Botswana Combination Prevention Project: -Evaluation Protocol (Protocol #1): Research Design and Impact Evaluation -Closed Clinical Cohort Protocol (Protocol #3) Implementation, Monitoring and Evaluation of Combination HIV Prevention Interventions in Rural and Peri-Urban Communities in Botswana
Phase: PHASE4
Conditions: HIV
Sponsor: Centers for Disease Control and Prevention

 
 
 
 
____________________________________________________
The Botswana Combination Prevention Project (BCPP)  
Evaluation Protocol (Protocol #1) 
____________________________________________________ 
 
Research Design and Impact Evaluation 
 
Version 7.0 
January 16, 2019 
 
 
 
 
 
 
 
 
Collaborating Institutions: 
Botswana–Harvard AIDS Institute Partnership (BHP) 
Botswana Ministry of Health (MOH) 
Harvard T.H. Chan School of Public Health 
U.S. Centers for Disease Control and Prevention (CDC) 
 
Funded by: The United States President’s Emergency Plan for AIDS Relief (PEPFAR)  
through the Centers for Disease Control and Prevention (CDC) 
 

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i. 
PRINCIPAL INVESTIGATORS 
 
Myron Essex, DVM, PhD 
Lasker Professor of Health Sciences 
Harvard T.H. Chan School of Public Health 
FXB 402, 651 Huntington Avenue 
Boston, MA 02115-6017 
Email: messex@hsph.harvard.edu 
Phone: +1-617-432-0975 
Fax: 
+1-617-739-8348 
 
 
Joseph Makhema, MBChB, FRCP 
Chief Executive Officer 
Botswana Harvard AIDS Institute 
Private Bag BO320 
Gaborone, Botswana 
Email:  jmakhema@bhp.org.bw 
Phone:  +267-390-2671 
Fax:  +267-390-1284 
 
Shahin Lockman, MD, MS 
Associate Professor of Medicine; Associate Professor in the Department of Immunology  
and Infectious Diseases 
Harvard T.H. Chan School of Public Health 
FXB 406a, 651 Huntington Avenue 
Boston, MA 02115 
Email: shahin.lockman@gmail.com 
Phone: +1-617-771-8780 
Fax: +1-617-739-8348 
 
Eric Tchetgen Tchetgen, PhD 
Professor of Biostatistics and Epidemiologic Methods 
Departments of Biostatistics and Epidemiology 
Kresge, Room 822 
677 Huntington Avenue 
Boston, MA 02115 
Email: etchetge@hsph.harvard.edu 
Phone: 617-432-5970 
Fax: 617-432-1884 
 
Molly Pretorius Holme, MS 
Senior Research Manager 
Department of Immunology and Infectious Diseases 
Harvard T.H. Chan School of Public Health 

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FXB 406a, 651 Huntington Avenue 
Boston, MA 02115 
Email: mpretori@hsph.harvard.edu 
Phone: +1-617-432-4377 
Fax: +1-617-739-8348 
 
ii. 
ROLES OF INSTITUTIONS AND PRINCIPAL INVESTIGATORS 
 
• Institutions:  Close coordination between MOH, Harvard Chan School, CDC, and BHP is 
needed to ensure seamless implementation of research and program activities.  However, 
MOH and CDC will lead, and ultimately be responsible for, program implementation and 
monitoring and evaluation, while Harvard Chan School/BHP will lead, and ultimately be 
responsible for, the evaluation of HIV incidence and viral genetic linkage analyses. 
 
• Principal Investigators: 
 
Myron Essex:  Harvard Principal Investigator (PI) responsible for preparation of the study 
protocol, design and evaluation of research, monitoring of research progress, creation and 
monitoring of research budgets, and preparation of research progress reports; responsible 
for design of initial proposal, including virological analyses, and supervision of Harvard and 
BHP investigators. 
 
Joseph Makhema:  BHP Co-Principal Investigator (Co-PI) responsible for preparation of 
study protocol, preparation of progress reports, and overseeing field research staff in 
Botswana. 
 
Shahin Lockman: Harvard Co-Principal Investigator (Co-PI) responsible for preparation of 
the study protocol, and monitoring of research progress / revisions of research protocol and 
procedures as needed; and assisting with monitoring/revision of research budgets and 
preparation and review of research progress reports. 
 
Eric Tchetgen Tchetgen: Harvard Co-Principal Investigator (Co-PI) responsible for 
monitoring of research progress, facilitation of internal and external study monitoring, and 
preparation of research progress reports;  responsible for overseeing statistical design and 
analyses as well as their interpretation. 
 
Molly Pretorius Holme: Harvard Co-Principal Investigator (Co-PI) responsible for 
preparation of the study protocol, and monitoring of research progress / revisions of 
research protocol and procedures as needed; and assisting with monitoring/revision of 
research budgets and preparation and review of research progress reports. 
 
 

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iii. 
INVESTIGATOR LISTS BY INSTITUTION 
 
Botswana Ministry of Health (MOH), Gaborone, Botswana (Alphabetical Order) 
 
Name 
Role 
Contact Email 
Marina Anderson, MD, MPH 
Surveillance 
manderson@gov.bw 
Shenaaz El-Halabi (DPS), MPH 
In-country oversight 
sel-halabi@gov.bw 
Ernest B. Fetogang, PhD 
M&E 
efetogang@gov.bw 
Refeletswe Lebelonyane, MD 
In-country oversight 
rlebelonyane@gov.bw 
Madisa Mine, PhD 
Laboratory 
mmine@bhp.org.bw 
 
Harvard T.H. Chan School of Public Health, Boston, MA, USA (Alphabetical Order) 
Name 
Role 
Contact Email 
Ingrid Bassett, MD 
Cost-effectiveness 
ibassett@partners.org 
Kara Bennett, MS 
Statistical Consultant 
karabennett@earthlink.net 
Victor DeGruttola, DSc 
Senior Statistical Scientist 
degrut@hsph.harvard.edu 
Scott Dryden-Peterson, MD 
Treatment and PMTCT 
scott_peterson@post.harvard.edu 
Kenneth Freedberg, MD 
Cost-effectiveness 
kfreedberg@partners.org 
Vladimir Novitsky, MD, PhD 
Lab 
vnovi@hsph.harvard.edu 
Kathleen Powis, MD, MPH 
Research Operations, Treatment 
and PMTCT 
kpowis@partners.org 
Roger Shapiro, MD, MPH 
Treatment and PMTCT 
rshapiro999@gmail.com 
Rochelle Walensky, MD 
Cost-effectiveness 
rwalensky@partners.org 
Rui Wang, PhD 
Statistics 
rwang8@partners.org 
Kathleen Wirth, ScD 
Statistics  
kwirth@hsph.harvard.edu 
 
Botswana–Harvard AIDS Institute Partnership (BHP), Gaborone, Botswana (Alphabetical Order) 
Name 
Role 
Contact Email 
Tendani Gaolathe, MD 
Treatment and PMTCT, 
Field research operations 
tgaolathe@bhp.org.bw 
Simani Gaseitsiwe, PhD 
Lab 
gaseitsiwe@bhp.org.bw 
Poloko Kebaabetswe, PhD, MPH 
Qualitative research consultant 
polokokebaabetswe@yahoo.com 
Mompati Mmalane, MD, FRCS-Ed, MSc 
BHP oversight and research 
operations 
mmmalane@bhp.org.bw 
Mosepele Mosepele, MBBS, MSc 
Clinical outcomes 
mmosepele@bhp.org.bw 
Sikhulile Moyo, MSc, MPH, PhD 
Lab 
smoyo@bhp.org.bw 
Rosemary Musonda, MSc, PhD 
Lab 
rmusonda@bhp.org. bw 
Erik van Widenfelt, BA 
Research data systems 
ewidenfelt@bhp.org.bw 
 

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Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA, and Gaborone, Botswana 
(Alphabetical Order) 
Name 
Role 
Contact Email 
Pam Bachanas, PhD, MS 
HTC 
dtt6@cdc.gov 
Ebi Bile, BSc, MA 
In-country lab oversight 
efb6@bw.cdc.gov 
Arielle Lasry, PhD 
HTC Costing 
ftn9@cdc.gov 
Tafireyi Marukutira, MD 
Clinical 
xwt5@cdc.gov 
Lisa A. Mills, MD 
Co-Investigator 
lmills1@cdc.gov 
Janet Moore, PhD 
Co-investigator 
jym3@cdc.gov 
Sherri Pals, PhD 
Statistics 
sfv3@cdc.gov 
Elliot Raizes, MD 
Clinical Consultant 
gwq0@cdc.gov 
Chunfu Yang, PhD 
Laboratory  
cxy0@cdc.gov 
 
 

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iv. 
TABLE OF CONTENTS 
 
I. 
PRINCIPAL INVESTIGATORS ........................................................................................................................... 2 
II. 
ROLES OF INSTITUTIONS AND PRINCIPAL INVESTIGATORS ............................................................................ 3 
III. 
INVESTIGATOR LISTS BY INSTITUTION ........................................................................................................... 4 
IV. 
TABLE OF CONTENTS ..................................................................................................................................... 6 
V. 
LIST OF TABLES AND FIGURES ........................................................................................................................ 9 
VI. 
ACRONYMS AND ABBREVIATIONS .............................................................................................................. 11 
VII. BOTSWANA COMBINATION PREVENTION PROJECT SCHEMA ...................................................................... 13 
VIII. EVALUATION PROTOCOL SYNOPSIS............................................................................................................. 20 
 
1. 
INTRODUCTION AND BACKGROUND ........................................................................................................... 22 
1.1. 
EPIDEMIC IN BOTSWANA .................................................................................................................................. 22 
1.2. 
COMBINATION PREVENTION ............................................................................................................................. 22 
1.3. 
THE PROPOSED COMBINATION PREVENTION (CP) PACKAGE ................................................................................... 23 
2. 
STUDY OBJECTIVES ...................................................................................................................................... 24 
2.1. 
PRIMARY STUDY HYPOTHESIS ............................................................................................................................ 24 
2.2. 
PRIMARY OBJECTIVES ...................................................................................................................................... 24 
2.3. 
EVALUATING THE IMPACT OF COMBINATION PREVENTION: DESIGN AND RATIONALE TO ADDRESS PRIMARY OBJECTIVES ..... 25 
2.4. 
SECONDARY OBJECTIVES .................................................................................................................................. 27 
2.5. 
DESIGN AND RATIONALE TO ADDRESS SECONDARY OBJECTIVES ............................................................................... 28 
3. 
OVERVIEW OF STUDY METHODS ................................................................................................................. 31 
4. 
STUDY POPULATIONS .................................................................................................................................. 32 
4.1. 
SELECTION OF STUDY COMMUNITIES .................................................................................................................. 32 
4.2. 
MATCHING OF STUDY COMMUNITIES ................................................................................................................. 33 
4.3. 
DEFINITION OF A STUDY COMMUNITY RESIDENT ................................................................................................... 34 
4.4. 
STUDY INCLUSION AND EXCLUSION CRITERIA ........................................................................................................ 35 
4.5. 
RATIONALE FOR ELIGIBILITY CRITERIA .................................................................................................................. 38 
5. 
SAMPLE SIZE AND SAMPLE SELECTION METHODS ....................................................................................... 41 
5.1. 
SAMPLE SIZE CALCULATIONS RELATED TO PRIMARY OBJECTIVE #1 ........................................................................... 41 
5.2. 
SAMPLE SIZE CALCULATIONS RELATED TO PRIMARY OBJECTIVE #2 ........................................................................... 50 
5.3. 
EXPECTED NUMBERS OF STUDY PARTICIPANTS ..................................................................................................... 58 
5.4. 
PLANNED INTERIM ANALYSIS OF DATA ................................................................................................................ 60 
6. 
STUDY PROCEDURES ................................................................................................................................... 61 
6.1. 
BASELINE HOUSEHOLD SURVEY (BHS) ................................................................................................................ 61 
6.2. 
HIV INCIDENCE COHORT (HIC) ......................................................................................................................... 69 

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6.3. 
FOCUS GROUP DISCUSSIONS AND INDIVIDUAL IN-DEPTH INTERVIEWS RELATED TO BARRIERS TO AND FACILITATORS OF 
LINKAGE TO CARE AND ART INITIATION AMONG A SUBSET OF BHS PARTICIPANTS...................................................................... 75 
6.4. 
RESEARCH BLOOD DRAW PROCEDURES IN COMBINATION PREVENTION COMMUNITIES, OUTSIDE OF THE BHS ................. 76 
6.5. 
THE END OF STUDY SURVEY (ESS) AND FINAL T2 STUDY VISIT FOR PREVIOUSLY ENROLLED 20% HOUSEHOLDS ................ 77 
7. 
COST EFFECTIVENESS ANALYSIS .................................................................................................................. 80 
7.1 
CEPAC MODEL STRUCTURE ............................................................................................................................. 81 
7.2  
DATA INPUTS ................................................................................................................................................. 82 
7.3 
MODEL VALIDATION AND APPROACH TO UNCERTAINTY ........................................................................................... 85 
7.4 
COST-EFFECTIVENESS ANALYSIS PLAN ................................................................................................................. 86 
8. 
LABORATORY METHODS ............................................................................................................................. 87 
8.1. 
OVERVIEW OF LABORATORY METHODS ............................................................................................................... 87 
8.2. 
TRAINING OF LABORATORY PERSONNEL .............................................................................................................. 88 
8.3. 
SPECIMEN COLLECTION, TRANSPORT, AND PROCESSING ......................................................................................... 88 
8.4. 
LABORATORY TESTING FOR BHS, HIC, AND ESS (RETURNED TO PARTICIPANT AND/OR PARTICIPANT FILE) ........................ 89 
8.5. 
RESEARCH LABORATORY TESTING (RESULTS NOT RETURNED TO PARTICIPANT) .............................................................. 90 
8.6. 
QUALITY ASSURANCE....................................................................................................................................... 94 
8.7. 
BIOSAFETY AND WASTE MANAGEMENT .............................................................................................................. 94 
8.8. 
SPECIMEN STORAGE AND SHIPMENT ................................................................................................................... 94 
9. 
DATA COLLECTION AND MANAGEMENT ..................................................................................................... 95 
9.1. 
DATA MANAGEMENT TEAM .............................................................................................................................. 95 
9.2. 
DATA FLOW ................................................................................................................................................... 95 
9.3. 
DATA FLOW FROM BHS, HIC, ESS, AND RESEARCH BLOOD DRAWS ........................................................................ 95 
9.4. 
THE BCPP RESEARCH DATA MANAGEMENT CENTER (DMC) .................................................................................. 97 
9.5. 
REPORTING STUDY PROGRESS ........................................................................................................................... 97 
10. ANALYSIS PLANS ......................................................................................................................................... 97 
10.1. 
ANALYSIS PLAN TO MEET PRIMARY OBJECTIVES .................................................................................................... 97 
10.2. 
ANALYSIS PLAN TO MEET KEY SECONDARY OBJECTIVES .......................................................................................... 99 
11. ETHICAL CONSIDERATIONS ........................................................................................................................ 103 
11.1. 
ETHICAL REVIEW ........................................................................................................................................... 103 
11.2. 
INFORMED CONSENT ..................................................................................................................................... 103 
11.3. 
RISKS .......................................................................................................................................................... 108 
11.4. 
BENEFITS OF RESEARCH PARTICIPATION ............................................................................................................ 108 
11.5. 
CONFIDENTIALITY .......................................................................................................................................... 108 
11.6. 
COMPENSATION AND INCENTIVES .................................................................................................................... 109 
11.7. 
PROTOCOL COMPLIANCE AND COMPLIANCE WITH UN CONVENTION ON THE RIGHTS OF THE CHILD .............................. 109 
11.8. 
FUTURE USE OF STORED SAMPLES ................................................................................................................... 109 
12. STUDY SAFETY AND MONITORING PLAN ................................................................................................... 110 
12.1. 
REPORTING ADVERSE EVENTS ......................................................................................................................... 110 
12.2. 
DSMB ....................................................................................................................................................... 111 
12.3. 
PROTOCOL VIOLATIONS ................................................................................................................................. 111 
12.4. 
STUDY MONITORING PLAN ............................................................................................................................. 111 

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13. ADMINISTRATIVE PROCEDURES AND INFORMATION DISSEMINATION ..................................................... 111 
13.1. 
STUDY RECORDS AND DOCUMENT RETENTION ................................................................................................... 111 
13.2. 
INFORMATION DISSEMINATION AND PUBLICATION PLAN ...................................................................................... 111 
14. REFERENCES .............................................................................................................................................. 112 
15.    APPENDICES 
Cross-
Protocol 
Appendix 
Number 
Title 
C2 
Table A: Study Communities and Matching Criteria for Community Pairs 
Table B: Back-up Communities if Selected 30 Communities Decline, are Unavailable or 
Deemed Unsuitable for Study Inclusion 
Figure A: Map of Study Communities in Three Regions 
Figure B: Map of Study Communities in the Southern Region 
Figure C: Map of Study Communities in the Central Region 
Figure D: Map of Study Communities in the Northern Region 
C3 
Table of Study Population Sizes 
C4 
Data Safety Monitoring Plan 
 
Protocol 1 
Appendix 
Title 
LOA#1 
Letter of Amendment #1 (December 13, 2013) to Protocol 1 v1.0 dated September 24, 
2013 
1-1 
Summary of Protocol Changes 

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v. 
LIST OF TABLES AND FIGURES 
 
Table 1A 
Original Model Input Parameters for the Primary Model to Estimate Impact of Combination 
Prevention (CP) Package Scale-Up in CP Communities Versus Enhanced Care (EC) Communities over 
4 Years 
Table 1B 
Model Input Parameters for the Updated Primary Model to Estimate Impact of Combination 
Prevention (CP) Package Scale-Up in CP Communities Versus Enhanced Care (EC) Communities over 
4 Years 
Table 2A 
Projected Cumulative HIV Incidence in Enhanced Care (EC) versus Combination Prevention (CP) 
Communities over 4 Years of Study Follow-Up Using Original Parameters and with ART for 
Individuals with CD4≤350 cells/µL or Viral Load ≥10,000 copies/ml in the CP Arm 
Table 2B 
Projected Cumulative HIV Incidence and Study Power  with Universal Test and Treat in the 
Combination Prevention (CP) Arm and Different Scenarios of Botswana National Guidelines 
Changes in the Enhanced Care (EC) Arm 
Table 3 
Cluster Size versus Cluster Number Needed to Achieve >85% Power to Detect Anticipated Effect 
Size by the End of the 3rd Year of Follow-up across a Range of Coefficients of Variation (k), 
Assuming ART is Offered to HIV-Infected Individuals with CD4≤350 or Viral Load≥10,000 copies/ml 
in the Combination Prevention Arm based on the original set of parameters 
Table 4 
Estimated Precision of 95% Confidence Interval Surrounding HTC, ART (including VL suppression), 
and MC Coverage Proportions at Baseline and Study End 
Table 5 
Inputs for Calculating CI Widths Surrounding HTC, ART (including VL suppression), and MC 
Coverage Proportions at Baseline and Study End 
Table 6 
Estimated Power of Detecting Differences in Coverages in HTC, ART, VL suppression, and MC 
between Enhanced Care (EC) and Combination Prevention (CP) Arms in the ESS 
Table 7 
Expected Numbers of Participants in Study Components 
Table 8 
Resource Utilization and Cost Data Needs 
Table 9 
Individual Healthcare Utilization, Cost, and Quality of Life Assessments 
Table 10 
Prevention Strategies and Outcomes of Interest 
Table 11 
BCPP Evaluation Protocol Laboratory Testing Responsibilities 
Table 12 
Summary of Approach to Consent, Various Components of the Study 
FIGURE S1 
Overview of Surveys and HIV Incidence Cohort in the Evaluation Protocol 
Figure 1 
Number of Clusters Versus Cluster Size Needed to Ensure >85% Power to Detect Anticipated 
Differences in Cumulative HIV Incidence Between Enhanced Care and Combination Prevention 
Arms 
Figure 2A 
Power to Detect Various Potential Reductions in Observed HIV Incidence In CP Communities when 
EC Communities have a Cumulative Incidence of 4.1% 
Figure 2B 
Power to Detect Various Potential Reductions in Observed HIV Incidence In CP Versus EC 
Communities under different Annual EC Incidence Rates 

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Figure 3 
Flow of participants from 20% Household Survey to BHS and HIC 
Figure 4A 
BHS Procedures for Individuals with no Documentation of HIV-Positive Status 
Figure 4B 
BHS Study Procedures for Individuals with Documentation of HIV-Positive Status 
Figure 4C  
Follow-up Procedures for HIC Enrollees During T1 
Figure 4D 
Procedures for Individuals in 20% Households who are Newly Identified During T1 and who have 
No Documentation of HIV-Positive Status 
Figure 4E 
Procedures for Individuals in 20%Households who are Newly Identified During T1 and who HAVE 
Documentation of HIV-Positive Status 
Figure 5A 
Procedures for the End of Study Survey in 80% Households in 6 Communities 
Figure 5B 
Procedures for the Final Survey Visit at T2 in 20% BHS/HIC Households 
Figure 6 
A simulated patient trace from South Africa 
Figure 7 
CD4 Trajectory in the CEPAC-I model as compared to the HPTN-052 trial 
 
 

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vi. 
ACRONYMS AND ABBREVIATIONS  
 
AE 
 
  
adverse event 
AHS 
 
  
annual household surveys (follow-up visits of the BHS and HIC) 
ANC 
 
  
antenatal clinic (or care) 
ART 
 
  
antiretroviral treatment (or therapy) 
ARV 
 
  
antiretroviral 
BCPP  
  
Botswana Combination Prevention Project 
BHHRL  
  
Botswana–Harvard HIV Reference Laboratory 
BHP 
 
  
Botswana–Harvard AIDS Institute Partnership 
BHS 
 
  
baseline household survey 
CCC 
 
  
closed clinical cohort 
CDC 
 
  
Centers for Disease Control and Prevention 
CEPAC  
  
Cost-Effectiveness of Preventing AIDS Complications 
CI 
 
  
confidence interval 
CP 
 
  
combination prevention 
CRT 
 
  
community-randomized trial 
DMC  
  
Data Management Center 
EDC 
 
  
electronic data capture (system used by BHP) 
EC 
 
  
enhanced care 
ELISA  
  
enzyme-linked immunosorbent assay 
ESS 
 
  
end-of-study survey 
ETC 
 
  
expanded treatment cohort 
FDE 
 
  
full disk encryption 
FGD 
 
  
focus group discussion 
FRR 
 
  
false recent rate 
FTE 
 
  
full-time equivalent 
GCLP  
  
Good Clinical and Laboratory Practice 
HIV-1 RNA   
HIV-1 RNA load in plasma, viral load 
HIC 
 
  
HIV Incidence Cohort 
HPLC  
  
high performance liquid chromatography 
HSPH  
  
Harvard School of Public Health 
 
 
 
HTC 
 
  
HIV testing and counseling 
IAS 
 
  
International AIDS Society 
IDI 
 
  
individual in-depth interviews 
IDR 
 
  
immunodominant region 
IRB 
 
  
institutional review board 
IPMS  
  
integrated patient management system 
ISPOR  
  
International Society for Pharmacoeconomics and Outcomes Research 
LTC 
 
  
linkage to care 
LTCM  
  
Linkage-to-care Manager 
LTFU  
  
loss/lost to follow-up 

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MC 
 
  
male circumcision 
M&E  
  
monitoring and evaluation 
MoH  
  
Botswana Ministry of Health 
MTCT  
  
mother-to-child (HIV) transmission 
NNRTI  
  
non-nucleoside reverse transcriptase inhibitor 
OHRP  
  
Office for Human Research Protections 
OI 
 
  
opportunistic infection 
Option B+ 
  
indefinite continuation of ART for women who start ART for PMTCT 
PEPFAR 
  
President’s Emergency Plan for AIDS Relief 
PI 
 
  
protease inhibitor 
PII 
 
  
personally identifiable information 
PIMS  
  
Patient Information Management System 
PMTCT  
  
prevention of mother-to-child (HIV) transmission 
POB 
 
  
pregnancy/breastfeeding 
POC 
 
  
point-of-care 
PSA 
 
  
probabilistic sensitivity analysis 
QA/QC  
  
quality assurance/quality control 
QALY  
  
quality adjusted life-year 
QOL 
 
  
quality of life 
RDS 
 
  
respondent driven sampling 
SAE 
 
  
serious adverse event 
SD 
 
  
standard deviation 
SMC 
 
  
Safe Male Circumcision (Botswana government initiative) 
SOC 
 
  
standard of care 
SOP 
 
  
standard operating procedures 
SRH 
 
  
sexual and reproductive health 
study arm 
  
a group of 15 communities that is randomized to receive either enhanced 
care or combination prevention 
TB 
 
  
tuberculosis 
TDR 
 
  
transmitted drug resistance 
UNAIDS 
 
Joint United Nations Programme on HIV/AIDS 
UTT 
 
 
universal test and treat 
VPN 
 
 
virtual private network 
VDC 
 
  
Village Development Committee 
WHO  
  
World Health Organization 
YLS 
 
 
Year of Life Saved 
 
 
 
 

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vii. 
BOTSWANA COMBINATION PREVENTION PROJECT SCHEMA 
 
INTRODUCTION 
 
Background on Combination Prevention 
In recent years, several new HIV prevention interventions have proven to be highly effective at 
reducing transmission of HIV and have offered hope for containing and possibly reversing epidemics in 
sub-Saharan Africa.  Despite considerable success in scaling up these interventions in many sub-
Saharan African countries, adult HIV incidence remains high in many regions in Southern Africa. This 
may in part be attributed to the insufficient scale and quality of HIV prevention interventions.  
Modeling studies suggest that investment in rapid, coordinated scale-up of a combination of evidence-
based HIV prevention interventions, including HIV testing and counseling (HTC), male circumcision 
(MC), antiretroviral therapy (ART) and prevention of mother-to-child transmission (PMTCT), can 
significantly reduce population-level HIV incidence and may be cost-effective or even cost-saving in the 
long term.  Rigorous evidence-based outcomes to support these projections of population-level impact 
are needed if national and international bodies are to justify further investment in combination 
prevention strategies.  
 
Study Hypothesis 
The BCPP study was designed to test the hypothesis that implementing a combination prevention 
package (described below) will impact the HIV/AIDS epidemic by significantly reducing population-
level, cumulative HIV incidence in a defined geographic area over a period of 3 years and will be cost-
effective. With the changes introduced in version 5.0 of this protocol, HIV incidence will be measured 
over a shorter period, approximately 2.5 years.   
 
Proposed Combination Prevention Package 
The proposed combination prevention package for the BCPP includes: 
• Rapid scale-up of HTC services, with a target of ensuring >90% of HIV-infected adults aged 16-64 
have documentation of their HIV-infected status. 
• Rapid scale-up of universal ART for all HIV-infected adults, with a target of ensuring that >93% of  
adults diagnosed with HIV infection are receiving ART. 
• Rapid scale-up of retention in care and adherence interventions, with a target of ensuring that 
>95% of HIV-infected adults receiving ART are virally suppressed with HIV-1 RNA <400 copies/ml. 
• Rapid scale-up of linkage to male circumcision services, with a target of ensuring >60% of HIV-
negative men (aged 16–49) are circumcised. 
• Rapid strengthening of PMTCT services, with a target of ensuring >90% of women initiated on 
indefinite ART (Option B+) during pregnancy remain in care and on treatment at 12 months post-
delivery. 
 
Study Arms 
Thirty communities (described in Appendix C2) in three geographic areas considered representative of 
Botswana have been proposed for inclusion in the community randomized trial (CRT): (1) around 
Gaborone in the south east, (2) around Francistown in the north east, and (3) in the region around 
Mahalapye, Serowe, and Palapye in the central eastern region. Communities will be randomized to 
either the Combination Prevention arm or the Enhanced Care arm. Combination Prevention 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
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communities will receive the proposed combination prevention package described above. Enhanced 
Care Communities will receive guidance and technical support for quality management and data 
systems at all laboratories and local clinics at which individuals receive HIV care and treatment (and 
participants in the survey occurring in ~20% of households in the Enhanced Care communities may 
benefit from study provision of home-based HIV counseling and testing and, for HIV-infected residents, 
point of care CD4 count and HIV-1 RNA testing).  
 
High Viral Load Treatment and Universal Test and Treat as Combination Prevention Package 
Components 
Data show that higher levels of HIV-1 RNA (viral load) are independently associated with both higher 
rates of HIV transmission and more rapid HIV clinical disease progression and CD4 decline. This study 
therefore originally included the use of a modified “treatment as prevention” approach that targeted 
not only those adults who need ART for their own health, but also those adults who are most likely to 
perpetuate HIV transmission within the community (those with viral load ≥10,000 copies/ml). At the 
time of designing the BCPP in 2012 there was strong experimental evidence supporting initiation of 
ART at CD4≤350 cells/µL, or WHO Stage III/IV, but conclusive experimental evidence supporting patient 
benefit of ART initiation at higher CD4 counts, especially CD4 >500 cells/µL was lacking. 
 
The 2013 WHO guidelines recommended initiation of ART in all HIV-infected adults with CD4≤500 
cells/µL regardless of clinical stage. In an attempt to provide programmatic data for an anticipated 
change in CD4 threshold for ART initiation in the future in Botswana and to enhance the power of the 
study to answer its primary objective, the threshold for ART initiation in the Combination Prevention 
arm was modified in early 2015 (from CD4≤350 to CD4≤500 regardless of viral load, in addition to 
offering expanded ART to persons with CD4>500 and viral load ≥10,000).  
 
Shortly thereafter, in July 2015, the WHO announced that it would revise ART guidelines to 
recommend universal treatment (regardless of CD4 count or HIV disease severity). The WHO’s plans 
were informed by results from two clinical ART trials. One, the START trial, reported that early drug 
treatment of people with HIV cut their risk of serious illness or death by 57% (Lundgren, Babiker et al. 
2015). Another, the TEMPRANO study, released findings that early ART significantly decreased 
morbidity overall and when restricted to patients with baseline CD4>500 cells/µL (Danel, Moh et al. 
2015). WHO published an early release guideline on when to start ART and on pre-exposure 
prophylaxis for HIV in September 2015 (World Health Organization 2015). The BCPP study team, with 
the support of the DSMB and funder, revised the intervention treatment initiation criteria to take these 
results and WHO guidelines into account. Universal test and treat (UTT) is therefore included in the 
combination prevention package starting with version 4.0 of the protocols as of June 2016. 
 
Also as of June 2016, with the launch of its “Treat All” campaign, Botswana  treatment guidelines allow 
initiation of ART for all HIV-infected citizens regardless of  CD4 count or WHO stage. Enhanced Care 
community residents are eligible to receive ART according to these updated Botswana national 
guidelines. Residents in the Combination Prevention communities are continuing to receive additional 
expanded treatment as prevention.    
 
Through additional modeling, the study team adjusted effect size and power calculations to reflect a 
move to universal ART in both the Combination Prevention and Enhanced Care arms, using a range of 
roll-out timelines. This revised modeling also used estimates of coverage (by HTC, linkage to care, ART, 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
15 
and MC) that are consistent with what had been observed in BCPP thus far, rather than using the 
higher coverage "targets".  Model-based estimates suggest that the impact of a change in treatment 
policy on the power to detect a difference in cumulative incidence (the primary objective of BCPP) may 
still yield at least 60% power, but the impact depends on the exact nature and timing of the actual 
implementation of changes in policy as well as other prevailing conditions.  The retention of this level 
of power even with Enhanced Care communities moving to expanded access to ART is at least in part 
attributable to the fact that BCPP is implementing multiple HIV prevention interventions (including 
higher HTC coverage, linkage to HIV care/treatment, adherence support, etc.). With version 5.0 of the 
protocol, we are dropping the third annual household survey and instead performing the second 
annual household survey approximately 6 months later than originally planned. This will result in a 
total average follow-up of the BHS/HIC participants of approximately 30 months rather than 36 
months. This change is being made for budgetary reasons, and also because the randomized arms are 
becoming more similar over time with regard to HIV treatment (particularly with the move to UTT in 
both arms in June 2016). Shortening the follow-up period from the originally planned 36 months to an 
average of 30 months with version 5.0 of the protocol reduces estimated power for the first primary 
objective to approximately 63%. 
 
Indefinite ART following PMTCT (Option B+)  
Women completing ART for PMTCT will be offered indefinite ART continuation (regardless of pre-
treatment CD4, viral load or clinical stage). Option B+ was part of the original combination prevention 
package at the launch of this study in 2013. Upon the Botswana government’s adoption of Option B+ 
as national policy (April 2015), Option B+ is offered to qualifying women in Enhanced Care 
communities as well as Combination Prevention communities per national guidelines.  
 
Relationship of BCPP Study Protocols 
The Botswana Combination Prevention Project and related procedures were initially described in three 
separate, but inter-related, protocols: an Evaluation Protocol (#1), Closed Clinical Cohort Protocol (#2), 
and Intervention Protocol (#3).  
 
In 2015, the Closed Clinical Cohort Protocol (#2) was terminated due to concerns about low study 
power, evolving ART guidelines, and feasibility.  
 
BCPP STUDY OBJECTIVES 
Primary objectives covered by the BCPP study protocols include: 
1. To determine whether implementation of a combination prevention (CP) package can 
significantly reduce population-level, cumulative HIV incidence in 16-64 year old residents in 
Botswana over a period of approximately 30 months.  This evaluation is a primary objective of 
the Evaluation Protocol. Implementation of the combination prevention package is described in 
detail in the Intervention Protocol. 
2. To estimate population-level uptake of HIV testing, ART, VL suppression, male circumcision, and 
PMTCT services and compare service uptake between Enhanced Care communities and 
Combination Prevention communities at baseline and at study end. This is a primary objective 
of the Evaluation Protocol.  
3. To estimate the cost per additional infection averted in Combination Prevention communities 
compared with Enhanced Care communities. This is a primary objective of the Evaluation 
Protocol.  

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16 
4. To implement the combination prevention intervention package in Combination Prevention 
communities and describe uptake of these interventions in Combination Prevention 
communities (expanded HIV Testing and Counseling, strengthened Male Circumcision, 
expanded HIV Care and Treatment, and strengthened PMTCT services). This is the primary 
objective of the Intervention Protocol.   
 
STUDY DESIGN  
The over-arching design is a pair-matched CRT that will be completed over the course of approximately 
5 years.  A randomized design is selected to provide experimental evidence of combination prevention 
package impact, and because population-level HIV incidence is the outcome of interest, we propose a 
community (rather than individual) randomized trial.  A detailed description of the combination 
prevention package and how these interventions go beyond standard of care (SOC) are described in 
detail in the Intervention Protocol. In brief, the interventions consist of the following four components: 
 
1) Expand HTC and strengthen linkage-to-care services 
2) Strengthened and expanded HIV care and treatment services 
3) Expand male circumcision (MC) services 
4) Strengthened PMTCT services, specifically identification, linkage, and treatment of HIV-
positive pregnant women 
 
STUDY METHODS 
The study communities will be matched into pairs based on community characteristics thought to be 
associated with the outcome of interest (adult HIV incidence).  Pair-matching is done to improve 
balance between study arms and statistical efficiency.   
 
The study methods are divided into five components that are described in detail in the BCPP protocols 
and summarized here. 
 
1) Baseline Household Survey (BHS) followed by Annual Household Survey (AHS)* Visits 
Following matching, within each community, a baseline household survey (BHS) of approximately 20% 
of randomly selected households will be implemented to (1) establish an HIV incidence cohort (HIC) 
consisting of all eligible consenting HIV-negative household members aged 16-64 years, and (2) 
estimate baseline and annual coverage of the combination prevention package. The BHS and 
subsequent annual household survey (AHS) visits are described in the Evaluation Protocol. Individuals 
who enroll in BHS will be followed with AHS visits, regardless of whether they are assigned to the HIC 
(see below) to assess uptake in both study arms of HTC, ART including viral suppression, MC and 
PMTCT services and describe major outcomes. 
*Revisions in Version 5.0 of the protocol extended the interval between the first annual household follow-up visit at T1 and 
the second/final household visit at T2 to approximately 18 months, rather than 12. “AHS” will still be used to refer to 
follow-up visits to the 20% households.  
 
2) HIV Incidence cohort (HIC) 
The HIC, enrolled during the BHS, will be followed to assess cumulative HIV incidence over 
approximately 30 months, which is the primary study outcome of interest. HIV genotypes of incident 
infections will be analyzed to allow description of which incident infections in the HIC are linked to HIV-

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17 
infected persons residing in the same study arm.  Comparison of linked HIV incidence rates between 
arms may inform analysis of intervention effectiveness. The HIC is described in the Evaluation Protocol. 
 
3) Programmatic Interventions (HTC, Universal ART, Strengthened PMTCT and MC Services) 
Matched community pairs will be randomized 1:1 to Enhanced Care or Combination Prevention arms 
(15 communities per arm).  Combination Prevention communities will receive the combination 
prevention intervention package, which includes strengthened HIV testing and counseling, universal 
ART, and strengthened male circumcision services. To reach high coverage levels of HTC, campaigns 
will be implemented after BHS and continue with ongoing services in the Combination Prevention arm.   
Universal ART with linkage to care and adherence support will be offered to eligible HIV-infected 
persons referred through the study from BHS/AHS or HTC services and routine testing, as well as to 
existing patients already enrolled in care at the Combination Prevention community clinics. Services for 
pregnant women will be strengthened for third trimester retesting of women with a previous HIV-
negative test; linkage to HIV treatment for all HIV-infected pregnant and post-partum women; and 
retention on ART post-delivery. To reach high coverage levels of male circumcision in HIV-uninfected 
adult men, MC campaigns with strengthened linkage to MC services will be conducted in Combination 
Prevention communities. Programmatic intervention activities are described in the Intervention 
Protocol.  
 
4) End of study survey (ESS) 
An end of study survey (ESS) targeting 100% of households in three community pairs (3 Combination 
Prevention communities and 3 Enhanced Care communities) will be used to estimate and compare 
Combination Prevention package uptake between arms.  The ESS is described in the Evaluation 
Protocol. 
 
 
5) Laboratory Research Activities (Viral Genotype Analysis and Point-of-Care Viral Load Validation) 
Laboratory research activities will be used to map genotypes from HIV-infected individuals identified 
during the BHS, HTC, and ESS and from seroconverted individuals in the HIC.  All HIV-infected adults 
will be asked for consent to allow viral genotype analysis. Genotyping will help to inform viral genotype 
maps of Enhanced Care community and Combination Prevention community arms.  These viral 
genotype analyses will be used to assess whether the proportion of new infections that are linked to 
circulating HIV-1 variants in the same arm, declines over time in the Combination Prevention arm. 
Procedures related to this genotyping are described in the Evaluation Protocol. The accuracy and 
feasibility of point-of-care viral load testing will also be assessed in comparison to standard viral load 
platforms. 
 

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18 
FIGURE S1:  Overview of Surveys and HIV Incidence Cohort in the Evaluation Protocol  
 
 
Equipoise 
In individually randomized trials involving human participants, equipoise is the ethical requirement 
that, at the start of a trial, there be a state of honest, professional disagreement in the community of 
expert practitioners as to the preferred treatment.  Beneficence, the moral obligation not to harm 
needlessly, and when possible, to promote the welfare of research subjects, is a key ethical principle 
underpinning the concept of equipoise.   
 
In this study, investigators believe there is equipoise, since impact of combination HIV prevention 
programs on population-level adult HIV incidence has not yet been rigorously demonstrated, and 
professional disagreement about the effectiveness of combination prevention and the need for a 
thorough evaluation of its impact has been published in the scientific literature. Therefore, based on 
current scientific evidence for and against the combination prevention package, randomizing a 
community to either Enhanced Care or Combination Prevention arms does not breach the trust 
relationship between the state and the community.    
 
Combination prevention will be compared to an enhanced standard of care in the Enhanced Care 
communities. The Enhanced Care communities will benefit in several ways from participation in the 
project. First, residents in the 20% households participating in the BHS and related activities (outlined 
in the Evaluation Protocol) will be offered the following procedures, which may confer direct health 
benefits: home-based HIV counseling and testing; point-of-care CD4 testing for HIV-infected, 
treatment-naive residents; HIV-1 RNA testing for HIV-infected residents (HIV-1 RNA sample drawn in 
the household); and referral to local HIV care and treatment clinics for HIV-infected residents who are 
not on treatment and/or not actively engaged in care. Second, the BCPP will also provide guidance and 
technical support for  quality management and data systems at all laboratories and local clinics at 
which individuals receive HIV care and treatment, including those in the Enhanced Care communities. 
The MOH will receive technical assistance to support improved implementation and utilization of 

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19 
clinical data systems (primarily PIMS2 and IPMS) in all 30 study communities. It is likely that resulting 
improvements in medical data systems and in quality management will help improve the general 
quality of care and treatment of all community residents attending these clinics. 
 
To maintain the trust relationship between the study team and the community during study conduct, 
analyses are proposed for interim DSMB review to ensure that the DSMB can recommend early 
stopping of the trial if efficacy is demonstrated early.  If efficacy is demonstrated, scale-up of the 
combination prevention package in Enhanced Care communities would be encouraged by 
investigators, although implementation would be based on funding availability and guidelines from the 
MOH. 
 
BCPP STUDY COORDINATION AND GOVERNANCE 
Implementation of the BCPP protocols will be coordinated using BCPP standard operating procedures 
and manuals, integrated across protocols where possible.  Roles and responsibilities for program 
implementers and study investigators are defined in each of the protocols and will be described in 
detail in the BCPP Study Manual. While some overlap exists due to the design of the different 
protocols, Harvard Chan School/BHP will have primary responsibility for the Evaluation Protocol and 
CDC/MOH will have primary responsibility for the Intervention Protocol. During its abbreviated 
implementation the CDC/MOH had primary responsibility for the CCC Protocol. Due to the interlocking 
nature of the BCPP protocols, a joint project data management team, chaired by representatives from 
MOH, Harvard Chan School, BHP, and CDC, will be formed to build and manage the research data 
collection systems/overall research database for the BCPP.    
    
 
 

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20 
viii. 
EVALUATION PROTOCOL SYNOPSIS 
 
The Evaluation Protocol of the BCPP describes the rationale for and procedures related to evaluation of 
the primary endpoint (HIV incidence), as well as some key related secondary endpoints. This protocol 
therefore focuses on the Baseline Household Survey; the HIV Incidence Cohort; research-related blood 
sample collection; and an End of Study Survey. 
 
Primary Objectives of the Evaluation Protocol: 
1. To determine whether implementation of a combination prevention (CP) package can 
significantly reduce population-level, cumulative HIV incidence in 16-64 year old residents in 
Botswana over a period of approximately 30 months.   
 
2. To estimate population-level uptake of HIV testing, ART, VL suppression, male circumcision, and 
PMTCT services and compare service uptake between Enhanced Care and Combination 
Prevention communities at baseline and at study end. 
 
3. To estimate the cost per additional HIV infection averted in combination prevention compared 
with Enhanced Care communities. 
 
Study Design: 
The study is a pair-matched community-randomized trial.   
 
Study Population: 
Thirty community clusters will be selected from three geographic regions in Botswana.  Prior to 
randomization, community pairs will be matched on community characteristics thought to be 
associated with the outcome of interest (HIV incidence).  The average total population size of each of 
the targeted communities is 6,027, giving a total population across all 30 communities of about 
180,800, of whom about 105,000 are adults aged 16-64.  
 
Study Procedures: 
Matched community pairs will be randomized 1:1 to Enhanced Care or Combination Prevention arms 
(15 communities per arm). Randomization will occur prior to initiation of study activities (including the 
BHS).   
 
Within each community, a baseline household survey (BHS) of approximately 20% of randomly 
selected households will be implemented to (1) establish an HIV incidence cohort (HIC) consisting of 
eligible consenting HIV-negative household members aged 16-64 years, and (2) estimate baseline 
coverage of the CP package. 
 
Combination Prevention communities will receive the Combination Prevention intervention package 
immediately after completion of the BHS. All study communities, including Enhanced Care 
communities will receive guidance and technical support for quality management and data systems at 
all laboratories and local clinics at which individuals receive HIV care and treatment.   
 
The HIC will be followed during AHS visits to assess cumulative HIV incidence over approximately 30 
months, which is the primary study outcome of interest.  Study participants who are not eligible for the 

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21 
HIC will also be followed in the AHS, to assess, in both study arms, uptake of HTC, ART, MC and PMTCT 
in each arm and to describe major health outcomes (such as death).  
 
To meet the second primary objective, an end-of-study survey (ESS) targeting 100% of households in 
selected pairs of communities will be used to estimate and compare CP package uptake between arms. 
 
To understand HIV transmission patterns in Combination Prevention and Enhanced Care communities, 
HIV-1 genotyping will be performed. Because sexual mixing outside of a study arm will likely be an 
important source of contamination, circulating HIV-1 variants in Combination Prevention and 
Enhanced Care communities will be genotyped, and genotyping data will be translated into HIV 
transmission network(s). The genotyping data will be used to estimate the spatial location (community) 
of HIV infection for identified newly infected individuals. Specifically, the HIV genotyping data will 
estimate a potential link for each incident case in the study, and distinguish between linked (new 
incident infections between members of the same study arm), and unlinked (new incident infections 
transmitted from outside the study arm).  The HIV-1 genotyping in Enhanced Care and Combination 
Prevention arms will be performed through sample collection from consenting HIV-infected adults in 
the BHS and newly infected individuals in the 20% households taking part in the household surveys 
throughout the study; from HIV-infected adults newly-identified through the HTC campaigns in the 
Combination Prevention communities; from all HIV-infected adults accessing HIV care and treatment at 
local clinics in the Combination Prevention communities; and from participants in the ESS in both the 
Enhanced Care and Combination Prevention arms. The HIV genotyping data will also be used to assess 
whether the proportion of new infections that are linked to circulating HIV-1 variants in the same arm 
declines over time at a different rate from those infections that are not linked to circulating variants 
from the same arm, in the Combination Prevention communities.  
 
Duration:  
 
Study activities will occur over a period of approximately 50 months. The BHS will be completed in 
approximately 24 months. Each incidence cohort will be followed for an average of approximately 30 
months. 
 
Sample Size:  
With approximately 300 HIV-negative individuals enrolled in the HIC in each of 30 communities, the 
estimated size of the HIC will be 4,500 per study arm or 9,000 in total.  Original model simulations 
estimate that over a 3-year study follow-up period of the HIC, rapid scale-up of interventions will result 
in cumulative adult HIV incidence of 0.024 in the Combination Prevention arm compared with 0.041 in 
the Enhanced Care arm (40% reduction).  Assuming a coefficient of variation (k) of 0.26, and alpha of 
0.05, an average community HIC size of 300, with 15 communities per arm, in a pair-matched design, 
should allow 86% power to detect the estimated difference in cumulative adult HIV incidence between 
study arms, by the end of three years of HIC follow-up. Sample size was determined based on these 
original power estimates. To update estimates of study power, a simulation study was undertaken 
using a range of updated input parameters. These were based on observed BCPP data from the first 
several community pairs and on speculation regarding roll-out of UTT. As expected, these demonstrate 
some reduction in power compared to that described in the previous versions of the protocol, but 
power exceeded 60% in the tables displayed in Section 5.1.1. 
 

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22 
1. INTRODUCTION AND BACKGROUND 
 
1.1. 
Epidemic in Botswana 
 
 
Thirty years into the global HIV pandemic, HIV prevalence and incidence remain high in sub-Saharan 
Africa.  Although this region represents only 12% of the world’s population, it accounts for 
approximately 67% of the world’s 34 million HIV-infected persons,  and annually, about 70% of the 
world’s 2.7 million new infections occur in this region (UNAIDS 2010). Despite Botswana's substantial 
progress in providing HIV treatment and prevention of mother-to-child transmission services (PMTCT) 
to its citizens, an estimated 25% of its adult residents are HIV-infected, the second highest adult HIV 
prevalence in the world; and about 14,000 persons in Botswana are newly infected with HIV annually, 
the third highest national HIV incidence rate globally (UNAIDS 2010).   
   
1.2. 
 Combination Prevention  
 
In recent years, several new HIV prevention interventions have proven to be highly effective at 
reducing transmission of HIV and have offered hope for containing and possibly reversing epidemics in 
sub-Saharan Africa.  For HIV-negative men, male circumcision has been shown to significantly reduce 
HIV acquisition from HIV-infected female partners.  Three randomized controlled trials of circumcision, 
involving more than 10,000 men in sub-Saharan Africa, demonstrated a 60% reduction in HIV 
acquisition risk (Auvert, Taljaard et al. 2005; Bailey, Moses et al. 2007; Gray, Kigozi et al. 2007).  
Additionally, antiretroviral treatment (ART) of HIV-infected persons has been shown to reduce viral 
load and consequently the risk of HIV transmission to uninfected partners in sero-discordant couples 
by as much as 96% (Cohen, Chen et al. 2011).  Similarly, the use of antiretrovirals to prevent 
transmission of HIV from infected mothers to their infants during pregnancy, birth, and breastfeeding 
can reduce transmission to about 1% (Shapiro, Hughes et al. 2010). 
 
Despite considerable success in scaling up these interventions in many sub-Saharan African countries, 
especially those supported by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), adult HIV 
incidence has remained high (>1%) in many regions in Southern Africa (Botswana, Swaziland, Lesotho, 
Kwa-Zulu Natal in South Africa, and Southern Mozambique).  Multiple factors may account for high HIV 
incidence in this part of the world.  Firstly, viral characteristics of HIV-1 subtype C, endemic in Southern 
Africa, may make it more infectious than other viral subtypes (Novitsky, Wang et al. 2010; Novitsky, 
Ndung'u et al. 2011).  For example, recent evidence suggests that about one third of persons infected 
with HIV-1 subtype C, maintain very high viral loads (VL>50,000 copies/ml) for more than 6 months 
after sero-conversion. 
 
Secondly, the scale and quality of the HIV prevention interventions (HTC, ART, MC and PMTCT) may 
have been insufficient to reduce HIV incidence among adults in Southern Africa to levels observed in 
other parts of the world.  For example, the main mechanism by which scale-up of HTC and ART reduces 
HIV transmission risk in the community, is by reducing viral load in resident HIV-infected persons, 
ideally to undetectable levels (VL<400 copies/ml).  Studies have suggested that every 0.5 log reduction 
in an individual’s HIV-1 viral load is equivalent to a 40% reduction in individual HIV transmission risk 
(Modjarrad, Chamot et al. 2008), and once the viral load is fully suppressed (VL <400 copies/ml) 
individual HIV transmission risk is virtually zero (Attia, Egger et al. 2009).  Despite considerable scale-up 

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23 
of access to HTC and ART, poor retention of HIV-infected persons in the HIV care and treatment 
cascade from diagnosis to ART follow-up (Rosen and Fox 2011), has certainly mitigated the ability of 
HTC and HIV care and treatment programs in Southern Africa to reduce the prevalence of HIV-infected 
persons with detectable viral loads (VL>400 copies/ml).  In a meta-analysis of pre-ART retention in 
Africa, Rosen et al. reported that only 59% of newly diagnosed adults are successfully linked to HIV 
care and treatment services, only 46% are retained from initial registration and staging at the facility to 
ART-eligibility, and only 68% are retained from ART eligibility to ART initiation (Rosen and Fox 2011). Of 
those adults who initiate ART, ~30% are no longer on therapy by 3 years of follow-up, with most of 
those no longer in care considered lost to follow-up (Fox and Rosen 2010).  Therefore, even if 50% of 
HIV-infected adults in Botswana know their HIV status (Central Statistics Office 2009), a considerably 
lower proportion are expected to have a suppressed viral load (Gardner, McLees et al. 2011).  The 
remaining HIV-infected adults with unsuppressed viral load are still infectious and spreading virus in 
the community.  Additionally, achieving high coverage of male circumcision among HIV-negative males 
has also been challenging with most countries, including Botswana, unable to meet ambitious 80% 
coverage targets to date (Curran, Njeuhmeli et al. 2011).   
 
In summary, despite having the tools to end the HIV epidemic (Fauci and Folkers 2012), insufficient 
scale, quality, and coordination of prevention interventions has significantly limited southern Africa’s 
ability to sufficiently curb the HIV epidemic.  This has led public health experts to call for a 
“combination prevention” strategy that involves implementing multiple prevention interventions with 
known efficacy in a geographic area at a scale, quality, and intensity to impact the epidemic (Merson, 
Padian et al. 2008).  Although most experts agree that synchronized implementation of a combination 
of prevention interventions is needed, there remains considerable debate about what components 
should be included in the essential combination prevention package (Merson, Padian et al. 2008; 
Halperin 2009).  However, four evidence-based interventions including HTC, ART, MC and PMTCT 
followed by indefinite ART are recommended for scale-up by almost all prevention experts and will 
form the cornerstone of the combination prevention package proposed as part of this project (see 
Section 1.3 below). 
 
1.3. 
The Proposed Combination Prevention (CP) Package  
 
Based on experimental evidence for prevention interventions discussed above, the proposed 
combination prevention (CP) package to be delivered as part of the BCPP Intervention Protocol will 
include accelerated scale-up and expansion of HTC, active linkage to HIV care and treatment according 
to local eligibility criteria, expanded ART among all HIV-infected residents regardless of WHO Stage or 
CD4 count;  strengthened support for retention in care and ART adherence, and strengthened active 
linkage to expanded MC and PMTCT services. Under versions 1.0 and 2.0 of this protocol, the 
combination prevention package included expanded ART for individuals with CD4>350 cells/µL plus 
HIV-1 RNA ≥10,000 copies/mL, or pregnancy/breastfeeding (Option B+). Under version 3.0 of this 
protocol, the combination package included expanded ART for individuals with WHO Stage I/II and CD4 
counts 351–500 cells/µL or with WHO Stage I/II and CD4 count>500 cells/µL and high HIV-1 RNA levels 
(≥10,000 copies/mL). Option B+ was offered beginning with version 3.0 in both Combination 
Prevention and Enhanced Care communities with the adoption of this policy by the Botswana 
government in April 2015. Beginning with version 4.0 of this protocol, universal test and treat was 
offered in the Combination Prevention arm. Enhanced Care communities have received the Botswana 
standard of care in effect as it changes over time (see the Schema and Section 5.1.1 for discussion of 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
24 
the standard of care and services in Enhanced Care communities). Version 5.0 of the Evaluation 
Protocol takes into account that universal ART is available to residents of both Enhanced Care and 
Combination Prevention Communities following the Botswana government’s adoption of “Treat All” in 
June 2016. 
 
In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) proposed new targets directed at 
ending the AIDS epidemic (UNAIDS 2014). Namely, that by 2020, 90% of all people living with HIV will 
know their HIV status; 90% of all people with diagnosed HIV infection will receive sustained 
combination antiretroviral therapy (ART); and 90% of all people receiving ART will have viral 
suppression The targets of the study combination prevention package meet, and in some cases exceed, 
those for the UNAIDS 90-90-90. 
 
To reach stated scale-up targets (see BCPP Schema) several service uptake initiatives will need to be 
implemented, including (1) community mobilization to encourage HTC and MC uptake, (2) 
strengthening linkage to ART and/or PMTCT services for newly diagnosed HIV-infected adults, (3) 
strengthening of linkage to MC services for HIV negative males identified at HTC services, (4) expansion 
of HTC, ART, PMTCT and MC services through recruitment of additional health care personnel, and 
where necessary, creation of new infrastructure (e.g. new male circumcision surgical units), and (5) 
monitoring and evaluation of prevention programs to ensure stated targets are reached. 
 
Adults aged 16-64 will be targeted for service uptake because recent, nationally representative surveys 
of HIV prevalence and incidence (Central Statistics Office 2009) suggest that HIV incidence remains 
high (>1%) throughout this age group. Modeling exercises (presented in Section 5) suggest that 
meeting scale-up targets by the end of two years of program implementation, and maintaining 
treatment coverage thereafter, could result in community HIV incidence reductions of approximately 
40% by the end of 2.5 years of implementation.  
 
The Intervention Protocol describes the details of implementing the CP package in the study 
communities. 
 
2. STUDY OBJECTIVES 
 
2.1. 
Primary Study Hypothesis 
 
Implementing the CP package will impact the HIV/AIDS epidemic by reducing the incidence of HIV 
infection in a defined geographic area within approximately 2.5 years and will be cost-effective. 
 
2.2. 
Primary Objectives 
 
1) To determine whether implementation of a combination prevention (CP) package can significantly 
reduce population-level, cumulative HIV incidence in 16-64 year old residents in Botswana over a 
period of approximately 30 months.  
 

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25 
2) To estimate population-level uptake of HIV testing, ART, VL suppression, male circumcision, and 
PMTCT services and compare service uptake between Enhanced Care and Combination Prevention 
communities at baseline and at study end. The service uptake indicators will include: 
• The proportion of 16-64 year-old community residents who report knowing that they are HIV-
infected, or report testing HIV-negative in the preceding 12 months. 
• The proportion of 16-49 year-old HIV-negative men, resident in the study communities who are 
circumcised. 
• The proportion of HIV-infected 16-64 year-old adult community residents who know they are 
HIV-positive and are receiving ART. 
• The proportion of HIV-infected 16-64 year-old community residents who know they are HIV-
positive, are receiving ART, and have HIV-1 RNA ≤400 copies/mL.  
• The proportion of eligible, HIV-infected pregnant women, resident in study communities, who 
remained in care and on treatment 12 months post-delivery after initiating ART for Option B+. 
 
3) To estimate the cost per additional HIV infection averted in Combination Prevention compared 
with Enhanced Care communities. 
 
2.3. 
Evaluating the Impact of Combination Prevention: Design and Rationale to Address Primary 
Objectives 
 
Although modeling studies suggest that implementation of the stated CP Package can significantly 
reduce HIV incidence and may be cost-effective, rigorous evidence to support these projections of 
population-level impact is needed if national and international bodies are to justify further investment 
in combination prevention strategies (Lancet 2010; Padian, McCoy et al. 2011).  For funders to be 
confident in the effectiveness of the proposed CP package, this evaluation would need to: (1) 
demonstrate a measureable reduction in adult HIV incidence and (2) be able to attribute any observed 
incidence reduction to scale-up of the CP package.  The first two primary study objectives for the BCPP 
Evaluation Protocol are designed to meet these needs. 
 
Current global economic realities have resulted in level or declining availability of funding for HIV/AIDS 
programs (Stover, Korenromp et al. 2011).  Therefore, the proposed third primary objective is to 
evaluate the cost-effectiveness of CP package implementation in Botswana. 
 
A randomized design is proposed to provide experimental evidence of CP package impact, and because 
population-level HIV incidence is the outcome of interest, we propose a community (rather than 
individual) randomized trial (CRT).   
 
In summary, 30 study communities, considered representative of the rural and peri-urban populations 
of Botswana, will be selected and matched into pairs based on community characteristics thought to 
be associated with HIV incidence, which is the outcome of interest (see section 4.2 and Appendix C2 
for matching criteria).  Pair-matching is done to improve balance between study arms and statistical 
efficiency (Hayes and Moulton 2009).  Communities within pairs will be randomized to Combination 
Prevention or Enhanced Care arms.  Following community matching and randomization, a baseline 20% 
household survey (BHS) will be implemented to recruit an HIV incidence cohort (HIC) of eligible, 
consenting, HIV-negative adults aged 16-64. Through activities described in the BCPP Intervention 
Protocol, the CP package will be scaled up to target levels within two years post-randomization in 

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26 
Combination Prevention communities with treatment coverage levels maintained thereafter.  The HIC 
will be followed at approximately 12 months (T1) and 30 months (T2) after enrollment to measure 
cumulative HIV incidence. A small number of communities may receive a third follow-up at 36 months 
(T3) as stipulated by protocol versions 1.0-4.0, depending upon the timing of approval and roll-out of 
version 5.0 of the Evaluation Protocol. In addition, a small number of communities will have had their 
second follow-up visit at T2 according to the original study design and schedule. All data collected from 
these study visits under previous versions of the protocol and the former study schedule will 
contribute to the final analyses. Cumulative HIV incidence will be compared between Enhanced Care 
and Combination Prevention arms to assess CP package impact. Households that participated in the 
BHS will be visited (as part of the HIC follow-up activities). Residents of these households who are not 
participating in the HIC will also be asked to complete a survey at each follow-up visit to help provide 
CP package coverage estimates during the course of the study. The overall evaluation study design is 
illustrated in Figure S1 in the BCPP Schema (section vii), and the rationale for the sample sizes is 
provided in Section 5. 
 
We propose a parallel group CRT design rather than a step-wedge design primarily because a step-
wedge design is considered infeasible.  A step-wedge design would entail enrollment of multiple HIV 
incidence cohorts sampled, recruited and followed within the short time period of any one “step” and 
this would be expensive and beyond the realm of feasibility.  In addition, a parallel group CRT is 
generally regarded as providing stronger experimental evidence of impact compared with a step-
wedge design because any pre-existing trends in HIV incidence will be controlled for at the design 
stage, rather than modeled in an adjusted analysis as would need to occur in a step-wedge trial 
(Hussey and Hughes 2007; Hayes and Moulton 2009). 
 
A pre- versus post-study design would not generate evidence of similar strength to that of a parallel 
group CRT (Habicht, Victora et al. 1999; Hayes and Moulton 2009). Previous pair-matched CRTs to 
assess impact of complex program interventions on adult HIV incidence have been successfully 
implemented in Africa, and this lends support to the feasibility of our proposed design (Hayes, Mosha 
et al. 1995). 
We propose directly measured HIV incidence as the primary outcome of interest, because fewer 
assumptions are required for direct HIV incidence measures, and this is still regarded as the gold 
standard technique for estimating incidence (Kim, Hallett et al. 2011).   
We propose that the HIV incidence cohort (HIC) remain open such that HIV-negative adults aged 16-64 
who migrate into HIC households, or adolescents who age into eligibility during study conduct, or other 
participants who become eligible during study conduct, be offered the opportunity to enroll in the HIC 
at T1.  An open, rather than a closed cohort, has been selected because (1) this should help to keep the 
incidence cohorts representative of their respective communities, (2) this has some sample size 
advantages, and (3) analysis techniques to manage open rather than closed HIV incidence measures 
are available and not inferior.  The advantages of an open, rather than a closed, cohort should 
outweigh the disadvantages, which includes possible intervention contamination of Enhanced Care 
communities (see Section 2.5.1). 
 
