................... 20 
1.2.1 
The HIV Epidemic in Sub-Saharan Africa............................................................... 21 
1.2.2 
HIV Prevention Methods.......................................................................................... 22 
1.2.3 
Anti-Retroviral Therapy (ART) for HIV Prevention ............................................... 24 
1.2.4 
Innovation ................................................................................................................. 26 
2.0 
STUDY OBJECTIVES AND DESIGN ............................................................................ 29 
2.1 
Primary Objective ............................................................................................................ 29 
2.2 
Secondary Objectives ...................................................................................................... 29 
2.3 
Study Design .................................................................................................................... 31 
2.4 
Timing of Deployment of Intervention and Research Components ................................ 33 
2.5 
Cross-Sectional HIV Incidence Estimation ..................................................................... 35 
3.0 
STUDY INTERVENTION ............................................................................................... 35 
3.1 
Implementation Team Experience ................................................................................... 35 
3.2 
Description of CHiP Teams ............................................................................................. 36 
3.3 
Universal HIV Testing and Linkage to Care ................................................................... 36 
3.4 
Male Circumcision........................................................................................................... 37 
3.5 
Universal Treatment ........................................................................................................ 37 
3.5.1 
Choice of ART Regimen .......................................................................................... 38 
3.6 
Treatment According to Local Guidelines (Arms B & C) .............................................. 38 
3.7 
Prevention of Mother-to-Child Transmission .................................................................. 39 
3.8 
Management of Sexually Transmitted Infections ............................................................ 39 
3.9 
Screening and Referral for TB ......................................................................................... 39 
3.10 
Provision of PrEP ......................................................................................................... 40 
3.11 
Standard of Care........................................................................................................... 40 
3.12 
Delivery of Intervention ............................................................................................... 40 
3.12.1 Activities with Local Health Centers/Community Institutions ................................ 40 
3.12.2 Collaborations .......................................................................................................... 41 
3.13 
Monitoring and Evaluation Plan .................................................................................. 43 
4.0 
STUDY POPULATION.................................................................................................... 45 
4.1 
Description/Selection of the 21 Study Communities....................................................... 45 

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4.2 
Randomization ................................................................................................................. 48 
4.3 
Community Engagement ................................................................................................. 48 
5.0 
RESEARCH PROCEDURES AND ACTIVITIES .......................................................... 49 
5.1 
Population Cohort ............................................................................................................ 50 
5.1.1 
Sampling/Recruitment of Population Cohort .......................................................... 50 
5.1.2 
Inclusion Criteria Population Cohort ....................................................................... 50 
5.1.3 
Exclusion Criteria Population Cohort ...................................................................... 50 
5.1.4 
Procedures and Activities ......................................................................................... 51 
5.1.5 
Reviewing Health Center Records for Population Cohort ...................................... 52 
5.1.6 
Retention in Population Cohort ............................................................................... 52 
5.2 
Population Cross-Sectional Survey (if funded) ............................................................... 53 
5.2.1 
Sampling/Recruitment of Population Cross-Sectional Survey Participants ............ 53 
5.2.2 
Inclusion Criteria ...................................................................................................... 53 
5.2.3 
Exclusion Criteria ..................................................................................................... 53 
5.2.4 
Procedures and Activities ......................................................................................... 54 
5.3 
Case-Control Studies ....................................................................................................... 54 
5.3.1 
Case-Control Study 1 - Uptake of Testing in the First Round of Home-Based 
Testing Provided by CHiP Teams in Arms A & B ................................................................ 54 
5.3.1.1 
Sampling/Recruitment of Case-Control Study 1 Participants........................... 55 
5.3.1.2 
Inclusion Criteria Case-Control Study 1 ........................................................... 55 
5.3.1.3 
Exclusion Criteria Case-Control Study 1 .......................................................... 55 
5.3.1.4 
Procedures and Activities.................................................................................. 55 
5.3.2 
Case-Control Study 2 - Uptake of Immediate Treatment in Arm A ........................ 55 
5.3.2.1 
Sampling/Recruitment of Case-Control Study 2 Participants........................... 56 
5.3.2.2 
Inclusion Criteria Case-Control Study 2 ........................................................... 56 
5.3.2.3 
Exclusion Criteria Case-Control Study 2 .......................................................... 56 
5.3.2.4 
Procedures and Activities.................................................................................. 56 
5.3.3 
Case-Control Study 3 - Uptake of Testing in the Second Round of Home-Based 
Testing Provided by CHiP Teams in Arms A & B ................................................................ 57 
5.3.3.1 
Sampling/Recruitment of Case-Control Study 3 Participants........................... 57 
5.3.3.2 
Inclusion Criteria Case-Control Study 3 ........................................................... 57 
5.3.3.3 
Exclusion Criteria Case-Control Study 3 .......................................................... 57 
5.3.3.4 
Procedures and Activities.................................................................................. 57 
5.4 
Qualitative Studies ........................................................................................................... 58 
5.4.1 
Evaluation of the Acceptability of the Intervention: ................................................ 58 
5.4.2 
Qualitative Longitudinal Study in Arms A and B – sub-set of Case-Control Study 1
 
59 
5.4.3 
Ethnography of the HIV landscape .......................................................................... 60 
5.4.4 
Graphical Summary of Qualitative Activities .......................................................... 60 
5.4.5 
Integration of Data from Case-Control and Qualitative Components ...................... 61 
5.5 
Collection of Health Center-Based Data ......................................................................... 61 
5.5.1 
Tuberculosis Case Notification ................................................................................ 61 
5.5.2 
Intervention Effect on Health Center Workload ...................................................... 62 
5.5.3 
Intervention Effect on Healthcare Costs .................................................................. 62 
5.5.4 
HIV Disease Progression and Death ........................................................................ 63 
5.5.5 
ART Adherence and ART Toxicity ......................................................................... 63 
5.5.6 
Uptake of Intervention Components ........................................................................ 63 

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5.6 
Proposed Additional Surveys .......................................................................................... 63 
5.7 
Comparative Table of Study Activities across All Study Arms ...................................... 64 
6.0 
SAFETY MONITORING AND SOCIAL HARM REPORTING.................................... 65 
6.1 
Safety Monitoring ............................................................................................................ 65 
6.2 
Social Harm Reporting .................................................................................................... 65 
6.2.1 
Participants in the Population Cohort ...................................................................... 65 
6.2.2 
Community at Large ................................................................................................. 66 
6.2.3 
Social Harm Monitoring ........................................................................................... 66 
7.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS ................................... 66 
7.1 
Sample Size ..................................................................................................................... 66 
7.1.1 
Mathematical Modeling and Sample Size Calculations ........................................... 66 
7.1.2 
Primary Endpoint - HIV Incidence Over 36 Months ............................................... 69 
7.1.3 
Secondary Endpoints ................................................................................................ 73 
7.2 
Random Assignment / Study Arm Assignment ............................................................... 77 
7.3 
Statistical Analysis........................................................................................................... 78 
7.4 
Interim Evaluation ........................................................................................................... 79 
7.4.1 
HIV Incidence .......................................................................................................... 79 
7.4.2 
Uptake of Intervention.............................................................................................. 80 
7.5 
Mathematical Modeling ................................................................................................... 80 
7.6 
Outcomes for Secondary Objectives ............................................................................... 81 
7.7 
Secondary Objectives for Case-Control Studies.............................................................. 83 
7.8 
Secondary Objectives for Qualitative Studies ................................................................. 84 
7.9 
Secondary Objectives Related to Economic Evaluation ................................................. 84 
7.10 
Process Measures ......................................................................................................... 89 
7.11 
Tabular Summary of Outcomes ................................................................................... 90 
8.0 
HUMAN SUBJECTS CONSIDERATIONS .................................................................... 94 
8.1 
Collaborative Partnerships ............................................................................................... 94 
8.2 
Social Value ..................................................................................................................... 94 
8.3 
Scientific Validity ............................................................................................................ 94 
8.4 
Fair Subject Selection ...................................................................................................... 95 
8.5 
Risk-Benefit Assessment ................................................................................................. 96 
8.5.1 
Community Level ..................................................................................................... 96 
8.5.1.1 
Benefits ............................................................................................................. 96 
8.5.1.2 
Risks .................................................................................................................. 96 
8.5.1.3 
Minimizing Risks to Communities ................................................................... 97 
8.5.1.4 
Risk-Benefit Assessment at Community Level ................................................ 97 
8.5.2 
Individual Level ....................................................................................................... 97 
8.5.2.1 
Benefits ............................................................................................................. 97 
8.5.2.2 
Risks .................................................................................................................. 98 
8.5.2.3 
Minimizing Risks to Individuals ....................................................................... 99 
8.5.2.4 
Risk- Benefit Assessment at Individual level ................................................. 100 
8.6 
Informed Consent .......................................................................................................... 100 
8.6.1 
Approval from Respective Authorities ................................................................... 101 
8.6.2 
‘Community’ Consent ............................................................................................ 101 
8.6.3 
Individual Consent ................................................................................................. 101 
8.6.4 
Waiver of Individual Consent to Access CHiP and Routine Clinic Data .............. 103 
8.7 
Independent Ethical Review .......................................................................................... 104 

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8.8 
Respect for Participants and Communities During and After the Study ....................... 104 
8.8.1 
Confidentiality ........................................................................................................ 104 
8.8.2 
Data and Safety Monitoring Plan ........................................................................... 105 
8.8.3 
Communicable Disease Reporting Requirements .................................................. 105 
8.8.4 
Post-Trial Management of Participants Exposed to the Early ARV Intervention . 105 
8.8.5 
Study Discontinuation ............................................................................................ 105 
9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT ...................... 106 
9.1 
Local Laboratory Specimens ......................................................................................... 106 
9.2 
HPTN Laboratory Center (LC) Specimens ................................................................... 106 
9.3 
Quality Control and Quality Assurance Procedures ...................................................... 107 
9.4 
Specimen Storage and Possible Future Research Testing ............................................. 107 
9.4.1 
Proposed Phylogenetics Study ............................................................................... 107 
9.5 
Biohazard Containment ................................................................................................. 108 
10.0 
ADMINISTRATIVE PROCEDURES ............................................................................ 108 
10.1 
Protocol Registration.................................................................................................. 108 
10.2 
Study Activation ........................................................................................................ 109 
10.3 
Study Coordination .................................................................................................... 109 
10.4 
Study Monitoring ....................................................................................................... 109 
10.5 
Protocol Compliance .................................................................................................. 110 
10.6 
Investigator's Records ................................................................................................ 110 
10.7 
Use of Information and Publications ......................................................................... 110 
11.0 
REFERENCES ................................................................................................................ 111 
12.0 
APPENDICES ................................................................................................................. 119 
APPENDIX I - SCHEDULES OF STUDY VISITS AND PROCEDURES .............................. 120 
APPENDIX II - SAMPLE INFORMED CONSENT FORM – POPULATION COHORT ...... 123 
APPENDIX III - SAMPLE INFORMED CONSENT FORM – QUALITATIVE STUDIES 
PARTICIPANTS ......................................................................................................................... 130 
APPENDIX IV - SAMPLE INFORMED CONSENT FORM – CASE CONTROL STUDIES 
PARTICIPANTS ......................................................................................................................... 136 
APPENDIX V - SAMPLE INFORMED CONSENT FORM –PARTICIPANTS STARTING 
ART OUTSIDE OF LOCAL GUIDELINES .............................................................................. 141 
APPENDIX VI - SAMPLE INFORMED CONSENT FORM – CHIP TEAM ACTIVITIES ... 147 
APPENDIX VII – SAMPLE SIZE CALCULATIONS .............................................................. 152 
APPENDIX VIII - PROPOSED POPULATION CROSS-SECTIONAL SURVEY ................. 163 

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HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
LIST OF TABLES AND FIGURES 
List of Tables 
Table 1- Summary of Intervention Components ............................................................................ 42 
Table 2- Twenty one proposed study clusters in Zambia and South Africa and relevant 
background data .............................................................................................................. 46 
Table 3- Study Activities across All Study Arms .......................................................................... 64 
Table 4- Parameter values assumed for the model of the impact of the intervention for central and 
optimistic target scenarios, and projected impact on HIV incidence in Arms A and B 
compared with Arm C, assuming intervention roll-out over a 6-month time period ...... 68 
Table 5- Parameter values assumed for the model of the impact of the intervention for central and 
optimistic target scenarios, and projected impact on HIV incidence in Arms A and B 
compared with Arm C, assuming intervention roll-out over a 12-month time period .... 69 
Table 6- Power for comparison of HIV incidence in Arm A or B with Arm C, with 7 communities 
per arm and Population Cohort of 2500 adults per community (assuming that on average 
2125 (85%) will be HIV-uninfected at baseline and that loss to follow-up will be 20% 
after 2 years and 25% after 3 years) with 5206 person-years per community over 36 
months (assuming 1912 person-years 0-12 months; 1700 person-years 12-24 months; 
1594 person-years 24-36 months) ................................................................................... 71 
Table 7- Power for comparison of HIV incidence between Arms A and B, with 7 communities per 
arm and Population Cohort of 2500 adults per community (assuming that on average 
2125 (85%) will be HIV-uninfected at baseline and that loss to follow-up will be 20% 
after 2 years and 25% after 3 years) ................................................................................ 72 
Table 8- Case-control studies of (1) uptake of HIV testing (2) uptake of re-testing for HIV and (3) 
uptake of immediate ART among HIV-positive individuals .......................................... 76 
Table 9- Summary, outcomes for secondary objectives related to the economic analysis ............ 87 
Table 10- Summary of Study Objectives and Related Outcomes .................................................. 91 
 
List of Figures 
Figure 1- Community Randomization Scheme, Zambia and South Africa ................................... 32 
Figure 2- Timing of Deployment of Intervention and Research Component ................................ 34 
Figure 3- Location of 21 clusters in Zambia and South Africa ...................................................... 47 
Figure 4- Qualitative Activities in HPTN 071 ............................................................................... 61 
Figure 5- Mathematical model of the epidemic and of the PopART interventions ....................... 67 

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LIST OF ABBREVIATIONS AND ACRONYMS 
AE 
 
 
Adverse Event 
AIDS  
 
Acquired Immunodeficiency Syndrome 
ANC  
 
Antenatal Clinic 
ART  
 
Anti-Retroviral Therapy 
ARV  
 
Anti-Retroviral 
CDC  
 
Centers for Disease Control and Prevention 
CFR 
 
 
Code of Federal Regulations 
CHiPs  
 
Community HIV-care Providers 
CORE  
 
(HPTN) Coordinating and Operations Center 
DAIDS 
 
Division of AIDS 
DALY  
 
Disability-Adjusted Life-Year 
DSMB  
 
Data Safety Monitoring Board 
EC 
 
 
Ethics Committee 
EQA  
 
External Quality Assurance 
FHCRC 
 
Fred Hutchinson Cancer Research Center 
GCLP   
 
Good Clinical Laboratory Practice 
GCP  
 
Good Clinical Practice 
HCT  
 
HIV Counseling and Testing 
HIV 
 
 
Human Immunodeficiency Virus 
HPTN  
 
HIV Prevention Trials Network 
HSV-2  
 
Herpes Simplex Virus, Type 2 
IATA  
 
International Air Transport Association 
ICF 
 
 
Informed Consent Forms 
IRB 
 
 
Institutional Review Board 
LC 
 
 
(HPTN) Laboratory Center 
LDMS  
 
Laboratory Data Management System 
MSM  
 
Men who have Sex with Men 
NIAID  
 
(United States) National Institute of Allergy and Infectious Diseases 
NIH 
 
 
(United States) National Institutes of Health 
PMTCT 
 
Prevention of Mother to Child Transmission of HIV 
PrEP  
 
Pre-Exposure Prophylaxis 
PRO  
 
Protocol Registration Office 
QA 
 
 
Quality Assurance 
QALY  
 
Quality-Adjusted Life-Year 
QC 
 
 
Quality Control 
RE 
 
 
Regulatory Entity 
RNA  
 
Ribonucleic Acid 
RR 
 
 
Rate Ratio 
RSC 
 
 
Regulatory Services Center 

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SAE 
 
 
Serious Adverse Event 
SANAC 
 
South African National AIDS Council 
SDMC  
 
(HPTN) Statistical and Data Management Center 
SMC  
 
Study Monitoring Committee 
SMS     
 
Short Message Service 
START 
 
Strategic Timing of Anti-Retroviral Treatment  
STI 
 
 
Sexually Transmitted Infection 
SSP 
 
 
Study Specific Procedures  
TB 
 
 
Tuberculosis 
UK 
 
 
United Kingdom 
UNAIDS 
 
United Nations Programme on HIV/AIDS 
US 
 
 
United States (of America) 
UTT 
 
 
Universal Testing and Treatment 
VCT  
 
Voluntary Counseling and Testing 
WHO  
 
World Health Organization 
ZAMBART 
 
Zambia AIDS Related Tuberculosis Project 
ZAMSTAR 
 
Zambia-South Africa TB and AIDS Reduction Program 
 
 

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HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
PROTOCOL TEAM ROSTER 
Yaw Agyei 
International HPTN LC QA/QC Coordinator 
Dept. of Pathology 
Johns Hopkins Univ. School of Medicine 
Pathology Building, Room 313 
600 North Wolfe Street 
Baltimore, MD 21287, USA 
Phone: +27-813766180/+001-410-614-6736 
Email: yagyei1@jhmi.edu 
 
Helen Ayles 
Clinical Scientist/Site Principal Investigator 
ZAMBART 
University of Zambia 
School of Medicine, Ridgeway Campus 
Lusaka, Zambia 
Dept of Clinical Research 
London School of Hygiene and Tropical 
Medicine 
Keppel Street 
London WC1E 7HT, UK 
Phone: +260 211 254710, 260 211257215 
Fax: +260 211 254710 
Email: helen@zambart.org.zm  
 
Mark Barnes 
HPTN Ethics Working Group Representative 
Partner, Ropes & Gray LLP 
Lecturer, Harvard Law School 
Prudential Tower, 800 Boylston Street 
Boston, MA 02199-3600 
Phone: +001-617-951-7827 
Email: mark.barnes@ropesgray.com 
 
 
 
 
 
 
 
Nulda Beyers 
Clinical Scientist/Site Principal Investigator 
Desmond Tutu TB Centre  
Stellenbosch University 
Francie van Zijl Avenue 
Clinical Building, K floor, Room 0065 
Tygerberg Campus 
Western Cape, 7505, South Africa 
Phone: +21-21 938 9114 
Fax: + 27-21 938 9719  
Email: nb@sun.ac.za  
 
Peter Bock 
Site Co- Principal Investigator 
Desmond Tutu TB Centre  
Stellenbosch University 
Francie van Zijl Avenue 
Clinical Building, K floor, Room 0065 
Tygerberg Campus 
Western Cape, 7505, South Africa 
Phone: +27 835 721470 
Email: peterb@sun.ac.za  
 
Virginia Bond 
Social Scientist 
London School of Hygiene & Tropical 
Medicine 
ZAMBART Project, School of Medicine 
P.O. Box 50697 
Lusaka, Zambia 
Phone: +260 211 254710 
Email: gbond@zambart.org.zm  
 
 
 
 
 
 
 
 

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Lisa Bunts 
Lab Data Manager, Lab Data Operations 
SCHARP-FHCRC 
1100 Fairview Ave. North, LE-400 
PO Box 19024 
Seattle, WA 98109, USA 
Phone: 206-667-3026 
Email: lbunts@scharp.org 
 
David Burns 
Prevention Sciences Branch Chief 
DAIDS Medical Officer 
NIAID/NIH 
5601 Fishers Lane, Room 8B40 
Rockville MD 20852, USA 
Phone: +001-301-435-8896 
Email: burnsda@niaid.nih.gov  
 
Anne Cori 
Mathematical Modeler 
Imperial College London 
Department of Infectious Disease 
Epidemiology 
St Mary’s Campus 
Norfolk Place 
London W2 1PG, UK 
Phone: +44 (0) 20 75943229 
Email: a.cori@imperial.ac.uk 
 
Vanessa Cummings 
HPTN LC QA/QC Representative 
Dept. of Pathology 
Johns Hopkins Univ. School of Medicine 
Pathology Building, Room 313 
600 North Wolfe Street 
Baltimore, MD 21287, USA 
Phone: +001-410-614-0479 
Fax: +001-410-614-0430 
Email: vcummin1@jhmi.edu  
 
Deborah Donnell 
SDMC Biostatistician 
SCHARP-FHCRC 
1100 Fairview Ave. North, LE-400 
PO Box 19024 
Seattle, WA 98109, USA 
Phone: +001-206-667-5661 
Fax: +001-206-667-4812 
Email: deborah@scharp.org  
 
Lynda Emel 
Associate Director, HPTN SDMC 
SCHARP-FHCRC 
1100 Fairview Ave. North, E3-129 
PO Box 19024 
Seattle, WA 98109, USA 
Phone: +001-206-667-5803  
Email: lemel@scharp.org  
 
Susan Eshleman 
HPTN Laboratory Center 
Johns Hopkins University School of 
Medicine 
720 Rutland Ave. 
Ross Building, Room 646 
Baltimore MD, 21205, USA 
Phone: +001-410-614-4734 
Fax: +001-410-502-9244 
Email: seshlem@jhmi.edu  
 
Sarah Fidler 
Protocol Co-Chair 
Imperial College London 
CSL in Communicable Diseases 
St Mary’s Campus 
HIV Clinical Trials Unit 
Winston Churchill Wing 
London W2 1NY, UK 
Phone: +44 (0) 203 312 6790 
Email: s.fidler@imperial.ac.uk  
 

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Sian Floyd 
Statistician  
Department of Infectious Disease 
Epidemiology 
London School of Hygiene & Tropical 
Medicine 
Keppel Street 
London, WC1E 7HT, UK 
Phone: +44-207-6127888 
Fax: +44-207-6368739 
Email: sian.floyd@lshtm.ac.uk  
 
Christophe Fraser 
Mathematical Modeler  
Imperial College London 
Department of Infectious Disease 
Epidemiology 
St Mary’s Campus 
Norfolk Place  
London W2 1PG, UK 
Phone: +44 (0) 20 75943397 
Email: c.fraser@imperial.ac.uk  
 
Peter Godfrey-Faussett 
Professor of International Health 
Room 303b 
London School of Hygiene & Tropical 
Medicine 
Keppel Street 
London WC1E 7HT 
Phone: +44 020 7958 8127 
Fax: +44 020 7612 7860 
Email: peter.godfrey-faussett@lshtm.ac.uk  
 
Sam Griffith 
Senior Clinical Research Manager 
FHI 360 
359 Blackwell Street, Suite 200 
Durham NC 27701, USA 
Phone: +001-919-544-7040 ext. 11571  
Email: sgriffith@fhi360.org  
 
James Hargreaves 
Senior Lecturer in Epidemiology 
Department of Infectious Disease 
Epidemiology 
London School of Hygiene & Tropical 
Medicine 
Keppel Street 
London WC1E 7HT, UK 
Phone: +44 (0)20 7927 2955 
Fax: +44 (0)20 7637 4314 
Email: james.hargreaves@lshtm.ac.uk 
 
Katharina Hauck 
Health Economist 
Imperial College Business School 
Tanaka Building 
South Kensington Campus 
London SW7 2AZ, UK 
Phone: +44 (0)20 7594 9197 
Fax: +44 (0)20 7594 9189 
Email: k.hauck@imperial.ac.uk  
 
Richard Hayes 
Protocol Chair, Lead Statistician 
Department of Infectious Disease 
Epidemiology 
London School of Hygiene & Tropical 
Medicine 
Keppel Street 
London WC1E 7HT, UK 
Phone: +44 (0)20 7927 2243 
Fax: +44 (0)20 7637 4314 
Email: richard.hayes@lshtm.ac.uk  
 
Tanette Headen 
Research Assistant II 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 277101 
Phone: +001-919-544-7040 ext. 11297 
Email: theaden@fhi360.org      
 

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Graeme Hoddinott 
Social Scientist 
Desmond Tutu HIV Centre 
Stellenbosch University 
Francie van Zijl Avenue 
Clinical Building, K Floor, Room 0081 
Tygerberg Campus 
Cape Town, Western Cape 7505 
South Africa 
Phone: + 27 21 938 9846  
Email: graemeh@sun.ac.za 
 
Lyn Horn 
Ethicist 
Desmond Tutu TB Centre 
Division Research Development 
Stellenbosch University  
Phone: +27 21 808 2670 
Email: lhorn@sun.ac.za        
 
Erin Hughes 
Project Manager 
SCHARP-FHCRC 
1100 Fairview Avenue North 
E3-129 
PO Box 19024 
Seattle, WA 09109 USA 
Phone: 206-667-7109 
Email: eehughes@scharp.org 
 
Mohammed Limbada 
Clinical scientist 
ZAMBART 
University of Zambia Ridgeway campus 
Lusaka 
Zambia 
Phone : +260 211254710 
Fax: +260 211254710 
Email: Mohaamed@zambart.org.zm 
 
Ayana Moore 
Scientist 
FHI 360 
359 Blackwell Street, Suite 200 
Durham NC 27701, USA 
Phone: +001-919-544-7040 ext. 11244  
Email: amoore@fhi360.org 
 
Albert Mwango 
ART Coordinator, Ministry of Health, 
Zambia 
ZAMBART 
University of Zambia 
School of Medicine, Ridgeway Campus 
Lusaka, Zambia 
Phone: +260 211 254710, 260 211257215 
Fax: +260 211 254710 
Email: albert.mwango@moh.gov.zm  
 
Alwyn Mwinga 
Implemention Coordinator 
ZAMBART 
University of Zambia 
School of Medicine, Ridgeway Campus 
Lusaka, Zambia 
Phone: +260 211 254710, 260 211257215 
Fax: +260 211 254710 
Email: Alwyn@Zambart.org.zm  
 
Michael Pickles 
Mathematical Modeler 
Imperial College London 
Department of Infectious Disease 
Epidemiology 
St Mary’s Campus 
Norfolk Place 
London W2 1PG, UK 
Phone: +44 (0) 20 75943266 
Email: m.pickles@imperial.ac.uk 

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Estelle Piwowar-Manning 
HPTN Laboratory Center, Department of 
Pathology  
Johns Hopkins Univ. School of Medicine  
600 North Wolfe St. 
Pathology 306 
Baltimore, MD 21287, USA 
Phone: +001-410-614-6736 
Fax: +001-410-614-0430  
Email: epiwowa@jhmi.edu 
 
Kalpana Sabapathy 
Clinical Epidemiologist 
Department of Infectious Disease 
Epidemiology 
London School of Hygiene & Tropical 
Medicine  
304-B, Keppel Street, Room 112 
London WC1E 7HT, UK 
Phone: +44 7927 2155 
Fax: +44 (0)20 7637 4314 
Email: kalpana.sabapathy@lshtm.ac.uk 
 
Ab Schaap 
Senior Data Manager 
ZAMBART Project 
London School of Hygiene & Tropical 
Medicine 
Ridgeway Campus 
P.O. Box 50697 
10101 Lusaka, Zambia 
Phone: +260 211 254710, Mobile: +260 977 
442965 
Fax: +260-211-254710 
Email: ab@zambart.org.zm 
 
Kwame Shanaube 
PopART Study Manager - Zambia 
ZAMBART Project  
PO Box 50697 
Ridgeway Campus 
Lusaka, Zambia 
ZAMBIA  
Phone : +260 211 254710,, 260-211-257215 
Fax : +260 211 254710 
Email : kshanaube@zambart.org.zm 
 
Musonda Simwinga 
Social Scientist/Community Coordinator 
ZAMBART 
University of Zambia 
School of Medicine, Ridgeway Campus 
Lusaka, Zambia 
Phone: +260 211 254710, 260 211257215 
Fax: +260 211 254710 
Email: Musonda@zambart.org.zm 
 
Peter C. Smith 
Emeritus Professor of Health Policy 
Imperial College Business School   
Centre for Health Policy 
Professor of Health Policy 
Exhibition Road 
London SW7 2AZ, UK 
Phone: +44 (0)20 7594 1904 
Email: peter.smith@imperial.ac.uk 
 
Sten Vermund 
HPTN Executive Committee Liaison 
Vanderbilt University, Institute for Global 
Health 
2525 West End Ave. 
Suite 750 
Nashville TN 32703, USA 
Phone: +001-615-322-9374 (office)  
Fax: +001-615-343-7797 
Email: sten.vermund@vanderbilt.edu 
 
Deborah Watson-Jones 
Clinical Epidemiologist 
Department of Clinical Research 
London School of Hygiene & Tropical 
Medicine 
Mwanza Intervention Trials Unit 
National Institute for Medical Research 
P.O. Box 11936 
Mwanza, Tanzania 
Phone: +255 (0) 28250 0019  
Email: deborah.watson-jones@lshtm.ac.uk  
 

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Rhonda White 
Community Program Manager 
FHI 360 
359 Blackwell Street, Suite 200 
Durham NC 27701, USA 
Phone: +001-919-544-7040 ext. 11515 
Email: rwhite@fhi360.org 
 
 
 

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HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
 
Final Version 3.0 
16 November 2015 
INVESTIGATOR SIGNATURE PAGE 
A Study of the HIV Prevention Trials Network (HPTN) 
 
Sponsored by: 
Division of AIDS, National Institute of Allergy and Infectious Diseases 
U.S. National Institutes of Health 
 
 
Funded by: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation 
US National Institutes of Health 
 
 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the provisions of 
this protocol. I agree to maintain all study documentation for a minimum of three years after 
submission of the site’s final Financial Status Report to the Division of AIDS (DAIDS), unless 
otherwise specified by DAIDS or the HIV Prevention Trials Network (HPTN) Coordinating and 
Operations Center.  Publication of the results of this study will be governed by HPTN policies. 
Any presentation, abstract, or manuscript will be made available by the investigators to the HPTN 
Manuscript Review Committee and DAIDS for review prior to submission. 
 
I have read and understand the information in this protocol and will ensure that all associates, 
colleagues, and employees assisting in the conduct of the study are informed about the obligations 
incurred by their contribution to the study.  
 
 
 
__________________________________ 
Name of Investigator of Record 
 
__________________________________   
_________________________________ 
Signature of Investigator of Record  
 
Date 
 

HPTN 071 Version 3.0 
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16 November 2015 
  
HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
SCHEMA 
 
Purpose:  The purpose of this study is to determine the impact of two community-level combination 
prevention packages, both of which include universal HIV testing and intensified provision of HIV 
antiretroviral therapy (ART) and care, on population-level HIV incidence. 
 
Design: This is a three-arm, cluster-randomized, longitudinal study to be implemented in 21 clusters 
(communities). 
 
Study Population: The prevention packages will be implemented throughout the communities 
randomized to the intervention arms.  Main study outcomes will be measured in a randomly-selected group 
drawn from the adult population of the communities: a Population Cohort. 
 
Study Size: The combined population of all 21 clusters is approximately 1.2 million individuals.  The 
interventions will be implemented in 14 of the 21 clusters with a combined population of approximately 
800,000 individuals (adults and children) in the intervention arms.  The approximate sizes of the 
randomly-selected groups for main study outcome assessments are:  
• 
Population Cohort: 52,500 individuals  
• 
Case-Control Studies: 2,400 individuals  
• 
Qualitative Studies: about 2,000 individuals   
• 
Population Cross-Sectional Survey: 10,500 individuals (if funded) 
Note: Final sample sizes for surveys pending funding may change and will be described in separate 
protocol. 
 
 
Study Arms/Interventions: 
Arm A - Universal Testing with Immediate ART: 
• 
Combination prevention package including: 
o House-to-house deployment of: 
▪ 
Universal HIV counseling and testing 
▪ 
Active linkage to care for individuals diagnosed as HIV-infected, with immediate 
eligibility for ART 
▪ 
Promotion of male circumcision and prevention of mother to child transmission 
(PMTCT) services  
▪ 
Provision of condoms 
o Strengthening of HIV testing and services at health facilities and other venues  
o Strengthening of male circumcision and PMTCT services available in the community 
o Treatment of sexually transmitted infections (STIs) and provision of condoms at health 
units 
 
 
 

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16 November 2015 
Arm B - Universal Testing with ART Eligibility According to Local Guidelines: 
• 
Combination prevention package including: 
o House-to-house deployment of:  
▪ 
Universal HIV counseling and testing 
▪ 
Active linkage to care for individuals diagnosed as HIV-infected, with ART 
eligibility according to local guidelines*  
▪ 
Promotion of male circumcision and PMTCT services  
▪ 
Provision of condoms 
o Strengthening of HIV testing and services at health facilities and other venues  
o Strengthening of male circumcision and PMTCT services available in the community 
o Treatment of STIs and provision of condoms at health units 
 
Arm C - Standard of Care (Control Arm) 
o Strengthening of HIV testing and ART services according to local guidelines* at health 
facilities and other venues  
o Strengthening of male circumcision and PMTCT services available at health facilities and 
other venues in the community 
o Treatment of STIs and provision of condoms at health facilities and other venues in the 
community  
*In the initial phases of the study, Arms B and C offered treatment according to local guidelines 
which, at the time, based treatment eligibility upon CD4 cell count or disease progression.  With 
protocol v.3.0, the study will (once funding is secured) provide immediate eligibility for ART in 
these arms (after participant consent if offered outside of local guidelines), in anticipation of 
changes in global standards of care.  
 
Study Duration:  The planned duration of the entire study will be approximately 6 years, with enrollment 
and follow-up of communities and delivery of the intervention occurring over 4 years.  Assessment of the 
primary outcome (HIV incidence) in the Population Cohort is planned to take place 12, 24, and 36 months 
after recruitment. Interim evaluation will take place during the first two years of intervention to determine 
whether to continue with the 36 month follow-up of the Population Cohort and the fourth year of 
intervention. 
 
Primary Objective:  
• 
To measure the impact of the two intervention packages on HIV incidence by enrolling and 
following a random sample of adults (the Population Cohort) in the trial communities for 3 years 
 
Secondary Objectives:  
• 
Measure the impact of the two intervention packages on the following: 
o HIV incidence over the first, second, and third years of follow-up 
o Community viral load (subject to funding) 
o ART adherence and viral suppression (subject to funding) 
o Anti-Retroviral (ARV) drug resistance (subject to funding) 
o HSV-2 incidence 
o Uptake of HIV testing and retesting over the entire study period 
o ART screening and uptake 
o Time between HIV diagnosis and initiation of care 
o Retention in care  
o HIV disease progression and death 
o ART toxicity based on clinic records 
o Sexual risk behavior 
o Case notification rate of tuberculosis 

HPTN 071 Version 3.0 
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16 November 2015 
o HIV-related stigma  
o Uptake of PMTCT 
o Uptake of male circumcision 
• 
Carry out case-control studies to examine factors related to: 
o Uptake of HIV testing during the first round of home-based testing in Arms A and B 
o Uptake of immediate treatment in Arm A 
o Uptake of HIV testing during the second round of home-based testing in Arms A and B 
• 
Use qualitative methods to:  
o Assess popular understanding of HIV testing and treatment at study initiation and during 
implementation 
o Evaluate the acceptability and functioning of the Community HIV-care Providers (CHiPs) 
in Arms A & B 
o Evaluate the acceptability of interventions and barriers to access in Arms A & B 
o Document the effect of the interventions on social networks, stigma, sexual behavior, 
alcohol use, gender-based violence, HIV identity, other HIV prevention options and 
community morale 
o Evaluate the process and challenges of community consultation and applying ethical 
principles 
• 
Measure the burden experienced by local health centers due to implementation of the intervention 
in the community 
• 
Measure the incremental cost of the two intervention packages through systematic recording of 
costs in intervention and control communities 
• 
Estimate the effectiveness and cost-effectiveness of the intervention packages and alternative 
packages, both in the chosen study populations and in other populations by fitting mathematical 
models based on the empirical data from the trial, including data related to cost.  
 
Study Sites:  The study is expected to be implemented in the communities identified below. 
 
• 
The study communities in Zambia are spread across 4 provinces and 6 districts. Each community 
is the catchment population of a government health facility.  
o Chimwemwe and Ndeke in Kitwe District (Copperbelt Province) 
o Chipulukusu and Chifubu in Ndola District (Copperbelt Province) 
o Makululu and Ngungu in Kabwe District (Central Province) 
o Chawama, Chipata and Kanyama in Lusaka District (Lusaka Province) 
o Maramba and Dambwa in Livingstone District (Southern Province) 
o Shampande in Choma District (Southern Province) 
 
• 
The study communities in South Africa are located in the Cape Metro District and Cape 
Winelands District of the Western Cape Province. As above, the communities are defined by the 
catchment population of a government health facility.  
o Delft South (Metro District) 
o Kuyasa (Metro District) 
o Luvuyo (Metro District) 
o Town II  (Metro District) 
o Ikhwezi (Metro District) 
o Bloekombos (Metro District) 
o Dalevale (Cape Winelands District) 
o Wellington (Cape Winelands District) 
o Cloetesville and Idas Valley (Cape Winelands District) 
 

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16 November 2015 
HPTN 071 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART):  
A cluster-randomized trial of the impact of a combination prevention package on 
population-level HIV incidence in Zambia and South Africa 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME 
 
 
* In initial phases of the study, treatment according to local guidelines; with protocol v.3.0, and once funding is 
secured, immediate eligibility for ART (after participant consent if offered outside of local guidelines). 
Note: Qualitative and case-control studies that will be undertaken to interpret and inform the results from the 
objectives above are not included in this diagram for simplicity, but are fully described in subsequent sections. 
21 Community Clusters 
12 in Zambia / 9 in South Africa 
Average of approx. 55,000 individuals in each cluster 
Approximately 600,000 total adults across all communities 
 
 
Arm B 
Clusters: 4 Zambia / 3 South Africa 
 
Intervention 
Combination prevention including: 
•Universal household-based testing 
•active linkage to care  
•ART eligibility according to local 
guidelines* 
 
Research/Evaluation 
Population Cohort B 
One adult from each of 2,500 randomly-
selected households in each cluster 
 
Health Center Data B 
Routinely-collected data from Health 
Centers in the community 
 
CHiPs Data B 
Data collected from community members 
during household visits 
 
 
 
Arm C 
Clusters: 4 Zambia / 3 South Africa 
 
Standard of Care 
Control Arm: 
•Existing prevention & testing services 
and referral for care 
•ART eligibility according to local 
guidelines* 
 
Research/Evaluation 
Population Cohort C 
One adult from each of 2,500 randomly-
selected households in each cluster 
 
Health Center Data C 
Routinely-collected data from Health 
Centers in the community 
Arm A 
Clusters: 4 Zambia / 3 South Africa 
 
Intervention 
Combination prevention including:  
•universal household-based testing 
•active linkage to care 
•immediate ART eligibility 
 
 
Research/Evaluation 
Population Cohort A 
One adult from each of 2,500 randomly-
selected households in each cluster 
 
Health Center Data A 
Routinely-collected data from Health 
Centers in the community 
 
CHiPs Data A 
Data collected from community 
members during household visits 
 
 
  
  
Primary Outcome Measure 
•HIV incidence measured over 3 years in Population Cohort 
Randomization 
Secondary Outcome Measures 
•Population Cohort: HIV incidence measured over 1st , 2nd , and 3rd years, HSV-2 incidence, sexual risk behavior+,  
community VL+*, viral suppression (ART patients)* +, drug resistance (ART patients with detectable VL)* +  
•Population Cohort and Health Center Data: ART Adherence+, HIV disease progression and death+, ART toxicity+, HIV 
stigma * 
•Health Center Data: TB notification and mortality rates 
•Population Cohort, Health Center Data, CHiPs Data: uptake of PMTCT+, uptake of male circumcision+, ART screening and 
uptake+, uptake of HIV testing and retesting+, time between diagnosis and initiation of care+ 
 
+ Objectives that will also be addressed by the Population Cross-Sectional Survey, if funded  
* Pending funding for these assessments.. 