To meet the second primary objective, CP package coverage in the community will be estimated at 
baseline and annually in the 20% households, and through an end of study survey (ESS) that targets all 

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27 
households in 6 of the 30 study communities.  Targeting 100% of households in 6 communities in the 
ESS allows for obtaining more precise estimates of CP package coverage (see Section 5 for precision 
estimates), and permits comparison of estimated coverage in the 20% households with that in the rest 
of the community.  
 
To meet the third primary objective, costing data will be collected prospectively, and used in 
combination with impact estimates derived from the CRT.  The cost-effectiveness analysis and methods 
for collecting costing data are described in Section 7. 
 
2.4. 
Secondary Objectives 
 
1) To estimate the extent to which incident HIV infections in Combination Prevention and in Enhanced 
Care communities arise from HIV strains circulating within communities randomized to the same 
study arm as the incident case or from strains circulating outside those communities (sexual 
network mixing) by: (1) genotyping the circulating HIV-1 variants in Enhanced Care and 
Combination Prevention arms, and (2) estimating the proportions of new HIV infections that can 
and cannot be phylogenetically linked to HIV-infected persons in the same study arm. 
 
2) To estimate the efficacy of the Combination Prevention package on reducing the rate of new 
infections with HIV strains circulating within communities in the same study arm. 
 
3) In the intervention arm only, to estimate over time, the proportion of incident HIV-1-infections that 
can be linked to HIV-infected adults of the same study arm. 
 
4) During the end of study survey (ESS) to compare Combination Prevention (CP) package uptake 
within 20% households to CP package uptake in the broader communities they represent.   
 
5) To obtain secondary cross-sectional estimates of community HIV incidence at baseline and study 
end in Enhanced Care and Combination Prevention communities through use of HIV-incidence 
assays. 
 
6) At baseline, during study conduct, and at study end, to estimate the proportion of recent HIV 
infections in Combination Prevention and Enhanced Care communities with evidence of 
transmitted HIV drug resistance.  
 
7) To estimate the proportion of HIV-infected adults with undetectable viral load (VL<400 copies/ml) 
and to estimate the community viral load at baseline, during study conduct, and study end in 
Combination Prevention and Enhanced Care communities. 
 
8) To estimate the association between HIV-1 viral load and HIV transmissions using viral linkage data. 
 
9) To project HIV infections and deaths (attributable to AIDS) averted in the combination prevention 
and Enhanced Care communities beyond the time frame of the trial. 
 
10) To estimate the cost of provision of intervention services. 
 

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28 
11) To estimate the cost-effectiveness of combination prevention (taking into account both infections 
averted and clinical costs) using the two arms from the trial as well as an additional model-based 
strategy.  
 
12) To compare CD4 and viral load trajectories over time, among HIV-infected ART-naive persons who 
reside in Combination Prevention vs. Enhanced Care communities. 
 
13) To assess the accuracy and feasibility of point-of-care viral load testing in comparison to standard 
viral load platforms. 
 
14) To understand (through qualitative interviews) barriers to and facilitators of linkage to care and 
ART initiation among BHS participants. 
 
15) To use BCPP data in analyses of the rates of and risk factors for major AIDS and non-AIDS 
illnesses/injuries/mortality among persons living with and without HIV in Botswana. 
 
2.5. 
Design and Rationale to Address Secondary Objectives 
 
2.5.1. Contamination 
 
There are several sources of potential contamination in the proposed trial. This contamination can 
affect interpretation of results concerning the efficacy of the ART-related interventions in reducing HIV 
transmission in this trial, and is hence addressed in secondary objectives #1-2 (sexual network 
contamination) and secondary objective #4 (intervention contamination). 
 
Sexual network contamination will almost certainly occur; available evidence from a recently 
conducted community survey in Mochudi (a district in southern Botswana) showed at least 30% of 
surveyed adults reported sexual partnerships with adults outside the community (unpublished data).  
Therefore, during trial conduct, sexual network contamination may occur in four ways: 
o Enhanced Care HIC members may become HIV-infected through relationships with: (1) non-
study community members, or (2) Combination Prevention community members 
o Combination Prevention HIC members may become HIV-infected through relationships 
with: (1) non-study community members, or (2) Enhanced Care community members 
 
Because Botswana’s population is congregated largely in the eastern part, which constitutes a 
relatively small geographic area, and because the population is widely mobile anyway (Central 
Statistics Office 2009), attempting to separate study communities by large “buffer zones” or 
geographic boundaries (e.g. mountainous regions) is not considered a feasible option for trying to 
reduce sexual network contamination.  Instead, investigators propose HIV-1 genotyping to enumerate 
circulating HIV-1 variants in Combination Prevention and Enhanced Care communities. Clustering of 
HIV-1 sequences implies that hosts are connected by a chain of viral transmission. Clustered HIV-1 
sequences represent viral variants that circulate and spread in the communities where the analyzed 
blood specimens originate. The planned genotyping will help assess which new incident infections in 
the HICs were transmitted from members of the same study arm (phylogenetically linked infections), 
and which were transmitted from outside the study arm (unlinked infections).  Similar methodology 

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29 
has been successfully used in HIV prevention trials involving sero-discordant couples (Cohen, Chen et 
al. 2011). More details related to the proposed analyses are described in Sections 8 and 10.  
 
A high density of sampling is necessary to increase the accuracy of viral linkage analysis. To assess 
patterns of HIV-1 transmission, blood samples for HIV-1 genotyping will be collected from: 
o All consenting HIV-infected individuals identified in the BHS upon enrollment, and at AHS 
visits and during the ESS in participating Combination Prevention and Enhanced Care 
communities. 
o All consenting newly identified HIV-infected adults identified in the HIC in both Combination 
Prevention and Enhanced Care communities, at T1 and T2. 
o All consenting HIV-infected adults who present to HIV care/treatment clinics after being 
identified in the first HTC campaigns in Combination Prevention communities. 
o All consenting HIV-infected adults receiving HIV care and/or treatment at local clinics in the 
Combination Prevention communities (including those already in care/on ART at the start of 
the study). 
o All consenting newly diagnosed HIV-infected adults in the second HTC campaign (HTC2) and 
thereafter in the Combination Prevention communities who present to HIV care/treatment 
clinics. 
 
The importance of genotyping in assessing and possibly controlling for sexual network contamination is 
captured in the first two secondary objectives. To meet the first secondary objective, we will assess the 
proportions of linked vs. unlinked incident cases in the Combination Prevention and Enhanced Care 
communities that are identified within the 20% of households participating in surveys, over the course 
of the study.  This will allow us to estimate the extent of sexual network contamination of the HIV 
incidence cohorts. 
 
To meet secondary objective #2, we will evaluate genotypes from the same groups as in secondary 
objective #1 (i.e., HIV-infected residents of the 20% of households participating in surveys over the 
course of the study, in both arms). This analysis, however, will include only phylogenetically linked 
incident cases. This analysis will therefore control for sexual network contamination by including only 
linked incident cases in the analysis of CP package impact.  
 
The additional purpose of HIV-1 genotyping is captured in the 3rd secondary objective, which targets all 
HIV-infected residents in Combination Prevention communities. In secondary objective #3, we will 
estimate how the proportion of linked incident cases (in Combination Prevention communities only) 
changes over time. If the CP package is effective in reducing population-level HIV incidence, there 
should be a reduction in the proportion of recent infections that can be phylogenetically linked to HIV-
infected persons in Combination Prevention communities.   
 
Intervention contamination will occur mainly in three ways: (1) through Enhanced Care community 
members accessing interventions in Combination Prevention communities, (2) through Combination 
Prevention community members accessing Enhanced Care outside the Combination Prevention 
communities, and (3) through study procedures (such as HIV counseling and testing) related to the BHS 
and HIC (which may affect the Enhanced Care communities, in particular). 
 

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30 
Several approaches (detailed in the Intervention Protocol) will be undertaken in an attempt to decrease 
intervention contamination between Enhanced Care and Combination Prevention communities. 
However, to assess the extent and nature of the intervention contamination that will inevitably occur, 
CP package uptake will be compared between Enhanced Care and Combination Prevention 
communities during the end of study survey (ESS), as described in primary objective #2. 
 
With regard to contamination related to the BHS and HIC, BHS and HIC study procedures include: (1) 
HTC and point-of-care CD4 and referral of HIV-infected persons to HIV care and treatment services, 
and (2) encouragement of annual HTC and risk reduction measures for HIV-negative adults, combined 
with counseling about MC benefits for HIV-negative males.  These procedures could introduce an 
unintentional intervention in the Enhanced Care communities (in the BHS and HIC participants). These 
procedures could also make the HIC less representative of the broader community of residents, even in 
the Combination Prevention communities. Unfortunately, this type of contamination is unavoidable as 
the study cannot be conducted without implementing these study procedures in all communities. To 
assess possible intervention contamination introduced by study procedures in the BHS and HIC, 
investigators propose the 4th secondary objective. 
 
Another aspect of study design may result in HIV incidence measured in the HIC not being 
representative of broader study communities (in addition to the intervention contamination described 
above): despite being an open cohort, observed incidence in the HIC may be different than incidence in 
the communities that it represents, because behavior of HIC enrollees may change simply because they 
are part of a study (the Hawthorne effect). Laboratory-based methods for estimation of HIV incidence 
are important tools for monitoring of HIV/AIDS epidemics and are attractive due to their simplicity, 
ease of use, low cost and application to single cross-sectional specimens collected during routine 
surveys. For accuracy of testing and reliable scale-up, cross-sectional HIV incidence estimates need to 
be compared with the longitudinal HIV incidence data and properly validated. Use of incidence assays 
will categorize HIV infections observed at baseline (during the BHS and first HTC campaign), and newly 
diagnosed and incident HIV-infections during study conduct (during HTC activities thereafter), during 
follow-up of the 20% households including the HIC, and at study end (during the ESS) as either 
prevalent or recent (new infection in the preceding 3-12 months depending on the algorithm of 
incidence testing). For cross-sectional estimates of HIV incidence, the cross-sectional assay-based data 
will be compared and validated by the longitudinal data on HIV incidence. In sum, the 5th secondary 
objective will assess whether cumulative HIV incidence observed in the HIC is representative of 
community incidence. 
 
2.5.2. Transmission Dynamics 
 
Surveillance of transmitted HIV drug resistance (TDR) among recently infected individuals can inform 
treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention 
programs. Increasing prevalence of transmitted drug-resistance mutations in the population may 
adversely impact the use of HIV treatment regimens. Therefore, surveillance of transmitted HIV drug 
resistance will address whether a rapid scale-up of ART in Combination Prevention communities is 
associated with the increasing prevalence of transmitted drug resistance (as compared with Enhanced 
Care communities). Secondary objective #6 addresses this concern. 
 

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31 
As described earlier, the mechanism by which expanded access to ART should achieve a prevention 
effect is through lowering the proportion of HIV-infected adults in the intervention community with 
detectable viral loads (VL>400 copies/ml) (Montaner, Lima et al. 2010).  To explore whether the 
treatment strategy in Combination Prevention communities achieved this aim, investigators propose to 
estimate the proportion of HIV-infected adults participating in the BHS, HIC and ESS with undetectable 
HIV-1 viral loads.  This is captured in the 7th secondary objective. 
 
Assessing the prevention efficacy of any single prevention intervention on its own will not be possible 
as part of this CRT as multiple prevention interventions will be implemented simultaneously.  However, 
among linked recent HIV infections that are identified at baseline, during 20% household follow-up, 
during HTC in Combination Prevention communities, and ESS, assessing the proportion that are 
associated with HIV transmission from adults with high viral load (e.g. VL ≥10,000 copies/ml and other 
thresholds) could improve understanding of the proportion of incident infections in study communities 
that might be averted by the initially proposed treatment-as-prevention strategy and/or UTT.  This is 
captured in the 8th secondary objective. 
 
2.5.3. Cost and Cost-effectiveness 
 
Assessing cost-effectiveness of the proposed CP package is crucial if potential funders and national 
governing bodies are to continue investment in the CP package after study completion.   
 
The Cost-Effectiveness of Preventing AIDS Complications International (CEPAC-I) model will be used to 
assess expected outcomes from the proposed combination prevention programs in Botswana. The cost 
effectiveness analysis will evaluate three combination HIV prevention strategies: the two arms from 
the trial and an additional model-based strategy, the “optimized package”. The “optimized package” 
provides a model-based scenario based on the intervention arm, but will assess the case where linkage 
to routine HIV care, ART, and HIV screening are further optimized, pre-exposure prophylaxis is 
administered, and may incorporate additional prevention strategies.  
 
Model-based cost-effectiveness analysis is critical to understanding the value of clinically effective 
prevention and therapeutic strategies. Model-based analyses have a number of attractive features, 
such as allowing one to: a) organize and synthesize trial data; b) handle uncertainty and forecast 
beyond a single trial via sensitivity and “what-if” analysis and c) extrapolate to longer time horizons, 
new geographic settings, and alternative target populations. With regard to HIV/AIDS, models have 
been used in multiple settings to evaluate the epidemiologic and policy implications of preventive 
interventions, to study the cost effectiveness of different treatments, to evaluate screening programs, 
to determine future resource needs, and to inform the design of clinical trials. 
 
Secondary objectives (#9-11) pertain to cost and cost-effectiveness analyses. These will provide critical 
information to policy makers, following completion of the trial. 
 
3. OVERVIEW OF STUDY METHODS 
 
As described in the BCPP Schema (section vii), the over-arching design is a pair-matched community 
randomized trial (CRT) that will be completed over the course of approximately 5 years. To facilitate 

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32 
description in this protocol the study methods are divided into six components. Harvard/BHP will have 
responsibility for 1, 2, 4, and 5 and CDC/MOH will have responsibility for 3. 
1) The baseline household survey (BHS) (with subsequent annual household surveys, AHS) 
2) Follow-up of the HIV incidence cohort (HIC) and BHS participants 
3) Programmatic interventions in Combination Prevention communities  
4) The End of Study Survey (ESS) 
5) Laboratory Research Activities (Viral Genotype Analyses) 
 
This protocol describes the BHS/AHS, HIC, and ESS, and the viral genotype analyses of the BCPP impact 
evaluation including the following:  study population eligibility criteria (Section 4.4), sample size 
estimates and sampling methods (Section 5), study procedures for the BHS/AHS, HIC and ESS and 
Research Blood Draws (Section 6), cost effectiveness analysis (Section 7), laboratory procedures 
(Section 8), data management issues (Section 9), approaches to analysis (Section 10) and issues related 
to ethical interaction with human subjects (Section 11).  Section 12 provides a suggested study safety 
and clinical monitoring plan, and Section 13 a description of study logistics and responsibilities, 
including a data dissemination plan.   
 
4. STUDY POPULATIONS 
 
4.1. 
Selection of Study Communities 
 
Thirty communities (Appendix C2) in three geographic areas in Botswana: (1) around Gaborone in the 
south east, (2) around Francistown in the north east, and (3) in the region around Mahalapye, Serowe, 
and Palapye in the central eastern region, are proposed for inclusion in the CRT.   The rationale for 
selecting 30 communities is provided in Section 5 (sample size calculations). The communities in 
Appendix C2 are purposively selected and proposed based on (1) desired size, and (2) feasibility. 
 
• Community size 
Communities need to be large enough to meet sample size requirements yet not be so large that 
achieving ambitious CP package coverage targets is infeasible.  Results of sample size calculations 
show that an average cluster size of about 300 HIV incidence cohort (HIC) enrollees per community 
is needed. To achieve this sample size, we are aiming to enroll approximately 500 potential HIC 
enrollees per community (300/0.85/0.70=500). The proportion of potential enrollees incorporates 
the expected impact of missing, refusal, capping the size of larger communities, and using back-up 
households. 
 
Because investigators wish to minimize intervention contamination that may be introduced by 
repeat HIV testing and counseling of the HIC in Enhanced Care communities, we propose to keep 
the community HIC size at no more than 20% of the entire study community.  Therefore, the ideal 
average community size proposed by investigators is about 5,750 persons [500/(0.58*0.75*0.2) = 
5,747] [Note: 0.58 is the proportion of the community considered age-eligible (Appendix C2), 0.75 
is the proportion of adults HIV-negative, and 0.2 is the desired sampling proportion for the HIC].   
Investigators therefore searched for communities of size 2,500—15,000, aiming for an average size 
of 5,750. Slightly less than 20% of households from the 30 study communities will take part in the 
BHS and HIC. Note that although this sample will likely be somewhat less than 20% of households, 

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33 
we will refer to these as the "20% households" from this point forward, for ease of reference 
(please see Sections 5.1.3 and 5.1.4 for details regarding selection of the 20% households). 
 
• Feasibility 
This project represents a significant logistical operation over the course of 5 years.  To maintain 
feasibility, investigators propose that all communities need to: 
o Have a health center, from which HIV care and treatment, PMTCT, and HTC or MC services can 
be provided. 
o Be reachable by road, via a <8 hour drive from Gaborone or Francistown.  (CDC and MOH have 
permanent, well-staffed offices in Gaborone and Francistown, while Harvard has a permanent 
office in Gaborone.  This makes the study easier to implement and monitor for quality control 
purposes). 
o Have a clear geographic boundary such that it is reasonably easy to identify a household as 
either being part of, or outside of, the study community.   
 
These feasibility inclusion criteria resulted in the exclusion of urban areas from the study, and the 
inclusion of rural and peri-urban areas.  
 
The 30 study communities proposed meet the criteria described above.  The average total 
population size of each of the targeted communities is 6,027.  Therefore, we estimate a total 
population in study communities of about 180,800 people, with 58% (104,864) aged 16-64 
(Appendix C3).  HIV prevalence among residents aged 16-64 is estimated at 25%, resulting in an 
estimated 26,216 HIV-infected residents aged 16-64, or 13,108 per study arm.   
 
4.2. 
Matching of Study Communities 
 
Due to the small number of communities that can be enrolled in community randomized trials for cost 
and feasibility reasons, there exists a chance of imbalance of potential confounders between study 
arms.  Therefore, in this study we considered restricted randomization, matching, and stratification as 
strategies to ensure balance between arms.  We chose a pair-matched design because: 
• This approach is more likely than stratification to achieve balance between study arms;  
• Matching has the added advantage of improving statistical efficiency compared with restricted 
randomization, and; 
• Chosen matching covariates (see below) are quite closely correlated with the outcome of interest 
(adult HIV incidence), making a matched design of similar or increased statistical efficiency 
compared with a stratified design, even though a matched design entails greater loss of degrees of 
freedom. 
 
Possible disadvantages of a pair-matched design include: 
• Loss of both communities in a pair if one community drops out. 
• It is not possible to assess whether the intervention effect varies between matched pairs, whereas, 
in a stratified design, opportunity to assess effect modification across strata would be possible.     
 
The following community matching criteria were chosen:  
 

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34 
• Community size:  Although community size in Botswana may not be associated with the outcome 
of interest (HIV incidence), achieving sample size balance between arms improves statistical 
efficiency.  Appendix C2 provides a comparison of communities within proposed matched pairs.  
Overall, proposed community HIC sizes range from 230 to 1,105; however, following matching, the 
median difference between community HIC size within matched pairs is 61, and ranges from 1-313. 
 
• Baseline Access to Health Services including ART:  Access to ART is associated with a decrease in 
new HIV diagnoses (Montaner, Lima et al. 2010; Tanser, Bärnighausen et al. 2013).  Although some 
communities within matched pairs have access to primary care clinics, and others have access to 
primary care hospitals, investigators believe that in the context of Botswana, this does not 
represent a significantly different level of access to health services. 
 
• Age structure:  Adult HIV prevalence and incidence are correlated with adult age (Central Statistics 
Office 2009).  Age structures are very similar within the study community pairs.  If we use the 
proportion of adults (16-64) who are at highest risk for HIV infection (25-34) as an indicator of age 
structure, the median difference in this proportion is 2% (range 0-7%). Note that residents up to 
age 64 are included in the study, due to relatively high HIV prevalence (15-25%) in persons aged 50-
64 years in Botswana, as well as a spike in HIV incidence (5.5%) in 60-64-year old men, both noted 
in the 2008 Botswana AIDS Indicator Survey, or BAIS.  [Note: we do not have age structure data for 
Mandunyane or Mmadinare, but based on the age structure of the other 28 selected communities, 
do not expect any significant differences in age structure within the matched pairs].  
 
• Geographic location as measured by proximity to major urban centers (Hayes, Mosha et al. 1995).  
Geographic locations of communities within pairs, as estimated by average distance to the nearest 
large urban centers, are quite similar.  For example, across 30 communities, the range of average 
distances to nearby urban centers ranges from 18-380 kilometers.  However, following matching, 
the median difference in distance to an urban center between communities in a matched pair is 20 
kilometers (range 3-150). 
 
We do not have access to community-specific measures of HIV prevalence [e.g. HIV prevalence 
measured from antenatal care (ANC) clinics].  Previous successful pair-matched CRTs (Hayes, Mosha et 
al. 1995), where HIV incidence was the outcome of interest, have also addressed the problem of 
absent baseline HIV prevalence estimates by using geographic location and other proxies of HIV 
prevalence as matching criteria.  
 
4.3. 
Definition of a Study Community Resident 
 
The following definitions of study community residents will be used in the protocol: 
 
• Permanent study community resident:  An individual who reports spending on average ≥14 nights 
each month in that community over the preceding 12 months or an individual who recently moved 
into the community and reports spending on average ≥14 nights each month since arriving. 
   

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35 
• Part-time study community resident:  An individual who reports spending on average 3–13 nights 
each month in that community over the preceding 12 months or an individual who recently moved 
into the community and reports spending on average 3-13 nights each month since arriving.   
 
• Non-study community resident:  An individual who reports spending on average <3 nights each 
month in that community over the preceding 12 months.   
 
• Household member:  an individual who reports spending more nights (on average) in the 
household being sampled than in any other household in the same community over the preceding 
12 months. 
 
• Botswana Citizen:  A Botswana citizen is anyone who can produce proof of Botswana citizenship. 
Usually this is the Omang number, which can be found on national ID cards, drivers licenses, 
Botswana passports, or an Omang application receipt. The Omang number is needed in Botswana 
to access routine government services. It is anticipated, based on a community survey in Mochudi, 
and the 2011 census (Central Statistics Office 2009), that less than 3% of residents will be non-
citizens.   
 
• Spouse of Botswana Citizen: A spouse of a Botswana citizen is a person who can produce evidence 
of being married to a Botswana citizen, usually a marriage certificate, and is therefore eligible to 
receive free medical services in Botswana. 
 
• Non-citizen: A non-citizen is anyone who declares himself or herself as a non-citizen and/or cannot 
produce proof of Botswana citizenship.  
 
 
4.4. 
Study Inclusion and Exclusion Criteria 
 
4.4.1. Baseline 20% Household Survey (BHS) 
 
The BHS will be conducted in the 20% households that are sampled from the participating study 
communities that have a total population of ≤6,000 residents; and approximately 273 households 
from the participating study communities that have a population over 6,000 residents (the latter is 
approximately 20% of residential and habitable plots for 6,000 residents). Eligible adults residing 
within these households will be asked to take part in the BHS. Eligible residents of the participating 
20% households who did not take part in the BHS at T0--e.g. due to absence, etc.--and who are 
present during the subsequent AHS visits (prior to the final visit) will also be asked to complete the 
same procedures that are offered in the BHS. Following, we define inclusion/exclusion criteria (with 
regard to the BHS) for: (1) households, and (2) adults living within selected households. 
 
• Household Eligibility Criteria for BHS: 
Inclusion criteria 
o The household should be located within the study community enumeration area map 
established for the 2011 national population census (Central Statistics Office 2009) or within 
established community boundaries where these maps are not available.   

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36 
 
• Household Representative Eligibility Criteria for BHS: 
Inclusion criteria: 
o Aged 18 years or older 
o Household member 
o Willing to provide household information following administration of verbal consent script 
 
• Household Member Eligibility Criteria for BHS: 
Inclusion criteria: 
o Aged 16-64 years 
o Permanent or part-time study community resident in any of the 30 study communities  
o Household member  
o Botswana citizen or spouse of a Botswana citizen 
o Able to provide informed consent if >18 years old, or able to provide assent to complement 
a guardian’s permission, if a minor (aged 16 or 17) 
 
 
4.4.2. HIV Incidence Cohort (HIC) 
 
The HIV Incidence Cohort (HIC) will be enrolled from the 20% households participating in the BHS.  
The HIC will largely be enrolled during the BHS at T0; however, eligible residents of the 
participating 20% households who are present during AHS visits (prior to the final visit) and who 
were not previously enrolled to the HIC (e.g. due to absence, 15 years of age, etc.) will also be 
asked to enroll in the HIC (i.e., the HIC is an open cohort). Therefore, the household inclusion 
criteria described above for the BHS will apply to the HIC.  Eligibility criteria for HIV Incidence 
Cohort members are as follows: 
 
Inclusion criteria: 
• Documented to be HIV-uninfected according to the rapid HIV test algorithm 
• Aged 16-64 years 
• Permanent study community resident in any of the 30 study communities 
• Household member  
• Does not intend to move out of the study community in the next 12 months  
• Botswana citizen or spouse of Botswana citizen 
• Agrees to annual home visits, as well as other study procedures 
• Provision of contact details (such as telephone numbers, physical and/or alternate addresses) 
that would allow the study team to trace him/her 
• Able to provide informed consent if >18 years old, or able to provide assent to complement a 
guardian’s consent, if a minor (aged 16 or 17)  
 
Note:  The above HIC eligibility criteria apply during the BHS (T0) and AHS visits prior to the final 
visit (i.e. the HIC is an open cohort).   
 
4.4.3. Individuals Eligible for Research Blood Draw in Combination Prevention Communities  
 

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37 
For HIV-infected residents of Combination Prevention communities who did not take part in the 
research blood draw through the BHS, the following eligibility criteria will apply for the blood draw 
for HIV-1 RNA and genotyping/incidence assay/TDR/storage: 
 
Inclusion Criteria: 
• Any individual with documented HIV infection, including newly-diagnosed individuals and HIV-
infected persons already receiving care and/or antiretroviral treatment at the clinic. (note: 
blood draws for HIV-1 RNA, genotyping, incidence assay, TDR and storage will be obtained once 
from HIV-infected clinic patients throughout the study.) 
• Adult aged 16-64 years 
• Permanent or part-time resident of combination prevention communities 
• Botswana citizen or spouse of Botswana citizen 
• Able to provide informed consent for study enrollment if >18 years old, or able to provide 
assent to complement a guardian’s permission, if a minor (aged 16 or 17) 
 
4.4.4. End of Study Survey (ESS) 
 
The ESS will be conducted at the end of the study in 3 pairs of communities (6 communities) 
selected out of the 30 participating communities. It will be conducted in the ~80% of the 
population that is not taking part in the 20% household surveys. At T2, residents of the 20% 
households will also contribute data toward the ESS analyses. 
 
Inclusion criteria: 
• Aged 16-64 years  
• Permanent or part-time study community resident in any of the selected 3 pairs of study 
communities  (for ~80% households to be newly enrolled at ESS), or any of the 30 communities 
(for ~20% BHS/HIC households having final evaluation at T2/ESS) 
 
• Able to provide informed consent for study enrollment if >18 years old, or able to provide 
assent to complement a guardian’s permission, if a minor (aged 16 or 17)  
 
4.4.5. Economic Assessment 
 
Participants in the 20% household surveys will be asked to answer questions to estimate healthcare 
costs and quality of life; these questions are included as supplemental sections in the annual 
resident survey that participants will complete.  The eligibility criteria for this group of participants 
in the economic assessments are therefore the same as for the BHS. 
 
There will be additional sampling of individuals with opportunistic illnesses or low CD4 cell count.  
The eligibility criteria for these assessments are as follows: 
 
Inclusion criteria for Supplemental Economic Assessment: 
• Permanent or part-time study community resident in any of the study communities  
• Aged 18-64 years 
• Documented to be HIV-infected 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
38 
• Measured CD4<200 cells/µL or WHO stage 3 or 4 illness 
• Botswana citizen or spouse of Botswana citizen 
• Able to provide informed consent for study enrollment  
 
Records for a small subset of community residents (up to 80 residents) who die during the course 
of the study will be abstracted to evaluate for healthcare costs at the end of life.  These individuals 
need not necessarily be part of one of the study cohorts.  This aspect of the research does not 
involve human subjects per the definition at 45CFR46.102(f) that a human subject is a living 
individual. The eligibility criteria for the record review is as follows: 
 
Inclusion criteria for Record Abstraction: 
• Resident in any of study communities (defined by at-home death in a study community and/or 
recorded as a resident in the medical record) 
• Aged 18-64 years at the time of death 
• Botswana citizen or spouse of Botswana citizen 
• Died during the years of the course of the study 
• 
Records available for review 
 
4.4.6. Barriers to and Facilitators of Linkage-to-Care (LTC) and ART Initiation 
 
A small subset of participants in the 20% household surveys will be invited to participate in a focus 
group discussion (FGD) or individual in-depth interview (IDI) to provide information on barriers to and 
facilitators of linkage-to-care (LTC) and ART initiation. Staff from the BHS (Research Assistants) and 
MOH (Nurse Prescribers) will be invited to participate in separate FGDs to provide insight into the 
dynamics surrounding linkage to care and initiation of ART. 
 
Inclusion Criteria for BHS Participants in FGDs or IDIs 
• BHS participant (enrolled in the 20% household survey prior to the FGD) 
• Resident of study community in the Combination Prevention arm 
• Aged 18-64 years 
• Documented to be HIV-infected 
• Eligible for ART initiation (to be used for purposive selection for focus group discussion and in-
depth interviews) 
• Able to provide informed consent for FGD or IDI participation 
 
Inclusion Criteria for Staff Participants in FGDs 
• BHS staff member or Nurse Prescriber in any of the Combination Prevention communities 
• At least 18 years of age 
• Able to provide informed consent for FGD participation 
 
4.5. 
Rationale for Eligibility Criteria   
 
• Rationale Surrounding Need for Botswana Citizenship for BHS/HIC: 
Although the Botswana Government provides free HTC services to non-citizens, free access to 
health services, including ART, MC and PMTCT is restricted to a) persons who can produce valid 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
39 
documentation of Botswana citizenship or b) spouses of Botswana citizens.  The BCPP package of 
intervention services will therefore not be available to non-citizens of Botswana unless married to a 
citizen, per regulations of the MOH (Presidential Directive Cab. 5 (b)/2004).  
 
As the households are followed longitudinally under the auspices of the study team but non-
citizens cannot access free public health services unless married to a citizen, the eligibility criterion 
of  Botswana citizenship (or being married to a Botswana citizen) is included for BHS/HIC 
participants, but not for ESS participants who are not followed longitudinally.  
 
• Rationale for Including Non-Citizens in ESS: The intervention package implemented in 
Combination Prevention communities includes the following for non-citizens: expanded HTC 
services, including a referral to the health clinic in their community of residence to connect them 
with available fee-based services including treatment; and enhanced linkage to MC services, 
including for men who decline HIV testing or have indeterminate results. A major goal of the ESS is 
to evaluate and compare coverage of the intervention package components between arms, 
particularly HTC coverage which cannot be evaluated in the 20% BHS cohort. Comprehensively 
surveying all potential recipients of services in the study communities is an important aspect of 
achieving the goal of the ESS. Other key objectives of the ESS are to improve mapping of viral 
genetic linkage, and to accurately estimate how viral burden and viral suppression are distributed 
across HIV-infected residents of the study communities. Obtaining a sample from as many HIV-
infected residents of the study communities as possible at ESS is critical for these objectives. 
Finally, the lack of access to free ART for non-citizens residing in Botswana represents a potentially 
significant gap in achieving the 90-90-90 goal for viral suppression that will be important to 
understand and quantify if Botswana is to consider expanding its treatment program, and for 
potentially further reducing HIV incidence in Botswana. Non-citizens will be included in the cross-
sectional survey at ESS only, and will be offered anonymous participation to protect their identity.  
Non-citizens living in Botswana without legal documentation and others in the same household 
may face the risk of penalty (see Section 11). Participation in ESS may help non-citizens by 
providing free HIV testing and counseling with referral to services that they would be able to 
access. 
 
• Rationale for Age Limits: 
Persons <16 years of age will be excluded from study participation because our intervention is 
targeting individuals age 16–64, and we hope to measure relevant study outcomes among this 
population.  In Botswana, all persons aged >16 can access medical services, including HTC, without 
needing guardian permission. Although individuals aged 16-17 can access medical services without 
guardian permission, participation in research still requires guardian permission, because the age 
of consent for research in Botswana is 18. Therefore, eligible 16-17 year-olds will be asked for 
assent to participate in research activities if/after permission is provided by the guardian. 
 
• Rationale for Number of Nights Spent per Month in the Community: 
For the BHS, we propose that adults who report spending >3 nights each month in the community 
over the past year, on average, be included, because these adults will be eligible for interventions if 
the community is randomized to the intervention arm (please see the Intervention Protocol for 
details on rationale for use of this definition of community residence vis a vis eligibility for 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
40 
interventions). We need to estimate baseline and subsequent service uptake among a similar 
(representative) group of adults enrolled in the BHS (and subsequent household surveys), to allow 
assessment of baseline use of and uptake of interventions over time, and comparison between 
study arms. 
 
For the HIC, we propose that adults who report spending on average >14 nights each month in the 
community over the past 12 months, and who do not intend to move out of the community over 
the next 12 months be included, because we believe that these adults are more likely to: 
1) have sexual relationships with individuals residing inside versus outside the study community 
(hopefully reducing sexual network contamination),  
2) access available health services in the community versus outside the study community 
(hopefully reducing intervention contamination of the HIC cohorts), and, 
3) be easier to retain in the study (hopefully avoiding possible selection bias introduced by 
excessive loss to follow-up). 
 
For research blood draws in all HIV-infected adults in the Combination Prevention arm, 
investigators propose that adults who report spending on average >3 nights per month in the 
community over the past year be included in blood draws for viral phylogenetic linkage.  
 
For the ESS, investigators propose that adults who report spending >3 nights per month in the 
community over the past year be eligible because: (1) we need to measure coverage of the CP 
package within this group of adults, and (2) consenting HIV-infected adults identified during the ESS 
will contribute blood samples to improve completeness of the HIV-1 genotype map in Enhanced 
Care and Combination Prevention communities (important for secondary objectives 1-3). 
 
• Rationale for Number of Nights Spent per Month in the Household: 
It is important to determine that participants in household-based procedures (BHS and HIC) are 
indeed at least part-time residents of the approximately 20% of households that are sampled 
(rather than casual visitors). The definition of household membership used (spending more nights 
on average in the household being sampled than in any other household in the same community 
over the preceding 12 months) is relatively straightforward to implement, and also helps decrease 
the chance of a given individual being asked to take part in household procedures in more than one 
household per community (although this criterion will not affect the chance of a participant 
enrolling in more than one community). 
 
Note: we intend to avoid enrolling the same individual more than once in the same component of 
the study (the BHS or the HIC). We will try to achieve this through the following means: 
• Inclusion of the household membership eligibility criterion.  
• Avoid enrollment of residents in the study if they state that they already took part in the study, 
with confirmation through other means. 
• Using the unique citizen Omang number to reduce the number of instances in which a resident 
is enrolled twice.  
 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
41 
5. SAMPLE SIZE AND SAMPLE SELECTION METHODS  
 
5.1. 
Sample Size Calculations Related to Primary Objective #1 
 
To estimate the required sample size to detect predicted differences in cumulative HIV incidence 
between combination prevention and enhanced care incidence cohorts, we: (1) modeled the potential 
impact of the originally proposed intervention package on adult HIV incidence, and (2) used impact 
estimates in standard formulae for pair-matched CRTs to estimate the number of community clusters, 
size of incidence cohorts, and duration of incidence cohort follow-up, required to detect the originally 
estimated impact with sufficient power (≥85% power). 
 
5.1.1. Estimating Impact of Combination Prevention on Adult HIV Incidence 
 
We used two epidemic models to estimate the potential impact on adult HIV incidence of scale-up 
of the CP package to high population-level coverage levels.   
 
• Primary model:  The primary model is an agent-based network epidemic simulation model. 
Using models for generating degree distribution for sexual network described by Jones and 
Handcock (Jones and Handcock 2003) and implemented as an R package (Handcock, Hunter et 
al. 2003), we constructed stochastic degree distributions based on data from Likoma Island 
(Helleringer and Kohler 2007).  Methods in Blitzstein and Diaconis (Blitzstein and Diaconis 2006) 
allow for the uniform sampling of networks with the prescribed degree sequence.  For the 
sampled networks we select only those networks that match the prescribed level of mixing 
between communities.  Using techniques similar to Eaton et al. (Eaton, Hallett et al. 2011), the 
model allows investigators to take into account community characteristics, including varying 
coverage levels for different prevention modalities, and population sizes, as well as individual 
characteristics including transmission risk, disease progression, condom use, linkage to care, 
and circumcision status. 
 
• Secondary model:  We also used the published Goals model available at 
(http://futuresinstitute.org/Default.aspx.) which is part of the Spectrum suite of models 
(Stover, Bollinger et al. 2011), to estimate CP impact on population-level HIV incidence.  The 
Goals model is widely used by national governments, including Botswana (Stover, Fidzani et al. 
2008), to plan HIV prevention programs and also estimate impact on HIV incidence and other 
indicators (e.g. number of AIDS deaths).  We used the Goals model primarily to assess whether 
Goals impact estimates were similar to impact estimates from the primary model. The Goals 
model produced comparable results when using the same set of input parameters. 
 
Table 1A lists input parameters used in the original primary model where we assumed the expanded 
ART intervention would be offered to HIV-infected individuals with CD4≤350 cells/µL or viral load 
≥10,000 copies/ml in the Combination Prevention arm throughout the study, and that the Botswana 
national guidelines for ART initiation would not change during the study period. Original estimates of 
model input parameters were obtained from Botswana Government data and from the population-
based Mochudi Prevention Project that was conducted from May 2010 to May 2013 (see below for a 
detailed explanation of input parameters). Timely linkage to care and treatment was assumed to be 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
42 
80% in Enhanced Care and 90% in Combination Prevention communities during the study period. We 
assume that sexual mixing between communities is on average 20% with a 95% confidence interval of 
15% to 25%. 
 
Table 1A:  Original Model Input Parameters for the Primary Model to Estimate Impact of 
Combination Prevention (CP) Package Scale-Up in CP Communities Versus Enhanced Care (EC) 
Communities over 4 Years 
 
EC Arm 
CP Arm 
Time 
Anticipated True Coverage of Services in the EC 
Community 
CP Scale-up with ART at CD4≤350 or VL≥10K in 
CP Arm 
HTC outside of study cohort 
Male Circumcision 
HTC* 
Male Circumcision* 
Baseline 
Survey 
37% 
12.7% 
37% 
12.7% 
End Y1 
41% 
31.4% 
90%** 
46.4% 
End Y2 
45% 
50.0% 
90% 
80% 
End Y3 
49% 
60.0% 
80% 
80% 
End Y4 
53% 
70.0% 
70% 
80% 
*Intervention Community scale-up targets 
**Allowing 4 months of scale-up period 
 
 
For version 5.0 of the protocol, we conducted new simulations using updated baseline parameters  
based upon observed data in the first several community pairs. Treatment initiation is assumed to be 
80% in the Enhanced Care communities and 90% in the Combination Prevention communities during 
the study period. Table 1B lists input parameters used in the updated primary model. Note that the 
updated model was undertaken to assess power under more realistic assumptions related to baseline 
parameters and coverage by interventions and under different scenarios for expanded ART.  
 
Table 1B:  Model Input Parameters for the Updated Primary Model to Estimate Impact of 
Combination Prevention (CP) Package Scale-Up in CP Communities Versus Enhanced Care (EC) 
Communities over 4 Years 
 
 
EC Arm 
CP Arm 
Time 
Anticipated True Coverage of Services in the EC 
Community 
CP Scale-up with Universal Test and Treat in CP 
Arm 
 
HTC outside of study 
cohort 
Male Circumcision 
HTC 
Male Circumcision 
Baseline 
Survey 
 
35% 
 
35% 
End Y1 
27% 
40% 
79% 
50% 
End Y2 
31% 
45% 
85% 
55% 
End Y3 
35% 
50% 
80% 
60% 
 
 
Explanation of input parameters: 
• HTC Service Uptake 
HTC coverage is defined as the probability of a person of unknown status being tested for HIV 
anytime in the previous 12 months.  We assumed 79% and 85% HTC coverage for the CP arm in 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
43 
the updated model, more conservative than the 90% target, in years one and two, respectively. 
HTC uptake will likely increase in Enhanced Care communities during the study period as well. 
We assumed that HTC coverage in Enhanced Care communities would increase 4% per year 
during the study period.   
 
• Male Circumcision Service Uptake 
A 2010–2011 survey of the Mochudi district in Botswana suggests MC coverage is 12.7% (the 
MOH Spectrum estimate is 11%).  Linkage to male circumcision services in Enhanced Care 
communities will be ongoing. The original model parameters assumed that MOH, and the 
original Intervention Protocol targets for MC would be met in the EC, and CP arm, respectively 
by the end of Year 4 post-randomization. According to BAIS reports, the prevalence of 
circumcision among males in Botswana aged 16–64 was approximately 13% in 2008 and 28% in 
2013, an increase of only 15% in 5 years. In addition, version 4.0 of the Intervention Protocol 
includes a lower MC target of 60% in Year 3. In the updated model, we therefore set the 
baseline MC prevalence at 35%, revised the coverage in the EC arm to increase by 5% per year, 
and assumed the revised MC coverage target of 60% would be achieved by the end of Year 3 in 
the CP arm. 
 
• ART Service Uptake 
In the primary model using either the original or updated parameters, ART coverage is an 
intermediate outcome of HTC coverage and linkage to care. In the updated model we assumed 
baseline ART coverage of 88.7%.   
 
• PMTCT service uptake 
We have not listed PMTCT coverage input parameters because in both models, PMTCT 
coverage increases have no direct impact on adult HIV incidence.  However, in real program 
settings, with an estimated 10% of adult women becoming pregnant each year, we expect ANC 
clinics to be an important avenue for adult HTC and entry into HIV care and treatment. The 
primary PMTCT coverage goal of the CP package is to increase the proportion of HIV-infected 
post-partum women who are enrolled in care clinics (linked) and are retained in care and on 
ART (Option B+).  
 
• Sexual Mixing between Study Communities 
One of the main reasons for building the primary model was to allow for potential sexual 
network contamination of HIV incidence cohorts in intervention and Enhanced Care 
communities.  Therefore, the primary model assumed that an average of 21% (SE: 2.6%) of 
sexual relationships occurred between persons in opposite study arms. Data from a survey of 
Mochudi district in Southern Botswana showed that 30% of the relationships were from outside 
of Mochudi, with 25% of the out-of-community relationships in Gaborone, the capital of 
Botswana. We decided to assume, on average, 21% sexual mixing for two primary reasons: (1) 
many of the study communities are more rural than Mochudi; and (2) some of the out-of-
community relationships in Enhanced Care communities will not be with Combination 
Prevention community residents.  
 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
44 
Table 2A below provides model estimates of differences in cumulative HIV incidence between 
Enhanced Care and Combination Prevention communities. Table 2A reflects modeling conducted 
with the original expanded ART design offered in CPCs at the time of launching the study in 2013. 
The input parameters are based on the Mochudi survey, Botswana government data before the 
study launched, and the HTC and MC coverage levels as listed in Table 1A.  
 
Table 2A: Projected Cumulative HIV Incidence in Enhanced Care (EC) versus Combination 
Prevention (CP) Communities over 4 Years of Study Follow-Up Using Original Parameters and 
with ART for Individuals with CD4≤350 cells/µL or Viral Load ≥10,000 copies/ml in the CP Arm 
Time 
EC Arm 
CP Arm 
CP Scale-up with ART at CD4≤350 or VL≥10K in CP Arm 
Cumulative Incidence 
(% Reduction vs. EC) 
End of Y1 
1.79% 
1.40% 
(22% ↓) 
End of Y2 
3.05% 
2.01% 
(34% ↓) 
End of Y3 
4.05% 
2.44% 
(40% ↓) 
 
 
Table 2B reflects modeling conducted with change in CD4 threshold from 350 to 500 in 2015, and 
move to UTT in Combination Prevention communities (implemented with version 4.0 of this protocol) 
and Botswana’s “Treat All” policy in place starting June 2016. The input parameters for the projections 
in Table 2B are based on observed data in the first several community pairs and HTC and MC coverage 
levels listed in Table 1B. In the updated models, we assumed 80% ART initiation in the EC arm and 90% 
in the CP arm.  
 
The Botswana MoH adoptetd universal ART as national policy effective June 2016. Therefore, we 
simulated this scenario of treatment eligibility in the Enhanced Care arm compared to UTT in the 
Combination Prevention arm: CD4≤350 followed by universal ART in 2016.  Guidelines changes are 
assumed to become policy in June 2016, and ramp up to full scale over the following 12 months. The 
CP arm was simulated as follows: launching with the original design (CD4≤350 or VL>10,000), followed 
by CD4≤500 or VL≥10,000 in the third quarter of 2015, followed by UTT in June 2016. These simulations 
were done with the updated input parameters shown in Table 1B above. 
 
Table 2B: Projected Cumulative HIV Incidence and Study Power  with Universal Test and Treat in the 
Combination Prevention (CP) Arm and ”Treat All” in the Enhanced Care (EC) Arm 
 
Treatment Eligibility 
Length of 
Follow-up 
Cumulative Incidence Rate (CIR) 
(%) 
Reduction 
in CIR (%) 
Power (%) 
ECC 
CPC 
ECC 
CPC 
CD4≤350 
→ 
universal 
ART in 
2016 
CD4≤350 or VL≥10k at 
study launch → 
CD4≤500 or VL≥10k  in 
2015 → UTT in 2016 
2 Years 
1.45 
0.93 
36 
47 
2.5 Years 
1.70 
1.00 
41 
63 
3 Years 
1.84 
1.06 
42 
70 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
45 
 
Since the exact timing of UTT roll-out is unknown in Enhanced Care communities under Botswana’s 
“Treat All” program, we made a simple assumption that each Enhanced Care community will have the 
same (reflecting the average) amount of time of follow-up before and after UTT. This assumption was 
also made for the Combination Prevention communities, but these communities will receive UTT 
earlier. While the reality will undoubtedly depart from these assumptions, the models are useful in 
providing a first-order approximation of power. 
 
5.1.2. Estimating Needed Number of Community Clusters and Size of Incidence Cohorts to Detect 
Estimated HIV Incidence Differences  
 
We examined the number of communities and incidence cohort size needed to detect a 40% 
difference in cumulative HIV incidence (originally 4.05% in the Enhanced Care arm vs. 2.44% in the 
Combination Prevention arm), which we hoped would be achieved by the end of the third year of 
follow-up if Botswana national guidelines remain at ART initiation for individuals with CD4≤350 
throughout the entire study. Required sample size was determined based on the original 
combination prevention package design prior to the launch of the study (see version 1.0 of the 
Evaluation Protocol). See Sections 5.1.1, 5.2.1, and 5.2.2 for updated study power estimates based 
on the current design and assumptions.  
 
We aimed to have ≥85% power to detect the anticipated effect size with alpha set at 0.05. 
 
We used the formula from Hayes and Moulton, appropriate for a pair-matched CRT (Hayes and 
Moulton 2009). 
 
𝑐𝑐= 2 + ቀ𝑧𝑧1−𝛼𝛼
2 + 𝑧𝑧1−𝛽𝛽ቁ
2 𝜋𝜋0(1−𝜋𝜋0) 𝑚𝑚
⁄
+𝜋𝜋1(1−𝜋𝜋1) 𝑚𝑚
⁄
+𝑘𝑘𝑚𝑚
2 (𝜋𝜋02+𝜋𝜋12)
(𝜋𝜋0−𝜋𝜋1)2
, where, 
 
c  is the number of clusters (community clusters) per arm, 
𝑍𝑍1−𝛼𝛼2
⁄  is the standard normal deviate corresponding to the upper tail probability of 𝛼𝛼2
⁄  where 
𝛼𝛼 is the probability of a type I error. 
𝑍𝑍1−𝛽𝛽 is the standard normal deviate corresponding to the upper tail probability of 𝛽𝛽 where 𝛽𝛽 is 
the probability of a type II error, 
𝜋𝜋0 is the cumulative HIV incidence in the control arm, 
𝜋𝜋1 is the cumulative HIV incidence in the intervention arm, 
𝑚𝑚 is the cluster size in each community cluster (examined a range – see below) 
𝑘𝑘𝑚𝑚 is the matched pair, between-cluster coefficient of variation of the true proportions in both 
the control and intervention arms (based on primary model simulations, the estimate of km is 
0.24. To be conservative, we used 0.26, but we examined a range of km from 0.2 - 0.35). 
 
The table and graph below illustrate the community and cluster sizes needed to ensure ≥85% 
power to detect the anticipated effect size by the end of the third year of follow-up. 
 
Table 3:  Cluster Size versus Cluster Number Needed to Achieve >85% Power to Detect 
Anticipated Effect Size by the End of the 3rd Year of Follow-up across a Range of Coefficients of 
Variation (k), Assuming ART is Offered to HIV-Infected Individuals with CD4≤350 or Viral 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
46 
Load≥10,000 copies/ml in the Combination Prevention Arm based on the original set of 
parameters 
Cluster size (m) 
Number of clusters required, depending on the size of k  
k=0.2 
k=0.24 
k=0.26 
k=0.3 
k=0.35 
1000 
7 
9 
9 
11 
14 
900 
7 
9 
10 
11 
14 
800 
8 
9 
10 
12 
14 
700 
8 
10 
10 
12 
15 
600 
9 
10 
11 
13 
15 
500 
9 
11 
12 
13 
16 
400 
10 
12 
13 
14 
17 
300 
12 
14 
14 
16 
19 
200 
16 
17 
18 
20 
22 
100 
27 
28 
29 
31 
33 
 
 
 
*Assumes ART is offered to HIV-infected individuals with CD4≤350 or viral load≥10,000 copies/ml in 
the Combination Prevention arm based on the original set of parameters 
 
With 15 clusters per arm and on average 300 HIV-negative HIC participants per community (i.e., 
4,500 HIC participants per arm or 9,000 HIC participants total), we have 86% power to detect the 
anticipated difference in cumulative HIV incidence between Enhanced Care and Combination 
Prevention communities (4.05% vs. 2.44%) by the end of the third year of follow-up, if Botswana 
national guidelines remain at ART initiation for individuals with CD4≤350 throughout the entire 
study, assuming the coefficient of variation (k) is 0.26. Under the Combination Prevention package 
introduced with version 4.0 of this protocol (ART for all HIV-infected individuals), the estimated 
0
5
10
15
20
25
30
35
100
200
300
400
500
600
700
800
900
1000
Number of Clusters 
Cluster Size 
Figure 1. Number of Clusters Versus Cluster Size Needed to Ensure 
85% Power to Detect Anticipated Differences in Cumulative HIV 
Incidence Between EC and CP Arms*  
k_0.2
k_0.24
k_0.26
k_0.3
k_0.35

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
47 
power based on more conservative assumptions (Table 1B) is >72% if national guidelines change to 
also offer universal ART in 2016. 
 
Investigators note that power calculations are based on differences in proportions of the 
population infected over the 3-year period for each pair of communities, and do not take into 
account all of the variability that could arise from the interval-censoring that allows for making use 
of partial information for dropouts, irregular schedules of visits, and delayed entry into the cohort. 
However, we believe that the power calculations will be reasonable because the available 
information should not be sharply reduced by these factors.  While some information will be lost 
because of dropout, the open nature of the HIC, use of the results from multiple tests throughout 
the study period, and the interval-censored data, which reflects the actual time of infection, would 
add information. 
 
Assuming cumulative HIV incidence in the Enhanced Care arm is 4.1% at 3 years, we examined the 
range of effect sizes that might be detected if 30 communities are enrolled with 300 HIV-negative 
adults per incidence cohort (see Figures 2A and 2B below). 
 
  
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
25
30
35
40
45
50
55
60
Power 
Percentage of Reduction in HIV Incidence Rate in Intervention vs SOC (%)   
Figure 2A. Power to Detect Various Potential Reductions in 
Observed HIV Incidence In CP Communities when EC Communities 
have a Cumulative Incidence of 4.1% 
k_0.2
k_0.24
k_0.26
k_0.3
k_0.35

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
48 
 
 
The above power estimates suggest that, for 15 matched pairs, with average HIC size 300 per 
community, if cumulative incidence in the Combination Prevention arm is >38% lower than in the 
Enhanced Care arm (4.1%), we should have >80% power to detect the difference by the end of the 
third year of follow-up, assuming k is 0.26 (Figure 2A). If the annual incidence rate in the Enhanced 
Care arm turns out to be as low as 1.0%, we will still have >80% power if we can achieve a 
reduction of at least 41% in cumulative incidence in the Combination Prevention arm (Figure 2B). 
 
5.1.3. Study Community Selection 
 
Our rationale for selection of the 30 study communities is provided in Section 4.1.  Here we 
describe in more detail how selected study communities facilitate enrollment of HIV incidence 
cohorts of sufficient average size (averaging 300 persons per HIC).  
 
The total estimated population in the 30 targeted communities is 180,800, on average 6,027 
individuals per community, ranging from 2,409 (Ranaka) to 12,086 (Mmadinare).  The age-eligible 
(16-64 year olds) subset is estimated at 58% or 3,495 per community including 2,622 HIV-negative 
and 874 (25%) HIV-positive individuals. Assuming 20% of household members are absent, and 85% 
of present members consent to participate in the study, sampling 20% of households from 
communities of population ≤6,000 and approximately 333 households from communities of 
population >6,000, should facilitate identification of on average 300 HIV-negative persons per 
community, sufficient to meet sample size requirements for the CRT.  Assuming 4.2 persons per 
household (Central Statistics Office 2009), 2.4 of whom are adults, and 1.8 of whom are HIV-
negative adults, this would suggest we need to visit at baseline and annually on average 240 
households per community. 
 
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
25
30
35
40
45
50
55
60
Power 
Reduction in HIV Incidence Rate in CP vs EC Arms (%)   
Figure 2B: Power to Detect Various Potential Reductions in 
Observed HIV Incidence In CP Versus EC Communities under 
different Annual EC Incidence Rates 
SOC_0.8%
SOC_0.9%
SOC_1%
SOC_1.2%

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
49 
5.1.4. Incidence Cohort Selection – the Baseline 20% Household Survey 
 
The primary purpose of the baseline 20% household survey is to identify and recruit HIV negative 
individuals for the HIV incidence cohort.  To reach a 20% household sample size (on average 240 
households per community), a 25% sample of households (possibly ranging from 115 to 576, and 
averaging 360 households per community) will initially be randomly selected. The initial unit of 
selection will be a plot using google area maps (and potentially population census and other 
publicly available sources); in some instances there may be more than one household on a plot and 
all houses on a selected plot will be asked to take part. The specifics of the household selection 
process are described in the BHS/HIC manual.  In villages with population under 6,000, the required 
20% households will be randomly selected from the 25% sample and approached first for 
participation in the study. In villages with population over 6,000, 333 households will be randomly 
selected from the 25% sample and approached first for participation in the study. 
 
The remaining households in the 25% sample will be ordered randomly (e.g. from 1-49).  If some of 
those households in the primary 20% sample in smaller villages (population ≤6,000) or the 333 
households in larger villages (population >6,000) do not participate (e.g. refuse consent), the 
additional households in the full 25% sample will be approached sequentially, in the order specified 
by the random sampling scheme. In villages with population under 6,000, the enrollment will stop 
when either a 20% sample of the entire community has been achieved or the full 25% household 
sample list is exhausted. In villages with population over 6,000, after at least 273 households have 
been enrolled, the enrollment will continue until 20% of the households in the village have 
enrolled, or 23 working days have been reached, whichever comes first. 
 
Based on previous survey experience in Mochudi and northern Botswana, we anticipate that we 
will be able to enroll 20% of households from the baseline 25% household sample.  Our reason for 
not wishing to approach more than 25% of households is to avoid excessive intervention 
contamination of the Enhanced Care arm.  
 
Figure 3 depicts the numbers and flow of participants from the 20% household sample. 
 

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50 
Figure 3: Flow of participants from 20% Household Survey to BHS and HIC 
 
 
 
5.2. 
Sample Size Calculations Related to Primary Objective #2 
 
5.2.1. Estimating Precision Surrounding HTC, ART, VL Suppression, MC, and PMTCT Coverage 
Proportions 
 
The rationale for the size of the baseline 20% household sample is provided above. 
 
The end of study survey (ESS) will provide the primary estimates of intervention coverage. It should 
be noted that the model inputs related to intervention coverage used to estimate power for 
Primary Objective #1 (Tables 1B and 2B) differ from the intervention coverage values used to 
estimate power for Primary Objective #2. Modeling for Primary Objective #1 used a combination of 
observed coverage (from the first several communities) and targets (for MC). For Primary Objective 
#2, actual coverage of the intervention package will generally be assessed in distinct populations 
according to the service uptake indicators outlined in Section 2.2 and the targets of the 
Intervention Protocol (Table 4).  
 
At the ESS we will compare coverage of HTC, ART, VL Suppression, and MC between the two study 
arms. We will have limited power (<60%) to detect a difference in PMTCT coverage proportions 
between study arms due to small sample size; the number of HIV-positive, pregnant women at ESS 
is estimated to be 270 per study arm. However, HIV-positive pregnant women will be included in 
measurement of coverage of the ART and VL suppression targets. 
 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
51 
The ESS will be conducted in 3 pairs of communities (6 communities in total, 3 in each arm) 
selected out of the 30 participating communities. The ESS will attempt to survey the ~80% of the 
population that is not taking part in the BHS/HIC, in these 6 communities (in addition, the 20% 
households in these communities will participate in T2 surveys (or T3 surveys, in a small number of 
communities completing T3 visits prior to the roll-out of version 5.0), leading to the target of 100% 
community assessment in these 6 communities at the end of the study). The final surveys among 
residents in the 20% households in the remaining 24 communities will also provide data. 
 
The rationale for seeking a 100% community census in three Enhanced Care and three Combination 
Prevention communities is as follows: (1) to measure HTC coverage in both study arms and more 
accurately measure study-end MC and ART coverage, (2) to improve mapping of viral genetic 
linkage, (3) to accurately estimate how the viral burden and viral suppression are distributed across 
HIV-infected people in Enhanced Care and Combination Prevention communities, (4) to compare 
CP package uptake within 20% households to CP package uptake in the broader communities they 
represent, and (5) to improve precision of cross-sectional assay-derived HIV-incidence estimates in 
Enhanced Care communities.  The ESS was restricted to 6 (rather than 30) communities as it 
provides sufficient data for these analyses and requires significantly fewer resources. 
 
The average total population size of the study communities is 6,027. Therefore, we estimate a total 
population in the six ESS communities of 36,162 people, with 58% (20,974) aged 16-64. 
Approximately 20% of these residents will be visited at T2 (or T3 in communities having this visit 
prior to version 5.0) as part of the BHS/HIC follow-up visits. Residents of the remaining 
approximately 80% will be invited to participate in the ESS as a one-time household survey. 
Assuming 80% of residents are present at the time of an ESS/T2 visit, and 85% consent to 
participate, there will be on average 2,377 participants per community, and approximately 14,262 
in total, including residents of the previously enrolled 20% households and new enrollees from the 
remaining 80% of households. 
 
In the table below we estimate precision of confidence intervals surrounding coverage proportions 
of the HIV prevention interventions to be compared (HTC, ART including VL suppression, and MC) in 
all study communities at baseline and, separately in Enhanced Care and Combination Prevention 
communities at study end. 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
52 
 
Table 4: Estimated Precision of 95% Confidence Interval Surrounding HTC, ART (including VL 
suppression) and MC Coverage Proportions at Baseline and Study End 
Baseline 
Household 
Survey (BHS) 
End of Study Survey (ESS) 
All Study 
Communities 
EC Arm 
CP Arm 
HTC 
Coverage 
Denominator (n=residents aged 16–64 years) 
12,000 
5,931 
5,931  
Numerator (n=residents aged 16–64 years who know 
they are HIV-positive or have tested HIV-negative within 
the past 12 months) 
4,440 
2,847 
5,338 
HTC coverage proportion 
37% 
48% 
90% 
Width of 95% CI (+-) 
±1.6% 
±4.9% 
±8.9% 
ART 
Coverage 
Denominator (n=HIV-positive people aged 16–64 years) 
3,000 
2,971 
2,971  
Numerator (n=HIV-positive people aged 16–64 years 
who know they are HIV-positive and are currently 
receiving ART) 
2,190 
2,405 
2,763 
ART coverage proportion 
73% 
79.5% 
93% 
Width of 95% CI (+-) 
±3.0% 
±4.3% 
±4.8% 
VL 
Suppression 
Denominator (n=HIV-positive people aged 16–64 years) 
3,000 
2,971 
2,971  
Numerator (n= HIV-positive people aged 16–64 years 
who know they are HIV-positive, are currently receiving 
ART and with HIV viral load ≤400 copies/mL) 
2,100 
2,264 
2,822 
VL suppression coverage proportion 
70% 
76.2% 
95% 
Width of 95% CI (+-) 
±3.0% 
±4.1% 
±4.9% 
MC 
Coverage 
Denominator (n=HIV-negative men aged 16-64 years) 
4,320 
4,278 
4,278 
Numerator (n=HIV-negative men aged 16-64 years who 
are circumcised) 
1,512 
2,139 
2,567 
MC coverage proportion 
35% 
50% 
60% 
Width of 95% CI (+-) 
±1.9% 
±2.9% 
±3.4% 
 
A detailed explanation of the contents of Table 4 is provided below. Total populations sizes may be 
found in Appendix C3. 
• HTC coverage numerators and denominators: 
o The BHS denominator is calculated as (average number of BHS enrollees per 
community)*number of communities = 400*30 = 12,000.   
o The BHS numerator is calculated as 12,000 (BHS enrollees)*(expected proportion of residents 
who either know they are HIV-positive or have tested HIV-negative within the past 12 months) 
= 12,000*0.37 = 4,440 (note that the definition of HTC coverage used here differs slightly from 
the definition used in section 5.1, due to requirements related to model structure). 
o The ESS denominator includes all residents aged 16-64 years outside of the BHS 20% sample in 
the 3 pairs of selected communities. The BHS 20% sample cannot be used to assess HTC 
coverage because all BHS participants are tested at enrollment per study design. The same 
proportions expected to be present and consent to BHS at T0 were assumed for the ESS at T2. 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
53 
Therefore the ESS denominator per arm is calculated as [ (average population size per 
community)*(proportion expected to be age-eligible)*(proportion expected to be 
present)*(proportion expected to consent) – (average number of BHS enrollees per community) 
]*(# communities per arm) = [ (6,027*0.58*0.80*0.85) – (400) ]*3 = (2,377–400)*3 = 5,931.  
o We assumed that HTC coverage in EC communities would increase 7% in the first year and 4% 
per year thereafter during the study period (note that the definition of HTC coverage used here 
differs slightly from the definition used in section 5.1, due to requirements related to model 
structure). Therefore the ESS numerator in the EC arm is calculated as 5,931*(expected 
proportion who know they are HIV-positive or have tested HIV-negative within the past 12 
months at T2) = 5,931*(0.48) = 2,847 
o The ESS numerator for the CP arm is calculated as 5,931*(target outlined in Protocol 3) = 
5,931*0.90 = 5,338. 
• ART coverage numerators and denominators: 
o The BHS denominator includes HIV-positive persons aged 16-64 years in the BHS 20% sample 
and is calculated as (the total number of BHS enrollees)*(proportion HIV-positive) = 
12,000*0.25 = 3,000.    
o The BHS numerator is calculated as 3,000*(proportion HIV-positive persons expected to know 
their status and currently on ART based on preliminary BHS data) = 3,000*0.73 = 2,190. 
o The ESS denominator includes HIV-positive adults from the BHS 20% sample in the 24 
communities not selected for participation in the ESS and all HIV-positive adults (100% sample) 
in the 6 ESS communities. Based on preliminary follow-up data at T1, we expect 90% of 
participants enrolled at T0 to be present at T2. In addition, we expect additional household 
members will be added to the cohort at T1. Based on preliminary data from T1, we assume an 
increase in enrollment of 10% at T1.  
The number of HIV-positive adults from the BHS 20% sample from the 24 non-ESS communities 
and 6 ESS communities is calculated as (average number of BHS enrollees per 
community)*(proportion expected to be present at T2)*(additional proportion newly enrolling 
at T1)*(proportion HIV-positive)*(number of communities) = 400*0.90*1.10*0.25*30 = 2,970.  
The number of HIV-positive adults in the 6 ESS communities outside the BHS 20% samples is 
calculated as [ (average population size per community)*(proportion expected to be age-
eligible)*(proportion expected to be present)*(proportion expected to consent)*(proportion 
HIV-positive)–(average number of HIV-positive BHS enrollees per community at T2) ]*(number 
of ESS communities) = [ (6,027*0.58*0.8*0.85*0.25) – (2,970/30) ]*6 = 2,972.  
Therefore the ESS denominator per arm is 2,970 + 2,972 = 6,050/2 = 2,971.  
o Based on preliminary BHS data, we found that 87% of HIV-positive participants who knew their 
status were on ART representing 73% of all HIV-positive persons (irrespective of prior 
knowledge of status). Assuming that HIV diagnosis among HIV-positives will increase by 3% over 
2 years in the EC arm and that 87% of these new diagnoses will initiate ART, we expect an 
additional 2.6% of all HIV positive-persons will be on ART by T2. Additionally, we expect that by 
T2 UTT will have been scaled up and available in EC communities for approximately 6 months.  
Therefore, all ART-naïve individuals will be eligible for ART including those with CD4≤350 at 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
54 
baseline.  Based on preliminary BHS data, 7.8% of HIV-positive, ART-naïve persons have a 
CD4>350 cells/mm3. Since UTT will only have been in place for approximately 6 months by T2, 
we assume that 50% of these ART-naïve individuals with a CD4>350 cell/mm3 will be on ART by 
T2 or 7.8%*0.5 = 3.9%.  
Thus, the ESS numerator for the EC arm is calculated as 2,971*[ (proportion of HIV-positive 
persons expected to know their status and currently on ART at T0) + (additional proportion of 
HIV-positive, ART-naïve at T0 expected to be on ART by T2 due to increased diagnosis and 
under UTT) ] = 2,971*(0.73+0.026+0.039) = 2,971*0.795 = 2,405 
o The ESS numerator for the CP arm is calculated as 2,971*(target outlined in Protocol 3) = 
3,516*0.93 = 2,763. 
• VL suppression numerators and denominators: 
o The BHS denominator includes HIV-positive persons aged 16-64 years in the 20% BHS sample 
and is calculated as described above for the BHS denominator for ART coverage = 3,000.    
o The BHS numerator is calculated as 3,000 * (proportion HIV-positive persons expected to know 
their status, be on ART and have a VL ≤400 copies/mL based on preliminary BHS data) = 
3,000*0.70 = 2,100. 
o The ESS denominator by arm includes all HIV-positive adults from the BHS 20% sample in the 
24 communities not selected for participation in the ESS and all HIV-positive adults in the 6 ESS 
communities as described above for the ESS denominator for ART coverage = 2,971. 
o Based on preliminary BHS data, we found that 96% of HIV-positive participants who knew their 
status and were on ART were virologically suppressed representing 70% of all HIV-positive 
persons (irrespective of prior knowledge of status and ART status). Therefore, the additional 3% 
increase in diagnosis among HIV-positive persons by T2 in the EC arm contributes to an increase 
in VL suppression coverage of 3%*87%*96% = 2.5%.  As described above, due to UTT, there will 
be an increase in VL suppression coverage among previously ART-naïve individuals with a 
CD4>350 cells/mm3 of 3.9%*96% = 3.7%.   
Therefore, the ESS numerator for the EC arm is calculated as 3,516*[(proportion of HIV-positive 
persons expected to know their status who are on ART and virologically suppressed) + 
(additional proportion on ART and virologically suppressed due to increased diagnosis and 
UTT)] = 2,971*(0.70+0.025+0.037) =  2,971*0.762 = 2,264. 
o The ESS numerator for the CP arm is calculated as 2,971*(target outlined in Protocol 3) = 
2,971*0.95 = 2,822. 
• MC coverage numerators and denominators: 
o The BHS denominator includes HIV-negative men in the BHS 20% sample and is calculated as 
average number of BHS enrollees per community)*(proportion who are male)*(proportion HIV-
negative)*(number of communities) =  400*0.45*0.8*30 = 4,320.  
o The BHS numerator is calculated as 4,320*(proportion of HIV-negative men circumcised based 
on preliminary BHS data) = 4,320*0.35 = 1,512. 
o The ESS denominator includes HIV-negative men from the BHS 20% sample in the 24 
communities not selected for participation in the ESS and all HIV-negative men (100% sample) 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
55 
in the 6 ESS communities. The assumptions regarding additional enrollment at T1 are described 
in detail above for ART coverage.   
The number of HIV-negative men from the BHS 20% sample in the 24 non-ESS communities and 
6 ESS communities is calculated as (average number of BHS enrollees per 
community)*(proportion expected to be present at T2)*(additional proportion newly enrolling 
at T1)*(proportion male)*(proportion HIV-negative)*(number of communities) = 
400*0.90*1.10*0.45*0.8*30 = 4,277.  
The number of HIV-negative men in the 6 ESS communities outside the BHS 20% sample is 
calculated as [ (average population size per community)*(proportion expected to be age-
eligible)*(proportion expected to be present)*(proportion expected to consent)*(proportion 
male)*(proportion HIV-negative) – (average number of HIV-negative BHS male enrollees per 
community at T2) ]*(number of ESS communities) = [ (6,027*0.58*0.8*0.85*0.45*0.8) – 
(4,277/30) ]*6 = 4,279.  
Therefore the ESS denominator per arm is 4,277 (HIV-negative from the BHS 20% sample in 30 
communities) + 4,279 (HIV-negative men from the 80% sampled in 6 ESS communities) = 
8,556/2 = 4,278.  
o The ESS numerator for the EC arm is calculated as 4,278* (proportion of HIV-negative men 
expected to be circumcised) = 4,278*0.5 = 2,139.  
o The ESS numerator for the CP arm is calculated as 4,278*(target outlined in Protocol 3) = 
4,278*0.6 = 2,567.  
 
• Widths of the 95% confidence intervals: 
o Based on the variance formula from Hayes and Moulton (2009), the 95% CI widths are 
calculated as follows: 
𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝= 1.96 ඨ𝑝𝑝(1 −𝑝𝑝)𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
𝑛𝑛
 
𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= 1 + (𝑚𝑚−1)𝑘𝑘2
𝑝𝑝
(1 −𝑝𝑝) 
𝑚𝑚= 𝑛𝑛
𝑐𝑐 
 
precision is the width of the 95% CI 
 
p is the proportion for which the 95% CI is calculated 
 
DEFF is the design effect 
 
n is the total sample size from which p is calculated (i.e., denominator) 
 
k is the between-cluster coefficient of variation of the true proportion 
 
c is the number of clusters (i.e., number of communities) 
 
Table 5 summarizes the inputs for calculating the widths of the 95% CIs shown in Table 4. 
 

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56 
Table 5: Inputs for Calculating CI Widths Surrounding HTC, ART (including VL suppression), and MC 
Coverage Proportions at Baseline and Study End 
Input 
Baseline Household 
Survey (BHS) 
End of Study Survey (ESS) 
All Study Communities 
EC Arm 
CP Arm 
HTC 
Coverage 
p 
0.37 
0.48 
0.90 
n 
12,000 
5,931 
5,931 
c 
30 
4 
4 
k 
0.1 
0.1 
0.1 
ART 
Coverage 
p 
0.73 
0.795 
0.93 
n 
3,000 
2,971 
2,971 
c 
30 
15 
15 
k 
0.1 
0.1 
0.1 
VL 
Suppression 
p 
0.70 
0.762 
0.95 
n 
3,000 
2,971 
2,971 
c 
30 
15 
15 
k 
0.1 
0.1 
0.1 
MC 
Coverage 
p 
0.35 
0.50 
0.60 
n 
4,320 
4,278 
4,278 
c 
30 
15 
15 
k 
0.1 
0.1 
0.1 
 
5.2.2. Power to detect difference in coverages of HTC, ART, VL suppression, and MC at the end of 
study 
 
The coverage of ART, VL suppression, and MC will be assessed in eligible participants in 100% of 3 
pairs of randomly selected communities and 20% of the remaining 12 pairs of communities. The 
coverages of ART, VL suppression, and MC in the 12 pairs of communities will be adjusted based on 
the difference in coverage observed between the 20% cohort and the remaining 80%. HTC 
coverage over the past 12 months and 24 months will be assessed in eligible participants in 80% of 
the 3 pairs of communities, outside of the 20% cohort. This is because the 20% cohort in both arms 
is expected to receive 100% HTC coverage by study design. 
 
The projected coverage of HTC, ART, VL suppression, and MC at the end of year 3 is 52%, 80%, 76% 
and 50%, respectively, in the Enhanced Care arm, and 90%, 93%, 95% and 60%, respectively, in the 
Combination Prevention arm (see Table 4 above).  Assuming a coefficient of variation of 0.1 for 
HTC, ART, VL suppression, and MC coverage, the power in detecting the aforementioned 
differences in coverage in the ESS is 99%, 96%, 99% and 98% for HTC, ART, VL suppression, and MC, 
respectively (see Table 6). 
 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
57 
 
 
 
 
Table 6. Estimated Power of Detecting Differences in Coverages in HTC, ART, VL Suppression, and 
MC between Enhanced Care (EC) and Combination Prevention (CP) Arms in the ESS 
 
HTC 
ART 
VL 
MC 
Projected 
Coverage at 
ESS 
EC 
48% 
80% 
76% 
50% 
CP 
90% 
93% 
95% 
60% 
Coefficient of Variation 
0.1 
0.1 
0.1 
0.1 
Power 
99% 
96% 
99% 
98% 
 
5.2.3. Sampling Strategy for End of Study Survey (ESS) 
 
To ensure on-time completion of the ESS, which will be conducted by one team in each arm, ESS 
communities must be selected with consideration given to the sequence of the rollout of BHS, 
population size and region. To select 3 feasible pairs of ESS communities, we considered the 
anticipated rollout sequence and selected one pair of communities from each of the three regions 
represented in the study. This resulted in the inclusion of the 5th, 7th and 13th pairs as the initial list 
of ESS communities. No further adjustment of selection is expected to be necessary, but in the 
event of unanticipated changes in logistical or operational activities, the selection procedure 
described above may be repeated prior to any outreach for the ESS.  
To sample 100% of households in 3 pairs of Combination Prevention and Enhanced Care 
communities at the end of the study, all households in the selected Combination Prevention and 
Enhanced Care communities will be approached for: (1) GPS mapping, (2) enumeration of number 
and demographics of persons living in households, and (3) offering of HTC services. The ESS will 
therefore include residents of the 80% of households not participating in the BHS/HIC in the 3 
selected pairs of communities, and ESS data will be complemented by data from the residents of 
the 20% of households participating in the BHS/HIC in all 30 communities at T2. 
 
Note that it is likely we will reach all 20% of households with BHS/HIC enrollees during the ESS, 
because HIC households will have previously agreed to study procedures. However, it is less certain 
what proportion of the remaining 80% of households will agree to the survey.   
 
Possible reasons for not reaching non-HIC households in Enhanced Care and Combination 
Prevention communities at study end include: 
• Refusal:  We expect rates of refusal for participation in the ESS to be <15%, based on 
experience from northern Botswana and Mochudi district.   
• Not at home during the household visit:  This may apply particularly to men.  If the survey 
team determines that certain household members are best reached for the survey after hours 
during the week or on weekends, arrangements will be made to visit the households during 
these convenient times. 
 
Investigators will need to assess whether participation rates in the household survey introduces 
any potential selection bias. 

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58 
 
5.3. 
Expected Numbers of Study Participants 
 
Study participants will be recruited to participate in and provide data for different aspects of the study 
per the Table below. 

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Table 7. Expected Numbers of Participants in Study Components 
Study component 
Targeted subjects 
Expected # of Participants 
Data Collection 
Household 
structure 
Household representative in 20% households 
7,244 
• 
Household Composition Form (updated at 
each visit) 
• 
Baseline Household Survey at T0 
BHS/HIC 
Age-eligible members of 20% households, a 
subset of whom will be enrolled into the HIC 
(HIV-negative and meeting additional HIC 
eligibility critieria)  
12,000 total (9,000 in HIC) 
• 
Baseline Resident Survey at first visit 
• 
Annual Resident Survey at subsequent 
visits 
Qualitative 
Research on 
Barriers to and 
facilitators of LTC 
and ART initiation 
among BHS 
participants 
HIV-infected BHS participants  
BHS Research Assistants and Nurse Prescribers 
60 BHS participants in FGDs 
40 BHS participants in IDIs 
20 Research Assistants and 
Nurse Prescribers inFGDs 
• 
Focus Group Discussions 
• 
In-depth semi-structured interview guide 
Blood draw for 
research purposes  
HIV-infected individuals (or seroconverters  in 
BHS/HIC 
3,270 (part of 12,000 above) 
Same as for BHS 
HIV-infected BHS residents who decline survey 
participation but are willing to give a blood 
sample 
150 
 
Research blood draw form 
All HIV-infected persons in CP community 
clinics 
11,934 
Research blood draw form 
End of study 
survey 
All eligible residents in 3 pairs of selected 
communities 
14,262 total: ~2,400 from the 
20% households at T2 and 
~11,862 from the remaining 
80% of households. 
 
End of Study Resident Survey (for participants 
enrolling for the first time at ESS) 
Final Resident Survey (modified annual follow-
up survey) for previous enrollees from 20% 
households) 
Supplemental 
Economic 
Assessment 
Individuals experiencing OIs seeking out- or 
inpatient care 
Up to 150 (depending on how 
many respondents from 20% 
households meet this criteria) 
Economic Assessment 
Individuals with low CD4 without OIs seeking 
out- or inpatient care 
Up to 300 (depending on how 
many respondents from 20% 
households meet this criteria) 
Economic Assessment 
Point-of-care Viral 
Load Pilot Study 
ART-naïve HIV-infected individuals in BHS 
Up to 400 
 

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60 
5.4. 
Planned Interim Analysis of Data  
 
The BCPP is divided into three interlocking protocols (two active protocols, after Protocol 2 was 
terminated in 2015), and the investigators expect that DSMB review will require information regarding 
interim study results and study conduct from all three.  The combination prevention package under 
study includes provision of ART for all HIV-infected adults regardless of WHO Stage or CD4 count. 
Hence, the reports will provide information needed to evaluate the adverse and favorable effects of 
this intervention on individually treated patients as well as on the villages in which they reside. The 
study will require at least 5 reviews, DSMB 1-5, proposed to take place at baseline and at the end of 
years 1, 2, 3, and 4. DSMB 3 will evaluate intervention rollout and safety. To demonstrate that the 
study has reasonable power to answer the study questions given information up to the time of each 
review, investigators will provide the DSMB with assessments of the adequacy of coverage of proposed 
interventions; estimated conditional power given available incidence information will be provided at 
DSMB 4. Investigators (other than statisticians preparing DSMB reports) will remain blinded to HIV 
incidence data collected from the HIC, during the conduct of the study.  Details of the DSMB review 
plan for each protocol are provided in that protocol, and the full detailed plan is provided in Appendix 
C4.   
 
5.4.1. Proposed Schedule of DSMB Reviews 
 
The incidence cohorts (HIC) will be enrolled in all 30 communities over a period of approximately 
two years.  The enrollment of incidence cohorts for one matched pair (2 study communities) will 
begin simultaneously. The number of  working days required to complete each community in the 
pair will vary depending on the sizes of the communities.The BHS/HIC households will be revisited  
approximately 12 months, and 30 months after they were enrolled.  Figure A in Appendix C4 
illustrates the planned schedule of enrollment and follow-up. 
 
As demonstrated in Figure A in Appendix C4, there are 5 proposed DSMB reviews.  The proposed 
components of each DSMB review are summarized in Table A in Appendix C4. Harvard investigators 
will provide at least 5 DSMB reports related to activities covered in this Evaluation Protocol: one for 
protocol review before enrollment, one each at DSMB 2 and 3 with reports of baseline parameters; 
one at DSMB 4 (after the end of calendar year 3) with assessment of conditional power based on 
available incidence information and relevant coverage information in intervention implementation, 
and one at study end at DSMB 5. At DSMB 5, we will provide reports on all data collected during 
the BHS, HIC follow-up, and ESS.  
 
 
 
 
 
 

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6. STUDY PROCEDURES 
 
In this section we describe detailed study procedures for each of the following study segments: (1) the 
Baseline Household Survey (BHS), (2) the HIV Incidence Cohort (HIC), (3) Research Blood Draws, and (4) 
the End of Study Survey (ESS).  
 
6.1. 
Baseline Household Survey (BHS) 
 
Overview: During the BHS conducted in the 20% households, voluntary HIV testing and counseling 
(HTC) will be conducted, and the HIC will be identified and enrolled (note: the HIC is an open cohort, so 
additional eligible residents of the same 20% households may enroll in the HIC in subsequent years). 
HIV-positive participants will be referred to the local clinic for evaluation and if eligible, related 
interventions in Combination Prevention communities. All eligible consenting residents of the 20% 
households will be asked to take part in a survey (and, if HIV-infected, a research blood draw). All of 
these participating residents will be asked to respond to the same core survey (Resident Survey, 
Baseline).  
 
Data collected under previous versions of the protocol with the original follow-up schedule will still be 
used, i.e. data and samples from participants whose communities had a T2 and/or T3 visit under the 
former follow-up schedule will be included in analyses. This protocol outlines the visit schedule and 
procedures to be implemented following the roll-out of version 5.0 but does not invalidate approved 
protocol procedures conducted prior to the roll-out of version 5.0.  
 
Starting with version 5.0 of the protocol, during the subsequent visit to the household at T1, newly-
identified eligible residents will be asked to enroll in the BHS/AHS, including the HIC (or, if HIV-infected, 
for a research blood draw); and all eligible residents will be asked to complete a survey focused on 
assessing uptake of key components of the combination prevention package (and changes in risk 
behavior), regardless of whether or not they are participating in the HIC or are referred for 
interventions. 
 
6.1.1. Selection and Recruitment of Households for the BHS 
 
• Random Selection:  As described in Section 5, for each study community, a complete list of 
households will be obtained from google area maps (and potentially complemented by data 
from other sources).  From this sample frame, 25% of households will be selected using 
simple random sampling.  In villages with population under 6,000, the required 20% 
households will be randomly selected from the 25% sample and approached first for 
participation in the study. In villages with population over 6,000, 333 households will be 
randomly selected from the 25% sample and approached first for participation in the study. 
The remaining 5% of selected households will be considered back-up households in case 
some of the households in the primary 20% sample refuse to participate.  Households in the 
back-up list will be ordered (e.g. 1-49) to indicate the order in which they should be 
approached to meet sample size requirements.   
 

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• Recruitment:  Trained community liaison officers (CLOs) may do reconnaissance visits in 
advance of the survey team, for example, to identify households in the sample that are not 
actually inhabited or are not residential dwellings. These staff may also try to find out the 
ideal time for the survey team to visit, and the approximate size of the household so that 
the survey team may plan to accommodate potential participants. Research staff may 
perform these functions in the absence of CLOs. Each of the households in the 20% primary 
sample will be approached by the survey team for participation in the study. If some of 
these selected 20% households elect not to participate (e.g., all residents are repeatedly 
absent or refuse consent), the additional households in the full 25% sample will be 
approached, in the order specified, until either the pre-specified sample (described above) 
has been achieved or this 25% sample list is exhausted. All eligible residents will be asked to 
take part in activities related to the BHS (using the BHS/HIC Consent). Those who are 
confirmed HIV-uninfected and meet additional HIC eligibility criteria will be enrolled in the 
HIC (see Section 6.2). ART-naive HIV-infected residents will be referred to local clinics for 
WHO staging and in CP communities immediate ART initiation (see Intervention Protocol). 
See Figure 3.   
 
Training:  Prior to approaching the community, survey staff will have been trained in study 
procedures, including the informed consent process, HTC counseling, questionnaires and 
sample collection/processing/transport methods.  Training will occur following structured 
procedures, to ensure that all study staff are trained in the same procedures.  Survey staff 
will be arranged into teams of sufficient size and number, such that the study schedule can 
be met. 
 
 
6.1.2. Household Visit Procedures for the BHS 
 
Interview of Household Representative:  Trained study staff will approach the household 
representative of a selected household, which will preferably be the household head when 
available, but may be any other eligible household representative.  Verbal consent will be 
requested using an IRB-approved script (Household Script).  If consent is granted, general 
household information will be obtained from the household representative using the 
Household Composition Form. Information to be recorded includes: 
o Household GPS 
o Household address 
o Household Size 
o Household Composition. For each household member:  
o Age 
o First name or initials  
o Gender 
o Presence at the time of the household visit 
o Estimated number of nights spent per month outside the community over the past 12 
months (which will be confirmed by individual household members) 
o Relationship to the head of the household or representative 
o Common household socioeconomic indicators (Household Survey, Baseline) 
 

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Classification of Households that Cannot be Enumerated 
All visited households selected for BHS need a final disposition status so that a decision can be 
made about whether any household is eligible for replacement. In cases where the residency 
status of a plot remains uncertain after a total of three visits, a research staff member will 
approach either a neighbor or a representative at the Village Development Committee (VDC) 
for assistance. This representative, who must be 18 years of age or older, will be asked whether 
a plot/household is regularly occupied by potentially eligible residents (Household Residency 
Status Assessment) to assist in making a final determination of the plots/households’ residency 
status. 
 
Interview with Age-Eligible Household Members (16-64): 
HIV counseling and testing (also, see HIV Testing Procedures below): to avoid creating an 
impediment to HIV testing that would not exist for residents accessing routine health services 
(by requiring written informed consent for, and participation in, study procedures), HTC (and 
POC CD4 as needed) will be offered to household members who decline participation in the 
research survey. Whereas only BHS study team members in Enhanced Care communities will 
offer HTC testing, HTC may be offered either by the BHS study team or by the HTC campaign 
team in Combination Prevention communities; the BHS study team will also refer individuals 
who decline testing to local clinics where HIV testing is available. Note: HIV and CD4 results 
(and accompanying information that is routinely collected as part of public HTC programs) will 
be collected on the HTC Intake form (see Intervention Protocol) in Combination Prevention 
communities and made available to the linkage to care manager  for monitoring and evaluation 
of the intervention package (and as will be done as part of the HTC campaigns in the 
Combination Prevention communities). The linkage to care manager and HTC campaign team 
will be aware of the location of households selected for BHS/HIC in Combination Prevention 
communities, and will be informed of numbers of those who were not reached during the 
household survey due to refusal or absence. Residents declining HIV testing can still take part in 
the BHS, if they agree. 
 
• Written informed consent for participation in the BHS and annual follow-up visits will be 
obtained from each willing individual aged >18 who meets BHS eligibility criteria (BHS/HIC 
Consent). For residents aged 16 or 17 who meet BHS eligibility criteria, parental permission 
followed by minor assent will be obtained. Up to two revisits will be scheduled for absent 
individuals.  The BHS consent will request permission for the study questionnaire, blood draws 
for research purposes for persons testing HIV-positive (including blood draw for HIV genotype, 
HIV incidence assay, and viral load) at the current visit or in cases of future seroconversion to 
HIV-positive status, optional storage of leftover blood for future testing, CD4 and viral load 
testing at T1 and/or T2 for HIV-positive individuals who are ART-naïve at enrollment or who 
seroconvert and are ART-naive after enrolling, and annual household questionnaire completion 
(at T1, T2--and T3 [for any communities completing T3 prior to the roll-out of version 5.0]) by all 
participants. With the elimination of the T3 visit in version 5.0 of this protocol, a Dear 
Participant letter will be used to inform enrolled participants that T2 will be their final visit. HIV-
infected participants who decline participation in the BHS survey can still provide informed 
consent to donate blood for HIV VL and genotyping/incidence assay, using a separate consent 
form (Research Blood Draw Consent). 
 

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64 
• Questionnaire:  
Each consenting eligible household member will be interviewed/complete a questionnaire in a 
private environment within the household or at an agreed upon space. A questionnaire will be 
completed at the BHS enrollment visit (Resident Survey, Baseline); in addition, a shorter follow-
up questionnaire (Resident Survey, Annual) will be administered to BHS participants, including 
HIC members, at subsequent visits. During the final T2 visit, a Final Resident Survey will be 
administered to BHS/HIC participants. The first questionnaire (Resident Survey, Baseline) will 
include questions on basic demographic variables, current health status, medical history, prior 
coverage of HTC, current coverage of MC, prior or current pregnancies, sexual risk behavior, 
basic screening for active tuberculosis by symptoms-questions, and (among HIV-infected 
persons), prior/current use of antiretrovirals for treatment or PMTCT.  All residents will 
complete a core questionnaire. When possible, residents may be randomly assigned to 
complete different short supplemental questionnaires in order to keep the duration of the 
interview as short as possible while still collecting key variables. Skip patterns will ensure that 
appropriate questions are asked depending on the self-reported HIV status, gender, and prior 
participation of the consenting adult. Subsequent questionnaires will include variables related 
to CP package intervention uptake, general health (e.g. history of serious illnesses, and in a 
sample of willing respondents, blood pressure and hip/waist circumference), and sexual risk 
behavior. Data will be collected on a mobile electronic device (e.g. notebook); these devices will 
use authentication/password protection and encryption to render information electronically 
unusable, unreadable, or indecipherable to unauthorized individuals. Mobile devices and the 
staff operating them will not be equipped with the encryption keys to decrypt select sensitive 
data fields. Secure and lockable rooms will be used to store mobile devices when not in use. 
 
• HIV testing procedures, BHS:   
HIV testing will be offered to all adults who do not have documentation of HIV-positive status.  
Documentation of HIV-positive status is participant self-report of positive HIV status, in 
combination with: (1) an official MOH HIV test result card indicating HIV-positive status, (2) 
documentation of prior ART or PMTCT ARV prescription, or (3) documentation of pre-ART care 
including either a CD4 count, a WHO Stage, or some specific mention of medical care for the 
HIV-infected patient by a clinical care provider.  When in doubt, HIV status will be considered 
“undocumented”.   
 
a) Adults with no Documentation of HIV-Positive Status, BHS:   
These individuals include those reporting being HIV-negative at their last test, 
individuals reporting never having HIV tested, or individuals reporting being HIV-
infected but not having documentation of HIV-positive status as described above. 
 Pre- and post-test counseling will be provided by trained staff, as per Botswana 
Government guidelines and standards. 
 Capillary blood samples will be collected by fingerprick using a sterile disposable 
lancet. Blood will be aliquoted into a microtube. This blood will be used for both the 
rapid HIV test and subsequently (among HIV-positive individuals), for point-of-care 
CD4 cell count (POC CD4). If a capillary blood sample cannot be obtained a venous 
blood sample (4-5 ml) may be drawn instead for the rapid HIV test and subsequently 
(among those testing HIV-positive), used for POC CD4. 

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65 
 The capillary (or venous) blood sample will first be tested using parallel HIV rapid 
testing algorithms (see Section 8.4).  HIV rapid test results will be released to the 
participant at the time of the visit.   
 Discordant HIV test results will be resolved by collection of a venous blood sample (~ 
4-5 ml) that will be sent to the laboratory for HIV enzyme immune-assay (EIA) 
testing as per the National Algorithm.  Contact details of individuals with sero-
discordant results will be obtained and when HIV EIA results are available, the study 
personnel make arrangements provide the results (either in the person’s home or in 
the clinic, depending on the participant’s preference) and perform the appropriate 
post-test counseling and remaining study procedures. 
 Subsequent management of the individual will depend on the HIV test result: 
 
 HIV Negative Participants:  HIV negative household members meeting eligibility 
criteria for the HIV Incidence Cohort (HIC) will be enrolled in the HIC (see 
Sections 4.4 and 6.2). HIV-negative participants meeting criteria for the BHS but 
not the HIC will participate only in the BHS and subsequent surveys.   
 
 HIV-Positive Participants: Residual blood remaining after HIV testing will be used 
to perform a POC CD4 test using the PIMA CD4 machine at the household. If 
insufficient blood remains from the sample taken for the HIV rapid test, venous 
blood should be drawn (4-5 ml) along with the tubes for VL and 
genotyping/incidence assay (see below) to avoid a separate prick. POC CD4 
results will be provided to the participant immediately following testing.  
Participants will have venous blood drawn for viral load/HIV incidence 
assay/genotyping/storage.  The blood for viral load, HIV genotyping, and HIV 
incidence assay testing will be collected in 2 tubes: 4-5 ml for viral load and up to 
10 ml for HIV genotype/incidence assay/storage. The viral load results will be 
returned to HIV care clinics. The pre-ART viral load is not standard of care and is 
not required to determine ART eligibility in Botswana. Therefore, while it will be 
shared with clinics, it will be of limited clinical use.  The incidence assay and viral 
phylogenetic tests are being performed primarily for research purposes, and will 
not be run in real time; therefore results will not be returned to the patient.  
Efforts will be made to avail results indicating transmitted drug resistance to 
participants. However, this testing will be done retrospectively and therefore 
may be of limited clinical utility. 
 
All HIV-infected persons who are not yet in HIV care and/or on ART will be 
referred for immediate HIV care and treatment at the study community clinic 
according to national guidelines in all Enhanced Care and Combination 
Prevention communities.  If the patient is treatment-naive, the patient will also 
be referred to the study community clinic in Combination Prevention 
communities for immediate ART initiation. Access to universal ART is described 
in the separate Intervention Protocol that is part of the BCPP. 
 

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66 
Figure 4A: BHS Procedures for Individuals with no Documentation of HIV-Positive Status 
 
Abbreviations: CPC, Combination Prevention Community; ECC, Enhanced Care Community; HH, 
Household; HTC, HIV Testing and Counseling; RT, Rapid Test; POC, Point-of-Care; C, consent procedures; 
IND, indeterminate; VL, viral load; EIA, enzyme immuno-assay; WB, Western Blot. 
*Eligible persons only (See section 4.4). 
^Leftover sample from either the fingerprick or 4-5mL sample will be run in a small subset of HIV+ 
participants not currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).   
 
 
b) Adults who Have Documentation of HIV-Positive Status, BHS: 
These individuals include residents who report being HIV-positive and have 
documentation supporting this (MOH HIV test card, documentation of prior ART, CD4, 
WHO staging, or specific mention of HIV-related clinical care). Subsequent management 
of the participant will depend on whether the participant reports taking ART: 
 All BHS participants documented to be HIV-infected (regardless of ART status):  A 
venous blood draw for a 4-5ml EDTA tube for HIV viral load, and a 10ml EDTA tube 
for genotyping/HIV incidence assay will be requested.  
 Residents documented to be HIV-infected but ART-naive: these residents will have 
a POC CD4 test run (and will be provided with the result). Generally, the sample for 
this POC CD4 in ART-naive residents documented to be HIV-infected will be drawn 
along with the venous blood for VL and genotyping/incidence assay, to avoid a 
separate prick. For residents declining the research blood draw, sample for POC CD4 
can be obtained by finger stick for capillary blood.  All HIV-infected persons who are 
not yet in HIV care and/or on ART will be referred for immediate HIV care and 
treatment at the study community clinic according to national guidelines in all 
Enhanced Care and Combination Prevention communities.  Patients will also be 

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67 
referred to the study community clinic in Combination Prevention communities, for 
universal ART, which is described in the separate Intervention Protocol that is part of 
the BCPP. 
 
Figure 4B: BHS Study Procedures for Individuals with Documentation of HIV-Positive Status 
 
Abbreviations: CPC, Combination Prevention Community; ECC, Enhanced Care Community; HH, Household; HTC, 
HIV Testing and Counseling; POC CD4, Point-of-Care CD4; C, consent procedures; VL, viral load. 
*Consent administered to eligible household members only (see section 4.4). 
^Leftover sample from either the fingerprick or 4-5mL sample will be run in a small subset of HIV+ participants not 
currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).   
 
Note about Test Results During BHS: Individuals participating in HTC will be offered the result of 
their rapid HIV test with post-test counseling. During the BHS, POC CD4 results will be given to 
the participants in all communities. The viral load results will be returned to HIV care clinics. The 
pre-ART viral load is not standard of care and is not required to determine ART eligibility in 
Botswana. Therefore, while it will be shared with clinics, it will be of limited clinical use.  The 
incidence assay and viral phylogenetic tests are being performed primarily for research 
purposes; therefore results will not be returned to the patient. Genotyping will not be run in real 
time and therefore will be of limited utility for patient care. However, if results indicate 
transmitted drug resistance, efforts will be made to avail this information to the participant 
upon completion of testing.   
 
• Compensation:   
BHS participants will receive 20 pula in cell phone airtime as compensation for their time to 
participate in the survey. 

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68 
 
6.1.3. Household Visit Procedures for Non-HIC Members at T1: 
 
These procedures pertain to consenting residents (both HIV-uninfected and HIV-infected) in 20% 
households who are not participating in the HIC. This group will include residents who took part in 
the original BHS, as well as residents newly-identified at T1 who are not enrolled in the HIC.  
 
For residents who already consented to and took part in the BHS (and are not in the HIC), a short 
survey will be administered at T1, primarily to assess combination prevention intervention uptake 
(and to assess risk behavior/risk compensation and general health). HTC will be offered to those 
without documentation of HIV-positive status. Point-of-care CD4 and viral load testing will be 
offered at T1 to HIV-positive individuals who were ART-naïve upon enrollment into BHS, or who 
seroconvert and are ART-naive after enrolling in BHS. POC CD4 results from T1 will be shared with 
participants in both arms, and viral load results will be shared with clinics (or with patients, if a 
validated point-of-care viral load test is introduced). A research blood draw (for HIV 
genotype/incidence assay testing/optional storage) will be obtained from anyone newly identified 
with HIV infection. Procedures for the final visit to BHS/HIC households at T2 are described with 
those for the end of study survey (ESS). See Figure 5B.   
 
For residents who did not take part in the BHS at T0 (and are not in the HIC), the same procedures 
as outlined for the BHS will be offered at T1.  
 
 
6.1.4. Data Collection and Handling:  
 
• Questionnaires:   For consenting BHS participants, all questionnaire data, HIV test results, POC 
CD4 test results, and information regarding collection of sample for genotyping/incidence 
assay/storage will be collected electronically using notebook computers. These devices will use 
authentication/password protection and encryption to render information electronically 
unusable, unreadable, or indecipherable to unauthorized individuals. Mobile devices and the 
staff operating them will not be equipped with the encryption keys to decrypt select sensitive 
data fields. Secure and lockable rooms will be used to store mobile devices when not in use. 
 
• Consent Forms:  Investigators will document consent procedures on the notebook application.  
One copy of the signed consent form will be kept by investigators while a second copy will be 
kept by the participant.    
 
• Blood samples will be labeled with barcoded stickers and transported to the study clinic or lab, 
as appropriate. 
 
6.1.5. Criteria for Study Discontinuation 
 
Participants will be discontinued from longitudinal follow-up in the BHS (or HIC) if the participant (or 
guardian if < age 18) requests to withdraw. 
 

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6.1.6. Data Collection on Cause-of-Death for Deceased Study Participants 
 
If study staff learn that an enrolled study participant has died during the course of the study, basic 
information related to the cause of death will be recorded. A deceased study participant is no longer a 
human subject per the definition at 45CFR46.102(f); a human subject is a living individual. Data for the 
Cause-of-Death Form may be collected from official sources, such as medical records, a death 
certificate, or from health care providers. 
 
6.2. 
HIV Incidence Cohort (HIC) 
 
Methods for household selection and identification of eligible persons for HIC enrollment are 
described above (Section 6.1). 
 
6.2.1. Enrollment Procedures, HIC 
 
• Consent: As described in Figure 4A above, residents of the 20% households will be asked for 
consent for survey participation (BHS/HIC Consent). This consent will request permission for the 
baseline study questionnaire,  subsequent HIV testing and questionnaire at follow-up visits, 
future blood draw for research purposes if seroconversion to HIV-positive status occurs (blood 
for HIV viral load/genotype/incidence assay/optional storage), POC CD4 and viral load at T1 
and/or T2 (among a subset, as described above) if seroconversion occurs, and storage of blood 
remaining from the HIV rapid test microtube finger prick draw. The latter will be used for 
confirmation of negative HIV status at enrollment, if future HIV seroconversion occurs. 
Consenting residents who are determined to meet HIC eligibility criteria will be enrolled in the 
HIC. 
• Venous blood draw: In the event that insufficient blood remains from the sample drawn for the 
HIV rapid test, HIC enrollees will have a venous blood sample drawn for storage at the research 
lab.  If the participant sero-converts during HIC follow-up the baseline sample will be available 
to confirm that the participant was truly HIV-negative at enrollment. The storage of this 
baseline blood sample is indicated for this protocol and covered in the main body of the 
BHS/HIC consent form. This blood draw will also mitigate the potential for inadvertent HIV 
status disclosure that could occur if venous blood draws only pertain to HIV-infected 
individuals. 
• Questionnaire and Forms:  All consenting residents will be administered an enrollment 
questionnaire (Resident Survey, Baseline), and contact information (mobile phone numbers, 
alternate addresses, and addresses of a friend/family member) will be obtained to facilitate 
tracing (Locator Form).  At T1, a shorter questionnaire (Resident Survey, Annual) including 
questions related to CP package intervention uptake, general health, and sexual risk behavior 
will be administered. Those who decline enrollment in the HIC will be asked to take part in the 
BHS only. Residents declining both the HIC and BHS will be thanked for their time and asked, via 
an IRB-approved verbal consent script (Refusal Script) to provide basic information about their 
reason for declining via the Refusal Survey Form. This will assist in characterizing the impact of 
refusal on study outcomes. 
 
6.2.2. HIC Follow-up 

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70 
 
• HIC Follow-up Schedule: Subsequent household surveys of the HIC will be conducted at 
approximately 12 and 30 months after enrollment (T1 and T2, respectively).  Procedures for the 
final visit at T2 visit are described with those for the end of study survey (ESS).  Therefore, in 
this section, we restrict description of procedures to those that apply to T1.  HIC activities 
conducted during the T1 follow-up household visits include: (1) updating the household 
structure to assess who might be newly eligible for BHS/HIC enrollment, (2) repeat HIV testing 
and questionnaire administration to HIC enrollees, and (3) screening non-HIC enrollees for HIC 
eligibility.  These three activities are described in detail below.  Wherever possible, via 
telephone or other communication channels, study teams will arrange a suitable time and 
venue to meet, and perform study procedures, for HIC household members. When necessary, 
study interviews may be conducted by phone. 
 
• Activity #1, HIC Follow-up:  Update Household Structure:  Study staff will approach the 
household head or representative of the selected household. A previously enrolled household 
member can serve as the household representative, where appropriate. Updated household 
information will be obtained. Information to be recorded includes: 
o Household GPS (confirmed – not re-measured) 
o Household address updated if there have been changes 
o Household Composition (updated) 
 
• Activity #2, HIC Follow-up:  Questionnaire, Repeat HIV Testing, and Other Lab Draws in 
Existing HIC Enrollees (Figure 4C):   
HIC participants will have previously consented to the questionnaires and blood draws 
described here (as part of the BHS/HIC consent process). Previous enrollees of the HIC will be 
engaged in a follow-up questionnaire (Resident Survey, Annual), administered using devices 
such as notebook computers; these devices will use authentication/password protection and 
encryption.  In addition, HIC enrollees will be re-tested for HIV using point of care rapid tests 
(two different rapid tests in parallel) performed on blood collected from a fingerstick in a 
microtube.  Even if the HIC enrollee indicates that he/she has tested HIV-positive and enrolled 
in care since the earlier negative HIV test, repeat HTC will be offered to existing HIC enrollees to 
confirm HIV positive status one time.   
 
If the existing HIC enrollee tests HIV-negative, the enrollee will be offered routine post-test 
counseling, and, in Combination Prevention communities only, those services for HIV-negative 
adults that constitute part of the CP package (TB screening and referral of uncircumcised HIV-
negative males for MC).  
 
If the participant tests HIV-positive, (or if the participant reports knowing HIV-positive status 
and refuses repeat HTC), a venous blood draw will be performed for HIV viral load (10mL EDTA 
tube) and for genotyping/incidence assay/optional storage (10mL EDTA tube) among HIC 
participants in both the Enhanced Care and Combination Prevention communities. 
 
Procedures will differ slightly for HIC members in the Enhanced Care vs. Combination 
Prevention communities with regard to linkage-to-care services: 

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71 
• Procedures For HIC Members Testing Positive for HIV During Follow-up:   
 Participants Reporting no Previous ART: a POC CD4 test will be run on residual 
sample from the HIV test, and the CD4 result shared with the participant. If the 
residual sample is insufficient a venous blood draw (4-5 ml) may be performed. 
Linkage-to-care services will be provided in Combination Prevention Communities. 
Participants in Enhanced Care communities will receive the Enhanced Care referral 
to care and treatment services described in the BCPP Intervention Protocol. 
 Participants Reporting Prior ART Initiation:  Management will be the same as for 
pre-ART participants, except no POC CD4 will be run. 
 HIC Members who test positive for HIV at T1: These participants will still have a 
follow-up visit at T2. Participants who seroconvert between T0 and T1, and report 
no previous ART at T1 will have point-of-care CD4 and viral load testing again at T2. 
See Figure 5B. 
 
*Note about Test Results During Follow-up: Individuals participating in HTC during T1 and T2 
will be offered the result of their rapid HIV test with post-test counseling. During follow-up, POC 
CD4 results will be given to the participant during the study visit. Viral load results will be 
returned to HIV care clinics. The pre-ART viral load is not standard of care and is not required to 
determine ART eligibility in Botswana.  The incidence assay and viral phylogenetic tests are 
being performed primarily for research purposes; therefore results will not be returned to the 
patient. Genotyping will not be run in real time and therefore will be of limited utility for patient 
care. However, if results indicate transmitted drug resistance, efforts will be made to avail this 
information to the participant upon completion of testing.   
 
Figure 4C:  Follow-up Procedures for HIC Enrollees During T1 
 
 

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Abbreviations: CP, Combination Prevention; EC, Enhanced Care; HH, Household; RT, Rapid Test; POC CD4, 
Point-of-Care CD4; IND, indeterminate; VL, viral load; EIA, enzyme immuno-assay; WB, Western Blot. 
#Verbal consent script need not be re-administered if the respondent is the same person at follow-up 
visits, or an enrolled survey participant.  
^Leftover sample from either the fingerprick or 10mL sample will be run in a small subset of HIV+ 
participants not currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).  
**At T1, previous HIC enrollees who have seroconverted since T0 will have POC CD4 run if they are ART-
naïve. At T2, these HIC enrollees who had POC CD4 at T1, i.e. those who were ART-naïve at T1, will have 
another POC CD4 at T2, even if they have started ART between the T1 and T2 visits (see Figure 5B).  
 
• Activity #3, HIC Follow-up:  Screening of non-HIC Members for HIC Eligibility:  Adults identified 
as possibly being newly eligible for the HIC, based on the interview with the household 
head/representative, will be approached at T1. For example, residents in the 20% of 
households originally selected who were too young to enroll in the HIC during the BHS may turn 
16 years of age during follow-up, and now be eligible for the HIC, or a new resident may be 
present.  These adults will be invited to participate in the research, asked to sign the BHS/HIC 
Consent, respond to the questionnaire, and then be offered HTC services, similar to procedures 
conducted during the BHS.  Similar to the BHS, adults in the HIC household will either have 
documentation of HIV status, or not.  Subsequent management depends on whether the adult 
already has documentation of HIV-positive status or not: 
 
o No documentation of HIV-positive Status:  These procedures are summarized in Figure 4D 
below.  Potential new participants will be asked consent to join the research study.  Eligible 
HIV-negative adults will be offered the opportunity to enroll in the HIC (refusers and those 
who are not eligible for the HIC will be asked to participate in the same procedures 
summarized in the BHS (see Section 6.1). If consent is granted, the same questionnaire 
administered during the BHS (Resident Survey, Baseline) will be administered to these 
newly identified individuals.  HTC will be offered. HIV-infected adults will be asked for 
research blood draws, and further managed according to whether the patient is in a 
Combination Prevention or Enhanced Care community (Figure 4D). 
 

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Figure 4D:  Procedures for Individuals in 20% Households who are Newly Identified During T1 and 
who have No Documentation of HIV-Positive Status
 
Abbreviations: HH, Household; HTC, HIV Testing and Counseling; RT, Rapid Test; POC CD4, Point-of-Care 
CD4; C, consent procedures; IND, indeterminate; VL, viral load; EIA, enzyme immuno-assay; WB, Western 
Blot. 
#Verbal consent script need not be re-administered if the respondent is the same person at follow-up 
visits, or an enrolled survey participant.  
*Eligible persons only (See section 4.4). 
^Leftover sample from either the fingerprick or 10mL sample will be run in a small subset of HIV+ 
participants not currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).   
**HIV-positive pre-ART participants enrolled at T1 will have POC CD4 and viral load tests at T1 (as shown 
above) and again at T2 (see section 6.1.3 for follow-up procedures of non-HIC enrollees).  
 
Documented HIV-Positive Status:  Newly identified household members with a 
documented HIV-positive status will be interviewed and asked for research blood draws and 
further managed according to whether the individual is in an Combination Prevention or 
Enhanced Care community (Figure 4E). These participants will still have a follow-up visit at 
T2. HIV-positive participants who enroll at T1, and report no previous ART will have point-
of-care CD4 and viral load testing again at T2 (see section 6.1.3 and Figure 5B). 
 

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Figure 4E:  Procedures for Individuals in 20% Households who are Newly Identified During 
T1 and who HAVE Documentation of HIV-Positive Status  
 
Abbreviations: HH, Household; HTC, HIV Testing and Counseling; POC CD4, Point-of-Care CD4; C, consent 
procedures; VL, viral load. 
#Verbal consent script need not be re-administered if the respondent is the same person at follow-up visits, or an 
enrolled survey participant.  
*Consent administered to eligible household members only (see section 4.4). 
^Leftover sample from either the fingerprick or 10mL sample will be run in a small subset of HIV+ participants not 
currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).   
**HIV-positive pre-ART participants enrolled at T1 will have POC CD4 and viral load tests at T1 (as shown above) 
and again at T2 (see section 6.1.3 for follow-up procedures of non-HIC enrollees and Figure 5B).  
 
• HIV Incidence Cohort Retention Procedures: Three attempts to make appointments for follow-up 
visits are made by phone for each study participant before the survey team returns to enrolled 
households. Once the survey resumes in the community, three attempts, either household visits or 
calls, will be performed in an effort to reach each enrolled member and complete follow-up study 
procedures.    
 
• Data Collection:  Questionnaires to be administed to HIC enrollees will be approved by IRBs prior to 
use in the field. All data will be collected electronically on devices such as notebook computers that 
are encrypted and password protected. Investigators will store signed paper consent forms and will 
also indicate electronically whether participant consent has been obtained. Paper copies of 
informed consent forms will be provided to the HIC enrollees.  Blood samples may have bar codes 
linked to study IDs that are applied at the point of sample collection. 
 

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• 
Compensation: Each HIC participant will receive 20 Pula (about $3) worth of air time as 
compensation for time dedicated to the study at each scheduled follow-up study home visit.  
 
6.3. 
Focus Group Discussions and Individual In-Depth Interviews related to barriers to and 
facilitators of linkage to care and ART initiation among a subset of BHS participants 
In order to understand locally-relevant barriers to and facilitators of linkage to care and ART 
initiation, including initiation of "expanded" ART outside of local guidelines, we will conduct 
focus group discussions (FGDs) and individual in-depth interviews (IDIs) with a subset of HIV-
infected BHS participants. The goal is to improve/optimize approaches to linkage to care and 
ART initiation in the context of the overall trial and ultimately in Botswana.  
 
1) Recruitment 
Recruitment will occur at or after T1, because at that time we will be assessing whether HIV-
infected persons referred for care and ART at T0 actually linked/started ART.  
 
We will invite HIV-infected BHS participants 18 years of age or older who, within their own 
community: 1) have not linked to care since initiation of the BHS, 2) have linked to care and 
were found to be eligible for treatment but did not start ART, or 3) linked to care, started and 
continued ART. We will convene up to two focus groups for each one of the three categories to 
learn about barriers to linkage and ART initiation as well as attitudes and approaches that can 
facilitate linkage to care and ART adherence. We aim to include in the FGDs a subset of 
individuals who were eligible to start ART by current local guidelines and a subset who were 
eligible by expanded ART guidelines. These FGDs will be semi-structured and done using an FGD 
guide. We will also conduct semi-structured IDIs focusing on the three groups described above. 
 
We will convene up to 6 FGDs among BHS participants from CPCs that will each include 
between 8 and 10 participants. Participants will be purposefully selected to participate in one 
of the three categories of focus groups based on demographic and laboratory values (data 
collected in BHS). The BHS/HIC consent form states that participants may be invited to 
participate in additional aspects of the research. Using the BHS database and the eligibility 
criteria (see section 4.4.6) a Research Assistant will contact potential participants and ask to 
schedule a dedicated home visit to discuss participation in the FGD or IDI. Potential participants 
will be given a consent form and, if selected for a FGD, a confidentiality agreement to review. If 
a participant agrees to participate in a FGD, he/she will be informed of the date and time of the 
scheduled event. IDIs will be scheduled with participants based on their and staff member 
availability. Written informed consent will be obtained at the time the participant arrives for 
the scheduled FGD or IDI, and before any study procedures take place.  
 
The BHS field team and the MOH nurse prescribers may have vital insight into the dynamics 
surrounding linkage to care and initiation of ART. Therefore, we will invite up to 20 members of 
these two groups to participate in separate FGDs. These FGDs will be semi-structured and done 
using an FGD guide.  Findings from these FGDs will be used to finalize the FGD guides for HIV-
infected BHS participants.   
 
In general, different individuals will participate in FGDs and IDIs. We will continue to invite 
participants for IDIs until thematic saturation is achieved. We plan to conduct up to 40 IDIs. As 

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76 
above, we will aim to include participants who met the eligibility criteria for expanded 
treatment (to investigate their understanding of expanded treatment, and motivators/barriers 
to starting ART) as well as those who were eligible by current local guidelines. Findings from the 
FGDs will be used to finalize the IDI guides.  
 
2) Consent 
All individuals taking part in the qualitative research will sign a separate written consent form 
(ART Start Focus Group Consent for BHS, ART Start Focus Group Consent for Staff, or ART Start 
Interview Consent).  Those participating in FGDs will also sign a confidentiality agreement.  
3) Data Collection and Handling 
FGDs and IDIs will be conducted in a private setting by a trained research assistant in the local 
language (usually Setswana). Focus group discussions and interviews will be audio recorded, 
transcribed and translated; all study records will be collected using study identification 
numbers (without personal identifiers), and will be kept locked and accessible only to relevant 
study staff. Overall results (without identifiers) will be shared with the study team and 
implementing partners, in an effort to enhance linkage to care and ART initiation. 
 
4) Compensation 
Participants in FGDs or IDIs will receive 30 Pula to compensate them for their time and up to 30 
pula in transport reimbursement to attend the FGD or IDI. 
6.4. 
Research Blood Draw Procedures in Combination Prevention Communities, Outside of the 
BHS 
Procedures for the HTC campaigns are detailed in the Intervention Protocol and described in 
brief below.  Under that protocol, community residents identified as HIV-infected in 
Combination Prevention communities will be referred by counselors and linked by Linkage-to-
Care Managers (LTCMs) to HIV care and treatment clinics. These patients will be asked to 
consent to research participation including a blood draw for viral load/HIV genotype/incidence 
assay testing/optional storage. In addition, all other HIV-infected residents of Combination 
Prevention communities (including those already in HIV care; those eligible for ART by 
Government guidelines; and those already on ART) will be invited at the clinic to participate in 
the research blood draw.  
 
1) Recruitment 
• Research blood draw eligibility:  All HIV-infected adult residents of Combination Prevention 
communities are eligible for the research blood draw.  All eligible adults presenting to the HIV 
care and treatment clinics will be offered the opportunity to participate in the research, 
including those already in care (even those on ART).  During the study (prior to the ESS), HIV-
infected Combination Prevention community residents will be asked/consented to give a 
sample for genotyping/phylogenetics/transmitted drug resistance. Each consenting participant 
will be asked a few basic questions (e.g. age, gender, ART status) that will permit interpretation 
of results even if the participant did not take part in other surveys/questionnaires. 
 
• Sample size: Based on the average population size of the study communities and 25% HIV 
prevalence, 11,608 HIV-infected individuals are estimated to reside in the 15 Combination 

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77 
Prevention communities at the time the study starts. These individuals will be invited at local 
clinics to participate in the research blood draw. The expected number of additional 
participants in the clinic-based research blood draws following the first year is based on 
incident cases and therefore expected to be much lower (approximately 326). 
 
• Consent:  Eligible research participants will be consented for a venous blood draw at the time 
of their visit to the clinic that will include a 10mL tube for HIV viral load and a 10ml EDTA tube 
for HIV genotyping/incidence assay/storage (Research Blood Draw Consent). The participant 
may elect to receive the program blood draws (for viral loads only) without the research blood 
draw (blood draw for HIV genotyping/incidence assay/storage), if he/she chooses.  
 
Blood draw: Trained staff will draw the relevant blood samples from consenting patients. 
Patients will receive their viral load result. Results of phylogenetic analysis and other research 
assays will not be returned to participants or their providers. Genotyping will not be run in real 
time and therefore will be of limited utility for patient care. However, if results indicate 
transmitted drug resistance, efforts will be made to avail this information to the participant 
upon completion of testing.   
 
2) Follow-up and Retention:  Program follow-up and retention of HIV-infected patients is 
described in the Intervention Protocol. 
 
3) Data Collection and Handling 
All research data will be collected electronically on devices such as notebook computers that 
are encrypted and password protected.  Investigators will: (1) securely store original written 
signed consent pages, (2) record participant granting of consent electronically, and (3) ensure 
paper copies of informed consent forms are provided to the research participants.  Blood 
samples may have barcodes linked to study IDs applied at the point of sample collection. 
 
4) Compensation 
There will be no compensation for participating in the HTC campaign nor for participating in 
blood/data collection for this research component of the study. 
 
6.5. 
The End of Study Survey (ESS) and Final T2 Study Visit for Previously Enrolled 20% Households 
 
1) ESS Recruitment 
 
• ESS Community Selection: 3 pairs of communities (6 communities in total) will be selected to 
take part in the ESS. Section 5.2.3 details the process for selecting the ESS communities. As 
noted previously, residents of the 20% households in all 30 communities will undergo final 
follow-up evaluations at this T2 time as well. 
 
• ESS Household Selection:  100% of households in the 3 pairs of Enhanced Care and 
Combination Prevention communities (6 total communities) will be targeted for the ESS--the 
20% households already participating in the repeat surveys (T2 survey), and the 80% of 
households not yet approached for participation in the evaluation research. Google maps (and 
other publicly available sources) will be used to identify eligible households.  

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78 
 
• Recruitment:  Each of the study community households will be approached for participation in 
the study. If the heads of eligible households, or a suitable household representative, are not 
available at the time of the first home visit, up to two re-visits to the household will be 
scheduled. 
 
Schedule:  The ESS will be scheduled to coincide with the T2 visit to 20% households.   
 
2) The remaining ESS study activities (training; household visit procedures; data collection and 
handling) will be very similar to those in the BHS, with a few exceptions: 
 Participants will be consenting to a one-time questionnaire and blood draw, and not 
longitudinal follow-up in any cohort. 
 Participants will be referred to local treatment facilities for HIV care and treatment (if 
HIV-infected) and male circumcision (if HIV-uninfected), and no linkage to care 
interventions will be implemented. 
 Non-citizens will be eligible to participate anonymously in this one-time survey. 
 
In sum, the ESS will consist of HTC (if not documented to be HIV-infected); informed consent of 
eligible residents of the 80% households in the participating 6 communities (or newly-eligible 
residents of the 20% households in the participating 6 communities), followed by completion of 
a questionnaire that focuses on combination prevention intervention uptake; and (among 
consenting HIV-infected residents) collection of a sample for HIV viral 
load/genotyping/incidence assay/optional storage (see Figure 5A). 
 
Figure 5A. Procedures for the End of Study Survey in 80% Households in 6 Communities 
 

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Abbreviations: HH, Household; C, consent procedures; RT, rapid test; VL, viral load; MC male circumcision; 
IND, indeterminate; EIA, enzyme immuno-assay; WB, Western Blot. 
*Consent administered to eligible household members only (see section 4.4). 
^Leftover sample from either the fingerprick or 10mL sample will be run in a small subset of HIV+ 
participants not currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5). 
# Sample for the POC CD4 in previously documented HIV-positive participants may be drawn along with 
the venous blood for VL, to avoid a separate finger prick. Otherwise, capillary blood sample leftover from 
rapid HIV test may be used. 
   
 
3) T2 visit: procedures during the T2 visit among 20% household residents will be very similar to 
those in the ESS participants (with the exception that participants who previously consented to 
taking part in the BHS or HIC will not need to provide additional consent for study procedures).  
Note that eligible consenting residents of 20% households in the 30 communities who did not 
previously participate in the BHS/AHS will complete the ESS consent and survey/procedures. 
 
Figure 5B. Procedures for the Final Survey Visit at T2 in 20% BHS/HIC Households 
                 
 
Abbreviations: HH, Household; C, consent procedures; RT, rapid test; VL, viral load; MC male circumcision; IND, 
indeterminate; EIA, enzyme immuno-assay; WB, Western Blot. 
#Verbal consent script need not be re-administered if the respondent is the same person at follow-up visits, or an 
enrolled survey participant.  
*Consent required from newly identified residents who did not enroll and consent previously at BHS or T1. Consent 
administered to eligible household members only (see section 4.4.4). 
^Leftover sample from either the fingerprick or 10mL sample will be run in a small subset of HIV+ participants not 
currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).   
**HIV-positive participants who were ART-naïve upon enrollment at a prior visit will have POC CD4 repeated at T2, 
even if they have started ART since enrollment. Generally, the sample for the POC CD4 at T2 in previously documented 
HIV-positive participants will be drawn along with the venous blood for VL, to avoid a separate finger prick. 

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80 
# Newly identified HIV-positive participants (i.e. no prior study documentation of HIV-positive status) who are ART-
naïve will have POC CD4 run on leftover capillary blood. If a capillary blood sample cannot be obtained, a venous blood 
sample (4-5 ml) may be drawn instead. 
 
Figure 5C. Procedures for the End of Study Survey for Non-Citizen/Spouse of Citizen Respondents 
 
Abbreviations: HH, Household; C, consent procedures; RT, rapid test; VL, viral load; MC male circumcision; IND, 
indeterminate; EIA, enzyme immuno-assay; WB, Western Blot. 
*Waiver of requirement for written documentation of informed consent. Administer Consent Script/Written Statement 
(see section 11.2). 
^Leftover sample from either the fingerprick or 10mL sample will be run in a small subset of HIV+ participants not 
currently on ART to validate POC VL (run in parallel with standard VL) (see Section 8.5).   
# Sample for the POC CD4 in previously documented HIV-positive participants may be drawn along with the venous 
blood for VL, to avoid a separate finger prick. Otherwise, capillary blood sample leftover from rapid HIV test may be 
used. 
**Sample will be collected for confirmatory testing and study staff will arrange for participant to obtain confirmed 
result. Real-time result will be made available to participant at mobile lab/clinic. Research Blood Draw and Viral Load 
will be collected simultaneously in the event the confirmed result is positive.Similar to other study participants, 
anonymous non-citizen participants may obtain their viral load results. Non-citizen participants will be provided with a 
receipt matching their coded specimen. They may present the receipt to the mobile lab/clinic to obtain their result. 
 