HPTN 071 Version 3.0 
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1.0 
INTRODUCTION 
1.1 
Background and Prior Research 
The global health burden associated with human immunodeficiency virus (HIV) infection 
continues to grow, with an estimated 33 million people living with HIV, including 22.5 
million adults and children in sub-Saharan Africa. While several countries have reported 
reductions in HIV prevalence, prevalence remains extremely high, especially in Southern 
Africa which continues to experience severe, generalized epidemics with persistently high 
rates of HIV incidence [1]. 
While considerable progress has been made in expanding the coverage of antiretroviral 
treatment (ART) for patients living with advanced disease (CD4 cell count < 200 
cells/µL), a large proportion of HIV-infected individuals who need treatment are not yet 
receiving it . ART is a lifelong commitment. Therefore, ongoing treatment costs continue 
to escalate as more patients require ART. There are 2.5 new HIV infections for every 
HIV-infected patient commencing ART, meaning that there is an ever-expanding pool of 
patients who will need treatment in the future [1]. Unless the number of new infections 
can be steeply reduced, it will be increasingly difficult and costly to provide ART for all 
those who need it [2, 3]. For these reasons, effective HIV prevention has become an even 
more pressing priority in the era of ART roll-out. 
There is increasing recognition that a combination of prevention methods will be needed 
to bring HIV transmission under effective control in the most severely affected countries, 
and combination prevention programs are being developed to meet this need [4, 5]. These 
may involve the provision of proven prevention methods, such as male circumcision[6] 
and PMTCT [7, 8], a range of behavioral and biomedical interventions specially targeted 
at those most at risk of infection, and expanded testing and treatment for individuals found 
to be HIV-infected [9-11]. Early treatment of HIV-infected individuals has been shown to 
reduce transmission to their sexual partners by 96% [11] and, more recently, to have 
significant beneficial effects upon the health of infected individuals themselves [12].  
While such strategies are based on sound epidemiological principles, they have not been 
adequately evaluated in the field [13, 14] and there are no data on their effectiveness or 
cost-effectiveness in reducing HIV incidence at population level. In particular, identifying 
specific groups at high risk of HIV infection and providing specially targeted interventions 
for them is likely to be very difficult to implement on a national scale, and is potentially 
stigmatizing. 
1.2 
Rationale 
Since the principles of combination HIV prevention were formulated, there has been new 
interest in the potential impact of universal testing and treatment (UTT) interventions [15]. 
This concept represents a paradigm shift in HIV prevention, since it focuses on identifying 
and intervening in HIV-infected individuals in preference to the much larger uninfected 
population [16]. Even in the high resource environment of the United States, only about a 
quarter of HIV-infected persons know their status, are linked to care, and are suppressed 
with ART [17-19]. Mathematical modeling has indicated that if a high proportion of the 

HPTN 071 Version 3.0 
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16 November 2015 
population can be tested, with those found to be HIV-infected offered immediate ART, 
HIV infection could be reduced substantially within two years, and potentially eliminated 
as a public health problem in the longer term [20-27].  While challenging to deliver [28, 
29], this approach would nevertheless have major advantages in terms of simplicity and 
universality, potentially reducing the need for interventions targeting specific groups at 
high risk of infection, who are often stigmatized, as well as bringing likely clinical benefit 
to those infected with HIV [30-33]. 
To guide health policy, data are needed on the population-level impact of different 
approaches to HIV prevention. We propose to evaluate a combination UTT HIV 
prevention package that includes universal voluntary HIV testing and counseling, 
provision of condoms, STI treatment, the offer of male circumcision to men who are HIV 
uninfected, referral to PMTCT services, and the offer of immediate ART for all those 
identified as HIV-infected. We will test this package in a cluster-randomized trial in 21 
communities in Zambia and South Africa, and measure its impact on HIV incidence in the 
general population by following a randomly-selected cohort of adults for 3 years. In order 
to measure the additional impact of offering immediate ART to those who are HIV-
infected, the study commenced with three treatment arms: Arm A  receiving the full UTT 
intervention described above, Arm B receiving the full intervention except that ART was 
provided according to current local guidelines, and Arm C acting as a control arm 
receiving standard of care services.  With version 3.0 of the protocol and once funding has 
been secured, Arms B and C will also receive immediate eligibility for ART, either 
through revision of local guidelines, or as specified by this protocol if local guidelines 
have not been revised by the time version 3.0 is approved for implementation by local 
authorities. 
Data from the trial will be combined with cost data and mathematical models to estimate 
the cost-effectiveness of the UTT intervention and alternative intervention approaches in 
these and other populations. 
1.2.1 The HIV Epidemic in Sub-Saharan Africa 
Sub-Saharan Africa bears over two-thirds of the worldwide burden of HIV infection [1]. 
The HIV epidemic in this region has had a devastating effect on morbidity, mortality and 
national economies, as well as wider societal effects. HIV infection is also a strong risk 
factor for tuberculosis (TB); people living with HIV who are also infected with TB are 
about 21–34 times more likely to develop TB disease compared with those who are HIV-
negative. Additionally, approximately 24% of global TB deaths are estimated to be HIV-
associated, adding to the health burden associated with HIV infection[34] . 
 
While recent declines in HIV prevalence and incidence have been observed in several 
African countries, HIV prevalence remains extremely high in many parts of the region [1]. 
In particular, Southern Africa remains severely affected, with an estimated 11.3 million 
people living with HIV infection, with extensive, generalized HIV epidemics and very 
high HIV prevalence in most countries. Zambia and South Africa are among the most 
severely-affected countries with an estimated 980,000 living with HIV in Zambia [35] and 
an estimated 5,600,000 living with HIV in South Africa [36]. 
 

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Despite the rapid expansion of access to ART (with an estimated 6.6 million people on 
ART by the end of 2010), an additional 10 million people are in urgent need of ART in 
accordance with current World Health Organization (WHO) treatment guidelines[37]. 
Both countries are making good progress towards achieving the targets set in the new 
guidelines regarding CD4 cell count and ART regimens however, there are practical 
constraints including access to laboratory testing, consistent drug supplies and linkage into 
care. The HPTN 071 study will work with the local Departments of Health and Ministries 
of Health along with the PEPFAR implementing partners, to utilize additional resources to 
strengthen the health systems.  
Globally, it is estimated that there are 2.5 new HIV infections for every patient started on 
ART. This means that there is an ever-increasing pool of untreated HIV-infected 
individuals who will need treatment in the next few years in addition to those already on 
treatment. It is clear that there will be major difficulties in sustaining treatment provision 
for a continuously expanding number of HIV-infected patients. The expansion of ART 
services needed in the coming years has increased the urgency for identifying more 
effective interventions for HIV prevention. Unless HIV incidence can be reduced, an 
estimated US$35 billion will be needed per year by 2030 to deliver ART to 80% of 
eligible patients (CD4 <350 cells/µL) in resource-limited settings[38]. 
1.2.2 HIV Prevention Methods 
Very few HIV prevention methods have been shown to be effective in randomized, 
controlled trials [39, 40]. Behavior change messages have been central to most national 
acquired immunodeficiency syndrome (AIDS) control programs in Africa, and changes to 
safer sexual behavior are assumed to have contributed to the reductions in HIV prevalence 
in Uganda, Zimbabwe, and other countries [41, 42]. However, there is a dearth of 
evidence from rigorously-designed trials on what specific behavioral interventions bring 
about the required behavioral changes leading to a reduction in HIV incidence [40]. 
Similarly, while HIV counseling and testing provide the gateway to key treatment and 
prevention services, evidence of their effects on behavior and HIV risk is inconclusive 
[43-45]. 
In contrast, stronger evidence of effectiveness is available for some biomedical 
interventions. Male circumcision was shown to reduce HIV incidence by around 60% in 
three trials in Kenya, South Africa and Uganda [46-48]. Safe services for male 
circumcision have been recommended for wide-scale roll-out by WHO and the United 
Nations Programme on HIV/AIDS (UNAIDS), but progress in implementation in many 
countries has been slow [49, 50]. HIV transmission is known to be facilitated by other 
sexually transmitted infections (STIs) [51]. One trial in Tanzania showed that improved 
STI treatment services reduced HIV incidence in the general population [52]. Other trials 
of a variety of STI interventions in different epidemiological settings have failed to show 
an impact on HIV incidence [53]. 
Despite the promising results of the RV144 vaccine trial in Thailand [54], there is general 
agreement that an effective HIV prophylactic vaccine will not be available for many years 
[55, 56]. However, the CAPRISA004 trial, reported in 2010, showed that a vaginal gel 
containing the antiretroviral drug, tenofovir, used periodically, reduced HIV incidence by 

HPTN 071 Version 3.0 
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39% among women in South Africa [57]. Vaginal microbicides have been shown to be 
highly acceptable in a wide range of studies, leading to optimism that a product of proven 
efficacy may achieve substantial coverage [58, 59]. However, further confirmatory and 
other trials will be needed before this and other microbicides are licensed and available for 
use in large-scale prevention programs, and it is unclear whether coverage and impact 
would be sufficient to bring the very high rates of HIV incidence in Southern Africa under 
control. 
Further promising data came from the iPrEx trial in 2010, showing that pre-exposure 
prophylaxis (PrEP) using a combination of two antiretroviral drugs (emtricitabine and 
tenofovir) among men who have sex with men (MSM) reduced HIV incidence by 44% in 
a multi-center study [60]. More recently, two trials of the effects of PrEP on heterosexual 
transmission among men and women reported a significant protective effect [61, 62], but 
two trials found no effect [62, 63]. It is currently unclear how the results of these trials will 
be translated into revised WHO and local guidelines. While such interventions may have a 
place in HIV prevention programs, particularly for discordant couples, sex workers, and 
other groups at particularly high risk, the feasibility of wide-scale delivery of PrEP and its 
population-level impact have been questioned. 
Given the limitations in current HIV prevention methods, there is increasing acceptance 
that effective HIV control in the most severely affected countries in Southern Africa is 
likely to require the concerted delivery of a combination of partially effective 
interventions. Combination prevention is therefore becoming the preferred approach to the 
prevention of HIV infection [4, 5, 9, 64]. Combination prevention packages may consist of 
different components, including expanded HIV testing and counseling, male circumcision, 
interventions to promote safer behavior, enhanced PMTCT services, expanded treatment 
services for HIV-infected patients, and special interventions targeted at groups at 
increased risk  of infection, such as those in HIV-discordant partnerships, injection drug 
users, commercial sex workers, truck drivers, MSM and others. The emphasis on targeted 
interventions emerges from the concept of “Know your Epidemic” [65], whereby 
information on the roles of different modes of transmission and different risk groups in 
local epidemics helps to guide the most efficient application of limited prevention 
resources for maximal reduction of HIV transmission. 
While the epidemiological basis for combination prevention is strong, there is a need for 
empirical field studies to evaluate the operational performance of such interventions when 
applied on a large scale, and to measure their impact on HIV incidence at population level. 
This would provide valuable data for policy makers who must choose the most appropriate 
intervention approaches to include in national prevention programs. HPTN 071 will 
provide such data using a rigorous, cluster-randomized trial design that tests the efficacy 
of specific combination prevention packages that are strongly supported by 
epidemiological and modeling data. 
One disadvantage of combination prevention strategies that require careful targeting of 
special groups is that they may be difficult to implement on a wide scale [66]. Optimal 
implementation of such approaches requires availability of baseline data to define the 
transmission dynamics and the size and role of different risk groups, development of 
programs designed specifically for those groups, intensive community liaison work to gain 

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the trust of groups that are often marginalized, stigmatized, or highly mobile, and the 
management and monitoring of these separate programs. While this may be achievable in 
demonstration projects in a small number of communities, it may prove very challenging 
in the context of national roll-out of such programs. In contrast, because the main 
intervention in HPTN 071 is universal and is offered to the entire community, it will 
obviate the need for specially-targeted interventions for different risk groups, should help 
to avoid stigmatization, and should encourage community-wide support for HIV 
prevention and care.  
1.2.3 Anti-Retroviral Therapy (ART) for HIV Prevention 
Incident HIV infections necessarily result from transmission of the virus between an HIV-
infected index case and an HIV-uninfected individual. This simple observation has led to 
an increasing interest in interventions focused on HIV-infected persons to prevent 
transmission to their contacts; this is referred to as positive prevention. 
HIV viral load is the key determinant of viral transmission, as demonstrated clearly in 
observational studies of sexual transmission among HIV-discordant couples; in those 
studies, no transmission was seen when the index case had a plasma viral load below 1000 
copies HIV ribonucleic acid (RNA)/ml [67, 68]. By reducing plasma viral load to 
undetectable levels (<50 copies HIV RNA/ml), it is assumed that ART will also suppress 
viral burden in the genital tract to levels at which transmission is unlikely to occur [69, 
70]. Although vertical HIV transmission occurs via a different route, proof of concept is 
provided by trials of PMTCT, which have demonstrated that HIV transmission from 
mother to child before, during, or after delivery is largely prevented by ART [71-73]. Of 
even more relevance to sexual transmission, are results of the HPTN 052 trial [74]. In this 
large, Phase III trial, the effects of early ART on transmission were investigated in 1750 
HIV-serodiscordant couples. HPTN 052 was powered to determine the impact of 
immediate ART initiation for the HIV-infected partner (at CD4 cell counts >350 cells/µl 
and <550 cells/µl) on HIV transmission, compared with ART initiation according to 
standard treatment guidelines [74]. This trial was unblinded early, after demonstrating a 
96% reduction in HIV transmission to sexual partners in the early treatment arm, as well 
as significant reductions in morbidity in HIV-infected index cases [74]. 
The increasing proportion of HIV-infected patients on ART has likely made some 
contribution to falling HIV prevalence in some countries. However, ART as currently 
delivered in resource-poor settings is unlikely to have a substantial effect on HIV 
transmission because of limited coverage of HIV testing, delays in provision of treatment 
and – importantly – because much HIV transmission occurs before HIV-infected index 
cases reach CD4 levels defined by current treatment guidelines [75] . The UTT strategy in 
this study aims to overcome these limitations by ensuring that all HIV-infected individuals 
are diagnosed as early as possible, and are provided with ART to lower their viral loads 
and minimize the risk of transmission. In addition, these interventions will provide 
important individual-level benefits in terms of reductions in morbidity and mortality 
among HIV-infected individuals. 
Ecological studies have reported promising outcomes of UTT-type interventions at a 
population level in North America. Among MSM in San Francisco, where 72% uptake of 

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HIV counseling and testing was followed by 95% acceptance of immediate ART for those 
identified as HIV-infected, an observed reduction in mean and total community viral load 
was accompanied by a significant decrease in new HIV diagnoses from 798 (in 2004) to 
434 (in 2008)[76, 77]. Similarly, among injection drug users in British Columbia, a study 
of expanded testing and treatment between 1996 and 2009 showed a 52% reduction in 
estimated HIV incidence [78]. However, the direct relevance of these findings in 
concentrated epidemics in North America to generalized epidemics in Southern Africa is 
unclear. While these data are promising, they are subject to many limitations, as they rely 
on incidence estimates based on diagnosed cases of HIV, and time-trends in HIV 
epidemics are notoriously difficult to interpret. No such data are available from sub-
Saharan Africa, where the need is greatest.  
Interest in the UTT approach to HIV prevention has grown following the publication of 
mathematical modeling studies suggesting that the approach has the potential to 
substantially reduce and possibly eliminate HIV transmission at a population level in sub-
Saharan Africa. In the much-discussed Granich model [26], ART for all individuals with a 
CD4 cell count <350 cells/µL is predicted to reduce population HIV incidence by 30%, 
based on assumptions about the distributions of plasma viral load and CD4 cell count. In 
that model, UTT is predicted to reduce the reproduction number to below 1, suggesting 
that elimination of HIV infection as a public health problem may be possible. However, 
concerns have been raised about the validity of the assumptions underlying this model, 
with considerable skepticism about the ability to treat everyone identified as HIV-infected 
in settings where ART coverage for individuals with CD4 < 200 cells/µL is currently 
below 50% [79]. The feasibility of the UTT strategy is compromised by weak health 
systems, insufficient numbers of health care personnel, potential problems with lifelong 
treatment adherence, drug toxicity, drug resistance and the need for durable second and 
third-line treatment regimens. The impact of a UTT intervention will also depend on the 
proportion of transmission events that occur during acute HIV infection, since most 
patients are not likely to be diagnosed during this highly infectious phase prior to 
seroconversion [80-82]. In addition, the feasibility and acceptability of regular HIV testing 
of whole populations, acceptance of immediate ART irrespective of disease stage or 
symptomatology, and the extent of behavioral risk disinhibition [83] will all be critical 
determinants of the ultimate success of a UTT intervention. Concerns regarding 
community acceptability, protection of voluntariness, avoidance of stigma, and 
preservation of human rights must also be addressed.  
Clearly, empirical field studies are needed to test the practical performance of UTT 
interventions and to measure their impact on HIV transmission. Universal testing is a key 
component of the UTT strategy and provides the framework for delivering proven 
preventive interventions to those who are HIV-uninfected at the same time as offering 
immediate treatment to those who are identified as HIV-infected. Therefore, UTT is 
fundamentally a combination prevention strategy - this is the approach that will be 
evaluated in this rigorously-designed, cluster-randomized trial in two severely affected 
countries in Southern Africa. 
Because of uncertainties regarding the additional impact provided by offering immediate 
ART (compared to offering ART according to current local guidelines) the trial 
commenced with three arms comparing: a full combination prevention package including 

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UTT (Arm A), a UTT package including all components of the intervention except for 
immediate ART irrespective of CD4 cell count (Arm B), and a control arm in which the 
population received standard of care (Arm C).  Research findings published in 2015 [84], 
showed that immediate ART has substantial clinical benefits for the health of HIV 
infected persons. WHO guidelines have been set to recommend immediate ART eligibility 
before the end of the 2015 [12]. Changes to local, country-specific guidelines are expected 
to follow soon thereafter. These antipated changes in guidelines mean that by the time 
findings from this trial are available, there will be little global interest for study results 
comparing immediate vs. delayed eligibility for ART. Because it is not known how long it 
will take for local guidelines to offer immediate ART, and so to ensure that the study 
produces findings of the greatest relevance to global public health, and to ensure optimal 
clinical management of all HIV infected individuals residing within the HPTN 071 
(PopART) communities, protocol version 3.0 will offer immediate eligibility for ART to 
all health center clients in Arms B and C once funding to support this change has been 
secured. As has been the case in Arm A from the start of the trial, health center clients in 
Arms B and C will be required to provide consent if the study is making immediate ART 
available to them outside of local guidelines. If local guidelines change to offer immediate 
ART as standard care either before or after implementation of version 3.0 of this protocol, 
then study consent will not be required for anyone to initiate ART from the time the 
change in guidelines.    
1.2.4 Innovation 
The PopART intervention moves the HIV prevention field forward in several important 
ways. 
First, this will be one of the first studies to evaluate the impact of the UTT prevention 
approach on population-level HIV incidence in sub-Saharan Africa. The concept of UTT 
for HIV control in Africa is relatively new; the landmark modeling paper of Granich et al 
appeared in 2009 [85]. While the epidemiological rationale for the intervention in HPTN 
071 is strong, the approach is controversial. Many question whether it is wise to ask health 
systems that are struggling to deliver ART even at low treatment thresholds (e.g., at CD4 
<200 cells/µL) to provide and supervise a program of immediate ART that goes well 
beyond the revised WHO guidelines. Nevertheless, there are many arguments in favor of 
using this approach for HIV prevention: 
• Combination prevention incorporating UTT is currently the only strategy that has 
the potential to eliminate HIV infection in the longer term in the most severely 
affected countries. 
• While initial costs may be high, model estimates suggest that the intervention will 
be cost-saving in the long run, especially if averted costs of hospital treatment for 
HIV-related disease are taken into account [27, 86, 87]. 
• Unless HIV incidence is reduced substantially, ART treatment services will have 
to meet an ever-increasing case-load  and this burden will greatly outweigh the 
initial costs of implementing UTT. 
• Those currently not treated because their CD4 cell counts do not meet ART 
eligibility criteria will in any case need to be treated in a short time; meanwhile 
they are at risk of transmitting the virus to partners, thus increasing the future care 

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burden. Moreover, patients are often lost to follow-up before they have CD4 cell 
counts below treatment thresholds. 
• Compelling research data [12], released in 2015 show that immediate ART confers 
substantial health benefit for HIV-infected patients irrespective of CD4 count and 
immediate ART is poised to rapidly become standard of care.  In light of these 
developments, the study team feels it is important to adopt immediate offer of 
ART for  all HIV infected individuals attending health care facilities within all 
clinics involved in the HPTN071 (PopART) trial. This will be offered ahead of 
local guidelines if protocol version 3.0 is approved (and funding to support the 
change can be secured) in advance of a change in local guidelines. Following this 
protocol change, the trial will continue to address a very important question: how 
much effect does a UTT intervention (including house-to-house testing, linkage to 
care and adherence support) have on population-level HIV incidence compared to 
standard of care. 
• UTT reduces the complexity of ART delivery, since all HIV infected patients can 
be managed through the same clinical pathway. Simplified approaches to testing, 
treatment and monitoring will partly offset the burden imposed by greater patient 
numbers. 
• Current treatment approaches often lead to severe delays in onset of treatment, so 
that CD4 cell counts are often extremely low when ART commences. This leads to 
greater morbidity, mortality and ongoing transmission, with the associated costs of 
additional health care for individuals who go on to present with HIV-related 
illnesses. 
• UTT is also projected to have a major impact on the incidence of TB, which often 
occurs at relatively high CD4 cell counts, thus reducing morbidity, mortality and 
the burden on overstretched TB control programs [88, 89]. 
Second, the UTT intervention will be delivered as part of a combination prevention 
package that also includes counseling, referral for PMTCT services, and other proven 
preventive interventions, including male circumcision. We argue that UTT is by its nature 
a combination prevention method, in that delivery of universal HIV testing and counseling 
itself comprises an important prevention package that has been shown to alter reported 
sexual risk behavior, especially when couples are tested together [90]. In addition, 
universal testing provides the framework for delivery of prevention services to both HIV-
uninfected and HIV-infected individuals. This trial will measure the overall impact of the 
UTT prevention package on HIV incidence, rather than measuring the impact of any 
particular component of the intervention. The three-arm study design will make it possible 
to estimate the additional impact provided by offering immediate ART (in addition to the 
other components of the package).  Despite the change to Arms B and C to offer 
immediate ART that will occur with protocol version 3.0, analysis of study results is still 
expected to provide insight into the differential value of immediate ART since 
approximately two years of the intervention will have been implemented with Arm B and 
C clinics offering ART based upon CD4 cell count or disease progression. Furthermore, 
empirical data from the trial on the operational performance of individual intervention 
components and the measured impact of the two intervention packages (Arms A and B) 
will be assessed using mathematical models; these models will also be used to explore the 
projected effects of alternative combinations. The rigorous data generated on the overall 

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effect of the packages, together with these model projections, will be of considerable value 
to policy makers. The change to offering immediate ART in all three arms of the trial will 
be incorporated into the statistical analysis plan as discussed in Section 7.  
Third, we believe that the proposed intervention package, if successful, will provide a 
conceptually simple approach that avoids some of the limitations of other combination 
prevention approaches that emphasize targeting of special interventions to groups at high 
risk. As we have argued above, while such interventions may still be needed, formulating 
and delivering locally-appropriate packages on a national scale would be extremely 
challenging. In contrast, the PopART intervention can potentially be implemented on a 
wide scale using a relatively uniform and standardized approach, as has been the case for 
other major public health interventions such as use of impregnated bednets for malaria 
prevention. 
Fourth, the universal test and treat strategy being investigated in the HPTN 071 study is 
likely to have a significant effect on TB [91, 92]. On an individual level it is well 
established that TB is increasingly common at lower CD4 cell counts. However, the risk 
of developing TB increases rapidly after acquisition of HIV[93]. ART has been shown to 
reduce the risk of developing TB in individuals by increasing CD4 cell counts[94]. The 
effects of ART on TB at community level are not known. The study will assess impact of 
the intervention on TB as determined from health center records and so begin to address 
this important question. 
If additional funding can be identified, the following would also be addressed: 
Fifth, in addition to measuring the primary endpoint of our cluster-randomized trial design 
(population-level HIV incidence), we will also measure the impact of the intervention on 
community viral load if funding for these activities is available. Despite some limitations, 
community viral load has been proposed as a valuable indicator for assessing the effect of 
treatment-based HIV interventions, and by making comparisons across our study 
communities, we hope to investigate how this indicator relates to the HIV incidence 
measure. 
Sixth, the primary strategy to prevent mother to child transmission of HIV is the provision 
of maternal and neonatal anti-retroviral (ARV) prophylaxis [7]. Scale-up of this 
intervention has taken place across sub-Saharan Africa. Despite this, there is evidence of 
on-going transmission to children in the continent, with up to 12% of children whose 
mothers received some form of PMTCT prophylaxis testing positive for HIV[72, 95, 96]. 
ART during pregnancy and breastfeeding provides more effective protection against 
mother-to-child transmission of HIV than standard short course ART regimens[97] which 
are still being implemented in many African countries. The PopART interventions, 
through immediate provision of ART, have the potential for a significant impact on HIV-
free survival in children through earlier initiation of maternal HIV treatment. They may 
also lead to an improvement in overall child survival through potential secondary benefits 
such as improved maternal health, changes in health-seeking behavior, improved care, and 
increased resources for better nutrition for both HIV infected mothers and their children. 

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Seventh, The development of drug resistant HIV infection will be compared between the 
three arms (dependent on additional funding). One of the key safety concerns about the 
population level implementation of a UTT approach is evolution of HIV resistance to 
ART. This will be examined amongst the HIV+ individuals enrolled into the PC who have 
detectable viral load measurements whilst on ART, as well as baseline viral genotyping 
for those who seroconvert through the study period to document the prevalence of 
transmitted drug resistant infection. 
Our preliminary modeling indicates that the intermediate intervention (Arm B) should 
have a substantial impact on HIV incidence, but that a much larger impact should be seen 
in Arm A (see Section 2.3). It is anticipated that guidelines will change to universal 
treatment independent of CD4 count during the course of the study, and implementation of 
version 3.0 of the protocol will ensure that the study offers universal treatment to all arms 
even if local guidelines have not yet changed. From this stage on, the interventions 
provided in Arm B and Arm A will be identical. The sooner this change occurs, the 
smaller the difference in impact on HIV incidence is predicted to be between Arms A and 
B. The difference between Arms A and C is predicted to remain large due to the impact of 
household testing and enhanced linkage to care. The three-arm study design will allow us 
to confirm these projections. Detailed data on the costs of these intervention packages, 
combined with the impact data from the trial, will provide critical policy guidance on the 
cost-effectiveness of combination prevention strategies and the priority that should be 
given to earlier treatment. Operational data from the trial will provide valuable 
information on the practical issues involved in delivering such programs to scale. The 
modeling projections will be updated regularly as the trial progresses, so that 
investigators, reviewers, stakeholders, and the Data Safety and Monitoring Board can 
assess up-to-date projections. Specifically, modeling projections will be adjusted in 
accordance with changes in the criteria for ART initiation, either through changes in local 
guideline or through this protocol amendment. 
2.0 
STUDY OBJECTIVES AND DESIGN 
2.1 
Primary Objective 
• The primary objective of this study is to measure the impact of the two 
intervention packages on HIV incidence by enrolling and following a random 
sample of adults (the Population Cohort) in the trial communities for 3years. 
2.2 
Secondary Objectives 
The secondary objectives of the study are to: 
 
• Measure the impact of the two intervention packages on the following: 
o 
HIV incidence over the first, second, and third years of follow-up 
o 
Community viral load (subject to funding) 

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o 
ART adherence and viral suppression (subject to funding) 
o 
ARV drug resistance (subject to funding) 
o 
HSV-2 incidence 
o 
HIV disease progression and death 
o 
ART toxicity 
o 
Sexual risk behavior 
o 
Case notification rate of tuberculosis 
o 
HIV-related stigma 
o 
Uptake of PMTCT 
o 
Uptake of male circumcision 
o 
ART screening and uptake 
o 
Uptake of HIV testing and retesting 
o 
Time between HIV diagnosis and initiation of care 
o 
Retention in care 
• Carry out case-control studies to examine factors related to: 
o 
Uptake of HIV testing during the first round of home-based testing 
in Arms A and B 
o 
Uptake of immediate treatment in Arm A 
o 
Uptake of HIV testing during the second round of home-based 
testing in Arms A and B 
• Use qualitative methods to: 
o 
Assess popular understanding of HIV testing and treatment at study 
initiation and during implementation 
o 
Evaluate the acceptability and functioning of the Community HIV-
care Providers (CHiPs) in Arms A & B 
o 
Evaluate the acceptability of interventions and barriers to access in 
Arms A & B 

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16 November 2015 
o 
Document the effect of the interventions on social networks, stigma, 
sexual behavior, alcohol use, gender-based violence, HIV identity, 
other HIV prevention options and community morale 
o 
Evaluate the process and challenges of community consultation and 
applying ethical principles 
• Measure the burden experienced by local health centers due to implementation 
of the intervention in the community 
• Measure the incremental cost of the two intervention packages through 
systematic recording of costs in intervention and control communities 
• Estimate the effectiveness and cost-effectiveness of the intervention packages 
and alternative packages, both in the chosen study populations and in other 
populations by fitting mathematical models based on the empirical data from 
the trial, including data related to cost.  
2.3 
Study Design 
The two intervention packages will be implemented in study communities and their 
impact on population-level HIV incidence will be evaluated using a cluster-randomized 
trial design.  
A total of 21 study communities (12 in Zambia and 9 in South Africa) will be  selected. 
The cluster or community for the purposes of this trial is defined as the catchment 
population of a local health unit (through which the intervention is delivered), and 
corresponds to a total population of between about 20,000 and 150,000 individuals 
(average size of approximately 55,000). These 21 communities will be formed into 7 
matched triplets, with 4 matched triplets in Zambia and 3 in South Africa. In each matched 
triplet, one community will be randomly selected to receive the full intervention (Arm A), 
a second community will receive the full intervention except that ART will be offered 
according to current local guidelines (Arm B) and the third act as a control community 
receiving standard of care. Within each country, communities will be matched based on 
the best available estimates of HIV prevalence, as described in Section 4.1, with the aim 
of minimizing the between-community variance in baseline HIV incidence within 
matched triplets. In addition, restricted randomization will beused to ensure overall 
balance in cluster size, ART uptake and mean HIV prevalence across the study arms.  The 
community randomization scheme is represented graphically in Figure 1. 
As described above, implementation of the changes in protocol version 3.0 will result in 
the offer of immediate ART in all three arms.   
The primary outcome of the study, HIV population-level incidence, will be measured 
through longitudinal follow-up of a cohort of approximately 2,500 adults in each 
community who consent to participation, drawn from a randomly selected list of 
households (the Population Cohort). 
 

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At the end of the third year of the intervention, to coincide with the 36 month follow-up 
visit of the Population Cohort, a random sample of houses will be selected (excluding 
houses in the Population Cohort) and visited by field staff to complete a final survey.  
Because this Population Cross-Sectional Survey will be a one-time survey, data obtained 
from these individuals will be uncontaminated by the potentially biasing effects of 
longitudinal cohort participation, and will provide additional data on community viral 
loads and other process measures. 
 
 
Figure 1- Community Randomization Scheme, Zambia and South Africa 
 

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2.4 
Timing of Deployment of Intervention and Research Components 
The total duration of the study will be approximately 6 years. During the first year, the 
protocol will be finalized, study procedures defined and manuals of operations developed, 
plans and procedures developed with community and implementing partners, and study 
staff trained.  Preliminary qualitative work will also be conducted in the communities to 
prepare for study initiation.  Shortly prior to deployment of the intervention, households in 
each community will be mapped.  Early in the second year, the intervention, implemented 
by the CHiP teams (home-based testing and linkage to medical care in the health centers) 
will be deployed in Arms A and B at the same time that the Population Cohort is enrolled 
by the research teams for evaluation in all arms.  It is expected that the first round of 
deployment of the intervention will take approximately one year, as will enrollment of the 
Population Cohort.   
 
CHiP teams will stay engaged in the community throughout the intervention period, but 
will return to all households to repeat rounds of home-based testing 12, 24, and 36 months 
after the initial round of testing.  Similarly, research teams will conduct evaluation visits 
to the homes of the Population Cohort members at enrollment, 12, 24 and 36 months. 
Whether or not an individual has been seen by a CHiP team will be asked during the 
Population Cohort survey to help interpret the data, particularly with regards to uptake.  
 
During the first two years of intervention, an interim evaluation will take place to 
determine whether to continue with the 36 month follow-up of the Population Cohort and 
the fourth year of intervention (see Figure 2). The evaluation will consider milestones 
such as uptake of the intervention and indicators of futility and will be described in the 
Statistical Analysis Plan. 
 
If funded, the Population Cross-Sectional Survey survey will occur at the same time as the 
36-month Population Cohort visits.  Case-Control studies and qualitative research by the 
research teams will occur at intervals during the entire follow-up period. 
 
Analysis and reporting of the primary outcome for the main HPTN 071 study (HIV 
incidence) is not  expected to occur  for a considerable time after completion of the 36-
month follow-up visits for the Population Cohort. This is because of the very large sample 
size of the PC, the need to perform HIV testing both in-country and at the HPTN LC, and 
the need to complete QA testing, including confirmation of HIV seroconversion, prior to 
data analysis. This timeline is represented graphically in Figure 2.   
 
 

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Figure 2- Timing of Deployment of Intervention and Research Components 
 
2012
2013
2014
2018
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2 Q3
Q4
Q1
Q2
Q3
Q4
Q2
Q3
Q4
Q2
Q3
Q4
Q1
Q2
Q3 Q4
Household Mapping of 
communities
CHiPs Intervention 
Population Cohort
Interim Assessment
Population Cross 
Sectional Survey1
Case Control Studies
Qualitative Studies
Analysis and reporting
1 Requires additional funding; to be described in and conducted according to an ancillary protocol
Analysis & 
Reporting
2015
Initial visits to all households
Return visits to 
households 
2016
Q1
Q1
2017
Return visits to 
households 
Return visits (PC36)
Return visits to 
households 
Rapid 
Community 
Assessment 
Assessment of community response to intervention, ethnography, longitudinal study of 
testing behaviors
Return visits 
(PC12)
Enrollment (PC0)
CC 
3
Enrollment and 
survey completion
Return visits 
(PC24)
CC 
1&2

HPTN 071 Version 3.0 
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16 November 2015 
 
2.5 
Cross-Sectional HIV Incidence Estimation 
In HPTN 071, HIV incidence estimates will be based on longitudinal assessment of HIV 
seroconversion. A robust, multi-assay approach for cross-sectional HIV incidence 
determination was recently validated for subtype B HIV. This algorithm uses a 
combination of two serologic assays (the limited antigen avidity assay [LAg] and a second 
antibody avidity assay), as well as two non-serologic biomarkers (CD4 cell count and HIV 
viral load) to identify individuals who are likely to be recently HIV-infected at the time of 
sample collection[98]. An alternate multi-assay algorithm has been developed that 
includes an HIV diversity measure rather than CD4 cell count[99]; an advantage of this 
alternate algorithm is that it can be performed entirely using stored plasma samples. Work 
is underway to optimize a similar multi-assay algorithm in subtype C HIV, the prevalent 
subtype in South Africa and Zambia.  
 
HPTN 071 provides an opportunity to apply these methods to achieve several objectives, 
including estimation of HIV incidence at baseline (prior to implementation of the study 
interventions) and comparison of HIV incidence estimates based on longitudinal and 
cross-sectional assessments. These assessments may be performed using stored plasma 
samples if an appropriate multi-assay algorithm for subtype C is developed and validated 
and funding is obtained.  
 
3.0 
STUDY INTERVENTION 
3.1 
 Implementation Team Experience 
The implementing team that will carry out this program has extensive prior experience in 
conducting community randomized research, including household-level incidence 
assessment, particularly in the conduct of the Zambia-South Africa TB and AIDS 
Reduction (ZAMSTAR) trial in the same communities that have been chosen for this 
study.  The leadership and much of the field team from the ZAMSTAR trial remain 
actively engaged in the communities and will be able to build on their knowledge of and 
acceptance within these populations when rolling out the community interventions 
described below. 
In addition, extensive effort has been put into developing in-country coordination 
structures for the trial. In both countries, there have been and will continue to be ongoing 
dialogues with national, provincial and district Departments of Health, PEPFAR 
secretariats, USAID and CDC HIV treatment and prevention representatives, other 
implementing partners, and community representation organizations. The study team has 
also developed sustainability plans and community engagement plans. 

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3.2 
Description of CHiP Teams 
As described above, seven communities will be randomized to receive the full intervention 
and seven will be randomized to receive the intervention except with eligibility for ART 
determined by current local guidelines.  In these two types of intervention communities 
(Arms A and B), delivery of the intervention will be carried out primarily by trained 
community health workers or ‘CHiPs’ (Community HIV-care Providers).  The CHiPs will 
provide HIV counseling and testing and active linkage to comprehensive care and 
prevention services. Each CHiP team will consist of a pair of individuals trained in HIV 
counseling and testing, and other aspects of HIV prevention and care. Each CHiP team 
will be responsible for implementing the intervention in an assigned subset of households, 
or “zone”. Although CHiP teams are affiliated with this research project (and this will be 
made clear to all those who interact with them), their role is primarily to deliver what is 
recognized by the WHO as a ‘best practice’ public health intervention. Hence for this 
project we regard ‘CHiP teams’ as separate from the ‘research teams’ and believe that the 
norms and standards governing their activities should largely be those accepted for the 
implementation of public health interventions rather than those applied to conventional 
clinical research projects. Regarding all CHiP team activities as research activities would 
make this complex public health research project logistically impossible to implement.  
A cadre of people currently exists in all the study communities who would be appropriate 
for recruitment as CHiPs. These include ART adherence supporters, TB Treatment 
Supporters, PMTCT and male circumcision peer educators, home based care volunteers 
and HIV/AIDS support group members. Most of these people have the necessary skills 
and have received training in basic HIV counseling, psychosocial counseling, adherence 
counseling and door-to-door HIV testing. However, successful candidates will be 
retrained to update their knowledge and harmonize the implementation of the study 
interventions. Community Advisory Boards (CABs) and other local stakeholders will be 
consulted in developing job descriptions for CHiPs. All CHiPs will be able to read and 
write English, and will be conversant with the local geography. 
3.3 
Universal HIV Testing and Linkage to Care 
Door-to-door voluntary HIV testing will be offered to all community members 16 years of 
age and older in Zambia and 12 years of age or older in South Africa, and any minors 
younger than these ages who request a test, with the consent of their guardians. The CHiP 
team will map, visit, and enumerate all households in their zone. Testing will occur during 
the first 9-12 months in year 1, and will be repeated at annual intervals for those who are 
HIV-uninfected or who are not tested for any reason during the first round. Household 
visits will be made at times convenient for community members, with repeat visits 
arranged for adult household members not present during the first visit. HIV testing will 
be done on finger-stick samples using rapid kits following appropriate local testing 
guidelines. The team may also pilot or adopt other testing approaches- such as oral swabs 
for self-testing- to achieve the study goal of universal testing annually in intervention 
communities.  Implementing such strategies would be subject to additional funding and 
agreement amongst the study team. Individuals with discordant or inconclusive test results 
will be further evaluated according to local guidelines. 