7. COST EFFECTIVENESS ANALYSIS 
 
In this section we describe the Cost-Effectiveness of Preventing AIDS Complications International 
(CEPAC-I) model, the novel data collection, and the analysis plan to determine the cost per HIV 
infection averted under the intervention and related secondary objectives of estimating cost per 
quality adjusted life year (QALY) saved under the observed and ideal conditions. 

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7.1 
CEPAC Model Structure 
 
The CEPAC model is comprised of a CEPAC-I state-transition model of HIV disease progression linked to 
a dynamic CEPAC model of HIV transmissions.  
 
1) CEPAC-I state transition model 
CEPAC-I, as a state-transition model characterizes disease progression as a sequence of monthly 
transitions from one “health state” to another as depicted in the following diagram: chronic, 
acute, and death (Kreke, Schaefer et al. 2004; Walensky, Wood et al. 2008).  
 
 
 
Health states are defined by current and setpoint HIV RNA, current and nadir CD4 count, and 
history of opportunistic infections (OIs). OIs are divided into groups based on country-specific 
data and are classified as severe or mild. From each health state in each month, individuals face 
competing mortality risks from non-HIV causes. The efficacy of sequential ART regimens is 
characterized by their impact on HIV RNA and CD4 count (Cole, Hernan et al. 2003; Losina, 
Yazdanpanah et al. 2007). A random number generator and set of estimated probabilities 
determine the clinical pathway that a patient follows until death. The entry characteristics of 
simulated patients (age, sex, CD4 count, HIV RNA) are randomly drawn from a distribution 
based on data from the setting of interest. A tally of clinical events, time spent in each health 
state, and cost associated with each health state is maintained. Upon the patient’s death, 
summary statistics for that person are recorded. Results from large numbers of individual 
simulations are averaged to develop stable population estimates. Simulation sizes of 1 million 
patients are typically sufficient for treatment strategies. 
 
2)   CEPAC HIV dynamic model 
We have completed a pilot transmission model incorporated into CEPAC-I (Walensky, Ross et al. 
2012) and are developing a full agent-based, dynamic transmission model of the HIV epidemic 
linked to the CEPAC-I Model. This transmission model will be incorporated into this analysis to 
estimate the additional potential population-wide impact of HIV treatment interventions on 
incidence. While several dynamic transmission models have been published (Alam, Meyer et al. 
2009; Leclerc, Matthews et al. 2009; Bendavid, Brandeau et al. 2010; Enns and Brandeau 2011; 
Gray, Ghaus et al. 2011; Hallett, Baeten et al. 2011; Phillips, Pillay et al. 2011; Prabhu, Farnham 
et al. 2011; Schneider, Puthanakit et al. 2011; Bershteyn, Klein et al. 2012; Ventelou, Arrighi et 
al. 2012), the CEPAC Dynamic Model combines behavioral, demographic, and biological 
parameters to project HIV transmission from and to individuals on a population level and links 
to the clinical detail of CEPAC-I (natural history, treatment outcomes, and costs of care). 
Outcomes include incidence and prevalence over user-defined time periods. Using a fitting 
procedure based on Bayesian melding methods (Poole and Raftery 2000; Alkema, Raftery et al. 
2008; Johnson, Alkema et al. 2010), we have fit the model to HIV prevalence in South Africa 
Chronic
Acute
Death
Entry

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from 1990-2002 prior to the introduction of ART, and are currently fitting it to 2003-2012 in the 
presence of ART (Joint United Nations Programme on HIV/AIDS (UNAIDS) 2010).  
 
7.2  
Data Inputs 
 
1)  
Natural History  
We have derived CD4-stratified model input parameters from Côte d’Ivoire and South Africa to 
describe the natural history of HIV in sub-Saharan Africa (Holmes, Wood et al. 2006; Losina, 
Anglaret et al. 2006; Wang, Kumarasamy et al. 2006). Natural history data from South Africa are 
primarily from the Cape Town AIDS Cohort (CTAC), a cohort of 2,088 patients followed by Wood 
et al. (Holmes, Wood et al. 2006). These model parameters will be compared with observed 
CD4 trajectories and clinical outcomes in the Baseline Household Survey to confirm that the 
model accurately describes the experience of the Botswana population. 
 
2)  
ART Efficacy 
Efficacy data for 1st-line NNRTI- or PI-based regimens (66-88% viral suppression at 48 weeks) 
are from both clinical trials and observational cohorts in Africa with similar efficacy for 2nd-line 
regimens (Coetzee, Hildebrand et al. 2004; Nachega, Stein et al. 2004; DART Virology Group and 
Trial Team 2006; Charalambous, Innes et al. 2007; Barth, van der Meer et al. 2008; Boulle, Van 
Cutsem et al. 2008; Delfraissy, Flandre et al. 2008; Hammond and Harry 2008; Losina, Chang et 
al. 2008; Wouters, Van Damme et al. 2008; Bierman, van Agtmael et al. 2009; Gandhi, Moll et 
al. 2009; Fox, Ive et al. 2010). CD4 increase on 1st-line ART averages 113-236 cells/µl at 48 
weeks, with the sharpest increase occuring in the first two months, followed by a more gradual 
increase (Charalambous, Innes et al. 2007; Seyler, Adje-Toure et al. 2007; Barth, van der Meer 
et al. 2008; Hammond and Harry 2008; Pujades-Rodriguez, O'Brien et al. 2008; Wouters, Van 
Damme et al. 2008; Gandhi, Moll et al. 2009; Fox, Ive et al. 2010). While data from clinical trials 
are more complete in terms of virologic and CD4 response, as well as loss to follow up (LTFU) 
and toxicity, they generally provide higher estimates of suppression than data from large 
community cohorts (DART Virology Group and Trial Team 2006; Delfraissy, Flandre et al. 2008; 
Hammond and Harry 2008). We will therefore use data from trials to represent primarily best-
case scenarios in terms of efficacy and LTFU (Cohen, Chen et al. 2011; Anglaret and Eholié 2012; 
Grinsztejn and Mugyenyi 2012) and cohorts (Cornell, Schomaker et al. 2012; Wandeler, Keiser 
et al. 2012) for more likely generalizable programmatic outcomes. Efficacy and effectiveness 
data will be updated as studies emerge with data from newer regimens (1st-, 2nd-, and 3rd- line) 
as treatment provision, regimens, and experience matures (Pujades-Rodriguez, O'Brien et al. 
2008; Fox, Ive et al. 2010; Saravanan, Madhavan et al. 2012). We will assess both trial- and 
cohort-reported efficacies to assess how differences may change policy conclusions.  
 
3) 
Costs 
We will fully update the cost parameters for direct medical care in the CEPAC-I model. We will 
carry out a facility-based costing study in Botswana using an ‘ingredients-based’ methodology 
(UNAIDS 2011) that leverages longitudinal utilization records over a retrospective two-year 
period in several of the community clinics. This will allow us to quantify utilization of services 
for routine care, OI treatment, treatment of HIV-related co-morbidities, and end-of-life care 
(see Table 8).  

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We will use facility-based staffing records, inventories, procurement and accounting records, 
and other site-specific data to generate a unit cost per outpatient visit, per inpatient day, per 
procedure, per laboratory test, and per monthly medication cost. To determine the total unit 
cost for each service we will define each facility’s service centers and measure their output, for 
example an inpatient day. We will then define and measure the input required by the service 
center in terms of capital resources (buildings, equipment and other one-off costs such as 
consultant fees) and recurrent resources (staff salaries, consumables and monthly costs such as 
electricity bills). Once we have determined the total input we will calculate the monetary value 
of each item to establish the current financial price and to calculate the unit cost of each service 
center output. Through this UNAIDS-recommended (UNAIDS 2011) costing methodology we 
will reflect the most current utilization patterns and unit costs, and will tailor HIV care 
recommendations to Botswana cost structures. All costs will be updated to constant year 
dollars and discounted at 3%/year (Gold, Siegel et al. 1996). 
Table 8. Resource Utilization and Cost Data Needs 
Parameter 
Stratified by 
Start-up costs 
Intervention, Site, Monthly for first 3 months 
Scale-up costs 
Incremental cost of increasing coverage levels by 10% 
increments; 
Quarterly 
Personnel costs 
FTEs for all hired staff per implemented intervention* 
Salaries for each staff member 
Medications 
1st and 2nd line ART 
Cotrimoxazole 
OI treatment 
Patient visits to healthcare 
setting 
Average frequency on ART 
Average frequency by CD4 stratum (off ART) 
Urgent care visits (by ART status) 
Hospitalizations and length of stay (by ART status and 
with diagnosis) 
Death costs 
Costs by visit type † 
Laboratory‡ 
HIV test, Confirmatory HIV test, CD4 monitoring, HIV-1 
RNA, Screening chemistries, Screening CBCs 
* Including but not limited to: home visits, nurses, care and treatment, doctors for ART, surgical sMC 
† Urgent care, per diem hospital stay, routine visit 
‡ Includes anticipated frequencies and associated costs 
 
The measurements of healthcare utilization and personal health care costs are included in the 
questionnaire to be used at T1 (Resident Survey, Annual) and during the ESS (Resident Survey, 
ESS).  These supplementary items will be requested from at least 1,500 participants drawn from 
both Enhanced Care and Combination Prevention communities at T1 and T2.  
 
In order to more accurately estimate changes in health resource utilization during periods of 
illness and during periods with low CD4 cell count (CD4200 cells/µL), supplementary sampling 
of individuals in clinics and hospitals serving study communities will be conducted. Up to 150 

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consenting participants experiencing opportunistic illnesses and 300 without opportunistic 
illness but with low CD4 counts will be recruited from outpatient and inpatient settings.  
 
Possible participants will be approached in three settings.  First, individuals participating in the 
20% household surveys with low CD4 count or current opportunistic illness will be identified 
and selected for completion of these supplemental items.  Second, qualifying individuals 
receiving care in the Combination Prevention community clinics will be identified and referred 
for possible participation in these questionnaires. Finally, if these settings are inadequate to 
achieve the target sample size, other patients seeking care in clinics or inpatient facilities 
serving study communities will be identified through review of care logs and conversations with 
clinical staff.  Participants recruited from the clinics, and those not previously part of a study 
cohort, will be required to provide written informed consent prior to completion of these 
questionnaires (Economic Consent).  Consenting participants will be interviewed for health 
resource utilization and quality of life (Economic Assessment).  
 
Health care costs frequently are concentrated at the end of life and these costs may be missed 
during community surveys and during a focused clinical survey described above. Consequently, 
we will abstract health resource utilization during the 30 days before death from existing 
medical records in up to 80 residents of study communities (40 HIV-infected, 40 HIV-
uninfected) who die during the course of the study (Death Economic Abstraction).  Of these, 20 
non-accidental deaths that occur outside of the hospital will be targeted as costs associated 
with these deaths are anticipated to be different.  Study teams will learn of deaths of 
community residents from the community clinic staff, and from review of inpatient care logs for 
facilities providing care for study communities.  Family members or contacts of the decedent 
will not be interviewed.  No identifiable information will be recorded during record abstraction. 
This aspect of the research does not involve human subjects per the definition at 
45CFR46.102(f) that a human subject is a living individual. 
 
Table 9. Individual Healthcare Utilization, Cost, and Quality of Life Assessments 
Instruments 
Sample Size 
Timing 
Recruitment 
Annual Resident Survey and End of 
Study Survey. These instruments 
include EQ5D5L, resource utilization 
(including HIV-related costs for HIV-
infected), lost economic activity 
At least 3,000 (at least 1,500 at 
each time point) 
T1 and T2 
Participants in BHS/AHS 
Economic Assessment: EQ5D5L, 
resource utilization (including HIV-
related costs for HIV-infected), lost 
economic activity 
 
CEA Enrollment checklist for 
participants outside BHS/ESS 
150 with opportunistic illness  
 
300 with low CD4 ≤200 cells/µL 
without opportunistic 
illnesses 
Throughout study 
1) Participants in 
BHS/ESS 
2) Participants in IDCC 
3) Other patients 
treated in facilities 
caring for residents 
of study 
communities 
Death Economic Abstraction: Resource 
utilization  
80 
 
Throughout study 
Clinics and hospitals 
caring for residents 
of study 
communities 
 

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4)  
Quality of Life 
Quality of life implications of HIV treatment in resource-limited settings are becoming more 
important in the evaluation of innovations that incrementally improve clinical management of 
HIV than a decade ago, when survival gains were appropriately the overriding concern. To 
enable the CEPAC-I model to estimate QALYs as an outcome, we will synthesize existing 
evidence on preference-based measures of QOL (EuroQol Group 1990; World Health 
Organization Division of Mental Health and Prevention of Substance Abuse 1997; Brazier, 
Usherwood et al. 1998; Brazier, Roberts et al. 2002; Sullivan, Lawrence et al. 2005) for HIV 
health states from the literature (Jelsma, Maclean et al. 2005; Louwagie, Bachmann et al. 2007; 
Zimpel and Fleck 2007; Lara, Wakholi et al. 2008; Robberstad and Olsen 2010; Rajeev, Yuvaraj 
et al. 2012; Tran, Ohinmaa et al. 2012). The largest study to date of QALY-weights in HIV used 
the EQ5D instrument in a trial involving 21,000 US patients and has been used in model-based 
analyses (Simpson, Luo et al. 2004; Pitter, Kahn et al. 2007; Meyer-Rath and Over 2012). To 
produce estimates that can be adapted to the CEPAC-I model structure, we will adjust the 
QALY-weights as needed by collecting EQ5D data at T1 and T2 and use new methods for 
synthesizing evidence on QALYs (Tengs and Lin 2002; Isogai, Rueda et al. 2012) and predicting 
health-related QOL among HIV-infected persons (Isogai, Rueda et al. 2012). 
 
The EQ5D is included in the questionnaire instrument used at T1 (Resident Survey, Annual) and 
at T2 to estimate QOL in the study communities. Supplementary sampling of individuals with 
opportunistic infections and low CD4 will be conducted. The EQ5D will be administered to up to 
150 consenting individuals with opportunistic illnesses and 300 individuals with CD4<200 
cells/µL receiving care in inpatient and outpatient facilities serving study communities 
(Economic Assessment), as described above for medical cost estimation. 
 
7.3 
Model validation and approach to uncertainty 
 
Medical decisions and guidelines for care are nearly always formulated without perfect information. 
This is particularly true with rapid advances in knowledge and, thus, justifies both the use of model-
based approaches and an inclusive attitude toward the data used in modeling studies. Because 
hypotheses cannot be tested using traditional measures of statistical significance in microsimulation 
modeling, we have a particular responsibility to both validate models and to investigate the impact of 
uncertainty with care and transparency. Here we describe approaches to model validation and 
sensitivity analysis. 
 
1) 
Validation 
We ascertain internal consistency in the model in several steps: First, we examine the face 
validity of randomly selected, individual patient “traces” (Figure 5). These detailed views of a 
patient’s month-to-month experience offer a check on the reasonableness of the output and a 
mechanism for debugging. Second, we check “internal validity,” verifying that model output 
accurately approximates the data used to derive input parameters. This is an area of increasing 
importance in disease policy modeling. Figure 6 illustrates the validation of model runs using 
HPTN 052 trial data inputs with trial outcomes (Losina, Yazdanpanah et al. 2007; Walensky, 
Ross et al. 2012). 

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86 
 
 
2) 
Deterministic sensitivity analysis 
The US Panel on Cost-Effectiveness in Health and Medicine and the International Society for 
Pharmacoeconomics and Outcomes Research (ISPOR) Task Force on Good Modeling Practice 
both recommend deterministic sensitivity analysis to provide insight about uncertainty where 
small changes in model input data produce large changes in model results (Weinstein, Siegel et 
al. 1996; Paltiel 2001; Drummond, Brown et al. 2003; Weinstein, O'Brien et al. 2003; Ades, 
Claxton et al. 2006; Briggs, Weinstein et al. 2012). We will use deterministic methods (one-way, 
multi-way, best-case, worst-case, and threshold approaches) to assess how uncertainty in 
current data or lack of data about treatments still in development may affect policy 
conclusions, or when application of data from alternative regions or countries yields different 
results (Gold, Siegel et al. 1996; Paltiel 2001; Uhler, Kumarasamy et al. 2010). 
 
Probabilistic approaches. In contrast to deterministic sensitivity analyses, probabilistic 
sensitivity analysis (PSA) generates values for multiple inputs simultaneously based on 
predefined probability distributions for each input. PSA is recommended under guidelines 
elaborated by the ISPOR-Medical Decision Making Task Force (Society for Medical Decision 
Making and International Society for Pharmacoeconomics and Outcomes Research ; Briggs, 
Weinstein et al. 2012). We have developed the capacity to conduct PSA on output from the 
CEPAC-I model. Parameters of interest will be chosen based on importance to the results (as 
identified by deterministic sensitivity analyses described above) and also on whether data are 
available to specify distributions (Ades, Claxton et al. 2006). We will use these analyses to 
calculate the expected cost-effectiveness of each prevention strategy, the uncertainty 
surrounding that result, and the number of times each strategy is optimal.  
 
7.4 
Cost-Effectiveness Analysis Plan 
 
The CEPAC International model will be used to assess expected outcomes from the proposed 
combination prevention programs.  Table 10 shows the prevention strategies and outcomes of interest 
that will be examined; the main outcome of interest will be the comparison of the three strategies to 
each other. An additional “no regular screen, no ART” strategy will be modeled for historical 
comparison only. In addition to life expectancy, cost, and cost-effectiveness of alternative HIV 
combination prevention strategies, the impact of these strategies on secondary transmission and HIV 
incidence will also be examined by estimating the number of secondary cases per infected individual in 

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87 
each combination prevention scenario. Results will be stratified showing life expectancy for the entire 
population, life expectancy for only the HIV-infected residents, and the number of new HIV infections 
averted. Table 8 shows resource utilization and cost data needs. 
 
Table 10. Prevention Strategies and Outcomes of Interest 
Prevention strategy 
Outcomes of interest 
Enhanced Care communities (Current Standard of 
Care) 
Total population QALYs 
Mortality at 2 years 
Number of new HIV infections at 2 years 
Reduction in HIV incidence 
Per person total direct costs 
Cost-effectiveness ($/HIV infection 
averted) 
Cost-effectiveness ($/YLS*, $/QALY) 
Combination Prevention communities (expanded 
HTC, MC, PMTCT, and universal testing and 
treatment) 
“Optimized Package” 
(model-based scenario based on the Combination 
Prevention arm, but will assess the case where 
linkage to routine HIV care is ideal, ART is 
optimized, HIV screening is more frequent, and 
pre-exposure prophylaxis is administered) 
 *year of life saved: YLS 
  
Incremental cost-effectiveness ratios – both dollars per year of life saved ($/YLS or $/QALY), and dollars 
per HIV infection averted ($/infection averted) – will be used to assess the comparative value of these 
alternative combination HIV prevention strategies. The incremental cost-effectiveness ratios will be 
determined by ranking strategies in order of increasing cost. Incremental cost-effectiveness is defined 
as ΔC/ΔE, where ΔC is the difference in costs between two rank-ordered strategies, and ΔE is the 
difference in effectiveness, as defined either by life expectancy (when calculating $/YLS or $/QALY) or 
number of new HIV infections (when calculating $/infection averted). Before assessing the incremental 
costs and benefits of increasingly expensive strategies, we will eliminate strategies that are less 
effective and more costly. Analyses will be conducted from the modified societal perspective (not 
including time and productivity costs), and discounted at 3% per annum. Additional analyses will be 
done to include time and productivity costs, with data derived from external sources and consistent 
with other combination prevention trials. 
 
8. LABORATORY METHODS  
 
Detailed laboratory procedures, including procedural guides during actual specimen and data 
collection and study-specific SOPs are described in the BCPP Manual and outlined in brief below.  
 
8.1. 
Overview of Laboratory Methods 
 
An overview of the types of laboratory tests, sample types, and the location of the testing is provided 
below.  The study will use the following laboratories and locations:   
 
1. BHHRL: Botswana Harvard HIV Reference Laboratory (Gaborone) 
2. NHHRL: MOH regional HIV Reference Lab (Francistown)  
3. MOH Local Program Labs (Botswana, multi-sites) 

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4. Field sites:  Households and community venues conducting surveys and HTC campaigns 
5. Harvard Chan: Harvard T.H. Chan School of Public Health (Boston) 
6. CDC: International Laboratory Branch at Centers for Disease Control and Prevention (Atlanta) 
 
Table 11: BCPP Evaluation Protocol Laboratory Testing Responsibilities: 
Test 
Location of Testing* 
HIV Rapid Tests 
Field Sites  
CD4  
MOH Local Program Lab and Field Sites (POC) 
HIV-1 RNA  Viral Load 
BHHRL/NHHRL 
Laboratory-based incidence assays 
BHHRL 
Viral linkage 
Harvard Chan/BHHRL or collaborators 
Minor drug-resistant variant genotyping 
Harvard Chan/BHHRL or collaborators 
QA/QC Procedures 
BHHRL and NHHRL 
Tandem mass spectrometry/HPLC 
Harvard Chan/BHHRL or collaborators 
Point of care viral load 
Field sites 
*Collaborating institutions may participate in testing activities if requested by the responsible 
institution listed above. 
 
8.2. 
Training of Laboratory Personnel 
 
All laboratory personnel will participate in study-specific training prior to study initiation.  Training will 
include an overview of the BCPP study design and study-specific laboratory methodologies in addition 
to Research Ethics, GCLP (Good Clinical and Laboratory Practice), QA/QC (quality assurance/quality 
control), and laboratory record keeping procedures.  Study staff responsible for providing HIV testing 
and counseling will complete the required training curriculum recognized by the MOH.  Staff will also 
be trained on the use and completion of all study forms related to these services.  Study staff members 
who will collect blood samples or conduct laboratory analyses will receive training in universal 
precautions, sample collection, and testing of study samples.  Additional refresher trainings will be 
scheduled during the study to ensure consistency and address training needs as they arise. 
 
8.3. 
Specimen Collection, Transport, and Processing 
 
Specimens will be collected from participants at study field sites and samples transported to 
designated laboratories for processing, testing and storage.  Testing may also occur at study field sites.  
 
Sample types: 
a) Capillary blood samples:  Finger prick samples will be collected in a microtube using a sterile 
disposable lancet, by trained staff at study field sites according to the appropriate blood collection 
SOP and used for the HIV rapid test, POC CD4 test, and (in a subset), POC viral load test. 
 

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b) Venous blood samples:  Samples will be collected by trained phlebotomists according to policies 
and procedures described in a SOP for blood collection.  The number and types of samples will vary 
by the study group as described in Section 6. Tube sizes have been standardized to streamline 
collection of specimen in the field and integration into existing laboratory testing sites.  Samples 
will be labeled with participant ID/barcodes and transported using coolers or portable refrigerators 
to the designated research laboratory, processed within 24 hours, and aliquots at -70oC.  In brief, 
the following specimen sizes will be used: 
 
• 4-5 ml EDTA tube or 10ml EDTA tube:  Viral Load 
• 10 ml EDTA tube:  Genotyping, TDR, incidence assays 
 
In cases in which sample for POC CD4 is obtained from venous blood (rather than lancet 
fingerstick)--e.g. among ART-naive patients with documented HIV infection in whom a rapid 
test is not being performed—an additional 4-5 ml EDTA tube will be collected. 
 
Note: consenting pre-ART participants may also have blood drawn for baseline safety labs as 
part of the "research blood draw" in Combination Prevention communities, to avoid multiple 
sticks and to help expedite time to treatment initiation. More detailed procedures related to 
this phlebotomy are described in the Intervention Protocol. 
 
 
c) Plasma and buffy coats:  Plasma and buffy coats will be collected from whole blood specimens 
(EDTA tube) by centrifugation (1,500 x g or ~3,000 rpm for 10 min), then aspirate plasma into 1 ml 
aliquots, followed by aspirate of buffy coat into 1 ml aliquots.  Both plasma and buffy coats will be 
stored frozen (-70°C).   
 
8.4. 
Laboratory testing for BHS, HIC, and ESS (returned to participant and/or participant file) 
 
a) HIV Diagnostic Testing: HIV diagnostic testing will be conducted by the study sites as per National 
HIV Testing guidelines using Botswana-government–approved parallel rapid tests.  The current 
algorithm includes KHB and Unigold™ HIV rapid test in parallel.  If results are discordant, a 4-5 ml 
blood specimen will be taken at the visit and sent to a reference laboratory for further testing using 
ELISA or Nucleic Acid testing per BHHRL HIV testing algorithm (e.g. Murex HIV 1.2.0 test, Genetic 
Systems Biorad HIV-1/2) and/or Western blot and/or DNA/RNA PCR. The results of EIA and/or 
Western Blot and/or DNA/RNA PCR at the BHHRL lab will supersede the discordant and/or 
indeterminate results obtained in the field.  All HIV tests will be conducted according to the 
manufacturer’s guidelines.    
 
If results of anonymous HIV diagnostic testing in the household are discordant, the confirmatory 
HIV testing will be performed at the mobile lab in real-time. The Cepheid Xpert POC HIV-1 Qual will 
be used according to the manufacturer’s instruction. Xpert HIV-1 Qual provides a total nucleic acid 
based test for viral RNA and proviral DNA in one integrated cartridge by using 100 ul of whole 
blood. If the result of Xpert HIV-1 Qual test is negative, the person is considered to be HIV-
negative.  If result of Xpert HIV-1 Qual test is positive, the person is considered to be HIV-positive.   
 

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b) POC CD4:  Capillary blood samples (obtained from the lancet fingerprick blood draw also used for 
the HIV rapid test) will be tested using the Pima™ CD4 with the Pima analyzer (Alere, Inc.) 
described previously (Mtapuri-Zinyowera, Chideme et al. 2010; Jani, Sitoe et al. 2011) to obtain an 
absolute count of CD4 cells. 
 
c) HIV-1 Viral Load: Testing will be conducted by NHHRL at Francistown and BHHRL at Gaborone using 
licensed assays. HIV-1 RNA VL in plasma will be performed by Roche TaqMan Assay using the Roche 
COBAS AmpliPrep/COBAS TaqMan version 2 HIV-1 Test or Abbott m2000sp/m2000rt.  The 
BioMeriuex platforms are also available in the reference  or national laboratories and may be used 
for viral load testing.  All results will be made available to be keyed or electronically transfered to 
the protocol database after appropriate user validation.   
 
Several POC VL devices are currently undergoing field performance characteristic evaluations 
[ALERE HIV NAT POC system (Alere, Inc.), Cepheid Xpert POC VL].  The potential future use of the 
POC VL tests through an amendment to the BCPP Evaluation Protocol may be considered 
depending on successful evaluation of the POC VL device. POC VL using best available devices will 
be conducted on a subset of treatment-naïve individuals and may also be conducted on individuals 
receiving ART. 
 
d) Transmitted Drug Resistance: Efforts will be made to return results indicating transmitted drug 
resistance to participants upon completion of testing. Note that these results will only be available 
retrospectively (e.g. about 1 year or later after sampling), and may therefore be of limited clinical 
utility. 
 
8.5. 
Research laboratory testing (results not returned to participant) 
 
a)  Viral Genotyping  
Plasma and buffy coats will be the primary sample source for viral genotyping. The algorithm of 
viral genotyping based on the V1C5 region of HIV-1 env gp120 and HIV-1 gag are in place in the 
Harvard Chan lab (Novitsky, Lagakos et al. 2009; Novitsky, Wang et al. 2009; Novitsky, Wang et al. 
2010; Novitsky, Wang et al. 2011). A newly developed technique of long-range HIV genotyping 
(Novitsky, Zahralban-Steele et al. 2015) will be also applied, as it provides better resolution of HIV 
transmission clusters (Novitsky, Moyo et al. 2015). 
 
• Details of sample processing, amplification, sequencing and troubleshooting are summarized in 
(Novitsky, Zahralban-Steele et al. 2015).  
• The “gray zone” samples will be resolved by applying more sensitive methods such as Single 
Genome Amplification and Sequencing and 454-based next generation “deep sequencing.”  
 
The viral linkage analysis includes all generated viral sequences. QA/QC procedures will be applied 
routinely.  
 
Cluster analysis using generated viral sequences from each participating community will be 
performed as described recently (Novitsky, Bussmann et al. 2013; Novitsky, Moyo et al. 2014; 
Novitsky, Kuhnert et al. 2015). Potential links and clustering will be analyzed for all available 

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91 
prevalent and incident HIV infections. The optimal evolutionary model will be identified for the 
aligned set of query sequences using jModelTest (Posada 2008).  
 
HIV clusters will be identified by a combination of bootstrapped ML (Felsenstein 1985; Nei and Kumar 
2000; Felsenstein 2004) and internode certainty (Salichos and Rokas 2013; Salichos, Stamatakis et al. 
2014). The ML phylogeny will be inferred in RAxML (Stamatakis 2006; Stamatakis 2014) under the 
GAMMA model of rate heterogeneity. To account for phylogenetic uncertainty, from 100 to 1,000 
bootstrap trees will be inferred using the rapid bootstrap in RAxML (Stamatakis 2006). The bootstrap 
threshold will be set to 0.80, and we will perform the sensitivity analysis at 0.70 and 0.90. We will use 
0.70 as the internode certainty threshold (Salichos and Rokas 2013; Salichos, Stamatakis et al. 2014).  
 
To estimate effective reproductive number R, HIV transmission rate λ, and the rate of becoming 
non-infectious δ for the identified HIV lineages, we will use the BDSKY model in BEAST2 (Bouckaert, 
Heled et al. 2014; Novitsky, Kuhnert et al. 2015). The chain length of Markov Chain Monte Carlo 
runs will be set to 2x108−3x108 with the first 25% of states of each run burned-in. The generated 
trees will be sampled to estimate effective reproductive number, R, HIV transmission rate, λ, rate 
of becoming non-infectious, δ, effective population size, Ne, and the tMRCA. Convergence will be 
evaluated by Tracer v1.5 (http://beast.bio.ed.ac.uk/Tracer) and effective sample sizes of >200. 
 
Transmitted drug resistance will be analyzed using samples from new incident cases and samples 
identified as recent HIV infections using laboratory-based incidence assays (see below). Up to 200 
samples will be analyzed annually. Identified incident cases will be prioritized for inclusion into TDR 
analysis.  
 
Viral mutations associated with HIV drug-resistance will be analyzed in bulk using plasma and buffy 
coat specimens (Novitsky, Zahralban-Steele et al. 2015). Analysis of viral mutations associated with 
HIV drug-resistance will be performed at the BHHRL lab using the IAS recommendations for ART-
experienced patients (Johnson, Calvez et al. 2011) and WHO-recommendations (Bennett, Camacho 
et al. 2009). Drug resistance testing at BHHRL will use the validated resistance testing assay 
developed at International Laboratory Branch, CDC, USA (Zhou, Wagar et al. 2011), or an 
alternative assay (Wallis, Papathanasopoulos et al. 2010).  In addition, more sensitive methods such 
as next-generation sequencing and allele-specific PCR will be used for analysis of HIV-1 drug-
resistant mutations at low frequency in a subset of samples at investigators discretion and this 
testing will be conducted at a Harvard Chan School lab.  
 
b) Laboratory-based tests for HIV Incidence 
Results of cross-sectional HIV incidence testing obtained at the BHHRL will be compared with the 
longitudinal HIV incidence data.  The study may also compare HIV incidence estimates derived from 
multi-assay algorithms including available laboratory and clinical data. HIV incidence tests and 
algorithms will be validated for accuracy and scale-up.  
 
HIV seropositive specimens will be tested using the LAg-Avidity assay in combination with 
additional information on antiretroviral treatment exposure (ART status) and HIV-1 RNA viral load 
for incidence estimate as described below. Contemporary methods for estimating incidence may 
be used as well, or instead, as these methods evolve. 

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• LAg-Avidity EIA: The LAg-Avidity EIA is a CDC-developed new incidence assay (Duong, Qiu et al. 
2012; Duong, Kassanjee et al. 2015) now commercially available from Sedia BioSciences 
(Portland, OR). The LAg-Avidity assay uses a multi-subtype recombinant protein that covers the 
immunodominant region (IDR) of gp41 of HIV-1, group M, rIDR-M.  Briefly, microwell plates are 
coated with limiting concentration of rIDR-M antigen.  Limiting the antigen allows binding of 
only high-avidity antibodies which are further dissociated by a pH 3.0 buffer step.  ODn values 
are calculated for each specimen using a pre-defined calibrator specimen (CAL) tested on the 
same plate as follows: ODn = specimen OD/Median CAL OD.  Specimens with an ODn value less 
than or equal to 2.0 during initial testing are confirmed by further testing of the sample in 
triplicate, where the median value of the three results is considered the final ODn for the 
specimen.  All specimens with ODn values greater than 1.5 are classified as long-term 
infections.  The HIV-1 sero-positive status of specimens with ODn values of <0.4 is confirmed 
with EIA, as any HIV-negative samples would incorrectly score as recent in the assay.  Any HIV 
seronegative specimens identified at this step are excluded from the total HIV positives and 
incorporated into the total number of negative specimens (N) for the incidence estimation.  
Recent (ODn<1.5) infections are likely to have seroconverted within a mean duration of recency 
of 130 days (Rehle, Johnson et al. 2015).  
 
ART status is collected routinely during the household surveys. Individuals who can provide 
evidence of being on ART during the household survey are considered long-term, not recent, 
cases of HIV infection for the purposes of cross-sectional estimates of HIV incidence. To rule out 
false recent infections, specimens with ODn in LAg-Avidity assay below 1.5 may be tested for 
the presence of ARV drugs, including but not limited to Tenofovir, Emtricitabine, Zidovudine, 
Nevirapine, Efavirenz, Lopinavir, Atazanavir and Darunavir by High Performance Liquid 
Chromatography (HPLC) coupled to Tandem Mass Spectrometry (Rehle, Johnson et al. 2015). 
Specimens with detectable traces of ARV drugs are considered long-term cases. Testing for the 
presence of ARVs is an evolving field and other methods will be considered and possibly used as 
they become available locally and regionally. 
 
HIV-1-positive specimens from ART-naïve individuals with an ODn value less than or equal to 
1.5 will be subjected to HIV-1 viral load (VL) analysis as an indirect indicator of ART usage or a 
natural ability to control HIV infection (elite controllers).  Specimens with a LAg ODn ≤1.5 from 
ART-naïve individuals and a VL ≥400 copies/mL will be classified as recent infections.  Results 
from the LAg-Avidity testing, including ART status and VL testing, will be maintained in a 
computer-based data management file.  Therefore, a separate false recent rate (FRR) 
correction is not relevant or necessary, and will be set to zero (Rehle, Johnson et al. 2015).  The 
use of multi-assay algorithms (see below) continues to provide evidence that use of additional 
data or assays improves accuracy of HIV recency testing.  
 
• Multi-assay algorithms:   
Other algorithms for cross-sectional estimation of HIV incidence may include a combination of 
BED-capture EIA, Avidity assay (AxSYM or BioRad),(Braunstein, Nash et al. 2011; Laeyendecker, 
Brookmeyer et al. 2012) and/or multi-assay algorithms that include a combination of BED and 
Avidity assays and accompanied by CD4 and VL data. These algorithms will be used in a subset 
of samples for validation and comparison with the data generated previously in the country 
and/or with other studies. 

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93 
 
Incidence calculations are assay- and algorithm-specific. Methods for calculating estimated 
incidence are described in section 10. 
 
c ) POC viral load assay 
A pilot study of POC viral load testing will be performed to permit assessment of accuracy of POC 
viral load vs. standard viral load assays as well as assessment of operating characteristics of POC 
viral load assay(s). The first component will include POC viral load testing in the mobile lab settings 
by XPERT HIV-1 Viral Load from Cepheid. The second component will include POC viral load testing 
in households. Both components of POC viral load testing will be accompanied by HIV-1 RNA 
testing in the Botswana-Harvard HIV Reference Lab (BHHRL) using standard protocol. Currently, we 
are awaiting a viable potential candidate to be used in the pilot study in the second component. 
Each component of POC viral load testing will use only one POC viral load platform (and it is 
possible that both components will use the same POC viral load platform). 
 
Mobile lab POC viral load testing procedures: The same blood sample that is already drawn for 
standard viral load testing by phlebotomy in households (and processed in the mobile lab placed in 
each participating community) will be used for POC viral load testing. Approximately 200 POC viral 
load tests will be performed in mobile labs in real-time (the same day) using whole blood and 
plasma from this blood draw. Results of POC viral load testing from this pilot study will not be 
returned to participants, as the platform will not yet have been validated; results of the standard 
viral load assay will be returned to the local clinic. The same plasma sample tested in the mobile lab 
will also be tested at BHHRL in Gaborone using standard procedures. The targeted population for 
this portion of the pilot will be approximately 200 (but up to 400) ART-naïve HIV-infected 
individuals. The range in sample size is necessary because investigators do not know the precise 
viral load distribution of participants and we need to ensure that 1/3 of the participants have a viral 
load below the threshold of 10,000 copies/ml to allow for assessment of the performance of POC 
viral load tests at lower viral loads. 
 
POC viral load testing in households procedures: Blood for POC viral load testing will be collected 
according to the manufacturer’s instructions in households. Approximately 200 POC viral load tests 
will be performed in households in real-time using these blood samples. Results of POC viral load 
testing from this pilot study will not be returned to participants, as the platform will not yet have 
been validated; results of the standard viral load assay will be returned to the local clinic. A parallel 
sample drawn in the household will be tested in BHHRL in Gaborone using standard procedures. 
The targeted population for this portion of the pilot will be approximately 200 (but up to 400) ART-
naïve HIV-infected individuals. The range in sample size is necessary because investigators do not 
know the precise viral load distribution of participants and we need to ensure that 1/3 of the 
participants have a viral load below the threshold of 10,000 copies/ml to allow for assessment of 
the performance of POC viral load tests at lower viral loads. 
 
If high concordance is observed between POC viral load assays and standard viral load assays, POC 
viral load may be used in lieu of standard viral load assays, among pre-ART BHS participants, as 
noted previously in Section 8.4c). If this is done, then viral load results will be shared with clinics.  
 

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Operational characteristics will be evaluated in both components. We will record the time it takes 
to obtain viral load result in each test, reported ease of use by field operators, and stability under 
different conditions. 
 
8.6. 
Quality Assurance 
 
A quality management plan with monitoring and evaluation of key indicators will be implemented at 
the BHHRL and NHHRL. Standard operating procedures (SOPs) will be used for all tests as well as 
QA/QC procedures.  Laboratory staff conducting testing will participate in proficiency testing and 5% of 
all tests will be subjected to internal QC processes.  The QA/QC plan will include periodic monthly 
reviews of EQA performance and corrective actions implemented. Procedures will be in place for 
performing and documenting the quality of a specimen, including storage and transport conditions, 
monitoring of equipment and temperatures, and function indicators.  The QA/QC plan will include 
routine collaboration with the CDC laboratories, enrollment in appropriate EQA schemes, and inter-
laboratory comparisons. Field sites will participate in EQA and proficiency testing for all POC assays 
used. 
 
Certification status for laboratory tests will be maintained including: HIV ELISA, POC HIV Rapid EIA, POC 
CD4 count, and HIV-1 RNA load. Laboratories will be monitored throughout the study by the study 
team and external monitors as requested by the study sponsor.   
 
8.7. 
Biosafety and Waste Management 
 
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 CDC.  All infectious specimens will be transported in 
accordance with the IATA (International Air Transport Association) guidelines using designated courier 
services. 
 
8.8. 
Specimen Storage and Shipment 
 
Specimens will be stored until all protocol-related and quality assurance testing have been completed. 
In addition, study participants will be asked to provide written informed consent for long term storage 
and potential future testing of their specimens. Specimens without consent for long-term storage and 
additional testing will be discarded at the end of the study and destruction documented in the study 
files. Future human subjects research on stored specimens will require submission and approval of a 
separate study protocol to all engaged IRBs and appropriate study team committee.  
 
The study site will coordinate shipment of specimens as required.  Samples (buffy coats, plasma, 
and/or isolated nucleic acid) for research components of viral genotyping will be shipped to a Harvard 
Chan School lab in Boston, MA. Selected samples may be transferred to the CDC Laboratories and 
HPTN Central Laboratory for cross-studies analyses. Other specimens will be stored at BHHRL.  

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95 
9. DATA COLLECTION AND MANAGEMENT  
 
9.1. 
Data Management team 
 
A project data management team, chaired by representatives from MOH, BHP, Harvard Chan School, 
and CDC, will be formed to build the research data collection systems.  The data management team 
will: 
(1) Design the data collection and management systems required for BCPP;  
(2) Coordinate data usage for project progress reports to funders;  
(3) Coordinate data usage by the DSMB (as described in Section5.4), and,  
(4) Coordinate data usage for analysis of primary and secondary study objectives. 
 
This section outlines data collection and management guidelines; detailed methodologies for data 
collection and management will be developed and placed into SOPs or described in the manual.  
 
9.2. 
Data Flow 
 
Research data will be collected on mobile electronic devices during household surveys.  Research data 
that are not collected during household surveys include routine clinical monitoring data collected in 
the electronic medical record system (PIMS2 or IPMS) for Combination Prevention community clinic 
patients (described in the Intervention Protocol); data from participants who consent to research-
related blood draws (see section 6.3); and data on health resource utilization and quality of life from a 
subset of participants experiencing opportunistic illnesses (see Section 7). 
 
9.3. 
Data Flow From BHS, HIC, ESS, and Research Blood Draws 
 
Data entry: Field teams will be trained in the use of appropriate mobile devices (e.g. notebooks) for 
data entry during the BHS, HIC, ESS, and research blood draws.  Skip patterns, legal ranges, and 
consistency checks will help to ensure high quality data are collected. 
 
From the point of entry, BHS study data will be synchronized from the field devices into the community 
server at the end of each shift.  Data from the community server will be synchronized over encrypted 
virtual private network (VPN) channels to the central server at the BHP Data Management Center 
(DMC) in Gaborone nightly. Backups of the community server are transferred to the BHP DMC nightly 
and then included in the DMC’s general backup routine. Database backups will be encrypted and 
stored on encrypted drives before transfer to removable media.  Secure and lockable rooms will be 
used to house all workstations and servers and to store mobile devices when not in use. 
 
All information will be collected and transmitted electronically except consent forms and laboratory 
labels. A paper copy of the informed consent/assent forms will be offered to the participants. The 
consent forms with participants’ signatures and Omang numbers will be collected and, at the end of 
the day, secured in locked file cabinets at the base sites. Laboratory labels with bar code will be used 
for sample tracking. The sample labels will contain a computer-generated Subject Identifier, sample 
date, date of birth, and coded HIV status, and the type of sample. No personal identifying information 
can be derived from the labels. 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
96 
 
Management of Personally Identifying Information (PII):  The national identity card, Omang, required 
by the MoH for access to health care services including ART, is also needed to: (1) help identify study 
participants during research follow-up, and (2) link study data to HIV care and treatment data collected 
in routine HIV care and treatment systems. 
 
However, once entered into the data system, observations with unique Omang numbers will be 
allocated, and referred to thereafter, by a unique computer-generated Subject Identifier. PII (such as 
first and last name, and omang number) may be viewed in the context of the BHP Electronic Data 
Capture (EDC) system by authorized EDC users. PII will only be used outside of the EDC in sending 
results to healthcare staff providing care who are required to reliably identify a patient. When EDC 
data are transferred to partners for operational purposes, the data will be transmitted through an 
encrypted VPN network between servers deployed with full disk encryption (FDE). When EDC data are 
transferred to partners for analytical purposes, PII values are not decrypted, if included, and the data 
will be transmitted through an encrypted VPN between servers deployed with FDE. 
 
Protection of Electronically Stored Subject Data:  Security of electronic records and data is a 
significant concern. All components of the distributed data systems will use authentication and 
encryption to render electronically stored subject identity and personal health information unusable, 
unreadable, or indecipherable to unauthorized individuals for “data in use” (e.g. data being analyzed 
by BCPP investigators), “data in motion” [e.g. data being transferred between data entry points and 
the Data Management Center (DMC) in Gaborone] and “data at rest” (e.g. data in storage at DMC in 
Gaborone).  
 
Full Drive Encryption will be implemented at the hardware layer of all devices storing protected health 
information. A three-factor scheme will be used to authenticate users through the hardware layer to 
the application layer where personal health information is available. The applications will have user 
profiles to control access to certain data and reports. The application and database layers will use a 
combination of hashing and encryption for sensitive and personal data. Mobile devices and the staff 
operating them will not be equipped with the encryption keys to decrypt select sensitive data fields.  
 
Special EDC/Data Considerations for Anonymous Participation of Non-citizens 
In the ESS, enumerated subjects who are non-citizens not married to a citizen of Botswana are eligible 
to participate anonymously. The EDC will be used to collect survey data for these subjects without 
collecting any PII should they choose to participate. Following enumeration, each subject will be asked 
about their citizenship status prior to completing the Eligibility Checklist. If the subject is willing to 
participate anonymously given their non-citizen status, the EDC will redirect the RA to the Anonymous 
Eligibility Checklist. If the non-citizen subject is eligible for the survey and accepting of verbal consent, 
the EDC will do the following to protect the anonymity of the participant and maintain data integrity 
and completeness across anonymous and identified participants: 1) de-link the participant’s 
enumeration record from the household; 2) generate an electronic consent record filling all PII 
variables with computer-generated ones; 3) allocate a Subject Identifier; 4) redirect the RA to the 
survey tool for completion with the participant. In this way there is no requirement for the RA to have 
proof of identification in order to proceed with data collection, electronically captured data will not be 
associated with a location in the community and PII will not be collected into the EDC nor in any 
manual manner.     

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
97 
 
9.4. 
The BCPP Research Data Management Center (DMC) 
 
All research data collected from the BHS, AHS, HIC, and ESS will be housed centrally at the BCPP 
Research Data Management Centre (DMC), a secure facility within the Botswana Harvard HIV 
Reference Laboratory (BHHRL) that is co-owned by the MOH and BHP.  Designated representatives 
from Harvard, MOH, and CDC will manage these data, and keep record of data management progress 
and access.  
 
Sharing of program clinical data, that are stored in the MOH M&E unit, and which reflect routine care 
of consenting research participants with BCPP investigators, will be described in a data sharing 
agreement.   
 
9.5. 
Reporting Study Progress 
 
On a monthly basis, a data manager at the Harvard Chan School will be responsible for providing 
indicators of project progress to project investigators and directors.   
 
10. ANALYSIS PLANS 
 
10.1. Analysis Plan to Meet Primary Objectives 
 
• 1st Primary Objective 
To estimate the impact of the CP package on cumulative HIV incidence, we will perform pairwise 
comparisons within matched pairs of communities using a method that estimates the incidence 
ratio between the two communities and allows for interval censored time to event data 
(Finkelstein 1986).  Interval censored time to HIV infection will arise from the fact that only the 
time interval in which subjects have become infected will be known and that some subjects will 
enter the incidence cohort after the start of the study, miss a follow-up survey, or drop-out. A 
permutation test will be used to test the null hypothesis of no intervention effect on incidence 
ratio.  The test statistic will be an inverse-variance weighted average of the incidence ratio of every 
pair. The null distribution of the test statistic will be obtained by calculating the test statistic with 
the treatment assignment permuted within each pair (resulting in a sign change of the log of the 
incidence ratio estimate for each pair). The permutation test is valid even if the variances for the 
incidence ratio estimates are not accurately estimated; however, efficiency increases as the 
variance estimates get closer to the truth. Assuming independence of the incidence ratio among 
different pairs, the variance of the overall estimate of the incidence ratio can be estimated as a 
weighted sum of the variance of incidence ratio for each pair, where the weights are the inverse of 
the variance squared. 
 
Secondary analyses will be performed to investigate the potential impact of informative censoring, 
which would arise if the probability of being tested was associated with risk of infection. Doubly 
robust methods based on weighting by the inverse of the probability of a subject receiving a test 
will be used for each pairwise comparison, and the method above will be employed for inference. 
To compare our results with those from other approaches, a secondary analysis will be performed 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
98 
based on the method of Zhang and Sun (Zhang, Sun et al. 2007) for interval-censored community-
level data. Missing data will be handled using approaches described in Tsiatis (Tsiatis 2006) and 
Little and Rubin (Little and Rubin 2002). Sensitivity analysis will be performed to assess the 
robustness of inference to various assumptions. 
 
Covariate-Adjusted Analyses:  Pair-matching in this CRT controls for certain factors associated with 
the outcome of interest, at the design stage.  Nonetheless, there could be imbalance between arms 
for a number of other baseline community covariates (e.g., despite best attempts at matching 
there may be baseline imbalances in HIV prevalence between arms). By adjusting for these 
covariates, precision and power of the trial can be improved. 
 
Covariate adjustment through a two-stage procedure has been proposed by Gail et al. (Gail, Byar et 
al. 1992).  First, a proportional hazard model for interval-censored data will be fit, including the 
covariates of interest, as well as terms for the matched pairs, but excluding the intervention effect.  
The expected incidence rate of each community will be estimated based on the fitted model.  We 
will then perform a permutation test on the difference between the expected and observed 
incidence rate to test the null hypothesis of no intervention effect while adjusting for imbalances in 
these covariates. 
 
• 2nd Primary Objective 
To estimate coverage of HTC, ART (including viral suppression), and MC at baseline and study end 
in Enhanced Care and Combination Prevention communities, the following proportions will be 
estimated with 95% confidence intervals: 
o The proportion of 16-64 year-old community residents who report knowing that they are HIV-
infected, or report testing HIV-negative in the preceding 12 months. 
o The proportion of 16-49 year-old HIV-negative men resident in the study communities who are 
circumcised. 
o The proportion of HIV-infected 16-64 year-old community residents who know they are HIV-
positive and are receiving ART.  
o The proportion of HIV-infected 16-64 year-old community residents who know they are HIV-
positive, are receiving ART, and have HIV-1 RNA ≤400 copies/mL. 
 
To compare proportions between arms at the end of study, we will use cluster-level analysis. The 
main outcome measure will be the proportion of eligible persons successfully covered by the 
intervention.  Cluster-specific proportions will first be calculated for each cluster within a pair.  
Then within-pair coverage rate ratios (𝑟𝑟1𝑗𝑗𝑟𝑟0𝑗𝑗
ൗ
),  coverage rate differences ൫𝑟𝑟1𝑗𝑗−𝑟𝑟0𝑗𝑗൯, and their 
standard errors will be estimated (where “r1” and “r0” are the coverage proportions for 
Combination Prevention and Enhanced Care clusters respectively, and “j” represents the jth cluster 
pair). The change in coverage between ESS and baseline will also be compared. 
 
To estimate the overall coverage proportion, we calculate coverage proportion among all eligible 
survey participants within each arm at baseline and ESS. The ratio and difference of coverage 
proportions between Enhanced Care and Combination Prevention communities at baseline and ESS 
are then calculated. We will additionally consider inclusion of data collected from non-citizens in 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
99 
analyses of the second primary objective. To this end, we will conduct both stratified and pooled 
analyses. 
 
Baseline characteristics of the two treatment arms will be examined to characterize the population 
and to identify any imbalance between the arms.  Where a large difference in baseline 
characteristics is observed between treatment groups the relevant covariate may be included in an 
adjusted analysis. 
 
• 3rd Primary Objective 
The estimated cost per additional HIV infection averted will be estimated using the CEPAC-I model.   
 
10.2. Analysis Plan to Meet Key Secondary Objectives 
 
• 1st Secondary Objective:  To estimate the extent to which incident HIV-infections in Combination 
Prevention and in Enhanced Care communities arise from HIV strains circulating within 
communities randomized to the same study arm as the incident case or from strains circulating 
outside those communities (sexual network mixing). 
 
Statistical concepts applicable to assessing genetic linkage of incident infections within the HIC are 
described in section 8.  Using these analysis techniques, incident infections observed in the HIC will 
be classified as either phylogenetically linked to HIV-1 variants in the same study arm, or unlinked.  
The proportion of incident infections that are unlinked will be provided with 95% confidence 
intervals. 
 
• 2nd Secondary Objective:  To estimate the efficacy of the Combination Prevention package on 
reducing the rate of new infections with HIV strains circulating within communities in the same 
study arm. 
 
Maps of circulating HIV-1 genotypes will be generated in Enhanced Care and Combination 
Prevention communities through sample collection during the BHS, HIC and ESS.  In addition, HIV 
genotyping will be done through blood sample collection among all HIV-infected persons attending 
clinics in Combination Prevention communities.  However, to avoid biased comparisons between 
Combination Prevention and Enhanced Care arms, only HIV-1 genotype maps generated from the 
BHS, HIC, and ESS in both Combination Prevention and Enhanced Care arms will be used to 
categorize incident infections as either linked or unlinked for analysis of this secondary objective.  
To meet this secondary objective, pairwise comparison of HIV incidence between Enhanced Care 
and Combination Prevention arms (as described in section 10.1 above), limited only to linked 
infections in each arm, will be performed.   
 
• 3rd Secondary Objective:  In the Combination Prevention arm only, to estimate over time, the 
proportion of recent HIV-1-infections that can be linked to HIV-infected adults of the same study 
arm. 
 
In Combination Prevention communities, we will carry out phylogenetic clustering using data 
collected at baseline and all subsequent timepoints. By comparing all newly diagnosed cases each 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
100 
year and at ESS against clusters established at baseline, we will be able to assess the trend in newly 
diagnosed cases linking to existing cases or with each other. 
 
• 4th Secondary Objective:  During the ESS, to compare Combination Prevention (CP) package 
uptake within 20% HIC households to CP package uptake in the broader communities they 
represent.   
 
Coverage of ART, MC, and PMTCT at the ESS will be estimated separately for participants within the 
20% households in all 30 communities, and in the remaining 80% of households in each of the 6 
communities selected for the ESS. The proportions for the coverage are as defined in 2nd primary 
objective. We will do pair-wise comparisons of the proportions between the study cohort and 
those in the same community outside of the cohort using cluster-level analysis stratified by 
treatment status. The within-community coverage ratio and difference and their standard errors 
will be calculated for ART, MC, and PMTCT, in Enhanced Care and Combination Prevention arms 
separately. 
• 5th Secondary Objective:  To obtain secondary cross-sectional estimates of community HIV 
incidence at baseline and study end in Enhanced Care and Combination Prevention communities 
through use of HIV-incidence assays. 
 
Assay-based HIV incidence is calculated as the number of recent infections divided by the 
population at risk (those testing HIV-negative plus those recently seroconverting), then annualized 
by multiplying by 365 divided by the accepted mean seroconversion duration for the assay.    
To calculate the incidence as an annual instantaneous rate (
) the following formula, or a 
contemporary equivalent, may be used: 
 
Where the survey counts (
,
,
) are as follows: 
 
= number of HIV negative individuals in the survey 
  
= number of HIV positive individuals in the survey 
  
= number of individuals classified incidence assay positive 
 
The calibration parameters are as follows: 
  
= mean incidence assay duration specified in units of years 
  
= false recent rate (FRR) of the incidence assay. In the presence of more data such as 
viral load, documented ART status and documented testing history, FRR adjustments may not 
be neccessary as per the WHO guideline on recent infection testing algorithm (World Health 
Organization 2011; UNAIDS 2013; Rehle, Johnson et al. 2015). 
 
rI
N
P
R
Ir
ω
ε
ε
)
1( −
−
=
N P R
N
P
R
ω
ε

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
101 
Confidence intervals are computed using a delta method approximation which may include the 
error, assumed to be normally distributed, associated with calibration parameters.  The coefficient 
of variation (
) is computed as follows: 
, 
where 
 
is the standard deviation of the mean RITA duration (assumed normally distributed) 
 
is the standard deviation of the FRR (assumed normally distributed). 
 
The 95% confidence interval (CI) for 
 is then computed as:  
 
Sampling weights will be applied accordingly in the national adult incidence estimate calculation 
(15-59 years and 15-49 years), and survey design effects will be computed to estimate the variance 
for calculating the 95% CI around the estimates.  Overall incidence estimates and sub-group 
incidence estimates (15-59 years and 15-49 years), where possible, will be calculated to highlight 
peak incidences that can be targeted by HIV prevention programs.  Bi- and multivariate analysis 
using STATA and or SAS software will examine associations between demographic, behavioral or 
other characteristics and HIV recency status. 
 
• 6th Secondary Objective:  At baseline, during study conduct, and at study end, to estimate the 
proportion of recent HIV infections in combination prevention and enhanced care communities 
with evidence of transmitted HIV drug resistance. 
 
The proportion of patients with evidence of transmitted HIV drug resistance will be calculated as 
the proportion of patients identified with drug resistance through drug resistance assays among 
patients with new or recent HIV infections identified through assay-based testing. Testing for TDR 
will be performed on samples from HIV-infected persons residing in the 20% BHS/HIC households 
and from ESS participants in both arms; and from consenting HIV-infected persons identified 
through the HTC campaigns in Combination Prevention communities. The proportion and its 
standard error will be calculated for each arm at baseline, annually, and at study end. 
• 7th Secondary Objective: To estimate the proportion of HIV-infected adults with undetectable 
viral load (VL<400 copies/ml) at baseline, during study conduct, and study end in Combination 
Prevention and Enhanced Care communities. 
 
This analysis will be performed using measurements of HIV-1 RNA throughout the study. The 
threshold of 400 copies/ml will be used for enumeration of HIV-infected individuals either above or 
below the threshold. Testing for HIV-1 RNA will be performed on samples from HIV-infected 
persons residing in the 20% BHS/HIC households and from ESS participants in both arms; and from 
consenting HIV-infected persons identified throughout the study in Combination Prevention 
v
C
v
C
2
4
2
2
2
2
2
2
)]
)(
1
/(
[
)
1(
)
(
)]
)(
1
/(
[
)]
1
/(
1[
)
(
1
R
P
R
R
P
R
P
R
R
R
P
N
P
N
P
Cv
−
−
−
−
−
+
+






−
−
−
−
+
−
+
+
=
ε
ε
ε
σ
ω
σ
ε
ε
ε
ε
ε
ω
ω
σ
ε
σ
rI
v
r
r
C
I
I
×
±
96
.1

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
102 
communities. The proportion and the 95% confidence intervals with transmitted drug resistance 
will be estimated and compared between Combination Prevention and Enhanced Care 
communities at baseline, annually, at the study end. 
• 8th Secondary Objective:  To estimate the association between HIV-1 viral load and HIV 
transmissions using viral linkage data. 
 
The hypothesis to be tested is that individuals with high HIV-1 RNA load are responsible for the 
majority of new HIV transmissions. To estimate HIV-1 RNA load within clusters we will use two sets 
of data, results of phylogenetic clustering and measurements of HIV-1 RNA load in HIV-positive 
individuals participating in the study. Specifically, HIV-infected individuals will be grouped based on 
clustering patterns of their viral sequences, and cluster-specific (within each cluster) HIV-1 RNA 
load will be estimated. We will compare HIV-1 RNA load between two groups of clusters, clusters 
with and without incident cases identified over the study. The assumption is that HIV-1 RNA is 
higher within clusters with incident cases.  
Analysis plans for Secondary Objectives 9-11 are covered in Section 7 (concerning cost-
effectiveness). 
 
• 12th Secondary objective: To compare CD4 and viral load trajectories over time, among HIV-
infected ART-naive persons who reside in Combination Prevention vs. Enhanced Care 
communities. 
 
We will compare CD4 count and viral load over time between randomized arms, among HIV-
infected persons who enroll into BHS with initial CD4>350 and while still ART-naive. The underlying 
rationale for this comparison is the assessment of the immunologic and virologic implications of 
expanded/early ART. The primary endpoints for this analysis will be the change in CD4 count over 
time, and the proportion of participants with HIV-1 RNA < 400 copies/mL by the final visit, by 
randomized arm. 
 
• 13th Secondary objective: To assess the accuracy and feasibility of point-of-care viral load testing 
in comparison to standard viral load platforms. 
 
Sensitivity and specificity of the POC viral load testing against BHHRL standard procedure using the 
threshold of viral load at 10,000 copies/ml will be evaluated.  
The POC and BHHRL measurements will be compared using Bablok and Passing regression analysis 
(Bablok and Passing 1985), which includes evaluation of the systematic and proportional errors, as 
well as correlation. For each phase, the difference of the POC value and the BHHRL standard 
procedure on the same sample will be plotted against the mean of the two measurements (Bland-
Altman plot) to assess the comparability of the POC method with the BHHRL standard procedure, 
and estimate the mean bias (with 95% confidence interval) (Bland and Altman 1986). 
Statistics and qualitative reports on operational characteristics of the POC procedures will be 
reported. 
 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
103 
• 14th Secondary objective: To understand (through qualitative interviews) barriers to and 
facilitators of linkage to care and ART initiation among BHS participants. 
 
Qualitative data related to linkage to care and initiation of ART will be gathered through focus 
group discussions (FGDs) and in-depth interviews (IDIs). Data will be collected in the CPCs from 
members of the BHS field team, the MOH nurse prescribers as well as from a subset of HIV-
infected BHS participants who are eligible for ART. FGDs and IDIs will be semi-structured and 
based on a standardized guide. All FGDs and IDIs will be audio-recorded, transcribed and 
translated (when not in English). Investigators will read the transcripts and develop and agree on a 
codebook. An iterative process will be used to read transcripts, apply codes, compare and revise 
codes until consensus is reached about salient motivators and barriers for linking to care and 
initiating ART.  
 
• 15th Secondary objective: To use BCPP data in analyses of the rates of and risk factors for major 
AIDS and non-AIDS illnesses/injuries/mortality among persons living with and without HIV in 
Botswana. 
 
Measurements and survey responses from participants in the BHS, AHS, and ESS will be utilized to 
estimate the distribution of risk factors and frequency of health events in Botswana.  The 
combined cohort (BHS, AHS, ESS) will also serve as a source for controls in case-control analyses 
and an estimate of population exposures in standardized incidence/morbidity/mortality 
analyses. Cases will be obtained from other sources, such as national registries, publicly available 
data, or other studies, with separate IRB approval where needed. Case-control and standardized 
incidence/mortality/morbidity analyses do not require release or sharing identifiable information 
outside of BCPP. 
 