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Following the household visit, the CHiP team will be responsible for ensuring linkage to 
HIV care at the health center for individuals identified as HIV-infected (defined as 
attending the health center and being given an “HIV care” patient number), offering male 
circumcision to men who are HIV-uninfected, facilitating linkage to the male circumcision 
service, and providing a regular supply of condoms to all households. They will 
subsequently make periodic revisits to appropriate households prior to the start of the next 
annual round to check on uptake of  services (including male circumcision and ART), 
encourage HIV testing for those who have not been tested recently, and to provide 
adherence support to those receiving ART (see below). Essential data on each household 
member will be captured electronically and to the degree possible will be used to confirm 
follow up on CHiPs referrals at the healthcare facility as documented in facilities’ patient 
record systems (see below). 
In addition to the door-to-door service provided by the CHiP team, provision of HIV 
testing at other venues will be strengthened. This will include opt-out, provider-initiated 
testing and counseling for all patients presenting to the health center for any reason, 
testing of all women attending antenatal clinics (ANC), voluntary counseling and testing 
services provided at the health center or other community venues, and (if appropriate for 
the community) services provided in occupational settings.  Information on how 
confidentiality of data captured into electronic databases will be maintained is provided 
below in Section 8.8.1. 
3.4 
Male Circumcision 
Services for safe medical male circumcision will be available in all study communities. In 
most cases, the service will be provided within the health center, but if this exceeds the 
capacity of the health center, a special service will be set up during the initial phase of the 
intervention at a convenient community location.  
3.5 
Universal Treatment 
Immediate eligibility for ART, irrespective of CD4 cell count, will be offered to all 
individuals attending adult HIV treatment and care services in the health centers in Arm A 
communities.  Commencing with implementation of the changes included in version 3.0 
of the study protocol, immediate ART will also be offered in Arm B and C communities.  
This offer will include those diagnosed during the door-to-door testing campaign as well 
as those diagnosed through other testing venues as described above. It will also include 
HIV-infected patients diagnosed previously who have not yet initiated ART, either 
because they have not been followed up at the health center or because they are not yet 
eligible for ART under current local guidelines. The clinics will however collect locator 
information so that the study team is aware of how many patients are coming from outside 
of the catchment area. 
Linkage from diagnosis to treatment is a critical component of the intervention in Arms A 
and B. The CHiP team for each zone will be responsible for ensuring that this linkage 
takes place. They will enter details of adults identified as HIV-infected in the electronic 
database and will provide referral to the health center for initial assessment. They will also 
offer to accompany patients to the health center. 

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On presentation at the health center, patients in all three arms will have baseline blood 
tests performed in accordance with current standards of care in Zambia and South Africa. 
CD4 testing will also be performed, and will be used to determine eligibility for ART in 
Arms B and C until such time as immediate ART is available in those arms (due to 
changing guidelines or due to implementation of protocol version 3.0).  Results of CD4 
testing will not be used to guide the initiation of ART in Arm A, or in Arms B or C after 
the shift to the offer of immediate ART; all patients without contraindications will be 
immediately eligible for ART regardless of CD4 cell count (although witten consent will 
be required if immediate ART is being provided through the study rather than through 
revised local guidelines). After exclusion of active TB, patients will be offered TB 
preventive therapy according to local guidelines.  Patients will also be offered antibiotic 
therapy for prophylaxis against opportunistic infections. The project team will endeavor to 
ensure that drug supplies are maintained without interruption. 
Ensuring a high level of adherence to ART is key to the success of the intervention in 
Arms A and B. The CHiP team will be responsible for making regular home visits to 
patients to provide psycho-social support and to check and support treatment adherence. 
Because the CHiP team will make multiple visits to many households in their zone for 
multiple reasons besides linkage to HIV care (see above), this will reduce stigmatization 
or identification of HIV-infected individuals. Activities of the CHiP team will be 
supported by automatic updates produced by the electronic database showing which 
clients are due for a home visit. 
 
Any patient initiating ART through the HPTN 071 (PopART) site clinics will continue to 
receive ART as any other clinic client would be.  They will not be taken off ART if the 
study ends early or at the natural end of the study. 
3.5.1 Choice of ART Regimen  
To simplify the implementation of the UTT approach, the study team will attempt to 
initiate all consenting individuals (barring contraindications) using the same simple, 
standard regimen, one that is in line with treatment guidelines in both countries.    
Regimen details are included in the Study Specific Procedures Manual (SSP). The small 
number of individuals for whom this regimen is contraindicated according to local 
guidelines will be treated using alternative regimens as recommended by local guidelines 
for ART patients. ART adherence and toxicity monitoring will be managed according to 
national recommendations. Switch to a second-line treatment regimen and choice of 
second-line regimens will also be according to standard guidelines. Reported levels of 
transmitted drug-resistant virus remain low in these settings (< 6%). Most cases of 
transmitted drug resistance are to nucleoside reverse transcriptase inhibitors or non-
nucleoside reverse transcriptase inhibitors, with minimal transmitted drug resistance to 
protease inhibitors [100]. 
3.6 
Treatment According to Local Guidelines (Arms B & C) 
Arrangements for linkage to care, treatment and monitoring in Arm B will be similar to 
those in Arm A, except that until immediate offer of ART is in place (due to change in 
local guidelines or due implementation of protocol version 3.0), ART will be initiated only 

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if the patient is eligible according to current local guidelines (e.g., based on CD4 cell 
count or HIV clinical stage). Treatment regimens will follow current local standards of 
care in all arms. Additional arrangements for linkage to care will not be offered in Arm C.  
 
With implementation of version 3.0 of the protocol, ART will be offered to all HIV-
infected clients at health centers in all three Arms (A, B and C) as described above. 
Research consent for ART will need to be obtained for all individuals initiating ART 
outside of local guidelines. Research consent will no longer be needed to initiate ART in 
any study arm once local treatment guidelines have changed to offer treatment to all 
infected clients.   
 
The change in protocol version 3.0 to offering universal treatment in Arms B and C will 
provide a unique and important opportunity to document the process of transition.  
Lessons learned through this process may thereby inform health policy at a time when 
many countries are expected to undertake a transition to universal treatment. 
3.7 
Prevention of Mother-to-Child Transmission  
In all three study arms, the project team will endeavor to ensure that local policy for 
PMTCT is delivered effectively at health centers providing antenatal or delivery care, 
which will usually be the same centers at which ART is delivered. 
In Arms A and B, the CHiP team will encourage women who may be pregnant to receive 
pregnancy testing at the health center. As well CHiPs will encourage pregnant women 
who are encountered during regular household visits in their zone to attend an ANC. If 
CHiPs encounter women who are HIV infected and pregnant or breastfeeding, they will 
refer them for PMTCT.  In both Zambia and the Western Cape of South Africa the “B+” 
option for PMTCT has been adopted as government policy, promoting lifelong ART for 
pregnant women with HIV infection.  Because of this,  the requirement to obtain written 
informed consent before initiating ART among clients who have CD4 cell count above the 
ART threshold per local guidelines or are at an early WHO stage, will not apply for HIV 
infected pregnant or breastfeeding women once “B+” is implemented in the local health 
care system; such women will be automatically eligible per government policy. The CHiP 
team will be responsible for  assisting these women with linkage to care, if this has not 
taken place.  
3.8 
Management of Sexually Transmitted Infections 
Services for STI treatment will be in place in all health centers according to national 
policies. In all three study arms, the project team will endeavor to ensure that these 
services are operating effectively, and that drug supplies for STI treatment are maintained 
without interruption. 
3.9 
Screening and Referral for TB 
While performing household visits, CHiPs will assess whether clients have symptoms or 
exposure to TB using a small number of questions included in the CHiPs’ standard 
information gathering tool (CHiPs register).  Clients who are suspected of possibly having 

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TB will be asked to provide sputa for laboratory testing.  CHiPs will follow up to ensure 
that clients receive their test results and to ensure that those positive for TB are seen at the 
healthcare facility for treatment. 
3.10 
Provision of PrEP  
There is growing evidence from randomized clinical trials that use of oral daily PrEP 
confers significant protection against HIV acquisition, but it is currently unclear how the 
results of those trials will be incorporated into WHO and national guidelines. New 
developments will be reviewed during the course of the trial. If the provision of PrEP is 
incorporated in local guidelines during the course of the trial, the combination prevention 
package will be adapted appropriately. 
3.11 
Standard of Care 
The primary objective of this trial is to evaluate the impact of an intensive combination 
prevention intervention program on HIV incidence when compared with current standard 
of care in Zambia and South Africa. The study team will work with in-country health 
authorities to ensure to the degree possible that existing services in the seven control 
communities meet current local guidelines for HIV prevention and care.  These activities 
include endeavoring to ensure that: 
• Community members have adequate access to services for voluntary HIV 
counseling and testing. 
• Referral services for male circumcision are available to men who are HIV-
uninfected and wish to be circumcised. 
• HIV treatment and care are provided according to current local guidelines prior to 
version 3.0 of the protocol, and, upon implementation of version 3.0 of the 
protocol, will be provided to all HIV-infected clients attending an Arm C health 
center. The study team will endeavor to ensure that antiretroviral drugs are 
available to all patients who qualify for treatment, using the current ART drug 
regimen employed in the government program in each country.  
• Adequate services for PMTCT are in place at antenatal and delivery services in the 
control communities. 
• Treatment services for STIs and condoms are available through health units in 
accordance with local HIV prevention guidelines. 
To help interpret the results of the trial, process data from the control communities on HIV 
testing uptake, ART delivery, male circumcision, and provision of PMTCT services will 
be collected for comparison with the intervention communities. These data will be used to 
inform model fitting and projections. 
3.12 
Delivery of Intervention 
3.12.1 Activities with Local Health Centers/Community Institutions  
The study team will collaborate with local health centers/community institutions to 
facilitate the following: 

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• Establishment of systems that will provide CHiPs teams with information about their 
clients’ follow up on referrals from patient record systems maintained at the healthcare 
facilities  
• Promotion of the study at the community level (Arms A & B only) 
• Strengthening the provision of HIV services at local health centers and elsewhere in all 
arms, including  
o ANC care 
o Voluntary Counseling and Testing (VCT) at health centers and other venues 
(e.g. occupational venues, community campaigns, etc.) 
o PMTCT services  
o STI treatment and referral services  
o Male circumcision services and referral 
o Activities with national/global health entities  
o Opt-out provider-initiated counseling and testing (strengthened in Arms A & 
B; in Arm C the study will support if already part of local services) 
 
The home-based HIV testing that is carried out by the CHiP teams will be captured on the 
CHiPs electronic data collection device.  (These data are stored on the device in encrypted 
form and are accessible only to authorized users after entry of an individual username and 
password.)  To the degree possible, the study team will obtain data from electronic patient 
record systems at the healthcare facilities on those clients documented as having 
consented to the CHiPS intervention who are captured in the CHiPs electronic database.  
This linkage will provide feedback to CHiPs on whether clients need further support to 
obtain care and will help the team to estimate the proportion of HIV-infected individuals 
who register for HIV care following an HIV diagnosis, and the time from HIV diagnosis 
to HIV care registration. In Arms A and B, but not Arm C, there will be active follow-up 
of HIV-infected individuals who have been referred for HIV care by CHiP teams, but who 
have not registered for HIV care. CHiP teams will also provide additional support for 
retention in HIV care and ART adherence, contributing to active follow-up of individuals 
who have missed scheduled visits. If an individual has left the community, they will not be 
followed up outside the community. 
 
3.12.2 Collaborations 
The study team will collaborate with national and global health entities to facilitate the 
following in all communities: 
 
• Adequate supplies of antiretroviral drugs for all who are prescribed them  
• Adequate STI care, including test kits and drugs for STI and treatment 
• Adequate supplies of condoms 
• Adequate clinic staffing 
• Approval of use of health center data 
• Adequate clinical supplies for HIV-infected individuals, including 
o TB tests and treatment 
o Blood tests for clinical care 

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o Antibiotics for TB and opportunistic infection prophylaxis 
 
Table 1- Summary of Intervention Components 
Study Arms 
Activity 
Arms A & B 
Study Start 
• 
Enumeration of all houses in each community  
• 
Division of houses into “zones” and assignment of a CHiP team to 
each zone 
• 
CHiP Team will: 
o Offer HIV testing with counseling to all household members 
(all individuals 16+ years old in Zambia and 12+ years old in 
South Africa and minors with the consent of their guardians) 
and will record HIV status with name in mobile device 
o Provide linkage-to-care at local health center for HIV-infected 
persons  
o Refer/link men who are uncircumcised to circumcision, if 
interested, focusing on men who are HIV-uninfected  
o Identify pregnant women and encourage them to get follow-up 
at an ANC; encourage HIV-infected pregnant women to 
initiate ART and PMTCT per local guidelines as part of their 
care 
o Provide on-going psycho-social support for ART adherence to 
those on ART 
o Encourage STI treatment and provide prevention resources 
including condoms 
o Screen clients for TB and assist in linkage to care for those 
with positive laboratory screening results. 
On-going Throughout the Study 
• 
CHiP team will: 
o Promote community-based HIV prevention services in their 
zone 
o Follow up with all persons in their zone who are identified as 
HIV-infected (by CHiP team or at other venues) to encourage 
and facilitate them to access HIV care 
o Return to houses where residents were not available for testing 
during original or subsequent visits, to complete testing of all 
willing residents 
o Encourage pregnant women to get follow-up at an ANC; 
encourage HIV-infected pregnant women to initiate ART or 
PMTCT per local guidelines as part of their care 
o Provide on-going psycho-social support for ART adherence to 
those on ART  
o Encourage STI treatment and provide prevention resources 
including condoms 
o Screen clients for TB and assist in linkage to care for those with 
positive laboratory screening results. 
Follow Up Testing at 12-, 24-, and 36-Months 

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• 
CHiP teams will cycle back through their zone at 12, 24, and 36 
months to repeat universal testing in each household for those not 
previously diagnosed as HIV-infected 
Procedures and Tests at the Health Centers 
• 
Community members who are identified as HIV-infected will 
receive clinical support and laboratory tests at local health centers, 
consistent with local guidelines for HIV treatment and care, with 
immediate eligibility for ART initiation (Arm A) or eligibility for 
ART according to local guidelines (Arm B).  Upon full 
implementation of protocol version 3.0, Arm B clients will also be 
offered immediate eligibility for ART as in Arm A. 
By Study Start and Throughout the Study Period 
• 
Endeavour to ensure that the following resources are available: 
o Voluntary HIV counseling and testing 
o Male circumcision 
o PMTCT 
o HIV treatment and care 
o STI treatment and prevention resources including condom 
distribution 
o Resources for TB testing and treatment 
o Clinical support and laboratory tests at local health centers for 
provision of prophylaxis against TB and other opportunistic 
infections for all HIV infected individuals, consistent with 
local guidelines for  HIV treatment and care 
Arm C 
By Study Start and Throughout the Study Period 
• 
Endeavour to ensure that the following standard-of-care resources 
are available: 
o Voluntary HIV counseling and testing 
o Male circumcision 
o PMTCT 
o HIV treatment and care according to local guidelines prior to 
protocol version 3.0. Upon full implementation of protocol 
version 3.0, Arm C clients will be offered immediate eligibility 
for ART. 
o STI treatment and prevention resources including condom 
distribution 
o Resources for TB testing and treatment 
o Clinical support and laboratory tests at local health centers for 
provision of prophylaxis against TB and other 
opportunistic infections for all HIV infected individuals, 
consistent with local guidelines for  HIV treatment and care 
 
3.13 
Monitoring and Evaluation Plan 
The delivery of the intervention will be monitored at frequent intervals from the time of initiation 
to evaluate the uptake of the intervention. Remedial action will be taken at cluster-level if delivery 
is behind schedule. Details of these procedures will be set out in the SSP Manual. 
  

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Briefly, during each round of CHiPs testing, HIV testing uptake is targeted at 90%. In each 
community, individual CHiP teams will report weekly to the CHiPs supervisors using data from 
electronic records. Where a team is not meeting the target level of testing uptake, this will be 
explored in real time and where necessary appropriate intervention, retraining or modification of 
strategies will take place. Following HIV diagnosis, the target will be for linkage to care and (in 
Arm A communities) initiation of ART in 80% of cases within 3 months. These targets of 90% 
uptake and 80% initiation should lead to an overall uptake of 72%, just above our central target of 
70% uptake (see Table 4). This will be supported by notification of CHiP teams, based on clinic 
and CHiPs databases. When patients have not presented within a defined interval, this will trigger 
repeat home visits for follow-up and support to access care. Data on linkage to care will be 
reviewed monthly to identify CHiP teams that are not meeting targets and to effect remedial 
actions as noted above.      
 
As stated in Section 2.4, interim evaluation will take place during the first two years of 
intervention to determine whether to continue with the 36 month follow-up of the Population 
Cohort and the fourth year of intervention. The evaluation will consider milestones such as uptake 
of the intervention and indicators of futility.  
 
The study team will also have a continuous presence in each community and will monitor other 
programs in the community that may affect uptake of the intervention.  
 
 
 
 

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4.0 
STUDY POPULATION 
4.1 
Description/Selection of the 21 Study Communities 
This study will be carried out in areas of Zambia and South Africa that are known to have 
high HIV prevalence and incidence and are continuing to experience severe generalized 
HIV epidemics, with prevalence levels of 15-20% in many areas. National estimates of 
HIV prevalence in adults aged 15-49 are 13.5% for Zambia and 17.8% for South Africa 
[35, 36], and incidence estimates are 1.17% and 1.49% respectively.[101]  
The specific communities selected for randomization in this trial are largely the 
communities that were selected for the ZAMSTAR trial. Selection criteria for 
communities included having a health facility that offered TB and HIV services, a high 
HIV prevalence, a TB notification rate of at least 400/100,000 per year and a total 
population of about 20,000 or more. The communities were selected in conjunction with 
national and local health authorities. All communities were willing to be included in a 
randomized trial.  Extensive work has been done with community representatives to 
ensure that they understand the fundamentals of research and they were all very supportive 
during the ZAMSTAR trial.  
Additional considerations that informed selection of these sites for the current study 
included: 
• Geographically distinct  
• No other major HIV prevention studies planned or ongoing 
• Adequate population size to minimize the effects of contamination on outcome 
measurements (due to contact with other communities or residents of other 
communities) 
• Community willingness to be involved in this current study 
The final endpoint measurement of the ZAMSTAR trial involved a community-level 
survey of 4000 randomly selected individuals from each community and allowed 
measurement of the uptake of HIV testing, uptake of ART, circumcision and HIV 
prevalence, which are presented in Table 2. These data would not otherwise be available at 
this level, as most surveys only provide data at provincial or district level. 
Due to differences between the designs of ZAMSTAR and the current study (requiring 
seven matched triplets) four ZAMSTAR communities from Zambia were excluded from 
the current study (the most rural communities with the lowest HIV prevalence) and an 
additional community was added in South Africa. Maps of the locations of the study 
communities are provided in Figure 3. 
 
 
 

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Table 2- Twenty one proposed study clusters in Zambia and South Africa and 
relevant background data   
 
Community 
Population 
Adult HIV 
prevalence 
Know HIV 
status 
HIV-
infected on 
ART 
Men 
circumcised 
ZAMBIA 
Dambwa 
Maramba 
Chawama 
Kanyama 
Shampande 
Chipata 
Ngungu 
Makululu 
Ndeke 
Chimwemwe 
Chifubu 
Chipulukusu 
 
 
 
 
 
 
31629 
55011 
129221 
124284 
41615 
166251 
38081 
34623 
33297 
42898 
60222 
45234 
26% 
19% 
15% 
17% 
16% 
15% 
17% 
20% 
13% 
15% 
19% 
18% 
65% 
66% 
35% 
65% 
58% 
59% 
30% 
52% 
56% 
51% 
56% 
52% 
24% 
30% 
16% 
28% 
38% 
24% 
18% 
30% 
31% 
25% 
32% 
19% 
14% 
21% 
8% 
19% 
14% 
8% 
7% 
8% 
17% 
16% 
17% 
12% 
S AFRICA 
Delft South 
Ikhwezi* 
Bloekombos* 
Dalevale* 
Wellington* 
Cloetesville* 
Luvuyo* 
Kuyasa 
Town II* 
 
 
 
 
 
31423 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
39168 
N/A 
14% 
18% 
22% 
13% 
13% 
16% 
19% 
19% 
19% 
48% 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
53% 
N/A 
23% 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
22% 
N/A 
53% 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
87% 
N/A 
*Seven South African sites – data not available from ZAMSTAR trial; accurate population size estimates 
will be available upon ethics approval,% HIV-infected on ART not yet available. Estimates of HIV 
prevalence based on sub-district antenatal clinic HIV prevalence, or (for Luvoyo and Town II) based on 
ZAMSTAR data for communities in the same sub-district. Estimates of % who know their HIV status, and 
% men circumcised, not available for 7 communities that were not included in ZAMSTAR trial. 
 
 
 
 
 

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Figure 3- Location of 21 clusters in Zambia and South Africa  
 

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4.2 
Randomization 
The first step in randomization will be to obtain agreement from communities to take part 
in the study and to accept the results of the random assignment to a study arm, whatever 
the outcome.  Randomization will then take place in a public ceremony at which the 
allocation of communities to study arms will be decided using a transparent and fair 
process.  After initiation of the intervention, if any community needs to be removed from 
the study (for example, if a community should cease to agree to participate in the study) 
then the study leadership will decide upon the most appropriate course of action, which 
would likely include replacement of the community. 
4.3 
Community Engagement 
This study will build on the community engagement and community capacity established 
during the ZAMSTAR trial. To work within a community successfully requires a trusting 
relationship which requires time to be built, and through the ZAMSTAR trial the research 
team spent seven years engaging with these communities. Community advisory bodies in 
all communities were worked with (and developed, where needed), and were trained in 
research ethics and conduct. These bodies were invaluable during the ZAMSTAR trial to 
represent community views and to assist the research teams during their work in the 
communities. The HPTN 071 study will build on these experiences, widening the 
constituency of these bodies where necessary. 
 
Direct community engagement for this study began early, during the formulation of the 
research questions, when various community groups (including CABs in former 
ZAMSTAR study communities), civil society organizations (such as the Cape Metro 
Health Forum, Treatment Action Campaign and South African National AIDS Council 
(SANAC)) and government authorities were consulted for their input before the final 
proposal was submitted, and again after the grant was awarded. Some members of these 
organizations have provided comments on the protocol and will provide additional input 
during the preparatory phase of the trial.  
 
A key aspect of the preliminary work during the first year of the study will be a 
stakeholder analysis, results of which will be used to identify relevant stakeholders to be 
considered in community engagement as well as membership for CABs. CABs in this 
study will have broad representation from various community groups and stakeholders 
such as churches, schools, law enforcement, government structures at community level, 
health-related committees, and development-related committees. Selection criteria will be 
arrived at through consultation with the stakeholders. Each study community will have a 
member of the study team responsible for community engagement activities. One of the 
main tasks of the staff will be to keep dialogue open and ongoing between researchers and 
community groups.  
 
Community engagement will be an ongoing process through regular contacts with 
community groups and CABs. A combination of mechanisms will be utilized, such as 
community meetings, workshops with key stakeholders, participant meetings, CHIPs 

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meetings and some existing avenues such as health committees, development committees, 
civil society groups and local HIV/AIDS coordinating forums such as the District AIDS 
Task Forces in Zambia and Treatment Action Campaign and SANAC in South Africa.  
This will enable the study management team to ensure that information about the study is 
disseminated widely in the communities involved and to keep the community stakeholders 
updated regarding progress of the study, events that may arise in conduct of the research, 
and new developments in HIV prevention and treatment. Community engagement will 
also allow researchers to receive feedback from the community on social harms, 
individual and community level risks, perceptions about the study in the community, and 
implementation challenges. All study staff and stakeholders will receive training in Good 
Clinical Practice (GCP)/research ethics before commencement of intervention 
implementation.  
 
Community engagement will also be factored into other study processes such as the 
communication plan, especially the dissemination of study results (preparation of the 
community). Overall, strong community engagement will allow the establishment of a 
partnership between communities, participants and researchers to ensure the latter 
discharge their responsibilities ethically in the study communities. A component of the 
qualitative research will focus on the application of ethical principles in practice as well as 
documenting and evaluating community engagement. 
 
In both countries, study committees will be formed on which community representatives 
will serve along with department of health and other stakeholder representatives. These 
committees will meet periodically for the duration of the trial and these meetings will 
provide a forum for trial staff to engage with community representatives around the 
progress of the trial and any relevant issues that may arise. 
5.0 
 RESEARCH PROCEDURES AND ACTIVITIES 
The deployment of the interventions among the communities assigned to Arms A and B is 
expected to lower HIV incidence throughout the communities. Measurement of HIV 
incidence, however, will occur in a subset of adults enrolled into the Population Cohort in 
each study community and followed longitudinally.  Secondary outcomes (among them 
process measures and qualitative research aims) will also be measured from data provided 
by this cohort, from routinely-collected health center data, and from data collected by 
CHiPs during household visits.  Other secondary outcomes will be measured from 
qualitative and case-control studies, and, if funded, from additional one-time surveys.  
Research activities, including identification and consent of participants, conduct of study 
procedures, and retention-related activities, will be performed by a trained research team, 
separate from the CHiP teams that will be responsible for delivering the intervention to the 
community-at-large. A table summarizing the secondary objectives and outcomes, 
including the source of outcome data, is provided in Section 7.11. 
Descriptions of the Population Cohort and surveys are provided below.  Detailed 
instructions to guide and standardize all study procedures across sites will be provided in 
the SSP Manual. 

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5.1 
Population Cohort  
5.1.1 Sampling/Recruitment of Population Cohort  
Prior to study commencement in each community, satellite maps will be used to 
enumerate and list all the houses in the community. A simple random sample of houses 
will be selected and visited by field staff who will list all household residents.  One adult 
per household, aged 18-44 years, will be randomly selected from this list for inclusion in 
the Population Cohort. This age range was chosen because individuals 18 years and older 
will be able to participate in the cohort without a guardian’s consent, and adults under 45 
years are believed to be most likely to experience a measurable change in HIV incidence 
as a result of the intervention. A randomization scheme will be used to select one age-
eligible resident from each ramdomly-chosen household. The selected individuals will be 
invited to join the Population Cohort, if they meet the other eligibility criteria. A blood 
sample will be collected and stored for retrospective testing which will include HIV 
testing and other secondary outcome measures (see Appendix IA). HIV counseling and 
testing using rapid HIV test kits will be offered to those who wish to know their test status 
(participants may refuse an HIV rapid test and still participate in the Population Cohort). 
All HIV-infected individuals (those testing positive on the rapid test as well as those who 
are already aware of their positive status) will be referred to a health center for further 
management. All cohort members, irrespective of HIV status, will be followed after 1 and 
2 years (interim surveys) and 3 years (final survey) to measure HIV incidence and other 
outcomes, as described below. 
Only one adult will be randomly selected from each randomly selected household to 
participate in the Population Cohort for outcome evaluation. This is to avoid the distortion 
of the trial results which might occur if whole households or several members of a 
household were to be evaluated, since this would in itself constitute a mass testing and 
counseling intervention. To avoid the possibility of coercion or biased study data, field 
staff will not enumerate a randomly selected household if someone in that household is an 
employee of ZAMBART or Desmond Tutu TB Centre.  If the person selected for the 
cohort from a given household is ineligible or refuses participation, the team will move on 
to the next household on the list. As described in Section 7, the statistical analysis will 
take into account the different sampling probabilities resulting from the selection of one 
individual irrespective of household size. 
5.1.2 Inclusion Criteria Population Cohort 
• 18 – 44 years of age 
• Able and willing to provide informed consent 
• Residing within catchment area of a designated local health unit and intending 
to remain so for the next three years 
• Residing in a randomly selected household 
5.1.3 Exclusion Criteria Population Cohort 
• Current enrollment in another HIV treatment, prevention, or PrEP study 
• Current, or prior enrollment in an HIV vaccine study 

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• Anything that, in the opinion of the investigator, would preclude informed 
consent, make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives.  
5.1.4 Procedures and Activities 
Population Cohort Creation 
• Generation of random sample of houses in the community for visits 
• Research staff visit selected houses and enumerate all adult residents (18-44)  
• Selection of one adult at random from the household for invitation to 
Population Cohort  
• Complete eligibility assessment 
• Complete informed consent  
 
Visit Procedures (Enrollment, 12 months, 24 months, and 36 months) 
Administrative, Behavioral, and Regulatory Procedures 
• Obtain informed consent for enrollment (study start only) 
• Solicit consent to store specimens for future testing and to use participant-
identified data from heath center for cohort analyses (study start only)  
• Obtain/update locator information 
• Complete survey to include topics of stigma and discrimination, and socio-
demographic, health, social, behavioral, and economic factors    
 
Clinical/Counseling Procedures 
• Perform HIV rapid tests, if participant agrees  
• Provide pre- and post-test counseling and test results, for those willing to have 
HIV rapid testing 
• Collect blood for laboratory testing and sample storage 
 
Laboratory Procedures (see Appendix IA) 
• HIV testing  
• HSV-2 testing*  
• Plasma storage**  
 
**HSV-2 testing will be performed at enrollment (PC0) and at 36 months (PC36); 
HSV-2 testing will not be performed for participants enrolled at PC12. 
**Stored samples will be used for retrospective, centralized testing, as described in 
Section 9. Additional details are provided in Appendix IA, the protocol for the 
Phylogenetics Ancillary Study, and the HPTN 071 SSP Manual. 
 
In the event that accrual falls far below target (greater than a ~20% shortfall in a particular 
community), additional participants may be enrolled in selected communities during the 
12 month follow-up survey. They will then be followed up during the 24 month and 36 
month surveys. Participants who are found to be HIV uninfected during this additioinal 
enrollment period will contribute to the primary outcome evaluation. 
 

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Results from laboratory tests are not returned to Population Cohort participants under 
normal circumstances.  However, if the results of in-country laboratory HIV tests at a 
particular visit differ from HIV rapid test results given to the participant at the same visit, 
study staff will attempt to contact the participant and encourage the participant to receive 
additional HIV testing to clarify his/her HIV infection status. 
5.1.5 Reviewing Health Center Records for Population Cohort  
For HIV-infected Population Cohort members who provide consent to access their health 
clinic records, the study team will attempt to link the research data to routine electronic 
HIV care data that are collected at the health center, to measure HIV disease progression 
and death, ART toxicity, and the time between HIV diagnosis and initiation of HIV. 
5.1.6 Retention in Population Cohort  
Once a participant is enrolled into the Population Cohort, the research team will make 
every effort to retain him/her for the follow-up surveys at 1, 2, and 3 year time points in 
order to minimize possible bias associated with loss-to-follow-up. The retention goals for 
the Population Cohort are 90% retained at 12 months, 80% at 24, and 75% at 36 months.  
Research staff are responsible for developing and implementing local standard operating 
procedures to reach this goal. Components of such procedures include: 
• Thorough explanation of the study visit schedule and procedural requirements 
during the informed consent process, with re-emphasis at the subsequent 12-
monthly study visits. 
• Thorough explanation of the importance of their participation to the overall 
success of the study. 
• Collection of detailed locator information at the study Enrollment Visit, and 
active review and updating of this information at each follow-up visit.  
• Regular communication with the study community at large to increase 
awareness about HIV/AIDS and explain the purpose of HIV prevention 
research and the importance of completing research study visits. 
In addition to the components described above, which are standard for all HPTN studies, 
the team will work with local community stakeholders, experienced in-country staff, and 
participants themselves to identify locally-effective, study-specific strategies for 
improving participant retention. Such approaches may include use of short message 
service (SMS) messages to remind participants about upcoming visits, enlisting the 
assistance of household members to support adherence to study visits and ART adherence, 
or other methods.   
Any member of the Population Cohort who leaves the community will be censored 
regardless of where they move to. Individuals who are reported to have moved within the 
community, but cannot be contacted for one follow-up visit, will not be censored. This is 
because they can still contribute to the study if they are contacted at a later follow-up 
visit: for example, if they miss the 12-month follow-up visit, they can still contribute to 
the study if they are contacted at one or both of the 24 and 36 month follow-up visits 

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Eligibility criteria for Population Cohort enrollment include current residence and 
intending to remain in the community during follow-up in an attempt to limit loss from the 
Population Cohort due to mobility. Retention rates are broadly in line with experience 
from previous trials.  
Participants may voluntarily withdraw from the study for any reason at any time. The 
Investigator also may withdraw participants from the study in order to protect their safety 
and/or if they are unwilling or unable to comply with required study procedures after 
consultation with the Protocol Chair, Division of AIDS (DAIDS) Medical Officer, 
Statistical and Data Management Center (SDMC) Protocol Statistician, and Coordinating 
and Operations Center (CORE) Protocol Specialist.   
Participants also may be withdrawn if the study sponsor, government or regulatory 
authorities, or site Institutional Review Board (IRB)/Ethics Committee (EC) terminates 
the study prior to its planned end date. 
5.2 
Population Cross-Sectional Survey (if funded) 
As noted, the Population Cross-Sectional Survey described below is currently not funded 
and is therefore not a part of the current study design.  However, the procedures that 
would be undertaken to implement this activity are described briefly below to illustrate 
what this work, if funded, would encompass.   
     
5.2.1 Sampling/Recruitment of Population Cross-Sectional Survey Participants 
A simple random sample of houses will be generated, similar to the method used for the 
Population Cohort.  Research staff will visit the houses in this list in order and all eligible 
adults in a household will be solicited to participate in the survey.  Recruitment will cease 
when five hundred participants per cluster have been enrolled into the survey. 
5.2.2 Inclusion Criteria 
• 18 – 44 years of age 
• Able and willing to provide informed consent 
• Residing within catchment area of a designated local health unit for the three 
years prior to conduct of the survey 
• Residing in a randomly selected household 
5.2.3 Exclusion Criteria 
• Current enrollment, or enrollment within the prior three years, in another 
HIV treatment, prevention, or PrEP study 
• Current or prior enrollment in an HIV vaccine study 
• Anything that, in the opinion of the investigator, would preclude informed 
consent, make study participation unsafe, complicate interpretation of study 
outcome data, or otherwise interfere with achieving the study objectives.  

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5.2.4 Procedures and Activities 
Population Cross-Sectional Survey Creation 
• Identify a random sample of houses in the community for visits 
• Research staff visit selected houses and invite all adult residents (18-44) to 
participate 
• Complete informed consent 
 
Visit Procedures (36 months only) 
Administrative, Behavioral, and Regulatory Procedures 
• Obtain informed consent for enrollment 
• Solicit consent for storage of specimens for future testing 
• Obtain/update locator information 
• Complete survey to include socio-demographic, health, social, behavioral, 
and economic factors 
• Perform qualitative interviews covering stigma and discrimination 
(randomly-selected HIV-infected participants only) 
 
Clinical/Counseling Procedures 
• Perform HIV rapid tests, if participant agrees  
• Provide pre- and post-test counseling and HIV rapid test results, for those 
willing to receive results 
• Collect blood for laboratory testing and sample storage 
 
Laboratory Procedures 
• HIV testing 
• Plasma storage* 
 
*Stored samples will be used for retrospective, centralized testing, as described in 
Section 9. Additional details are provided in Appendix 1A,  and the HPTN 071 
SSP Manual. 
5.3 
Case-Control Studies 
Three case-control studies will be undertaken to improve our understanding of 
participation in three key steps of the intervention, each of which is essential to the 
success of the trial interventions. These studies will provide information about which 
factors are associated with non-engagement with particular components of the intervention 
and will be important for interpreting the findings of the trial, informing mathematical 
models, and guiding policy. 
5.3.1 Case-Control Study 1 - Uptake of Testing in the First Round of Home-Based 
Testing Provided by CHiP Teams in Arms A & B  
A case-control study of refusers (cases) and acceptors (controls) of home-based HIV 
testing by CHiPs will be undertaken to identify the characteristics of refusers/acceptors 
and reasons for refusal/acceptance. As this is the first step in the cascade of interventions 

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in Arms A and B, this will be key in interpreting uptake of subsequent steps of the 
interventions, and will be important for identifying ways to increase testing uptake. The 
CHiP teams will request permission from individuals declining the intervention to be 
approached by the research team for potential enrollment into the case-control studies. 
5.3.1.1 Sampling/Recruitment of Case-Control Study 1 Participants 
Four hundred cases (refusers of CHiP testing) and 400 randomly selected controls 
(acceptors) from the communities in Arms A and B will be enrolled.  Potential participants 
will be selected at random and approached by CHiP personnel, who will seek verbal 
consent for follow-up by a research team. The latter will then obtain the formal informed 
consent for case-control study participation. Recruitment will cease when 400 participants 
have been enrolled in each of the two groups. 
5.3.1.2 Inclusion Criteria Case-Control Study 1 
• At least 18 years of age 
• Able and willing to provide informed consent  
• Resident in the cluster during the first round of testing 
• Visited by a CHiP team and offered testing during the first round of home-
based testing 
5.3.1.3 Exclusion Criteria Case-Control Study 1 
• Individuals belonging to the Population Cohort or other case-control studies 
• Individuals known to be HIV-infected after testing elsewhere  
• Individuals working on, or living in the same household as a member of staff 
working on, the HPTN 071 (PopART) trial 
5.3.1.4 Procedures and Activities 
Administrative, Behavioral, and Regulatory Procedures 
• Obtain informed consent for enrollment 
• Complete questionnaire of socio-demographic, clinical, and behavioral 
characteristics 
 
Standardized questionnaires will encompass sexual and health seeking behavior, previous 
HIV testing, as well as stigma and psycho-social questions.  Cases and controls will also 
have separate sections in the questionnaire, to explore reasons for not testing and 
motivation to test, respectively. The standardized surveys will be carried out by case-
control study teams after the end of the first CHiP home-based testing round within a 
community, at the household or an alternative community location chosen by the 
participant. 
5.3.2 Case-Control Study 2 - Uptake of Immediate Treatment in Arm A  
A case-control study of cases (who do not start ART within 6 months of being identified 
as HIV-infected and referred for HIV care by CHiPs) and controls (who start ART within 

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6 months of referral) selected randomly from HIV-infected individuals from Arm A 
communities, will be undertaken to identify the characteristics of those who do/do not 
start ART within 6 months and reasons for starting/not starting. As timely treatment is the 
linchpin of the PopART intervention, understanding the barriers to wide-scale uptake (if 
any) will be crucial in understanding the trial findings.  
5.3.2.1 Sampling/Recruitment of Case-Control Study 2 Participants 
Four hundred cases (non-receivers of ART within 6 months after first receiving an HIV 
positive test from a CHiP, or disclosing previously-diagnosed HIV infection to a CHiP 
and being referred to HIV care) and 400 randomly selected controls (HIV-infected 
initiators of ART within this timeframe) from the communities in Arm A will be enrolled.  
Potential participants will be selected at random and approached by CHiP personnel, who 
will seek verbal consent for follow-up by a research team. The latter will then obtain the 
formal informed consent for Case-Control Study 2 participation. Recruitment will cease 
when 400 participants have been enrolled in each of the two groups. 
5.3.2.2 Inclusion Criteria Case-Control Study 2 
• At least 18 years of age 
• Able and willing to provide informed consent  
• Resident in the cluster during the first round of testing  
• Tested HIV-infected in CHiP home-based testing, or HIV-infected and 
disclosed that they were previously diagnosed as HIV-infected to CHiP team 
5.3.2.3 Exclusion Criteria Case-Control Study 2 
• Individuals enrolled in the Population Cohort or other case-control studies  
• HIV-infected individuals already on ART before study commences 
• Individuals working on, or living in the same household as a member of staff 
working on, the HPTN 071 (PopART) trial 
5.3.2.4 Procedures and Activities 
Administrative, Behavioral, and Regulatory Procedures 
• Obtain informed consent for enrollment 
• Complete questionnaire of socio-demographic, clinical, process uptake and 
behavioral factors 
 
Standardized questionnaires will encompass sexual and health seeking behavior, as well as 
stigma and psycho-social questions.  Cases and controls will also have separate sections in 
the questionnaire, depending on whether: i) they did not attend the health center in the first 
place (cases), ii) attended but did not initiate treatment within 6 months (cases), iii) 
attended and initiated treatment within 6 months (controls) to explore their reasons for not 
starting ART within 6 months or motivation to start timely treatment. The standardized 
surveys will be carried out by case-control study teams after the end of the first CHiP 
home-based testing round within a community, at the household or an alternative 
community location chosen by the participant. 

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5.3.3 Case-Control Study 3 - Uptake of Testing in the Second Round of Home-Based 
Testing Provided by CHiP Teams in Arms A & B  
A case-control study of refusers (cases) and acceptors (controls) of home-based HIV 
testing by CHiPs in the second round of testing will be undertaken to identify the 
characteristics of refusers/accepters and reasons for refusal/acceptance at this stage. 
Because regular re-testing of individuals who were HIV-uninfected when last tested is a 
crucial step in the cascade of interventions in Arms A and B, the understanding of reasons 
for not accepting CHiP home-based testing in the second round is key for interpreting 
uptake of subsequent steps of the interventions, and for identifying ways to increase the 
uptake of re-testing. The CHiP teams will request permission from individuals declining 
the intervention to be approached by the research team for potential enrollment into the 
case-control studies. 
5.3.3.1 Sampling/Recruitment of Case-Control Study 3 Participants 
Four hundred cases (refusers of CHiP testing) and 400 randomly selected controls 
(acceptors) from the communities in Arms A and B will be enrolled.  Potential participants 
will be selected at random and approached by CHiP personnel, who will seek verbal 
consent for follow-up by a research team. The latter will then obtain the formal informed 
consent for case-control study participation. Recruitment will cease when 400 participants 
have been enrolled in each of the two groups. 
5.3.3.2 Inclusion Criteria Case-Control Study 3 
• At least 18 years of age 
• Able and willing to provide informed consent  
• Resident in the cluster during the second round of testing 
• Visited by a CHiP team and offered testing during the second round of home-
based testing 
5.3.3.3  Exclusion Criteria Case-Control Study 3 
• Known HIV infected from CHiP data.   
• Individuals belonging to the Population Cohort or other case-control studies  
• Individuals working on, or living in the same household as a member of staff 
working on, the HPTN 071 (PopART) trial 
5.3.3.4 Procedures and Activities 
Administrative, Behavioral, and Regulatory Procedures 
• Obtain informed consent for enrollment 
• Complete questionnaire of socio-demographic, clinical, process uptake and 
behavioral factors 
 
Standardized questionnaires will encompass sexual and health seeking behavior, previous 
HIV testing, as well as stigma and psycho-social questions.  The primary analysis will 
compare refusers and acceptors of testing at this stage. There will also be sub-group 

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analyses to consider participants who: (i) accepted, tested and were found negative at the 
first round, (ii) refused testing at the first round, (iii) were absent at the baseline testing 
round (away from home or newly moved into community). The standardized surveys will 
be carried out by case-control study teams at the end of the second CHiP home-based 
testing round (i.e. 12 month round) within a community, at the household or an alternative 
community location chosen by the participant. 
5.4 
Qualitative Studies 
Qualitative studies will be conducted in both Zambia and South Africa by an experienced 
social science team. The research will be conducted in two phases.  A first rapid phase 
using participatory social research methods carried out in all communities will be 
described and conducted in an ancillary protocol.  A second in-depth phase, with a 
longitudinal component, related to the different arms of the trial and core questions around 
uptake and outcomes, is described below. 
The first phase will identify key features of each community (including social 
organization and networks) and will involve community mapping of the history of ART, 
local HIV prevention initiatives, HIV treatment and support services, and key stakeholders 
(including other HIV research studies). This and initial work on community attitudes to 
different prevention methods will help to inform the design and delivery of the trial 
interventions (including the design and content of information/sensitization messages and 
instruments) and to enable effective stakeholder co-ordination in all communities.  In 
principle, the qualitative studies will work closely with the community engagement 
process throughout the study. 
In the second phase, the qualitative research will have three core components, namely: 
qualitative research evaluating the acceptability of the intervention including, critically, 
the acceptability and functioning of the CHiPs and the process of community engagement; 
a qualitative longitudinal study of representative individuals nested within the first Case-
Control study described above; and an ethnographic component.  These are briefly 
detailed below. 
5.4.1 Evaluation of the Acceptability of the Intervention: 
In Arms A and B, social science research will be carried out at community level using a 
mix of social research methods (including fieldworker structured diaries, in-depth 
interviews, focus-group discussion, participatory rapid appraisal tools, participant 
observation, structured observation) to assess over time popular understanding of HIV 
testing and treatment and how communities actually respond to the combination 
prevention intervention, including linkage to care and the innovation of immediate HIV 
treatment.  This research component will be carried out throughout the intervention period 
at intervals linked to the intervention timeline – e.g. at the outset, three months into the 
intervention, a year into the intervention and towards the end of the intervention. 
Comparative research will also be carried out in Arm C – evaluating community response 
to HIV testing and treatment in the absence of trial interventions. Following full 
implementation of protocol version 3.0, social science research will be conducted on the 

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transition to immediate eligilibility for ART in Arm B and C communities and the 
continued response to this change over time. 
 
Building on the rapid formative research, qualitative insights will be collected in a 
structured diary form throughout the intervention period from all communities using 
resident fieldworkers who would dedicate a few days a month to document local response.  
More in-depth work will also be carried out in communities of a certain type.  In these 
communities, roughly 100 participants, including key local stakeholders, CHIP teams and 
different age and gender groups from the community,  will be questioned about the 
acceptability of the intervention, any problems experienced or foreseen, and suggested 
solutions to these problems, and findings will be fed back into community engagement 
and trial practice.  Research on the process of community engagement and the application 
of ethical guidelines will also be embedded within this component.  In addition, this 
component will include any urgent research on significant events at community level (e.g. 
significant rumors including Satanism accusations, community withdrawal, explicit 
confrontation with faith healing or other alternative prevention options) which threaten the 
continuation or practice of the trial and require qualitative investigation.   
5.4.2 Qualitative Longitudinal Study in Arms A and B – sub-set of Case-Control 
Study 1 
A small number (roughly 12 in each selected community) of representative individuals 
from Case-Control Study 1 will be enrolled and seen longitudinally over the intervention 
period in selected communities across Arms A and B to explore and document the 
longitudinal trajectory of individual behavior in relation to uptake of HIV testing and 
treatment, complementing the findings of the case-control studies.   
 
Individuals who have refused testing at baseline and individuals who have accepted 
testing with different outcomes (tested HIV-uninfected or HIV-infected) from different 
genders, age groups, and socio-demographic backgrounds will be selected and approached 
to participate in this longitudinal study.  This cohort of individuals would be recruited 
following their participation in Case-Control Study 1– with the first in-depth interview 
taking place after the Case-Control Study 1survey, and subsequent in-depth interviews 
being held at one to three month intervals until the end of the intervention period. This 
research will document experiences over time and establish how the micro-level 
continuum of experiences influence decision making processes related to uptake of HIV 
testing and treatment services. Additional locator information will be collected and 
separate informed consent obtained for the study for each visit.    
 
A mix of methods will be used including semi-structured interviews, observations and 
respondent records of significant events pertaining to individual health and health seeking 
behavior.  In-depth interviews will be conducted by local social science research assistants 
supervised by a social scientist.   
 
As a result of changes to the protocol in version 3.0, and in addition to the above, a small 
number of individuals in some Arm C communities representing different decisions 
concerning HIV testing and treatment (following the shift to immediate eligibility to ART) 
will also be recruited and followed to the end of the intervention period.   

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5.4.3 Ethnography of the HIV landscape    
This component aims to provide more contextual and comparative understanding of how 
communities are experiencing the roll-out of UTT, including immediate HIV treatment.  
The inquiry will build on and extend current knowledge of the impact of ART on HIV 
stigma, the long-term realities of ART in low-resource settings, the influence of 
alternative prevention options, the role of welfare and food insecurity in shaping uptake of 
ART, popular knowledge of ART, sexual risk disinhibition, alcohol and drug use, gender-
based violence, HIV identity, the reproductive health of people living with HIV, the 
acceptability of and response to male circumcision, the influence of local systems, social 
networks and community morale, and the role of different stakeholders.  This 
ethnographic research will use a mix of social research methods – with the most key 
method being the continued presence of a social scientist in a community over a period of 
3-6 months, mostly likely 6-18 months into the intervention period.  It will be carried out 
in two communities in each country and most of the inquiry will be carried out at 
household level. 
5.4.4 Graphical Summary of Qualitative Activities 
A summary of the timing, flow and logic of the qualitative activities is provided in 
Figure 4. 
 

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Figure 4- Qualitative Activities in HPTN 071 
 
 
 
 
 
5.4.5 Integration of Data from Case-Control and Qualitative Components 
The social science team will be involved in helping to develop the themes and questions 
for the case-control studies. Within the case-control studies there is a qualitative 
component that aims to provide a more detailed picture of HIV testing and treatment 
pathways for a small number of representative individuals. The lead investigator for the 
case control studies will work closely with a social scientist who will carry out the 
qualitative component as well as supporting the quantitative measures/data collection. 
Broader ethnographic enquiry will also explore core themes (all related to secondary 
outcomes). 
5.5 
Collection of Health Center-Based Data 
In addition to the conduct of specific surveys described in previous sections, routine health 
center-based data in all study communities will be used to measure several secondary 
outcomes.  To maximize the validity of this information, the research team will work with 
the health centers to improve the collection and management of these routine data and to 
the extent possible, harmonize these processes across health centers. 
5.5.1 Tuberculosis Case Notification 
TB cases in the study communities are routinely diagnosed and treated at the same health 
centers as those delivering HIV treatment and care. In all of the study communities, the 
Formative Qualitative Research 
Qualitative Enquiry 
Acceptability of Interventions 
(Arms A & B)
Indepth exploration of HIV test 
and treat pathway
(Arms A & B)
Ethnography of Combination 
Prevention
Quantitative measures in 
Population Cohort surveys and 
case-control  studies
Some Arms A, B & C; some 
limited to two Arms.  To include: 
sexual risk behaviour, alcohol & 
drug use, HIV stigma, structural 
barriers 

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TB notification process will be strengthened by the use of additional diagnostic tests and 
enhanced monitoring of the TB case registration system.  Data from this system will be 
compiled at regular intervals during the trial and used to measure the following outcomes: 
• Notification rate of bacteriologically confirmed pulmonary tuberculosis 
• Mortality rate of bacteriologically confirmed pulmonary tuberculosis 
 
These data will be collected for each time period, and will be classified according to HIV 
status. 
5.5.2 Intervention Effect on Health Center Workload 
To address concerns that the intervention may substantially add to the case-load of clinics, 
data from clinic registers will be compiled at regular intervals to determine the total 
numbers of outpatient and inpatient attendances. These data will be collected at regular 
time intervals, and efforts will be made to broadly classify medical reasons for attendance. 
5.5.3 Intervention Effect on Healthcare Costs 
A multi-step procedure will be used to determine the impact of the intervention on 
healthcare costs. First, data will be collected on individuals’ healthcare utilization by self-
report of the members of the Population Cohort. Data will be collected on use of 
outpatient healthcare facilities (number of visits) and secondary and tertiary facilities 
(number of visits, duration of visit if overnight). Direct costs of providing care to 
individuals will also be evaluated, including travel costs and reimbursements by third 
parties (e.g. private insurers). In addition, Population Cohort patient records held at the 
healthcare facilities along with CHiPs data will be reviewed where available to obtain 
detailed information on healthcare use across treatment arms. We will use both participant 
self-report and clinic records in order to generate population level estimates of changes in 
health care utilization, document care sought from providers where linkage to records is 
not possible, and collect data on patients’ cost of seeking care. Second, facility level costs 
will be collected in all facilities in selected trial communities. Both one-time capital costs 
(e.g. investments in buildings) and recurrent costs (e.g. salaries) will be collected. Lastly, 
facility level costs will be apportioned to the visits reported by the cohort members by 
applying average costs for typical use of healthcare facilities. For members with linked 
patient records, we will calculate more precise cost estimates of health care use based on 
actual treatments provided. This final analysis will be based on various assumptions, 
which will be tested with sensitivity analysis.  

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5.5.4 HIV Disease Progression and Death 
Aggregate data from the health center database for health center attendees on ART such as 
WHO staging events (including opportunistic infections such as TB), hospitalizations 
(where documented), CD4 cell counts, and death will be used to  monitor effects of the 
interventions on HIV disease progression and death.   
5.5.5 ART Adherence and ART Toxicity 
To assess the rates of ART adherence under different intervention conditions, aggregate 
data will be collected from all health centers about missed follow-up visits among those 
on ART and missed dispensations of ARV drugs.  To assess rates of ART toxicity under 
different intervention conditions, aggregate clinical data related to ART related side 
effects, ART drug interruptions and treatment switches will also be collected from each 
health center. 
5.5.6 Uptake of Intervention Components 
Process measures of the uptake of key components of the intervention will be measured in 
Arms A and B using data from the health centers on the rates of utilization of PMTCT 
services and medical male circumcision and the proportion of community members 
initiating HIV care within three months of receiving an HIV diagnosis. 
5.6 
Proposed Additional Surveys 
Three additional surveys have been proposed to support or enhance the research described 
above.  The three surveys have not been described in detail in the body of this protocol 
because funding is not available for them at the current time.  However, each is briefly 
described below and described in detail in Appendices VIII, VI and X. 
 
Population Cross-Sectional Survey (Appendix VIII) 
Because participants in the Population Cohort will be followed longitudinally over 3 
years, their interactions with the research staff could bias the data they provide for certain 
outcome measures.  The Population Cross-Sectional Survey would be a snapshot 
evaluation to provide unbiased data for comparison on many of the measures evaluated in 
the Population Cohort.  Approximately 500 participants per cluster would be recruited 
from randomly-selected homes for this survey, to be conducted at the end of the second 
year of the intervention. Procedures would include a questionnaire and blood sampling for 
HIV testing and sample storage. 
 
 

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5.7 
Comparative Table of Study Activities across All Study Arms 
Table 3- Study Activities across All Study Arms 
Study Procedures/ Activity 
Arm A 
Arm B 
Arm C 
Strengthening the provision of HIV services in the community 
 
Endeavour to ensure ART service delivery to at least local 
guidelines 
X 
X 
X 
Endeavour to ensure PMTCT services to at least local guidelines 
X 
X 
X 
Endeavour to ensure STI treatment to at least local guidelines 
X 
X 
X 
Endeavour to ensure male circumcision services to at least local 
guidelines 
X 
X 
X 
Promotion of voluntary counseling and testing at non-HIV clinics 
and other venues  
X 
X 
X1 
Opt-out provider-initiated counseling and testing 
X 
X 
X1 
Implementation of interventions including deployment of CHiP 
teams to all houses in the community 
 
Offering initial and recurrent HIV testing and counseling to all 
household members aged 16 years or above in Zambia/12 years or 
above in South Africa, and younger children with parental consent 
X 
X 
 
Linkage-to-care for HIV-infected persons 
X 
X 
 
Immediate eligibility for ART  
X 
X2 
X2 
Eligibility for ART based on local guidelines 
 
X2 
X2 
Referral of willing HIV-uninfected men for circumcision 
X 
X 
 
Referral of pregnant, HIV-infected women to PMTCT services or 
immediate ART 
X 
X 
 
Ongoing promotion of ART adherence and HIV prevention 
services during the study period 
X 
X 
 
Enrollment and follow-up of Population Cohort by research 
team 
 
Informed consent 
X 
X 
X 
Offer of HIV rapid test and counseling 
X 
X 
X 
Complete survey to include socio-demographic, health, social, 
behavioral, and economic factors 
X 
X 
X 
Blood draw and laboratory-based testing 
See Sections 5.1 and Appendix IA. 
X 
X 
X 
Execution of a Population Cross-Sectional Survey at 36 months 
(if funded) 
 
 
 
Same procedures as for Population Cohort, but without HSV-2 
testing 
X 
X 
X 
Conduct of qualitative studies 
 
 
 
Informed consent 
X 
X 
X 
Completion of qualitative data collection  
X 
X 
X 
Conduct of Case-Control studies 
 
 
 
Informed consent 
X 
X 
 
Completion of behavioral questionnaire 
X 
X 
 
 
1Where these are already provided locally as standard services. 
2ART eligibility according to local guidelines prior to protocol versions 3.0; immediate eligibility after full 
implementation of protocol version 3.0. 

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6.0 
SAFETY MONITORING AND SOCIAL HARM REPORTING 
6.1 
Safety Monitoring  
All drugs used in this study for the treatment of HIV have regulatory approval for this 
purpose in both Zambia and South Africa and are widely used with well-established safety 
profiles. Community members receiving ART will be seen by the regular staff at the 
health center for their care and will receive safety assessments according to local standard 
of care.  Data from these tests are not routinely entered into electronic medical records at 
the health center.  The research team therefore will not have access to, nor monitor or 
report adverse events/serious adverse events (AE/SAEs) for community members on 
ART.  Instead, information about the impact of the different interventions on the health 
and safety of community members on ART will be assessed through analysis of aggregate, 
anonymous data from the health centers, and data from Population Cohort participants, 
including measures of HIV disease progression and death, self-reported drug adherence, 
ART toxicity, and, if funded, viral suppression, drug resistance, and community viral load. 
6.2 
Social Harm Reporting 
The HPTN defines social harms as any untoward social occurrences that happen to a 
participant as a result of their participation in the study, with examples including loss 
of employment, harassment by neighbors, shunned by family, rejection by partner, etc.  
Because this study is a community-randomized trial of a multi-faceted intervention, the 
majority of people in the community affected by the implementation of the study will not 
be participants in the evaluation surveys, and so the definition of social harm for this study 
will be expanded to also include any untoward social occurrences that happen to a 
community, or groups or individuals within a community, as a result of 
implementation of the study intervention.  Social harms will be monitored throughout 
the study. 
 
It is important to note that the number of people who live in the communities involved in 
this study is very large and the number of social harms unrelated to the study intervention 
or study participation that will occur during the trial period is expected to be very high 
due to social, economic and cultural factors unrelated to the study.  Therefore it will be 
important that study staff are well trained to report only those social harms that they deem 
to be directly related to the intervention, or participation in the research program.   
6.2.1 Participants in the Population Cohort  
The Population Cohort is intended to provide study data representative of the populations 
from which it is drawn, and this will apply for social harms monitoring as well.  
Information on social harms experienced by cohort participants - either because of the 
deployment of the intervention in their community or because of their individual 
participation as research subjects in the cohort - will be actively solicited from participants 
at follow-up visits and captured in the study database. When a cohort participant reports a 
social harm, every effort will be made by the study staff to provide appropriate counseling 
to the participants, and/or referral to appropriate resources, as needed.  

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6.2.2 Community at Large 
Monitoring of social harms in the community will be accomplished using several 
approaches.  In each household during their annual testing visit, CHiPs will inquire about 
any social harms due to the implementation of the intervention in their community, and 
will document qualifying harms in the study database.  Because study staff work 
intimately among, and are often from, the randomized communities, they may become 
aware on a passive basis of social harms that are occurring within the community.  Staff 
will report these harms as well.  The study team will include discussion of social harms as 
one of the topics regularly covered in work with the community liaison board in each 
community, and will report on any harms reported in those meetings. Finally, the 
qualitative research to be conducted includes exploration of social harms in the 
community.  
6.2.3 Social Harm Monitoring 
The study management team will review the social harms reports on a quarterly basis, or 
sooner, if a concerning trend or event is identified.  If the management team judges an 
individual social harm, or a trend in social harms, to be serious or unexpected, they will 
work together with appropriate bodies (in-country investigator, community liaison board, 
sponsor, IRB, etc.) to determine if a response is indicated, and if so, what it should be.  
The nature and frequency of reported social harms will be reviewed by the HPTN Study 
Monitoring Committee (SMC).  Investigators of record will report serious or unexpected 
social harms to the responsible IRB/EC at least annually, or according to their individual 
requirements. The study team notes that although most of the activities for detecting social 
harms listed above will be conducted equally in all three arms of the study, CHiPs will 
only be deployed in Arms A and B.  Therefore a greater number of reported social harms 
may be seen in these arms, relative to Arm C, due to differential ascertainment, rather than 
differential incidence of harms, a possibility that will be considered when reviewing trends 
in social harms. 
7.0 
STATISTICAL CONSIDERATIONS AND DATA ANALYSIS 
7.1 
Sample Size  
The trial has been powered to detect intervention impact on the primary endpoint, and on 
key secondary endpoints, as detailed below. All sample size calculations have been carried 
out using methods for matched cluster-randomized trials. 
7.1.1 Mathematical Modeling and Sample Size Calculations  
The development of the interventions has been guided by the results of mathematical 
modeling. Early work on the intervention was based on the papers by Granich et al. 
Subsequently, the modeling team at Imperial College developed a model fitted to current 
UNAIDS prevalence data from Zambia and South Africa and used it to predict the impact 
of the proposed packages of interventions relative to the standard of care arm (Figure 5). 

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Figure 5- Mathematical model of the epidemic and of the PopART interventions 
 
A model was developed to aid development of the trial protocol, and more specifically to develop targets for the 
process variables (coverage, contamination, etc.), and to provide scenarios for the power calculations. The model is a 
conventional HIV epidemic model, and has been validated by a recent systematic model comparison exercise (Eaton 
et al, submitted). The model is calibrated to country-specific UNAIDS data on adult HIV prevalence (green lines in A 
and B). Prevalence in the 24 ZAMSTAR communities in 2010 is shown by the green circles, and the predicted 
incidence curves are shown as red lines. C and D, starting from 2012, the PopART intervention package is 
implemented; the packages are implemented in six-monthly cycles, which results in a characteristic ‘saw-tooth’ 
pattern in incidence. The Just-on-target scenarios are based on the optimistic scenario (75% annual coverage, 95% 
treatment efficacy, 5% contamination, 50% uptake of male circumcision, 10% annual drop out and no behavior 
change). E, predicted sources of infection for incident cases for Arm A in Zambia, and F as E for Arm B. 
. 
 

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Briefly, the model assumes three sexual activity classes, and the proportions in each class, 
the assortativity in sexual mixing, rates of partner acquisition and HIV transmissibility are 
fitted to the prevalence data in each country. The model assumes that male circumcision 
reduces HIV acquisition by 60%, with rates of male circumcision based on data from the 
study communities (Table 2- Section 4.1). ART roll-out is assumed to commence in 2004 
with coverage amongst those with CD4<200 and CD4<350 matched to ZAMSTAR 
data.[102] The model includes variable infectivity by stage of infection, matched to data 
from the Rakai study.[68, 103] To allow for contamination, we assumed that 5% of sexual 
contacts occur with partners from outside the study community. The fit of the model to the 
HIV prevalence data is considered to be good. 
The model fits assume that interventions commence in 2012, and that during each annual 
round of testing in Arms A and B, the intervention is delivered over a period of 26 weeks. 
Figure 5 shows projected HIV incidence over time for Arms A and B compared with the 
control arm for the optimistic target scenario. Table 4 shows the assumptions made for the 
central and optimistic target scenarios and the projected impact on cumulative HIV 
incidence over three years, over the first two years, and also in each year separately, for 
Arms A and B compared with Arm C. The projections indicate that an impact is expected 
over three years of 55-65% in Arm A and 20-30% in Arm B. Impact is substantially higher 
in Years 2 and 3 as expected. As a sensitivity analysis, assuming roll-out takes 12 rather 
than 6 months, projected impact over three years is 50-60% for Arm A and 20-30% for Arm 
B (Table 5). 
 
Table 4- Parameter values assumed for the model of the impact of the intervention for 
central and optimistic target scenarios, and projected impact on HIV incidence in 
Arms A and B compared with Arm C, assuming intervention roll-out over a 6-month 
time period 
 
Parameter 
Central Target 
Optimistic Target 
Annual coverage of test and treat campaign 
70% 
75% 
Treatment failure & drop-out rate, per year 
10% 
10% 
Effectiveness of ART in blocking transmission 
90% 
95% 
Take up of male circumcision when offered 
50% 
50% 
 
Arm A 
Arm B 
Arm A 
Arm B 
Zambia 
Impact on cumulative incidence (3 years) 
61% 
25% 
63% 
27% 
Impact on cumulative incidence (2 first years) 
58% 
24% 
61% 
25% 
Impact on HIV incidence during Year 1 
51% 
20% 
54% 
21% 
Impact on HIV incidence during Year 2  
65% 
27% 
67% 
28% 
Impact on HIV incidence during Year 3  
67% 
29% 
68% 
30% 
South Africa 
Impact on cumulative incidence (3 years) 
62% 
26% 
64% 
27% 
Impact on cumulative incidence (2 first years) 
59% 
25% 
61% 
26% 
Impact on HIV incidence during Year 1  
52% 
22% 
55% 
23% 
Impact on HIV incidence during Year 2  
65% 
28% 
67% 
29% 
Impact on HIV incidence during Year 3  
68% 
29% 
69% 
30% 

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Table 5- Parameter values assumed for the model of the impact of the intervention for 
central and optimistic target scenarios, and projected impact on HIV incidence in 
Arms A and B compared with Arm C, assuming intervention roll-out over a 12-month 
time period 
Parameter 
Central Target 
Optimistic Target 
Annual coverage of test and treat campaign 
70% 
75% 
Treatment failure & drop-out rate, per year 
10% 
10% 
Effectiveness of ART in blocking transmission 
90% 
95% 
Take up of male circumcision when offered 
50% 
50% 
 
Arm A 
Arm B 
Arm A 
Arm B 
Zambia 
Impact on cumulative incidence (3 years) 
58% 
24% 
60% 
25% 
Impact on cumulative incidence (2 first years) 
53% 
21% 
56% 
22% 
Impact on HIV incidence during Year 1 
42% 
16% 
45% 
17% 
Impact on HIV incidence during Year 2  
64% 
27% 
66% 
28% 
Impact on HIV incidence during Year 3  
68% 
29% 
69% 
31% 
South Africa 
Impact on cumulative incidence (3 years) 
59% 
25% 
61% 
26% 
Impact on cumulative incidence (2 first years) 
54% 
23% 
57% 
24% 
Impact on HIV incidence during Year 1  
44% 
18% 
47% 
19% 
Impact on HIV incidence during Year 2  
64% 
27% 
67% 
29% 
Impact on HIV incidence during Year 3  
68% 
30% 
70% 
31% 
 
 
The targets appear achievable based on published evaluations of interventions in Africa. 
Because there is most uncertainty in the effects on behavior change, the model 
conservatively assumed no effect on behavior when deriving these targets. Process 
indicators will be monitored as described in Sections 7.1.3 (6) and 7.10, and used to 
modify and adapt the intervention as necessary. 
7.1.2 Primary Endpoint - HIV Incidence Over 36 Months 
The incidence of HIV infection among initially HIV-uninfected Population Cohort 
members will be measured during the follow-up period of 36 months. Based on national 
estimates of HIV incidence and on HIV prevalence in the chosen study areas, it is 
expected that HIV incidence in the control arm will be in the range 1.0-1.5/100py. With a 
matched study design, and based on the between-community variation in HIV prevalence 
observed in the 2010 survey of several thousand adults in each of the trial communities, 
and the between-community variation in HIV incidence among adults living in the 
households of TB cases during 2006-2010, it is expected that the between-community 
coefficient of variation will be in the range 0.15-0.20. Seven communities were chosen per 
study arm and a Population Cohort of 2,500 adults per community to attain adequate 
power to detect a difference in incidence between Arms A and C (reflecting the full 
impact of the intervention), as well as the difference in intervention effect between Arms 
A and B (reflecting the additional effect of immediate HIV treatment compared with 
current local guidelines). Based on mathematical modeling, the anticipated effect of Arms 

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A and B is to reduce cumulative HIV incidence over a three-year period by 55-65% and 
20-30% respectively, compared with Arm C (Figure 5), with a difference in impact 
between Arms A and B of about 30-35%. A standard formula for cluster-randomized trials 
was used for the comparison of incidence rates over 36 months, with matched triplets as 
the trial design[104]. 
Table 6 shows that the study will be very well powered to detect an effect of 35% or larger 
in Arm A compared with Arm C, and moderately well powered to detect an effect of 30% 
under favorable assumptions. For the direct comparison of Arms A and B, Table 7 shows 
that the study will be well powered to detect a difference between effects of 60% and 
30%, 55% and 25%, and 50% and 20%. Tables 6 and 7 allow for a baseline HIV 
prevalence of 15% and assume losses to follow-up of 20% over two years, and 25% over 
three years. 
 
 
 

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Table 6- Power for comparison of HIV incidence in Arm A or B with Arm C, with 7 
communities per arm and Population Cohort of 2500 adults per community (assuming 
that on average 2125 (85%) will be HIV-uninfected at baseline and that loss to follow-
up will be 20% after 2 years and 25% after 3 years) with 5206 person-years per 
community over 36 months (assuming 1912 person-years 0-12 months; 1700 person-
years 12-24 months; 1594 person-years 24-36 months) 
HIV incidence 
rate/ 100py 
(control arm) 
Between-cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
 
Power (%) 
 
1.0 
0.15 
25% 
57% 
1.0 
0.15 
30% 
74% 
1.0 
0.15 
35% 
87% 
1.0 
0.15 
40% 
95% 
1.0 
0.15 
45% 
99% 
1.0 
0.15 
50% 
100% 
1.0 
0.15 
55% 
100% 
1.0 
0.15 
60% 
100% 
1.0 
0.15 
65% 
100% 
 
 
 
 
1.0 
0.20 
25% 
44% 
1.0 
0.20 
30% 
60% 
1.0 
0.20 
35% 
75% 
1.0 
0.20 
40% 
87% 
1.0 
0.20 
45% 
94% 
1.0 
0.20 
50% 
98% 
1.0 
0.20 
55% 
99% 
1.0 
0.20 
60% 
100% 
1.0 
0.20 
65% 
100% 
 
 
 
 
1.5 
0.15 
25% 
64% 
1.5 
0.15 
30% 
81% 
1.5 
0.15 
35% 
92% 
1.5 
0.15 
40% 
98% 
1.5 
0.15 
45% 
100% 
1.5 
0.15 
50% 
100% 
1.5 
0.15 
55% 
100% 
1.5 
0.15 
60% 
100% 
1.5 
0.15 
65% 
100% 
 
 
 
 
1.5 
0.20 
25% 
48% 
1.5 
0.20 
30% 
65% 
1.5 
0.20 
35% 
80% 
1.5 
0.20 
40% 
91% 

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1.5 
0.20 
45% 
96% 
1.5 
0.20 
50% 
99% 
1.5 
0.20 
55% 
100% 
1.5 
0.20 
60% 
100% 
1.5 
0.20 
65% 
100% 
 
 
Table 7- Power for comparison of HIV incidence between Arms A and B, with 7 
communities per arm and Population Cohort of 2500 adults per community (assuming 
that on average 2125 (85%) will be HIV-uninfected at baseline and that loss to follow-
up will be 20% after 2 years and 25% after 3 years) 
 
HIV incidence 
rate/ 100py 
(control arm) 
Between-cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
Arm A 
Effectiveness (%) 
Arm B 
Power (%) 
 
1.0 
0.15 
50% 
20% 
89% 
1.0 
0.15 
50% 
25% 
78% 
1.0 
0.15 
55% 
25% 
92% 
1.0 
0.15 
55% 
30% 
82% 
1.0 
0.15 
60% 
25% 
98% 
1.0 
0.15 
60% 
30% 
94% 
1.0 
0.15 
65% 
25% 
99% 
1.0 
0.15 
65% 
30% 
99% 
 
 
 
 
 
1.0 
0.20 
50% 
20% 
78% 
1.0 
0.20 
50% 
25% 
65% 
1.0 
0.20 
55% 
25% 
83% 
1.0 
0.20 
55% 
30% 
71% 
1.0 
0.20 
60% 
25% 
93% 
1.0 
0.20 
60% 
30% 
87% 
1.0 
0.20 
65% 
25% 
98% 
1.0 
0.20 
65% 
30% 
96% 
 
 
 
 
 
1.5 
0.15 
50% 
20% 
94% 
1.5 
0.15 
50% 
25% 
86% 
1.5 
0.15 
55% 
25% 
96% 
1.5 
0.15 
55% 
30% 
90% 
1.5 
0.15 
60% 
25% 
99% 
1.5 
0.15 
60% 
30% 
98% 
1.05 
0.2015 
65% 
25% 
99% 
1.05 
0.2015 
65% 
30% 
99% 
 
 
 
 
 
1.5 
0.20 
50% 
20% 
84% 
1.5 
0.20 
50% 
25% 
72% 
1.5 
0.20 
55% 
25% 
88% 

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1.5 
0.20 
55% 
30% 
78% 
1.5 
0.20 
60% 
25% 
96% 
1.5 
0.20 
60% 
30% 
92% 
1.05 
0.20 
65% 
25% 
99% 
1.05 
0.20 
65% 
30% 
98% 
 
 
While the study is adequately powered to answer the primary research question, it has not 
been powered to undertake any stratified analysis by country or to assess difference in 
impact between countries. 
 
7.1.3 Secondary Endpoints  
Note: Tables showing the calculations for secondary endpoints are provided in 
Appendix VII. 
 
(1)  HIV Incidence During Months 12-24,  and Months 24-36 from Start of 
Intervention 
Assuming baseline HIV prevalence of 15% and loss to follow-up of around 20% by the 
end of Year 2 and 25% by the end of Year 3, this incidence estimate will be based on a 
sample size of approximately 1700 person-years per community in Year 2 and 1594 
person-years per community in Year 3.  
 
Our model projections show that under the optimistic scenario the impact on HIV 
incidence during Year 2 will be 70% and 30-35% in Arms A and B respectively, and for 
the central target it will be 60% and 25-30% respectively, with a difference in impact 
between Arms A and B of about 35%. For a comparison of Arm A with Arm C, study 
power is 96% or higher with the central target of a 60% reduction, with k up to 0.20 and 
HIV incidence in Arm C of at least 1 per 100 person-years. For a comparison of Arm B 
with Arm C, study power is 71% with the optimistic target of a 35% reduction, k=0.15 and 
HIV incidence in Arm C of 1.5 per 100 person-years, but lower than this for the central 
target, and/or higher k, and/or lower HIV incidence in Arm C. For comparison of Arms A 
and B, we will have moderate power (around 70% or more) for the central target and 1% 
HIV incidence, and good power (>80%) for all other conditions.  
 
Our model projections show that under the optimistic scenario the impact on HIV 
incidence during Year 3 will be approximately 75% and 35% in Arms A and B 
respectively, and for the central target it will be 65-70% and 30% respectively, with a 
difference in impact between Arms A and B of about 35%. For a comparison of Arm A 
with Arm C, study power is 98% or higher with the central target of a 65% reduction, with 
k up to 0.20 and HIV incidence in Arm C of at least 1 per 100 person-years. For a 
comparison of Arm B with Arm C, study power is 69% with the optimistic target of a 35% 
reduction, k=0.15 and HIV incidence in Arm C of 1.5 per 100 person-years, but lower 
than this for the central target, and/or higher k, and/or lower HIV incidence in Arm C. For 

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comparison of Arms A and B, we will have good power for the central target of 65-70% 
vs 30% (74%-97% power depending on assumptions).  
 
 
(2) Community Viral Load 12, 24, and 36 Months after the Start of Intervention 
(Subject to Funding) 
In the Population Cohort at 24 months, viral load will be measured in all HIV-infected 
individuals (irrespective of seroconversion date), estimated to be approximately 300 in 
each community (subject to funding for HIV viral load testing). 
Assuming that the mean of log10 (viral load) is 4 in Arm C, that k=0.15 and the standard 
deviation of viral load within communities is 0.9 on the log10 scale, there is 84% power to 
show a reduction of 1 in log10 viral load in each of the other two trial arms. Alternatively, 
comparisons between arms can be made on the basis of what proportion of HIV-infected 
individuals have undetectable viral load. Assuming these proportions are 20% in Arm C, 
40% in Arm B, and 60% in Arm A, the study is well powered to show a difference 
between Arms A and B, and very well powered to show a difference between Arms A or 
B and Arm C. 
 
At 12 and 36 months, viral load will be measured in approximately 75 HIV-infected 
individuals in each community (subject to funding for HIV viral load testing). Assuming 
20% with undetectable viral load in Arm C, 40% in Arm B, and 60% in Arm A, and 
k=0.20, there is 77% power to show a difference between Arms A and B and 97% power 
to show a difference between Arm B and Arm C. 
 
(3) HSV-2 Incidence Over 36 Months 
This will be measured in the Population Cohort. Assuming that baseline HSV-2 
prevalence is approximately 70% and that by 24 months the loss to follow-up is 20% and 
by 36 months it is 25%, the estimate of intervention effect on HSV-2 incidence will be 
based on 1837 person-years per community. If HSV-2 incidence in Arm C is 
approximately 5 per 100 person-years, there is >90% power to detect an increase to 7.5 
per 100 person-years or a reduction to 3.0 per 100 person-years if k = 0.15, and 80-90% 
power to detect such effects if k = 0.20. 
 
(4) Retention in HIV Care, and Viral Load Suppression and Drug Resistance Among 
HIV-Infected Individuals Who Are Taking ART 
These outcomes will be measured in HIV-positive participants in the Population Cohort. 
(i) 
Retention in care at 12 months after registering for HIV care 
 
This will be measured in HIV-positive participants who present for HIV care for 
the first time after the start of the intervention period, an estimated 198 per 
community in Arms A and B, and 99 per community in Arm C. First, assuming 
that retention in care at 12 months is 85% in Arm C, and that k=0.2, there is 85% 
power to show a reduction to 75%, and >95% power to show an increase to 95%, 
in each of Arms A and B. Second, assuming that retention in care is 90% in Arm 

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C, there is 96% power to show a reduction to 80% in each of Arms A and B, and 
79% power to show an increase to 95%. Third, assuming retention in Arm C is 
80%, there is 71% power to show a reduction to 70% in each of Arms A and B, 
and 94% power to show an increase to 90%.  
 
(ii) 
Viral load suppression, and drug resistance, measured among HIV-positive 
members of the Population Cohort at 24 months (subject to funding) 
Sample size calculations assume that, by the time of the 24-month follow-up in the 
Population Cohort, and among individuals who registered for HIV care for the 
first time after the start of the intervention period, 67% of patients will have started 
ART in Arm C, 50% in Arm B and80% in Arm A; and that 80% of patients will 
participate in the Population Cohort survey at 24 months. This gives sample sizes 
in each community of 141, 88 and 59 patients who start ART and will be available 
for viral load and drug resistance measurement in Arms A, B, and C respectively. 
Assuming 10% are not virally suppressed in Arm C, there is 91% power to show 
an increase to 20% in Arm A and 63% power to show a reduction to 5%.  The 
corresponding figures for a comparison with Arm B are 86% and 60%. 
The percentage of patients with acquired drug resistance will be a subset of those 
who are not virally suppressed, but the range of scenarios considered above 
includes plausible values for this endpoint as well. 
(5) Case-Control Studies 
 
Three Case-Control studies will be conducted as follows: 
 
(i) 
Uptake of CHiP home-based HIV testing during Round 1 of intervention in Arms 
A and B, with cases selected at random from individuals who did not accept 
testing, and controls selected at random from individuals who accepted testing; 
(ii) 
Acceptance of immediate ART in Arm A, among individuals who were first 
diagnosed, or self-reported, as HIV-infected as part of CHiP home-based testing in 
Round 1 of intervention and who were not already on ART. Controls are selected 
from among individuals who started ART within 6 months of being identified as 
HIV-infected and referred for HIV care by CHiPs, and cases from among 
individuals who did not; 
(iii) 
Uptake of CHiP home-based HIV testing during Round 2 of intervention in Arms 
A and B, excluding individuals who were diagnosed as HIV-infected in Round 1, 
and also individuals who self-reported they were HIV-infected in Round 1 or 
Round 2. 
 