11. ETHICAL CONSIDERATIONS  
 
11.1. Ethical Review  
 
The protocol, informed consent/assent forms, research participant education and recruitment 
materials, and other requested documents — and any subsequent modifications — will be reviewed 
and approved by the ethical review bodies responsible for oversight of research conducted at the study 
sites.  Subsequent to initial review and approval, the responsible Institutional Review Boards/Ethical 
Committees (IRBs/ECs) will review the protocol at least annually. 
 
11.2. Informed Consent 
 
Please see Table 12 below for a summary of the various approaches to informed consent for this 
protocol. 
 
Potential participants will be given the opportunity to ask questions about the study. It will be 
emphasized that participation in any component of the research is completely voluntary. The 
informed consent process will occur in the language most comfortable for participants (usually in 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
104 
Setswana). Consent materials will be translated into the local language and back-translated to 
ensure accuracy. Staff will obtain informed consent who have been designated this responsibility in 
study staff signature logs. Usually staff obtaining informed consent during household surveys and 
research blood draws will be healthcare auxiliaries and research assistants.   
 
• BHS/AHS, HIC and ESS Household Representatives - Verbal Consent for Household 
Representative: Consent will be obtained from the household representative to obtain the 
household structure.  Informed consent for this aspect of study participation will be obtained from 
research volunteers aged 18 or older, without documenting the process in writing.  A waiver of 
documentation of informed consent will be requested from IRBs and the informed consent script 
approved prior to use. The consent script (Household Script) will describe the purpose of the 
research activity, procedures to be followed, and the risks and benefits of participation. Only 
participants who verbally agree to participate will be asked to provide the requested data for this 
part of the study. A copy of the informed consent script will be offered to the participant. The 
reading level of the script has been estimated using Flesch-Kincaid and is below 6.0.   
 
• BHS/AHS, HIC, ESS – Citizen/Spouse of Citizen Participants in Household Surveys and Cohort, and 
individuals consenting to research blood draws or qualitative interviews: Written informed 
consent will be obtained from each eligible individual before completion of individual 
questionnaires and/or blood draws for study purposes. Residents aged 16-17 years old, if eligible, 
will be asked to provide written assent with a guardian’s written permission.  The informed 
consent/assent form will be given to the participant to read (for literate participants), or read by a 
trained study staff member (for illiterate participants).  Required steps in the process will be driven 
electronically in household visits to ensure quality, consistency and completeness. Consent/assent 
will be documented by having the participant sign the informed consent/assent form or make a 
mark if the participant is illiterate; the latter will be witnessed by a third party.  A copy of the 
informed consent/assent form will be offered to the participant, and if applicable, parent or legal 
guardian giving permission for a minor to participate.  Staff will ensure that the participant takes a 
copy of a study contact card that contains study information and telephone numbers if the 
participant does not wish to take a copy of the consent. The reading levels of each consent/assent 
form have been estimated using Flesch-Kincaid and are below 6.0. 
 
• ESS – Non-Citizen Adult Participants in ESS: A waiver of the requirement to obtain a signed 
consent/assent form is requested from IRBs for non-citizen participants in the ESS. The request for 
this waiver is based on the U.S. Code of Federal Regulations Title 45 Part 46.117(c)(1). All data and 
specimens will be collected anonymously from these participants. Therefore, the only record 
linking the subject and the research would be the consent document and the principal risk would 
be potential harm resulting from a breach of confidentiality. A written statement regarding the ESS 
will be IRB-approved and provided to non-citizen participants prior to conducting survey 
procedures, but it will not bear the participant’s name or signatures. The written statement will be 
given to the participant to read (for literate participants), or read by a trained study staff member 
(for illiterate participants in the presence of a witness). Parental permission will be sought with 
assent from any non-citizen participants 16-17 years old, but signatures will not be obtained per 
the waiver. Required steps in the process will be recorded with a checklist. 
 

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
105 
o Special Populations 
Minors:  Minors (participants ages 16-17) will only be enrolled in research activities if they can 
provide informed assent and with the written permission of a parent/legal guardian.  
 Under circumstances where study staff suspect, or there is a reported incident of sexual 
abuse of a person under age 18, the study staff member must inform the relevant 
authorities; this is stated in the informed consent/assent forms.   
 Referrals will be made to youth services if needed. 
 
Institutionalized populations:  Persons residing in institutions such as prisons will not be 
included in the study as they will not be available for household and community surveys. An 
enrolled participant who becomes imprisoned or involuntarily confined in a medical facility (e.g. 
for psychiatric illness) during the study will not undergo any study procedures during 
confinement. Visits missed due to absence will be recorded. Study procedures would only 
resume if the participant is released from confinement during the study period and is available 
and willing to complete any remaining study visits.   
 
Non-citizens: Non-citizens who are not married to Botswana citizens are eligible to participate 
in the ESS, a one-time household survey at the end of the study. Increased likelihood of 
experiencing problems with securing housing, travel, exploitation in employment, and access to 
healthcare make non-citizens a potentially vulnerable population. Anonymous participation in 
the ESS will be offered to ensure protection for non-citizen participants. In particular, the 
sociodemographic information collected from non-citizens will be limited, including only age 
(year of birth, but not date of birth), gender, immigration status, place of primary residence (at 
the community level, not a physical address), for example. No names or personal identifiers will 
be collected from participants who are non-citizens. Referrals will be made to services that are 
available to non-citizens.

BCPP Evaluation Protocol Version 7.0 | January 16, 2019 
 
106 
Table 12: Summary of Approach to Consent, Various Components of the Study 
Project 
component 
Targeted subjects 
Activity 
Consent 
Type/Waiver 
Requested 
Consent 
Material to be 
Used 
Provision for 
Parental 
Permission with 
Assent? 
Timing of 
Obtaining 
Consent 
Household 
structure 
Head of household/representative 
in 20% households 
Questionnaire regarding 
household structure and 
socioeconomic indicators 
Verbal/Waiver 
requested for 
documentation of 
consent 
Household 
Script 
No 
BHS T0 
BHS 
Age-eligible members of 20% 
households, including HIV-infected 
persons and HIV-uninfected persons  
Baseline and follow-up 
questionnaires  
Repeat HTC if not 
documented HIV-positive 
Research blood draws, if 
applicable 
Repeat CD4/VL, if applicable 
POC VL, if applicable 
Written  
BHS/HIC 
Consent 
Yes 
BHS T0 
New 
participants 
may consent at 
T1 
New 
participants at 
T2 will sign ESS 
consent 
HIC 
Age-eligible HIV-uninfected 
members of 20% households who 
meet HIC eligibility criteria (a subset 
of BHS participants) 
Baseline and follow-up 
questionnaires 
Repeat HTC 
Research blood draws, 
CD4/VL/POC VL if applicable 
(i.e. for seroconverters) 
Written  
BHS/HIC 
Consent 
Yes 
BHS T0, New 
participants 
may consent at 
T1 
Blood draw for 
research 
purposes  
• 
All HIV-infected persons in 
Combination Prevention 
communities  
• 
BHS residents who decline 
survey participation but are 
willing to give a blood sample 
Blood for HIV-1 RNA, stored 
sample for HIV 
genotyping/resistance testing 
and incidence assay 
Written 
Research Blood 
Draw Consent 
Yes 
Upon referral  
to or 
recruitment by 
research staff  
End of study 
survey 
All eligible residents (new enrollees 
from 20% BHS/HIC householdsand 
~80% of remaining community 
members will be newly enrolled to 
ESS in 3 pairs of selected 
communities) 
ESS questionnaire 
Research blood draw, if 
applicable 
CD4/VL/POC VL if applicable 
Written for 
Citizens/Spouses 
of Citizens; Waiver 
requested for 
non-citizens 
ESS Consent 
Yes for 
Citizens/Spouses 
of Citizens 
No for Non-
Citizens 
T2/ESS 
Supplemental 
Economic 
Assessment for 
Low CD4/OI 
Residents with low CD4 or OIs 
seeking care (out- or inpatient) 
Questionnaire regarding 
economic activity and quality 
of life  
Written 
Economics 
Consent 
No 
Upon referral to 
research staff 

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107 
Barriers to and 
facilitators of 
LTC and ART 
initiation 
HIV-infected BHS participants 
BHS Research Assistants and Nurse 
Prescribers 
Focus group discussions 
Individual in-depth interviews 
Written 
ART Start 
Interview 
Consent; ART 
Start Focus 
Group Consent 
for BHS; ART 
Start Focus 
Group Consent 
for Staff 
No 
At T1 or later 

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108 
11.3. Risks 
 
The risks, discomforts, and inconveniences that could be posed to subjects participating in this study 
include the following: 
 
• Survey Participants in the BHS, HIC, research blood draw after HTC, and ESS: 
o Blood drawing may cause pain and bruising, and rarely, infection at the site where blood is 
drawn. Study participants may feel lightheaded or faint as a result. 
o Repeated HIV testing and counseling in the HIC participants may cause stress, anxiety, or 
embarrassment. Participants are likely to become distressed if they learn they are HIV positive.  
o Participants may become embarrassed, worried, or anxious when discussing their sexual 
practices, HIV risk factors, ways to protect their partner(s) against HIV, and/or ways to prevent 
acquiring HIV infection.  
o Participants may experience discrimination as a result of being perceived by others to be HIV-
infected or at high risk for HIV infection. 
o Participants may have difficulty or conflict in their relationships if they choose to participate 
couples HIV testing, particularly if this results in perceived or disclosed infidelity. 
 
11.4. Benefits of Research Participation 
 
Survey Participants in the BHS, HIC, research blood draw after HTC, and ESS: 
Potential health benefits for 20% household residents include: earlier HTC delivered to their place of 
residence, earlier diagnosis of HIV-infection (and access to point-of-care CD4 result if ART-naive) with 
subsequent earlier enrollment in care and treatment or PMTCT, and earlier awareness of the 
importance of annual HTC and risk reduction practices for adults who test HIV-negative. HIV-infected 
individuals who consent to participate in the household surveys will also have access to a pre-ART viral 
load result at BHS enrollment and then repeat CD4 and viral load if ART-naïve at enrollment or at the 
study visit when HIV-positive status is recorded.  
 
Those who participate in research blood draws independently of the household surveys may also 
benefit from a pre-ART viral load result; however, the test may not be run in real-time. 
 
11.5. Confidentiality 
 
No identifiable study data will be released to any unauthorized third party, without prior written 
approval of the participant, except as necessary for monitoring by the IRBs, the study sponsor, external 
monitors, OHRP, or the Botswana Ministry of Health.   
 
During BHS, HIC, research blood draw after HTC, and ESS study procedures: 
Project staff visiting households for study visits will identify an appropriately private space to counsel 
participants, perform HIV tests, and collect individual data.  If private space is not available, or the 
participant does not wish to carry out study activities in the home, an appointment will be made to 
visit one of the study clinics instead.  All study documents will be stored in a secure location and 
electronic data will be password protected. Full Drive Encryption will be implemented at the hardware 
layer of all devices storing protected health information.  Only designated study staff will have access 
to study records.   

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109 
 
De-identified data: 
When de-identified datasets are created the following variables will be excluded: name, national 
identity number, phone numbers, address (other than community of residence), GPS coordinates, and 
all elements of dates (except year) for events related to the individual (birth, death, hospitalizations, 
clinic visits, etc.). BCPP does not collect data on persons >89 years, nor any biometric data or other 
identifiers.  
 
11.6. Compensation and Incentives 
 
• Baseline Household Survey (BHS) and HIV Incidence Cohort (HIC): Each participating resident will 
receive 20 Pula (about $3) worth of air time as compensation for time dedicated to the study at 
each attended scheduled study visit.  
• End of Study Survey (ESS): Each participating resident will receive 20 Pula (about $3) worth of air 
time as compensation for time dedicated to the study at the End of Study Survey.   
 
11.7. Protocol Compliance and Compliance with UN Convention on the Rights of the Child 
 
Study staff will adhere to the ethical principles that have their origin in the Declaration of Helsinki (e.g., 
ICH E6, 45 CFR 46). The study will be conducted in accordance with the regulations of Botswana and 
the sponsor.  
 
The US government is a signatory on the UN Convention on the Rights of the Child (defined as anyone 
under the age of 18) which requires that any research study or program activity which includes 
children that are identified as engaged in sex work, trafficked or victims of violence make special 
provisions for referral of these individuals to services. BCPP will report suspected cases to service 
providers (local police or social workers) as outlined in the Botswana National Guidelines for reporting 
child abuse or neglect.Contact information for the local police and social workers, and procedures for 
reporting suspected cases of child abuse or neglect are described in the study-specific SOP in the BCPP 
Study Manual. Local police and social workers will be contacted prior to the initiation of study activities 
in the community to ensure they are aware of the study activities in the community and the 
porcedures that will be followed should BCPP staff encounter suspected cases of abuse or neglect. As 
per national guidelines, reports of suspected abuse or neglect will be made to local authorities within 
24 hours. Study personnel who may come in contact with these study participants will receive training 
on the appropriate procedures for handling these cases if they arise during the course of the study and 
training on the SOP documented in the regulatory files. The study will retain documentation of all 
reports that includes date of report, age of participant, and the name and type of service provider.  No 
identified information will be retained in the documentation; documentation will be retained by the 
study for 2 years after study close-out.   The informed consents for the study contain language that 
makes clear to the participant what is required to be reported to authorities and the impact on 
confidentiality. 
 
11.8.  Future Use of Stored Samples 
 
Study participants will be asked to provide written informed consent for their specimens to be stored 
after the end of the study for possible future research testing.  Any residual specimens of participants 

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110 
who do not consent to long-term storage and additional testing will be destroyed at the end of the 
study after all protocol-required and quality assurance testing has been completed. 
 
12. STUDY SAFETY AND MONITORING PLAN  
 
12.1.  Reporting Adverse Events 
 
The Evaluation Protocol does not involve the administration of any study products.  
 
The study team will report in real-time, to IRB's and to sponsors, any serious adverse events (SAEs) 
experienced by a participant or other individual, that in the opinion of the investigator are BOTH 
unexpected and at least possibly related to the research procedures. An SAE is defined as any 
untoward occurrence that: 
• Results in death 
• Is life-threatening (grade 4) 
• Requires hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above. 
This level of reporting is chosen for this observational aspect of the BCPP to avoid real-time reporting 
of all events (e.g. deaths, hospitalizations etc.) occurring in study communities that are definitely not 
related to study procedures (but to remain compliant with reportable new information generally 
required by IRBs). 
 
Timing of reporting: 
Reportable events will be reported in accordance with institutional, sponsor, and study specific 
guidelines delineated in standard operating procedures for the study.  
 
AE reporting period: 
The AE reporting period for this study is from the time of enrollment to the end of study follow-up for a 
participant. 
 
AE reporting process 
Reportable events will be documented by the in-country study team who will then notify the IRBs, 
MoH, CDC-Atlanta, and Harvard teams.  The incident will be discussed and a written action plan will be 
devised and implemented within 1 week of the initial report, if needed.  Written documentation of all 
reportable events and event resolution will be retained in the study file.  Reporting of events to IRBs 
and the study sponsor will follow institutional and IRB policies.  If necessary, a formal report will be 
sent to the appropriate IRBs using the CDC’s Incident Report Form 1254.  
 

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111 
12.2.  DSMB  
 
DSMB review will take place prior to the start of the study and annually thereafter.  Details of 
recommended interim analyses by the DSMB are provided in Section 5.4. 
 
12.3.  Protocol Violations 
 
The study will be conducted in full compliance with the protocol.  The research team will ensure that 
volunteers are informed of and understand the risks of their participation in research. Protocol 
violations and cases of social harm will be documented using the appropriate study forms and reported 
to IRBs and sponsors in accordance with the institutional policies.  Minor protocol violations that do 
not pose a threat to the health of participants will be compiled and reported to the IRBs at the time of 
annual IRB review.  Incident reporting is the responsibility of the Principal Investigators of this study.  
Emergency departures from protocol that eliminate an apparent immediate hazard to a participant 
and are deemed crucial for the safety and well-being of that participant may be instituted for that 
participant only.  In that case the Investigator will contact the IRBs and sponsor as soon as possible to 
document the reasons for violation and ensuing events.   
 
12.4.  Study Monitoring Plan 
 
A complete monitoring plan will be developed and the site will complete a site activation checklist 
prior to study initiation.   Internal (sponsor) and external monitors will travel to the study site 
according to a pre-determined monitoring schedule specified in the monitoring plan to conduct 
general monitoring.  The study site will maintain a monitoring log to document all monitoring visits. 
Investigators and staff will grant access to the monitors to allow inspection and review study 
documents (e.g., consent forms, data collection forms, other source documents) and pertinent clinic 
records for confirmation of the study data. Study monitors will also inspect study facilities and 
documentation and may observe the performance of study procedures. 
 
13. ADMINISTRATIVE PROCEDURES AND INFORMATION DISSEMINATION 
 
13.1. Study Records and Document Retention 
 
Complete, accurate, and current study records will be maintained and stored in a secure manner 
throughout the duration of the study and additionally for five years after study close-out. Study 
records include administrative documentation— including all reports and correspondence relating to 
the study — as well as documentation related to each participant screened 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. Necessary documents to be maintained by the 
site before, during and after the study will be in accordance with GCP regulations and guidance. A 
complete list of needed documentation will be provided prior to initiation of the study and will appear 
in the study manual. 
 
13.2. Information Dissemination and Publication Plan 
 

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112 
Study findings will be disseminated through presentations, reports and publication in peer-reviewed 
journals and other publications.  In-country data and country specific information will be made 
available to national policy-makers, organizational, and implementing partners.  A detailed publication 
and communication plan will be developed that describes the number and types of reports and 
manuscripts planned for the study and criteria for authorship.  Formal presentations at conferences 
and scientific publications will follow CDC, Harvard, and MOH guidelines.  A data sharing plan will also 
be developed that details the requirements and process for requesting access to stored data and 
samples for sub-studies and future analysis. 
 
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BCPP Intervention Protocol 3_ v6.0 | September 22, 2017,    
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Botswana Combination Prevention Project  
(BCPP)   
Intervention Protocol  
(Protocol #3) 
__________________________________________ 
 
Implementation, Monitoring, and Evaluation of a Combination 
of HIV Prevention Interventions in Rural and Peri-Urban 
Communities in Botswana 
 
Version 6.0 
September 22, 2017 
Collaborating Institutions: 
Botswana Ministry of Health (MOH) 
Harvard T. H. Chan School of Public Health (Harvard Chan School) 
U.S. Centers for Disease Control and Prevention (CDC) 
 
Funded by:  
The United States President’s Emergency Plan for AIDS Relief (PEPFAR) through 
United States Centers for Disease Control and Prevention (CDC) 
 
 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017,    
 Page 2 of 59 
PRINCIPAL INVESTIGATORS: 
 
Janet Moore, PhD 
Branch Chief, HIV Prevention Branch 
Division of Global HIV/AIDS (DGHA), Center for Global Health (CGH) 
United States Centers for Disease Control and Prevention (CDC) 
Address: 1600 Clifton Road, Atlanta, GA, 30333, U.S.A 
Email: jym3@cdc.gov    
 
 
Office Phone: 404.639.8954  
 
Refeletswe Lebelonyane, MD 
Combination Prevention Coordinator, MOH 
Ministry of Health, Botswana Government  
Enclave Plot No. 54609  
Gaborone, Botswana 
Email:  rlebelonyane@gov.bw 
 
Shenaaz El Halabi, (PS) MPH 
Permanent Secretary 
Botswana Ministry of Health 
Address: Private Bag 0038, Gaborone, Botswana 
Email: sel-halabi@gov.bw  
 
 
Office Phone: +267-363-2069 
 
Pamela Bachanas, PhD 
Behavioral Scientist, HIV Prevention Branch 
Division of Global HIV/AIDS (DGHA), Center for Global Health (CGH) 
United States Centers for Disease Control and Prevention (CDC) 
Address: 1600 Clifton Road, Atlanta, GA, 30333, U.S.A 
Email: ddt6@cdc.gov    
 
 
Office Phone: 404.639.8110 
 
ROLES OF INSTITUTIONS AND PRINCIPAL INVESTIGATORS 
Institutions:  Close coordination between MOH, CDC, HSPH, BHP, and other implementing 
partners is needed to ensure seamless implementation of research and program activities.  
MOH and CDC will lead and ultimately be responsible the Intervention Protocol and HSPH and 
BHP will lead the Evaluation Protocol. 
Principal Investigators: 
 
Janet Moore/ Pamela Bachanas:  CDC (PIs) responsible for preparation and design of the study 
protocol, monitoring of study progress, creation and monitoring of research budgets, and 
preparation of monthly progress reports.   
Refeletswe Lebelonyane/ Shenaaz El Halabi:  MOH Co-Principal Investigator (Co-PI) responsible 
for protocol review and in-country implementation oversight. 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 3 of 59 
 
CO-INVESTIGATOR LISTS BY INSTITUTION   
 
Botswana Ministry of Health (MOH), Gaborone, Botswana 
 Name 
Role 
           Contact Email 
Ms. Dinah Ramaabya (Nursing) 
        ARV Program 
                    dramaabya@gov.bw 
Ms. Chipo Phetlo (Nursing) 
        PMTCT 
 
                    cphetlo@gov.bw 
Mr. S. Makathaye, Dip Health Educ.        BCIC 
                                    smalathaye@gov.bw 
Mr. C. Ntsuape, BEd (Nursing Educ)          SMC                                                   ontsuape@gov.bw                 
Ms. Nokuthula Manjingo (Nursing)         HIV Testing & Counselling 
      mmajingo@gov.bw 
Dr. Joe Theu ((Medical Officer) 
         Clinical Care  
 
     jtheu@gov.bw  
 
 
Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA, and Gaborone, Botswana 
Name  
Role 
Contact Email 
Elliot Raizes, MD 
Clinical Consultant 
gwq0@cdc.gov  
Ebi Bile, BSc. MA, DU 
In-country Lab Oversight 
efb6@bw.cdc.gov 
Peter Fonjungo, PhD 
HQ Lab Oversight 
pdf4@cdc.gov 
Sherri Pals, PhD 
Statistics 
sfv3@cdc.gov 
Chunfu Yang, PhD 
Laboratory 
cxy0@cdc.gov 
Mary Grace Alwano 
In Country HTC/ LTC 
Project Coordinator 
         mea9@bw.cdc.gov 
Stephanie Behel, MPH 
HTC and LTC 
         zmd7@cdc.gov 
Naomi Bock, MD 
Voluntary Medical MC 
        neb2@cdc.gov 
Stephanie Davis, MD, MPH 
Voluntary Medical MC 
        vic6@cdc.gov 
Lisa Block, MS 
Project Manager 
        kwk5@cdc.gov 
Lisa Mills, MD 
William Abrams 
Co-investigator 
Program Administration 
        Ioj7@cdc.gov 
        hvf8@cdc.gov  
Arielle Lasry PhD 
HTC Costing 
        ftn9@cdc.gov 
 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 4 of 59 
Harvard T. H. Chan School of Public Health, Boston, MA, USA 
Name 
Role 
Contact Email 
Myron Essex, DVM, PhD 
Co-Investigator 
messex@hsph.harvard.edu  
Eric Tchetgen, PhD 
Statistics and Epidemiology 
etchetge@hsph.harvard.edu 
Scott Dryden-Peterson, MD 
Treatment and PMTCT 
scott_peterson@post.harvard.edu  
Shahin Lockman, MD, MSc 
Treatment and PMTCT 
slockman@hsph.harvard.edu  
Rebeca Plank, MD 
SMC 
rplank@partners.org  
Molly Pretorius Holme, MSc 
Research operations 
mpretori@hsph.harvard.edu  
Roger Shapiro, MD, MPH 
Treatment and PMTCT 
rshapiro@hsph.harvard.edu 
Kate Powis, MD, MPH 
Research Operations, 
Treatment and PMTCT 
kpowis@mgh.harvard.edu 
 
 
Botswana–Harvard AIDS Institute Partnership (BHP), Gaborone, Botswana 
Name 
Role 
Contact Email 
Tendani Gaolathe, MD 
Treatment and PMTCT, 
Field research operations 
tgaolathe@bhp.org.bw  
Joseph Makhema, MD 
BHP research operations 
jmakhema@bhp.org.bw  
Sikhulile Moyo, BSc, MSc, MPH 
Lab 
smoyo@bhp.org.bw  
Mompati Mmalane, MD, FRCS-Ed, MSc 
Community mobilization and 
research operations 
mmmalane@bhp.org.bw 
Erik van Widenfelt, BA 
Research data systems 
ewidenfelt@bhp.org.bw  
  
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 5 of 59 
TABLE OF CONTENTS 
  
Principal Investigators ............................................................................................................ 2 
List of Co-Investigators ........................................................................................................... 3 
Table of Contents ................................................................................................................... 5 
List of Tables and Figures ....................................................................................................... 7 
List of Acronyms and Abbreviations ........................................................................................ 8 
 
Intervention Protocol Synopisis ............................................................................................ 10 
 
1.0 INTRODUCTION .............................................................................................................. 12 
1.1   Epidemic in Botswana    
1.2  Combination Prevention Interventions          
1.3  Antiretroviral Treatment as a Component of the Combination Prevention Package 
1.4  Proposed Combination Prevention (CP) Package      
1.5  Relationship Between  Intervention Study Design and Impact Evaluation  
 
2.0 STUDY OBJECTIVES ......................................................................................................... 16 
 
3.0 OVERVIEW OF STUDY  METHODS  ................................................................................... 16 
 
4.0 STUDY POPULATIONS ..................................................................................................... 16 
4.1  Selection of Study Communities  
4.2  Matching of Study Communities 
4.3  Eligibility of Community Members  
4.4 Enhancement of Services in all Study Communities 
4.5  Eligibility Criteria for Inclusion in Interventions in CP Communities 
4.6  Rationale for Exclusion in Interventions in CP Communities 
 
5.0 SAMPLE SIZE AND SAMPLE SELECTION METHODS…………………………………………………………….21 
 
6.0 INTERVENTION PROCEDURES  ......................................................................................... 22 
6.1 Overview of Intervention Strategy 
6.2 Stakeholder Involvement, Community Engagement, and Community Mobilization 
6.3 HIV Testing and Counseling (HTC) 
6.4 Linkage to HIV Care and Treatment 
6.5 Male Circumcision (MC) 
6.6 Identification, Linkage, and Treatment of HIV+ Pregnant Women 
6.7 HIV Care and Treatment 
 
7.0 LABORATORY METHODS ................................................................................................. 32 
7.1 Overview of Laboratory Methods  
7.2 Training of Laboratory Personnel  
7.3  Specimen Collection, Transport, and Processing  

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 6 of 59 
7.4  Laboratory Testing for HTC Campaigns 
7.5  Laboratory Testing for IDCC Patients 
7.6 Quality Assurance   
7.7 Biosafety and Waste Management   
7.8 Specimen Storage and Shipment    
 
8.0 DATA SYSTEMS AND MANAGEMENT ....................................................................... ………35 
8.1 Data Collection, Capture, and Flow 
8.2 Data Security   
8.3 Data Quality  
8.4 Confidentiality of data 
 
9.0 DATA AND ANALYSIS PLANS…………………………………………………………………………………………….40 
9.1 HIV Testing and Counseling and Linkage to Care  
9.2 Care and Treatment    
9.3 PMTCT Services    
9.4 Male Circumcision  
9.5  Analysis Plans  
 
10.0 ETHICAL CONSIDERATIONS… ........................................................................................... 5 
10.1  Ethical Review 
10.2  Informed Consent 
10.3  Risks 
10.4  Benefits of Research Participation 
10.5  Confidentiality 
10.6  Protocol Compliance and Compliance with UN Convention on the Rights of the Child 
10.7  Future Use of Stored Samples 
 
11.0 STUDY SAFETY AND MONITORING PLAN ....................................................................... 49 
11.1  Reporting Adverse Events  
11.2  Data Safety and Monitoring Board (DSMB) 
11.3  Protocol Violations 
11.4  Monitoring Plan 
 
12.0 ADMINISTRATIVE PROCEDURES AND INFORMATION DISSEMINATION ........................... 52 
12.1  Study Records and Document Retention 
12.2  Information Dissemination and Publication Plan 
 
13.0 REFERENCES ................................................................................................................. 53 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 7 of 59 
APPENDICES:   
_________________________________________________________________________________ 
Cross-Protocol Appendices: 
Appendix C2 
 
A.  List of Study Communities and Matching Criteria for Community Pairs 
B. Back-up Communities in Selected 30 Communities Decline, unavailable or 
deemed unsuitable for study inclusion 
Figure A: Map of Study Communities in Three Regions 
Figure B: Map of Study Communities in the Southern Region 
Figure C: Map of Study Communities in the Central Region 
Figure D: Map of Study Communities in the Northern Region 
Appendix C3 
 
Size of Study Populations 
Appendix C4 
 
Data Safety Monitoring Plan 
 
Protocol 3 Appendix: 
Appendix P1 
 
Summary of Variables to be Collected for Ya Tsie Protocol 3 
_________________________________________________________________________________ 
 
 
 
 
LIST OF TABLES AND FIGURES 
 
 
Figure 1: Data Flow for Combination Prevention Communities 
 
Table 1: Precision for 95% confidence intervals for uptake of CP interventions in CP 
communities 
Table 2: BCPP Key Indicators 
Table 3:  Summary of approach to consent for various components of the study 
 
 
 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017,    
 Page 8 of 59 
ACRONYMS AND ABBREVIATIONS  
 
AE 
 
  
adverse event 
AIDS 
 
  
acquired immunodeficiency syndrome 
AHS 
 
  
annual household surveys (follow-up visits of the BHS and HIC) 
ANC 
 
  
antenatal clinic (or care) 
ART 
 
  
antiretroviral treatment (or therapy) 
ARV 
 
  
antiretroviral (drug) 
BCPP 
 
  
Botswana Combination Prevention Project 
BHHRL  
  
Botswana–Harvard HIV Reference Laboratory 
BHP 
 
  
Botswana–Harvard AIDS Institute Partnership 
BHS 
 
  
baseline household survey 
CDC 
 
  
Centers for Disease Control and Prevention 
CI 
 
  
confidence interval 
CP 
 
  
combination prevention 
CPC 
 
  
combination prevention community 
CRT 
 
  
community-randomized trial 
DSMB  
  
Data Safety Monitoring Board 
ECC 
 
  
enhanced care communities 
ELISA 
 
  
enzyme-linked immunosorbent assay 
ESS 
 
  
end of study survey 
ETC 
 
  
expanded treatment cohort 
HIC 
 
  
HIV incidence cohort 
HIV 
 
  
human immunodeficiency virus  
 
 
 
HIV-1 RNA 
  
HIV-1 RNA load in plasma, viral load 
HIVDR  
  
HIV drug resistance 
HTC 
 
  
HIV testing and counseling 
HVL 
 
  
high viral load  
IAS 
 
  
International AIDS Society 
IDCC 
 
  
infectious disease care clinic 
IPMS 
 
  
integrated patient management system 
IRB 
 
  
institutional review board 
LFT 
 
  
liver function test 
LTC 
 
  
linkage-to-care 
MC 
 
  
male circumcision 
M&E 
 
  
monitoring and evaluation 
MOH 
 
  
Ministry of Health 
 
 
 
MTCT  
  
mother-to-child (HIV) transmission 
OHRP  
  
Office for Human Research Protections 
OI 
 
  
opportunistic infection 
Option B+ 
  
indefinite continuation of ART for women who start ART for PMTCT 
PEP 
 
  
post-exposure prophylaxis 
PEPFAR  
  
President’s Emergency Plan for AIDS Relief 
PII 
 
  
personally identifiable information 
PIMS 
 
  
patient information management system 
PMTCT  
  
prevention of mother-to-child (HIV) transmission 
PLHIV  
  
people living with HIV 
POC 
 
  
point-of-care 
POB 
 
  
pregnant/pregnancy or breastfeeding 
QA 
 
  
quality assurance 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 9 of 59 
QC 
 
  
quality control 
RHT 
 
  
Routine HIV testing 
SAE 
 
  
serious adverse event 
SD 
 
  
standard deviation 
SMC 
 
  
safe male circumcision (Botswana government initiative) 
SMS 
 
  
short message service 
SOC 
 
  
standard of care 
SoE 
 
  
schedule of events 
SOP 
 
  
standard operating procedure 
study arm 
  
a group of 15 communities that is randomized to receive either standard of care or 
study interventions with respect to HIV prevention measures 
TB 
 
  
tuberculosis 
UN 
 
  
United Nations 
UNAIDS 
 
Joint United Nations Program on HIV/AIDS 
UTT 
 
 
Universal Test and Treat 
VDC 
 
 
village development committee 
VF 
 
 
virologic failure 
VL 
 
  
viral load 
VPN 
 
 
virtual private network 
WHO 
 
  
World Health Organization 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 10 of 59 
 
 
 
 
BCPP Intervention Protocol (#3) 
Protocol Synopsis 
 
Overview:  The BCPP study is composed of 2 active interlocking protocols, the Evaluation Protocol (1) 
and the Intervention Protocol (3).  The Closed Clinical Cohort Protocol (Protocol 2) was withdrawn in 
2015.  An overview of the overarching BCPP study is provided in the BCPP Overall Schema located in 
the Evaluation Protocol.    
 
Primary Objective of Protocol 3 
1) To implement the combination prevention (CP) intervention package in combination 
prevention communities (CPC) and describe uptake of these interventions in CPCs (expanded 
HIV Testing and Counseling (HTC), strengthened Male Circumcision (MC), expanded HIV Care 
and Treatment, and strengthened PMTCT services). 
 
Secondary Objectives of Protocol 3 
1) To describe retention in the clinical cascade of care from HIV diagnosis to viral suppression 
among all HIV-infected persons. 
2) To describe uptake of expanded antiretroviral treatment (ART) and clinical outcomes including 
viral suppression among HIV-positive persons receiving expanded ART.  
3) To examine demographic, clinical, and social/behavioral facilitators and barriers to uptake of CP 
interventions.  
4) To examine demographic factors, including community of residence, that affect access to health 
care services.  
 
Study Design: 
The BCPP study is a pair-matched community-randomized trial. This protocol describes the 
programmatic interventions, including expanded ART, and program monitoring activities that will be 
conducted as part of the larger BCPP project.  
 
Study Population: 
Thirty community clusters were selected from three geographic regions in Botswana.  Pre-
randomization, community pairs were matched on community characteristics thought to be associated 
with the outcome of interest of the BCPP (HIV incidence) to improve balance between arms and 
statistical efficiency.  The average total population size of each of the targeted communities is 6,000 
(range 2,400 - 12,000), giving a total population across all 30 communities of about 180,800, of whom 
about 105,000 are adults aged 16-64.  
 
Study Procedures:  
Matched community pairs (15 communities per arm) were randomized 1:1 to Enhanced Care (ECC; 
Comparison) or Combination Prevention (CPC; Intervention) arms prior to the baseline household 
survey (BHS) that is conducted as part of the BCPP Evaluation Protocol.  Initiation of intervention 
activities in the CPCs begin immediately following completion of enrollment in the BHS and continue 
for the duration of the study.  CPCs receive the combination prevention intervention package, which 
includes strengthened HTC, MC linkage, PMTCT services, and expanded HIV care and treatment for 
HIV-infected persons 16-64 years. In addition, expanded ART for existing HIV-infected community clinic 

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patients will be offered in the CPCs.  Routinely collected clinical data will be used to assess the clinical 
outcomes for all HIV positive patients.  
 
Study Duration:  All study activities will occur over a period of approximately 60 months. 
 
 

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1.0 INTRODUCTION AND BACKGROUND 
 
 1.1 Epidemic in Botswana 
Thirty years into the global HIV pandemic, HIV prevalence and incidence remain high in sub-Saharan 
Africa.  Although this region represents only 12% of the world’s population, it accounts for 
approximately 67% of the world’s 34 million HIV-infected persons,  and annually, about 70% of the 
world’s 2.7 million new infections occur in this region (UNAIDS 2010). Despite substantial progress in 
providing HIV treatment and prevention of mother-to-child transmission services (PMTCT) to its 
citizens, an estimated 25% of adult residents of Botswana are HIV-infected, the second highest adult 
HIV prevalence in the world, and about 14,000 persons are newly infected with HIV annually, the third 
highest national HIV incidence rate globally (UNAIDS 2010). 
 
 1.2 Combination Prevention Interventions 
In the past five years several HIV prevention interventions have proven to be highly effective at 
reducing transmission of HIV and have offered hope for containing and possibly reversing epidemics in 
sub-Saharan Africa.  For HIV-negative men, MC has been shown to significantly reduce HIV acquisition 
from HIV-infected female partners.  Three randomized controlled trials of circumcision, involving more 
than 10,000 men in sub-Saharan Africa, demonstrated a 60% reduction in HIV acquisition risk (Auvert, 
Taljaard et al. 2005, Bailey, Moses et al. 2007, Gray, Kigozi et al. 2007).  Additionally, antiretroviral 
treatment (ART) of HIV-infected persons has been shown to reduce viral load (VL) and consequently 
the risk of HIV transmission to uninfected partners in sero-discordant couples by as much as 96% 
(Cohen, Chen et al. 2011).  Similarly, the use of antiretrovirals to prevent transmission of HIV from 
infected mothers to their infants during pregnancy, birth, and breastfeeding can reduce transmission 
to below 5% (Mahy, Stover et al. 2010; Shapiro, Hughs et al. 2013).   
 
Despite considerable success in scaling up these interventions in many sub-Saharan African countries, 
especially those supported by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), adult HIV 
incidence has remained high (>1%) in many regions in Southern Africa (Botswana, Swaziland, Lesotho, 
Kwa-Zulu Natal in South Africa, and Southern Mozambique).  Multiple factors may account for high HIV 
incidence in this part of the world.  Firstly, viral characteristics of HIV-1 subtype C, endemic in Southern 
Africa, may make it more infectious than other viral subtypes (Novitsky, Wang et al. 2010, Novitsky, 
Ndung'u et al. 2011).  For example, recent evidence suggests that about one third of persons infected 
with HIV-1 sub-type C, maintain very high viral loads (VL>50,000 copies/ml) for more than 6 months 
after sero-conversion.  In contrast, viral load following HIV-1 subtype B infection (the prevalent 
subtype in the United States and Europe) resolves to a steady-state viral set point below 50,000 
copies/ml in almost all individuals within four to six months (Daar, Moudgil et al. 1991, Mellors, Munoz 
et al. 1997, Kaufmann, Cunningham et al. 1998, Little, McLean et al. 1999).   
 
Secondly, the scale and quality of the HIV prevention interventions may have been insufficient to 
reduce HIV incidence among adults in Southern Africa to levels observed in other parts of the world.  
For example, the main mechanism by which scale-up of HTC and antiretroviral therapy reduces HIV 
transmission risk in the community, is by reducing viral load in resident HIV-infected persons, ideally to 
undetectable levels (VL<400 copies/ml).  Studies have suggested that every 0.5 log reduction in an 
individual’s HIV-1 viral load is equivalent to a 40% reduction in individual HIV transmission risk 

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(Modjarrad, Chamot et al. 2008), and once the viral load is fully suppressed (VL <400 copies/ml) 
individual HIV transmission risk is virtually zero (Attia, Egger et al. 2009).  Despite considerable scale-up 
of access to HTC and ART, poor retention of HIV-infected persons in the HIV care and treatment 
cascade from diagnosis to ART follow-up (Rosen and Fox 2011), has mitigated the ability of HTC and 
HIV care and treatment programs in Southern Africa to reduce the prevalence of HIV-infected persons 
with detectable viral loads (VL>400 copies/ml).  In a meta-analysis of pre-ART retention in Africa, Rosen 
et al. reported that only 59% of newly diagnosed adults are successfully linked to HIV care and 
treatment services, only 46% are retained from initial registration and staging at the facility to ART-
eligibility, and only 68% are retained from ART eligibility to ART initiation (Rosen and Fox 2011). Of 
those adults who initiate ART, ~30% are no longer on therapy by 3 years of follow-up, with most of 
those no longer in care considered lost to follow-up (Fox and Rosen 2010).  Therefore, even if  50% of 
HIV-infected adults in Botswana know their HIV status (BAIS 2008), a considerably lower proportion 
have a suppressed viral load (Gardner, McLees et al. 2011).  The remaining HIV-infected adults with 
unsuppressed viral load are still infectious and spreading virus in the community.  Achieving high 
coverage of MC among HIV-negative males has also been challenging with most countries, including 
Botswana, unable to meet ambitious 80% coverage targets to date (Curran, Njeuhmeli et al. 2011).   
 
In summary, despite having the tools to end the HIV epidemic (Fauci and Folkers 2012), insufficient 
scale, quality, and coordination of prevention interventions have significantly limited southern Africa’s 
ability to sufficiently curb the HIV epidemic.  This has led public health experts to call for a 
“combination prevention” strategy that involves implementing multiple prevention interventions with 
known efficacy in a geographic area at a scale, quality, and intensity to impact the epidemic (Merson, 
Padian et al. 2008, Piot, Bartos et al. 2008).  Although most experts agree that synchronized 
implementation of a combination of prevention interventions is needed, there remains considerable 
debate about what components should be included in the essential combination prevention package 
(Merson, Padian et al. 2008, Halperin 2009).  Four evidence-based interventions (HTC, ART, MC and 
PMTCT) are recommended for scale-up by almost all prevention experts and will form the cornerstone 
of the combination prevention package proposed as part of this project (see Section 1.4 below). 
 
1.3 ART as a Component of the Combination Prevention Package 
Data show that higher levels of HIV-1 RNA (viral load) are independently associated with both higher 
rates of HIV transmission and more rapid HIV clinical disease progression and CD4 decline. This study 
therefore originally included the use of a modified “treatment as prevention” approach that targeted 
not only those adults who need ART for their own health, but also those adults who are most likely to 
perpetuate HIV transmission within the community (those with viral load ≥10,000 copies/ml). At the 
time of designing the BCPP in 2012 there was strong experimental evidence supporting initiation of 
ART at CD4≤350 cells/µL, or WHO Stage III/IV, but conclusive experimental evidence supporting patient 
benefit of ART initiation at higher CD4 counts, especially CD4 >500 cells/µL was lacking. 
 
The 2013 WHO guidelines recommended initiation of ART in all HIV-infected adults with CD4≤500 
cells/µL regardless of clinical stage. In an attempt to provide programmatic data for an anticipated 
change in CD4 threshold for ART initiation in Botswana and to enhance the power of the study to 
answer its primary objective, the threshold for ART initiation in the Combination Prevention arm was 
modified in early 2015 (from CD4≤350 to CD4≤500 regardless of viral load, in addition to offering 
expanded ART to persons with CD4>500 and viral load ≥10,000).   
 

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Shortly thereafter, in July 2015, the WHO announced that it would revise ART guidelines to 
recommend universal treatment (regardless of CD4 count or HIV disease severity). The WHO’s plans 
were informed by results from two clinical ART trials. One, the START trial, reported that early drug 
treatment of people with HIV cut their risk of serious illness or death by 57% (Lundgren, Babiker et al. 
2015). Another, the TEMPRANO study, released findings that early ART significantly decreased 
morbidity overall and when restricted to patients with baseline CD4>500 cells/µL (Danel, Moh et al. 
2015). WHO published an early release guideline on when to start ART and on pre-exposure 
prophylaxis for HIV in September 2015 (World Health Organization 2015). The BCPP study team, with 
the support of the DSMB and funder, is revising the intervention treatment initiation criteria once 
more to take these new results and WHO guidelines into account. Universal Test and Treat (UTT) is 
therefore included in the combination prevention package with version 4.0 of the protocols. 
 
In June 2016, Botswana treatment guidelines changed to UTT. All PLHIV living within the Enhanced 
Care communities (ECC) are now eligible to receive ART according to these updated Botswana national 
guidelines.  Residents in the Combination Prevention communities will also continue to receive 
universal treatment as prevention.   
 
Through additional modeling, the study team has adjusted effect size and power calculations to reflect 
a move to UTT in both the Combination Prevention and Enhanced Care arms, using a range of roll-out 
timelines.  This revised modeling also uses estimates of coverage (by HTC, LTC, ART, MC) that are 
consistent with what has been observed in BCPP thus far, rather than using the higher coverage 
“targets”.  Model-based estimates suggest that the impact of a change in treatment policy on the 
power to detect a difference in cumulative incidence (the primary objective of BCPP) may still yield at 
least 70% power (Protocol 1, v4.0, section 5.1.1), but the impact depends on the exact nature and 
timing of the implementation of changes in policy as well as other prevailing conditions.  The retention 
of this level of power even with Enhanced Care communities moving to expanded access to ART is at 
least in part attributable to the fact that BCPP is implementing multiple HIV prevention interventions 
(including higher HTC coverage, linkage to HIV care/treatment, etc.). 
 
1.4. 
 Proposed Combination Prevention (CP) Package  
In version 4.0 of this protocol, the combination package includes universal treatment of all PLHIV along 
with a package of interventions that are designed to:  1) Identify all HIV-infected adults in CP 
communities,  2) reduce barriers to ART initiation, 3) support adherence and retention on ART, 4) 
increase capacity of clinics to support aggressive ART scale-up, and 5) enhance the use of both 
individual and clinic-level data to ensure maintenance of quality of HIV care and treatment.  
 
The revised combination prevention package for this project includes: 
 
 Rapid scale-up of HTC services, with a target of ensuring >90% of HIV-infected adults aged 16-64 
have documentation of their HIV-infected status. 
 Rapid scale-up of universal ART for all HIV-infected adults, with a target of ensuring that >93% of 
adults diagnosed with HIV infection are receiving ART. 
 Rapid scale-up of retention in care and adherence interventions, with a target of ensuring that 
>95% of HIV-infected adults receiving ART are virally suppressed with HIV-1 RNA < 400 copies per 
ML. 

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 Scale-up of linkage to MC services, with a target of ensuring >60% of HIV-negative men (aged 16–
49) are circumcised. 
 Rapid strengthening of PMTCT services, with a target of ensuring >90% of women initiated on 
indefinite ART (Option B+) during pregnancy remain in care and on treatment post-delivery.   
 
The targets for intervention communities in this version of the Protocol have been revised from the 
targets in Protocol 3, version 3.0.  Targets for ART initiation and viral load suppression have been raised 
based on the higher than expected baseline levels of ART initiation and viral load suppression coverage 
as measured in BCPP BHS and HTC campaign.  The MC target has been lowered from 80% to 60%.  This 
change is in accordance with the DSMB’s 2013 recommendation based on concerns that the 80% 
target might not be realistic; results to date support these expectations. 
 
To reach stated scale-up targets (cumulative over 3 years) several service uptake initiatives will be 
implemented, including (1) community mobilization to encourage HTC and MC uptake, (2) targeted HIV 
testing to include hard-to- reach populations, (3) strengthening linkage to care, treatment and/or 
PMTCT services for known HIV-infected adults not in care and newly diagnosed HIV-infected adults, (4) 
strengthening linkage to MC services for HIV-negative or HIV-unknown status males identified at HTC 
services, (5) strengthening retention in care and adherence to ART services at clinics (6) expansion and 
strengthening of HTC, ART, PMTCT services, and MC services through recruitment of additional health 
care personnel and counselors, and (7) strengthened monitoring and evaluation of prevention, care 
and treatment programs to ensure stated targets are reached.  
 
Adults aged 16-64 will be targeted for service uptake because recent, nationally representative surveys 
of HIV prevalence and incidence (BAIS 2008) suggest that HIV incidence remains high (>1%) throughout 
this age group. Modeling exercises suggest that meeting scale-up targets by the end of two years of 
program implementation, and maintaining treatment coverage thereafter, could result in community 
HIV incidence reductions of 40% by the end of three years of implementation.    
 
1.5. 
Relationship Between  Intervention Study Design and Impact Evaluation  
A separate protocol (BCPP Evaluation, Protocol #1) describes in detail the proposed plans for 
evaluating the impact of the combination prevention (CP) package on adult population level HIV 
incidence.  In brief, a randomized design was proposed to provide experimental evidence of CP 
package impact and because population-level HIV incidence is the outcome of interest, a community 
(rather than individual) randomized trial is proposed.  Thirty study communities have been selected 
and matched into pairs.  Pair-matching is done to improve balance between study arms and statistical 
efficiency (Hayes and Moulton 2009).  Communities within pairs were randomized to Combination 
Prevention Community and Enhanced Care Community (CPC and ECC) arms.  Following community 
matching, a baseline 20% household survey (BHS) was implemented to recruit an HIV Incidence Cohort 
(HIC) of eligible, consenting, and HIV-negative adults aged 16-64.  The HIC will be followed annually 
during Annual Household Survey (AHS) visits to assess cumulative HIV incidence over 30 months.  Study 
participants who are not eligible for the HIC will also be followed annually in the AHS, to assess, in both 
study arms, uptake of HTC, ART, MC services and PMTCT services in each arm and to describe major 
health outcomes (such as death).  Cumulative incidence will be compared between study arms to 
assess CP package impact.   
 

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Combination prevention package coverage in the community will be estimated at baseline (in the 20% 
BHS) and through a large end of study survey (ESS).  In addition, during study conduct, progress in 
reaching target coverage levels will be captured from monitoring data collected as part of routine 
programmatic activities. 
 
2.0 STUDY OBJECTIVES 
 
Primary Objective  
1) To implement the combination prevention (CP) intervention package in CPCs and describe 
uptake of these interventions (expanded HTC, strengthened MC, expanded HIV Care and 
Treatment, and strengthened PMTCT services). 
 
Secondary Objectives 
1) To describe retention in the clinical cascade of care from HIV diagnosis to viral suppression for 
HIV-infected persons. 
2) To describe uptake of expanded ART and clinical outcomes including viral suppression among 
HIV-positive persons receiving ART (UTT).  
3) To examine demographic, clinical, and social/behavioral facilitators and barriers to uptake of CP 
interventions.  
4) To examine demographic factors, including community of residence, that affect access to health 
care services.  
 
3.0 OVERVIEW OF STUDY METHODS 
As described in the introduction, the over-arching design is a pair-matched community-randomized 
trial (CRT).  The full details of the CRT, including how communities were selected, how they were 
matched, community randomization, the BHS, enrollment of the HIV incidence cohorts (HIC), and the 
end of study survey (ESS), are described in the BCPP Evaluation Protocol.  This protocol describes the 
interventions implemented in 15 communities randomly selected from the 30 study communities 
(Appendix C2), monitoring and evaluation (M&E) plans, and the program data systems. 
 
4.0 STUDY POPULATIONS 
 
4.1 Selection of Study Communities 
Thirty communities (Appendix C2) in three geographic areas in Botswana: (1) around Gaborone in the 
south east, (2) around Francistown in the north east, and (3) in the region around Mahalapye, Serowe, 
and Palapye in the central eastern region, are included in the study.   These communities were selected 
based on two criteria: (1) communities needed to be of sufficient size to meet sample size 
requirements for the HIV Incidence Cohort (described in BCPP Evaluation Protocol), and (2) 
implementation of the proposed combination prevention package needed to be feasible.  Feasibility 
requirements are listed below: 
 
 Community Criteria 
All communities must: 
o Have a health center from which HIV care and treatment, PMTCT, or HTC can be provided. 
o Be reachable by road via a <8 hour drive from Gaborone or Francistown.  (CDC and the Ministry 
of Health have permanent, well-staffed offices in Gaborone and Francistown, while the Harvard 

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Chan School has a permanent office in Gaborone.  This distance parameter makes the study 
easier to implement and monitor for quality control purposes). 
o Have a clear geographic boundary such that it is reasonably easy to identify a household as 
either being part of, or outside of, the study community.   
 
These inclusion criteria resulted in the exclusion of urban areas from the study.  Approximately 61% of 
Batswana (plural noun for Botswana citizens) live in urban areas with a rate of urbanization of about 
2.3% per year (annual rate of migration from rural or peri-urban regions into urban areas).  Restricting 
the study to rural and peri-urban areas, besides being necessary for study feasibility, should not limit 
the generalizability of study findings to urban areas.  If the combination prevention package is shown 
to be effective at reducing adult HIV incidence, the principle of scaling up combination prevention 
package coverage for prevention effectiveness should be applicable to urban settings.   
 
The 30 study communities selected meet the criteria described above.  The average total population 
size of each of the targeted communities is 5,855.  Assuming an average community size of 5,855, we 
estimate a total population in all 30 study communities of about 175,664 people; 87,832 persons in the 
CPC arm of which ~58% of community residents are aged 16-64 (Appendix C2/C3).  HIV prevalence 
among residents aged 16-64 is estimated at 25%, resulting in an estimated 25,471 HIV-infected 
residents aged 16-64 (12,736 per study arm).   
 
4.2  Matching of Study Communities 
Due to the small number of communities that can be enrolled in a community randomized trial for cost 
and feasibility reasons, the likelihood of imbalance of potential confounders between study arms is 
increased.  A restricted randomization, matching, and stratification were considered as strategies to 
ensure balance between arms.  A pair-matched design was chosen because: 
 This approach is more likely than stratification to achieve balance between study arms;  
 Matching has the added advantage of improving statistical efficiency compared with restricted 
randomization, and; 
 Chosen matching covariates (see below) are quite closely correlated with the outcome of interest 
(adult HIV incidence), making a matched design of similar or increased statistical efficiency 
compared with a stratified design, even though a matched design entails greater loss of degrees of 
freedom. 
 
Possible disadvantages of a pair-matched design include: 
 Loss of both communities in a pair if one community drops out. 
 It is not possible to assess whether the intervention effect varies between matched pairs, whereas, 
in a stratified design, opportunity to assess effect modification across strata would be possible.     
 
The following matching criteria were chosen:  
 Community size:  Although community size in Botswana may not be associated with the outcome 
of interest (HIV incidence), achieving sample size balance between arms improves statistical 
efficiency.   
 
 Baseline Access to Health Services including ART:  Access to ART is associated with HIV incidence 
(Montaner, Lima et al. 2010, Tanser, Bärnighausen et al. 2012).  Although some communities within 
matched pairs have access to primary care clinics and others have access to primary care hospitals, 

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in Botswana this does not appear to represent a significantly different level of access to health 
services. 
 
 Age structure:  Adult HIV prevalence and incidence are correlated with adult age (Central Statistics 
Office 2009).  Age structures are very similar within the study community pairs.  If we use the 
proportion of adults (16-64) who are in the highest risk for HIV infection (25-34) as an indicator of 
age structure, the median difference in this proportion is 2% (range 0-7%).  [Note: we do not have 
age structure data for Gumare, Shakawe, Mandunyane, or Mmadinare, but based on the age 
structure of the other 26 selected communities, do not expect any significant differences in age 
structure within the matched pairs].  
 
 Geographic location as measured by proximity to major urban centers (Hayes, Mosha et al. 1995).  
Geographic locations of communities within pairs, as estimated by average distance to the nearest 
large towns, are quite similar.  For example, across 30 communities, the range of average distances 
to nearby urban centers ranges from 18-380 kilometers.  However, following matching, the median 
difference in distance to an urban center between communities in a matched pair is 20 kilometers 
(range 3-150). 
 
Access to community-specific measures of HIV prevalence [e.g., HIV prevalence measured from 
antenatal care (ANC) clinics] were not available prior to community selection/randomization.  Previous 
successful pair-matched CRTs (Hayes, Mosha et al. 1995) where HIV incidence was the outcome of 
interest have also addressed the problem of absent baseline HIV prevalence estimates by using 
geographic location and other proxies of HIV prevalence as matching criteria.  
 
 
4.3   Eligibility of Community Members The following definitions of the study community will be used 
in the protocol: 
 
 Botswana Citizen:  A Botswana citizen is anyone who can produce proof of Botswana citizenship. 
(Usually this is the Omang number or Omang application receipt).  The Omang number is needed in 
Botswana to access routine government services.   It is anticipated, based on a community survey 
in Mochudi, and the 2011 census (Census 2011), that less than 3% of residents will be non-citizens. 
  
 Spouse of Botswana citizen: A spouse of a Botswana citizen is a person who can produce evidence 
of being married to a Botswana citizen, usually a marriage certificate, and is therefore eligible to 
receive free medical services in Botswana. 
 
 Permanent study community resident:  An individual who reports spending on average >14 
nights/month each month in that community for the past 12 months or an individual who recently 
moved into the community and reports spending on average ≥14 nights each month since arriving. 
   
 Part-time study community resident:  An individual who reports spending 3—13 nights (on average) 
each month in that community for the past 12 months or an individual who recently moved into 
the community and reports spending on average 3-13 nights each month since arriving. 
 

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 Non-residents:  An individual who reports living outside of the community but is receiving 
treatment in the CP community clinic as well as those individuals with an unknown community of 
residence who are receiving treatment in the CP community clinic. 
  
4.4   Enhancement of services in all study communities 
One of the goals of BCPP is to provide enhancement of HIV prevention, care and treatment services in 
non-intervention (ECC) communities as well as expansion and strengthening of these services in the 
combination prevention communities. This goal is primarily motivated by two factors:   
 
1) A commitment to offering the enhanced care communities tangible benefits from participating 
in this community randomized trial, and 
 
2) The imperative to bring the standard of practice in all study community clinics close to the 
standard of care, so that the BCPP study is assessing the effect of the combination prevention 
interventions on HIV incidence. 
 
For the purposes of BCPP, the term ‘enhanced’ will be used to signify activities done in all study 
communities (including Enhanced Care Communities) for the purposes delineated above, whereas the 
terms ‘strengthened’ and ‘expanded’ will be used to signify activities done in Combination Prevention 
Communities only, as part of the study’s combination prevention intervention package.   
‘Strengthened’ will signify that activities are already part of national policy and practice, whereas 
‘expanded’ will signify that activities are beyond current national policy and practice (for example, 
‘expanded’ antiretroviral therapy in the CPCs).   
 
The following enhancements will be provided in all 30 study communities, including the ECCs: 
a) Baseline and Annual Household Surveys (Evaluation Protocol): As part of the BHS that occurs in all 
30 communities (in both study arms), ~20% of adults are offered home-based HIV testing, point-of-
care CD4 count if treatment-naïve, viral load testing, and referral for HIV care and treatment, 
PMTCT services, MC, and other health services as appropriate (TB screening, for example). HIV-
infected persons who were ART naïve at entry to BHS or who seroconvert between study visits and 
are ART-naive will also have annual point of care CD4 and viral load tests, and these results will be 
shared with participants/clinics respectively.  HTC is also offered to household residents who do 
not wish to take part in the BHS/AHS, either by the BHS study team, the HTC campaign team, or by 
referral to local clinics where HIV testing is available.  
 
b) Clinical care quality assessment and quality improvement: BCPP and/or CDC Botswana will work 
through the Ministry of Health to support clinical quality care assessment and improvement.   
Existing or new Ministry of Health and CDC tools and quality improvement documents will be used 
or expanded in this effort.   
 
c) Clinical data system support:  BCPP will provide technical assistance to the Ministry of Health to 
support improved implementation and utilization of clinical data systems (primarily PIMS2 and 
IPMS) in all 30 study communities.    
 

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d) Laboratory support: BCPP will provide technical assistance to Ministry of Health to help 
laboratories supporting clinics in all 30 study communities to perform at a level sufficient to meet 
the standard of care.  Existing or new Ministry of Health and CDC tools and quality improvement 
documents may be used or expanded in this effort. 
 
4.5   Eligibility Criteria for Inclusion in Interventions in CP Communities 
This protocol provides the inclusion and exclusion criteria for access to the services provided as part of 
the Combination Prevention intervention package.  Adults aged 16-64 will be targeted for service 
uptake because recent, nationally representative surveys of HIV prevalence and incidence (BAIS 2008) 
suggest that HIV incidence remains high (>1%) throughout this age group.  
 
For clinical services, only those who are Botswana citizens or spouses of Botswana citizens can receive 
free services from Ministry of Health facilities.  Non-citizen/non-spouse of citizen HIV-infected adults 
identified during testing will receive a referral to the health clinic in their community of residence, but 
will not be eligible for free services from Ministry of Health facilities, and thus will not be eligible for 
strengthened free services in intervention clinics.   
 
Investigators propose that eligibility for interventions in the CPC arm be grouped into three categories 
(a) eligibility for expanded HTC services and (b) eligibility for strengthened linkage-to-MC services, and 
(c) eligibility for expanded treatment and follow-up. 
 
a) Eligibility for Expanded HTC   
All adults >16 who wish to receive HTC services at health facilities, mobile testing units, or door-to-
door programs in combination prevention communities (CPCs), are eligible to receive these HTC 
services.  The rationale for proposing that non-residents of the CPC be able to access expanded HTC 
services is to improve community acceptance of the door-to-door and mobile HTC activities.  
Preliminary discussions with community leaders suggest that restricting access to a service like HTC 
which is being delivered to family homes and neighborhoods would be met with considerable 
resistance and community discontent.   
 
Non-citizens of Botswana will also be provided HTC services in the CPC.  Non-citizen/non-spouse of 
citizen HIV-infected adults identified during testing will receive a referral to the health clinic in their 
community of residence to connect them with available fee-based services including treatment.   
 
b) Eligibility for Strengthened Linkage-to-MC services 
Noncitizens will continue to be eligible for enhanced linkage- to-MC services if they meet other 
eligibility criteria. Under the national MC programs, noncitizens who present directly to the MC tent 
requesting MC will be offered free services. Thus, all adult men 16 years or older who are HIV-negative 
or have unknown HIV status are eligible for strengthened linkage-to-MC services including men who 
decline HIV testing or have indeterminate results.   Under current national guidelines, boys 13-15 years 
old will not be actively mobilized or included in linkage-to-MC though they can continue to receive free 
MC services at national locations if they present with parental permission. 
 
c) Eligibility for Universal Treatment  
Universal treatment will be offered to all HIV-infected adults aged 16-64 who are Botswana citizens or 
spouses of Botswana citizens.   HIV-infected persons referred through the study via BHS/AHS, HTC or 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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routine HIV testing (RHT) as well as existing patients already enrolled in care at the CPC clinics will be 
offered expanded treatment.  The Infectious Disease Care Clinics (IDCC) treat all Botswana citizens and 
spouses of Botswana citizens regardless of the community in which they reside.  Therefore, both 
residents and non-residents of the community will be included. 
 