Calculations assume 400 cases and 400 controls, for each of the three case-control studies, 
assuming an unmatched design. Cases are individuals who refuse HIV testing, re-testing 
for HIV, or immediate ART for studies (1)-(3) respectively; controls are individuals who 
accept testing, re-testing for HIV and immediate ART for studies (1)-(3) respectively. 

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Assuming that the percentage of controls exposed to a particular risk factor is 10%, 15%, 
or 20%, and that the odds ratio comparing exposed with unexposed individuals is 1.75, the 
corresponding study power to show an effect of the risk factor is 71%, 85%, and 91% 
respectively. With an odds ratio of 2, the corresponding figures for study power are 90%, 
97%, and 99% respectively. When the proportion of controls exposed to a particular risk 
factor is 15% or more, the sample size is sufficient for stratified analyses, such as separate 
analyses by country or by gender. For example, with 200 cases and controls for women, 
and an odds ratio of 2, then if 15% and 20% of controls respectively are exposed to the 
risk factor, study power is 75% and 83% respectively. 
 
 
Table 8- Case-control studies of (1) uptake of HIV testing (2) uptake of re-testing for 
HIV and (3) uptake of immediate ART among HIV-positive individuals 
Percentage of 
controls with  a 
risk factor 
Odds ratio for refusing 
testing/re-testing/immediate 
ART, comparing individuals 
with a risk factor characteristic 
to those without 
Power (%) 
10% 
1.75 
71% 
15% 
1.75 
85% 
20% 
1.75 
91% 
10% 
2.0 
90% 
15% 
2.0 
97% 
20% 
2.0 
99% 
 
(6)  Process Measures – Uptake of HIV Testing, ART and Male Circumcision 
 
(a) CHiP Data – Arms A and B 
 
(i) 
HIV testing uptake 
 
With an average community adult population of 25000, and acceptance of 
home-based HIV testing in the range 50-80% in each round of testing, in each 
community the 95% confidence interval for testing uptake will be +/-1-2% of 
the point estimate. 
 
(ii) 
Screening for ART eligibility, and uptake of ART, among HIV-infected 
individuals 
 
If it is assumed that 80% of individuals accept CHiP home-based HIV testing 
in the first round of testing, that 15% are HIV-infected, and that 25% of HIV-
infected individuals are already taking ART, approximately 2250 ART-naïve 
HIV-infected individuals will be identified through home-based testing in each 
community. With uptake of immediate ART in Arm A, and screening for ART 

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eligibility in Arm B, in the range 30-80%, in each community the 95% 
confidence interval for screening/uptake will be +/-2% of the point estimate. 
 
(iii) 
Male circumcision 
 
With an average community adult male population of 12500, there will be 
approximately 10625 HIV-uninfected men in each community. In the 2010 
ZAMSTAR TB/HIV prevalence survey, in the Western Cape trial communities 
77% of men aged 18 or above reported that they were circumcised, and in the 
Zambian trial communities 13%. So if uptake of CHiP home-based HIV testing 
in the first round of testing is 80%, an average of 1955 HIV-uninfected men 
will be eligible for medical male circumcision in each Western Cape trial 
community, and 7395 in each Zambian trial community. If 50% of these men 
are circumcised during the first year of trial intervention, the 95% confidence 
interval for the percentage who are circumcised will be +/-2% of the point 
estimate in Western Cape communities and +/-1% of the point estimate in 
Zambian communities. 
 
(b) Arms A, B, and C – Population Cross-Sectional Survey at 24 Months 
As noted above, funding has not been obtained to include a Population Cross-
Sectional Survey as part of the study.  If funded, the survey would provide 
additional useful data for all of the process measures described above for the 
Population Cohort.  The analysis plan for this survey is described in Appendix 
VIII. 
7.2 
Random Assignment / Study Arm Assignment 
Random assignment to study arms will take place at the cluster level. First, the 21 clusters 
will be matched into triplets based on best available estimates of HIV prevalence in the 
general adult population of these clusters, and taking into consideration geographic 
proximity of the sites to one another. This will be done separately in each country 
(stratified randomization), with 4 matched triplets in Zambia and 3 matched triplets in 
South Africa. The matched design will be used with the aim of minimizing the between-
community variance in baseline HIV incidence, which is assumed to be correlated with 
baseline HIV prevalence.  
 
After dividing the 21 clusters into 7 matched triplets, allocation to the three study arms 
will be carried out using a process of restricted randomization. This procedure will be used 
to ensure overall balance across study arms on cluster size, current ART uptake and HIV 
prevalence. There are (3!)7 = 279,936 possible ways of allocating the clusters to the three 
study arms within matched triplets. These allocations will be evaluated against balance 
criteria to determine a restricted list of allocations that achieve adequate balance on the 
three variables defined above. The final allocation will be selected randomly from this 
restricted list of balanced allocations. 

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7.3 
Statistical Analysis 
The primary analysis will be based on a comparison of the incidence of HIV infection 
during the follow-up period of 3years between Arms A and C, Arms B and C, and Arms A 
and B. This will be carried out using appropriate analytical methods for cluster-
randomized trials. 
 
Because the number of clusters per arm is small, we will use methods based on Student's t-
test, which have been shown to be highly robust for small numbers of clusters especially 
when sample sizes are similar in all clusters as in this study. We will compute the 
incidence of HIV infection in each cluster, weighted to take account of the sampling 
design which involves random selection of one adult from each household irrespective of 
household size. To test the null hypothesis of no impact, the paired t-test will be applied to 
these summary measures (7 matched pairs for each comparison), with 6df. The 
effectiveness of the intervention is defined as follows: 
 
Protective effectiveness = 1 – RR 
 
where the rate ratio (RR) is the ratio of incidence rates in the two study arms under 
comparison. This will be estimated by taking the geometric mean of the RR observed in 
each of the matched pairs, and a 95% confidence interval will be obtained using a normal 
approximation.  
 
Evidence for intervention effect will also be assessed using a non-parametric permutation 
test, based on the list of all possible allocations of trial arms to communities that met the 
restricted randomization criteria. For each of these possible allocations, and including the 
allocation that was randomly selected, incidence rate ratios for intervention effect 
(comparing Arm A and Arm B, Arm B and Arm C, and Arm A and Arm C) will be 
calculated as above. The number of allocations (n) for which the incidence rate ratio is as 
extreme as or more extreme (further away from 1) than the value observed in the trial will 
be counted, and a 2-sided p-value calculated as n divided by the total number of possible 
allocations. 
 
A description of how the analysis will control for migration contamination among the 
communities in the different treatment arms will be given in the Statistical Analysis Plan 
along with methods used to analyze the secondary outcomes. 
 
Following the full implementation of changes to the protocol in version 3.0 such that Arm 
B communities will in future receive the full UTT intervention as in Arm A, it is 
envisaged that data on the primary outcome of HIV incidence will continue to be analysed 
in the three separate study arms, with separate comparisons between Arms A and C, Arms 
B and C, and Arms A and B. Effects on incidence will be analysed over the full three 
years of follow-up of the PC, and also in each individual year of follow-up. The results of 
these analyses, together with information on the timing of changes to the criteria for ART 
initiation in Arms B and C, will be used in combination with mathematical model outputs 
to derive information on the effects of UTT under different conditions of ART delivery.  
Full details of these analyses will be given in the Statistical Analysis Plan. 

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7.4 
Interim Evaluation 
 
As stated in Section 2.4, interim evaluation will take place during the first two years of 
intervention to determine whether to continue with the 36 month follow-up of the 
Population Cohort and the fourth year of intervention. 
 
Because decisions on delivery of the intervention need to be taken at least 12 months in 
advance, to enable sufficient time for planning in the context of the annual PEPFAR 
funding cycle, the main evaluation is expected to be conducted in 2016 when the second 
round of intervention and the 12 month follow-up of the Population Cohort should be 
complete or close to completion (Figure 2). 
 
The main criteria for evaluation will be: 
  
• Observed HIV incidence in the control arm during the first 12 months of follow-up  
• Measures of uptake and coverage of the intervention during the first two rounds of 
intervention 
 
The evaluation will be carried out by the DSMB and detailed criteria for the evaluation 
will be agreed with the DSMB before the start of the trial. 
 
7.4.1 HIV Incidence 
 
Sample size calculations for the trial were based on an assumed HIV incidence of between 
1.0 and 1.5 per 100 person-years in both Zambia and South Africa. While this assumption 
is consistent with epidemiological data from the study populations, there remains 
uncertainty about the current and future level of HIV incidence in the 21 study 
communities. The study may be under-powered if incidence is substantially below 1.0 per 
100 person-years. 
 
Data on estimated HIV incidence in the control arm (Arm C) based on the 12 month 
follow-up of the Population Cohort will be presented to the DSMB. These data will be 
prepared by a statistician independent of the study team so that they are not inadvertently 
unblinded to data on the effect size after 12 months. The DSMB will evaluate the 
implications of this incidence estimate on study power and will consider whether any 
change in the duration of the study would be appropriate. Note that results from the 12-
month survey may not be available for a considerable time after sample collection is 
completed. This is because of the very large sample size of the PC, the need to perform 
HIV testing both in-country and at the HPTN LC, and the need to complete QA testing, 
including confirmation of HIV seroconversion, prior to data analysis. 
 
Review of estimated effect size (by comparing HIV incidence between study arms) would 
be of limited value after 12 months of follow-up. If the effect is small, this would be 
consistent with a projected impact that increases steeply over time. If it is large, there 
would remain a need to measure the longer-term effects of the intervention including the 
occurrence of adverse effects. 

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7.4.2 Uptake of Intervention 
 
Data on the uptake and coverage of the intervention components during the first two years 
of intervention delivery will be collated and presented to the Data Safety Monitoring 
Board (DSMB). These uptake statistics will be used to populate the mathematical model 
(Section 7.5) in order to obtain estimates of the projected effect of the interventions in 
Arms A and B relative to Arm C by time since the start of intervention roll-out. These 
projected estimates together with the HIV incidence estimates from the control arm will be 
used to obtain power estimates to guide a recommendation on the duration of follow-up. 
 
The main purpose of the interim evaluation is to assess indicators of futility, suggesting 
that the trial is unlikely to achieve its aims even if intervention and follow-up are 
continued. Conversely, if the evaluation suggests a substantial effect of intervention, 
follow-up for at least three years is likely to be needed to adequately evaluate potential 
adverse effects of the intervention. 
 
7.5 
Mathematical Modeling 
The compartmental model used for this protocol will be updated regularly as the trial 
progresses to allow investigators, stakeholders and the Data Safety and Monitoring Board 
to assess revised projections. Revisions to the model will include data from the baseline 
survey of the population cohort (PC0) on baseline characteristics, especially prevalence 
and ART uptake, and data from the CHiPS on testing and ART uptake.  
 
Concurrently, a  more sophisticated individual-based stochastic model of HIV 
transmission will be developed during the project and fitted to data from the trial, routine 
data and published sources to address four main objectives: 
 
• To help interpret the results of the trial: Process data showing the extent of uptake of 
the intervention compared with similar data from the control arm will be used to 
obtain model projections of expected impact under these conditions. By examining 
projected impact under the conditions prevailing in Zambia and South Africa, and in 
different trial communities, we will be able to examine whether the level of impact and 
variations in impact are in accordance with expectations. 
 
• To project longer-term impact: Modeling shows that the full impacts of UTT as well 
as male circumcision are not seen for several years. Impact measured during 3 years of 
intervention may therefore underestimate the long-term impact of the program. Models 
fitted to the impact seen during the first 3 years will be used to project the likely 
impact over longer time periods. 
 
• To explore likely impact in different settings: If the trial demonstrates impact, it is 
likely that similar interventions will be implemented in a wide range of settings. The 
model will be used to explore how impact would be expected to vary depending on 
epidemiological, demographic and other characteristics of populations, and thus to 
project likely impact in a range of settings. 
 

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• To explore the likely impact of alternative intervention packages: Our study design 
will provide empirical data on the impact of the specific packages of preventive 
interventions incorporated in the PopART program. However, the model can be used 
to explore the effect of adding or removing components. For example, we can project 
the impact of an intervention in which male circumcision is not promoted, or where 
the threshold for starting ART is set at different levels. 
 
Like all HIV models, the model will be over-parameterized compared to the amount of 
data available. The model will thus be fitted to baseline and follow-up data using Bayesian 
Monte Carlo integration methods. Priors for parameters will be determined by literature 
review, and a body of informed persons not including the modelers working on this study 
will pick the prior distributions of parameters so as to avoid bias. Comparison of priors 
with posteriors will be used to inform the extent to which the trial has improved our 
estimates of the likely efficacy of the different components of the intervention, and of 
other epidemiologically relevant parameters. 
 
We acknowledge the importance of the prevention cascade in achieving population-level 
impact. Specifically, achieving high levels of uptake and effectiveness requires guiding 
individuals through a cascade of individual steps, starting from an initial test, through 
linkage to care, CD4 testing, circumcision, counseling, and ultimately antiretroviral 
treatment and adherence counseling for HIV-infected and eligible individuals. The 
contribution of different levels in the cascade, as well as their contribution to intervention 
cost, will be explored in our modeling and cost-effectiveness work.  Our prior hypothesis 
based on preliminary modeling is that uptake of testing and prompt initiation of treatment 
will be critical. 
7.6 
Outcomes for Secondary Objectives 
Multiple secondary objectives for this study are listed in Section 2.2.  The majority of 
these objectives are to measure the effect of the intervention on various outcomes using 
standard quantitative analyses; the outcome measures for these secondary objectives are 
listed below and will be measured in all study arms unless otherwise noted.  Those 
secondary objectives that are considered process measures, or that require a different sort 
of analysis, are described in separate sections below. 
• HIV incidence over the first, second, and third years of follow-up 
o HIV diagnosis at 12 months, 24 months, and 36  months among those who 
were HIV-uninfected at enrollment in the Population Cohort  
• Community viral load (subject to funding) 
o Viral load in HIV-infected members of the Population Cohort 
(approximately 75 per cluster, randomly-selected) at enrollment, 12 
months, and 36 months  
o Viral load in HIV-infected members of the Population Cohort  (all, 
estimated to be 300 per cluster) at 24 months  
• ART adherence and viral suppression (subject to funding) 

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o HIV viral load at 24 months in HIV-infected members of the Population 
Cohort who initiated HIV care and ART after commencement of the 
PopART intervention in the community (subject to funding) 
o HIV viral loads of health center attendees who initiated HIV care and ART 
after commencement of the PopART intervention in the community, drawn 
from routinely-collected data at health centers (if available at a given health 
center)  
o Self-reported adherence to ART in HIV infected members of the  
Population Cohort who initiated HIV care and ART after commencement 
of the PopART intervention in the community, measured at 12 months, 24 
months, and 36 months  
o Loss-to-follow-up rates and missed dispensations of ARVs among health 
center attendees who initiated HIV care and ART after commencement of 
the PopART intervention in the community (and also in the control 
community during the same period of time), measured using routine health 
center data  
• ARV drug resistance (subject to funding) 
o ARV drug resistance at 24 months in HIV-infected members of the 
Population Cohort who initiated HIV care and ART after commencement 
of the PopART intervention in the community, among individuals who are 
not virally suppressed at 24 months (subject to funding) 
o ARV drug resistance in HIV-infected members of the Population Cohort 
who initiated HIV care and ART after commencement of the PopART 
intervention in the community, measured retrospectively on samples 
collected at enrollment and 12 months, among individuals who are not 
virally suppressed at 24 months (subject to funding) 
o ARV drug resistance, measured at 12 months, 24 months, and 36 months, 
among participants with incident HIV infection after enrollment in the 
Population Cohort (subject to funding) 
 
Note: Viral load/drug resistance testing will be performed at the 24 month 
visit, as a measure of treatment adherence, among HIV infected members of 
the Population Cohort, rather than delaying to 36 months. If the 24 month data 
on this indicate a significant number of participants not virally suppressed/with 
drug resistance, then additional funding may be sought to analyse these data 
again at 36 months in the Population Cohort and/or the Population Cross-
Sectional Survey. Data from the 24-month visit may not be available until some 
time after the study ends. 
 
• HSV-2 incidence 
o Incident HSV-2 infections at 36 months for all individuals in the 
Population Cohort who were HSV-2-uninfected at PC0. 

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• HIV disease progression, retention in care, and death 
o CD4 cell counts, WHO staging events, retention in care and death among 
Population Cohort participants initiating ART after commencement of the 
PopART intervention in the community, measured using routine health 
center data  
o CD4 cell counts, WHO staging events, retention in care and death among 
health center attendees who initiated ART after commencement of the 
PopART intervention in the community, measured using routine health 
center data 
• ART toxicity  
o ART safety and clinical events among Population Cohort participants 
initiating ART after commencement of the PopART intervention in the 
community, measured using routine health center data  
o ART safety and clinical events among health center attendees who  
initiated ART after commencement of the PopART intervention in the 
community, measured using routine health center data 
• Sexual risk behavior 
o Self-reported sexual risk behavior at Enrollment, 12 months, 24 months, 
and 36 months in the Population Cohort  
o HSV-2 incidence, listed above as a separate secondary outcome, serving as 
a biomarker for sexual risk behavior 
• Case notification rate of tuberculosis 
o Case notification rates of bacteriologically-confirmed TB diagnosed among 
the general population of patients seeking care at health centers as recorded 
by health centers  
o TB mortality among TB cases in the community as recorded by health 
centers  
• HIV-related stigma  
o Self-reported data on stigma indicators at enrollment, 12 months, 24 
months, and 36 months in the Population Cohort  
o Qualitative interviews in selected members of the general population in 
Arms A, B, and C 
 
7.7 
Secondary Objectives for Case-Control Studies 
• Carry out case-control studies to examine factors related to: 
o Uptake of HIV testing during the first round of home-based testing in Arms 
A and B 
o Uptake of immediate treatment in Arm A 

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o Uptake of HIV testing during the second round of home-based testing in 
Arms A and B 
7.8 
Secondary Objectives for Qualitative Studies 
• Use qualitative and quantitative methods to: 
o Assess popular understanding of HIV testing and treatment at study 
initiation and during implementation 
o Evaluate the acceptability and functioning of the CHiPs in Arms A & B 
o Evaluate the acceptability of interventions and the barriers to access in 
Arms A & B 
o Document the effect of the intervention on social networks, stigma, sexual 
behavior, alcohol use, gender-based violence, HIV identity, other HIV 
prevention options and community morale. 
o Evaluate the process and challenges of community consultation and 
applying ethical principles. 
7.9 
Secondary Objectives Related to Economic Evaluation 
Three secondary objectives of this study are concerned with economic evaluation of the 
intervention: 
• Measure the incremental cost of the two intervention packages through 
systematic recording of costs in intervention and control communities. 
• Estimate the effectiveness and cost-effectiveness of the intervention packages 
and alternative packages, both in the chosen study populations and in other 
populations by fitting mathematical models based on the empirical data from 
the trial, including data related to cost. 
• Measure the burden experienced by local health centers due to implementation 
of the intervention in the community  
Economic analysis will seek to assess the incremental health benefits of the intervention in 
relation to its incremental cost, and will be integrated with the modeling described above in 
Section 7.5. The main focus will be on costs to the health services, including equipment, 
materials and personnel. Incremental cost of the intervention will be estimated by 
comparing health services utilization and associated costs between the three study arms. We 
will be careful to separate out the costs of the intervention and the costs of the evaluation.  
 
Benefits will be assessed in terms of lifetime change in quality adjusted life years (QALYs) 
and/or disability adjusted life years (DALYs) brought about by the interventions relative to 
the control arm. Health related quality of life will be measured with a generic instrument 
such as SF36 or SF12. Lifetime projections of health and health services utilization will be 

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modeled under a range of assumptions based on current epidemiological and health service 
evidence. Probabilistic sensitivity analysis will be used to assess uncertainty. 
 
By combining cost data with impact estimates from the trial, we will be able to obtain direct 
estimates of cost per HIV infection averted. The costing data will be integrated with 
modeling results and quality of life information to derive cost per QALY and/or DALY 
using different time horizons. These data will also be used in mathematical models to 
explore the likely cost-effectiveness of the same intervention in different settings, and of 
alternative intervention packages in these or other settings. 
 
The 3-arm trial design will allow us to compare the short and long term differences in cost-
effectiveness for the two combination prevention packages based on immediate treatment 
or treatment according to current local guidelines. Additional data on secondary outcomes 
including TB incidence and other clinical events will provide improved QALY and/or 
DALY estimates. 
 
The economic evaluation will mainly rely on data from the Population Cohort via a 
questionnaire, supplemented by health service facilities data. More specifically, we will 
collect data that will allow us to calculate the following benefits and costs. 
 
We will estimate the benefits of the interventions to individuals, measured by the impact on 
QALYs/DALYs, and impact on work and home duty productivity (caring for children and 
seniors), approximated by employment status, occupation and educational status. Another 
benefit of the interventions is a reduced rate of HIV-related illnesses, with positive health 
impacts to the individual, and saved health care costs to society. 
 
We will estimate the wider benefits of the interventions to the community. This is mainly 
the prevention effect of the interventions, in the form of averted secondary HIV infections. 
We place an economic value on those averted infections. This comprises a) the health 
benefit (saved QALYs/DALYs) of averted HIV and related illnesses, and b) the averted 
health care costs (assuming standard care) for the study communities. Further, we consider 
the indirect benefit to children (both infected and not infected) of mothers receiving the 
interventions, measured in probability of survival (we do not collect quality of life 
information for children).  
 
We will generate estimates of the costs to the health care system of providing the 
interventions, such as clinical assessment, testing and drug provision for ART. This includes 
costs for treating drug resistance, toxicities, side effects and adverse events. We will 
consider one-time costs, for example for building and training, and apportion them to the 
interventions. We will also consider recurrent costs for personnel (wages and related costs, 
e.g. pensions), the ART drugs, other drugs, laboratory tests, materials, equipment and 
supplies, transport costs for staff or patients (if covered by the health care system), and 
overheads. We will collect aggregate data from health service facilities involved in the trial, 
and apportion these to individuals based on health service usage information. If we can 
obtain reliable data from patient records held at healthcare facilities, through some members 
of the Population Cohort and/or a small scale additional survey of a random sample of 
patients as they visit healthcare facilities in selected communities, we will calculate actual 

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costs of treatments; otherwise, we will calculate average costs for typical use of healthcare 
facilities. This process requires assumptions, and we will conduct sensitivity analysis to 
validate our estimates. Further, as the cost estimates rely on health service utilization 
information collected via questionnaire retrospectively for the past period, we will conduct 
validation to address potential recall bias. 
 
The program may divert scarce resources from other health programs, and in order to 
evaluate this indirect effect, we will obtain information via qualitative interviews with 
senior health care management in selected communities. We will further collect 
information on the costs to the patients of receiving the interventions, including the costs 
of adverse events and drug resistance. Costs to individuals may comprise costs directly 
associated with treatment (frequency, duration and nature of contacts with health services, 
travel time), user fees, costs of tests, drug costs and other payments related to treatment, 
time costs (valued by lost earning opportunity) and other costs. Information on those items 
will be collected from the survey members.  
 
We plan to complement the economic evaluation with additional work looking at broader 
outcomes, such as the impact on children of improved parental survival, and the impact of 
improved health status on individual productivity, participation in the labor market, 
poverty and wider macro-economic effects on the economy. Estimates of the benefits of 
improved survival and health from other studies can be integrated with the modeling work 
to obtain estimates of broader societal gains. If the trial shows that interventions are 
effective, it will also be important to model the projected cost-effectiveness of wider-scale 
intervention using more streamlined systems of delivery. 
 
Outcomes for secondary objectives related to the economic analysis are summarized in 
Table 9.  
 

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Table 9- Summary, outcomes for secondary objectives related to the economic analysis 
 
Secondary 
outcomes 
Data sources 
Subsample 
Specific measures 
Assumptions 
Secondary data 
sources required? 
When 
collected? 
Health care 
utilization and 
costs  
 
Population 
Cohort 
All 
Frequency, types and 
reason of visits 
 
Yes, lifetime costs of 
HIV care 
Each visit 
Routine patient 
records 
HIV+ and MC 
patients 
Diagnoses and types 
of treatments 
Aggregation into groups 
with homogenous 
resource use 
Yes, lifetime costs of 
HIV care from other 
studies 
Throughout 
trial 
Routine facility 
data  
Selected 
facilities 
Health care utilization 
aggregated 
Facilities are 
representative 
Yes, aggregate data 
from Dept. of Health 
One time, 
rolling 
Survey of facility 
costs  
Selected 
facilities 
One time and recurrent 
costs 
Facilities are 
representative; 
Yes, aggregate data 
from Dept. of Health 
One time, 
rolling 
Costs of 
accessing care to 
individuals 
Population 
Cohort 
HIV+ and MC 
patients 
User fees, travel costs, 
time costs 
Aggregation into groups 
of typical travel costs 
Yes, private insurance 
coverage, travel costs 
Each visit 
Quality of life 
Population 
Cohort 
All 
Generic measure of 
health  
Standard assumptions 
of generic quality of life 
instruments 
Yes, preference weights 
Each visit 
Work and home 
productivity 
Population 
Cohort 
All 
Data on employment 
occupation  
Association between 
occupation and wage 
rate 
Yes, wage rates for 
occupations 
Each visit 

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Burden on care-
givers 
Population 
Cohort 
Care-givers of 
HIV+ and 
orphans 
Data on caring 
activities 
Alternative occupation 
Yes, burden of care, 
wage rates 
Each visit 
Child survival 
Population 
Cohort 
All 
Mortality information  
 
Yes, official death 
records 
Each visit 
Routine patient 
records 
All 
Mortality information 
 
Yes, official death 
records 
Throughout 
trial 
 

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7.10 
Process Measures 
Several process measures will be recorded in Arms A, B, and C to evaluate the 
implementation and delivery of the PopART interventions. These measures evaluate 
processes that are intermediary between the provision of the intervention and achievement 
of the primary outcome. These measures will be important therefore in understanding how 
and why the intervention is (or is not) successful in producing that outcome.  Further, 
those data that are collected from CHiP teams or health centers (as opposed to research 
cohorts) can be reviewed by the study team during the study period and can be used to 
make real-time adjustments to deployment of the intervention to improve its effectiveness. 
 
• Uptake of PMTCT 
o Self-reported use of services for PMTCT at Enrollment, 12 months, 24 
months, and 36 months among HIV-infected women in the Population 
Cohort who had been pregnant in the prior 12 months 
o Uptake of PMTCT services at health centers 
o Uptake of PMTCT as indicated in data collected in households by CHiPs 
• Uptake of male circumcision 
o Self-reported circumcision status/uptake at Enrollment, 12 months, 24 
months, and 36 months of men in the Population Cohort  
o Uptake of circumcision in the community as indicated in health center data 
o Uptake of circumcision as indicated in data collected in households by 
CHiPs 
• ART screening and uptake 
o The proportion of Population Cohort members, identified as HIV-infected 
who screen for ART eligibility, and who subsequently initiate ART 
o Proportion of community members, identified as HIV-infected in data from 
CHiP teams, who screen for ART eligibility, and who subsequently initiate 
ART, as indicated in health center data 
• HIV testing and retesting 
o Self-reported recent HIV testing at Enrollment, 12 months, 24 months, and 
36 months in the Population Cohort  
o The number of adults (16 years and older) in the household and the number 
of HIV tests performed as indicated in data from CHiP teams and health 
centers 
• Time between HIV diagnosis and initiation of care 
o The proportion of Population Cohort members initiating HIV care within 3 
months of a positive HIV diagnosis  

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o The proportion of community members initiating HIV care within 3 
months of HIV diagnosis as indicated in data from CHiP teams (provision 
of HIV positive result) and health center data (date of care initiation)  
7.11 
Tabular Summary of Outcomes 
Table 10 provides a summary of HPTN 071 objectives and outcomes including the source 
of the outcome data. 

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Table 10- Summary of Study Objectives and Related Outcomes 
 
PC= Population Cohort 
PX= Population Cross-Sectional Survey     Ca-Co= Case-control  
CHiPs= Community HIV-care Providers 
Objectives and Outcome Measures 
Research Participants 
Community 
members 
PC at 
baseline 
PC at 
12m 
PC 
at 
24m 
PC at 
36m 
PX at 
36ma 
Uptake 
Ca-Co 
Qualitative 
Research 
CHiPs 
Data 
(Arm 
A&B) 
Routine 
Health 
Center 
Data 
Effect of the interventions on… 
 
 
 
 
 
 
 
 
 
HIV incidence 
 
 
 
 
 
 
 
 
 
HIV infection between 0 and 36 months among those 
testing HIV negative at enrollment (primary objective) 
X 
X 
X 
X 
 
 
 
HIV infection between 0 and 12 months in those testing HIV 
negative at enrollment; HIV infection between 12 and 24 
months in those testing HIV negative at 12 months; 
HIV infection between 24 and 36 months in those testing 
HIV negative at 24 months 
 (secondary objective) 
X 
X 
X 
X 
 
 
 
Community viral load (subject to funding)a 
 
 
 
 
 
Viral load in a subset of approximately 75 HIV-infected 
cohort/survey members per community 
X 
X 
 
X 
X 
 
 
 
 
Viral load in all HIV-infected cohort members 
 
 
X 
 
 
 
 
 
 
ART adherence and viral suppression  
 
 
 
HIV viral load among cohort/survey members initiating ART 
after intervention roll-out (if funded)a 
 
 
X 
 
 
 
 
 
 
HIV viral loads among health center attendees initiating 
ART after intervention roll-out (if viral load available)   
 
 
 
 
 
 
 
 
X 
Self-reported ART adherence among cohort/survey 
members initiating ART after intervention roll-out 
 
X 
X 
X 
X 
 
 
 
 
Loss-to-follow-up rates and missed dispensations of ARVs 
among health center attendees on ART 
 
 
 
 
 
 
 
 
X 
Antiretroviral drug resistance (subject to funding) a 
 
 
 
Drug resistance among a subset of cohort/survey members 
who are on ART with detectable viral load  
 
 
X 
 
 
 
 
 
 
Drug resistance testing for cohort/survey members who 
have resistance at 24 months 
X 
X 
 
 
 
 
 
 
 
ART resistance at 12 months, 24 months, and 36 months 
among cohort members who acquire HIV infection during 
the follow-up period 
 
X 
X 
X 
 
 
 
 
 
HSV-2 incidence 
 
 
 
Incident HSV-2 among cohort members who are HSV-2 
negative at PC0 (does not include PC participants enrolled 
at the PC12 visit) 
X 
 
 
X 
 
 
 
 
 

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HIV disease progression, retention in care, and death 
 
 
 
CD4 cell counts, WHO staging events, retention in care and 
death among Population Cohort participants initiating ART 
after commencement of the PopART intervention in the 
community, measured using routine health center data b 
 
 
 
 
 
 
 
 
X 
CD4 cell counts, WHO staging events, retention in care and 
death among health center attendees who initiated ART 
after commencement of the PopART intervention in the 
community, measured using routine health center data 
 
 
 
 
 
 
 
 
X 
ART toxicity 
 
 
 
ART safety and clinical events among cohort/survey 
members b 
X 
X 
X 
X 
X 
 
 
 
 
ART safety and clinical events among health center 
attendees (based on clinic data) 
 
 
 
 
 
 
 
 
X 
Sexual risk behavior 
 
 
 
HSV-2 incidence (independent secondary objective above) 
serving as a biomarker for sexual risk behavior 
 
X 
X 
X 
 
 
 
 
 
Self-reported sexual risk behavior 
X 
X 
X 
X 
X 
Xc 
Xc 
 
 
Case notification rate of tuberculosis 
 
 
 
Case notification rates of bacteriologically-confirmed TB 
diagnosed among health center attendees as recorded by 
health centers 
 
 
 
 
 
 
 
 
X 
TB mortality among TB cases in the community as recorded 
by health centers 
 
 
 
 
 
 
 
 
X 
HIV-related stigma 
 
 
 
Self-reported data on stigma  indicators collected from 
cohort members 
X 
X 
X 
X 
X 
 
 
 
 
Qualitative interviews conducted with members of general 
population 
 
 
 
 
 
 
X 
 
 
Process Measures 
 
 
 
 
 
 
 
 
 
Uptake of PMTCT services 
 
 
 
Self-reported use of PMTCT services at among HIV-infected 
cohort/survey members who were pregnant in the prior 12 
months 
X 
X 
X 
X 
X 
 
 
 
Uptake of PMTCT services at health centers 
 
 
 
X 
Self-reported uptake of PMTCT in the community 
 
 
X 
 
Uptake of male circumcision 
 
 
 
Self-reported circumcision status/uptake among 
cohort/survey participants 
X 
X 
X 
X 
X 
 
 
 
Uptake of circumcision at health centers 
 
 
 
X 
Self-reported uptake of circumcision in the community 
 
 
X 
 
ART Screening and uptake  
 
 
 
The proportion of cohort/survey members identified as HIV-
infected who screen for ART eligibility, and who 
subsequently initiate ART  
X 
X 
X 
X 
X 
 
 
X 
X 

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The proportion of community members identified as HIV-
infected who screen for ART eligibility, and who 
subsequently initiate ART 
 
 
 
 
 
 
 
X 
X 
Uptake of HIV testing and retesting  
 
 
 
Self-reported recent HIV testing among cohort/survey 
X 
X 
X 
X 
X 
 
 
 
 
Number of adults in households and the number of HIV 
tests performed in each community 
 
 
 
 
 
 
 
X 
X 
Time between HIV diagnosis and initiation of care 
 
 
 
The proportion of cohort members initiating care within 3 
months of HIV diagnosisb 
X 
X 
X 
X 
X 
 
 
X 
X 
The proportion of community members initiating HIV care 
within 3 months of HIV diagnosis 
 
 
 
 
 
 
 
X 
X 
Using qualitative methods… 
 
 
 
 
 
 
 
 
 
Assess popular understanding of HIV testing and treatment  
 
 
 
 
 
 
X 
 
 
Evaluate the acceptability and functioning of the CHiPs in 
Arms A & B 
 
 
 
 
 
 
X 
 
 
Evaluate the acceptability of interventions and barriers to 
access in Arms A & B 
 
 
 
 
 
 
X 
 
 
Document effect of the interventions on social networks, 
stigma, sexual behavior, alcohol use, gender-based violence, 
HIV identity, other HIV prevention options & community 
morale 
 
 
 
 
 
 
X 
 
 
Evaluate the process and challenges of community 
consultation and applying ethical principles 
 
 
 
 
 
 
X 
 
 
Through mathematical modeling and health economics 
methods… 
 
 
 
 
 
 
 
 
 
Measure the incremental cost of the two intervention 
packages through systematic recording of costs in 
intervention and control communities d 
 
 
X 
 
 
 
 
 
X 
Estimate the effectiveness and cost-effectiveness of the 
intervention packages and alternative packages d 
 
 
X 
 
 
 
 
 
X 
Measure the burden experienced by local health centers due 
to implementation of the intervention in the community d 
 
 
X 
 
 
 
 
 
X 
a Not currently funded.  Will be implemented if funding can be acquired  
b Consent must be obtained to access health center records for Population Cohort members 
c Explanatory research related to the outcomes/objectives indicated   
d Cost and effectiveness objectives will be addressed through analysis of deidentified data from health centers regarding costs and clinic use, in addition to specific questions asked of the 
Population Cohort    

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8.0 
HUMAN SUBJECTS CONSIDERATIONS 
8.1 
Collaborative Partnerships 
At all stages of the development of this research protocol community representatives have 
been involved in the design and have engaged with the research team to finalize the 
intervention and study questions. The research teams will continue to actively engage with 
the study communities at various levels (for example with government structures, 
healthcare facilities at management and worker level, existing community forums and 
stakeholder groups) utilizing a range of communication and interaction strategies, as 
appropriate. In both countries, study committees will be formed with representation from 
trial staff and in-country stakeholders (from governmental to community representation) 
to provide guidance and feedback to the study team.  As indicated in the earlier section on 
community engagement, partnerships and CABs worked with/established during the 
ZAMSTAR study will be reviewed for this study to ensure that all community groups and 
interests are represented.  
8.2 
Social Value  
As described in Section 1, the worldwide burden of HIV infection continues to grow, with 
populations in sub-Saharan Africa particularly afflicted with high rates of HIV prevalence 
and incidence.  If this study is able to show that providing a combination prevention 
intervention including universal testing and treatment is effective in slowing the spread of 
HIV in communities and is cost-effective, it could provide a path forward to lowering the 
burden of HIV in sub-Saharan Africa and throughout the world and, importantly, in the 
communities and countries in which the study will be performed.  The value of a highly 
effective prevention intervention for the economies of countries, communities and 
persons, the reduction in morbidity and mortality, the value to health infrastructure and 
even political stability could potentially be large.  The multifaceted approach of the 
intervention, incorporating strengthening and promotion of PMTCT, male circumcision, 
and universal testing and treatment, offers value to community members whether they are 
men or women, already infected with HIV or uninfected. The health systems 
strengthening component of the study, which will be implemented in all three study arms, 
promises to offer value to all of the communities in the study, even if the intervention 
cannot be shown to lower HIV incidence. 
 
8.3 
Scientific Validity 
This study will provide evidence to either support or refute the mathematical model 
discussed earlier, which has indicated that if a high proportion of the population can be 
tested, with those found HIV-infected offered immediate ART, HIV infection may be 
reduced substantially within two years, and potentially eliminated as a public health 
problem in the longer term. The study has been powered to determine the impact of the 
interventions on the primary and secondary endpoints.  The multi-community cluster-
randomized study design chosen for this study has, we believe, the best chance of 

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providing an answer to the research question: "Can universal HIV testing and intensified 
provision of HIV treatment and care reduce population-level HIV incidence?" 
 
The study will be conducted according to the most rigorous standards of research and is 
therefore expected to give definitive answers about the process of implementing the 
intervention as well as the impact of such an intervention at community level. The study 
results will be shared throughout the study with national and international policy-makers 
to ensure that the findings are understood and that lessons from the study are 
implemented. 
8.4 
Fair Subject Selection 
This study will be carried out in areas of Zambia and South Africa that are known to have 
a high prevalence and incidence of HIV infection. These areas are continuing to 
experience severe generalized HIV epidemics with prevalence levels of 15-20% in many 
areas. Most of the communities chosen for this project are communities that have already 
been involved in similar community-based research projects such as ZAMSTAR (Zambia 
and South African TB and AIDS Reduction Study). There are both advantages and 
disadvantages to involving ‘research experienced’ communities in a new research project 
such as this. Communities can theoretically become over researched and placed at risk for 
“research burn-out”- with community members reluctant to become involved in additional 
research and becoming disillusioned with research related burdens (e.g. time spent, 
intervention risks, risks to privacy etc.). On the other hand, communities that are already 
accustomed to and well informed about research processes can be considered to be in a 
more empowered position to engage in a research initiative such as HPTN 071, than 
"research naïve" communities. Community leaders will be accustomed to engaging with 
research teams and structures such as community advisory boards (CABs) will already be 
established and functioning. 
The research teams in both Zambia and SA have discussed this issue with the respective 
government authorities and a joint decision was taken favoring existing research sites and 
communities over new ones for this very reason. Formative research will be conducted 
prior to the start of the study to document existing community engagement structures in 
each community and their level of functioning with additional action taken to improve the 
functioning of these structures, where necessary. 
Care will be taken to ensure that community related research risks and burdens are 
minimized and that community benefits are maximized (See Section 8.5). 
 
All population members in the intervention communities will be encouraged to receive 
home-based HIV counseling and testing and to receive the health education, symptom 
screening and referrals that are included in the intervention.  The health information of 
adult household members who provide consent (and information of minors for whom 
consent has been obtained from parents or guardians) will be recorded in the CHiPs 
database to allow follow up on referrals and linkage to care by CHiPs.  The CHiPs 
intervention will be offered throughout the community, including to women and minors, 
hard-to-reach populations and “high HIV-risk groups” because this study is directly 
relevant to the health needs of these groups. In communities where the immediate ART is 

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offered outside of local guidelines, those younger than 18 will not be eligible , in 
accordance with local regulations regarding the age of consent for research.  However, to 
the degree that local guidelines do allow minors to initiate immediate ART, this will be 
implemented. 
8.5 
Risk-Benefit Assessment 
This community-based, cluster-randomized study can potentially incur risk of harm at 
both a community and an individual level. Likewise study-related benefits may accrue at 
both an individual and a community level. 
8.5.1 Community Level  
8.5.1.1 Benefits 
At the community level, mathematical modeling suggests that the PopART intervention 
may result in a substantial reduction in HIV incidence and, if sustained over time, to the 
eventual elimination of HIV as a public health problem, with a wide range of health and 
socio-economic benefits. Child morbidity and mortality should also be significantly 
decreased through both the direct effects of the intervention on mother-to-child 
transmission of HIV and the protection of the health of HIV-infected mothers. In addition 
to intervention effects on HIV transmission, the universal testing and counseling program 
is designed to promote acknowledgement and acceptance of HIV as a community-wide 
health problem potentially resulting in lessening of HIV-related stigma and discrimination. 
While the control communities will not benefit directly from the intervention, at least until 
such time as immediate eligibility for ART is offered in Arm C communities, the project 
will ensure that a standard of care is provided in these communities. In addition, if the trial 
shows that the intervention is highly effective and cost-effective, leading to wider scale 
roll-out of the program, efforts will be made to ensure that the control communities are 
among the first to benefit from this wider implementation. 
Networks of stakeholders that will be created through the implementation of the study 
interventions will not only improve communication between community groups but will 
also be a catalyst for reinvigorating social connections that have been threatened in the 
wake of poverty and HIV/AIDS. Previous experience with the ZAMSTAR study suggests 
that these networks can be useful for advocating for research and improving research 
literacy. 
8.5.1.2 Risks 
Any community-based research project may present risks to a community. Communities 
may feel disempowered by having a research agenda imposed on them or they may be 
placed at risk of stigmatization by the publication or dissemination of research results.  
Large community research projects may disrupt intra-community social structures and 
networks that are not always easily understood by an external research team.  
For this particular project at community level, there is the risk of behavioral disinhibition 
if the wide-scale provision of testing, treatment and male circumcision are assumed to 
reduce risk and thus encourage unsafe sexual behavior.  Extensive counseling at an 

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individual level and HIV prevention education at a broader community level will attempt 
to minimize this risk, which unfortunately is known to be potentially present with most 
HIV prevention studies.  We will also seek to measure such harms through collection of 
process data as well as specific sub-studies as outlined in the Research Plan. 
 
An additional potential community related risk involves the possible burden that could be 
placed on existing health services. Existing health services are already over-burdened due 
to inadequate resources and overwhelming disease rates. Health-care workers may be 
recruited into study teams and leave their current positions, worsening the problem.  
8.5.1.3 Minimizing Risks to Communities 
Communities will not be named in any publication or dissemination of results of the study. 
Well-functioning community engagement structures (such as CABs) will help to mitigate 
risks at community level by advising the study team and representing the views of the 
communities. In addition the research team will actively solicit and report any instances of 
perceived social harm. We will aim to recruit CHiPs that are residents of their respective 
study communities and many of the field study staff will have either previously lived or 
worked in the communities which will give them an advantage in terms of relating with 
participants and other stakeholders. 
 
Health service burden will be minimized by leveraging additional funding to the 
Ministry/Department of Health to enable additional staff to be trained and recruited. These 
staff will work for the duration of the study and it is likely they will continue on as 
Ministry/Department of Health employees at the end of the study due to natural attrition 
and increased demand (many services are currently understaffed in respect to the stated 
staffing establishment). Study teams will work closely with government agencies and will 
not entice staff away from them by offering differential salary packages. 
 
Communication will be maintained with study communities for the duration of the study 
and a well-developed exit strategy will be planned with the input of all stakeholders and 
community engagement structures to ensure that there is a seamless transition from study 
to routine health services at the end of the study 
8.5.1.4 Risk-Benefit Assessment at Community Level 
The mathematical models suggest, and we believe, that overall benefits from the proposed 
intervention program would greatly outweigh any risks or harms at community level. 
Nevertheless, we acknowledge that some communities and individuals may be placed at 
increased risk as a result of the intervention. It is therefore important to put appropriate 
measures in place, as described above, to mitigate these possible harms.  
8.5.2 Individual Level 
8.5.2.1 Benefits 
There is a wide range of benefits at individual level. Knowledge of personal HIV status 
provides a portal to treatment and care services for HIV-infected patients while HIV-

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uninfected individuals can be supported in adopting preventive measures. Early treatment 
of HIV-infected patients has been shown to be of substantial clinical benefit [12], and the 
treatment provided (including antibiotic prophylactic therapy) can be confidently expected 
to reduce the incidence of TB and other infectious diseases as well as protecting the 
immune system and significantly slowing HIV clinical progression [89, 105-107]. It will 
also significantly reduce the risk of onward transmission to sexual partners, with a 
consequent decrease in the anxiety and psychological distress associated with HIV 
infection. WHO has also recently endorsed this approach in a programmatic update[108]  
8.5.2.2 Risks 
A key component of the intervention package is an annual HIV testing campaign that aims 
to encourage all adult community members to undergo HIV testing and counseling. Such 
approaches involve some risks. These include possible social harm, stigmatization or 
intimate-partner violence related to intended or unintended disclosure of HIV status, either 
within or beyond the household; and psychological trauma from learning one's HIV test 
status. 
 
Community members who report to the health center to undertake HIV care (including 
ART) or to receive HIV testing will have sensitive data collected in clinic records, some 
of which will be then be harvested into an electronic research database.  Most of these 
research data will be collected without personal identifiers, but research cohort members 
may provide consent for use of identified data.  Collection and storage of sensitive health 
information carries with it the risk of unwanted disclosure if there is a breach of data 
security or incomplete removal of personal identifiers from “anonymous” data sets. 
 
Men who test negative for HIV infection will be offered circumcision through a locally 
provided service. Circumcision will also be provided to HIV-infected men who request it. 
While data from randomized trials and routine male circumcision programs in sub-
Saharan Africa have shown very low levels of adverse effects, there are some risks of the 
surgical procedure, including pain, bleeding and infection [50, 109, 110]. There is also a 
risk of enhanced HIV transmission if men resume sexual activity before the circumcision 
wound is fully healed [111, 112]. 
 
At the time of preparation of version 3.0 of this protocol, the offer of immediate ART goes 
beyond current national and international guidelines for HIV care, although these 
treatment guidelines are expected to change rapidly [12]. Immediate initiation of ART 
presents some potential risks, but data from the START trial has identified that overall, 
immediate ART initiation confers significant clinical benefit over deferral. The risks of 
starting ART for any HIV infected individual includes side effects, the development of 
drug resistance if treatment adherence is sub-optimal and consequent limitation of future 
treatment options, and the inconvenience of having to attend the study clinic and starting 
on a lifelong course of treatment when still asymptomatic. 
 
There are additional minor risks for the research cohort participants including the taking of 
specimens, which may include pain or bruising when blood samples are taken. Also, there 
is the risk that some questions addressed to participants, for example relating to their 
sexual behavior or HIV infection status may result in discomfort or distress. 

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The main risks associated with the evaluation research for those individuals who are not 
directly exposed to the ART intervention are similar to risks relevant to any population-
based epidemiological HIV research and primarily involve risks to privacy and 
confidentiality. These risks are discussed below as well as in Section 8.8. 
8.5.2.3 Minimizing Risks to Individuals 
To minimize social and other harms relating to the intensive testing program, staff 
delivering the program will be carefully trained and supervised to ensure that they have 
the required skills to provide individual or couple counseling according to national and 
international guidelines. In particular, although couples will be encouraged to undergo 
testing and counseling together, individual testing will be provided for those not wishing 
to take this up. Participants will be given information about community-based 
organizations providing support and guidance for those dealing with the psychological 
consequences of HIV infection or suffering from domestic violence. Follow-up counseling 
will be offered by the community counseling teams as is required by individuals or 
households according to their wishes. 
 
Data systems and data handling procedures for capturing, transferring, analyzing and 
storing electronic data obtained from health centers, Population Cohort participants and 
community members contacted by CHiPs will be developed and tested to verify their 
ability to preserve participant confidentiality.  Electronic systems in which these data are 
kept will be password protected with access limited to authorized staff.  Personal 
identifiers (name, address, plot number, telephone number, GPS coordinates) collected by 
study staff on mobile devices are stored encrypted.  The devices are programmed to time 
out after a period of disuse and then require re-entry of username and password to log in.  
Decrypted electronic personal identifiers will only be generated to support specific field 
operations (e.g. male campaigns) and will be stored temporarily in separate datasets with 
password protection, accessible only to designated staff (for computers and servers).  
  
Phylogenetic studies are proposed (pending funding) that would be carried out using 
stored samples to evaluate the phylogenetic relationship of viruses in the community. 
These studies are described in the Phylogenetics Ancillary Protocol. Any such analyses  
would only be carried out after removing linkage to personal identifiers.  We will ensure 
that data provided to the team performing any such analyses, and any reports of such 
analyses, cannot inadvertently identify specific individuals or transmission events. A 
detailed description of human subjects protections specifically related to the phylogenetics 
study can be found in the Phylogenetics Ancillary Protocol. 
 
Male circumcision will be provided by existing service providers through the routine 
health service and therefore all staff will be carefully trained in line with local guidelines 
to ensure that the operation is carried out safely, with minimal risk of adverse events. 
Patients will be seen for a follow-up visit after circumcision according to local guidelines. 
Staff will be trained to deliver effective counseling about the importance of abstaining 
from sexual activity until the wound is fully healed and also to explain carefully that the 
operation is only partially protective against HIV infection and to warn against the hazard 
of risk disinhibition. 

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As noted above, the only component of the intervention that goes beyond current 
guidelines is the offer of immediate ART regardless of CD4 cell count. The team plans to 
inform all patients seeking ART at health centers in PopART communities where 
immediate ART is offered of the differences between current and previous treatment 
guidelines and the strategy being offered by the  study in their community, including 
known risks and benefits. Individuals must provide written informed consent for initiation 
of ART if not eligible according to current local guidelines.  Information provided to 
patients will have been developed partly in consultation with CABs and have been piloted 
and translated into vernacular text.  The treatment regimen has been chosen carefully to be 
convenient to take, to be appropriate for the widest possible range of patients, and to 
minimize the risk of toxicity or side effects. No additional adverse events are expected in 
patients with intact immune systems.  The most significant risks are associated with poor 
adherence to treatment. To minimize this, community health workers will support patients 
on treatment, making regular household visits to check on treatment adherence and in 
particular checking up on patients when they do not attend routine clinic visits. Toxicity 
associated with antibiotic prophylaxis will also be monitored and treatment modified if 
necessary. 
 
All project staff will undergo training in GCP and human research protections in 
accordance with the U.S. National Institutes of Health (NIH) requirements. There will be a 
strong emphasis in staff training and supervision on the importance of strict confidentiality 
of participant information as well as on supportive interviewing skills. Blood collection 
will be carried out by fully trained staff using appropriate sterile procedures. 
8.5.2.4 Risk- Benefit Assessment at Individual level 
There are risks associated with this study for the individuals involved. However as 
indicated above, most of these risks are no more than those encountered in everyday life.  
Individuals exposed to the early ART intervention are likely to encounter a greater than 
minimal level of risk and some of these risks or burdens may as yet be poorly quantified 
(e.g. risks associated with extended ARV exposure). However, immediate ART for all 
individuals with HIV infection irrespective of CD4 count has now been shown to confer 
clinical benefit on those individuals [12]. All patients receiving ART at the health centers 
in all study arms will be monitored for reactions to their ART regimen, in accordance with 
the local standard of care. Thus we believe that the overall risk-benefit assessment for this 
study is favorable at both a community and an individual level. 
8.6 
Informed Consent 
In a community-based, cluster-randomized trial such as this one, informed consent needs 
to take place at several levels ranging from consent from the government authorities, to 
so-called "community consent", and finally to individual consent. However obtaining 
individual consent from every individual living in every community involved in this study 
would be unfeasible. As discussed earlier in Section 3.2 the CHiP teams, while an integral 
part of this research will deliver a community health care package that is recognized as 
good practice and as such is not a research intervention. Much of the routine healthcare 
surveillance data collected as part of this study, particularly from the control 

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communities will be made available to the research team by the respective public health 
authorities (who are in full support of the project) and collected without specific individual 
informed consent. This information will be collected, coded, stored and managed in such a 
way as to ensure individual identity and privacy are protected at all times. 
8.6.1 Approval from Respective Authorities 
Approval for this project has been obtained from the respective healthcare authorities in 
both South Africa and Zambia. Additionally during the planning process of the study 
approval will be sought from other authorities such as district or local councilors, political 
leaders and traditional leaders. 
8.6.2 ‘Community’ Consent 
It is of the nature of a cluster-randomized trial of this kind that entire communities are 
assigned to one study arm or the other, and individual consent for community allocation is 
not possible. The term ‘community consent’ can be misleading. True ‘Community 
Consent’ is only possible if the “community has a legitimate political authority, e.g.  a 
tribal council that has the authority to make binding decisions on behalf of its members.” 
[113]. If used inappropriately, the concept of ‘community consent’ may result in a false 
sense of security or mandate. We will seek consent for community participation from 
community-level stakeholders who will be defined through the community engagement 
process (see Research Plan) and who will include local leaders. Following agreement to 
participate, community representatives will take part in a public randomization ceremony 
at which the allocation of communities to study arms will be decided using a transparent 
and fair process. 
8.6.3 Individual Consent 
Individual consent for CHiP team activities 
Because the proposed CHiP team activities are poised between an established public 
health intervention (home–based testing and outreach) and a public health research project 
(data collection and additional follow-up), the team will seek from the appropriate ethics 
committees, an alteration of consent (verbal consent) for participation in the community 
intervention. Verbal consent will also permit data collected by CHiPs to be used in 
aggregate form for research purposes.  This verbal consent will be accompanied by a 
written information leaflet that will be provided to all households. This information leaflet 
will contain information about the project as a whole, as well as appropriate local research 
team contact details, and will also describe the option of each household not to engage 
with the CHiP teams or receive any additional visits.  
 
There is adequate prior research to show that household delivery of HIV testing, and 
linkage to services by community health workers is safe and effective, such that its 
deployment in this study could be considered a public health intervention, and therefore 
not requiring written research consent from each of the approximately 800,000 people to 
be reached by the CHiPs workers.  However there are aspects of the CHiPs intervention 
that are innovative, and go beyond what would be considered an extension of government 
health services. For example, it is not routine to have CHiP-performed HIV test results 

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entered into a database which is also populated by health center data, and then have those 
data prompt CHiPs to return to households to follow up with HIV diagnosed participants 
who have not reported to the health center, in order to provide linkage to care (e.g. early 
ART and circumcision). These aspects will thus be included in the initial verbal consent 
process. 
 
In summary, an alteration of consent (verbal) will be requested based on the following 
considerations which comply with the U.S. Code of Federal Regulations (CFR) 45 CFR 
46.116 (d): 
 
(i) 
As already described CHiP activities involve delivering community based health 
care (rather than primarily research activities) and involve minimal risk. 
(ii) 
 Requiring full written research consent from all individuals that come into contact 
with the CHiP teams would make this project logistically unfeasible 
(iii) 
Rights and welfare of individuals will not be adversely affected by a verbal consent 
process that will be documented by the CHiP teams 
(iv) 
Pertinent written information about the project will be provided to all households 
visited. 
 
Individual written consent for HIV testing and other interventions such as male 
circumcision will be obtained using standard procedures as these interventions are 
considered part of the routine delivery of HIV prevention services and not specifically 
study related.  Thus individuals who undergo these procedures in the study communities 
will not specifically be asked to participate in a research study, but rather will be asked to 
consent to these activities as part of their health care.     
 
Individual consent for ART outside of local guidelines 
The main aspect of the intervention that goes beyond current guidelines is the offer of 
immediate commencement of ART regardless of CD4 cell count or clinical stage. As 
described above, the study team will obtain consent for research from patients in any arm 
who are offered immediate treatment that is not considered standard of care according to 
prevailing local treatment guidelines. Any patients declining this offer will be provided 
with follow-up and treatment in the same health facilities according to current standard of 
care.  Participants consenting to commencement of ART regardless of CD4 or clinical 
stage will continue to be asked to consent (verbally) to any CHiP team activities and 
related data collection, as described above. Once local implementation of immediate ART 
is in place, individual consent will not longer be necessary. 
 
Individual consent for research studies in all Arms 
Written informed consent to participate in research will be required before enrolling 
individuals in the Population Cohort and Case-Control studies.  Written informed consent 
will also be required of individuals participating in qualitative research activities that 
involve collection of participant-identified responses to interviewer questions (such as 
interviews and focus groups). However written consent will not be sought for other types 
of qualitative methods, such as observation of persons who are not participants.  
 

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The study team has considerable experience of designing and implementing suitable 
models of informed consent for study populations in resource-poor settings in Zambia and 
South Africa that may have low levels of functional literacy. Care will be taken to ensure 
that information materials are developed that are appropriate to the study population, with 
translation into a local language where necessary and back-translation into English to 
ensure accuracy. Project staff will go through the information sheets with participants and 
questions will be asked to check their understanding of key points before signed consent is 
sought. Illiterate participants will be asked to give fingerprint consent witnessed by a 
literate individual who will sign that the individual has been given sufficient information 
to allow for an informed decision and has given their full consent voluntarily. 
 
8.6.4 Waiver of Individual Consent to Access CHiP and Routine Clinic Data 
A waiver of individual consent will be requested to access and link CHiP 
and routine clinic data.  The linked data will be used to monitor and 
facilitate linkage of CHiPs clients to care at health clinics, and so its 
primary use is to provide benefit to clients. Data so collected will also be 
used for research purposes in coded form. This request is justified by the 
following considerations which comply with 45 CFR 46.116 (d): 
 
(i) 
The research involves no more than minimal risk to participants as 
the data will be de-identified and presented in aggregate form to 
the research teams that will be analyzing the data for research 
purposes.  
(ii) The rights and welfare of research participants will not be adversely 
affected in any way by the collection of these data, which will be 
stored confidentially by the CHiP team members and shared only 
in de-identified form with the research teams 
(iii) The research could not practicably be carried out without the 
waiver, as attempting to obtain written informed consent from all 
community members involved in a study of this scale would not 
be feasible. 
(iv)  Household members will be provided with pertinent data about the 
project and the need to gather and report on the information 
gathered by the CHiP teams as well as certain routine clinic data. 
 
In the CHiPs intervention, health data from consenting individuals will be captured in 
association with personally-identifying information (such as name, age, and gender) and 
will be assigned identification numbers unique to the household and to the individual from 
whom it is obtained. During follow up, CHiP teams will have access to the personally-
identified data for the clients in their CHiP zone because they need this information to find 
individuals and provide individualized care. Data captured by CHiPs in the field, and any 
client-linked data retrieved from clinics, will only be shared for research use after 
personally identifying information has been removed.  Besides the CHiPs (whose access 
to personally-identified data is limited to clients in their zone) only the study data manager 
will have access to personally-identified client data, which will be stored in an encrypted 

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database. The encryption method and encryption key for this database are embedded in the 
software and can only be accessed by designated data managers.   
 
8.7 
Independent Ethical Review 
Approval to conduct this study will be obtained from the following IRBs/ECs. In instances 
where there is disagreement or discordant IRB requirements the condition providing the 
highest level of human subject protection will be implemented. Approval must be obtained 
from the local, and national (where relevant) IRBs before the study can be initiated. 
 
Ethical clearance for the trial will be sought from Institutional Review Boards (IRBs) in 
the United Kingdom (UK), Zambia and South Africa. Adverse events will be reported on 
a regular basis according to the individual requirements of these IRBs. 
8.8 
Respect for Participants and Communities During and After the Study 
8.8.1 Confidentiality 
Strict measures will be in place to safeguard confidentiality of data. All laboratory 
specimens, reports, study data collection, process, and administrative forms will be 
identified by coded numbers only to maintain participant confidentiality.   
Personal identifiers (name, address, global positioning system coordinates) will only be 
collected for (1) informed consent and (2) operational and logistical purposes (i.e. to 
ensure tracing of participants by intervention staff and to locate cohort participants for 
follow-up visits). Personal identifiers will appear on paper or electronically on 
appointment books, consent forms, log books, follow up lists and other listings. These 
listings will NOT include any (sensitive) study information (including laboratory data). A 
unique study number will be used to link personal identifiers to study information. 
 
Personal identifiers on paper will be stored in a locked cabinet. Electronically kept 
personal identifiers will be stored in separate datasets with password protection only 
accessible for designated staff (for computers and servers). Hand-held devices will also be 
password protected and personal identifiers will be stored in an encrypted format. 
 
Participants’ study information will not be released without the written permission of the 
participant, except as necessary for monitoring by the National Institute of Allergy and 
Infectious Diseases (NIAID) and/or its contractors, representatives of the HPTN CORE, 
SDMC, and/or LC, other government and regulatory authorities, and/or site IRBs/ECs.  
Datasets transferred to locations outside the study sites (e.g. for analyses, progress reports) 
will be stripped of any personal identifier before transfer. 
 
All electronic data will be stored in password protected database systems. Read and write 
authorization of data will depend on the designation of the staff member. A second layer 
of protection is hardware password protection on computers, servers and networks. 
Thirdly data transfer over wireless or mobile networks will use Virtual Private Networks 
or router protected dedicated internet protocol addresses. 
 

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All collected study data on central computers and servers, remote computers and hand-
held devices, will be backed up daily. Backup tapes/discs will be stored separately from 
the primary electronic storage. 
8.8.2 Data and Safety Monitoring Plan 
An independent data safety monitoring board (DSMB) will be established according to 
accepted international norms. The membership of the committee will include expertise in 
HIV prevention, statistics, cluster-randomized trials and clinical medicine (including 
antiretroviral therapy). The responsibilities of the DSMB will be to monitor data from the 
trial and to advise the sponsor and study leadership on any recommended changes to the 
conduct of the study including early termination for futility on the primary endpoint if 
appropriate. A formal interim analysis is not anticipated as it is important to measure the 
effect of the intervention over the full three year follow-up period. However, data from the 
study communities on operational performance including uptake, retention and adverse 
events will be reported to the DSMB and reviewed on an ongoing basis.  
 
Data on the uptake of trial interventions - in particular HIV testing and treatment, retention 
in HIV care and medical male circumcision - will be captured electronically in all trial 
communities, facilitating timely analysis. We will monitor intervention uptake on a 
monthly basis. We will use these data for the trial comparison of Arm A (immediate 
treatment) vs. Arm C (standard-of-care).  If study power falls below a pre-specified 
threshold, then the DSMB will consider whether the trial should be stopped for futility. 
This pre-specified threshold will be defined in consultation with the DSMB prior to the 
start of trial interventions. 
8.8.3 Communicable Disease Reporting Requirements 
Study staff will comply with national requirements to notify tuberculosis identified among 
study participants to local health authorities. Participants will be made aware of all 
reporting requirements during the study informed consent process. HIV is not a notifiable 
disease in either country. 
8.8.4 Post-Trial Management of Participants Exposed to the Early ARV 
Intervention 
Any individual started on ART during the trial will continue this therapy after the trial 
since there is no current guidance to stop ART once it has been started. This treatment will 
be provided through the national health systems and this has been discussed and is 
understood by all HIV care implementing agencies in the study communities. 
8.8.5 Study Discontinuation 
The study also may be discontinued at any time by NIAID, the HPTN, other government 
or regulatory authorities, and/or site IRBs/ECs.  

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9.0 
 LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
9.1 
Local Laboratory Specimens 
“Local Laboratory” in this study refers to regional laboratories and centralized laboratories 
in each country. Laboratory testing will be performed using stored samples to meet study 
objectives. The results of testing performed using stored samples will not be returned to 
study sites or participants. The HPTN LC will determine the location of testing. Tests 
performed by Local Laboratories are described in more detail in Appendix I and the SSP 
Manual. Local Laboratories performing these tests will receive External Quality 
Assurance (EQA) panels for HIV and HSV-2 testing from the HPTN LC.    
 
Each study site and Local Laboratory will adhere to standards of Good Clinical 
Laboratory Practice (GCLP), the laboratory SSP Manual, and all activities related to 
processing, labeling, testing, storage, transport and shipping (to centralized laboratories or 
to the HPTN LC).  Specimen collection and storage at selected Local Laboratories will be 
documented using the HPTN Laboratory Data Management System (LDMS), as described 
in the SSP Manual. 
 
All specimens will be shipped in accordance with local shipping regulations as well as 
International Air Transport Association (IATA) specimen shipping regulations.  The 
HPTN LC will determine which shipments will be documented using the HPTN LDMS, 
as described in the SSP Manual. 
 
As described in Section 5, the following types of specimens will be collected for testing at 
the Local Laboratory:  
 
Population Cohort:  
• Blood specimens for the following: 
o HIV testing 
o HSV-2 testing 
o Plasma storage 
9.2 
HPTN Laboratory Center (LC) Specimens 
Stored samples will be used for retrospective, centralized testing at the HPTN LC. This 
will include HIV and HSV-2 testing (e.g., to confirm results obtained in country, 
determine HIV infection status, and for quality assurance (QA), including confirmation of 
HIV and HSV-2 seroconversion events).  Results will not be returned to study sites or 
participants, unless directed by the HPTN LC for specific cases.  If funded, viral load 
testing and antiretroviral drug resistance testing will also be performed. Other testing may 
include: cross-sectional HIV incidence testing and testing for antiretroviral drugs and 
other substances (e.g., other medications,  substances of abuse). Selected samples may 
also be tested to characterize the HIV virus (e.g., HIV subtyping, HIV tropism) and the 
host response to HIV infection. In some cases, testing may be performed at a commercial 
laboratory or other laboratory designated by the HPTN LC. If the Phylogenetics Ancillary 

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Study is funded, samples will also be used for that work (see Section 9.4.1). Results from 
the Phylogenetics Ancillary Study will not be returned to study sites or participants. 
 
The study sites will ship samples to the HPTN LC on a routine basis and will ship 
additional samples as requested by the HPTN LC.  Additional information will be 
provided in the SSP Manual.  
 
It is important to note that the volume of plasma stored at each study visit will be limited, 
due to the very large number of participants in the study. In some cases, testing will be 
performed at the HPTN LC (rather than at the Local Laboratories) so that specialized 
methods can be used that require lower plasma volumes, and so that derivatives generated 
during testing (e.g., plasma supernatant, HIV RNA, polymerase chain reaction amplicons) 
can be saved and used for other types of testing. This will increase the likelihood that there 
will be sufficient stored plasma for all of the planned assessments.  
9.3 
Quality Control and Quality Assurance Procedures 
HPTN LC staff will conduct periodic visits to each site to assess the implementation of 
on-site laboratory quality control (QC) procedures, including proper processing, labeling, 
storage, proper maintenance of laboratory testing equipment and use of appropriate 
reagents.  HPTN LC staff will follow up directly with site staff to resolve any QC or QA 
problems identified through proficiency testing and/or on-site assessments.   
 
Throughout the course of the study, the HPTN LC will work with HPTN SDMC to select 
a random sample of stored specimens to test for QA purposes. HPTN LC staff will follow-
up directly with site staff to resolve any QA problems identified through this process. 
9.4 
Specimen Storage and Possible Future Research Testing 
Study site staff will store plasma collected in this study until the HPTN LC confirms that 
all protocol testing has been completed. Note that some protocol testing will be performed 
retrospectively, after the last participant completes the final study visit. Protocol testing 
will include QC testing and other testing performed at or coordinated by the HPTN LC 
(see Section 9.2).  
 
In addition to protocol testing (see Sections 9.1 and 9.2), study participants will be asked 
to provide written informed consent for their specimens to be stored for possible 
additional, future testing (long-term storage), unless disallowed by local laws or 
regulations. The specimens of participants who do not consent to long-term storage for 
future research will be destroyed after the HPTN LC confirms that all protocol-related 
testing has been completed.  
 
9.4.1 Proposed Phylogenetics Study 
If the Phylogenetics Ancillary Study is funded, some stored plasma specimens from the 
Population Cohort will be transferred to other laboratories for HIV sequencing and 
analysis. Samples from the Population Cohort will only be made available for the 
phylogenetics study after all of the primary assessments for the main HPTN 071 study 

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have been completed (including quality assurance testing, HIV and HSV-2 testing, 
confirmation of HIV seroconversion events) and after the HPTN LC has determined that 
sufficient plasma would remain for any secondary assessments (e.g., , viral load testing, 
resistance testing). Samples from the Population Cohort will only be made available for 
the Phylogenetics Ancillary Study if the participant consented to be included in that study.  
 
9.5 
Biohazard Containment 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the U.S. Centers for 
Disease Control and Prevention (CDC).  All infectious specimens will be transported in 
accordance with U.S. regulations [42 Code of Federal Regulations (CFR) 72]. 
10.0 ADMINISTRATIVE PROCEDURES 
10.1 Protocol Registration 
Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol consent form(s) approved, as 
appropriate, by their local IRB/EC and any other applicable regulatory entity (RE). Upon 
receiving final approval, sites will submit all required protocol registration documents to 
the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Services Center 
(RSC). The DAIDS PRO will review the submitted protocol registration packet to ensure 
that all of the required documents have been received. 
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the 
DAIDS PRO and sites will receive an Initial Registration Notification from the DAIDS 
PRO that indicates successful completion of the protocol registration process. A copy of 
the Initial Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, 
sites should implement the amendment immediately. Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all the required documents 
have been received. Site-specific ICF(s) WILL NOT be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the 
DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents 
required for initial and amendment registrations, refer to the current version of the DAIDS 
Protocol Registration Manual. 

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10.2 Study Activation 
Pending successful protocol registration and submission of all required documents (see 
Section 10.1 above); CORE staff will “activate” the site to begin study operations. Study 
implementation may not be initiated until a study activation notice is provided to the site. 
10.3 Study Coordination 
Study implementation will be directed by this protocol as well as the SSP Manual. The 
SSP Manual — which will contain reference copies of the Requirements for Source 
Documentation in DAIDS Funded and/or Sponsored Clinical Trials, as well as the DAIDS 
Manual for Expedited Reporting of Adverse Events to DAIDS, Version 2.0, dated January 
2010 and the DAIDS Toxicity Tables — will outline procedures for conducting study 
visits; data and forms processing; AE assessment, management and reporting; dispensing 
study products and documenting product accountability; and other study operations. 
Study case report forms, electronic data capture tools, and other study instruments will be 
developed by the protocol team and HPTN SDMC.  The study data from all sources 
ultimately will be transferred to the HPTN SDMC for storage and analysis. Quality 
control reports and queries will be generated and distributed to the study sites on a routine 
schedule for verification and resolution.    
Close coordination between protocol team members will be necessary to track study 
progress, respond to queries about proper study implementation, and address other issues 
in a timely manner. Rates of accrual, adherence, follow-up, and AE incidence will be 
monitored closely by the team as well as the HPTN Study Monitoring Committee.  The 
Protocol Chair, DAIDS Medical Officer, Protocol Biostatistician, SDMC Project 
Manager, and CORE Protocol Specialist will address issues related to study eligibility and 
AE management and reporting as needed to assure consistent case management, 
documentation, and information-sharing across sites.  
10.4 Study Monitoring 
On-site study monitoring will be performed in accordance with DAIDS policies. Study 
monitors will visit the site to 
• Verify compliance with human subjects and other research regulations and 
guidelines;  
 
• Assess adherence to the study protocol, study-specific procedures manual, and 
local counseling practices; and 
 
• Confirm the quality and accuracy of information collected at the study site and 
entered into the study database.   
 
Site investigators will allow study monitors to inspect study facilities and documentation 
(e.g., informed consent forms, health center and laboratory records, other source 
documents, case report forms), as well as observe the performance of study procedures. 

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Investigators also will allow inspection of all study-related documentation by authorized 
representatives of the HPTN CORE, SDMC, LC, NIAID,US and in-country government 
and regulatory authorities and IRBs/ECs. A site visit log will be maintained at the study 
site to document all visits.  
10.5 Protocol Compliance 
The study will be conducted in full compliance with the protocol. The protocol will not be 
amended without prior written approval by the Protocol Chair and NIAID Medical 
Officer.  All protocol amendments must be submitted to and approved by the relevant 
IRB(s)/EC(s) and the DAIDS Regulatory Support Center (RSC) prior to implementing the 
amendment. 
10.6 Investigator's Records 
The study site investigator will maintain, and store in a secure manner, complete, accurate 
and current study records throughout the study.  The investigator will retain all study 
records for at least three years after submission of the CTU’s final Financial Status Report 
to DAIDS, which is due within 90 days after the end of the CTU’s cooperative agreement 
with DAIDS, unless otherwise specified by DAIDS or the HPTN CORE.  Study records 
include administrative documentation — including protocol registration documents and all 
reports and correspondence relating to the study — as well as documentation related to 
each participant screened for and/or enrolled in the study — including informed consent 
forms, locator forms, case report forms, notations of all contacts with the participant, and 
all other source documents. 
10.7 Use of Information and Publications 
Publication of the results of this study will be governed by the HPTN Manual of 
Operations and policies. Any presentation, abstract, or manuscript will be submitted by the 
Investigator to the HPTN Manuscript Review Committee for review prior to submission. 

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prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a 
randomised controlled trial. Lancet Infect Dis, 2011. 11(3): p. 171-80. 
73. 
Shapiro, R.L., et al., Antiretroviral regimens in pregnancy and breast-feeding 
in Botswana. N Engl J Med, 2010. 362(24): p. 2282-94. 

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74. 
Cohen, M.S., et al., Prevention of HIV-1 Infection with Early Antiretroviral 
Therapy. N Engl J Med, 2011. 
75. 
Lawn, S.D., et al., Early mortality among adults accessing antiretroviral 
treatment programmes in sub-Saharan Africa. AIDS, 2008. 22(15): p. 1897-
908. 
76. 
Donnell, D., et al., Heterosexual HIV-1 transmission after initiation of 
antiretroviral therapy: a prospective cohort analysis. The Lancet, 2010. 
375(9731): p. 2092-8. 
77. 
Das, S., Risk of cardiovascular disease in HIV-infected patients. J 
Antimicrob Chemother, 2010. 65(3): p. 386-9. 
78. 
Montaner, J.S., et al., Association of highly active antiretroviral therapy 
coverage, population viral load, and yearly new HIV diagnoses in British 
Columbia, Canada: a population-based study. Lancet, 2010. 376(9740): p. 
532-9. 
79. 
Garnett, G.P. and R.F. Baggaley, Treating our way out of the HIV pandemic: 
could we, would we, should we? Lancet, 2009. 373(9657): p. 9-11. 
80. 
Pinkerton, S.D., Probability of HIV transmission during acute infection in 
Rakai, Uganda. AIDS Behav, 2008. 12(5): p. 677-84. 
81. 
Brenner, B.G., et al., High rates of forward transmission events after 
acute/early HIV-1 infection. J Infect Dis, 2007. 195(7): p. 951-9. 
82. 
Hollingsworth, T.D., R.M. Anderson, and C. Fraser, HIV-1 transmission, by 
stage of infection. J Infect Dis, 2008. 198(5): p. 687-93. 
83. 
Bunnell, R., et al., Changes in sexual behavior and risk of HIV transmission 
after antiretroviral therapy and prevention interventions in rural Uganda. 
AIDS, 2006. 20(1): p. 85-92. 
84. 
Lundgren, J.D., et al., Initiation of Antiretroviral Therapy in Early 
Asymptomatic HIV Infection. N Engl J Med, 2015. 373(9): p. 795-807. 
85. 
Granich, R., et al., Universal voluntary HIV testing with immediate 
antiretroviral therapy as a strategy for elimination of HIV transmission: a 
mathematical model. Lancet, 2009. 373(9657): p. 48-57. 
86. 
Walensky, R.P., et al., Test and treat DC: forecasting the impact of a 
comprehensive HIV strategy in Washington DC. Clin Infect Dis, 2010. 51(4): 
p. 392-400. 
87. 
Johnston, K.M., et al., Expanding access to HAART: a cost-effective 
approach for treating and preventing HIV. AIDS, 2010. 24(12): p. 1929-35. 
88. 
Lawn, S.D., K. Kranzer, and R. Wood, Antiretroviral therapy for control of 
the HIV-associated tuberculosis epidemic in resource-limited settings. Clin 
Chest Med, 2009. 30(4): p. 685-99, viii. 
89. 
Williams, B.G., et al., Antiretroviral therapy for tuberculosis control in nine 
African countries. Proc Natl Acad Sci U S A, 2010. 107(45): p. 19485-9. 

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90. 
Stephenson, R., et al., The influence of motivational messages on future 
planning behaviors among HIV concordant positive and discordant couples 
in Lusaka, Zambia. AIDS Care, 2008. 20(2): p. 150-60. 
91. 
Wood, R. and S.D. Lawn, Antiretroviral treatment as prevention: impact of 
the 'test and treat' strategy on the tuberculosis epidemic. Curr HIV Res, 
2011. 9(6): p. 383-92. 
92. 
Lawn, S.D., et al., Time to initiation of antiretroviral therapy among patients 
with HIV-associated tuberculosis in Cape Town, South Africa. J Acquir 
Immune Defic Syndr, 2011. 57(2): p. 136-40. 
93. 
Sonnenberg, P., et al., How soon after infection with HIV does the risk of 
tuberculosis start to increase? A retrospective cohort study in South African 
gold miners. J Infect Dis, 2005. 191(2): p. 150-8. 
94. 
Badri, M., D. Wilson, and R. Wood, Effect of highly active antiretroviral 
therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet, 
2002. 359(9323): p. 2059-64. 
95. 
Leroy V, E.D., Becquet R, Viho I, Dequae-Merchadou L, Tonwe-Gold B, et 
al., 18-month effectiveness of short-course antiretroviral regimens combined 
with alternatives to breastfeeding to prevent HIV mother-to-child 
transmission. PLoS One, 2008. 3(2): p. 1645. 
96. 
Thomas TK, M.R., Borkowf CB, Ndivo R, Zeh C, Misore A, et al., Triple-
antiretroviral prophylaxis to prevent mother-to-child HIV transmission 
through breastfeeding - the Kisumu Breastfeeding Study, Kenya: a clinical 
trial. PLoS Med, 2011. 8(3): p. 1001015. 
97. 
Cooper ER, C.M., Mofenson L, Hanson IC, Pitt J, Diaz C, et al., 
Combination antiretroviral strategies for the treatment of pregnant HIV-1-
infected women and prevention of perinatal HIV-1 transmission. J Acquir 
Immune Defic Syndr, 2002. 29(5): p. 484-94. 
98. 
Konikoff, J., et al., Performance of a Limiting-Antigen Avidity Enzyme 
Immunoassay for Cross-Sectional Estimation of HIV Incidence in the United 
States. PLoS One, 2013. 8(12): p. e82772. 
99. 
Cousins, M.M., et al., HIV Diversity as a Biomarker for HIV Incidence 
Estimation: Including a High-Resolution Melting Diversity Assay in a 
Multiassay Algorithm. J Clin Microbiol, 2014. 52(1): p. 115-21. 
100. Price, M.A., et al., Transmitted HIV type 1 drug resistance among individuals 
with recent HIV infection in East and Southern Africa. AIDS Res Hum 
Retroviruses, 2011. 27(1): p. 5-12. 
101. UNAIDS. Report on the Global AIDS Epidemic. 2010 12 May 2011. 
102. Ayles, H., Personal Communication 11 January 2012. 
103. Hollingsworth TD, A.R., Fraser C, HIV-1 transmission, by stage of infection. 
J Infect Dis, 2008. 198: p. 687-693. 