4.6   Rationale for Exclusion from Interventions in CP Communities    
 
 Rationale Surrounding Need for Botswana Citizenship or for Being Spouse of Botswana Citizen: 
Although the Botswana Government provides free HTC services to non-citizens, free access to 
health services, including ART and PMTCT is restricted to a) persons who can produce valid 
documentation of Botswana citizenship or b) spouses of Botswana citizens. Combination 
prevention interventions will therefore not be available to non-citizens of Botswana unless 
married to a citizen, except in the case of HTC and MC services. The exception for MC will be 
made to bring study goals closer to aligning with WHO goals for protection of communities 
through MC provided to 60% of HIV-uninfected men - regardless of citizenship status - as 
noncitizens living in the community may share the same sexual networks with citizens. 
 
Additionally, men who decline HIV testing may actually be those at greatest risk for HIV 
acquisition and thus could benefit most from MC.  If such men were not offered MC and were 
later found to be positive at end of study they would have represented a missed opportunity 
for prevention. 
 
 Rationale for Age Limits: Persons <16 years of age will be excluded from study participation 
because our intervention is targeting adults, and relevant study outcomes will be measured 
among adults.  In Botswana, adults are considered those aged 16 or older.  For example, all 
persons aged >16 can access medical services, including HTC, without guardian consent. 
Although individuals aged 16-17 can access medical services without guardian permission, 
participation in research still requires guardian permission, because the age of consent for 
research in Botswana is 18.  Therefore, eligible 16-17 year-olds will be asked for assent to 
participate in research activities only after permission has been provided by the guardian. 
 
 
5.0 SAMPLE SIZE AND  SAMPLE SELECTION METHODS  
 
The primary objective for the intervention protocol is to implement and describe uptake of CP 
interventions in CP communities. Combined (BHS and HTC) data for 7 intervention communities was 
used to derive average denominator sizes for the estimates of interest. These community-average 
sample sizes were multiplied by 15 to yield an estimate of the total denominator (see Table 1). For the 
estimate of uptake of HTC, we used the number of participants interviewed to be conservative, 
although estimates of HTC coverage will be extrapolated to persons not interviewed. 
Table 1 presents confidence limits for all of the indicators of uptake of CP interventions for protocol 3, 
using targets presented earlier in the protocol. Sample size calculations were done using a simple 
binomial method to obtain standard errors and then multiplying standard errors by the square root of 
the variance inflation factor (VIF), which is [1+(m-1)*ICC], where m is the average number of members 
of each group (here, participants within community), and ICC is the intraclass correlation coefficient, 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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reflecting the magnitude of the correlation within communities for the outcome measure of interest. 
No published ICCs were available for these outcomes, so we used one small and one large value, based 
on prior publications reporting ICCs for behavioral variables in HIV and STD studies (Zhang et al., 2013 
and Pals et al., 2003). 
 
Table 1. Precision for 95% confidence intervals for uptake of CP interventions in CP communities 
Outcome 
Denominator 
(per community) 
Denominator 
(Total across CP 
communities) 
ICC 
Coverage 
95% 
Confidence 
Interval 
CI 
Width 
HTC 
2469 
37035 
.02 
90% 
87.8, 92.2 
2.2 
 
2469 
37035 
.05 
90% 
86.5, 93.5 
3.5 
PMTCT 
50 
750 
.02 
90% 
87.0, 93.0 
3.0 
 
50 
750 
.05 
90% 
86.0, 94.0 
4.0 
MC 
794 
11910 
.02 
60% 
56.4, 63.6 
3.6 
 
794 
11910 
.05 
60% 
54.4, 65.6 
5.6 
ART 
528 
7920 
.02 
93% 
91.1, 94.9 
1.9 
 
528 
7920 
.05 
93% 
90.0, 96.0 
3.0 
 
Table 1 shows that where sample sizes are large and we expect rates of uptake closer to 100% (HTC 
and ART), precision is excellent. Where sample sizes are small (PMTCT) or rates expected closer to 50% 
(MC), we have less precision for estimates, but confidence interval widths are still less than ±6%. As the 
rate of the outcome variable of interest moves away from 50%, standard errors and confidence 
interval width will decrease. With a larger ICC, the variance inflation factor increases and confidence 
intervals will widen. 
 
6.0 INTERVENTION PROCEDURES  
6.1   Overview of Intervention Strategy 
Interventions described below are intended to: 1) be consistent with new WHO guidelines on 
treatment of HIV infection (World Health Organization, 2015), 2) streamline clinic procedures to 
accommodate expansion of treatment to all PLHIV, and 3) incorporate lessons learned during the first 
year of BCPP.   Targeted strategies will be implemented to meet UNAIDS goals of 90% of PLHIV know 
their status, 90% of PLHIV who know their status are on treatment, and 90% of PLHIV on treatment are 
virally suppressed.  Through reaching the UNAIDS goals, it is anticipated that there will be a reduction 
in HIV incidence in the CP communities as assessed in Protocol 1.  The proposed BCPP interventions 
will demonstrate UTT and introduce a streamlined approach to finding, testing, and starting PLHIV on 
immediate treatment and retaining them on effective treatment over time.  Specific engagement 
activities as well as the specific interventions being deployed are outlined in detail below. 
 
6.2   Stakeholder Involvement, Community Engagement, and Community Mobilization 
To enhance communities’ acceptance and effectiveness of the combination prevention package, local 
government and community stakeholders will be highly engaged.  Program implementers, including 
MOH at central-, district-, and facility-level, and NGOs supporting the MOH’s public health mission in 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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study districts, have been engaged in the planning and continue to be involved in implementing all 
combination prevention interventions. These governing bodies include: 
 
o National Government:  MOH, CDC and Harvard Chan School investigators and program planners 
have presented project plans to (1) the Parliamentary Sub-committee on Health, (2) the 
Parliamentary Sub-committee on HIV/AIDS, and, (3) the House of Chiefs (a body of traditional 
leadership made of representatives of all communities in the country).  
o District Government:  Study communities are distributed across 13 of 29 districts in Botswana.  
Meetings and consultations have been held with the District AIDS Coordinator, District Multi-
Sectoral AIDS Committee, and the District Health Management Teams. 
o Community Government:  At the community level, village political leadership has been 
consulted, including the traditional leadership of Dikgosi and Dikgosana (Chiefs and sub-chiefs), 
the Village Development Committees (VDCs), church leaders, and sporting clubs.  Project plans 
were shared and discussed prior to initial implementation and ongoing support for the project 
is sought.   
 
Investigators meet regularly with members of study Community Advisory Boards (CAB) to discuss 
community perceptions of the project.  Minutes of these meeting are documented and shared with the 
study principals.  Specific issues raised during CAB meetings are addressed as needed.  There are four 
CABs located in the following regions:  South, Central, North, and Northwest.  The CABS have 
representatives from the study communities in that region. 
 
Community mobilization activities are conducted in all communities; however, the scope and duration 
of the activities are greater in the CPCs. Activities focus primarily on increasing uptake of HTC and MC 
so that HIV-infected adults can access treatment and/or PMTCT and HIV-negative adults can access 
MC.  Some of the methods to improve uptake of services include: 
 
o Public announcements from vehicles with loudspeakers (very common in Botswana), 
o Community (kgotla) meetings, civic society activities, schools, and clinics as a platform to 
inform the community. 
o Door-to-door canvassing of the community informing community members of the services that 
are available in the community, location and duration. 
o Specific mobile activities (e.g., location of an HTC caravan near work and sporting locations or 
in residential areas after business hours (e.g., after 5 pm) targeting hard to reach populations 
like men.  
 
6.3 HIV Testing and Counseling (HTC)  
 
a) Target:  90% of PLHIV know their status. 
  
b) Strategy: Based on the first round of HTC in BCPP, the HTC strategy is being modified for years 2 
and 3.  During the first year of HIV testing, approximately 70-% of HIV+ persons in the community 
were identified through concentrated testing efforts lasting 6-8 weeks.  During the 2nd year of the 
study, HTC activities will be provided through continuous availability of services in the community 
and will focus on 1) finding incident cases of HIV infection by retesting persons found to be 

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negative during the 1st year; 2) finding the 25-30% of community members missed by the 1st year of 
testing in BCPP; and 3) identifying HIV+ persons who are new arrivals to the community.  
 
 The activities to fulfill the first objective of finding incident HIV cases include 1) repeating door-to-
door HIV testing during year 2 in all homesteads from year 1; 2) monthly mobile testing at targeted 
community locations; and 3) strengthening routine HIV testing (RHT)   in health facilities with a 
focus on antenatal clinics, outpatient departments and IDCC.  To fulfill the 2nd objective, targeted 
testing activities will be used to find community members missed in the first year of testing in 
BCPP. Based on data collected in year 1 of BCPP, approximately 50% of men and 30% of women are 
missed through home-based testing.  Targeted testing strategies to locate those missing in year 1 
will include workplace testing, home-based testing on holidays and weekends, mobile testing at 
venues frequented by men and large-scale community activities that attract the majority of 
community members. To fulfill the 3rd objective, new arrivals to the community who are HIV+ will 
be found through re-enumeration of households and HIV testing while going door-to-door.  New 
arrivals will also be identified during community mobile testing and large-scale community events 
that offer HIV testing.  The HTC strategy for year 3 of BCPP will be based on findings from year 2 of 
the study, but is likely to focus on targeting populations missed in year 2. 
 
In order to reach the target of the 90% of PLHIV knowing their status, cost-effective community-
based HIV testing strategies are needed to find unidentified HIV-positive persons who are not 
accessing health care facilities, such as young women and men. An understanding of the 
incremental costs between strategies is key to determine the  optimal mix of strategies to 
implement. Therefore, a cost analysis of different HTC models implemented through BCPP will be 
undertaken.  
 
c) Specific HIV Testing and Counseling Services: 
 
1) Home-Based HTC:   HTC counselors will go door-to-door and request verbal consent to: (1) map 
household GPS location, (2) record numbers of persons in each household, their age, and sex by 
interviewing the head of household or, if the head of household is absent, a household member 
18 years of age or older (Household Enumeration Form), and (3) offer HTC services (HTC Intake 
Form).  The following individuals will not be offered HTC: 
 
a. Adults who have documentation of an HIV-positive status  
b. Adults who have documentation of HIV-negative results obtained within the last 3 
months of the HTC encounter. (Documentation of HIV test results are recorded on the 
HTC Intake Form) 
c. Persons <16 years old 
 
If a household member is absent, the team conducting the home-based HTC activities will ask 
about an appropriate time to return to the household (Household Enumeration Form).   Up to 3 
repeat visits will be scheduled. 
 

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2) Mobile HTC:  Mobile HTC caravans and tents will be placed in prominent locations of the 
community [e.g., at kgotlas (community meeting locations), or shopping centers].  Community 
mobilizers will engage the community via door-to-door ‘mobilization’ visits and in high traffic 
areas in the community such as shopping and transport areas and invite residents to get tested 
in the mobile units and tents.  Lay counselors and support staff will be stationed in mobile 
venues consisting of a waiting area, private HTC area and a phlebotomy area.  HTC will be 
offered to all individuals (residents and non-residents, citizens and non-citizens) who are not 
known to be HIV-infected according to national guidelines (i.e., adults who do not have an HIV 
test result card indicating HIV-positive status).  Persons who tested will be asked to keep the 
card with their results safely for any future contact, e.g., during subsequent household visits 
(below). 
 
3) Routine Facility-Based HTC: Routine HTC activities at health facilities will be strengthened by 
training facility-based counselors to offer RHT as part of integrated routine services in 
outpatient, IDCC, and antenatal (ANC) clinics. Facility-based counselors will be encouraged to 
provide testing to all adults receiving health care services at the clinic and to offer testing to all 
friends, family members, relatives, visitors, etc. (so-called non-patients) accompanying the 
patient to the clinic. In addition, the study will assist MOH ANC staff with strengthening of 3rd 
trimester re-testing among pregnant woman (see section 6.6).  Routine HIV testing data will be 
extracted from PIMS2/IPMS to monitor coverage of testing in health facilities. 
 
4)  Targeted Testing:  HTC for groups that are difficult to access through home-based, clinic-based, 
or other routine services will be targeted by providing services where these groups work or 
congregate and by offering HTC services at large, well-attended community events such as 
barbecues, health fairs, concerts, etc. 
 
5) Additional Services for Persons Testing HIV-Positive:  All HIV positive adults not on treatment 
are eligible for ART under current national guidelines so will not need to consent for treatment 
in the UTT intervention.  HTC counselors are trained to integrate treatment preparation, 
adherence and readiness messages into their post-test counseling for HIV-positive persons to 
begin preparing participants for initiating ART at their first clinic visit.  In addition, they will be 
counseled to expect a confirmation test for HIV positive results before initiating ART which will 
be conducted at the IDCC.  All participants of HTC will be tested using the MOH rapid testing 
algorithm along with pre-test and post-test counseling that is recommended in the national 
guidelines. 
 
6) Additional Services for Persons Testing HIV-Negative: The following services will be offered to 
newly identified or known HIV-negative adults:  
- 
Screening of all adults for TB, with a simple screening question, and referral of TB 
suspects to the nearest clinic for TB testing. TB suspects will be prioritized for evaluation 
at the clinic. In Zimbabwe and Zambia, this has been shown to reduce community 
prevalence of infectious TB and was well-accepted by the community (Corbett, 
Bandason et al. 2010) .   
- 
Encourage MC uptake by HIV-negative males through linkage-to-MC services. These 
services also are offered to men with unknown HIV status.   Further details of the 
linkage-to-MC service are provided in Section 6.5 below. 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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- 
HIV-negative pregnant women will be encouraged to enroll in ANC care and be retested   
in their 3rd trimester.  
 
6.4 Linkage to HIV Care and Treatment   
 
a) Targets:  80% of adults identified as newly diagnosed or not currently in care are registered at the local 
study IDCC or are documented in care at another IDCC within 90 days of BCPP interview and 90% 
within 180 days of BCPP interview  
  
b)  Strategy:   To ensure that 90% of persons identified as HIV-infected initiate ART, persons newly 
identified as HIV-infected or PLHIV not connected to care and treatment must be linked to an IDCC.  
Data from the first year of BCPP suggest that about half of PLHIV link to care with very little prompting 
or follow-up.  Another 50%, however, require additional supports.  The linkage intervention package 
for BCPP includes: 1) counseling after diagnosis on the importance of immediate treatment and 
appointments made for PLHIV not already in care; 2) appointment reminders; and 3) tracking and 
tracing of persons who miss appointments at the IDCC.  In addition, to enhance linkage rates, patients 
wishing to receive care/ART outside of their community will be able to link to any MOH IDCC. 
 
c) Specific Activities: 
 
1) Counseling After Diagnosis and Scheduling Appointments at IDCC:  Counselors will be available 
to: (1) provide immediate psychosocial support to help clients cope with their HIV-positive test 
result, (2) counsel participants on the importance of early entry into HIV care or PMTCT services 
and prepare them for treatment initiation and adherence at first clinic visit, and (3) help clients  
establish and achieve plans to enter care by identifying and troubleshooting real and perceived 
barriers to care (Gardner, Metsch et al. 2005, Gardner, Marks et al. 2007, Craw, Gardner et al. 
2008, Gardner, Marks et al. 2009).  Appointments at IDCCs in intervention communities will be 
scheduled as soon as possible for newly diagnosed individuals or PLHIV who are not enrolled in 
care and treatment.  Some PLHIV may prefer to obtain care and treatment services at a clinic 
outside their community for privacy, proximity to job, or other reasons.  For those PLHIV who 
choose to obtain care outside the study community, verification of enrollment in care will be 
obtained from the MOH data systems. 
 
2)  Appointment Reminders: PLHIV will be sent short message service (SMS) reminders about 
their upcoming appointments. 
 
3) Tracking and Tracing:  A record of all patients referred to care by BHS, HTC and RHT will be 
submitted to Site Coordinator at the local IDCC.  The Site Coordinator at the IDCC will access 
names of those referred and will track them to ensure they keep their first appointment.  
Names and contact information of those who don’t keep their appointments will be turned 
over to the community counselor for tracing and case management. The intensified participant 
tracing program includes telephone calls and home visits for persons who missed a scheduled 
appointment up to 180 days after either diagnosis or BCPP interview for known HIV positive 
persons (Participant Tracing Log).  
 
4) Counseling, Appointments and Tracing for PLHIV Identified who are already on ART 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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o Patients who are on ART, enrolled in care at the study IDCC, are not late for an appointment, 
and have a future appointment scheduled will be encouraged to remain adherent to ART and 
appointments.  
o Patients who have initiated ART and are enrolled in care at the IDCC and are late for their next 
appointment or who do not have a future appointment scheduled will be (1) counseled on the 
importance of adherence and appointment keeping, (2) given a new appointment at the clinic, 
and (3) have phone number and residential address information obtained to facilitate follow-up 
(retention tracing of participants already in care and late for their scheduled appointments is 
described in section 6.7 below).   
o Patients who are on ART and not enrolled in care at the study clinic will be counseled to remain 
adherent to ART and in care; they will also be informed of expanded and strengthened services 
available at the study clinic and will be given an appointment to the study clinic. Follow-up for 
these patients will be limited to only an SMS reminder for their appointment. Verification of the 
patients’ enrollment at another clinic outside the study community and ART status will be 
obtained from MOH data systems. 
 
5) Retrospective Tracking and Tracing of PLHIV who Did Not Link to Care: Given the change in the 
2016 Botswana national treatment guidelines, HIV-positive participants not on ART who did not 
link to care from Round 1 (October 2013 – February 2016) will be retrospectively contacted by 
the Ministry of Health clinic staff or a community counselor and informed that all HIV-positive 
persons are now eligible for ART, regardless of CD4 count or condition. Participants from Round 
1 and Round 2 (June 2016 – present) who previously did not give permission for follow-up may 
also be contacted, as the new guidelines recommend tracking all HIV-posiitive persons 
identified to care and treatment sites. Specifically,  
o Contact with the participant will be attempted by a Ministry of Health clinic staff 
member or a community counselor to inform the participant that the national 
guidelines have changed and all persons that are HIV-positive are now eligible for ART. 
They will also be informed that it is critical for their health and the health of their 
partners and children to get on ART as early as possible, and that the clinic offers 
services to help community members get into care and on treatment. Staff will use the 
updated talking points from the Linkage to Care SOP – revised (see Appendix XX, Section 
3.8).  
o Participants will be given an appointment at the clinic with a health care provider and 
will be encouraged to keep it.   
o If there is no current phone number for the participant, a home visit will be conducted 
by a clinic staff member or a community counselor. Up to 3 attempts to contact the 
participant will be made through alternating phone and home visits. 
o Participants from Round 1 who have not linked to care will be contacted beyond the 
follow-up period specified in the protocol (e.g., 180 days) in order to ensure the new 
guidelines are being implemented with all participants. Paricipants from Round 2 who 
were enrolled during the time between the introduction of the new guidelines and field 
implementation (November 2016) may also be followed beyond the 180 day window. 
 
A note to file will be documented at each of the 15 intervention sites noting the procedural 
changes and follow-up provided to those individuals who previously did not link and declined 
follow-up. 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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6.5 Male Circumcision   
 
a) Target:  60% of HIV-negative 16-49-year-old males are circumcised   
 
b) Strategy:   BCPP’s SMC intervention in the second year will be streamlined from the full-service 
campaign model used in the first year to a program that mobilizes and links interested men to existing 
services in nearby locations.  MC services are expected to be provided in five of the 15 CPC sites using 
PEPFAR programmatic support.  In all other districts, nearby services funded by Global Fund or MOH 
will be used, though distances to these services from CPCs is likely to vary.  All CPCs are expected to 
have at least one service option available.  Therefore, BCPP funding will not be used to support direct 
service delivery but to mobilize and link men in BCPP communities to existing MC services.  Modified 
SMC services are expected to begin when the second round of BCPP interventions are implemented, 
approximately February 2016.    
 
c) Specific Activities:   
 
1) Mobilization:  In the first round of BCPP activities, SMC depended heavily on community-based 
mobilizers and referrals from the BCPP HTC Campaign and BHS to generate client demand.  A basic 
level of this ongoing mobilization will continue.  HTC and BHS will refer men to community mobilizers 
by passing contact information with consent; the mobilizers will then follow up with these men and 
link them to nearby services.   Mobilizers will also work directly with communities to mobilize men for 
services.  Incentives for mobilizers through a performance-based contract may be utilized to improve 
mobilization efforts.  In addition to encouraging potential clients to obtain MC, mobilizers will 
disseminate service information about linkage sites, transport schedules, and assist with coordinating 
transportation.  
2) Coordination: A small number of full-time coordinators will oversee all the CPCs. Their 
responsibilities will include identifying and liaising with locally-available SMC services to confirm their 
schedules and notify them of expected clientele numbers on transportation days; supervising 
mobilizers; coordinating transportation; and follow-up with service sites to collect the necessary data. 
A senior BCPP staff member will keep the MOH SMC coordinator up to date on these activities.  
3) Transportation: In each CPC, transportation will be offered at least monthly to nearby SMC services, 
on days of the week determined to be optimal. Transportation will also be provided for day-2 and day-
7 follow-up visits, and will remain available for adverse event emergencies.  
4) Data collection:  Individual-level data will not be collected at SMC service provision sites by BCPP, 
but aggregate data will be requested from these sites.  Specifically, at these sites, the coordinator will 
make attempts at least quarterly via physical visits and register reviews to ascertain how many HIV-
negative/unknown men 16-49 years of age from the CPC were served.  The coordinator will also collect 
aggregate data from the transfer logs to gather numbers of men transported to SMC services.  Finally, 
the coordinator will collect aggregate data on number of men referred and mobilized from demand 
creation records completed by HTS and BHS staff as well as SMC mobilizers (Male Circumcision 
Tracking Sheet).   
  

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6.6 Identification, Linkage, and Treatment of HIV+ Pregnant Women  
 
a) Target:  90% of women initiated on indefinite ART (Option B+) during pregnancy remain in care and 
on treatment post-delivery.   
 
b) Strategy:  Strengthening PMTCT activities is important to ensure that HIV-infected pregnant women 
are identified, linked to care, and remain on ART post-delivery.  Currently, Option B+ is the national 
standard of prevention of mother-to-child transmission in Botswana.  Therefore, BCPP intervention 
and control communities will provide Option B+ interventions for all HIV+ pregnant women.  The BCPP 
program for pregnant women will focus on strengthening three activities in PMTCT settings in 
intervention communities: 1) strengthening of third trimester retesting within the ANC; 2) linkage to 
HIV treatment for all HIV-infected pregnant and post-partum women; and 3) retention on ART post-
delivery.  
 
c) Specific Activities: 
 
1) Strengthening third trimester retesting:  BCPP staff work with MOH clinic staff to strengthen 
capacity to identify women who are due for third trimester retesting. MOH clinic staff will use client 
contact information from the ANC register to make phone calls and schedule appointments with all 
HIV-negative pregnant women who have not completed third trimester retesting. MOH clinic staff will 
keep a record of clients called for third trimester retesting. Third trimester retesting will be monitored 
through PIMS/IPMS by the IDCC clinic. 
2) Linkage and Retention for HIV-infected Women:   Ensuring HIV-positive pregnant women receive 
ART and remain on ART following delivery is a key priority. All HIV positive pregnant women identified 
through the BHS and HTC campaigns are referred to the IDCC for HIV care and treatment.  In addition, 
HIV+ post-partum women are referred to the IDCC to continue ART indefinitely (Option B+). Those who 
do not keep IDCC appointments will be tracked by the IDCC Site Coordinator and followed by 
community counselors to ensure they link or re-link to the IDCC post-delivery. Similarly, retention 
activities will track women who have begun Option B+ to ensure that they stay in care and on ART 
indefinitely.  Those who are 14 or more days late for an appointment or pharmacy pick up will be 
contacted by MOH clinic staff and/or the IDCC Site Coordinator (Linkage, Retention and Adherence 
Tracing Verbal Consent Script) and community counselors will provide supportive counseling and new 
appointments through phone and home visits (Participant Tracing Log) as outlined in section 6.4. 
6.7 HIV Care and Treatment  
 
a) Targets:  
1) 93% of PLHIV aged 16–64 who know their status are receiving ART  
2) 95% of PLHIV aged 16-64 who are on ART are virally suppressed 
 
b) Strategy: Prior versions of BCPP Protocol 3 introduced anti-retroviral treatment outside Botswana 
national guidelines (CD4 < 350, WHO stage III or IV).  With the revised WHO recommendations to treat 
all HIV-infected persons, Version 4.0 of Protocol 3 proposes to start all HIV+ adults in CPCs on 
immediate treatment and retain them on treatment (UTT).  To demonstrate methods for 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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implementation of UTT for later adoption by the Botswana MOH, BCPP will embed UTT treatment 
interventions within the national ART program (MASA). The package of interventions described below 
are designed to 1) reduce barriers to ART initiation by simplifying procedures and making services 
easily available 2) increase capacity of IDCCs to support aggressive ART scale-up, and 3) enhance the 
use of both individual and clinic-level data to monitor uptake of HIV care and treatment. 
 
c) Specific HIV Care and Treatment Activities: 
 
1) Confirmation of HIV status: All HIV+ referrals into the clinic as well as existing pre-ART patients will be 
confirmed with an HIV test administered by IDCC staff as recommended by WHO before initiating ART 
(World Health Organization, July 2015). 
 
2) Same day ART initiation: Patients who are not on ART will be offered initiation (or re-initiation) of 
ART on the day of their first clinic visit if blood draws are possible that day.  Adherence counseling, 
screening for opportunistic infections, and blood draw for baseline pre-ART safety labs will occur on 
the day of ART initiation.  Patients who decline ART initiation (or re-initiation) will be given a 1 month 
follow-up appointment for re-consideration of ART initiation.   
 
3) Frequency of clinic follow-up visits:  Patients on ART who are stable (e.g., virally suppressed, no 
opportunistic infections, keeping appointments, etc.) will be offered a reduced frequency of scheduled 
visits as compared to the current MASA standards.  Patients will be followed according to national 
program standards for the first year.  For stable patients on ART for longer than 12 months, visits with 
a clinician every 6 months will be implemented. IDCC patients already on ART will follow the 
streamlined schedule according to their time on ART. 
 
4) Frequency of visits for laboratory testing: Routine laboratory testing will be offered to patients 
according to the national guidelines with the exception of CD4 counts which will only be measured at 
baseline, after 12 months on ART, and at the discretion of the clinician.  Also, wherever possible, 
patients will have their blood drawn at the time of routine clinic visits rather than on separate days to 
further reduce the frequency of clinic visits and clinic congestion.  All laboratory results will be 
reviewed by the clinic staff within 4 weeks of blood draws, and patients will be contacted by clinic staff 
for review of any abnormal lab results. 
 
5) Frequency of dispensing visits: Patients who are stable after 12 months of ART (e.g., virally 
suppressed, no opportunistic infections, keeping appointments, etc.) will be dispensed up to 3 months 
of ARVs if there is adequate stock in the clinic at the time of dispensing rather than being required to 
return after only 1 month for a dispensing visit. The pharmacy will update a patient’s next refill 
appointment in PIMS2/IPMS if more than one month is dispensed.  Stable patients will have monthly, 
bi-monthly or quarterly refill appointments, which may coincide with the semi-annual clinician visits. 
 
6) Retention Intervention:  Resources will be available in CP communities to ensure that all PLHIV are 
retained in care. The retention intervention will focus efforts on those who have missed treatment 
appointments and/or pharmacy pick-ups.  Persons eligible for retention tracing will be identified by the 
IDCC staff using their electronic data system.  
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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Existing IDCC patients who have missed appointments or pharmacy pick-ups are contacted by MOH 
clinic staff by phone or home visits and are asked if they agree to have a community counselor contact 
them to provide retention support activities.  Patients who do not consent to retention support 
intervention activities are reminded about the importance of staying in care/linking back into care, and 
thanked for their time (Linkage, Retention and Adherence Tracing Verbal Consent Script; Retention 
Tracing Contact Log).  
 
Patients who consent to intervention activities receive retention support services by clinic staff and 
community counselors including SMS reminders of appointments, rescheduling of missed 
appointments, and tracing and supportive counseling through home visits and telephone calls for 
defaulters (>14 days late for appointment or pharmacy pick-up) and Lost to Follow Up (LTFU; > 90 days 
late for an appointment). Clinic data systems are monitored to determine if these patients have 
relinked to the IDCC (Retention Tracking Log, Participant Tracing Form).  
 
 
7)  Adherence Intervention:  IDCCs typically use self-reports, pill counts, pharmacy refill data and viral 
loads to monitor adherence. These adherence monitoring strategies are promoted in all study sites. All 
PLHIV on ART in CPCs are offered an increased level of adherence counseling and support above and 
beyond what is routinely offered within the setting of government clinics.  Eligible persons who would 
benefit from increased adherence support are identified by the clinic staff. 
 
Eligible patients are contacted by MOH clinic staff by phone or home visit (Retention and Adherence 
Outreach Script and are asked if they agree to have a community counselor contact them to provide 
adherence support activities (Linkage, Retention and Adherence Tracing Verbal Consent Script).  
Patients who do not consent to adherence support intervention activities are reminded about the 
importance of taking ART as prescribed, and thanked for their time.   
 
Patients who consent to intervention activities (Adherence Intervention Verbal Consent/Assent Script) 
receive adherence intervention services including an assessment (Adherence Assessment Tool), 
assignment of case manager, and additional counseling to assess and resolve individual adherence 
challenges. In addition, the following services may also be delivered depending upon the person’s 
circumstances and assessment: referral to social worker; SMS reminders; home visits; pill box issuance; 
depression screening; support with HIV disclosure; alcohol assessment; treatment buddy/mopati; VL 
repeat; assignment of earlier appointment; and change in ART regimen (for those in whom side 
effects/medication acceptability might be mitigated through substitution). All adherence interventions 
will be documented as will the outcome of the efforts, on the Adherence Intervention Tracing Log.   
 
Patient CARE in Other Study Clinics or Non-Study Clinics  
 
Finding solutions so that as many BCPP patients  as possible can receive expanded ART initiation is 
important for reaching ART saturation in CP communities, however the study is constrained and cannot 
easily perform study activities or install study staff at sites which are not CP community clinics.  As a 
solution, the following options will be offered to patients, if during counseling it is determined that 
they face challenges to participation in study activities at the IDCC in their own community: 
 
1) BCPP activities at any CP community clinic:  Initiation and receipt of ART will be allowed at any 
CP community clinic at which a participant would be able to receive services.  Note that the 

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study will not be able to provide transport or any additional compensation for these individuals.  
Follow-up data from PIMS2 or IPMS will be obtained on these individuals for study purposes 
from the CPC clinic the participant chooses.   
 
2)  ART initiation activities at own community clinic, followed by transfer to any MOH clinic: 
Services including ART initiation will be provided at the participant’s own CPC, followed by 
facilitated transfer to any MOH HIV care and treatment facility (including those not in study 
communities) for continued ART.  Follow-up data on these individuals will be obtained from 
routine medical information sources such as PIMS2 or the national HIV data warehouse. 
 
Identifying Patients for UTT 
To find all eligible PLHIV not currently on ART and initiate them on treatment, BCPP priorities will 
include approaching the Expanded Treatment Cohort  (described in BCPP Protocol 3 version 3.0) in 
early 2016 
to offer ART initiation for those not on ART.  Another strategy to identify eligible PLHIV not currently on 
ART will include data mining of the MOH electronic patient systems to seek PLHIV categorized as “pre-
ART” to approach them about immediate ART initiation (Script for Outreach Pre-ART Clinic Patients).  
These two mechanisms in combination with expanded HTC activities outlined earlier will yield the 
scale-up of ART initiation necessary to meet both treatment and viral suppression targets. 
 
7.0 LABORATORY METHODS 
Detailed laboratory procedures are described in Standard Operating Procedures (SOPs) that are 
maintained at each laboratory supporting the study.  The BCPP Laboratory Manual provides an 
overview of routine testing that is conducted at Ministry of Health laboratories and more detailed 
study specific procedures for testing conducted at CDC, Harvard Chan School, BHP laboratories.  In 
addition, all study staff has received a Field Operations Procedures Manual which serves as a 
procedural guide during actual specimen and data collection.   
 
7.1 Overview of Laboratory Methods 
An overview of the types of laboratory tests, sample types, and the location of the testing is provided 
below.  The intervention component of the project uses the following laboratories and locations:   
1. BHHRL: MOH regional HIV Reference Lab (Gaborone). BHHRL is a hybrid institution with 
management shared by Harvard and MOH. 
2. NHHRL: MOH regional HIV Reference Lab (Francistown)  
3. MOH District and primary Labs (Botswana-multi-sites) 
4. MOH clinics in CPC communities 
5. Field sites: households and community venues conducting surveys and HTC campaigns 
6. CDC: International Laboratory Branch at Centers for Disease Control and Prevention (Atlanta) 
and CDC Laboratories (Gaborone and Francistown) 
7. BHP (Botswana Harvard Partnership Laboratory) 
8. Harvard T. H. Chan School of Public Health (Boston) 
 
A minimum laboratory enhancement package has been implemented in laboratories supporting study 
sites.  Each study-associated laboratory adheres to site and study specific SOPs for proper processing, 
labelling, transport, testing and storage of specimens as outlined in the BCPP Laboratory Manual.  The 
laboratory study team provides guidance and technical support to the laboratories to implement and 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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maintain a quality management system which includes continuous quality improvement, adherence to 
biosafety, enrollment in EQA programs, review and maintenance of standard operating procedures for 
laboratory testing, timely procurement and forecasting reagent and supply needs, and documentation 
of training for all laboratory personnel. Adherence to these standards is routinely monitored by the 
laboratory study team. 
 
7.2 Training of Laboratory Personnel 
All laboratory personnel participate in study-specific training prior to study initiation.  Training includes 
an overview of the BCPP study design and study-specific laboratory methodologies (with assessment 
for competency) in addition to Research Ethics and good clinical laboratory practices including QA/QC 
(quality assurance/quality control) and laboratory record keeping procedures. Study staff responsible 
for providing HTC complete the required training curriculum recognized by the Ministry of Health.  
Study staff members who collect blood samples and conduct laboratory analyses receive training in 
universal precautions, sample collection, and testing of study samples.  Additional refresher trainings 
are scheduled during the study to ensure consistency and address training needs as they arise. 
 
7.3 Specimen Collection, Transport, and Processing 
Specimens are collected from participants at study field sites and samples transported to designated 
laboratories for processing, testing, and storage.  Testing may also occur at study field sites.  
 
Sample Types and Sources 
a) Capillary blood samples:  Finger prick samples are collected in a microtube using a blade lancet by 
trained staff at study field sites according to BCPP finger prick SOP and used for the HIV rapid tests.   
b) Venous blood samples:  Several types of venous blood draws occur at the IDCC during routine 
management of patients, and will be done following MOH procedures for phlebotomy, (including 
appropriate blood volumes and processing).  At the IDCC, venous blood samples will be collected 
for drug resistance testing per national guidelines. 
 
7.4 Laboratory testing for HTC campaigns (returned to participant and/or participant file with 
exception of viral load test) 
a) HIV Diagnostic Testing: HIV diagnostic testing will be conducted in the study communities and 
clinics per national HIV testing guidelines using Botswana government–approved  serial rapid tests 
as outlined in the 2016 testing algorithm in the national treatment guidelines.    Other testing 
algorithms may be substituted if in alignment with national guidelines.  Verification will be 
conducted on all newly diagnosed and known HIV-positive persons before initiating ART according 
to WHO recommendations (World Health Organization, July 2015). All HIV tests will be conducted 
according to the manufacturer’s guidelines and BCPP SOPs. If results of the initial  serial rapid tests 
are discordant, then per national guidelines two rapid tests will again be performed in parallel.  If 
the second pair of tests is discordant, the participant will be referred to the clinic for re-testing in 2-
4 weeks with a referral recommending ELISA testing.  A 3 ml venous blood specimen will be taken 
at the visit and sent to a reference laboratory for further testing using ELISA (Murex HIV 1.2.0 test, 
Genetic Systems HIV 1.2 plus O, BioRad HIV-1/HIV-2 plus O EIA,) and/or Western blot). The results 
from the EIA and/or Western Blot will supersede the discordant and/or indeterminate results 
obtained in the field. The IDCC Site Coordinator reviews the HTC register at the clinic in PIMS2 or 
IPMS to determine if HTC campaign participants with indeterminate results received confirmatory 

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testing.  HTC participants with indeterminate rapid test results, and who do not have a 
documented retest at the clinic are referred to a community counselor for tracing and follow-up 
services. 
 
7.5    Laboratory Testing for IDCC patients 
Clinical laboratory testing is performed in MOH labs in accordance with the National Guidelines. 
Testing procedures follow approved standard operating procedures for each laboratory where testing 
is conducted.   
 
a)  Hematology and Clinical Chemistry 
Basic blood work is used to assess participant health status for initiation and monitoring ARV treatment 
in HIV-infected individuals; however, ART initiation will occur before all lab results are available. The 
following tests may be conducted per MOH guidelines: 
 
 Hematology: Full Blood Count (FBC) to include hemoglobin, hematocrit, red blood cell count 
(RBC), mean corpuscular volume (MCV), white blood cell count (WBC), differential WBC, 
absolute neutrophil count (ANC), and platelets.  
 Clinical Chemistry:   
o Liver Function Tests (LFT): Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase. 
o Glucose (fasting or non-fasting) 
o Electrolytes: sodium and chloride 
o Renal Function Tests (RFT):  Urea and Creatinine: An estimated creatinine clearance  
o CrCl in cc/minute can be estimated from formulas using patient sex, age, weight, and serum 
creatinine (in um/L):           
  
 
Males: 1.22 x [(140 - age in yrs) x wt (kg)]/ [serum Cr] 
                  
 
  
Females: 1.037 x [(140 – age in yrs) x wt (kg)]/[serum Cr] 
 
b)  Syphilis testing (RPR and VDRL): As per Botswana guidelines, non-treponemal tests for syphilis 
(rapid plasma reagin or Venereal Disease Research Laboratory tests) will be performed according to 
the manufacturer’s instructions.  
 
c)  CD4:  Point of care and flow-based CD4 methods are used dependent upon availability of CD4 
instruments.  Testing follows manufacturer’s instructions and national guidelines for use.  
 
d) HIV-1 RNA Viral Load: HIV-1 plasma RNA viral load is quantified for monitoring of ART-naïve HIV-
infected individuals and monitoring of viral suppression in HIV-infected individuals receiving ART (at 3 
and 6 months after ART initiation and every 6 month thereafter – according to current national ART 
guidelines or per Adherence Intervention Procedures).  
e) HIV drug resistance testing: Drug resistance testing is offered per national guidelines and under 
circumstances described in section 6.11.  
 
f) Pap smear:  Pap smears are performed and findings managed according to national guidelines.  
 
g) Pregnancy Testing: If pregnancy is suspected but not confirmed by LMP (last menstrual period) or 
exam, a urine pregnancy test is performed for confirmation of pregnancy as per MOH procedure.   

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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7.6 Quality Assurance 
Standard operating procedures (SOPs) are used for all tests as well as quality assurance/quality control 
(QA/QC) procedures.  Laboratory staff conducting testing participate in a proficiency testing and 5% of 
all tests (or as indicated by laboratory specific SOP) are subjected to internal quality control processes.  
The QA/QC plan includes periodic monthly reviews of EQA performance, collaboration with the CDC 
laboratories, enrollment in appropriate EQA schemes, and inter-laboratory comparisons.  External 
quality assurance and proficiency testing programs includes: CD4 count, HIV-1 RNA load, Hematology 
(FBC), and clinical chemistry analytes. Laboratories are monitored throughout the study by the study 
team and external monitors as requested by the study sponsor.  QA for HTC conducted in the 
communities and through RHT in the clinics include weekly QC exercises for counselors in the field, 
participation in proficiency testing programs, monitoring and site visits from lab personnel, and bi-
weekly monitoring of the concordance rates of HIV serial tests conducted in the field. A small sample of 
HIV-positive tests  may be retested in the lab for QA purposes. 
 
7.7 Biosafety and Waste Management 
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 are 
employed by all personnel in the drawing of blood and shipping and handling of all specimens for this 
study, as currently recommended by the United States Centers for Disease Control and Prevention.  All 
infectious specimens are transported in accordance with the IATA guidelines using designated courier 
services. 
 
7.8 Specimen Storage and Shipment 
The IDCC Site Coordinator coordinates shipment of specimens as required.  Selected samples may be 
transferred to the CDC (Atlanta) or Harvard Chan School (Boston) laboratories for external quality 
assurance, viral load, and drug resistance/level testing.  Specimens are stored until all protocol-related 
and quality assurance testing have been completed. 
 
8.0 DATA SYSTEMS AND MANAGEMENT 
 
The overall system to capture data, record outcomes and analyze results is an integration of multiple 
data collection sources for all BCPP interventions into a single research data base or data warehouse. 
Each BCPP activity has underlying systems of data capture and management which serve as the 
“system of record” containing the source records for all study data captured within the scope of that 
activity.  A variety of data capture methodologies are used across the BCPP activities including online 
reference data retrieval (e.g., community maps), paperless point of service/survey capture, and paper 
and electronic chart/registry abstraction. Process, study participant status, and calculated data are also 
generated by the data systems of the BCPP activities and exchanged between systems and stored in 
the research database.  
 
Each system must also interface with other activity data systems to exchange data as required to 
successfully implement the study. This includes maintaining participant registries, referrals, and key 
eligibility and status data, as well as underlying denominators within study arms and components.   In 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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this section, we provide an overview of the data management for BCPP including data capture, data 
flow, security, confidentiality, access and quality.  
 
8.1 Data collection, Capture and Flow 
HTC data forms (Household Enumeration Form, HTC Intake Form) are collected with the OpenDataKit 
(ODK) software using handheld tablets running the Android operating system. HTC counselors are 
trained in the use of these handheld tablets for electronic data entry at the point of HTC, which 
includes door-to-door home visits and mobile HTC sites.  
 
Community counselors also record their tracing activities for linkage and retention on the Participant 
Tracing Log using these handheld mobile devices.  
 
HTC and Linkage to Care forms are synced to the clinic-level study database at least daily.  Completed 
forms are deleted from the tablets following the sync.  
 
Clinic Site Coordinators manage screening, adherence and retention activities using both the hand-held 
data devices and OpenClinica.  
 
The MOH has an electronic data system known as the Patient Information Management System 2 or 
PIMS2. PIMS2 is a SQL-based, client-server application which runs on a local clinic network and has 
been implemented in BCPP community clinics. PIMS2 captures data for a variety of programs, 
including: facility-based routine HTC, MC, ANC, maternity, and post-natal care.  HIV care and treatment 
data are regularly extracted from PIMS into the clinic-level study database via a secured Virtual LAN 
(VLAN) connection between the local clinic network on which PIMS2 operates and the BCPP network. 
 
Some larger BCPP community clinics have migrated to a web-based system to record patient-level data 
which runs on the Botswana Government’s data network. This Integrated Patient Management System 
or IPMS captures program data that are similar to PIMS and includes an integrated laboratory 
information system. IPMS data will be regularly extracted from the IPMS central data repository onto 
the BCPP central data server. 
 
The MOH strongly encourages the use of PIMS or IPMS where available.  Therefore, nurse prescribers, 
physicians, midwives, lay counselors and other clinic staff within the 30 BCPP communities record 
patient registration and appointments, and enter consultation, laboratory and pharmacy data into 
PIMS or IPMS. Appendix P1 outlines the selected data elements transferred from MOH systems to the 
BCPP central data server.  
 
MC staff members responsible for the coordinating linkage of eligible men to MC will distill aggregate 
data on numbers of total and eligible men transported to MC from the transportation logs and will also 
engage with service delivery providers to obtain numbers of eligible men served on non-transport 
days.  This data will be entered into an electronic or paper-based custom data collection form monthly.  
 
On a daily basis during the BHS/AHS surveys in all 30 communities, BHS/AHS referral and locator data 
files are transferred from BHP’s electronic data capture system to the clinic via secure copy on the 
BCPP network in the clinic and processed into the clinic-level study database. At CPCs, BHS referrals are 
combined with HTC referrals. In all community clinics, referral data is used to produce operational 

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reports for use in the clinic. In CPCs, an encrypted flash drive is used to retrieve updated referral files 
from the clinic’s study database and to transfer updated data from the MC client tracking tool to the 
clinic-level study database. 
 
On a nightly basis, data from all clinic-level study databases is copied to the BCPP central data server in 
Gaborone over the secure BCPP VPN.  As needed, the BCPP senior data manager in Gaborone will work 
with IDCC Site Coordinators or other clinic level staff to reconcile data issues. 
   
The Research Database is designed in PostgreSQL and housed on the BCPP central data server at the 
CDC-Botswana Gaborone office. It is populated with data pulled up from all the clinic level study 
databases as well as data from IPMS, PIMS, CD4 data from PIMAs, and baseline, annual and end of 
study survey data transferred from BHP’s EDC via secure copy.   
 
The diagram in Figure 1 offers a schematic representation of the data flows from all sources described 
above to the central BCPP data warehouse for the intervention communities (CPCs).  For all PLHIV in 
the study communities we obtain clinical data from the existing MOH’s electronic patient data systems 
(PIMS or IPMS). 
 
 

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Harvard Macbook
Clinic Level Study Database
SQL Server
Open SSH
Central Data Server
Research DB
OpenClinica
Clinic
BHS
CDC Botswana
External Services
External Services
HTC/
TVCT
Study status,
 retention and 
adherence data 
captured by SSC
Alere Data Point
PIMA Data
PIMAs
PIMS II Computer
MOH
IPMS
Central Data Repository
 
Figure 1: Data Flow diagram for CPCs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 Data Security 
The CDC Data Manager is responsible the security of BCPP data collected for the Intervention protocol. 
The Botswana MOH is responsible for the security of data collected through routine MOH systems, 
including PIMS and IPMS. All BCPP-specific systems supporting clinic data reside within the clinic 
network where a firewall, encryption keys, user logins, and physical security and access, and routine 
data back-up measures have been put into place to ensure data security and integrity.  
 
Laptops and tablets used for data capture and processing are encrypted and require user logins to 
prevent unauthorized users from accessing data. Laptops, tablets and all study related paper-based 
forms and logs are stored in locked cabinets or locked trunks when not in active use. The clinic laptops 
which serve as the local clinic-level study databases are locked in secure cabinets. Daily data transfers 
from tablets and the MC Epi Info system minimize the risk of data loss should the device be lost or 
corrupted.  Clinic-level study databases are backed up on to the local encrypted hard drive and the 
backup files are transferred to the BCPP central data server in Gaborone using secure copy. The 

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backups from all of the clinic-level study databases and the central data server will be backed up to 
tape daily. The BCPP central data server at the CDC-Botswana Gaborone office is located in a locked, 
climate controlled server room managed by CDC IT staff in compliance with CDC IT policies.  
 
A virtual private network (VPN) connects each clinic-level study database to the BCPP data center. The 
VPN provides a secure network over which data can be transmitted and through which data managers 
and IT staff can access clinic systems. VPN accounts are provided to study staff as needed and CDC DM 
lead approval is required for access to study data systems managed by CDC. Within the BCPP network, 
access to devices, databases, and directories are managed based on user roles. Data in transit over the 
BCPP network is encrypted, password protected and transmitted through secure connections using 
secure-shell (SSH) protocols; encrypted, password protected memory sticks are used for data transfer 
when direct network connections are not available.  
 
The Botswana MOH is responsible for the security of PIMS and IPMS data. PIMS resides on secure local 
networks at each clinic and IPMS runs on the secure Government Data Network (GDN). Both the local 
network and the GDN use PIMS are regularly backed up via secure memory sticks. IPMS backups are 
managed through the IPMS central data store in compliance with Botswana MOH IT policies. CDC DM 
and IT will work with MOH counterparts to strengthen data security policies and practices. 
 
8.3 Data quality 
ODK Surveys on the tablets and EpiInfo have built-in validation tools to minimize data entry errors. 
These include range restrictions for numeric data, pre-defined values (code sets) for categorical data, 
and logic checks. Valid responses are required for key fields to ensure completeness and skip patterns 
will be used to prevent extraneous data entry and encourage proper form completion. Error messages 
and caution notices will be used to alert staff when they enter faulty data so that they are aware and 
can correct the problem.   
 
HTC and linkage to care staff receive training on both the contents of the tools and use of the tablets 
and ODK software.  Supervisors review the data forms for completeness and supervise corrections 
prior to synching of the tablets. SMC staff will receive training on proper completion of MOH tools and 
use of the Epi Info client tracker. Data managers will monitor system performance throughout 
implementation.  
 
8.4 Confidentiality of data 
CDC DM is responsible for protecting the privacy of all study participants and ensuring the proper 
handling of all personal health information and contact information collected for BCPP under Protocol 
3.  All components of the distributed data systems implement both electronic and physical security 
procedures for “data in use” within secure networks and devices.  Encryption is implemented to render 
electronically stored subject identity and personal health information unusable, unreadable, or 
indecipherable to unauthorized individuals for “data in motion” and “data at rest”. Encrypted 
personally identifiable information (PII) will be transmitted within the BCPP system by way of the 
secured VPN only. 
  
PII, including name, national identity card number (Omang) and locator data (address, phone 
numbers), is collected as part of HTC to facilitate referral and linkage of clients with services (e.g. IDCC, 
ANC, SMC).  BHS collects similar information and includes necessary PII in the transfer of referral and 

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locator data to the clinic.  PII is collected as a part of patient registration in both PIMS and IPMS as 
required by MOH to ensure patients are eligible to receive services.   
 
PII maintained in the clinic study databases are not transferred to the central database on the BCPP 
server; Omang is encrypted with a one-way hash prior to transfer to the BCPP server for the purpose of 
linking data across data systems. Where there is consent from the client to access medical records or a 
waiver of consent to extract identified data from the clinic systems (PIMS and IPMS), clinic data can be 
linked with BHS referrals and HTC data using the hashed Omang.  
 
All study staff are trained on data confidentiality. Site staff access to PII and locator data is limited to 
health care providing staff which are required to reliably identify a participant, and staff engaged in 
linking patients consenting for contact with services. A minimal number of staff have access to the 
study databases where PII is stored and the operational reports which present PII to site staff; DM can 
access these data when required for system maintenance or to provide user support.  
 
9.0 DATA AND ANALYSIS PLANS 
The primary objective of the Intervention Protocol is to implement and describe uptake of 
Combination Prevention interventions in CPCs.  Secondary objectives will describe retention in the 
clinical cascade of care from HIV diagnosis to viral suppression among all HIV-infected persons.  The 
key indicators for analyzing results of BCPP objectives are outlined in Table 2.   
 
. 
 
 

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Table 2.  BCPP Key Indicators 
Indicator Name 
 
Coverage vs. 
BCPP 
Performance 
Numerator 
Denominator 
1. % of HIV+ Adults* 
who Know their 
Status  
Coverage  
 
# of HIV+ Adults estimated to know 
their HIV status 
# of Adults estimated to 
be HIV+ 
2. % of HIV+ Adults in 
Care 
Coverage 
# of HIV+ Adults in Care 
# of HIV+ Adults 
estimated to know their 
HIV status 
3. % of HIV+ Adults on 
ART 
Coverage  
 
#of HIV+ Adults on ART 
# of HIV+ Adults 
estimated to know their 
HIV status 
4. % of HIV+ Adults with 
Viral Suppression 
Coverage  
 
# of HIV+ Adults with 
VL<1000Copies/ML 
#of HIV+ Adults on ART 
5. % of HIV+ Adults 
Identified through 
BCPP who know their 
status  
BCPP 
Performance 
# of HIV+ Adults Identified (new & 
known) through BCPP who know their 
status 
# of Adults estimated to 
be HIV+ 
6. % of PLHIV Newly 
Diagnosed through 
BCPP 
BCPP 
Performance 
# of Adults Identified as Newly 
Diagnosed HIV+ through BCPP 
# of HIV+ Adults 
Identified (new & known) 
through BCPP who know 
their status  
7. % of  PLHIV  Linked to 
Care 
BCPP 
Performance 
# of HIV+ Adults Identified as Newly 
Diagnosed or Not Currently in Care at 
IDCC who were seen at IDCC within 90 
and 180 days of Interview 
# HIV+ Adults Identified 
as Newly Diagnosed or 
Currently Not in Care at 
IDCC 
8. % of PLHIV Initiating 
(or re-starting) ART 
BCPP 
Performance 
# of Eligible HIV+ Adults Identified Not 
on ART who Start or Re-Start ART  
# of HIV+ Adults 
Identified not on ART 
9. % of PLHIV Retained 
on ART (12 months 
Post ART Start or 
Restart) 
BCPP 
Performance 
# of HIV+ Adults Identified Not on ART 
who Start or Re-Start ART and Remain 
on ART after 12 Months 
# of Eligible HIV+ Adults 
Identified Not on ART 
who Start or Re-Start ART  
10. % of PLHIV on ART 
with Viral 
Suppression (12 
Months post ART 
Initiation or Restart) 
BCPP 
Performance 
# of HIV+ Adults Identified Not on ART 
who Start or Re-Start ART and have 
VL<1000Copies/ML  after 12 Months 
# of Eligible HIV+ Adults 
Identified Not on ART 
who Start or Re-Start ART  
 
 
 In the section below, data and the data sources for the outcomes of interest are identified for each 
intervention within the combination prevention package of services (HTC and Linkage to care, HIV care 
and treatment, MC and PMTCT services).  In addition, the data analysis plans are provided for the study 
objectives.  
 
9.1 HIV Testing and Counseling and Linkage to Care 
The HTC services aim to maximize the number of PLHIV who know their status within the community. 
Predictors of HTC uptake will be examined including demographics, prior testing history, partner 
status, etc.  Participants reached through mobile vs home-based testing will be described including age 

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and gender. Characteristics of HIV-positive persons identified will be described, including but not 
limited to demographics, testing history, new or previous HIV diagnosis, history of HIV care, CD4 count, 
and ART status. Data sources will include the Household Enumeration Form, HTC Intake Form, and 
BHS collected during the HTC activities. In addition, facility-based testing will be monitored in CPCs 
through RHT data in PIMS2 or IPMS.  
 
All HIV-positive participants given appointments at the HIV care and treatment clinic in the study 
communities are tracked to ensure they link to care. Those who keep appointments at the study clinic 
within 90 and up to 180  days of the BCPP interview as recorded in PIMS2 or IPMS are considered 
“linked” to care.  Those participants who report they are receiving care at another clinic outside the 
study community will be verified by PIMS2 or IPMS and will be considered linked to care if that have an 
IDCC appointment within 90 and up to 180  days of their BCPP interview date.  In addition, at  one year 
from the interview data, electronic data systems will be checked to determine if participants who did 
not link or register within 90 days have registered in care.   
 
Predictors of linkage to care will be examined including but not limited to, demographics, new or 
previous diagnosis, CD4 count, and time to first appointment from interview. In addition, rates of 
linkage to care will be compared among participants who received interventions services and those 
who did not.   
 
Data sources include referrals from HTC and BHS (HTC Intake, BHS), PIMS2 and IPMS for details of 
registration into care and treatment, and the Participant Tracing Log where all linkage to care follow-
up activities are recorded. In addition, the Ministry of Health’s Central Data Warehouse will be queried 
to identify (or confirm self-reported enrollment) of community residents who register for HIV care and 
treatment outside of the local study community.  
Further, estimations of the operational costs associated with the expanded HTC and linkage to care 
interventions paired with the total cost by intervention with their corresponding BCPP performance 
indicator will be used to estimate the average costs per person. The financial costing approach is 
described below, in the cost analysis plan. 
 
9.2 Care and Treatment 
For HIV care and treatment objectives, the overall number of PLHIV enrolled in the IDCC and on ART 
including community residents getting care at clinics outside the community will be described.  Specific 
focus will be given to examination of patterns of health care utilization by residents and non-residents 
of the community.  The key outcomes for analysis are ART initiation, adherence, retention and virologic 
suppression. We will also describe the laboratory results showing toxicity, and adverse events among 
the clinic population on ART.  ART initiation will be measured by start date of ART among all HIV-
positive patients initiated on ART as recorded in the electronic patient management system.  Length of 
time from BCPP interview or encounter to date of initiation on ART will be recorded and monitored. 
ART coverage will be measured by the number of HIV-positive community residents receiving ART out 
of the estimated number of HIV-positive community residents.  
Adherence levels will be assessed through self-reports, pill counts and pharmacy refill data from the 
electronic data systems and also from the adherence intervention tools. Based on the self-reports, pill 
counts and pharmacy refill data, an aggregate measure of adherence will be calculated (e.g., good, 

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limited or poor). Adherence levels at a community clinic will be measured by the percentage of clinic 
patients with an adherence assessment of good, limited and poor adherence. Retention of HIV-positive 
persons in care and on treatment will be measured during a defined period of time (e.g. 12 and 24 
months). The number of HIV-positive clinic patients who are community residents and who remain in 
care (had a clinic visit within 6 months) and on treatment (pharmacy pick up and clinic visit within 3 
months) during a defined period among all patients from the community who were registered at the 
clinic during that time will be considered retained in care or on treatment. The number of patients who 
missed clinic visits, defaulted from care and were lost to follow up will also be recorded from the 
electronic patient management system during a defined period. Virologic suppression will be assessed 
from the electronic data systems and will be defined as those HIV-positive patients on ART with a viral 
load of less than or equal to 400 copies/ml among all patients on ART.   
Predictors of retention, ART initiation, adherence and virologic suppression will be examined. As the 
inverse of retention, predictors of loss to follow will be examined.  For those on ART, predictors of 
defaulting on ART will be examined.  
All clinic patients will have data captured in the existing MOH electronic patient management systems. 
Clinical outcomes, including but not limited to ART eligibility and initiation, WHO stage, lab results, 
death, adherence, retention, viral suppression, and adverse events, will be assessed using routinely 
collected clinical data that is captured in the electronic medical record (see Appendix P1). In addition, 
the Ministry of Health’s Central Data Warehouse or other sources of routine medical information will 
be queried to identify clinic participation, ART eligibility, ART initiation and virologic suppression among 
community residents receiving services outside of the local study community clinic. Secondary 
descriptive analyses for key clinical indicators will be conducted on these data. In the CPCs, retention 
intervention data will be recorded on the Participant Tracing Log, and adherence intervention data 
will be recorded on the Adherence Assessment Tool and the Adherence Intervention Tracing Form.  
9.3 PMTCT Services 
Rates of 3rd trimester retesting among pregnant women will be assessed using the MOH Antenatal 
Care and Maternity registers and the MOH patient management systems. Among HIV-negative 
pregnant women enrolled in ANC care, the percent who were retested for HIV between 32-36 weeks 
will be recorded and monitored over the course of the study. 
 
Rates of linkage to care among HIV-positive post-partum women will be reported. Once discharged 
from ANC care, HIV-positive post-partum women will be given appointments at the local IDCC. Those 
who kept the appointments and registered at the clinic as recorded in the electronic patient 
management system will be “linked” to care. Those who were previously registered patients in the 
IDCC who re-link to care will be considered re-linked. Predictors of linkage to care among HIV-positive 
post-partum women will be examined including but not limited to, demographics, time since diagnosis, 
CD4 count, viral load, and time since delivery. In addition, rates of linkage to care will be compared 
among participants who received intervention services and those who did not. Retention in care 
among post-partum women will be measured the same as among all HIV-positive patients in the IDCCs 
(see above) and recorded in the electronic patient management system.  Rates of retention on ART in 
post-partum women at one year post-delivery will be described. In addition, predictors of post-partum 

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women who default from ART will be examined including demographics, time since diagnosis, time 
since delivery, CD4 count, and viral load.     
 
Tracing activities with HIV-positive post-partum women referred to the HIV care and treatment clinic 
will be recorded on the Participant Tracing Log. The MOH patient management system will be used to 
verify registration of post-partum women in the IDCC. In addition, the Ministry of Health’s Central Data 
Warehouse will be queried to identify women who temporarily access care and treatment services 
outside of the local study community during their period of postpartum confinement.  
 
9.4 Male Circumcision 
Through linkage to MC services, the MC program aims to maximize coverage of circumcision among 
males, which is defined as the percentage of HIV-uninfected men (aged 16-49) residing in CPC 
communities who are circumcised.  Community-level MC uptake among all and eligible men will be 
reported.  BHS and ESS surveys will be used to obtain cross-sectional true estimates of MC coverage, 
based on self-report.  These surveys are described in the BCPP Evaluation Protocol (Protocol 1).  
Further, MC coverage will be estimated using records of MCs performed as well as the baseline MC 
prevalence reported by the HTC and BHS campaigns. MC coverage will be evaluated based on the most 
recent census estimates of the study community population as well as on the enumerated study 
population. 
 
9.5 ANALYSIS PLANS 
For the primary outcomes, uptake of the CP interventions, we will estimate the percentage of 
participants eligible for and receiving the intervention using BHS and HTC data to identify those 
eligible, and BHS, HTC and clinic data to identify those receiving interventions. Confidence limits for 
each outcome will be estimated using robust standard errors to account for within-community 
clustering. 
The first secondary objective is to examine demographic, clinical, and social/behavioral facilitators and 
barriers to uptake of CP interventions. We will fit Generalized Estimating Equations (GEE) models with 
robust standard errors to account for the clustering within communities.  Independent variables for 
these models will be chosen based on prior literature and hypotheses about how various demographic, 
clinical and social/behavioral factors impact uptake of HTC, PMTCT, ART and MC.  For MC, this type of 
analysis will only be possible for year 1 interventions because individual-level data on men obtaining 
MC will not be collected in subsequent years. Variables will be chosen a priori based on theoretical 
justification rather than statistical results and all chosen variables retained in the model to adjust for 
confounding. 
To compare clinical outcomes, including viral suppression, among HIV-positive persons in CPCs who 
initiate expanded ART to those who initiate ART according to national guidelines, we will use tests 
appropriate to clustered data and the distribution of the outcomes of interest. For example, for viral 
suppression, we will use GEE models to account for the clustering within communities and test for a 
difference between groups (those initiating expanded ART vs. those who initiate according to 
guidelines). Since each community will contain both of these groups of participants, clustering has less 
impact on statistical tests, but still should be taken into account in the analysis to provide appropriate 
effect estimates and confidence limits. 