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104. Hayes, R. and L. Moulton, Cluster Randomised Trials. Equations 7.132009. 
105. Getahun, H., et al., Development of a standardized screening rule for 
tuberculosis in people living with HIV in resource-constrained settings: 
individual participant data meta-analysis of observational studies. PLoS 
Med, 2011. 8(1): p. e1000391. 
106. Harries, A.D., et al., The HIV-associated tuberculosis epidemic--when will 
we act? Lancet, 2010. 375(9729): p. 1906-19. 
107. Lawn, S.D., et al., Antiretrovirals and isoniazid preventive therapy in the 
prevention of HIV-associated tuberculosis in settings with limited health-care 
resources. Lancet Infect Dis, 2010. 10(7): p. 489-98. 
108. Organization, W.H., Antiretroviral Treatment as Prevention (Ta sP) of HIV 
and TB, 2012. 
109. Weiss, H., M. Quigley, and R. Hayes, Male circumcision and risk of HIV 
infection in sub-Saharan Africa: a systematic review and meta-analysis. 
AIDS, 2000. 14(15): p. 2361-2370. 
110. Lissouba, P., et al., Adult male circumcision as an intervention against HIV: 
an operational study of uptake in a South African community (ANRS 12126). 
BMC Infect Dis, 2011. 11: p. 253. 
111. Wawer, M., G. Kigozi, and D. Swerwadda, Trial of male circumcision in 
HIV+ men, Rakai Uganda: effects in HIV+ men and in women partners, in 
15th CROI2008, CROI: Boston. 
112. Mehta, S.D., et al., Does sex in the early period after circumcision increase 
HIV-seroconversion risk? Pooled analysis of adult male circumcision clinical 
trials. AIDS, 2009. 23(12): p. 1557-64. 
113. Weijer, C. and E.J. Emanuel, Protecting communities in biomedical research. 
Science, 2000. 289: p. 1142-1144. 
 
 
 
 

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12.0 APPENDICES 
 
 

 
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APPENDIX I - SCHEDULES OF STUDY VISITS AND 
PROCEDURES 
 
APPENDIX IA: POPULATION COHORT- ALL ARMS 
PROCEDURES 
Enrollment 
12 Month 
Follow-Up 
24 Month 
Follow-Up 
36 Month 
Follow-Up 
ADMINISTRATIVE, BEHAVIORAL, AND REGULATORY 
PROCEDURES 
 
 
 
 
Obtain informed consent for enrollment.   
Solicit consent for storage of specimens for future testing and for access 
to data collected at health centers 
X 
 
 
 
Obtain/update locator information. 
X 
X 
X 
X 
Administer survey to include socio-demographic, health, social, 
behavioral, and economic factors 
X 
X 
X 
X 
CLINICAL/COUNSELING PROCEDURES 
 
 
 
 
Perform HIV rapid testing2   
X 
X 
X 
X 
Collect blood for laboratory testing and sample storage. 
X 
X 
X 
X 
Provide HIV pre- and post-test counseling and test results, for those 
receiving HIV rapid testing and willing to receive results 
X 
X 
X 
X 
LABORATORY PROCEDURES 
 
 
 
 
 
HIV testing3 
X 
X 
X 
X 
HSV-2 testing4 
X 
 
 
[X]4 
Plasma  storage5 
 
X 
X 
X 
X 
 

 
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Footnotes for the Population Cohort 
1 Consent for the Phylogenetics Ancillary Study will be solicited at the 12 month follow-up visit of the 
Population Cohort. If it is determined operationally feasible, consent may also be solicited at the 24 
and 36 month follow-up visits for those participants not available to be offered participation at the 12 
month follow-up visit. This decision will be subject to review and approval by the study team.  
2Rapid testing will be offered at home visits and performed according to in-country guidelines. This 
testing will not be used to estimate HIV incidence or prevalence; however, the data may be captured 
along with other data from the home visit. Tie-breaker testing may or may not be performed in the 
home. 
3 Preliminary testing to assess HIV status will be performed in-country at a centralized laboratory. 
Additional HIV testing will be performed at the HPTN LC to confirm/determine HIV infection status. 
Results will not be returned to study sites or participants, unless directed by the HPTN LC for specific 
cases. 
4 Preliminary testing to assess HSV-2 status will be performed in-country at a centralized laboratory. 
Additional HSV-2 testing will be performed at the HPTN LC. HSV-2 testing will be performed for all 
participants at PC0; samples from PC36 will be selected for testing at the end of the study based on 
PC0 test results (see SSP Manual). Some samples may be tested for quality assurance (QA) 
assessments. Results will not be returned to study sites or participants. 
5 Plasma samples will be stored at in-country centralized laboratories. The study site will ship samples to 
the HPTN LC on a routine basis, and will ship additional samples as requested by the HPTN LC. 
Additional information will be provided in the SSP Manual. Information about the use of stored 
samples is provided in Section 9.2.  
 
  
 
 
 
 
 
 

 
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APPENDIX 1B- CASE-CONTROL STUDIES 1-3- ARMS A & B 
 
PROCEDURES 
Enrollment 
ADMINISTRATIVE, BEHAVIORAL, AND REGULATORY PROCEDURES 
 
Obtain informed consent for enrollment 
X 
Complete questionnaire of socio-demographic, clinical, and behavioral characteristics 
X 
 
 
 
 
 
 

 
HPTN 071 Version 3.0 
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APPENDIX II - SAMPLE INFORMED CONSENT FORM – 
POPULATION COHORT 
 
NOTE: Sample informed consent forms are adapted from NIH templates.  It is understood that 
sites will modify these consents to meet the requirements of their setting and of their ethics 
committees.  Modifications made locally to prior versions of the consents that have already 
been approved for use in-country are expected to be maintained in subsequent site-specific 
consent versions. 
 
 
SUBJECT INFORMATION AND CONSENT FORM  
 
Title of Research Study: 
Population Effects of Antiretroviral Therapy to Reduce 
HIV Transmission (PopART): A cluster-randomized 
trial of the impact of a combination prevention package 
on population-level HIV incidence in Zambia and South 
Africa 
 
Protocol #: 
HPTN 071, Version 3.0   16 November 2015 
 
DAIDS ID: 11865 
 
Sponsor: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
(U.S. National Institutes of Health) 
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation  
 
Investigator of Record: 
(insert name) 
 
Research Site Address(es):  
(insert address) 
 
Daytime telephone number(s): 
(insert number) 
 
24-hour contact number(s): 
(insert number) 
 
Subject Information and Consent Form 
Please ask the study investigator or the study staff to explain any words or procedures that you 
do not clearly understand. 
 
The purpose of this form is to give you information about the research study you are being asked 
to join.  If you sign this form, you will be giving your permission to take part in the study.  The 
form describes the purpose, procedures, benefits, and risks of the research study.  You should 
take part in the study only if you want to do so.  You may choose not to join the research project 
or withdraw from this study at any time. Choosing not to take part in this research will not in any 
way affect the health care or benefits that you or your family will receive.  Please read this 

 
HPTN 071 Version 3.0 
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16 November 2015 
Subject Information and Consent Form and ask as many questions as needed.  You should not 
sign this form if you have any questions that have not been answered to your satisfaction. 
 
This study is being funded by the U.S. National Institutes of Health, the Office of the United 
States Global AIDS Coordinator, and the Bill and Melinda Gates Foundation 
 
Your participation is voluntary 
You do not have to take part in this study.  If you decide today to take part in this research 
project, you may refuse to take part in any portion of the study or stop at any time without 
reducing or affecting any care that you receive at the health centers in your community.   
 
Purpose of the Research in the Communities 
The HPTN 071 or PopART study is testing a program to try to reduce HIV infection in a 
community like yours.  Twenty one communities that include about 600,000 adults are included 
in this research (about 400,000 adults in twelve Zambian communities and 200,000 adults in nine 
South African communities).  
 
In some communities, the level of care that people are used to will stay the same, in terms of 
HIV testing, and care of those who have HIV.  
 
In other communities, to make HIV testing easier, community health care workers will go to all 
homes and will offer to do an HIV test on each adult (or younger people with permission of 
guardian) wishing to have a test.  For anyone infected with HIV, they will be offered to start 
taking drugs to treat HIV according to the standard treatment guidelines that are in place for 
doing so in your country.  The health workers will visit every home again once a year for up to 
three more years to repeat the HIV testing and to refer people to care.   
 
In other communities, health care workers will go to all houses offering HIV testing, as was just 
described.  In these communities if someone tests HIV positive however, they will be offered to 
start taking medicines to treat HIV right away.  The health workers will visit every home again 
once a year for up to three more years to repeat the HIV testing and to refer people to care.   
 
At the end of the study, the researchers will see if offering HIV tests in each household and 
offering people the chance to start HIV treatment right away has reduced HIV infection. They 
will also see if starting ART early has any negative effects on people’s health.  
 
Your community is one of the communities participating in this research.  If health care workers 
are visiting homes in your community, you will notice that they provide some other information 
and services to people, but the most important thing is the testing and HIV treatment they offer. 
 
In each community, around 2,700 people will be asked to participate in additional activities such 
as completing questionnaires and providing additional samples for laboratory testing.  These 
questionnaires and tests will let the researchers understand how the community feels about the 
program and if the program is working.  You have been selected to be one of the people from 
your community who we are asking to participate in these additional activities.  That is why you 
are being asked to read this document.  
 

 
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What will happen during this study? 
If you participate in this study, you will have up to four study visits: today, in 12 months, in 24 
months, and possibly a final visit in 36 months.  We will contact you to remind you about your 
visits. For example, we may call you or send a short text message (SMS). Today’s visit will take 
approximately 2 hours.  Future visits may be slightly shorter.  Today we will:  
• Ask you questions about a number of topics including you and your sexual practices, HIV 
testing, male circumcision, and how you and others feel about HIV. 
• Collect up to 15 mL blood (about 3 teaspoons) for HIV testing and other HIV-related tests 
as well as herpes simplex-2 testing. Some blood will be stored for study-related testing. 
Sometimes at the end of a study, some blood or other specimens are left-over that could be useful 
for testing in the future.  These tests would be for research that is not a part of this study.  If you 
agree to participate in the study, we will also ask if you if are willing to let us keep your left-over 
samples for future tests. 
 
Some specimens will be shipped and/or securely stored outside of the country for study-related 
testing, long-term storage, and future testing. 
 
If you agree to participate in the study, we will offer to perform an on-the-spot HIV test at each 
visit, and will provide counseling if you would like to know the result of your test.  If these tests 
say that you are positive for HIV, we will refer you for care at the local health center.  The staff 
at the health center keep records of all their patients as part of their normal procedures.  We 
would like to look at these medical records for any study participant who is HIV infected.  Doing 
so will help us better understand how the study activities in the community are affecting the 
health of people diagnosed with HIV.  If you agree to participate in this study, we will ask you 
for your permission to look at your records at the health center. This may include information 
collected by the community health workers if they are visiting homes in your community.  
 
What are the possible risks or discomforts? 
You may become embarrassed, worried or anxious when learning your HIV status and 
discussing sexual risk behavior and other topics.  A trained staff member will help you deal with 
any feelings or questions you have. You may feel that being part of this study could lead to you 
feeling stigmatized or separated from our community  
 
It is very unusual to have any problems from having a blood test but you may feel discomfort, 
dizzy, or even faint when your blood is drawn.  Redness, pain, swelling, bruising may occur 
where the needle goes into your arm but this is rare. 
 
What are the potential benefits? 
During the study, you can decide if you would like to learn your HIV status and be provided with 
information on where to receive treatment and care services if needed.  You will also be able to 
ask questions about your health.   
 
In addition, knowledge gained from this study may help reduce the spread of HIV in the future 
and promote better health for you and your family as well as helping with acknowledgement and 
acceptance of HIV as a community-wide health problem. 

 
HPTN 071 Version 3.0 
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Are there any alternatives to participation? 
If you decide not to participate in this study, we will refer you to other places where you can 
receive an HIV test. If it is offered in your community, you can also receive testing from a health 
worker visiting your home during the study period. 
 
How will my confidentiality and privacy be protected? 
We cannot guarantee absolute confidentiality.  However, we will do everything possible to 
protect your confidentiality if you join this study. We do this by giving you a study number and 
any information will be labeled with this number only, so people working in the health centers 
and laboratories will only see a number not your name, only the research staff will be able to link 
this number to your name. Your personal information (name, address, phone number) will be 
protected by the research staff. This information will not be used in any publication of 
information about this study. 
 
To protect your privacy, you will meet with the researcher in a private area where others cannot 
overhear conversations with you.   
 
People who may review your records include: [insert name of site IRB/EC], local regulatory 
agencies, US National Institutes of Health (NIH), study staff, and study monitors.  Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) are committees that watch over the safety 
and rights of research participants. 
 
What happens if I am injured by participating in this study? 
It is very unlikely that you could be injured as a result of participating in this study.  However, if 
you are injured while participating in this study, you will be given immediate treatment for your 
injuries.  You [will/will not] have to pay for this care.  There [is a/is no] program for 
compensation either through this institution or the United States NIH. You will not be giving up 
any of your legal rights by signing this Subject Information and Consent Form. 
 
What are some reasons why I may be withdrawn from this activity without my consent? 
You may be withdrawn from the study without your consent for the following reasons: 
 
• The research study, or this part of the study, is stopped or canceled 
• The study staff feels that completing the study or this part of the study would be harmful 
to you or others 
 
Persons to Contact for Problems or Questions 
If you have any questions about your participation in this research study, your rights as a 
research subject, or if you feel that you have experienced a research-related injury, contact: 
 
Investigator of Record Name: 
(site insert name of the investigator or other study staff) 
 
Research Site Address(es): (site insert physical address of above) 
 
Daytime telephone number(s): 
(site insert telephone number) 
 

 
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24-hour contact number(s): 
(site insert telephone number) 
 
If you have any questions or concerns about your rights as a research subject or want to discuss a 
problem, get information or offer input, you may contact: 
 
Independent Review Board/Ethics Committee: 
(site insert name or title of person on the IRB, 
EC or other organization appropriate for the site) 
 
Address of Independent Review Board:(site insert physical address of above) 
 
Daytime Telephone Number: 
(site insert telephone number of above) 
 
 

 
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SUBJECT’S STATEMENT OF CONSENT 
 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART): A 
cluster-randomized trial of the impact of a combination prevention package on population-
level HIV incidence in Zambia and South Africa 
 
• I have been given sufficient time to consider whether to take part in this study. 
• My taking part in this research study is voluntary.  I may decide not to take part or to 
withdraw from the research study at any time without penalty or loss of benefits or 
treatment to which I am entitled. 
• The research study may be stopped at any time without my consent. 
• I have had an opportunity to ask my study investigator questions about this research 
study.  My questions so far have been answered to my satisfaction. 
• I have been told how long I may be in the research study. 
• I have been informed of the procedures and tests that may be performed during the 
research study. 
• I have been told what the possible risks and benefits are from taking part in this research 
study.  I may not benefit if I take part in this research study. 
• I do not give up my legal rights by signing this form. 
• I have been told that before any study related procedures being performed, I will be asked 
to voluntarily sign this Subject Information and Consent Form. 
• I will receive a signed and dated copy of this Subject Information and Consent Form. 
 
If you have either read or have heard the information in this Subject Information and Consent 
Form, if all of your questions have been answered, and if you agree to take part in the study, 
please print and sign your name and write the date on the line below. 
 
 
 

 
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Specimen Storage for Future Testing 
 
_____  My initials indicate that any left-over blood or other specimens may be stored for future 
testing after the study has ended. I understand that any future research on my specimens may 
need to be approved by an ethics committee.  
 
_____  I do not agree to allow leftover samples to be saved for long-term storage and future 
testing after the study has ended. 
 
Access of Data from Heath Center 
 
 
_____  My initials indicate that I agree to allow my records at the health center to be accessed 
and used for this study.   
 
_____  I do not agree to allow my health care records to be accessed and used for this study. 
 
 
 
 
I voluntarily agree to take part in this research study. 
 
 
_______________________  
 
________________________________________ 
Subject’s Name (print) 
 
 
Subject’s Signature and Date 
 
I certify that the information provided was given in a language that was understandable to the 
subject. 
 
 
_______________________  
 
________________________________________ 
Name of Study Staff  
 
 
Study Staff Signature and Date 
Conducting Consent Discussion (print) 
 
 
_______________________  
 
________________________________________ 
Witness’ Name (print) 
 
 
Witness’ Signature and Date 
(As appropriate) Date 
 
 
 

 
HPTN 071 Version 3.0 
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APPENDIX III - SAMPLE INFORMED CONSENT FORM – 
QUALITATIVE STUDIES PARTICIPANTS 
 
NOTE: Sample informed consent forms are adapted from NIH templates.  It is understood that 
sites will modify these consents to meet the requirements of their setting and of their ethics 
committees.  Modifications made locally to prior versions of the consents that have already 
been approved for use in-country are expected to be maintained in subsequent site-specific 
consent versions. 
 
SUBJECT INFORMATION AND CONSENT FORM  
 
Title of Research Study: 
Population Effects of Antiretroviral Therapy to Reduce 
HIV Transmission (PopART): A cluster-randomized 
trial of the impact of a combination prevention package 
on population-level HIV incidence in Zambia and South 
Africa 
 
Protocol #: 
HPTN 071, Version 3.0   16 November 2015 
 
DAIDS ID: 11865 
 
Sponsor: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
(U.S. National Institutes of Health) 
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation  
 
Investigator of Record: 
(insert name) 
 
Research Site Address(es):  
(insert address) 
 
Daytime telephone number(s): 
(insert number) 
 
24-hour contact number(s): 
(insert number) 
 
Subject Information and Consent Form 
Please ask the study investigator or the study staff to explain any words or procedures that you 
do not clearly understand. 
 
The purpose of this form is to give you information about the research study you are being asked 
to join.  If you sign this form, you will be giving your permission to take part in the study.  The 
form describes the purpose, procedures, benefits, and risks of the research study.  You should 
take part in the study only if you want to do so.  You may choose not to join the research project 
or withdraw from this study at any time. Choosing not to take part in this research will not in any 
way affect the health care or benefits that you or your family will receive.  Please read this 
Subject Information and Consent Form and ask as many questions as needed.  You should not 
sign this form if you have any questions that have not been answered to your satisfaction. 

 
HPTN 071 Version 3.0 
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16 November 2015 
 
This study is being funded by the U.S. National Institutes of Health, the Office of the United 
States Global AIDS Coordinator, and the Bill and Melinda Gates Foundation 
 
Your participation is voluntary 
You do not have to take part in this study.  If you decide today to take part in this research 
project, you may refuse to take part in any portion of the study or stop at any time without 
reducing or affecting any care that you receive at the health centers in your community.   
 
Purpose of the Research in the Communities 
The HPTN 071 or PopART study is testing a program to try to reduce HIV infection in a 
community like yours.  Twenty one communities that include about 600,000 adults are included 
in this research (about 400,000 adults in twelve Zambian communities and 200,000 adults in nine 
South African communities).  
 
In some communities, the level of care that people are used to will stay the same, in terms of 
HIV testing, and care of those who have HIV.  
 
In other communities, to make HIV testing easier, community health care workers will go to all 
homes and will offer to do an HIV test on each adult (or younger people with permission of 
guardian) wishing to have a test.  For anyone infected with HIV, they will be offered to start 
taking drugs to treat HIV according to the standard treatment guidelines that are in place for 
doing so in your country.  The health workers will visit every home again once a year for up to 
three more years to repeat the HIV testing and to refer people to care.   
 
In other communities, health care workers will go to all houses offering HIV testing, as was just 
described.  In these communities if someone tests HIV positive however, they will be offered to 
start taking medicines to treat HIV right away.  The health workers will visit every home again 
once a year for up to three more years to repeat the HIV testing and to refer people to care.   
 
At the end of the study, the researchers will see if offering HIV tests in each household and 
offering people the chance to start HIV treatment right away has reduced HIV infection. 
 
Your community is one of the communities participating in this research.  If health care workers 
are visiting homes in your community, you will notice that they provide some other information 
and services to people, but the most important thing is the testing and HIV treatment they offer. 
 
In each community, around 2,700 people will be asked to participate in additional activities such 
as completing questionnaires and providing additional samples for laboratory testing.  These 
questionnaires and tests will let the researchers understand how the community feels about the 
program and if the program is working.  You have been selected to be one of the people from 
your community who we are asking to participate in these additional activities.  That is why you 
are being asked to read this document. 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
What will happen during this study? 
 
[For participants providing a single interview] 
If you agree to participate in this study, you will have one interview today. We will ask you 
questions about the reasons why people in this community chose to test for HIV or not to test for 
HIV.  We will also ask about how people in this community experience HIV treatment and any 
other HIV prevention methods.  
 
[For participants being followed longitudinally] 
If you agree to participate in this study, we will interview you every three months until the end of 
the study. We will ask you questions about the reasons why people in this community chose to 
test for HIV or not to test for HIV.  We will also ask about how people in this community 
experience HIV treatment and any other HIV prevention methods.  
 
[For individuals participating in a focus group] 
You have been selected to participate in this group discussion because of either your knowledge 
of the community or your association with HIV/AIDS related programs and activities in this 
community. If you agree to participate in this study, you will be a part of a group and questions 
will be directed towards the group, but you are free to answer any question and comment on the 
answers of others. In some instances, the facilitator may ask you to elaborate on your answer for 
the benefit of others but you may choose not to if you are not entirely comfortable with the 
request. The questions will be broad/ general in nature and will touch on many aspects of the 
community’s experiences with HIV. 
 
What are the possible risks or discomforts? 
The risk to you in participating in this study is that some of the questions may be uncomfortable 
and may make you feel worried or embarrassed. If any of the questions make you feel upset, the 
interviewer may go to another question or totally stop the interview.   
 
There is also a risk that following up individuals at home may lead to rumors in the community.  
To minimize this risk we will ask you to propose places where we can talk in private. 
 
What are the potential benefits? 
You will not receive any direct benefit from being in this study. You or others may benefit in the 
future from the information learned in this study. 
 
Are there any alternatives to participation? 
If you decide not to participate in this study, you can still receive HIV tests and other services 
from your local health center. 
 
How will my confidentiality and privacy be protected? 
We cannot guarantee absolute confidentiality.  However, we will do everything possible to 
protect your confidentiality if you join this study. We do this by giving you a study number and 
any information you provide will be labeled with this number only, not your name. Only the 
research staff will be able to link this number to your name. Your personal information (name, 
address, phone number) will be protected by the research staff. This information will not be used 
in any publication of information about this study. 

 
HPTN 071 Version 3.0 
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16 November 2015 
 
To protect your privacy, you will meet with the researcher in a private area where others cannot 
overhear conversations with you.   
 
People who may review your records include: [insert name of site IRB/EC], local regulatory 
agencies, US National Institutes of Health (NIH), study staff, and study monitors.  Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) are committees that watch over the safety 
and rights of research participants. 
 
What happens if I am injured by participating in this study? 
It is very unlikely that you could be injured as a result of participating in this study.  However, if 
you are injured while participating in this study, you will be given immediate treatment for your 
injuries.  You [will/will not] have to pay for this care.  There [is a/is no] program for 
compensation either through this institution or the United States NIH. You will not be giving up 
any of your legal rights by signing this Subject Information and Consent Form. 
 
What are some reasons why I may be withdrawn from this activity without my consent? 
You may be withdrawn from the study without your consent for the following reasons: 
 
• The research study, or this part of the study, is stopped or canceled 
• The study staff feels that completing the study or this part of the study would be harmful 
to you or others 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
Persons to Contact for Problems or Questions 
If you have any questions about your participation in this research study, your rights as a 
research subject, or if you feel that you have experienced a research-related injury, contact: 
 
Investigator of Record Name: 
(site insert name of the investigator or other study staff) 
 
Research Site Address(es): (site insert physical address of above) 
 
Daytime telephone number(s): 
(site insert telephone number) 
 
24-hour contact number(s): 
(site insert telephone number) 
 
If you have any questions or concerns about your rights as a research subject or want to discuss a 
problem, get information or offer input, you may contact: 
 
Independent Review Board/Ethics Committee: 
(site insert name or title of person on the 
IRB/EC or other organization appropriate for the site) 
 
Address of Independent Review Board:(site insert physical address of above) 
 
Daytime Telephone Number: 
(site insert telephone number of above) 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
SUBJECT’S STATEMENT OF CONSENT 
 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART): A 
cluster-randomized trial of the impact of a combination prevention package on population-
level HIV incidence in Zambia and South Africa 
 
• I have been given sufficient time to consider whether to take part in this study. 
• My taking part in this research study is voluntary.  I may decide not to take part or to 
withdraw from the research study at any time without penalty or loss of benefits or 
treatment to which I am entitled. 
• The research study may be stopped at any time without my consent. 
• I have had an opportunity to ask my study investigator questions about this research 
study.  My questions so far have been answered to my satisfaction. 
• I have been told how long I may be in the research study. 
• I have been informed of the procedures and tests that may be performed during the 
research study. 
• I have been told what the possible risks and benefits are from taking part in this research 
study.  I may not benefit if I take part in this research study. 
• I do not give up my legal rights by signing this form. 
• I have been told that before any study related procedures being performed, I will be asked 
to voluntarily sign this Subject Information and Consent Form. 
• I will receive a signed and dated copy of this Subject Information and Consent Form. 
 
If you have either read or have heard the information in this Subject Information and Consent 
Form, if all of your questions have been answered, and if you agree to take part in the study, 
please print and sign and your name and write the date on the line below. 
 
 
I voluntarily agree to take part in this research study. 
 
 
_______________________  
 
________________________________________ 
Subject’s Name (print) 
 
 
Subject’s Signature and Date 
 
I certify that the information provided was given in a language that was understandable to the 
subject. 
 
 
_______________________  
 
________________________________________ 
Name of Study Staff  
 
 
Study Staff Signature and Date 
Conducting Consent Discussion (print) 
 
 
_______________________  
 
________________________________________ 
Witness’ Name (print) 
 
 
Witness’ Signature and Date 
(As appropriate) Date 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
APPENDIX IV - SAMPLE INFORMED CONSENT FORM – CASE 
CONTROL STUDIES PARTICIPANTS 
 
NOTE: Sample informed consent forms are adapted from NIH templates.  It is understood that 
sites will modify these consents to meet the requirements of their setting and of their ethics 
committees.  Modifications made locally to prior versions of the consents that have already 
been approved for use in-country are expected to be maintained in subsequent site-specific 
consent versions. 
 
SUBJECT INFORMATION AND CONSENT FORM  
 
Title of Research Study: 
Population Effects of Antiretroviral Therapy to Reduce 
HIV Transmission (PopART): A cluster-randomized 
trial of the impact of a combination prevention package 
on population-level HIV incidence in Zambia and South 
Africa 
 
Protocol #: 
HPTN 071, Version 3.0   16 November 2015 
 
DAIDS ID: 11865 
 
Sponsor: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
(U.S. National Institutes of Health) 
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation  
 
Investigator of Record: 
(insert name) 
 
Research Site Address(es):  
(insert address) 
 
Daytime telephone number(s): 
(insert number) 
 
24-hour contact number(s): 
(insert number) 
 
Subject Information and Consent Form 
Please ask the study investigator or the study staff to explain any words or procedures that you 
do not clearly understand. 
 
The purpose of this form is to give you information about the research study you are being asked 
to join.  If you sign this form, you will be giving your permission to take part in the study.  The 
form describes the purpose, procedures, benefits, and risks of the research study.  You should 
take part in the study only if you want to do so.  You may choose not to join the research project 
or withdraw from this study at any time. Choosing not to take part in this research will not in any 
way affect the health care or benefits that you or your family will receive.  Please read this 
Subject Information and Consent Form and ask as many questions as needed.  You should not 
sign this form if you have any questions that have not been answered to your satisfaction. 
 

 
HPTN 071 Version 3.0 
Page 137 of 166 
16 November 2015 
This study is being funded by the U.S. National Institutes of Health, the Office of the United 
States Global AIDS Coordinator, and the Bill and Melinda Gates Foundation 
 
Your participation is voluntary 
You do not have to take part in this study.  If you decide today to take part in this research 
project, you may refuse to take part in any portion of the study or stop at any time without 
reducing or affecting any care that you receive at the health centers in your community.   
 
Purpose of the Research in the Communities 
The HPTN 071 or PopART study is testing a program to try to reduce HIV infection in a 
community like yours.  Twenty one communities that include about 600,000 adults are included 
in this research (about 400,000 adults in twelve Zambian communities and 200,000 adults in nine 
South African communities).  
 
In some communities, the level of care that people are used to will stay the same, in terms of 
HIV testing, and care of those who have HIV.  
 
In other communities, to make HIV testing easier, community health care workers will go to all 
homes and will offer to do an HIV test on each adult (or younger people with permission of 
guardian) wishing to have a test.  For anyone infected with HIV, they will be offered to start 
taking drugs to treat HIV according to the standard treatment guidelines that are in place for 
doing so in your country.  The health workers will visit every home again once a year for up to 
three more years to repeat the HIV testing and to refer people to care.   
 
In other communities, health care workers will go to all houses offering HIV testing, as was just 
described.  In these communities if someone tests HIV positive however, they will be offered to 
start taking medicines to treat HIV right away.  The health workers will visit every home again 
once a year for up to three more years to repeat the HIV testing and to refer people to care.   
 
At the end of the study, the researchers will see if offering HIV tests in each household and 
offering people the chance to start HIV treatment right away has reduced HIV infection. 
 
Your community is one of the communities participating in this research.  If health care workers 
are visiting homes in your community, you will notice that they provide some other information 
and services to people, but the most important thing is the testing and HIV treatment they offer. 
 
In each community, around 2,700 people will be asked to participate in additional activities such 
as completing questionnaires and providing additional samples for laboratory testing.  These 
questionnaires and tests will let the researchers understand how the community feels about the 
program and if the program is working.  You have been selected to be one of the people from 
your community who we are asking to participate in these additional activities.  That is why you 
are being asked to read this document.  
 
What will happen during this study? 
You will have one study visit which will occur today. This visit will take approximately 1 hour.  
During this visit, a researcher will ask you questions about sexual behavior, health services, 
previous HIV testing, HIV-related stigma and other HIV-related questions. 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
What are the possible risks or discomforts? 
The risk to you in participating in this study is that some of the questions may be uncomfortable 
and may make you feel worried or embarrassed. If any of the questions make you feel upset, the 
interviewer may go to another question or totally stop the interview. 
 
What are the potential benefits? 
You will not receive any direct benefit from being in this study. You or others may benefit in the 
future from the information learned in this study. 
 
Are there any alternatives to participation? 
If you decide not to participate in this study, you can still receive HIV tests and other services 
from your local health center. 
 
How will my confidentiality and privacy be protected? 
We cannot guarantee absolute confidentiality.  However, we will do everything possible to 
protect your confidentiality if you join this study. We do this by giving you a study number and 
any information you provide will be labeled with this number only, not your name. Only the 
research staff will be able to link this number to your name. Your personal information (name, 
address, phone number) will be protected by the research clinic. This information will not be 
used in any publication of information about this study. 
 
To protect your privacy, you will meet with the researcher in a private area where others cannot 
overhear conversations with you.   
 
People who may review your records include: [insert name of site IRB/EC], local regulatory 
agencies, US National Institutes of Health (NIH), study staff, and study monitors.  Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) are committees that watch over the safety 
and rights of research participants. 
 
What happens if I am injured by participating in this study? 
It is very unlikely that you could be injured as a result of participating in this study.  However, if 
you are injured while participating in this study, you will be given immediate treatment for your 
injuries.  You [will/will not] have to pay for this care.  There [is a/is no] program for 
compensation either through this institution or the United States NIH. You will not be giving up 
any of your legal rights by signing this Subject Information and Consent Form. 
 
What are some reasons why I may be withdrawn from this activity without my consent? 
You may be withdrawn from the study without your consent for the following reasons: 
 
• The research study, or this part of the study, is stopped or canceled 
• The study staff feels that completing the study or this part of the study would be harmful 
to you or others 
 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
Persons to Contact for Problems or Questions 
If you have any questions about your participation in this research study, your rights as a 
research subject, or if you feel that you have experienced a research-related injury, contact: 
 
Investigator of Record Name: 
(site insert name of the investigator or other study staff) 
 
Research Site Address(es): (site insert physical address of above) 
 
Daytime telephone number(s): 
(site insert telephone number) 
 
24-hour contact number(s): 
(site insert telephone number) 
 
If you have any questions or concerns about your rights as a research subject or want to discuss a 
problem, get information or offer input, you may contact: 
 
Independent Review Board/Ethics Committee: 
(site insert name or title of person on the 
IRB/EC or other organization appropriate for the site) 
 
Address of Independent Review Board:(site insert physical address of above) 
 
Daytime Telephone Number: 
(site insert telephone number of above) 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
SUBJECT’S STATEMENT OF CONSENT 
 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART): A 
cluster-randomized trial of the impact of a combination prevention package on population-
level HIV incidence in Zambia and South Africa 
 
• I have been given sufficient time to consider whether to take part in this study. 
• My taking part in this research study is voluntary.  I may decide not to take part or to 
withdraw from the research study at any time without penalty or loss of benefits or 
treatment to which I am entitled. 
• The research study may be stopped at any time without my consent. 
• I have had an opportunity to ask my study investigator questions about this research 
study.  My questions so far have been answered to my satisfaction. 
• I have been told how long I may be in the research study. 
• I have been informed of the procedures and tests that may be performed during the 
research study. 
• I have been told what the possible risks and benefits are from taking part in this research 
study.  I may not benefit if I take part in this research study. 
• I do not give up my legal rights by signing this form. 
• I have been told that before any study related procedures being performed, I will be asked 
to voluntarily sign this Subject Information and Consent Form. 
• I will receive a signed and dated copy of this Subject Information and Consent Form. 
 
If you have either read or have heard the information in this Subject Information and Consent 
Form, if all of your questions have been answered, and if you agree to take part in the study, 
please print and sign and your name and write the date on the line below. 
 
 
I voluntarily agree to take part in this research study. 
 
 
_______________________  
 
________________________________________ 
Subject’s Name (print) 
 
 
Subject’s Signature and Date 
 
I certify that the information provided was given in a language that was understandable to the 
subject. 
 
 
_______________________  
 
________________________________________ 
Name of Study Staff  
 
 
Study Staff Signature and Date 
Conducting Consent Discussion (print) 
 
 
_______________________  
 
________________________________________ 
Witness’ Name (print) 
 
 
Witness’ Signature and Date 
(As appropriate) Date 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
APPENDIX V - SAMPLE INFORMED CONSENT FORM –
PARTICIPANTS STARTING ART OUTSIDE OF LOCAL 
GUIDELINES 
 
NOTE: Sample informed consent forms are adapted from NIH templates.  It is understood that 
sites will modify these consents to meet the requirements of their setting and of their ethics 
committees.  Modifications made locally to prior versions of the consents that have already 
been approved for use in-country are expected to be maintained in subsequent site-specific 
consent versions. 
 
SUBJECT INFORMATION AND CONSENT FORM  
 
Title of Research Study: 
Population Effects of Antiretroviral Therapy to Reduce 
HIV Transmission (PopART): A cluster-randomized 
trial of the impact of a combination prevention package 
on population-level HIV incidence in Zambia and South 
Africa 
 
Protocol #: 
HPTN 071, Version 3.0   16 November 2015 
 
DAIDS ID: 11865 
 
Sponsor: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
(U.S. National Institutes of Health) 
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation  
 
Investigator of Record: 
(insert name) 
 
Research Site Address(es):  
(insert address) 
 
Daytime telephone number(s): 
(insert number) 
 
24-hour contact number(s): 
(insert number) 
 
Subject Information and Consent Form 
Please ask the study investigator or the study staff to explain any words or procedures that you 
do not clearly understand. 
 
The purpose of this form is to give you information about the research study you are being asked 
to join.  If you sign this form, you will be giving your permission to take part in the study.  The 
form describes the purpose, procedures, benefits, and risks of the research study.  You should 
take part in the study only if you want to do so.  You may choose not to join the research project 
or withdraw from this study at any time. Choosing not to take part in this research will not in any 
way affect the health care or benefits that you or your family will receive. Please read this 
Subject Information and Consent Form and ask as many questions as needed.  You should not 
sign this form if you have any questions that have not been answered to your satisfaction. 

 
HPTN 071 Version 3.0 
Page 142 of 166 
16 November 2015 
 
This study is being funded by the U.S. National Institutes of Health, the Office of the United 
States Global AIDS Coordinator, and the Bill and Melinda Gates Foundation. 
 
Your participation is voluntary 
You do not have to take part in this study.  If you decide today to take part in this research 
project, you may refuse to take part in any portion of the study or stop at any time without 
reducing or affecting any care that you receive at the clinics in your community.   
 
Purpose of the Research in the Communities 
The HPTN 071 or PopART study is testing a program to try to reduce HIV infection in a 
community like yours.  Twenty one communities that include about 600,000 adults are included 
in this research (about 400,000 adults in twelve Zambian communities and 200,000 adults in nine 
South African communities).  
 
In some communities, the level of care that people are used to will stay the same, in terms of 
HIV testing.  
 
In other communities, to make HIV testing easier, community health care workers will go to all 
homes and will offer to do an HIV test on each adult (or younger people with permission of 
guardian) wishing to have a test.  The health workers will visit every home again once a year for 
up to three more years to repeat the HIV testing and to refer people to care.   
 
In all communities in the study,  anyone infected with HIV will be offered to start taking 
medicines to treat HIV right away, even if local treatment guidelines would typically require 
people to wait before starting treatment.  Other studies have shown that if someone with HIV 
starts treatment right away, they are much less likely to pass HIV to their partner.   
 
At the end of the study, the researchers will see if offering HIV tests in each household and 
offering people the chance to start HIV treatment right away has reduced HIV infection. 
 
What will happen during this study? 
If you agree to participate in this study, you will start taking anti-HIV drugs immediately. Local 
guidelines suggest starting people on anti-HIV drugs when their immune cells, called CD4 cells, 
drop below a certain level.  So by agreeing to this study you would begin taking anti-HIV drugs 
sooner than if you waited for treatment under local guidelines.   
 
It is expected that local guidelines will change in the future to allow all HIV-infected patients to 
start taking anti-HIV drugs immediately.   This is because studies show that taking anti-HIV 
drugs improves the health of a person with HIV and prevents them from passing HIV to their 
partners.  But local guidelines have not changed yet. 
 
Your clinic visit schedule and routine health testing will occur according to the local standards at 
this clinic.   
 
What are the possible risks or discomforts? 
Anti-HIV Drugs: 

 
HPTN 071 Version 3.0 
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16 November 2015 
There are many drugs available to treat HIV and AIDS. The doctors in the clinic will determine 
the best combination of these drugs to treat you. It is possible that the drugs may make you feel 
sick or will affect your blood tests, in which case the doctors may either switch you to different 
drugs, or stop them all together. It is very important for you to return to the clinic whenever you 
feel sick. Feeling sick may be due to the pills or it may be due to a sickness caused by your HIV 
infection or it may be caused by something completely different, such as malaria. Either way, 
you should return to the clinic so that you can be treated. 
 
As with any medication, anti-HIV drugs can cause side effects. Most of the medicines for HIV 
are very safe and are well tolerated with only very few side effects. Some of these side effects 
are mild and may go away after you have taken the drugs for a few weeks. Examples of these 
types of side effects include upset stomach, vomiting, headache, and changes in your mood, 
sleep, or concentration. Other side effects can be severe but are rare and may require treatment or 
hospitalization. Examples of these types of side effects include rash, liver problems, severe 
depression or psychosis, and pancreas problems. 
 
If you take your anti-HIV medicines very regularly they will work and keep the amount of virus 
in your body low. If for any reason you do not keep taking the medicines every day, the amount 
of virus in your body can increase and the anti-HIV pills you are taking may stop working 
against the virus (the virus becomes resistant), and your doctors will have fewer medicines to 
choose from to try to keep you healthy. If that happens, the doctors will try to give you different 
drugs that will work.  
 
A doctor will explain all of the possible side-effects of any drugs before you begin taking them.  
 
There is a risk of serious and life-threatening side effects when other drugs are taken with anti-
HIV medications. For your safety, you must tell your doctor about all medications you are taking 
before you start taking anti-HIV medications. 
 
Risks Associated with Early versus Delayed Treatment with Anti-HIV Drugs: 
If you agree, you will begin taking anti-HIV drugs immediately. If you begin the drugs 
immediately, there is a chance that when you start taking the medicines, especially at the 
beginning, the drugs may make you feel sick. As with any medication some drugs may have side 
effects so severe that the nurse or doctor may need to take you off that drug and give you 
another. It is important that the medical teams check that the drugs you start taking are safe for 
you and change the drugs if they are not.  
It is really important that once you start taking anti-HIV medicines, you try to take them every 
single day and do not miss doses, share tablets with other people or suddenly stop them. If you 
take the tablets but only very irregularly then there is a chance that they will no longer work 
against your virus and the virus will becomes ‘resistant’ to the medicine. If this happens it limits 
the choices for other treatment and if it carries on there may be no medicines that can work to 
suppress your virus when you become sick. 
 
What are the potential benefits? 
At the moment, the national guidelines inform medical teams when to start ART and this is 
decided based on a measure of your immune system (CD4 cell count). Doctors and researchers 

 
HPTN 071 Version 3.0 
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16 November 2015 
are always trying to find better ways to keep people healthy and new research has shown that 
starting ART earlier may be better for your health.   
 
In addition to providing health benefits for you, taking ART to suppress the HIV virus has been 
shown to reduce the risk of passing on HIV to sexual partners or babies. Also, starting treatment 
early may help prevent Tuberculosis which occurs more often in people who are HIV positive. 
 
There is no cure for HIV and no method is 100% effective in preventing the spread of HIV, 
except abstinence. ART does not protect you from getting other infections that can be passed on 
through unprotected sex, so it is important to continue using condoms correctly during every sex 
act. 
 
Are there any alternatives to participation? 
If you do not agree to take anti-HIV drugs at this time, you can still be seen here at the health 
clinic for HIV care and you will be offered treatment according to the local guidelines. 
 
How will my confidentiality and privacy be protected? 
We cannot guarantee absolute confidentiality.  However, we will do everything possible to 
protect your confidentiality if you join this study. We do this by giving you a study number and 
any information will be labeled with this number only, so people working in the clinics and 
laboratories will only see a number not your name, only the research staff will be able to link this 
number to your name. Your personal information (name, address, phone number) will be 
protected by the research clinic. This information will not be used in any publication of 
information about this study. 
 
To protect your privacy, you will meet with the researcher in a private area where others cannot 
overhear conversations with you.   
 
People who may review your records include: [insert name of site IRB/EC], local regulatory 
agencies, US National Institutes of Health (NIH), study staff, and study monitors.  Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) are committees that watch over the safety 
and rights of research participants. 
 
What happens if I am injured by participating in this study? 
It is very unlikely that you could be injured as a result of participating in this study.  However, if 
you are injured while participating in this study, you will be given immediate treatment for your 
injuries.  You [will/will not] have to pay for this care.  There [is a/is no] program for 
compensation either through this institution or the United States NIH. You will not be giving up 
any of your legal rights by signing this Subject Information and Consent Form. 
 
What are some reasons why I may be withdrawn from this  study without my consent? 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
If you agree to begin taking anti-HIV drugs at this time, your only study activity will be to start 
ART earlier than suggested by local guidelines. You will not be taken off ART if the study ends 
early or at the natural end of the study. Your usual care will continue at the health center, 
including receiving ART.  Your ART will only stop or change if your health care provider 
decides that it is important to do so for your health. 
 
Persons to Contact for Problems or Questions 
If you have any questions about your participation in this research study, your rights as a 
research subject, or if you feel that you have experienced a research-related injury, contact: 
 
Investigator of Record Name: 
(site insert name of the investigator or other study staff) 
 
Research Site Address(es): (site insert physical address of above) 
 
Daytime telephone number(s): 
(site insert telephone number) 
 
24-hour contact number(s): 
(site insert telephone number) 
 
If you have any questions or concerns about your rights as a research subject or want to discuss a 
problem, get information or offer input, you may contact: 
 
Independent Review Board/Ethics Committee: 
(site insert name or title of person on the 
IRB/EC or other organization appropriate for the site) 
 
Address of Independent Review Board:(site insert physical address of above) 
 
Daytime Telephone Number: 
(site insert telephone number of above) 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
SUBJECT’S STATEMENT OF CONSENT 
 
Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART): A 
cluster-randomized trial of the impact of a combination prevention package on population-
level HIV incidence in Zambia and South Africa 
 
• I have been given sufficient time to consider whether to take part in this study. 
• My taking part in this research study is voluntary.  I may decide not to take part or to 
withdraw from the research study at any time without penalty or loss of benefits or 
treatment to which I am entitled. 
• The research study may be stopped at any time without my consent. 
• I have had an opportunity to ask my study investigator questions about this research 
study.  My questions so far have been answered to my satisfaction. 
• I have been told how long I may be in the research study. 
• I have been informed of the procedures and tests that may be performed during the 
research study. 
• I have been told what the possible risks and benefits are from taking part in this research 
study.  I may not benefit if I take part in this research study. 
• I do not give up my legal rights by signing this form. 
• I have been told that before any study related procedures being performed, I will be asked 
to voluntarily sign this Subject Information and Consent Form. 
• I will receive a signed and dated copy of this Subject Information and Consent Form. 
 
If you have either read or have heard the information in this Subject Information and Consent 
Form, if all of your questions have been answered, and if you agree to take part in the study, 
please print and sign and your name and write the date on the line below. 
 
 
I voluntarily agree to take part in this research study. 
 
 
_______________________  
 
________________________________________ 
Subject’s Name (print) 
 
 
Subject’s Signature and Date 
 
I certify that the information provided was given in a language that was understandable to the 
subject. 
 
 
_______________________  
 
________________________________________ 
Name of Study Staff  
 
 
Study Staff Signature and Date 
Conducting Consent Discussion (print) 
 
 
_______________________  
 
________________________________________ 
Witness’ Name (print) 
 
 
Witness’ Signature and Date 
(As appropriate) Date 
 

 
HPTN 071 Version 3.0 
Page 147 of 166 
16 November 2015 
 
 
APPENDIX VI - SAMPLE INFORMED CONSENT FORM – CHIP 
TEAM ACTIVITIES 
 
NOTE: Sample informed consent forms are adapted from NIH templates.  It is understood that 
sites will modify these consents to meet the requirements of their setting and of their ethics 
committees.  Modifications made locally to prior versions of the consents that have already 
been approved for use in-country are expected to be maintained in subsequent site-specific 
consent versions. 
 
SUBJECT INFORMATION SHEET  
 
Title of Research Study: 
Population Effects of Antiretroviral Therapy to Reduce 
HIV Transmission (PopART): A cluster-randomized 
trial of the impact of a combination prevention package 
on population-level HIV incidence in Zambia and South 
Africa 
 
Protocol #: 
HPTN 071, Version 3.0   16 November 2015 
 
DAIDS ID: 11865 
 
Sponsor: 
National Institute of Allergy and Infectious Diseases 
National Institute of Mental Health  
(U.S. National Institutes of Health)  
Office of the United States Global AIDS Coordinator 
Bill and Melinda Gates Foundation 
 
Investigator of Record: 
(insert name) 
 
Research Site Address(es):  
(insert address) 
 
Daytime telephone number(s): 
(insert number) 
 
24-hour contact number(s): 
(insert number) 
 
What is the PopART study? 
 
• HIV is still a big problem in Zambia and South Africa 
• We now have good treatment (called ART) for people living with HIV which is freely available 
from health facilities. 
• There are various methods that are known to help prevent someone from catching HIV such 
as using condoms, male circumcision and prevention of mother to child transmission (PMTCT) 
programs  
• Getting people who are HIV positive onto treatment earlier may also help to prevent them from 
infecting their partners. 

 
HPTN 071 Version 3.0 
Page 148 of 166 
16 November 2015 
• It has been suggested that combining these HIV prevention strategies and offering ART to all 
people who test HIV positive right away might lead to a big reduction in the number of new 
HIV infections in the community.  
 
The PopART study will try to answer the above question. Its purpose is to find out if offering HIV 
tests in each household and offering people the chance to start HIV treatment right away can 
reduce HIV infection in a community like yours.  
 
Where and who is conducting this study? 
 
This study is being carried out in two countries, Zambia and South Africa, for a period of about 5 
years from 2012 to 2017. It will be done in 21 communities, 12 of which are in Zambia and 9 in 
South Africa. Researchers from the Zambia AIDS Related Tuberculosis (ZAMBART) Project 
and the Desmond Tutu TB Centre (DTTC) at Stellenbosch University, South Africa, will work 
closely together with colleagues from different institutions including the Ministry of Health 
(Zambia) and the Department of Health (South Africa). This study is being funded by the U.S. 
National Institutes of Health, the Office of the United States Global AIDS Coordinator, and the 
Bill and Melinda Gates Foundation. 
 
How is the study being carried out? 
 
• The PopART study has 3 Arms (Arms A, B and C). In each arm a package of HIV prevention 
services will be available including HIV testing, care and treatment, male circumcision, 
PMTCT and condoms: 
o In Arm C all of these activities will be available at the health facility. In arms A and B, 
community HIV workers (called CHiPs) will visit each household and offer HIV 
testing in the home and help people to link to care services at the health facility or in 
the community. 
o In all arms of the study, people who are HIV-positive will receive ART from the health 
facility. In Arms B and C this will be for all people who have a CD4 cell count below 
the threshold set bylocal guidelines. In Arm A, ALL people who are HIV-positive will 
be offered ART at any CD4 cell count.   
o In Arms A and B, the CHiP teams will encourage pregnant women who are met during 
regular household visits, to attend an antenatal clinic in their community. 
• The 21 study communities were put in these arms using a process called randomization, which 
is like a lottery. Your community was put in Arm [A/B]. 
 
The CHiPs worker is your link to all of these services. If you agree, they will visit your house 
regularly. They will take down the names and basic information of all household members. This 
is to ensure that the CHiPs do not miss some members of the household now or in future.  
 
The CHiPs will ask all household members to participate in a health education session in the home. 
CHiPs will also offer HIV testing to everyone in the home.  CHiPs will refer household members 
to care based upon their health needs.  For example, if a person is HIV positive, the CHiP will 
refer them for care or treatment at the local clinic.CHiPs can also be contacted at any time if you 
have specific questions or need help with accessing care.  Household members may choose not to 
receive any services recommended by the CHiPs without penalty. 

 
HPTN 071 Version 3.0 
Page 149 of 166 
16 November 2015 
 
CHiPs will seek permission from each person in the household to ask additional health-related 
questions and record those answers in an electronic device to help provide better services. This is 
described more fully below.  
 
How will the researchers find out if the program worked? 
 
To find out if the PopART program works in reducing the number of HIV infections, some people 
in the community will be asked to take part in some special studies. If you are chosen for one of 
these studies, you will be asked to choose whether or not to take part in that study. But right now, 
we are only asking if you will let us collect some health information from you as part of the CHiPs 
program. 
 
What will happen if I agree to having my health information recorded in the electronic 
device? 
 
You are being asked for your permission to let the CHiPs ask additional health-related questions 
and record your health data in an electronic device.  For example, we will ask you if you have  
symptoms of TB or sexually transmitted infections. The additional questions will help us 
understand your health history better and provide you with better referrals for care.  For example 
if you have symptoms of TB, we will ask you to produce a sputum sample by coughing that can 
be tested in the laboratory, and if it is positive for TB, we will tell you and refer you to the clinic 
for care.   
 
Recording your answers in the electronic device will allow us to follow up and make sure you 
receive care for any referrals we make.  The data on the electronic device can only be seen by 
authorized staff with a secret password. We may follow up by coming back to the house and 
asking you whether you received care, or we may get this information from the health center.  If 
we get this information from the health center, the information collected will all be kept 
confidential.  
 
Allowing CHiPs to collect your health information in this way is voluntary and therefore you are 
completely free to refuse to take part. 
 
CHiP teams will follow national requirements to notify local health authorities when a TB case 
is identified. 
 
Risks and Benefits 
 
There are unlikely to be additional risks other than those associated with HIV testing, care and 
treatment.  
 
Both HIV positive and negative individuals will benefit from the linkages to care provided by 
the CHiPs program. In addition, taking ART reduces the likelihood that HIV will be passed on 
to a sexual partner or baby.  
 
Persons to Contact for Problems or Questions 

 
HPTN 071 Version 3.0 
Page 150 of 166 
16 November 2015 
If you have any questions about this research study, your rights, or if you feel that you have 
experienced a research-related injury, contact: 
 
Investigator of Record Name: 
(site insert name of the investigator or other study staff) 
 
Research Site Address(es): (site insert physical address of above) 
 
Daytime telephone number(s): 
(site insert telephone number) 
 
24-hour contact number(s): 
(site insert telephone number) 
 
If you have any questions or concerns about your rights or want to discuss a problem, get 
information or offer input, you may contact: 
 
Independent Review Board/Ethics Committee: 
(site insert name or title of person on the 
IRB/EC or other organization appropriate for the site) 
 
Address of Independent Review Board:(site insert physical address of above) 
 
Daytime Telephone Number: 
(site insert telephone number of above) 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
 
Verbal Consent Administered by CHiPs 
 
As you have heard from the information leaflet you have just read/ I have just read to you, I am 
one of the CHiPs working with the PoPART study in this community. Now I would like to find 
out if you have understood this information and if you would like to take part in this CHiPs 
program. 
 
[CHiP records in a log the decision by the participant(s)] 
 
Parent or Guardian Verbal Consent for Minors to Participate in the Intervention: 
As a parent or guardian, you are being asked if you give your permission for the child in your 
care to participate in the CHiPs program.  The procedures, risks and benefits for your child 
would be the same as has just been described. 
 
If you do not give permission for your child to participate in the CHiPs program, we will still 
offer to provide him/her health screening here at the household. However, we would not have 
information to allow us to check that your child has received the care they need. 
 
Now I will ask you if you have understood this information and whether you consent for your 
child to participate in the CHiPs program. 
 
Do you give your consent (permission) for your child’s participation in the CHiPs program? 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
APPENDIX VII – SAMPLE SIZE CALCULATIONS 
 
(1) Primary endpoint - HIV incidence over 36 months 
 
N=2500 individuals in population cohort, 85% HIV-negative at baseline, 25% loss to follow-
up by 36 months; 5206 person-years per community over 36 months (assuming 1912 person-
years 0-12 months; 1700 person-years 12-24 months; 1594 person-years 24-36 months) 
 
 
 

 
HPTN 071 Version 3.0 
Page 153 of 166 
16 November 2015 
(a) Comparison between Arms A or B and Arm C 
HIV 
incidence 
rate/ 100py 
(control 
arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness 
(%) 
 
Power (%) 
 
1.0 
0.15 
30% 
74% 
1.0 
0.15 
35% 
87% 
1.0 
0.15 
40% 
95% 
1.0 
0.15 
45% 
99% 
1.0 
0.15 
50% 
100% 
1.0 
0.15 
55% 
100% 
1.0 
0.15 
60% 
100% 
1.0 
0.15 
65% 
100% 
 
 
 
 
1.0 
0.20 
30% 
60% 
1.0 
0.20 
35% 
75% 
1.0 
0.20 
40% 
87% 
1.0 
0.20 
45% 
94% 
1.0 
0.20 
50% 
98% 
1.0 
0.20 
55% 
99% 
1.0 
0.20 
60% 
100% 
1.0 
0.20 
65% 
100% 
 
 
 
 
1.5 
0.15 
30% 
81% 
1.5 
0.15 
35% 
92% 
1.5 
0.15 
40% 
98% 
1.5 
0.15 
45% 
100% 
1.5 
0.15 
50% 
100% 
1.5 
0.15 
55% 
100% 
1.5 
0.15 
60% 
100% 
1.5 
0.15 
65% 
100% 
 
 
 
 
1.5 
0.20 
30% 
65% 
1.5 
0.20 
35% 
80% 
1.5 
0.20 
40% 
91% 
1.5 
0.20 
45% 
96% 
1.5 
0.20 
50% 
99% 
1.5 
0.20 
55% 
100% 
1.5 
0.20 
60% 
100% 
1.5 
0.20 
65% 
100% 
 
 
 

 
HPTN 071 Version 3.0 
Page 154 of 166 
16 November 2015 
(b) Comparison between Arms A and B 
HIV 
incidence 
rate/ 100py 
(control 
arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness 
(%) 
Arm A 
Effectiveness 
(%) 
Arm B 
Power (%) 
 
1.0 
0.15 
50% 
20% 
89% 
1.0 
0.15 
50% 
25% 
78% 
1.0 
0.15 
55% 
25% 
92% 
1.0 
0.15 
55% 
30% 
82% 
1.0 
0.15 
60% 
25% 
98% 
1.0 
0.15 
60% 
30% 
94% 
 
 
 
 
 
1.0 
0.20 
50% 
20% 
78% 
1.0 
0.20 
50% 
25% 
65% 
1.0 
0.20 
55% 
25% 
83% 
1.0 
0.20 
55% 
30% 
71% 
1.0 
0.20 
60% 
25% 
93% 
1.0 
0.20 
60% 
30% 
87% 
 
 
 
 
 
1.5 
0.15 
50% 
20% 
94% 
1.5 
0.15 
50% 
25% 
86% 
1.5 
0.15 
55% 
25% 
96% 
1.5 
0.15 
55% 
30% 
90% 
1.5 
0.15 
60% 
25% 
99% 
1.5 
0.15 
60% 
30% 
98% 
 
 
 
 
 
1.5 
0.20 
50% 
20% 
84% 
1.5 
0.20 
50% 
25% 
72% 
1.5 
0.20 
55% 
25% 
88% 
1.5 
0.20 
55% 
30% 
78% 
1.5 
0.20 
60% 
25% 
96% 
1.5 
0.20 
60% 
30% 
92% 
 
 
(2A) HIV incidence during months 12-24 from start of intervention 
 
Number of person-years of follow-up in each community = 1700 during months 12-24 from 
start of intervention 
 
 
 

 
HPTN 071 Version 3.0 
Page 155 of 166 
16 November 2015 
(a) Comparison between Arms A or B and Arm C 
HIV 
incidence 
rate/ 100py 
(control 
arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
 
Power (%) 
 
1.0 
0.15 
35% 
59% 
1.0 
0.15 
40% 
72% 
1.0 
0.15 
45% 
83% 
1.0 
0.15 
50% 
91% 
1.0 
0.15 
55% 
96% 
1.0 
0.15 
60% 
98% 
1.0 
0.15 
65% 
99% 
1.0 
0.15 
70% 
100% 
 
 
 
 
1.0 
0.20 
35% 
51% 
1.0 
0.20 
40% 
64% 
1.0 
0.20 
45% 
76% 
1.0 
0.20 
50% 
85% 
1.0 
0.20 
55% 
92% 
1.0 
0.20 
60% 
96% 
1.0 
0.20 
65% 
99% 
1.0 
0.20 
70% 
100% 
 
 
 
 
1.5 
0.15 
35% 
71% 
1.5 
0.15 
40% 
83% 
1.5 
0.15 
45% 
92% 
1.5 
0.15 
50% 
97% 
1.5 
0.15 
55% 
99% 
1.5 
0.15 
60% 
100% 
1.5 
0.15 
65% 
100% 
1.5 
0.15 
70% 
100% 
 
 
 
 
1.5 
0.20 
35% 
61% 
1.5 
0.20 
40% 
74% 
1.5 
0.20 
45% 
85% 
1.5 
0.20 
50% 
92% 
1.5 
0.20 
55% 
97% 
1.5 
0.20 
60% 
99% 
1.5 
0.20 
65% 
100% 
1.5 
0.20 
70% 
100% 
 
  
 

 
HPTN 071 Version 3.0 
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16 November 2015 
(b) Comparison between Arms A and B 
HIV 
incidence 
rate/ 100py 
(control 
arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
Arm A 
Effectiveness (%) 
Arm B 
Power (%) 
 
1.0 
0.15 
60% 
25% 
77% 
1.0 
0.15 
60% 
30% 
66% 
1.0 
0.15 
65% 
30% 
81% 
1.0 
0.15 
65% 
35% 
71% 
1.0 
0.15 
70% 
30% 
92% 
1.0 
0.15 
70% 
35% 
85% 
 
 
 
 
 
1.0 
0.20 
60% 
25% 
71% 
1.0 
0.20 
60% 
30% 
61% 
1.0 
0.20 
65% 
30% 
76% 
1.0 
0.20 
65% 
35% 
66% 
1.0 
0.20 
70% 
30% 
88% 
1.0 
0.20 
70% 
35% 
81% 
 
 
 
 
 
1.5 
0.15 
60% 
25% 
89% 
1.5 
0.15 
60% 
30% 
80% 
1.5 
0.15 
65% 
30% 
92% 
1.5 
0.15 
65% 
35% 
84% 
1.5 
0.15 
70% 
30% 
98% 
1.5 
0.15 
70% 
35% 
94% 
 
 
 
 
 
1.5 
0.20 
60% 
25% 
82% 
1.5 
0.20 
60% 
30% 
72% 
1.5 
0.20 
65% 
30% 
86% 
1.5 
0.20 
65% 
35% 
78% 
1.5 
0.20 
70% 
30% 
95% 
1.5 
0.20 
70% 
35% 
90% 
 
 
(2B) HIV incidence during months 24-36 from start of intervention 
 
Number of person-years of follow-up in each community = 1594 during months 24-36 from 
start of intervention 
 
  
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
(a) Comparison between Arms A or B and Arm C 
HIV 
incidence 
rate/ 100py 
(control 
arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
 
Power (%) 
 
1.0 
0.15 
35% 
57% 
1.0 
0.15 
40% 
70% 
1.0 
0.15 
45% 
81% 
1.0 
0.15 
50% 
89% 
1.0 
0.15 
55% 
95% 
1.0 
0.15 
60% 
98% 
1.0 
0.15 
65% 
99% 
1.0 
0.15 
70% 
100% 
 
 
 
 
1.0 
0.20 
35% 
50% 
1.0 
0.20 
40% 
62% 
1.0 
0.20 
45% 
74% 
1.0 
0.20 
50% 
84% 
1.0 
0.20 
55% 
91% 
1.0 
0.20 
60% 
96% 
1.0 
0.20 
65% 
98% 
1.0 
0.20 
70% 
99% 
 
 
 
 
1.5 
0.15 
35% 
69% 
1.5 
0.15 
40% 
82% 
1.5 
0.15 
45% 
91% 
1.5 
0.15 
50% 
96% 
1.5 
0.15 
55% 
99% 
1.5 
0.15 
60% 
100% 
1.5 
0.15 
65% 
100% 
1.5 
0.15 
70% 
100% 
 
 
 
 
1.5 
0.20 
35% 
60% 
1.5 
0.20 
40% 
73% 
1.5 
0.20 
45% 
84% 
1.5 
0.20 
50% 
92% 
1.5 
0.20 
55% 
96% 
1.5 
0.20 
60% 
99% 
1.5 
0.20 
65% 
100% 
1.5 
0.20 
70% 
100% 
 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
(b) Comparison between Arms A and B 
HIV 
incidence 
rate/ 100py 
(control 
arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
Arm A 
Effectiveness (%) 
Arm B 
Power (%) 
 
1.0 
0.15 
60% 
25% 
75% 
1.0 
0.15 
60% 
30% 
64% 
1.0 
0.15 
65% 
30% 
79% 
1.0 
0.15 
65% 
35% 
69% 
1.0 
0.15 
70% 
30% 
90% 
1.0 
0.15 
70% 
35% 
84% 
 
 
 
 
 
1.0 
0.20 
60% 
25% 
69% 
1.0 
0.20 
60% 
30% 
59% 
1.0 
0.20 
65% 
30% 
74% 
1.0 
0.20 
65% 
35% 
64% 
1.0 
0.20 
70% 
30% 
86% 
1.0 
0.20 
70% 
35% 
79% 
 
 
 
 
 
1.5 
0.15 
60% 
25% 
87% 
1.5 
0.15 
60% 
30% 
78% 
1.5 
0.15 
65% 
30% 
90% 
1.5 
0.15 
65% 
35% 
82% 
1.5 
0.15 
70% 
30% 
97% 
1.5 
0.15 
70% 
35% 
93% 
 
 
 
 
 
1.5 
0.20 
60% 
25% 
81% 
1.5 
0.20 
60% 
30% 
71% 
1.5 
0.20 
65% 
30% 
85% 
1.5 
0.20 
65% 
35% 
76% 
1.5 
0.20 
70% 
30% 
94% 
1.5 
0.20 
70% 
35% 
89% 
 
 
 
 

 
HPTN 071 Version 3.0 
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16 November 2015 
(3A) Community viral load 24 months after start of intervention  
 
N=300 HIV-positive individuals in each community 
 
 (a) Comparison between Arms A or B and Arm C 
Percentage with 
undetectable 
viral load 
(control arm) 
Between-cluster 
coefficient of 
variation (k) 
Percentage with 
undetectable 
viral load, Arm A 
or B 
Power (%) 
20% 
0.15 
40% 
99% 
20% 
0.15 
60% 
99% 
20% 
0.20 
40% 
99% 
20% 
0.20 
60% 
99% 
 
(b) Comparison between Arms A and B 
Between-
cluster 
coefficient 
of variation 
(k) 
Percentage 
with 
undetectable 
viral load, 
Arm A 
Percentage 
with 
undetectable 
viral load, 
Arm B 
Power (%) 
0.15 
60% 
40% 
97% 
0.20 
60% 
40% 
85% 
 
(3B) Community viral load 12 and 36 months after start of intervention 
 
N=approximately 75 HIV-positive individuals in each community 
 
(a) Comparison between Arms A or B and Arm C 
Percentage 
with 
undetectable 
viral load 
(control arm) 
Between-
cluster 
coefficient 
of variation 
(k) 
Percentage 
with 
undetectable 
viral load, 
Arm A or B 
Power (%) 
20% 
0.15 
40% 
99% 
20% 
0.15 
60% 
99% 
20% 
0.20 
40% 
97% 
20% 
0.20 
60% 
99% 
 
(b) Comparison between Arms A and B 
Between-
cluster 
coefficient 
of variation 
(k) 
Percentage 
with 
undetectable 
viral load, 
Arm A 
Percentage 
with 
undetectable 
viral load, 
Arm B 
Power (%) 
0.15 
60% 
40% 
91% 

 
HPTN 071 Version 3.0 
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16 November 2015 
0.20 
60% 
40% 
77% 
 
(4) HSV2 incidence over 36 months 
 
Number of person-years of follow-up in each community = 1837 over 36 months 
 
Comparison between Arms A or B and Arm C 
HSV2 incidence 
rate/ 100py 
(control arm) 
Between-cluster 
coefficient of 
variation (k) 
HSV2 incidence 
rate / 100py, 
Arm A or Arm B 
Power (%) 
5.0 
0.15 
3.0 
98% 
5.0 
0.15 
7.5 
94% 
5.0 
0.20 
3.0 
92% 
5.0 
0.20 
7.5 
81% 
 
(5) Retention in HIV care, and viral load suppression and drug resistance among HIV-
positive individuals who are taking ART – measured among HIV-positive members of 
the Population Cohort 
 
(i) Retention in HIV care 12 months after registering for HIV care 
 
N=198 in each community in Arm A and B; N=99 in each community in Arm C 
 
This assumes:  N=375 HIV-positive individuals per community in the population cohort; 
that 65% of these individuals are not yet registered at the clinic for HIV care (N=244); that 
among these 244 individuals, in Arms A and B 90% subsequently register at the clinic for 
HIV care (N=220) and in Arm C 45% subsequently register at the clinic for HIV care 
(N=110), and that 10% cannot be included in analysis due to migration out of the 
community, giving N=198 included in analysis in Arms A and B and N=99 included in 
analysis in Arm C 
 
Comparison between Arm A or Arm B, with Arm C 
Percentage 
retained in care 
(control arm) 
Between-cluster 
coefficient of 
variation (k) 
Percentage 
retained in care, 
Arm A or Arm B 
Power (%) 
80% 
0.20 
70% 
71% 
80% 
0.20 
90% 
94% 
85% 
0.20 
75% 
85% 
85% 
0.20 
95% 
99% 
90% 
0.20 
80% 
96% 
90% 
0.20 
95% 
79% 
 
(ii) Viral load suppression and drug resistance, measured among HIV-positive 
members of the Population Cohort at 24 months 
 

 
HPTN 071 Version 3.0 
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Calculations assume that, among population cohort members, N=220 HIV-positive 
individuals per community register for HIV care for the first time in Arms A and B and 
N=110 in Arm C, as above. 
 
It is further assumed that, by the time of the 24-month follow-up in the population cohort, 
67% of such patients will have started ART in Arm C, 50% in Arm B, and 80% in Arm A; 
and that 80% of such patients will participate in the Population Cohort at 24 months (PC24). 
This gives N=141, N=88, and N=59 per community in Arms A, B, and C respectively, for 
viral load and drug resistance measurement at PC24. 
 
(a) Comparison between Arm A and Arm C 
Percentage with 
detectable viral 
load (control 
arm) 
Between-cluster 
coefficient of 
variation (k) 
Percentage with 
detectable viral 
load, Arm A 
Power (%) 
5% 
0.20 
10% 
72% 
5% 
0.20 
2.5% 
39% 
10% 
0.20 
20% 
91% 
10% 
0.20 
15% 
45% 
10% 
0.20 
5% 
63% 
 
(b) Comparison between Arm B and Arm C 
Percentage with 
detectable viral 
load (control 
arm) 
Between-cluster 
coefficient of 
variation (k) 
Percentage with 
detectable viral 
load, Arm B 
Power (%) 
5% 
0.20 
10% 
64% 
5% 
0.20 
2.5% 
36% 
10% 
0.20 
20% 
86% 
10% 
0.20 
15% 
40% 
10% 
0.20 
5% 
60% 
 
(6) Prevalence of bacteriologically-confirmed pulmonary tuberculosis 36 months after 
start of intervention 
 
Calculations assume 4250 adults included in TB prevalence survey in each community 
Pulmonary TB 
prevalence 
(control arm) 
Between-cluster 
coefficient of 
variation (k) 
Effectiveness 
(%) 
 
Pulmonary TB 
prevalence (Arm 
A, or Arm B) 
Power (%) 
1.00% 
0.25 
40% 
0.60% 
73% 
1.00% 
0.25 
45% 
0.55% 
84% 
1.00% 
0.25 
50% 
0.50% 
91% 
0.80% 
0.25 
40% 
0.48% 
69% 
0.80% 
0.25 
45% 
0.44% 
81% 
0.80% 
0.25 
50% 
0.40% 
89% 

 
HPTN 071 Version 3.0 
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16 November 2015 
 
(7) HIV-free child survival among children born during the 36 months of trial 
intervention 
 
Calculations assume 229 person-years of follow-up on HIV-free child survival, among 
children born to HIV-positive mothers, in each community 
 
Comparison between Arm A or Arm B, with Arm C 
Rate of child mortality 
and/or HIV infection 
per 100py, among 
children born to HIV-
positive mother 
(control arm) 
Between-
cluster 
coefficient of 
variation (k) 
Effectiveness (%) 
 
Power (%) 
11 
0.15 
35% 
71% 
11 
0.15 
40% 
83% 
11 
0.15 
45% 
92% 
11 
0.15 
50% 
97% 
11 
0.20 
35% 
61% 
11 
0.20 
40% 
74% 
11 
0.20 
45% 
85% 
11 
0.20 
50% 
92% 
10 
0.15 
35% 
68% 
10 
0.15 
40% 
81% 
10 
0.15 
45% 
90% 
10 
0.15 
50% 
96% 
10 
0.20 
35% 
59% 
10 
0.20 
40% 
72% 
10 
0.20 
45% 
83% 
10 
0.20 
50% 
91% 
9 
0.15 
35% 
65% 
9 
0.15 
40% 
78% 
9 
0.15 
45% 
88% 
9 
0.15 
50% 
94% 
9 
0.20 
35% 
56% 
9 
0.20 
40% 
69% 
9 
0.20 
45% 
81% 
9 
0.20 
50% 
89% 
 
 
 
 

 
HPTN 071 Version 3.0 
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APPENDIX VIII - PROPOSED POPULATION CROSS-SECTIONAL 
SURVEY 
Because participants in the Population Cohort will be followed longitudinally over three years, 
their interactions with the research staff could bias the data they provide for certain outcome 
measures.  The Population Cross-Sectional Survey, if funded, would be a snapshot evaluation to 
provide unbiased data for comparison on many of the measures evaluated in the Population 
Cohort.   
 
Analyses for process measures, secondary outcome measures, and the Schedule of Study Visits 
and Procedures planned for the Population Cross-Sectional Survey are provided below. 
 
Statistical Analysis of Process Measures in the Population Cross-Sectional Survey at 36 
Months (Arms A, B, and C) 
With a sample size of 500 adults aged 18-44 in the Population Cross-Sectional Survey in 
each community, estimates will be obtained for each trial arm of (i) the percentage of the 
adult population who have accessed HIV counseling and testing (HCT) services during 
the 36 months of trial intervention (ii) the percentage of HIV-infected individuals who 
have been screened for ART eligibility during the 36 months of trial intervention (iii) the 
percentage of HIV-infected individuals who are on ART at the time of the cross-sectional 
survey, and (iv) the percentage of initially uncircumcised men who have had medical 
male circumcision during the 36 months of trial intervention. 
(i) 
HIV testing uptake 
 
Assuming that the uptake of HIV testing during the past 36 months is 50% in Arm 
C, compared with 70% in each of Arm A and Arm B, and that k=0.2, there is 73% 
power to show an effect of the CHiP intervention on testing uptake. With higher 
testing uptake of 80% in each of Arm A and Arm B, there is 94% power to show 
an effect of the CHiP intervention. 
 
(ii) 
Screening for ART eligibility, and uptake of ART, among HIV-infected 
individuals 
On average there will be 75 HIV-infected individuals (15% of 500) included in 
the Population Cross-Sectional Survey in each community. Assuming that 25% 
were already on ART at the start of the trial, on average 56 will have been ART-
naïve at the start of the trial. With the percentage screened for ART eligibility 
70% or higher in Arm B, and 40% or lower in Arm C, and k=0.2, study power is 
at least 95% to show an effect of the trial intervention on the uptake of ART 
eligibility screening. Similarly, with the percentage started on ART 70% or higher 
in Arm A, and 40% or lower in Arm C, and k=0.2, study power is at least 95% to 
show an effect of the trial intervention on ART uptake. 

 
HPTN 071 Version 3.0 
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16 November 2015 
(iii) 
Male circumcision 
On average there will be 250 men in the Population Cross-Sectional Survey. In 
the Western Cape trial communities, approximately 49 will be HIV-uninfected 
and not circumcised prior to the start of the PopART trial and approximately 185 
in the Zambian trial communities, giving a harmonic mean of 91 in each 
community. With the uptake of medical male circumcision 40% or more in each 
of Arms A and B, but 25% or less in Arm C, and k=0.2, study power is at least 
82% to show an effect of the trial intervention. 
 
Outcomes for Secondary Objectives 
 
• Community viral load (subject to funding) 
o Viral load in approximately 75 HIV-infected individuals per cluster at 36 
months in the Population Cross-Sectional Survey 
• ART adherence and viral suppression 
o HIV viral load at 36 months in HIV-infected members of the Population 
Cross-Sectional Survey who initiated HIV care and ART after 
commencement of the PopART intervention in the community (subject to 
funding) 
o Self-reported adherence to ART in HIV infected members of the  
Population Cross-Sectional Survey who initiated HIV care and ART after 
commencement of the PopART intervention in the community, measured 
at 36 months  
• ARV drug resistance (subject to funding) 
o ARV drug resistance at 36 months in HIV-infected members of the 
Population Cross-Sectional Survey who initiated HIV care and ART after 
commencement of the PopART intervention in the community, among 
individuals who are not virally suppressed at 36 months  
• HIV disease progression 
o CD4 cell counts, WHO staging events, and retention in care among 
members of the Population Cross-Sectional Survey initiating ART after 
commencement of the PopART intervention in the community, measured 
using routine health center data (consent to use linked routine clinical data 
required) 
• ART toxicity  
o ART safety and clinical events among members of the Population Cross-
Sectional Survey initiating ART after commencement of the PopART 
intervention in the community, measured using routine health center and 
laboratory data (consent to use linked clinical data required)  

 
HPTN 071 Version 3.0 
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16 November 2015 
• Sexual risk behavior 
o Self-reported sexual risk behavior at 36 months in the Population Cross-
Sectional Survey 
• HIV-related stigma  
o Answers to questionnaire evaluating stigma at 36 months in the 
Population Cross-Sectional Survey 
• Uptake of PMTCT 
o Self-reported use of services for PMTCT among HIV-infected women in 
the Population Cross-Sectional Survey who had been pregnant in the prior 
36 months 
• Uptake of male circumcision 
o Self-reported circumcision uptake in the prior 36 months of men in the 
Population Cross-Sectional Survey  
• ART screening and uptake 
o The proportion of members of the Population Cross-Sectional Survey 
identified as HIV-infected who have been screened for ART eligibility, 
and who subsequently initiated ART 
• HIV testing and retesting 
o Self-report of prior HIV testing  at 36 months in the Population Cross-
Sectional Survey  
• Time between HIV diagnosis and initiation of care 
o The proportion of members of the Population Cross-Sectional Survey 
initiating HIV care within 3 months of a positive HIV diagnosis  
• Other testing may be performed using stored samples, as noted in the Section 9. 
 
 

 
HPTN 071 Version 3.0 
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SCHEDULE OF STUDY VISITS AND PROCEDURES:  
PROPOSED POPULATION CROSS-SECTIONAL SURVEY-ALL 
ARMS 
PROCEDURES 
Single Visit 
at 36 Month 
Time Point 
ADMINISTRATIVE, BEHAVIORAL, AND REGULATORY 
PROCEDURES 
 
Obtain informed consent for enrollment.   
Solicit consent for storage of specimens for future testing and for access to data 
collected at health centers 
X 
Obtain locator information. 
X 
Administer survey to include socio-demographic, health, social, behavioral, and 
economic factors 
X 
CLINICAL/COUNSELING PROCEDURES 
 
Perform HIV rapid testing1   
X 
Collect blood for laboratory testing and sample storage 
X 
Provide HIV pre- and post-test counseling and HIV rapid test results, for those 
willing to receive results. 
X 
LABORATORY PROCEDURES 
 
HIV testing2 
X 
Plasma storage3  
X 
 
 
 
 
 
 
 
Footnotes for the Population Cross-Sectional Survey 
1 Rapid testing will be offered at home visits and performed according to in-country guidelines. This 
testing will not be used to estimate HIV incidence or prevalence; however, the data may be 
captured along with other data from the home visit. Tie-breaker testing may or may not be 
performed in the home. 
2 Preliminary testing to assess HIV status will be performed in-country at a centralized laboratory. 
Additional HIV testing will be performed at the HPTN LC to confirm/determine HIV infection 
status. Results will not be returned to study sites or participants. 
3 Plasma samples will be stored at in-country centralized laboratories. The study site will ship samples 
to the HPTN LC on a routine basis, and will ship additional samples as requested by the HPTN 
LC. Additional information will be provided in the SSP Manual. Information about the use of 
stored samples is provided in Section 9.