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To estimate the percentage of participants retained on ART among HIV-positive pregnant or 
breastfeeding women who initiate Option B+ (indefinite ART post-delivery), we will determine the 
number of HIV-positive pregnant women who initiate Option B+ during the study using BHS, HTC and 
clinic data, and determine the number retained on ART using clinic data. Confidence limits will be 
estimated using robust standard errors as for the primary outcome. Three costing studies of HTC and 
LTC services are planned. First, estimates of costs of home-based testing and mobile testing during the 
community-based HTC campaigns, including the cost per person and per new HIV case identified will 
be compared. Second, incremental costs and outcomes of strengthening facility-based routine testing 
relative to the standard of care will be estimated.  Lastly, to assess the impact of the expanded linkage 
activities, estimates of the costs and outcomes of these tracking & tracing services will be calculated. 
Outcomes are defined as the number of new or previously diagnosed HIV-infected persons not in care, 
who register at an IDCC without engaging tracking and tracing services, and who register at an IDCC 
within 90 and 180 days of their HTC encounter. 
A mixed top-down and micro-costing approach will be used to estimate costs. All relevant direct 
medical costs such as labor and materials, and direct non-medical costs such as program support and 
administrative overhead will be considered.   
Analyses will be conducted from the perspective of the health care system indicating that the costs 
included would be those typically associated with the providers and payers of care, and would exclude 
the costs and productivity losses incurred by patients and their informal caregivers. The most 
significant cost component is expected to be labor, for which the main categories include: HTC lay 
counselors and supervisors, LTC Coordinators, drivers, and community mobilizers.  
Labor time will be estimated by analyzing data records on clients seen, then confirmed through 
communication with staff and managers, and, as needed, through observation. Other cost items will be 
estimated through a combination of resource utilization and expenditure records. Any research related 
expenses will be removed in order for the resulting cost analyses to be useful for the projection of 
operational program costs. Costs of tests conducted through the baseline and annual household 
surveys administered by the Botswana Harvard Partnership will not be considered. 
Cost and outcome data will be collected, retrospectively, from routine monitoring program data stored 
in the central study database and from actual program expenditures incurred over the period 
corresponding to the HTC and LTC programmatic efforts from all BCPP communities.  The analytic 
horizon will begin in November 2013 and correspond to the period during which the HTC campaign and 
LTC program are delivered in a community. Unit costs (e.g. Cost per tested, Cost per new diagnosis, 
Cost per person linked) will estimated by dividing total costs by the relevant BCPP performance 
indicator. Where applicable any future costs will be discounted to their present value at a standard 
rate of 3%.   As needed, costs will be converted from Botswana Pula to US dollars. Costs will be 
presented in 2015 US dollars. We will conduct univariate sensitivity analysis to identify the inputs 
which most impact the results and gauge the robustness of the conclusions. Data analysis will be 
conducted using Microsoft Excel and SAS. 
 
 
10.0 ETHICAL CONSIDERATIONS  
 

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10.1 Ethical Review  
The protocol, informed consent/parental permission forms/assent forms, research participant 
education and recruitment materials, and other requested documents — and any subsequent 
modifications — will be reviewed and approved by the ethical review bodies responsible for oversight 
of research conducted at the study sites.  The Institutional Review Boards/Ethical Committees 
(IRBs/ECs) for CDC and the Health Research & Development Committee, Botswana Ministry of Health 
will review the protocol at least annually. 
 
10.2 Informed Consent 
 
a) Interventions and strengthened programs: 
HTC:  National guidelines for obtaining verbal consent prior to receiving HTC services, for adults aged 
16 or older, will be followed.  Linkage-to-care interventions  now fall under  the Ministry of Health’s 
2016 national treatment guidelines which recommend that all HIV-positive persons identified be 
referred and tracked to the HIV care and treatment clinic. Therefore, all linkage to care follow up 
tracking will now be considered standard of care and will not require permission. However, 
participants who do not link to care and receive tracking and tracing follow  up services will have the 
option to discontinue those services at any time they request.   Similarly, active retention tracing of 
participants late for appointments has been implemented in several ART clinics in Botswana with plans 
to expand the scope of this program.  For Retention Tracing, clinic patient contact information (name, 
phone number, address), OMANG (patient medical ID number) and appointment history are abstracted 
from MOH register and PIMS2 database for retention tracing of clinic patients who have missed 
scheduled clinic appointments These patients will be contacted by an MOH staff member and 
permission will be obtained to send BCPP counselors out for tracing and follow up services.  
Adherence Intervention:  Clinic patients identified as being non-adherent will be asked to consent for 
the adherence intervention (Linkage, Retention & Adherence Intervention Verbal Consent) which 
requests permission to administer the Adherence Assessment Form. 
The informed consent process will occur in the language most comfortable for participants (usually in 
Setswana) at 8.0 reading level or below. Permission/assent will be documented by having the 
participant sign the permission/assent form or make a mark if the participant is illiterate; the latter will 
be witnessed by a third party.  A copy of the informed consent/assent form will be offered to the 
participant, and if applicable, parent or legal guardian giving permission for a minor to participate.  
Staff will ensure that the participant takes a copy of a study contact card that contains study 
information and telephone numbers if the participant does not wish to take a copy of the 
permission/assent form.   
 
b) Special Populations 
Minors:  Minors (participants ages 16-17) are only enrolled with the written permission of a 
parent/legal guardian and if they provide informed assent.  
 Under circumstances where clinical or study staff suspect, or there is a reported incident of 
sexual abuse of a person under age 18, the study staff member must inform the relevant 
authorities; this is stated in the permission/assent forms.   
 Referrals will be made to youth services if needed. 
 

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c) Use of Routine Programmatic Data:  A waiver of informed consent was previously granted for the 
following activities: 
 
1) Medical record use in accordance with 45CFR 46.116 (d) to extract a limited, preselected 
dataset (Appendix P1) from MOH clinical data systems in the clinic population in Enhanced Care 
and Combination Prevention Communities.   This is done by linking BHS and HTC data with clinic 
data to monitor the care and treatment cascade from HIV testing and referral through clinic 
enrollment, ART initiation and adherence, and retention in care.  Procedures for extracting, 
matching between sources, and de-identification of this data are described in Section 8.  
Limitation of data-to-data elements based on consent/waiver-of-consent will be applied during 
the transfer of data from the clinics into the study database.  Although not all data elements are 
part of the matching algorithm, data are matched using date of birth and Omang number.  
Once match is assigned, the data retained for analysis is de-identified in accordance with the 
consent/waiver-of-consent and the stipulations of the study protocols.   
 
2) A waiver of informed consent was previously granted for the following: a) data from the HTC 
Intake questionnaire that is collected as part of HTC programmatic services in households and 
tent venues in the Combination Prevention Communities, and b) abstraction of aggregate 
program data from MC and HTC facilities. 
 
The waiver is appropriate because (1) the analysis involves no more than minimal risk to human 
subjects, and personal identifiers are encrypted for data handlers and analysts; (2) the evaluation does 
not adversely affect the rights and welfare of the subjects; (3) the evaluation cannot practicably be 
carried out without the waiver because it is not possible to obtain consent from all service recipients 
without infringing on the ability to carry out the program in an efficient manner; and (4) if consent for 
routine data use from all participants was requested, this might reasonably constitute an unnecessary 
waste of an individual’s time.  The types of consents being requested for activities in this study are 
described in Table 3. 
 
Table 3: Summary of approach to consent for various components of the study 
Project 
component 
Targeted subjects 
Activity 
Consent 
Comment 
HTC  
Persons not documented 
to be HIV-infected 
Routine HIV counseling 
and testing 
Verbal consent  
 
Programmatic 
Interventions 
Eligible residents of study 
communities 
Use of testing (rapid test) 
and intake data from HTC, 
linkage to HIV care, TB 
screening, retention 
support and PMTCT 
services 
Waiver of 
consent/assent 
granted 
45 CFR 
46.116 (d) 
Use of routine- 
clinical data 
Clinic population, all  
communities 
Use of routinely-collected, 
program data-see 
Appendix P1  
 Waiver of 
consent/assent 
granted 
45 CFR 
46.116 (d) 
Clinic Patient 
Retention and 
Adherence  
IDCC patient population in 
CPCs  
Data collection and 
permission to follow-up 
Linkage, Retention & 
Adherence Tracing 
Verbal Consent Script 
 
 

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10.3 Risks 
The risks, discomforts, and inconveniences that could be posed to subjects participating in this project 
include the following: 
 
 HTC Participants: 
o Blood drawing may cause pain and bruising, and rarely, infection at the site where blood is 
drawn. Study participants may feel lightheaded or faint as a result. 
o Repeated HTC may cause stress, anxiety, or embarrassment. Participants are likely to become 
distressed if they learn they are HIV positive.  
o Participants may become embarrassed, worried, or anxious when discussing their sexual 
practices, HIV risk factors, ways to protect their partner(s) against HIV, and/or ways to prevent 
acquiring HIV infection.  
o Participants may experience discrimination as a result of being perceived by others to be HIV-
infected. 
 
 Other Strengthened Program Interventions: 
o Other strengthened interventions, including linkage for HIV care, ANC, TB screening, and 
retention support all carry very minimal risk to participants. 
 
 Persons starting ART: In addition to the risks described above for survey participants, risks for 
patients initiating ART include: 
 
Adults starting ART are at risk of ART-related adverse events (e.g., hepatitis, severe skin rash, 
renal dysfunction, drug resistance, need for regimen change, etc.).   
 
10.4 Benefits of Research Participation 
 HTC:  Potential health benefits include: earlier HTC delivered to their place of residence, earlier 
diagnosis of HIV-infection with subsequent earlier enrollment in care and treatment or PMTCT, 
earlier awareness of the importance of annual HTC and risk reduction practices for adults who test 
HIV-negative, and earlier awareness of the benefits of MC for HIV negative males.   
 
 Other Strengthened Program Interventions: Evidence for health benefits of linkage-to-care and 
adherence/ retention interventions are described in Section 6.  
 
 UTT: The benefits of earlier initiation of ART might include improved survival and reduction in 
incidence of adverse events [such as serious non-AIDS events like myocardial infarction, or AIDS-
related morbidity (e.g., a new WHO stage III/IV condition)] as well as decreased likelihood of 
transmitting HIV to others.   
 
10.5 Confidentiality 
No information concerning the study or the data will be released to any unauthorized third party, 
without prior written approval of the participant, except as necessary for monitoring by the IRBs, the 
study sponsor, OHRP, or the Botswana Ministry of Health.  No data with subject identifiers will be 
released. 

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 HTC, linkage to care, and HIV care and treatment following HIV diagnosis: 
Project staff visiting households for study visits will identify an appropriately private space to 
counsel participants, perform HIV tests, and collect individual data.  If private space is not available, 
or the participant does not wish to carry out study activities in the home, an appointment will be 
made to visit one of the mobile units or study clinics instead.  All study documents, including any 
papers or files containing personal contact information (such as telephone numbers and 
addresses), will be stored in a secure location and electronic data will be password protected. Full 
Drive Encryption will be implemented at the hardware layer of all devices storing protected health 
information.  Only designated study staff will have access to study records.   
 
 Linkage to MC and MC  
MC mobilization will be conducted according to national standards for mobilization.  These standards 
include protections for transport registers and mobilization registers with PII.  
IDCC Care and Treatment: 
Care at the clinic will be provided in adherence with MOH confidentiality guidelines.  Consultations 
between  patients and clinic/research staff will occur in a private location.  All consent forms kept by 
investigators are stored in locked steel cabinets at the clinic or on password-protected electronic 
devices (e.g., tablets).  All paper forms are stored in locked steel cabinets and transported in sealed 
boxes to Gaborone.  All data collected via MOH data systems or entered from paper questionnaires are 
kept securely on password-protected log-in screens. 
 
10.6 Protocol Compliance and Compliance with UN Convention on the Rights of the Child 
Study staff will adhere to the ethical principles that are reflected in the Declaration of Helsinki (e.g., 
ICH E6, 45 CFR 46). The study will be conducted in accordance with the Botswana and Sponsor 
regulations.  
 
The US government is a signatory on the UN Convention on the Rights of the Child (defined as anyone 
under the age of 18) which requires that any research study or program activity which includes 
children that are identified as engaged in sex work, trafficked or victims of violence make special 
provisions for referral of these individuals to services. BCPP will report suspected cases to designated 
service providers (local police or social workers) as outlined in the Botswana National Guidelines for 
reporting child abuse or neglect. Contact information for the local police and social workers, and 
procedures for reporting suspected cases of child abuse or neglect are described in study specific SOP 
in the BCPP Study Manual. Local police and social workers will be contacted prior to the initiation of 
study activities in the community to ensure they are aware of the study activities in the community and 
the procedures that will be followed should BCPP staff encounter suspected cases of abuse or neglect. 
As per national guidelines, reports of suspected abuse or neglect will be made to local authorities 
within 24 hours. Study personnel who may come in contact with these study participants will receive 
training on the appropriate procedures for handling these cases if they arise during the course of the 
study and training on the SOP documented in the regulatory files. The study will retain documentation 
of all reports that includes date of report, age of participant, and the name and type of service 
provider.  No identified information will be retained in the documentation; documentation will be 
retained by the study for 2 years after study close-out.   The informed consents for the study contain 

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language that makes clear to the participant what is required to be reported to authorities and the 
impact on confidentiality. 
 
11.0 
STUDY SAFETY AND MONITORING PLAN 
 
11.1 Reporting Adverse Events 
Expedited Adverse Event (EAE) Reporting Requirements for this Study:                                                       
The study team will report in real-time, to overseeing IRB's and to sponsors, any AE following any 
exposure to the study interventions that is BOTH possibly related to study intervention and 
unexpected, and which is a Serious Adverse Event (SAE).  An SAE is defined as any untoward 
occurrence that:  
 Results in death 
 Is life-threatening (grade 4) 
 Requires hospitalization or prolongation of hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 
This level of reporting is chosen to avoid real-time EAE reporting of all deaths, hospitalizations, etc. 
occurring in study communities that are definitely not related to study procedures. 
 
Study interventions are defined as: 
1. Antiretroviral therapy implemented as per BCPP protocol 
2. HIV testing as part of the HTC campaigns 
3. Any other study-related activity in which harm (including social harm) could occur.   
With regard to ART intervention, EAE reporting will be restricted to SAEs that are possibly related to 
initiating ART beyond national guidelines.   
 
Timing of EAE reporting: 
EAEs will be reported to CDC and HRDC within 2 business days of the study investigators becoming 
aware of the event.   
 
Grading Severity of Events: 
The most current Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table) dated November 2014 will be used (or more current version, if applicable), 
and is available on the RSC website ( http://rsc.tech-res.com/).   
 
Non-EAE Adverse Event and Incident Reporting: 
The risk of adverse events related to the use of ART has been established and there is no indication 
that enrollees, with intact immune systems, who are receiving ART, are likely to have a higher risk of 
adverse events.   
 

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SAEs that do not meet the criteria for EAEs (i.e. an SAE that is NOT related to the study intervention) 
will be submitted quarterly to the IRB.  A table listing all unrelated SAEs that occurred in the specified 
quarter will be submitted to the IRB along with a brief narrative of each event.  Per discussions with 
the CDC IRB, SAEs that are unrelated to the study intervention will NOT be reported using the official 
CDC forms (.1254/.1254S).  
 
Adverse Event Reporting Period: 
The expedited AE reporting period for this study is from the time of initial study contact to the last 
study contact for a participant. 
 
AE reporting process 
Reportable events will be documented by the in-country study team who will then notify the IRBs, 
MOH, CDC-Atlanta, and Harvard Chan School teams.  The incident will be discussed and a written 
action plan will be devised and implemented within 1 week of the initial report, if needed.  Written 
documentation of all events and event resolution will be retained in the study file.  Reporting of EAEs, 
SAEs and AEs to IRBs and the study sponsor will follow institutional and IRB policies.  If applicable, a 
formal report will be sent to the appropriate IRBs using the CDC’s Incident Report Form 1254.  
 
11.2  DSMB  
Proposed Schedule of DSMB Reviews and Interim Data Analysis 
The BCPP is divided into three interlocking protocols (two active protocols, after Protocol 2 was 
terminated in 2015), and the investigators expect that DSMB review will require information regarding 
interim study results and study conduct from all three.  The combination prevention package under 
study includes the following interventions that are outside of current SOC in Botswana: provision of 
ART for all HIV-infected adults regardless of WHO Stage or CD4 count and streamlined ART delivery. 
Hence, the reports will provide information needed to evaluate the adverse and favorable effects of 
such interventions on individually treated patients as well as on the communities in which they reside. 
The study will require at least 6 reviews, DSMB 1-6, proposed to take place at baseline and at the end 
of years 1, 2, 3, 4, and 5. DSMB 3 and 4 will evaluate intervention rollout and safety. At DSMB 5, the 
DSMB can recommend stopping for efficacy or extending the study by 1 year should there be low 
intervention coverage or a lower than expected incidence rate in the Enhanced Care arm. To 
demonstrate that the study has reasonable power to answer the study questions given information up 
to the time of each review, investigators will provide the DSMB with assessments of the adequacy of 
coverage of proposed interventions; estimated conditional power given available incidence 
information will be provided at DSMB 4 and all subsequent reviews.  While there will be separate 
reports for each of the protocols, each report will make use of the data available from all protocols.  
Details of the DSMB review plan for each protocol are provided in that protocol, and the full detailed 
plan is provided in Appendix C4.  
 
11.3 Protocol Violations 
The study will be conducted in full compliance with the protocol.  The research team will ensure that 
volunteers are informed of and understand the risks of their participation in research. Protocol 
violations and cases of social harm will be documented using the appropriate study forms and reported 
to IRBs and sponsors in accordance with the institutional policies.  Minor protocol violations that do 
not pose a threat to the health or welfare of participants will be compiled and reported to the IRBs at 
the time of annual IRB review.  Incident reporting is the responsibility of the Principal Investigators of 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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this study.  Emergency departures from protocol that eliminate an apparent immediate hazard to 
participants and are deemed crucial for the safety and well-being of that participant may be instituted 
for that participant only.  In that case the Investigator will contact the IRBs and sponsor as soon as 
possible to document the reasons for violation and ensuing events.   
 
11.4 Monitoring Plan 
A complete monitoring plan has been developed and the site will complete a study site activation 
checklist prior to study initiation.   Internal (sponsor) and external monitors will travel to the study site 
according to a pre-determined monitoring schedule specified in the monitoring plan to conduct 
general monitoring.  The study site will maintain a monitoring log to document all monitoring visits. 
Investigators and staff will grant access to the monitors to allow inspection and review study 
documents (e.g., consent forms, data collection forms, other source documents) and pertinent clinic 
records for confirmation of the study data. Study monitors will also inspect study facilities and 
documentation and may observe the performance of study procedures. 
 
12.0 ADMINISTRATIVE PROCEDURES AND INFORMATION DISSEMINATION 
 
12.1 Study Records and Document Retention 
Complete, accurate, and current study records will be maintained and stored in a secure manner 
throughout the duration of the study and additionally for five years after study close-out. Study 
records include administrative documentation— including all reports and correspondence relating to 
the study — as well as documentation related to each participant screened 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. Necessary documents to be maintained by the 
site before, during and after the study will be in accordance with GCP regulations and guidance. A 
complete list of needed documentation will be provided prior to initiation of the study and will appear 
in the study manual. 
 
12.2 Information Dissemination and Publication Plan 
Study findings will be disseminated through presentations, reports and publication in peer-reviewed 
journals and other publications.  In-country data and country specific information will be made 
available to national policy-makers, organizational, and implementing partners.  A detailed publication 
and communication plan will be developed that describes the number and types of reports and 
manuscripts planned for the study and criteria for authorship.  Formal presentations at conferences 
and scientific publications will follow CDC, Harvard Chan School, and MOH guidelines.  A data sharing 
plan will also be developed that details the requirements and process for requesting access to stored 
data and a samples for sub-studies and future analysis. 
 
 
 
 

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13.0 REFERENCES 
 
Ananworanich, J., Gayet-Ageron, A., Le Braz, M., Prasithsirikul, W., Chetchotisakd, P., Kiertiburanakul, S., et al. 
(2006). CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected 
with HIV-1: results of the Staccato randomised trial. Lancet, 368(9534), 459–465. doi:10.1016/S0140-
6736(06)69153-8. 
Attia, S., M. Egger, M. Muller, M. Zwahlen and N. Low (2009). "Sexual transmission of HIV according to viral load 
and antiretroviral therapy: systematic review and meta-analysis." AIDS 23(11): 1397-1404. 
 
Auld, A. F., N. Wambua, J. Onyango, B. Marston, G. Namulanda, M. Ackers, T. Oluoch, A. Karisa, A. Hightower, R. 
W. Shiraishi, A. Nakashima and J. Sitienei (2010). "Piloting the use of personal digital assistants for tuberculosis 
and human immunodeficiency virus surveillance, Kenya, 2007." Int J Tuberc Lung Dis 14(9): 1140-1146. 
 
Auvert, B., D. Taljaard, E. Lagarde, J. Sobngwi-Tambekou, R. Sitta and A. Puren (2005). "Randomized, controlled 
intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial." PLoS Med 2(11): 
e298. 
 
Bailey, R. C., S. Moses, C. B. Parker, K. Agot, I. Maclean, J. N. Krieger, C. F. Williams, R. T. Campbell and J. O. 
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Botswana Combination Prevention Project  
(BCPP)   
Intervention Protocol  
(Protocol #3) 
__________________________________________ 
 
Implementation, Monitoring, and Evaluation of a Combination 
of HIV Prevention Interventions in Rural and Peri-Urban 
Communities in Botswana 
 
Version 6.0 
September 22, 2017 
Collaborating Institutions: 
Botswana Ministry of Health (MOH) 
Harvard T. H. Chan School of Public Health (Harvard Chan School) 
U.S. Centers for Disease Control and Prevention (CDC) 
 
Funded by:  
The United States President’s Emergency Plan for AIDS Relief (PEPFAR) through 
United States Centers for Disease Control and Prevention (CDC) 
 
 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017,    
 Page 2 of 59 
PRINCIPAL INVESTIGATORS: 
 
Janet Moore, PhD 
Branch Chief, HIV Prevention Branch 
Division of Global HIV/AIDS (DGHA), Center for Global Health (CGH) 
United States Centers for Disease Control and Prevention (CDC) 
Address: 1600 Clifton Road, Atlanta, GA, 30333, U.S.A 
Email: jym3@cdc.gov    
 
 
Office Phone: 404.639.8954  
 
Refeletswe Lebelonyane, MD 
Combination Prevention Coordinator, MOH 
Ministry of Health, Botswana Government  
Enclave Plot No. 54609  
Gaborone, Botswana 
Email:  rlebelonyane@gov.bw 
 
Shenaaz El Halabi, (PS) MPH 
Permanent Secretary 
Botswana Ministry of Health 
Address: Private Bag 0038, Gaborone, Botswana 
Email: sel-halabi@gov.bw  
 
 
Office Phone: +267-363-2069 
 
Pamela Bachanas, PhD 
Behavioral Scientist, HIV Prevention Branch 
Division of Global HIV/AIDS (DGHA), Center for Global Health (CGH) 
United States Centers for Disease Control and Prevention (CDC) 
Address: 1600 Clifton Road, Atlanta, GA, 30333, U.S.A 
Email: ddt6@cdc.gov    
 
 
Office Phone: 404.639.8110 
 
ROLES OF INSTITUTIONS AND PRINCIPAL INVESTIGATORS 
Institutions:  Close coordination between MOH, CDC, HSPH, BHP, and other implementing 
partners is needed to ensure seamless implementation of research and program activities.  
MOH and CDC will lead and ultimately be responsible the Intervention Protocol and HSPH and 
BHP will lead the Evaluation Protocol. 
Principal Investigators: 
 
Janet Moore/ Pamela Bachanas:  CDC (PIs) responsible for preparation and design of the study 
protocol, monitoring of study progress, creation and monitoring of research budgets, and 
preparation of monthly progress reports.   
Refeletswe Lebelonyane/ Shenaaz El Halabi:  MOH Co-Principal Investigator (Co-PI) responsible 
for protocol review and in-country implementation oversight. 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 3 of 59 
 
CO-INVESTIGATOR LISTS BY INSTITUTION   
 
Botswana Ministry of Health (MOH), Gaborone, Botswana 
 Name 
Role 
           Contact Email 
Ms. Dinah Ramaabya (Nursing) 
        ARV Program 
                    dramaabya@gov.bw 
Ms. Chipo Phetlo (Nursing) 
        PMTCT 
 
                    cphetlo@gov.bw 
Mr. S. Makathaye, Dip Health Educ.        BCIC 
                                    smalathaye@gov.bw 
Mr. C. Ntsuape, BEd (Nursing Educ)          SMC                                                   ontsuape@gov.bw                 
Ms. Nokuthula Manjingo (Nursing)         HIV Testing & Counselling 
      mmajingo@gov.bw 
Dr. Joe Theu ((Medical Officer) 
         Clinical Care  
 
     jtheu@gov.bw  
 
 
Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA, and Gaborone, Botswana 
Name  
Role 
Contact Email 
Elliot Raizes, MD 
Clinical Consultant 
gwq0@cdc.gov  
Ebi Bile, BSc. MA, DU 
In-country Lab Oversight 
efb6@bw.cdc.gov 
Peter Fonjungo, PhD 
HQ Lab Oversight 
pdf4@cdc.gov 
Sherri Pals, PhD 
Statistics 
sfv3@cdc.gov 
Chunfu Yang, PhD 
Laboratory 
cxy0@cdc.gov 
Mary Grace Alwano 
In Country HTC/ LTC 
Project Coordinator 
         mea9@bw.cdc.gov 
Stephanie Behel, MPH 
HTC and LTC 
         zmd7@cdc.gov 
Naomi Bock, MD 
Voluntary Medical MC 
        neb2@cdc.gov 
Stephanie Davis, MD, MPH 
Voluntary Medical MC 
        vic6@cdc.gov 
Lisa Block, MS 
Project Manager 
        kwk5@cdc.gov 
Lisa Mills, MD 
William Abrams 
Co-investigator 
Program Administration 
        Ioj7@cdc.gov 
        hvf8@cdc.gov  
Arielle Lasry PhD 
HTC Costing 
        ftn9@cdc.gov 
 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 4 of 59 
Harvard T. H. Chan School of Public Health, Boston, MA, USA 
Name 
Role 
Contact Email 
Myron Essex, DVM, PhD 
Co-Investigator 
messex@hsph.harvard.edu  
Eric Tchetgen, PhD 
Statistics and Epidemiology 
etchetge@hsph.harvard.edu 
Scott Dryden-Peterson, MD 
Treatment and PMTCT 
scott_peterson@post.harvard.edu  
Shahin Lockman, MD, MSc 
Treatment and PMTCT 
slockman@hsph.harvard.edu  
Rebeca Plank, MD 
SMC 
rplank@partners.org  
Molly Pretorius Holme, MSc 
Research operations 
mpretori@hsph.harvard.edu  
Roger Shapiro, MD, MPH 
Treatment and PMTCT 
rshapiro@hsph.harvard.edu 
Kate Powis, MD, MPH 
Research Operations, 
Treatment and PMTCT 
kpowis@mgh.harvard.edu 
 
 
Botswana–Harvard AIDS Institute Partnership (BHP), Gaborone, Botswana 
Name 
Role 
Contact Email 
Tendani Gaolathe, MD 
Treatment and PMTCT, 
Field research operations 
tgaolathe@bhp.org.bw  
Joseph Makhema, MD 
BHP research operations 
jmakhema@bhp.org.bw  
Sikhulile Moyo, BSc, MSc, MPH 
Lab 
smoyo@bhp.org.bw  
Mompati Mmalane, MD, FRCS-Ed, MSc 
Community mobilization and 
research operations 
mmmalane@bhp.org.bw 
Erik van Widenfelt, BA 
Research data systems 
ewidenfelt@bhp.org.bw  
  
 

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TABLE OF CONTENTS 
  
Principal Investigators ............................................................................................................ 2 
List of Co-Investigators ........................................................................................................... 3 
Table of Contents ................................................................................................................... 5 
List of Tables and Figures ....................................................................................................... 7 
List of Acronyms and Abbreviations ........................................................................................ 8 
 
Intervention Protocol Synopisis ............................................................................................ 10 
 
1.0 INTRODUCTION .............................................................................................................. 12 
1.1   Epidemic in Botswana    
1.2  Combination Prevention Interventions          
1.3  Antiretroviral Treatment as a Component of the Combination Prevention Package 
1.4  Proposed Combination Prevention (CP) Package      
1.5  Relationship Between  Intervention Study Design and Impact Evaluation  
 
2.0 STUDY OBJECTIVES ......................................................................................................... 16 
 
3.0 OVERVIEW OF STUDY  METHODS  ................................................................................... 16 
 
4.0 STUDY POPULATIONS ..................................................................................................... 16 
4.1  Selection of Study Communities  
4.2  Matching of Study Communities 
4.3  Eligibility of Community Members  
4.4 Enhancement of Services in all Study Communities 
4.5  Eligibility Criteria for Inclusion in Interventions in CP Communities 
4.6  Rationale for Exclusion in Interventions in CP Communities 
 
5.0 SAMPLE SIZE AND SAMPLE SELECTION METHODS…………………………………………………………….21 
 
6.0 INTERVENTION PROCEDURES  ......................................................................................... 22 
6.1 Overview of Intervention Strategy 
6.2 Stakeholder Involvement, Community Engagement, and Community Mobilization 
6.3 HIV Testing and Counseling (HTC) 
6.4 Linkage to HIV Care and Treatment 
6.5 Male Circumcision (MC) 
6.6 Identification, Linkage, and Treatment of HIV+ Pregnant Women 
6.7 HIV Care and Treatment 
 
7.0 LABORATORY METHODS ................................................................................................. 32 
7.1 Overview of Laboratory Methods  
7.2 Training of Laboratory Personnel  
7.3  Specimen Collection, Transport, and Processing  

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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7.4  Laboratory Testing for HTC Campaigns 
7.5  Laboratory Testing for IDCC Patients 
7.6 Quality Assurance   
7.7 Biosafety and Waste Management   
7.8 Specimen Storage and Shipment    
 
8.0 DATA SYSTEMS AND MANAGEMENT ....................................................................... ………35 
8.1 Data Collection, Capture, and Flow 
8.2 Data Security   
8.3 Data Quality  
8.4 Confidentiality of data 
 
9.0 DATA AND ANALYSIS PLANS…………………………………………………………………………………………….40 
9.1 HIV Testing and Counseling and Linkage to Care  
9.2 Care and Treatment    
9.3 PMTCT Services    
9.4 Male Circumcision  
9.5  Analysis Plans  
 
10.0 ETHICAL CONSIDERATIONS… ........................................................................................... 5 
10.1  Ethical Review 
10.2  Informed Consent 
10.3  Risks 
10.4  Benefits of Research Participation 
10.5  Confidentiality 
10.6  Protocol Compliance and Compliance with UN Convention on the Rights of the Child 
10.7  Future Use of Stored Samples 
 
11.0 STUDY SAFETY AND MONITORING PLAN ....................................................................... 49 
11.1  Reporting Adverse Events  
11.2  Data Safety and Monitoring Board (DSMB) 
11.3  Protocol Violations 
11.4  Monitoring Plan 
 
12.0 ADMINISTRATIVE PROCEDURES AND INFORMATION DISSEMINATION ........................... 52 
12.1  Study Records and Document Retention 
12.2  Information Dissemination and Publication Plan 
 
13.0 REFERENCES ................................................................................................................. 53 
 
 

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APPENDICES:   
_________________________________________________________________________________ 
Cross-Protocol Appendices: 
Appendix C2 
 
A.  List of Study Communities and Matching Criteria for Community Pairs 
B. Back-up Communities in Selected 30 Communities Decline, unavailable or 
deemed unsuitable for study inclusion 
Figure A: Map of Study Communities in Three Regions 
Figure B: Map of Study Communities in the Southern Region 
Figure C: Map of Study Communities in the Central Region 
Figure D: Map of Study Communities in the Northern Region 
Appendix C3 
 
Size of Study Populations 
Appendix C4 
 
Data Safety Monitoring Plan 
 
Protocol 3 Appendix: 
Appendix P1 
 
Summary of Variables to be Collected for Ya Tsie Protocol 3 
_________________________________________________________________________________ 
 
 
 
 
LIST OF TABLES AND FIGURES 
 
 
Figure 1: Data Flow for Combination Prevention Communities 
 
Table 1: Precision for 95% confidence intervals for uptake of CP interventions in CP 
communities 
Table 2: BCPP Key Indicators 
Table 3:  Summary of approach to consent for various components of the study 
 
 
 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017,    
 Page 8 of 59 
ACRONYMS AND ABBREVIATIONS  
 
AE 
 
  
adverse event 
AIDS 
 
  
acquired immunodeficiency syndrome 
AHS 
 
  
annual household surveys (follow-up visits of the BHS and HIC) 
ANC 
 
  
antenatal clinic (or care) 
ART 
 
  
antiretroviral treatment (or therapy) 
ARV 
 
  
antiretroviral (drug) 
BCPP 
 
  
Botswana Combination Prevention Project 
BHHRL  
  
Botswana–Harvard HIV Reference Laboratory 
BHP 
 
  
Botswana–Harvard AIDS Institute Partnership 
BHS 
 
  
baseline household survey 
CDC 
 
  
Centers for Disease Control and Prevention 
CI 
 
  
confidence interval 
CP 
 
  
combination prevention 
CPC 
 
  
combination prevention community 
CRT 
 
  
community-randomized trial 
DSMB  
  
Data Safety Monitoring Board 
ECC 
 
  
enhanced care communities 
ELISA 
 
  
enzyme-linked immunosorbent assay 
ESS 
 
  
end of study survey 
ETC 
 
  
expanded treatment cohort 
HIC 
 
  
HIV incidence cohort 
HIV 
 
  
human immunodeficiency virus  
 
 
 
HIV-1 RNA 
  
HIV-1 RNA load in plasma, viral load 
HIVDR  
  
HIV drug resistance 
HTC 
 
  
HIV testing and counseling 
HVL 
 
  
high viral load  
IAS 
 
  
International AIDS Society 
IDCC 
 
  
infectious disease care clinic 
IPMS 
 
  
integrated patient management system 
IRB 
 
  
institutional review board 
LFT 
 
  
liver function test 
LTC 
 
  
linkage-to-care 
MC 
 
  
male circumcision 
M&E 
 
  
monitoring and evaluation 
MOH 
 
  
Ministry of Health 
 
 
 
MTCT  
  
mother-to-child (HIV) transmission 
OHRP  
  
Office for Human Research Protections 
OI 
 
  
opportunistic infection 
Option B+ 
  
indefinite continuation of ART for women who start ART for PMTCT 
PEP 
 
  
post-exposure prophylaxis 
PEPFAR  
  
President’s Emergency Plan for AIDS Relief 
PII 
 
  
personally identifiable information 
PIMS 
 
  
patient information management system 
PMTCT  
  
prevention of mother-to-child (HIV) transmission 
PLHIV  
  
people living with HIV 
POC 
 
  
point-of-care 
POB 
 
  
pregnant/pregnancy or breastfeeding 
QA 
 
  
quality assurance 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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QC 
 
  
quality control 
RHT 
 
  
Routine HIV testing 
SAE 
 
  
serious adverse event 
SD 
 
  
standard deviation 
SMC 
 
  
safe male circumcision (Botswana government initiative) 
SMS 
 
  
short message service 
SOC 
 
  
standard of care 
SoE 
 
  
schedule of events 
SOP 
 
  
standard operating procedure 
study arm 
  
a group of 15 communities that is randomized to receive either standard of care or 
study interventions with respect to HIV prevention measures 
TB 
 
  
tuberculosis 
UN 
 
  
United Nations 
UNAIDS 
 
Joint United Nations Program on HIV/AIDS 
UTT 
 
 
Universal Test and Treat 
VDC 
 
 
village development committee 
VF 
 
 
virologic failure 
VL 
 
  
viral load 
VPN 
 
 
virtual private network 
WHO 
 
  
World Health Organization 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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BCPP Intervention Protocol (#3) 
Protocol Synopsis 
 
Overview:  The BCPP study is composed of 2 active interlocking protocols, the Evaluation Protocol (1) 
and the Intervention Protocol (3).  The Closed Clinical Cohort Protocol (Protocol 2) was withdrawn in 
2015.  An overview of the overarching BCPP study is provided in the BCPP Overall Schema located in 
the Evaluation Protocol.    
 
Primary Objective of Protocol 3 
1) To implement the combination prevention (CP) intervention package in combination 
prevention communities (CPC) and describe uptake of these interventions in CPCs (expanded 
HIV Testing and Counseling (HTC), strengthened Male Circumcision (MC), expanded HIV Care 
and Treatment, and strengthened PMTCT services). 
 
Secondary Objectives of Protocol 3 
1) To describe retention in the clinical cascade of care from HIV diagnosis to viral suppression 
among all HIV-infected persons. 
2) To describe uptake of expanded antiretroviral treatment (ART) and clinical outcomes including 
viral suppression among HIV-positive persons receiving expanded ART.  
3) To examine demographic, clinical, and social/behavioral facilitators and barriers to uptake of CP 
interventions.  
4) To examine demographic factors, including community of residence, that affect access to health 
care services.  
 
Study Design: 
The BCPP study is a pair-matched community-randomized trial. This protocol describes the 
programmatic interventions, including expanded ART, and program monitoring activities that will be 
conducted as part of the larger BCPP project.  
 
Study Population: 
Thirty community clusters were selected from three geographic regions in Botswana.  Pre-
randomization, community pairs were matched on community characteristics thought to be associated 
with the outcome of interest of the BCPP (HIV incidence) to improve balance between arms and 
statistical efficiency.  The average total population size of each of the targeted communities is 6,000 
(range 2,400 - 12,000), giving a total population across all 30 communities of about 180,800, of whom 
about 105,000 are adults aged 16-64.  
 
Study Procedures:  
Matched community pairs (15 communities per arm) were randomized 1:1 to Enhanced Care (ECC; 
Comparison) or Combination Prevention (CPC; Intervention) arms prior to the baseline household 
survey (BHS) that is conducted as part of the BCPP Evaluation Protocol.  Initiation of intervention 
activities in the CPCs begin immediately following completion of enrollment in the BHS and continue 
for the duration of the study.  CPCs receive the combination prevention intervention package, which 
includes strengthened HTC, MC linkage, PMTCT services, and expanded HIV care and treatment for 
HIV-infected persons 16-64 years. In addition, expanded ART for existing HIV-infected community clinic 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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patients will be offered in the CPCs.  Routinely collected clinical data will be used to assess the clinical 
outcomes for all HIV positive patients.  
 
Study Duration:  All study activities will occur over a period of approximately 60 months. 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 12 of 59 
 
1.0 INTRODUCTION AND BACKGROUND 
 
 1.1 Epidemic in Botswana 
Thirty years into the global HIV pandemic, HIV prevalence and incidence remain high in sub-Saharan 
Africa.  Although this region represents only 12% of the world’s population, it accounts for 
approximately 67% of the world’s 34 million HIV-infected persons,  and annually, about 70% of the 
world’s 2.7 million new infections occur in this region (UNAIDS 2010). Despite substantial progress in 
providing HIV treatment and prevention of mother-to-child transmission services (PMTCT) to its 
citizens, an estimated 25% of adult residents of Botswana are HIV-infected, the second highest adult 
HIV prevalence in the world, and about 14,000 persons are newly infected with HIV annually, the third 
highest national HIV incidence rate globally (UNAIDS 2010). 
 
 1.2 Combination Prevention Interventions 
In the past five years several HIV prevention interventions have proven to be highly effective at 
reducing transmission of HIV and have offered hope for containing and possibly reversing epidemics in 
sub-Saharan Africa.  For HIV-negative men, MC has been shown to significantly reduce HIV acquisition 
from HIV-infected female partners.  Three randomized controlled trials of circumcision, involving more 
than 10,000 men in sub-Saharan Africa, demonstrated a 60% reduction in HIV acquisition risk (Auvert, 
Taljaard et al. 2005, Bailey, Moses et al. 2007, Gray, Kigozi et al. 2007).  Additionally, antiretroviral 
treatment (ART) of HIV-infected persons has been shown to reduce viral load (VL) and consequently 
the risk of HIV transmission to uninfected partners in sero-discordant couples by as much as 96% 
(Cohen, Chen et al. 2011).  Similarly, the use of antiretrovirals to prevent transmission of HIV from 
infected mothers to their infants during pregnancy, birth, and breastfeeding can reduce transmission 
to below 5% (Mahy, Stover et al. 2010; Shapiro, Hughs et al. 2013).   
 
Despite considerable success in scaling up these interventions in many sub-Saharan African countries, 
especially those supported by the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), adult HIV 
incidence has remained high (>1%) in many regions in Southern Africa (Botswana, Swaziland, Lesotho, 
Kwa-Zulu Natal in South Africa, and Southern Mozambique).  Multiple factors may account for high HIV 
incidence in this part of the world.  Firstly, viral characteristics of HIV-1 subtype C, endemic in Southern 
Africa, may make it more infectious than other viral subtypes (Novitsky, Wang et al. 2010, Novitsky, 
Ndung'u et al. 2011).  For example, recent evidence suggests that about one third of persons infected 
with HIV-1 sub-type C, maintain very high viral loads (VL>50,000 copies/ml) for more than 6 months 
after sero-conversion.  In contrast, viral load following HIV-1 subtype B infection (the prevalent 
subtype in the United States and Europe) resolves to a steady-state viral set point below 50,000 
copies/ml in almost all individuals within four to six months (Daar, Moudgil et al. 1991, Mellors, Munoz 
et al. 1997, Kaufmann, Cunningham et al. 1998, Little, McLean et al. 1999).   
 
Secondly, the scale and quality of the HIV prevention interventions may have been insufficient to 
reduce HIV incidence among adults in Southern Africa to levels observed in other parts of the world.  
For example, the main mechanism by which scale-up of HTC and antiretroviral therapy reduces HIV 
transmission risk in the community, is by reducing viral load in resident HIV-infected persons, ideally to 
undetectable levels (VL<400 copies/ml).  Studies have suggested that every 0.5 log reduction in an 
individual’s HIV-1 viral load is equivalent to a 40% reduction in individual HIV transmission risk 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 13 of 59 
(Modjarrad, Chamot et al. 2008), and once the viral load is fully suppressed (VL <400 copies/ml) 
individual HIV transmission risk is virtually zero (Attia, Egger et al. 2009).  Despite considerable scale-up 
of access to HTC and ART, poor retention of HIV-infected persons in the HIV care and treatment 
cascade from diagnosis to ART follow-up (Rosen and Fox 2011), has mitigated the ability of HTC and 
HIV care and treatment programs in Southern Africa to reduce the prevalence of HIV-infected persons 
with detectable viral loads (VL>400 copies/ml).  In a meta-analysis of pre-ART retention in Africa, Rosen 
et al. reported that only 59% of newly diagnosed adults are successfully linked to HIV care and 
treatment services, only 46% are retained from initial registration and staging at the facility to ART-
eligibility, and only 68% are retained from ART eligibility to ART initiation (Rosen and Fox 2011). Of 
those adults who initiate ART, ~30% are no longer on therapy by 3 years of follow-up, with most of 
those no longer in care considered lost to follow-up (Fox and Rosen 2010).  Therefore, even if  50% of 
HIV-infected adults in Botswana know their HIV status (BAIS 2008), a considerably lower proportion 
have a suppressed viral load (Gardner, McLees et al. 2011).  The remaining HIV-infected adults with 
unsuppressed viral load are still infectious and spreading virus in the community.  Achieving high 
coverage of MC among HIV-negative males has also been challenging with most countries, including 
Botswana, unable to meet ambitious 80% coverage targets to date (Curran, Njeuhmeli et al. 2011).   
 
In summary, despite having the tools to end the HIV epidemic (Fauci and Folkers 2012), insufficient 
scale, quality, and coordination of prevention interventions have significantly limited southern Africa’s 
ability to sufficiently curb the HIV epidemic.  This has led public health experts to call for a 
“combination prevention” strategy that involves implementing multiple prevention interventions with 
known efficacy in a geographic area at a scale, quality, and intensity to impact the epidemic (Merson, 
Padian et al. 2008, Piot, Bartos et al. 2008).  Although most experts agree that synchronized 
implementation of a combination of prevention interventions is needed, there remains considerable 
debate about what components should be included in the essential combination prevention package 
(Merson, Padian et al. 2008, Halperin 2009).  Four evidence-based interventions (HTC, ART, MC and 
PMTCT) are recommended for scale-up by almost all prevention experts and will form the cornerstone 
of the combination prevention package proposed as part of this project (see Section 1.4 below). 
 
1.3 ART as a Component of the Combination Prevention Package 
Data show that higher levels of HIV-1 RNA (viral load) are independently associated with both higher 
rates of HIV transmission and more rapid HIV clinical disease progression and CD4 decline. This study 
therefore originally included the use of a modified “treatment as prevention” approach that targeted 
not only those adults who need ART for their own health, but also those adults who are most likely to 
perpetuate HIV transmission within the community (those with viral load ≥10,000 copies/ml). At the 
time of designing the BCPP in 2012 there was strong experimental evidence supporting initiation of 
ART at CD4≤350 cells/µL, or WHO Stage III/IV, but conclusive experimental evidence supporting patient 
benefit of ART initiation at higher CD4 counts, especially CD4 >500 cells/µL was lacking. 
 
The 2013 WHO guidelines recommended initiation of ART in all HIV-infected adults with CD4≤500 
cells/µL regardless of clinical stage. In an attempt to provide programmatic data for an anticipated 
change in CD4 threshold for ART initiation in Botswana and to enhance the power of the study to 
answer its primary objective, the threshold for ART initiation in the Combination Prevention arm was 
modified in early 2015 (from CD4≤350 to CD4≤500 regardless of viral load, in addition to offering 
expanded ART to persons with CD4>500 and viral load ≥10,000).   
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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Shortly thereafter, in July 2015, the WHO announced that it would revise ART guidelines to 
recommend universal treatment (regardless of CD4 count or HIV disease severity). The WHO’s plans 
were informed by results from two clinical ART trials. One, the START trial, reported that early drug 
treatment of people with HIV cut their risk of serious illness or death by 57% (Lundgren, Babiker et al. 
2015). Another, the TEMPRANO study, released findings that early ART significantly decreased 
morbidity overall and when restricted to patients with baseline CD4>500 cells/µL (Danel, Moh et al. 
2015). WHO published an early release guideline on when to start ART and on pre-exposure 
prophylaxis for HIV in September 2015 (World Health Organization 2015). The BCPP study team, with 
the support of the DSMB and funder, is revising the intervention treatment initiation criteria once 
more to take these new results and WHO guidelines into account. Universal Test and Treat (UTT) is 
therefore included in the combination prevention package with version 4.0 of the protocols. 
 
In June 2016, Botswana treatment guidelines changed to UTT. All PLHIV living within the Enhanced 
Care communities (ECC) are now eligible to receive ART according to these updated Botswana national 
guidelines.  Residents in the Combination Prevention communities will also continue to receive 
universal treatment as prevention.   
 
Through additional modeling, the study team has adjusted effect size and power calculations to reflect 
a move to UTT in both the Combination Prevention and Enhanced Care arms, using a range of roll-out 
timelines.  This revised modeling also uses estimates of coverage (by HTC, LTC, ART, MC) that are 
consistent with what has been observed in BCPP thus far, rather than using the higher coverage 
“targets”.  Model-based estimates suggest that the impact of a change in treatment policy on the 
power to detect a difference in cumulative incidence (the primary objective of BCPP) may still yield at 
least 70% power (Protocol 1, v4.0, section 5.1.1), but the impact depends on the exact nature and 
timing of the implementation of changes in policy as well as other prevailing conditions.  The retention 
of this level of power even with Enhanced Care communities moving to expanded access to ART is at 
least in part attributable to the fact that BCPP is implementing multiple HIV prevention interventions 
(including higher HTC coverage, linkage to HIV care/treatment, etc.). 
 
1.4. 
 Proposed Combination Prevention (CP) Package  
In version 4.0 of this protocol, the combination package includes universal treatment of all PLHIV along 
with a package of interventions that are designed to:  1) Identify all HIV-infected adults in CP 
communities,  2) reduce barriers to ART initiation, 3) support adherence and retention on ART, 4) 
increase capacity of clinics to support aggressive ART scale-up, and 5) enhance the use of both 
individual and clinic-level data to ensure maintenance of quality of HIV care and treatment.  
 
The revised combination prevention package for this project includes: 
 
 Rapid scale-up of HTC services, with a target of ensuring >90% of HIV-infected adults aged 16-64 
have documentation of their HIV-infected status. 
 Rapid scale-up of universal ART for all HIV-infected adults, with a target of ensuring that >93% of 
adults diagnosed with HIV infection are receiving ART. 
 Rapid scale-up of retention in care and adherence interventions, with a target of ensuring that 
>95% of HIV-infected adults receiving ART are virally suppressed with HIV-1 RNA < 400 copies per 
ML. 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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 Scale-up of linkage to MC services, with a target of ensuring >60% of HIV-negative men (aged 16–
49) are circumcised. 
 Rapid strengthening of PMTCT services, with a target of ensuring >90% of women initiated on 
indefinite ART (Option B+) during pregnancy remain in care and on treatment post-delivery.   
 
The targets for intervention communities in this version of the Protocol have been revised from the 
targets in Protocol 3, version 3.0.  Targets for ART initiation and viral load suppression have been raised 
based on the higher than expected baseline levels of ART initiation and viral load suppression coverage 
as measured in BCPP BHS and HTC campaign.  The MC target has been lowered from 80% to 60%.  This 
change is in accordance with the DSMB’s 2013 recommendation based on concerns that the 80% 
target might not be realistic; results to date support these expectations. 
 
To reach stated scale-up targets (cumulative over 3 years) several service uptake initiatives will be 
implemented, including (1) community mobilization to encourage HTC and MC uptake, (2) targeted HIV 
testing to include hard-to- reach populations, (3) strengthening linkage to care, treatment and/or 
PMTCT services for known HIV-infected adults not in care and newly diagnosed HIV-infected adults, (4) 
strengthening linkage to MC services for HIV-negative or HIV-unknown status males identified at HTC 
services, (5) strengthening retention in care and adherence to ART services at clinics (6) expansion and 
strengthening of HTC, ART, PMTCT services, and MC services through recruitment of additional health 
care personnel and counselors, and (7) strengthened monitoring and evaluation of prevention, care 
and treatment programs to ensure stated targets are reached.  
 
Adults aged 16-64 will be targeted for service uptake because recent, nationally representative surveys 
of HIV prevalence and incidence (BAIS 2008) suggest that HIV incidence remains high (>1%) throughout 
this age group. Modeling exercises suggest that meeting scale-up targets by the end of two years of 
program implementation, and maintaining treatment coverage thereafter, could result in community 
HIV incidence reductions of 40% by the end of three years of implementation.    
 
1.5. 
Relationship Between  Intervention Study Design and Impact Evaluation  
A separate protocol (BCPP Evaluation, Protocol #1) describes in detail the proposed plans for 
evaluating the impact of the combination prevention (CP) package on adult population level HIV 
incidence.  In brief, a randomized design was proposed to provide experimental evidence of CP 
package impact and because population-level HIV incidence is the outcome of interest, a community 
(rather than individual) randomized trial is proposed.  Thirty study communities have been selected 
and matched into pairs.  Pair-matching is done to improve balance between study arms and statistical 
efficiency (Hayes and Moulton 2009).  Communities within pairs were randomized to Combination 
Prevention Community and Enhanced Care Community (CPC and ECC) arms.  Following community 
matching, a baseline 20% household survey (BHS) was implemented to recruit an HIV Incidence Cohort 
(HIC) of eligible, consenting, and HIV-negative adults aged 16-64.  The HIC will be followed annually 
during Annual Household Survey (AHS) visits to assess cumulative HIV incidence over 30 months.  Study 
participants who are not eligible for the HIC will also be followed annually in the AHS, to assess, in both 
study arms, uptake of HTC, ART, MC services and PMTCT services in each arm and to describe major 
health outcomes (such as death).  Cumulative incidence will be compared between study arms to 
assess CP package impact.   
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
Page 16 of 59 
Combination prevention package coverage in the community will be estimated at baseline (in the 20% 
BHS) and through a large end of study survey (ESS).  In addition, during study conduct, progress in 
reaching target coverage levels will be captured from monitoring data collected as part of routine 
programmatic activities. 
 
2.0 STUDY OBJECTIVES 
 
Primary Objective  
1) To implement the combination prevention (CP) intervention package in CPCs and describe 
uptake of these interventions (expanded HTC, strengthened MC, expanded HIV Care and 
Treatment, and strengthened PMTCT services). 
 
Secondary Objectives 
1) To describe retention in the clinical cascade of care from HIV diagnosis to viral suppression for 
HIV-infected persons. 
2) To describe uptake of expanded ART and clinical outcomes including viral suppression among 
HIV-positive persons receiving ART (UTT).  
3) To examine demographic, clinical, and social/behavioral facilitators and barriers to uptake of CP 
interventions.  
4) To examine demographic factors, including community of residence, that affect access to health 
care services.  
 
3.0 OVERVIEW OF STUDY METHODS 
As described in the introduction, the over-arching design is a pair-matched community-randomized 
trial (CRT).  The full details of the CRT, including how communities were selected, how they were 
matched, community randomization, the BHS, enrollment of the HIV incidence cohorts (HIC), and the 
end of study survey (ESS), are described in the BCPP Evaluation Protocol.  This protocol describes the 
interventions implemented in 15 communities randomly selected from the 30 study communities 
(Appendix C2), monitoring and evaluation (M&E) plans, and the program data systems. 
 
4.0 STUDY POPULATIONS 
 
4.1 Selection of Study Communities 
Thirty communities (Appendix C2) in three geographic areas in Botswana: (1) around Gaborone in the 
south east, (2) around Francistown in the north east, and (3) in the region around Mahalapye, Serowe, 
and Palapye in the central eastern region, are included in the study.   These communities were selected 
based on two criteria: (1) communities needed to be of sufficient size to meet sample size 
requirements for the HIV Incidence Cohort (described in BCPP Evaluation Protocol), and (2) 
implementation of the proposed combination prevention package needed to be feasible.  Feasibility 
requirements are listed below: 
 
 Community Criteria 
All communities must: 
o Have a health center from which HIV care and treatment, PMTCT, or HTC can be provided. 
o Be reachable by road via a <8 hour drive from Gaborone or Francistown.  (CDC and the Ministry 
of Health have permanent, well-staffed offices in Gaborone and Francistown, while the Harvard 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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Chan School has a permanent office in Gaborone.  This distance parameter makes the study 
easier to implement and monitor for quality control purposes). 
o Have a clear geographic boundary such that it is reasonably easy to identify a household as 
either being part of, or outside of, the study community.   
 
These inclusion criteria resulted in the exclusion of urban areas from the study.  Approximately 61% of 
Batswana (plural noun for Botswana citizens) live in urban areas with a rate of urbanization of about 
2.3% per year (annual rate of migration from rural or peri-urban regions into urban areas).  Restricting 
the study to rural and peri-urban areas, besides being necessary for study feasibility, should not limit 
the generalizability of study findings to urban areas.  If the combination prevention package is shown 
to be effective at reducing adult HIV incidence, the principle of scaling up combination prevention 
package coverage for prevention effectiveness should be applicable to urban settings.   
 
The 30 study communities selected meet the criteria described above.  The average total population 
size of each of the targeted communities is 5,855.  Assuming an average community size of 5,855, we 
estimate a total population in all 30 study communities of about 175,664 people; 87,832 persons in the 
CPC arm of which ~58% of community residents are aged 16-64 (Appendix C2/C3).  HIV prevalence 
among residents aged 16-64 is estimated at 25%, resulting in an estimated 25,471 HIV-infected 
residents aged 16-64 (12,736 per study arm).   
 
4.2  Matching of Study Communities 
Due to the small number of communities that can be enrolled in a community randomized trial for cost 
and feasibility reasons, the likelihood of imbalance of potential confounders between study arms is 
increased.  A restricted randomization, matching, and stratification were considered as strategies to 
ensure balance between arms.  A pair-matched design was chosen because: 
 This approach is more likely than stratification to achieve balance between study arms;  
 Matching has the added advantage of improving statistical efficiency compared with restricted 
randomization, and; 
 Chosen matching covariates (see below) are quite closely correlated with the outcome of interest 
(adult HIV incidence), making a matched design of similar or increased statistical efficiency 
compared with a stratified design, even though a matched design entails greater loss of degrees of 
freedom. 
 
Possible disadvantages of a pair-matched design include: 
 Loss of both communities in a pair if one community drops out. 
 It is not possible to assess whether the intervention effect varies between matched pairs, whereas, 
in a stratified design, opportunity to assess effect modification across strata would be possible.     
 
The following matching criteria were chosen:  
 Community size:  Although community size in Botswana may not be associated with the outcome 
of interest (HIV incidence), achieving sample size balance between arms improves statistical 
efficiency.   
 
 Baseline Access to Health Services including ART:  Access to ART is associated with HIV incidence 
(Montaner, Lima et al. 2010, Tanser, Bärnighausen et al. 2012).  Although some communities within 
matched pairs have access to primary care clinics and others have access to primary care hospitals, 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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in Botswana this does not appear to represent a significantly different level of access to health 
services. 
 
 Age structure:  Adult HIV prevalence and incidence are correlated with adult age (Central Statistics 
Office 2009).  Age structures are very similar within the study community pairs.  If we use the 
proportion of adults (16-64) who are in the highest risk for HIV infection (25-34) as an indicator of 
age structure, the median difference in this proportion is 2% (range 0-7%).  [Note: we do not have 
age structure data for Gumare, Shakawe, Mandunyane, or Mmadinare, but based on the age 
structure of the other 26 selected communities, do not expect any significant differences in age 
structure within the matched pairs].  
 
 Geographic location as measured by proximity to major urban centers (Hayes, Mosha et al. 1995).  
Geographic locations of communities within pairs, as estimated by average distance to the nearest 
large towns, are quite similar.  For example, across 30 communities, the range of average distances 
to nearby urban centers ranges from 18-380 kilometers.  However, following matching, the median 
difference in distance to an urban center between communities in a matched pair is 20 kilometers 
(range 3-150). 
 
Access to community-specific measures of HIV prevalence [e.g., HIV prevalence measured from 
antenatal care (ANC) clinics] were not available prior to community selection/randomization.  Previous 
successful pair-matched CRTs (Hayes, Mosha et al. 1995) where HIV incidence was the outcome of 
interest have also addressed the problem of absent baseline HIV prevalence estimates by using 
geographic location and other proxies of HIV prevalence as matching criteria.  
 
 
4.3   Eligibility of Community Members The following definitions of the study community will be used 
in the protocol: 
 
 Botswana Citizen:  A Botswana citizen is anyone who can produce proof of Botswana citizenship. 
(Usually this is the Omang number or Omang application receipt).  The Omang number is needed in 
Botswana to access routine government services.   It is anticipated, based on a community survey 
in Mochudi, and the 2011 census (Census 2011), that less than 3% of residents will be non-citizens. 
  
 Spouse of Botswana citizen: A spouse of a Botswana citizen is a person who can produce evidence 
of being married to a Botswana citizen, usually a marriage certificate, and is therefore eligible to 
receive free medical services in Botswana. 
 
 Permanent study community resident:  An individual who reports spending on average >14 
nights/month each month in that community for the past 12 months or an individual who recently 
moved into the community and reports spending on average ≥14 nights each month since arriving. 
   
 Part-time study community resident:  An individual who reports spending 3—13 nights (on average) 
each month in that community for the past 12 months or an individual who recently moved into 
the community and reports spending on average 3-13 nights each month since arriving. 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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 Non-residents:  An individual who reports living outside of the community but is receiving 
treatment in the CP community clinic as well as those individuals with an unknown community of 
residence who are receiving treatment in the CP community clinic. 
  
4.4   Enhancement of services in all study communities 
One of the goals of BCPP is to provide enhancement of HIV prevention, care and treatment services in 
non-intervention (ECC) communities as well as expansion and strengthening of these services in the 
combination prevention communities. This goal is primarily motivated by two factors:   
 
1) A commitment to offering the enhanced care communities tangible benefits from participating 
in this community randomized trial, and 
 
2) The imperative to bring the standard of practice in all study community clinics close to the 
standard of care, so that the BCPP study is assessing the effect of the combination prevention 
interventions on HIV incidence. 
 
For the purposes of BCPP, the term ‘enhanced’ will be used to signify activities done in all study 
communities (including Enhanced Care Communities) for the purposes delineated above, whereas the 
terms ‘strengthened’ and ‘expanded’ will be used to signify activities done in Combination Prevention 
Communities only, as part of the study’s combination prevention intervention package.   
‘Strengthened’ will signify that activities are already part of national policy and practice, whereas 
‘expanded’ will signify that activities are beyond current national policy and practice (for example, 
‘expanded’ antiretroviral therapy in the CPCs).   
 
The following enhancements will be provided in all 30 study communities, including the ECCs: 
a) Baseline and Annual Household Surveys (Evaluation Protocol): As part of the BHS that occurs in all 
30 communities (in both study arms), ~20% of adults are offered home-based HIV testing, point-of-
care CD4 count if treatment-naïve, viral load testing, and referral for HIV care and treatment, 
PMTCT services, MC, and other health services as appropriate (TB screening, for example). HIV-
infected persons who were ART naïve at entry to BHS or who seroconvert between study visits and 
are ART-naive will also have annual point of care CD4 and viral load tests, and these results will be 
shared with participants/clinics respectively.  HTC is also offered to household residents who do 
not wish to take part in the BHS/AHS, either by the BHS study team, the HTC campaign team, or by 
referral to local clinics where HIV testing is available.  
 
b) Clinical care quality assessment and quality improvement: BCPP and/or CDC Botswana will work 
through the Ministry of Health to support clinical quality care assessment and improvement.   
Existing or new Ministry of Health and CDC tools and quality improvement documents will be used 
or expanded in this effort.   
 
c) Clinical data system support:  BCPP will provide technical assistance to the Ministry of Health to 
support improved implementation and utilization of clinical data systems (primarily PIMS2 and 
IPMS) in all 30 study communities.    
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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d) Laboratory support: BCPP will provide technical assistance to Ministry of Health to help 
laboratories supporting clinics in all 30 study communities to perform at a level sufficient to meet 
the standard of care.  Existing or new Ministry of Health and CDC tools and quality improvement 
documents may be used or expanded in this effort. 
 
4.5   Eligibility Criteria for Inclusion in Interventions in CP Communities 
This protocol provides the inclusion and exclusion criteria for access to the services provided as part of 
the Combination Prevention intervention package.  Adults aged 16-64 will be targeted for service 
uptake because recent, nationally representative surveys of HIV prevalence and incidence (BAIS 2008) 
suggest that HIV incidence remains high (>1%) throughout this age group.  
 
For clinical services, only those who are Botswana citizens or spouses of Botswana citizens can receive 
free services from Ministry of Health facilities.  Non-citizen/non-spouse of citizen HIV-infected adults 
identified during testing will receive a referral to the health clinic in their community of residence, but 
will not be eligible for free services from Ministry of Health facilities, and thus will not be eligible for 
strengthened free services in intervention clinics.   
 
Investigators propose that eligibility for interventions in the CPC arm be grouped into three categories 
(a) eligibility for expanded HTC services and (b) eligibility for strengthened linkage-to-MC services, and 
(c) eligibility for expanded treatment and follow-up. 
 
a) Eligibility for Expanded HTC   
All adults >16 who wish to receive HTC services at health facilities, mobile testing units, or door-to-
door programs in combination prevention communities (CPCs), are eligible to receive these HTC 
services.  The rationale for proposing that non-residents of the CPC be able to access expanded HTC 
services is to improve community acceptance of the door-to-door and mobile HTC activities.  
Preliminary discussions with community leaders suggest that restricting access to a service like HTC 
which is being delivered to family homes and neighborhoods would be met with considerable 
resistance and community discontent.   
 
Non-citizens of Botswana will also be provided HTC services in the CPC.  Non-citizen/non-spouse of 
citizen HIV-infected adults identified during testing will receive a referral to the health clinic in their 
community of residence to connect them with available fee-based services including treatment.   
 
b) Eligibility for Strengthened Linkage-to-MC services 
Noncitizens will continue to be eligible for enhanced linkage- to-MC services if they meet other 
eligibility criteria. Under the national MC programs, noncitizens who present directly to the MC tent 
requesting MC will be offered free services. Thus, all adult men 16 years or older who are HIV-negative 
or have unknown HIV status are eligible for strengthened linkage-to-MC services including men who 
decline HIV testing or have indeterminate results.   Under current national guidelines, boys 13-15 years 
old will not be actively mobilized or included in linkage-to-MC though they can continue to receive free 
MC services at national locations if they present with parental permission. 
 
c) Eligibility for Universal Treatment  
Universal treatment will be offered to all HIV-infected adults aged 16-64 who are Botswana citizens or 
spouses of Botswana citizens.   HIV-infected persons referred through the study via BHS/AHS, HTC or 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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routine HIV testing (RHT) as well as existing patients already enrolled in care at the CPC clinics will be 
offered expanded treatment.  The Infectious Disease Care Clinics (IDCC) treat all Botswana citizens and 
spouses of Botswana citizens regardless of the community in which they reside.  Therefore, both 
residents and non-residents of the community will be included. 
 
4.6   Rationale for Exclusion from Interventions in CP Communities    
 
 Rationale Surrounding Need for Botswana Citizenship or for Being Spouse of Botswana Citizen: 
Although the Botswana Government provides free HTC services to non-citizens, free access to 
health services, including ART and PMTCT is restricted to a) persons who can produce valid 
documentation of Botswana citizenship or b) spouses of Botswana citizens. Combination 
prevention interventions will therefore not be available to non-citizens of Botswana unless 
married to a citizen, except in the case of HTC and MC services. The exception for MC will be 
made to bring study goals closer to aligning with WHO goals for protection of communities 
through MC provided to 60% of HIV-uninfected men - regardless of citizenship status - as 
noncitizens living in the community may share the same sexual networks with citizens. 
 
Additionally, men who decline HIV testing may actually be those at greatest risk for HIV 
acquisition and thus could benefit most from MC.  If such men were not offered MC and were 
later found to be positive at end of study they would have represented a missed opportunity 
for prevention. 
 
 Rationale for Age Limits: Persons <16 years of age will be excluded from study participation 
because our intervention is targeting adults, and relevant study outcomes will be measured 
among adults.  In Botswana, adults are considered those aged 16 or older.  For example, all 
persons aged >16 can access medical services, including HTC, without guardian consent. 
Although individuals aged 16-17 can access medical services without guardian permission, 
participation in research still requires guardian permission, because the age of consent for 
research in Botswana is 18.  Therefore, eligible 16-17 year-olds will be asked for assent to 
participate in research activities only after permission has been provided by the guardian. 
 
 
5.0 SAMPLE SIZE AND  SAMPLE SELECTION METHODS  
 
The primary objective for the intervention protocol is to implement and describe uptake of CP 
interventions in CP communities. Combined (BHS and HTC) data for 7 intervention communities was 
used to derive average denominator sizes for the estimates of interest. These community-average 
sample sizes were multiplied by 15 to yield an estimate of the total denominator (see Table 1). For the 
estimate of uptake of HTC, we used the number of participants interviewed to be conservative, 
although estimates of HTC coverage will be extrapolated to persons not interviewed. 
Table 1 presents confidence limits for all of the indicators of uptake of CP interventions for protocol 3, 
using targets presented earlier in the protocol. Sample size calculations were done using a simple 
binomial method to obtain standard errors and then multiplying standard errors by the square root of 
the variance inflation factor (VIF), which is [1+(m-1)*ICC], where m is the average number of members 
of each group (here, participants within community), and ICC is the intraclass correlation coefficient, 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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reflecting the magnitude of the correlation within communities for the outcome measure of interest. 
No published ICCs were available for these outcomes, so we used one small and one large value, based 
on prior publications reporting ICCs for behavioral variables in HIV and STD studies (Zhang et al., 2013 
and Pals et al., 2003). 
 
Table 1. Precision for 95% confidence intervals for uptake of CP interventions in CP communities 
Outcome 
Denominator 
(per community) 
Denominator 
(Total across CP 
communities) 
ICC 
Coverage 
95% 
Confidence 
Interval 
CI 
Width 
HTC 
2469 
37035 
.02 
90% 
87.8, 92.2 
2.2 
 
2469 
37035 
.05 
90% 
86.5, 93.5 
3.5 
PMTCT 
50 
750 
.02 
90% 
87.0, 93.0 
3.0 
 
50 
750 
.05 
90% 
86.0, 94.0 
4.0 
MC 
794 
11910 
.02 
60% 
56.4, 63.6 
3.6 
 
794 
11910 
.05 
60% 
54.4, 65.6 
5.6 
ART 
528 
7920 
.02 
93% 
91.1, 94.9 
1.9 
 
528 
7920 
.05 
93% 
90.0, 96.0 
3.0 
 
Table 1 shows that where sample sizes are large and we expect rates of uptake closer to 100% (HTC 
and ART), precision is excellent. Where sample sizes are small (PMTCT) or rates expected closer to 50% 
(MC), we have less precision for estimates, but confidence interval widths are still less than ±6%. As the 
rate of the outcome variable of interest moves away from 50%, standard errors and confidence 
interval width will decrease. With a larger ICC, the variance inflation factor increases and confidence 
intervals will widen. 
 
6.0 INTERVENTION PROCEDURES  
6.1   Overview of Intervention Strategy 
Interventions described below are intended to: 1) be consistent with new WHO guidelines on 
treatment of HIV infection (World Health Organization, 2015), 2) streamline clinic procedures to 
accommodate expansion of treatment to all PLHIV, and 3) incorporate lessons learned during the first 
year of BCPP.   Targeted strategies will be implemented to meet UNAIDS goals of 90% of PLHIV know 
their status, 90% of PLHIV who know their status are on treatment, and 90% of PLHIV on treatment are 
virally suppressed.  Through reaching the UNAIDS goals, it is anticipated that there will be a reduction 
in HIV incidence in the CP communities as assessed in Protocol 1.  The proposed BCPP interventions 
will demonstrate UTT and introduce a streamlined approach to finding, testing, and starting PLHIV on 
immediate treatment and retaining them on effective treatment over time.  Specific engagement 
activities as well as the specific interventions being deployed are outlined in detail below. 
 
6.2   Stakeholder Involvement, Community Engagement, and Community Mobilization 
To enhance communities’ acceptance and effectiveness of the combination prevention package, local 
government and community stakeholders will be highly engaged.  Program implementers, including 
MOH at central-, district-, and facility-level, and NGOs supporting the MOH’s public health mission in 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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study districts, have been engaged in the planning and continue to be involved in implementing all 
combination prevention interventions. These governing bodies include: 
 
o National Government:  MOH, CDC and Harvard Chan School investigators and program planners 
have presented project plans to (1) the Parliamentary Sub-committee on Health, (2) the 
Parliamentary Sub-committee on HIV/AIDS, and, (3) the House of Chiefs (a body of traditional 
leadership made of representatives of all communities in the country).  
o District Government:  Study communities are distributed across 13 of 29 districts in Botswana.  
Meetings and consultations have been held with the District AIDS Coordinator, District Multi-
Sectoral AIDS Committee, and the District Health Management Teams. 
o Community Government:  At the community level, village political leadership has been 
consulted, including the traditional leadership of Dikgosi and Dikgosana (Chiefs and sub-chiefs), 
the Village Development Committees (VDCs), church leaders, and sporting clubs.  Project plans 
were shared and discussed prior to initial implementation and ongoing support for the project 
is sought.   
 
Investigators meet regularly with members of study Community Advisory Boards (CAB) to discuss 
community perceptions of the project.  Minutes of these meeting are documented and shared with the 
study principals.  Specific issues raised during CAB meetings are addressed as needed.  There are four 
CABs located in the following regions:  South, Central, North, and Northwest.  The CABS have 
representatives from the study communities in that region. 
 
Community mobilization activities are conducted in all communities; however, the scope and duration 
of the activities are greater in the CPCs. Activities focus primarily on increasing uptake of HTC and MC 
so that HIV-infected adults can access treatment and/or PMTCT and HIV-negative adults can access 
MC.  Some of the methods to improve uptake of services include: 
 
o Public announcements from vehicles with loudspeakers (very common in Botswana), 
o Community (kgotla) meetings, civic society activities, schools, and clinics as a platform to 
inform the community. 
o Door-to-door canvassing of the community informing community members of the services that 
are available in the community, location and duration. 
o Specific mobile activities (e.g., location of an HTC caravan near work and sporting locations or 
in residential areas after business hours (e.g., after 5 pm) targeting hard to reach populations 
like men.  
 
6.3 HIV Testing and Counseling (HTC)  
 
a) Target:  90% of PLHIV know their status. 
  
b) Strategy: Based on the first round of HTC in BCPP, the HTC strategy is being modified for years 2 
and 3.  During the first year of HIV testing, approximately 70-% of HIV+ persons in the community 
were identified through concentrated testing efforts lasting 6-8 weeks.  During the 2nd year of the 
study, HTC activities will be provided through continuous availability of services in the community 
and will focus on 1) finding incident cases of HIV infection by retesting persons found to be 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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negative during the 1st year; 2) finding the 25-30% of community members missed by the 1st year of 
testing in BCPP; and 3) identifying HIV+ persons who are new arrivals to the community.  
 
 The activities to fulfill the first objective of finding incident HIV cases include 1) repeating door-to-
door HIV testing during year 2 in all homesteads from year 1; 2) monthly mobile testing at targeted 
community locations; and 3) strengthening routine HIV testing (RHT)   in health facilities with a 
focus on antenatal clinics, outpatient departments and IDCC.  To fulfill the 2nd objective, targeted 
testing activities will be used to find community members missed in the first year of testing in 
BCPP. Based on data collected in year 1 of BCPP, approximately 50% of men and 30% of women are 
missed through home-based testing.  Targeted testing strategies to locate those missing in year 1 
will include workplace testing, home-based testing on holidays and weekends, mobile testing at 
venues frequented by men and large-scale community activities that attract the majority of 
community members. To fulfill the 3rd objective, new arrivals to the community who are HIV+ will 
be found through re-enumeration of households and HIV testing while going door-to-door.  New 
arrivals will also be identified during community mobile testing and large-scale community events 
that offer HIV testing.  The HTC strategy for year 3 of BCPP will be based on findings from year 2 of 
the study, but is likely to focus on targeting populations missed in year 2. 
 
In order to reach the target of the 90% of PLHIV knowing their status, cost-effective community-
based HIV testing strategies are needed to find unidentified HIV-positive persons who are not 
accessing health care facilities, such as young women and men. An understanding of the 
incremental costs between strategies is key to determine the  optimal mix of strategies to 
implement. Therefore, a cost analysis of different HTC models implemented through BCPP will be 
undertaken.  
 
c) Specific HIV Testing and Counseling Services: 
 
1) Home-Based HTC:   HTC counselors will go door-to-door and request verbal consent to: (1) map 
household GPS location, (2) record numbers of persons in each household, their age, and sex by 
interviewing the head of household or, if the head of household is absent, a household member 
18 years of age or older (Household Enumeration Form), and (3) offer HTC services (HTC Intake 
Form).  The following individuals will not be offered HTC: 
 
a. Adults who have documentation of an HIV-positive status  
b. Adults who have documentation of HIV-negative results obtained within the last 3 
months of the HTC encounter. (Documentation of HIV test results are recorded on the 
HTC Intake Form) 
c. Persons <16 years old 
 
If a household member is absent, the team conducting the home-based HTC activities will ask 
about an appropriate time to return to the household (Household Enumeration Form).   Up to 3 
repeat visits will be scheduled. 
 

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2) Mobile HTC:  Mobile HTC caravans and tents will be placed in prominent locations of the 
community [e.g., at kgotlas (community meeting locations), or shopping centers].  Community 
mobilizers will engage the community via door-to-door ‘mobilization’ visits and in high traffic 
areas in the community such as shopping and transport areas and invite residents to get tested 
in the mobile units and tents.  Lay counselors and support staff will be stationed in mobile 
venues consisting of a waiting area, private HTC area and a phlebotomy area.  HTC will be 
offered to all individuals (residents and non-residents, citizens and non-citizens) who are not 
known to be HIV-infected according to national guidelines (i.e., adults who do not have an HIV 
test result card indicating HIV-positive status).  Persons who tested will be asked to keep the 
card with their results safely for any future contact, e.g., during subsequent household visits 
(below). 
 
3) Routine Facility-Based HTC: Routine HTC activities at health facilities will be strengthened by 
training facility-based counselors to offer RHT as part of integrated routine services in 
outpatient, IDCC, and antenatal (ANC) clinics. Facility-based counselors will be encouraged to 
provide testing to all adults receiving health care services at the clinic and to offer testing to all 
friends, family members, relatives, visitors, etc. (so-called non-patients) accompanying the 
patient to the clinic. In addition, the study will assist MOH ANC staff with strengthening of 3rd 
trimester re-testing among pregnant woman (see section 6.6).  Routine HIV testing data will be 
extracted from PIMS2/IPMS to monitor coverage of testing in health facilities. 
 
4)  Targeted Testing:  HTC for groups that are difficult to access through home-based, clinic-based, 
or other routine services will be targeted by providing services where these groups work or 
congregate and by offering HTC services at large, well-attended community events such as 
barbecues, health fairs, concerts, etc. 
 
5) Additional Services for Persons Testing HIV-Positive:  All HIV positive adults not on treatment 
are eligible for ART under current national guidelines so will not need to consent for treatment 
in the UTT intervention.  HTC counselors are trained to integrate treatment preparation, 
adherence and readiness messages into their post-test counseling for HIV-positive persons to 
begin preparing participants for initiating ART at their first clinic visit.  In addition, they will be 
counseled to expect a confirmation test for HIV positive results before initiating ART which will 
be conducted at the IDCC.  All participants of HTC will be tested using the MOH rapid testing 
algorithm along with pre-test and post-test counseling that is recommended in the national 
guidelines. 
 
6) Additional Services for Persons Testing HIV-Negative: The following services will be offered to 
newly identified or known HIV-negative adults:  
- 
Screening of all adults for TB, with a simple screening question, and referral of TB 
suspects to the nearest clinic for TB testing. TB suspects will be prioritized for evaluation 
at the clinic. In Zimbabwe and Zambia, this has been shown to reduce community 
prevalence of infectious TB and was well-accepted by the community (Corbett, 
Bandason et al. 2010) .   
- 
Encourage MC uptake by HIV-negative males through linkage-to-MC services. These 
services also are offered to men with unknown HIV status.   Further details of the 
linkage-to-MC service are provided in Section 6.5 below. 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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- 
HIV-negative pregnant women will be encouraged to enroll in ANC care and be retested   
in their 3rd trimester.  
 
6.4 Linkage to HIV Care and Treatment   
 
a) Targets:  80% of adults identified as newly diagnosed or not currently in care are registered at the local 
study IDCC or are documented in care at another IDCC within 90 days of BCPP interview and 90% 
within 180 days of BCPP interview  
  
b)  Strategy:   To ensure that 90% of persons identified as HIV-infected initiate ART, persons newly 
identified as HIV-infected or PLHIV not connected to care and treatment must be linked to an IDCC.  
Data from the first year of BCPP suggest that about half of PLHIV link to care with very little prompting 
or follow-up.  Another 50%, however, require additional supports.  The linkage intervention package 
for BCPP includes: 1) counseling after diagnosis on the importance of immediate treatment and 
appointments made for PLHIV not already in care; 2) appointment reminders; and 3) tracking and 
tracing of persons who miss appointments at the IDCC.  In addition, to enhance linkage rates, patients 
wishing to receive care/ART outside of their community will be able to link to any MOH IDCC. 
 
c) Specific Activities: 
 
1) Counseling After Diagnosis and Scheduling Appointments at IDCC:  Counselors will be available 
to: (1) provide immediate psychosocial support to help clients cope with their HIV-positive test 
result, (2) counsel participants on the importance of early entry into HIV care or PMTCT services 
and prepare them for treatment initiation and adherence at first clinic visit, and (3) help clients  
establish and achieve plans to enter care by identifying and troubleshooting real and perceived 
barriers to care (Gardner, Metsch et al. 2005, Gardner, Marks et al. 2007, Craw, Gardner et al. 
2008, Gardner, Marks et al. 2009).  Appointments at IDCCs in intervention communities will be 
scheduled as soon as possible for newly diagnosed individuals or PLHIV who are not enrolled in 
care and treatment.  Some PLHIV may prefer to obtain care and treatment services at a clinic 
outside their community for privacy, proximity to job, or other reasons.  For those PLHIV who 
choose to obtain care outside the study community, verification of enrollment in care will be 
obtained from the MOH data systems. 
 
2)  Appointment Reminders: PLHIV will be sent short message service (SMS) reminders about 
their upcoming appointments. 
 
3) Tracking and Tracing:  A record of all patients referred to care by BHS, HTC and RHT will be 
submitted to Site Coordinator at the local IDCC.  The Site Coordinator at the IDCC will access 
names of those referred and will track them to ensure they keep their first appointment.  
Names and contact information of those who don’t keep their appointments will be turned 
over to the community counselor for tracing and case management. The intensified participant 
tracing program includes telephone calls and home visits for persons who missed a scheduled 
appointment up to 180 days after either diagnosis or BCPP interview for known HIV positive 
persons (Participant Tracing Log).  
 
4) Counseling, Appointments and Tracing for PLHIV Identified who are already on ART 

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o Patients who are on ART, enrolled in care at the study IDCC, are not late for an appointment, 
and have a future appointment scheduled will be encouraged to remain adherent to ART and 
appointments.  
o Patients who have initiated ART and are enrolled in care at the IDCC and are late for their next 
appointment or who do not have a future appointment scheduled will be (1) counseled on the 
importance of adherence and appointment keeping, (2) given a new appointment at the clinic, 
and (3) have phone number and residential address information obtained to facilitate follow-up 
(retention tracing of participants already in care and late for their scheduled appointments is 
described in section 6.7 below).   
o Patients who are on ART and not enrolled in care at the study clinic will be counseled to remain 
adherent to ART and in care; they will also be informed of expanded and strengthened services 
available at the study clinic and will be given an appointment to the study clinic. Follow-up for 
these patients will be limited to only an SMS reminder for their appointment. Verification of the 
patients’ enrollment at another clinic outside the study community and ART status will be 
obtained from MOH data systems. 
 
5) Retrospective Tracking and Tracing of PLHIV who Did Not Link to Care: Given the change in the 
2016 Botswana national treatment guidelines, HIV-positive participants not on ART who did not 
link to care from Round 1 (October 2013 – February 2016) will be retrospectively contacted by 
the Ministry of Health clinic staff or a community counselor and informed that all HIV-positive 
persons are now eligible for ART, regardless of CD4 count or condition. Participants from Round 
1 and Round 2 (June 2016 – present) who previously did not give permission for follow-up may 
also be contacted, as the new guidelines recommend tracking all HIV-posiitive persons 
identified to care and treatment sites. Specifically,  
o Contact with the participant will be attempted by a Ministry of Health clinic staff 
member or a community counselor to inform the participant that the national 
guidelines have changed and all persons that are HIV-positive are now eligible for ART. 
They will also be informed that it is critical for their health and the health of their 
partners and children to get on ART as early as possible, and that the clinic offers 
services to help community members get into care and on treatment. Staff will use the 
updated talking points from the Linkage to Care SOP – revised (see Appendix XX, Section 
3.8).  
o Participants will be given an appointment at the clinic with a health care provider and 
will be encouraged to keep it.   
o If there is no current phone number for the participant, a home visit will be conducted 
by a clinic staff member or a community counselor. Up to 3 attempts to contact the 
participant will be made through alternating phone and home visits. 
o Participants from Round 1 who have not linked to care will be contacted beyond the 
follow-up period specified in the protocol (e.g., 180 days) in order to ensure the new 
guidelines are being implemented with all participants. Paricipants from Round 2 who 
were enrolled during the time between the introduction of the new guidelines and field 
implementation (November 2016) may also be followed beyond the 180 day window. 
 
A note to file will be documented at each of the 15 intervention sites noting the procedural 
changes and follow-up provided to those individuals who previously did not link and declined 
follow-up. 

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6.5 Male Circumcision   
 
a) Target:  60% of HIV-negative 16-49-year-old males are circumcised   
 
b) Strategy:   BCPP’s SMC intervention in the second year will be streamlined from the full-service 
campaign model used in the first year to a program that mobilizes and links interested men to existing 
services in nearby locations.  MC services are expected to be provided in five of the 15 CPC sites using 
PEPFAR programmatic support.  In all other districts, nearby services funded by Global Fund or MOH 
will be used, though distances to these services from CPCs is likely to vary.  All CPCs are expected to 
have at least one service option available.  Therefore, BCPP funding will not be used to support direct 
service delivery but to mobilize and link men in BCPP communities to existing MC services.  Modified 
SMC services are expected to begin when the second round of BCPP interventions are implemented, 
approximately February 2016.    
 
c) Specific Activities:   
 
1) Mobilization:  In the first round of BCPP activities, SMC depended heavily on community-based 
mobilizers and referrals from the BCPP HTC Campaign and BHS to generate client demand.  A basic 
level of this ongoing mobilization will continue.  HTC and BHS will refer men to community mobilizers 
by passing contact information with consent; the mobilizers will then follow up with these men and 
link them to nearby services.   Mobilizers will also work directly with communities to mobilize men for 
services.  Incentives for mobilizers through a performance-based contract may be utilized to improve 
mobilization efforts.  In addition to encouraging potential clients to obtain MC, mobilizers will 
disseminate service information about linkage sites, transport schedules, and assist with coordinating 
transportation.  
2) Coordination: A small number of full-time coordinators will oversee all the CPCs. Their 
responsibilities will include identifying and liaising with locally-available SMC services to confirm their 
schedules and notify them of expected clientele numbers on transportation days; supervising 
mobilizers; coordinating transportation; and follow-up with service sites to collect the necessary data. 
A senior BCPP staff member will keep the MOH SMC coordinator up to date on these activities.  
3) Transportation: In each CPC, transportation will be offered at least monthly to nearby SMC services, 
on days of the week determined to be optimal. Transportation will also be provided for day-2 and day-
7 follow-up visits, and will remain available for adverse event emergencies.  
4) Data collection:  Individual-level data will not be collected at SMC service provision sites by BCPP, 
but aggregate data will be requested from these sites.  Specifically, at these sites, the coordinator will 
make attempts at least quarterly via physical visits and register reviews to ascertain how many HIV-
negative/unknown men 16-49 years of age from the CPC were served.  The coordinator will also collect 
aggregate data from the transfer logs to gather numbers of men transported to SMC services.  Finally, 
the coordinator will collect aggregate data on number of men referred and mobilized from demand 
creation records completed by HTS and BHS staff as well as SMC mobilizers (Male Circumcision 
Tracking Sheet).   
  

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6.6 Identification, Linkage, and Treatment of HIV+ Pregnant Women  
 
a) Target:  90% of women initiated on indefinite ART (Option B+) during pregnancy remain in care and 
on treatment post-delivery.   
 
b) Strategy:  Strengthening PMTCT activities is important to ensure that HIV-infected pregnant women 
are identified, linked to care, and remain on ART post-delivery.  Currently, Option B+ is the national 
standard of prevention of mother-to-child transmission in Botswana.  Therefore, BCPP intervention 
and control communities will provide Option B+ interventions for all HIV+ pregnant women.  The BCPP 
program for pregnant women will focus on strengthening three activities in PMTCT settings in 
intervention communities: 1) strengthening of third trimester retesting within the ANC; 2) linkage to 
HIV treatment for all HIV-infected pregnant and post-partum women; and 3) retention on ART post-
delivery.  
 
c) Specific Activities: 
 
1) Strengthening third trimester retesting:  BCPP staff work with MOH clinic staff to strengthen 
capacity to identify women who are due for third trimester retesting. MOH clinic staff will use client 
contact information from the ANC register to make phone calls and schedule appointments with all 
HIV-negative pregnant women who have not completed third trimester retesting. MOH clinic staff will 
keep a record of clients called for third trimester retesting. Third trimester retesting will be monitored 
through PIMS/IPMS by the IDCC clinic. 
2) Linkage and Retention for HIV-infected Women:   Ensuring HIV-positive pregnant women receive 
ART and remain on ART following delivery is a key priority. All HIV positive pregnant women identified 
through the BHS and HTC campaigns are referred to the IDCC for HIV care and treatment.  In addition, 
HIV+ post-partum women are referred to the IDCC to continue ART indefinitely (Option B+). Those who 
do not keep IDCC appointments will be tracked by the IDCC Site Coordinator and followed by 
community counselors to ensure they link or re-link to the IDCC post-delivery. Similarly, retention 
activities will track women who have begun Option B+ to ensure that they stay in care and on ART 
indefinitely.  Those who are 14 or more days late for an appointment or pharmacy pick up will be 
contacted by MOH clinic staff and/or the IDCC Site Coordinator (Linkage, Retention and Adherence 
Tracing Verbal Consent Script) and community counselors will provide supportive counseling and new 
appointments through phone and home visits (Participant Tracing Log) as outlined in section 6.4. 
6.7 HIV Care and Treatment  
 
a) Targets:  
1) 93% of PLHIV aged 16–64 who know their status are receiving ART  
2) 95% of PLHIV aged 16-64 who are on ART are virally suppressed 
 
b) Strategy: Prior versions of BCPP Protocol 3 introduced anti-retroviral treatment outside Botswana 
national guidelines (CD4 < 350, WHO stage III or IV).  With the revised WHO recommendations to treat 
all HIV-infected persons, Version 4.0 of Protocol 3 proposes to start all HIV+ adults in CPCs on 
immediate treatment and retain them on treatment (UTT).  To demonstrate methods for 

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implementation of UTT for later adoption by the Botswana MOH, BCPP will embed UTT treatment 
interventions within the national ART program (MASA). The package of interventions described below 
are designed to 1) reduce barriers to ART initiation by simplifying procedures and making services 
easily available 2) increase capacity of IDCCs to support aggressive ART scale-up, and 3) enhance the 
use of both individual and clinic-level data to monitor uptake of HIV care and treatment. 
 
c) Specific HIV Care and Treatment Activities: 
 
1) Confirmation of HIV status: All HIV+ referrals into the clinic as well as existing pre-ART patients will be 
confirmed with an HIV test administered by IDCC staff as recommended by WHO before initiating ART 
(World Health Organization, July 2015). 
 
2) Same day ART initiation: Patients who are not on ART will be offered initiation (or re-initiation) of 
ART on the day of their first clinic visit if blood draws are possible that day.  Adherence counseling, 
screening for opportunistic infections, and blood draw for baseline pre-ART safety labs will occur on 
the day of ART initiation.  Patients who decline ART initiation (or re-initiation) will be given a 1 month 
follow-up appointment for re-consideration of ART initiation.   
 
3) Frequency of clinic follow-up visits:  Patients on ART who are stable (e.g., virally suppressed, no 
opportunistic infections, keeping appointments, etc.) will be offered a reduced frequency of scheduled 
visits as compared to the current MASA standards.  Patients will be followed according to national 
program standards for the first year.  For stable patients on ART for longer than 12 months, visits with 
a clinician every 6 months will be implemented. IDCC patients already on ART will follow the 
streamlined schedule according to their time on ART. 
 
4) Frequency of visits for laboratory testing: Routine laboratory testing will be offered to patients 
according to the national guidelines with the exception of CD4 counts which will only be measured at 
baseline, after 12 months on ART, and at the discretion of the clinician.  Also, wherever possible, 
patients will have their blood drawn at the time of routine clinic visits rather than on separate days to 
further reduce the frequency of clinic visits and clinic congestion.  All laboratory results will be 
reviewed by the clinic staff within 4 weeks of blood draws, and patients will be contacted by clinic staff 
for review of any abnormal lab results. 
 
5) Frequency of dispensing visits: Patients who are stable after 12 months of ART (e.g., virally 
suppressed, no opportunistic infections, keeping appointments, etc.) will be dispensed up to 3 months 
of ARVs if there is adequate stock in the clinic at the time of dispensing rather than being required to 
return after only 1 month for a dispensing visit. The pharmacy will update a patient’s next refill 
appointment in PIMS2/IPMS if more than one month is dispensed.  Stable patients will have monthly, 
bi-monthly or quarterly refill appointments, which may coincide with the semi-annual clinician visits. 
 
6) Retention Intervention:  Resources will be available in CP communities to ensure that all PLHIV are 
retained in care. The retention intervention will focus efforts on those who have missed treatment 
appointments and/or pharmacy pick-ups.  Persons eligible for retention tracing will be identified by the 
IDCC staff using their electronic data system.  
 

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Existing IDCC patients who have missed appointments or pharmacy pick-ups are contacted by MOH 
clinic staff by phone or home visits and are asked if they agree to have a community counselor contact 
them to provide retention support activities.  Patients who do not consent to retention support 
intervention activities are reminded about the importance of staying in care/linking back into care, and 
thanked for their time (Linkage, Retention and Adherence Tracing Verbal Consent Script; Retention 
Tracing Contact Log).  
 
Patients who consent to intervention activities receive retention support services by clinic staff and 
community counselors including SMS reminders of appointments, rescheduling of missed 
appointments, and tracing and supportive counseling through home visits and telephone calls for 
defaulters (>14 days late for appointment or pharmacy pick-up) and Lost to Follow Up (LTFU; > 90 days 
late for an appointment). Clinic data systems are monitored to determine if these patients have 
relinked to the IDCC (Retention Tracking Log, Participant Tracing Form).  
 
 
7)  Adherence Intervention:  IDCCs typically use self-reports, pill counts, pharmacy refill data and viral 
loads to monitor adherence. These adherence monitoring strategies are promoted in all study sites. All 
PLHIV on ART in CPCs are offered an increased level of adherence counseling and support above and 
beyond what is routinely offered within the setting of government clinics.  Eligible persons who would 
benefit from increased adherence support are identified by the clinic staff. 
 
Eligible patients are contacted by MOH clinic staff by phone or home visit (Retention and Adherence 
Outreach Script and are asked if they agree to have a community counselor contact them to provide 
adherence support activities (Linkage, Retention and Adherence Tracing Verbal Consent Script).  
Patients who do not consent to adherence support intervention activities are reminded about the 
importance of taking ART as prescribed, and thanked for their time.   
 
Patients who consent to intervention activities (Adherence Intervention Verbal Consent/Assent Script) 
receive adherence intervention services including an assessment (Adherence Assessment Tool), 
assignment of case manager, and additional counseling to assess and resolve individual adherence 
challenges. In addition, the following services may also be delivered depending upon the person’s 
circumstances and assessment: referral to social worker; SMS reminders; home visits; pill box issuance; 
depression screening; support with HIV disclosure; alcohol assessment; treatment buddy/mopati; VL 
repeat; assignment of earlier appointment; and change in ART regimen (for those in whom side 
effects/medication acceptability might be mitigated through substitution). All adherence interventions 
will be documented as will the outcome of the efforts, on the Adherence Intervention Tracing Log.   
 
Patient CARE in Other Study Clinics or Non-Study Clinics  
 
Finding solutions so that as many BCPP patients  as possible can receive expanded ART initiation is 
important for reaching ART saturation in CP communities, however the study is constrained and cannot 
easily perform study activities or install study staff at sites which are not CP community clinics.  As a 
solution, the following options will be offered to patients, if during counseling it is determined that 
they face challenges to participation in study activities at the IDCC in their own community: 
 
1) BCPP activities at any CP community clinic:  Initiation and receipt of ART will be allowed at any 
CP community clinic at which a participant would be able to receive services.  Note that the 

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study will not be able to provide transport or any additional compensation for these individuals.  
Follow-up data from PIMS2 or IPMS will be obtained on these individuals for study purposes 
from the CPC clinic the participant chooses.   
 
2)  ART initiation activities at own community clinic, followed by transfer to any MOH clinic: 
Services including ART initiation will be provided at the participant’s own CPC, followed by 
facilitated transfer to any MOH HIV care and treatment facility (including those not in study 
communities) for continued ART.  Follow-up data on these individuals will be obtained from 
routine medical information sources such as PIMS2 or the national HIV data warehouse. 
 
Identifying Patients for UTT 
To find all eligible PLHIV not currently on ART and initiate them on treatment, BCPP priorities will 
include approaching the Expanded Treatment Cohort  (described in BCPP Protocol 3 version 3.0) in 
early 2016 
to offer ART initiation for those not on ART.  Another strategy to identify eligible PLHIV not currently on 
ART will include data mining of the MOH electronic patient systems to seek PLHIV categorized as “pre-
ART” to approach them about immediate ART initiation (Script for Outreach Pre-ART Clinic Patients).  
These two mechanisms in combination with expanded HTC activities outlined earlier will yield the 
scale-up of ART initiation necessary to meet both treatment and viral suppression targets. 
 
7.0 LABORATORY METHODS 
Detailed laboratory procedures are described in Standard Operating Procedures (SOPs) that are 
maintained at each laboratory supporting the study.  The BCPP Laboratory Manual provides an 
overview of routine testing that is conducted at Ministry of Health laboratories and more detailed 
study specific procedures for testing conducted at CDC, Harvard Chan School, BHP laboratories.  In 
addition, all study staff has received a Field Operations Procedures Manual which serves as a 
procedural guide during actual specimen and data collection.   
 
7.1 Overview of Laboratory Methods 
An overview of the types of laboratory tests, sample types, and the location of the testing is provided 
below.  The intervention component of the project uses the following laboratories and locations:   
1. BHHRL: MOH regional HIV Reference Lab (Gaborone). BHHRL is a hybrid institution with 
management shared by Harvard and MOH. 
2. NHHRL: MOH regional HIV Reference Lab (Francistown)  
3. MOH District and primary Labs (Botswana-multi-sites) 
4. MOH clinics in CPC communities 
5. Field sites: households and community venues conducting surveys and HTC campaigns 
6. CDC: International Laboratory Branch at Centers for Disease Control and Prevention (Atlanta) 
and CDC Laboratories (Gaborone and Francistown) 
7. BHP (Botswana Harvard Partnership Laboratory) 
8. Harvard T. H. Chan School of Public Health (Boston) 
 
A minimum laboratory enhancement package has been implemented in laboratories supporting study 
sites.  Each study-associated laboratory adheres to site and study specific SOPs for proper processing, 
labelling, transport, testing and storage of specimens as outlined in the BCPP Laboratory Manual.  The 
laboratory study team provides guidance and technical support to the laboratories to implement and 

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maintain a quality management system which includes continuous quality improvement, adherence to 
biosafety, enrollment in EQA programs, review and maintenance of standard operating procedures for 
laboratory testing, timely procurement and forecasting reagent and supply needs, and documentation 
of training for all laboratory personnel. Adherence to these standards is routinely monitored by the 
laboratory study team. 
 
7.2 Training of Laboratory Personnel 
All laboratory personnel participate in study-specific training prior to study initiation.  Training includes 
an overview of the BCPP study design and study-specific laboratory methodologies (with assessment 
for competency) in addition to Research Ethics and good clinical laboratory practices including QA/QC 
(quality assurance/quality control) and laboratory record keeping procedures. Study staff responsible 
for providing HTC complete the required training curriculum recognized by the Ministry of Health.  
Study staff members who collect blood samples and conduct laboratory analyses receive training in 
universal precautions, sample collection, and testing of study samples.  Additional refresher trainings 
are scheduled during the study to ensure consistency and address training needs as they arise. 
 
7.3 Specimen Collection, Transport, and Processing 
Specimens are collected from participants at study field sites and samples transported to designated 
laboratories for processing, testing, and storage.  Testing may also occur at study field sites.  
 
Sample Types and Sources 
a) Capillary blood samples:  Finger prick samples are collected in a microtube using a blade lancet by 
trained staff at study field sites according to BCPP finger prick SOP and used for the HIV rapid tests.   
b) Venous blood samples:  Several types of venous blood draws occur at the IDCC during routine 
management of patients, and will be done following MOH procedures for phlebotomy, (including 
appropriate blood volumes and processing).  At the IDCC, venous blood samples will be collected 
for drug resistance testing per national guidelines. 
 
7.4 Laboratory testing for HTC campaigns (returned to participant and/or participant file with 
exception of viral load test) 
a) HIV Diagnostic Testing: HIV diagnostic testing will be conducted in the study communities and 
clinics per national HIV testing guidelines using Botswana government–approved  serial rapid tests 
as outlined in the 2016 testing algorithm in the national treatment guidelines.    Other testing 
algorithms may be substituted if in alignment with national guidelines.  Verification will be 
conducted on all newly diagnosed and known HIV-positive persons before initiating ART according 
to WHO recommendations (World Health Organization, July 2015). All HIV tests will be conducted 
according to the manufacturer’s guidelines and BCPP SOPs. If results of the initial  serial rapid tests 
are discordant, then per national guidelines two rapid tests will again be performed in parallel.  If 
the second pair of tests is discordant, the participant will be referred to the clinic for re-testing in 2-
4 weeks with a referral recommending ELISA testing.  A 3 ml venous blood specimen will be taken 
at the visit and sent to a reference laboratory for further testing using ELISA (Murex HIV 1.2.0 test, 
Genetic Systems HIV 1.2 plus O, BioRad HIV-1/HIV-2 plus O EIA,) and/or Western blot). The results 
from the EIA and/or Western Blot will supersede the discordant and/or indeterminate results 
obtained in the field. The IDCC Site Coordinator reviews the HTC register at the clinic in PIMS2 or 
IPMS to determine if HTC campaign participants with indeterminate results received confirmatory 

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testing.  HTC participants with indeterminate rapid test results, and who do not have a 
documented retest at the clinic are referred to a community counselor for tracing and follow-up 
services. 
 
7.5    Laboratory Testing for IDCC patients 
Clinical laboratory testing is performed in MOH labs in accordance with the National Guidelines. 
Testing procedures follow approved standard operating procedures for each laboratory where testing 
is conducted.   
 
a)  Hematology and Clinical Chemistry 
Basic blood work is used to assess participant health status for initiation and monitoring ARV treatment 
in HIV-infected individuals; however, ART initiation will occur before all lab results are available. The 
following tests may be conducted per MOH guidelines: 
 
 Hematology: Full Blood Count (FBC) to include hemoglobin, hematocrit, red blood cell count 
(RBC), mean corpuscular volume (MCV), white blood cell count (WBC), differential WBC, 
absolute neutrophil count (ANC), and platelets.  
 Clinical Chemistry:   
o Liver Function Tests (LFT): Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase. 
o Glucose (fasting or non-fasting) 
o Electrolytes: sodium and chloride 
o Renal Function Tests (RFT):  Urea and Creatinine: An estimated creatinine clearance  
o CrCl in cc/minute can be estimated from formulas using patient sex, age, weight, and serum 
creatinine (in um/L):           
  
 
Males: 1.22 x [(140 - age in yrs) x wt (kg)]/ [serum Cr] 
                  
 
  
Females: 1.037 x [(140 – age in yrs) x wt (kg)]/[serum Cr] 
 
b)  Syphilis testing (RPR and VDRL): As per Botswana guidelines, non-treponemal tests for syphilis 
(rapid plasma reagin or Venereal Disease Research Laboratory tests) will be performed according to 
the manufacturer’s instructions.  
 
c)  CD4:  Point of care and flow-based CD4 methods are used dependent upon availability of CD4 
instruments.  Testing follows manufacturer’s instructions and national guidelines for use.  
 
d) HIV-1 RNA Viral Load: HIV-1 plasma RNA viral load is quantified for monitoring of ART-naïve HIV-
infected individuals and monitoring of viral suppression in HIV-infected individuals receiving ART (at 3 
and 6 months after ART initiation and every 6 month thereafter – according to current national ART 
guidelines or per Adherence Intervention Procedures).  
e) HIV drug resistance testing: Drug resistance testing is offered per national guidelines and under 
circumstances described in section 6.11.  
 
f) Pap smear:  Pap smears are performed and findings managed according to national guidelines.  
 
g) Pregnancy Testing: If pregnancy is suspected but not confirmed by LMP (last menstrual period) or 
exam, a urine pregnancy test is performed for confirmation of pregnancy as per MOH procedure.   

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7.6 Quality Assurance 
Standard operating procedures (SOPs) are used for all tests as well as quality assurance/quality control 
(QA/QC) procedures.  Laboratory staff conducting testing participate in a proficiency testing and 5% of 
all tests (or as indicated by laboratory specific SOP) are subjected to internal quality control processes.  
The QA/QC plan includes periodic monthly reviews of EQA performance, collaboration with the CDC 
laboratories, enrollment in appropriate EQA schemes, and inter-laboratory comparisons.  External 
quality assurance and proficiency testing programs includes: CD4 count, HIV-1 RNA load, Hematology 
(FBC), and clinical chemistry analytes. Laboratories are monitored throughout the study by the study 
team and external monitors as requested by the study sponsor.  QA for HTC conducted in the 
communities and through RHT in the clinics include weekly QC exercises for counselors in the field, 
participation in proficiency testing programs, monitoring and site visits from lab personnel, and bi-
weekly monitoring of the concordance rates of HIV serial tests conducted in the field. A small sample of 
HIV-positive tests  may be retested in the lab for QA purposes. 
 
7.7 Biosafety and Waste Management 
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 are 
employed by all personnel in the drawing of blood and shipping and handling of all specimens for this 
study, as currently recommended by the United States Centers for Disease Control and Prevention.  All 
infectious specimens are transported in accordance with the IATA guidelines using designated courier 
services. 
 
7.8 Specimen Storage and Shipment 
The IDCC Site Coordinator coordinates shipment of specimens as required.  Selected samples may be 
transferred to the CDC (Atlanta) or Harvard Chan School (Boston) laboratories for external quality 
assurance, viral load, and drug resistance/level testing.  Specimens are stored until all protocol-related 
and quality assurance testing have been completed. 
 
8.0 DATA SYSTEMS AND MANAGEMENT 
 
The overall system to capture data, record outcomes and analyze results is an integration of multiple 
data collection sources for all BCPP interventions into a single research data base or data warehouse. 
Each BCPP activity has underlying systems of data capture and management which serve as the 
“system of record” containing the source records for all study data captured within the scope of that 
activity.  A variety of data capture methodologies are used across the BCPP activities including online 
reference data retrieval (e.g., community maps), paperless point of service/survey capture, and paper 
and electronic chart/registry abstraction. Process, study participant status, and calculated data are also 
generated by the data systems of the BCPP activities and exchanged between systems and stored in 
the research database.  
 
Each system must also interface with other activity data systems to exchange data as required to 
successfully implement the study. This includes maintaining participant registries, referrals, and key 
eligibility and status data, as well as underlying denominators within study arms and components.   In 

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this section, we provide an overview of the data management for BCPP including data capture, data 
flow, security, confidentiality, access and quality.  
 
8.1 Data collection, Capture and Flow 
HTC data forms (Household Enumeration Form, HTC Intake Form) are collected with the OpenDataKit 
(ODK) software using handheld tablets running the Android operating system. HTC counselors are 
trained in the use of these handheld tablets for electronic data entry at the point of HTC, which 
includes door-to-door home visits and mobile HTC sites.  
 
Community counselors also record their tracing activities for linkage and retention on the Participant 
Tracing Log using these handheld mobile devices.  
 
HTC and Linkage to Care forms are synced to the clinic-level study database at least daily.  Completed 
forms are deleted from the tablets following the sync.  
 
Clinic Site Coordinators manage screening, adherence and retention activities using both the hand-held 
data devices and OpenClinica.  
 
The MOH has an electronic data system known as the Patient Information Management System 2 or 
PIMS2. PIMS2 is a SQL-based, client-server application which runs on a local clinic network and has 
been implemented in BCPP community clinics. PIMS2 captures data for a variety of programs, 
including: facility-based routine HTC, MC, ANC, maternity, and post-natal care.  HIV care and treatment 
data are regularly extracted from PIMS into the clinic-level study database via a secured Virtual LAN 
(VLAN) connection between the local clinic network on which PIMS2 operates and the BCPP network. 
 
Some larger BCPP community clinics have migrated to a web-based system to record patient-level data 
which runs on the Botswana Government’s data network. This Integrated Patient Management System 
or IPMS captures program data that are similar to PIMS and includes an integrated laboratory 
information system. IPMS data will be regularly extracted from the IPMS central data repository onto 
the BCPP central data server. 
 
The MOH strongly encourages the use of PIMS or IPMS where available.  Therefore, nurse prescribers, 
physicians, midwives, lay counselors and other clinic staff within the 30 BCPP communities record 
patient registration and appointments, and enter consultation, laboratory and pharmacy data into 
PIMS or IPMS. Appendix P1 outlines the selected data elements transferred from MOH systems to the 
BCPP central data server.  
 
MC staff members responsible for the coordinating linkage of eligible men to MC will distill aggregate 
data on numbers of total and eligible men transported to MC from the transportation logs and will also 
engage with service delivery providers to obtain numbers of eligible men served on non-transport 
days.  This data will be entered into an electronic or paper-based custom data collection form monthly.  
 
On a daily basis during the BHS/AHS surveys in all 30 communities, BHS/AHS referral and locator data 
files are transferred from BHP’s electronic data capture system to the clinic via secure copy on the 
BCPP network in the clinic and processed into the clinic-level study database. At CPCs, BHS referrals are 
combined with HTC referrals. In all community clinics, referral data is used to produce operational 

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reports for use in the clinic. In CPCs, an encrypted flash drive is used to retrieve updated referral files 
from the clinic’s study database and to transfer updated data from the MC client tracking tool to the 
clinic-level study database. 
 
On a nightly basis, data from all clinic-level study databases is copied to the BCPP central data server in 
Gaborone over the secure BCPP VPN.  As needed, the BCPP senior data manager in Gaborone will work 
with IDCC Site Coordinators or other clinic level staff to reconcile data issues. 
   
The Research Database is designed in PostgreSQL and housed on the BCPP central data server at the 
CDC-Botswana Gaborone office. It is populated with data pulled up from all the clinic level study 
databases as well as data from IPMS, PIMS, CD4 data from PIMAs, and baseline, annual and end of 
study survey data transferred from BHP’s EDC via secure copy.   
 
The diagram in Figure 1 offers a schematic representation of the data flows from all sources described 
above to the central BCPP data warehouse for the intervention communities (CPCs).  For all PLHIV in 
the study communities we obtain clinical data from the existing MOH’s electronic patient data systems 
(PIMS or IPMS). 
 
 

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Harvard Macbook
Clinic Level Study Database
SQL Server
Open SSH
Central Data Server
Research DB
OpenClinica
Clinic
BHS
CDC Botswana
External Services
External Services
HTC/
TVCT
Study status,
 retention and 
adherence data 
captured by SSC
Alere Data Point
PIMA Data
PIMAs
PIMS II Computer
MOH
IPMS
Central Data Repository
 
Figure 1: Data Flow diagram for CPCs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 Data Security 
The CDC Data Manager is responsible the security of BCPP data collected for the Intervention protocol. 
The Botswana MOH is responsible for the security of data collected through routine MOH systems, 
including PIMS and IPMS. All BCPP-specific systems supporting clinic data reside within the clinic 
network where a firewall, encryption keys, user logins, and physical security and access, and routine 
data back-up measures have been put into place to ensure data security and integrity.  
 
Laptops and tablets used for data capture and processing are encrypted and require user logins to 
prevent unauthorized users from accessing data. Laptops, tablets and all study related paper-based 
forms and logs are stored in locked cabinets or locked trunks when not in active use. The clinic laptops 
which serve as the local clinic-level study databases are locked in secure cabinets. Daily data transfers 
from tablets and the MC Epi Info system minimize the risk of data loss should the device be lost or 
corrupted.  Clinic-level study databases are backed up on to the local encrypted hard drive and the 
backup files are transferred to the BCPP central data server in Gaborone using secure copy. The 

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backups from all of the clinic-level study databases and the central data server will be backed up to 
tape daily. The BCPP central data server at the CDC-Botswana Gaborone office is located in a locked, 
climate controlled server room managed by CDC IT staff in compliance with CDC IT policies.  
 
A virtual private network (VPN) connects each clinic-level study database to the BCPP data center. The 
VPN provides a secure network over which data can be transmitted and through which data managers 
and IT staff can access clinic systems. VPN accounts are provided to study staff as needed and CDC DM 
lead approval is required for access to study data systems managed by CDC. Within the BCPP network, 
access to devices, databases, and directories are managed based on user roles. Data in transit over the 
BCPP network is encrypted, password protected and transmitted through secure connections using 
secure-shell (SSH) protocols; encrypted, password protected memory sticks are used for data transfer 
when direct network connections are not available.  
 
The Botswana MOH is responsible for the security of PIMS and IPMS data. PIMS resides on secure local 
networks at each clinic and IPMS runs on the secure Government Data Network (GDN). Both the local 
network and the GDN use PIMS are regularly backed up via secure memory sticks. IPMS backups are 
managed through the IPMS central data store in compliance with Botswana MOH IT policies. CDC DM 
and IT will work with MOH counterparts to strengthen data security policies and practices. 
 
8.3 Data quality 
ODK Surveys on the tablets and EpiInfo have built-in validation tools to minimize data entry errors. 
These include range restrictions for numeric data, pre-defined values (code sets) for categorical data, 
and logic checks. Valid responses are required for key fields to ensure completeness and skip patterns 
will be used to prevent extraneous data entry and encourage proper form completion. Error messages 
and caution notices will be used to alert staff when they enter faulty data so that they are aware and 
can correct the problem.   
 
HTC and linkage to care staff receive training on both the contents of the tools and use of the tablets 
and ODK software.  Supervisors review the data forms for completeness and supervise corrections 
prior to synching of the tablets. SMC staff will receive training on proper completion of MOH tools and 
use of the Epi Info client tracker. Data managers will monitor system performance throughout 
implementation.  
 
8.4 Confidentiality of data 
CDC DM is responsible for protecting the privacy of all study participants and ensuring the proper 
handling of all personal health information and contact information collected for BCPP under Protocol 
3.  All components of the distributed data systems implement both electronic and physical security 
procedures for “data in use” within secure networks and devices.  Encryption is implemented to render 
electronically stored subject identity and personal health information unusable, unreadable, or 
indecipherable to unauthorized individuals for “data in motion” and “data at rest”. Encrypted 
personally identifiable information (PII) will be transmitted within the BCPP system by way of the 
secured VPN only. 
  
PII, including name, national identity card number (Omang) and locator data (address, phone 
numbers), is collected as part of HTC to facilitate referral and linkage of clients with services (e.g. IDCC, 
ANC, SMC).  BHS collects similar information and includes necessary PII in the transfer of referral and 

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locator data to the clinic.  PII is collected as a part of patient registration in both PIMS and IPMS as 
required by MOH to ensure patients are eligible to receive services.   
 
PII maintained in the clinic study databases are not transferred to the central database on the BCPP 
server; Omang is encrypted with a one-way hash prior to transfer to the BCPP server for the purpose of 
linking data across data systems. Where there is consent from the client to access medical records or a 
waiver of consent to extract identified data from the clinic systems (PIMS and IPMS), clinic data can be 
linked with BHS referrals and HTC data using the hashed Omang.  
 
All study staff are trained on data confidentiality. Site staff access to PII and locator data is limited to 
health care providing staff which are required to reliably identify a participant, and staff engaged in 
linking patients consenting for contact with services. A minimal number of staff have access to the 
study databases where PII is stored and the operational reports which present PII to site staff; DM can 
access these data when required for system maintenance or to provide user support.  
 
9.0 DATA AND ANALYSIS PLANS 
The primary objective of the Intervention Protocol is to implement and describe uptake of 
Combination Prevention interventions in CPCs.  Secondary objectives will describe retention in the 
clinical cascade of care from HIV diagnosis to viral suppression among all HIV-infected persons.  The 
key indicators for analyzing results of BCPP objectives are outlined in Table 2.   
 
. 
 
 

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Table 2.  BCPP Key Indicators 
Indicator Name 
 
Coverage vs. 
BCPP 
Performance 
Numerator 
Denominator 
1. % of HIV+ Adults* 
who Know their 
Status  
Coverage  
 
# of HIV+ Adults estimated to know 
their HIV status 
# of Adults estimated to 
be HIV+ 
2. % of HIV+ Adults in 
Care 
Coverage 
# of HIV+ Adults in Care 
# of HIV+ Adults 
estimated to know their 
HIV status 
3. % of HIV+ Adults on 
ART 
Coverage  
 
#of HIV+ Adults on ART 
# of HIV+ Adults 
estimated to know their 
HIV status 
4. % of HIV+ Adults with 
Viral Suppression 
Coverage  
 
# of HIV+ Adults with 
VL<1000Copies/ML 
#of HIV+ Adults on ART 
5. % of HIV+ Adults 
Identified through 
BCPP who know their 
status  
BCPP 
Performance 
# of HIV+ Adults Identified (new & 
known) through BCPP who know their 
status 
# of Adults estimated to 
be HIV+ 
6. % of PLHIV Newly 
Diagnosed through 
BCPP 
BCPP 
Performance 
# of Adults Identified as Newly 
Diagnosed HIV+ through BCPP 
# of HIV+ Adults 
Identified (new & known) 
through BCPP who know 
their status  
7. % of  PLHIV  Linked to 
Care 
BCPP 
Performance 
# of HIV+ Adults Identified as Newly 
Diagnosed or Not Currently in Care at 
IDCC who were seen at IDCC within 90 
and 180 days of Interview 
# HIV+ Adults Identified 
as Newly Diagnosed or 
Currently Not in Care at 
IDCC 
8. % of PLHIV Initiating 
(or re-starting) ART 
BCPP 
Performance 
# of Eligible HIV+ Adults Identified Not 
on ART who Start or Re-Start ART  
# of HIV+ Adults 
Identified not on ART 
9. % of PLHIV Retained 
on ART (12 months 
Post ART Start or 
Restart) 
BCPP 
Performance 
# of HIV+ Adults Identified Not on ART 
who Start or Re-Start ART and Remain 
on ART after 12 Months 
# of Eligible HIV+ Adults 
Identified Not on ART 
who Start or Re-Start ART  
10. % of PLHIV on ART 
with Viral 
Suppression (12 
Months post ART 
Initiation or Restart) 
BCPP 
Performance 
# of HIV+ Adults Identified Not on ART 
who Start or Re-Start ART and have 
VL<1000Copies/ML  after 12 Months 
# of Eligible HIV+ Adults 
Identified Not on ART 
who Start or Re-Start ART  
 
 
 In the section below, data and the data sources for the outcomes of interest are identified for each 
intervention within the combination prevention package of services (HTC and Linkage to care, HIV care 
and treatment, MC and PMTCT services).  In addition, the data analysis plans are provided for the study 
objectives.  
 
9.1 HIV Testing and Counseling and Linkage to Care 
The HTC services aim to maximize the number of PLHIV who know their status within the community. 
Predictors of HTC uptake will be examined including demographics, prior testing history, partner 
status, etc.  Participants reached through mobile vs home-based testing will be described including age 

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and gender. Characteristics of HIV-positive persons identified will be described, including but not 
limited to demographics, testing history, new or previous HIV diagnosis, history of HIV care, CD4 count, 
and ART status. Data sources will include the Household Enumeration Form, HTC Intake Form, and 
BHS collected during the HTC activities. In addition, facility-based testing will be monitored in CPCs 
through RHT data in PIMS2 or IPMS.  
 
All HIV-positive participants given appointments at the HIV care and treatment clinic in the study 
communities are tracked to ensure they link to care. Those who keep appointments at the study clinic 
within 90 and up to 180  days of the BCPP interview as recorded in PIMS2 or IPMS are considered 
“linked” to care.  Those participants who report they are receiving care at another clinic outside the 
study community will be verified by PIMS2 or IPMS and will be considered linked to care if that have an 
IDCC appointment within 90 and up to 180  days of their BCPP interview date.  In addition, at  one year 
from the interview data, electronic data systems will be checked to determine if participants who did 
not link or register within 90 days have registered in care.   
 
Predictors of linkage to care will be examined including but not limited to, demographics, new or 
previous diagnosis, CD4 count, and time to first appointment from interview. In addition, rates of 
linkage to care will be compared among participants who received interventions services and those 
who did not.   
 
Data sources include referrals from HTC and BHS (HTC Intake, BHS), PIMS2 and IPMS for details of 
registration into care and treatment, and the Participant Tracing Log where all linkage to care follow-
up activities are recorded. In addition, the Ministry of Health’s Central Data Warehouse will be queried 
to identify (or confirm self-reported enrollment) of community residents who register for HIV care and 
treatment outside of the local study community.  
Further, estimations of the operational costs associated with the expanded HTC and linkage to care 
interventions paired with the total cost by intervention with their corresponding BCPP performance 
indicator will be used to estimate the average costs per person. The financial costing approach is 
described below, in the cost analysis plan. 
 
9.2 Care and Treatment 
For HIV care and treatment objectives, the overall number of PLHIV enrolled in the IDCC and on ART 
including community residents getting care at clinics outside the community will be described.  Specific 
focus will be given to examination of patterns of health care utilization by residents and non-residents 
of the community.  The key outcomes for analysis are ART initiation, adherence, retention and virologic 
suppression. We will also describe the laboratory results showing toxicity, and adverse events among 
the clinic population on ART.  ART initiation will be measured by start date of ART among all HIV-
positive patients initiated on ART as recorded in the electronic patient management system.  Length of 
time from BCPP interview or encounter to date of initiation on ART will be recorded and monitored. 
ART coverage will be measured by the number of HIV-positive community residents receiving ART out 
of the estimated number of HIV-positive community residents.  
Adherence levels will be assessed through self-reports, pill counts and pharmacy refill data from the 
electronic data systems and also from the adherence intervention tools. Based on the self-reports, pill 
counts and pharmacy refill data, an aggregate measure of adherence will be calculated (e.g., good, 

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limited or poor). Adherence levels at a community clinic will be measured by the percentage of clinic 
patients with an adherence assessment of good, limited and poor adherence. Retention of HIV-positive 
persons in care and on treatment will be measured during a defined period of time (e.g. 12 and 24 
months). The number of HIV-positive clinic patients who are community residents and who remain in 
care (had a clinic visit within 6 months) and on treatment (pharmacy pick up and clinic visit within 3 
months) during a defined period among all patients from the community who were registered at the 
clinic during that time will be considered retained in care or on treatment. The number of patients who 
missed clinic visits, defaulted from care and were lost to follow up will also be recorded from the 
electronic patient management system during a defined period. Virologic suppression will be assessed 
from the electronic data systems and will be defined as those HIV-positive patients on ART with a viral 
load of less than or equal to 400 copies/ml among all patients on ART.   
Predictors of retention, ART initiation, adherence and virologic suppression will be examined. As the 
inverse of retention, predictors of loss to follow will be examined.  For those on ART, predictors of 
defaulting on ART will be examined.  
All clinic patients will have data captured in the existing MOH electronic patient management systems. 
Clinical outcomes, including but not limited to ART eligibility and initiation, WHO stage, lab results, 
death, adherence, retention, viral suppression, and adverse events, will be assessed using routinely 
collected clinical data that is captured in the electronic medical record (see Appendix P1). In addition, 
the Ministry of Health’s Central Data Warehouse or other sources of routine medical information will 
be queried to identify clinic participation, ART eligibility, ART initiation and virologic suppression among 
community residents receiving services outside of the local study community clinic. Secondary 
descriptive analyses for key clinical indicators will be conducted on these data. In the CPCs, retention 
intervention data will be recorded on the Participant Tracing Log, and adherence intervention data 
will be recorded on the Adherence Assessment Tool and the Adherence Intervention Tracing Form.  
9.3 PMTCT Services 
Rates of 3rd trimester retesting among pregnant women will be assessed using the MOH Antenatal 
Care and Maternity registers and the MOH patient management systems. Among HIV-negative 
pregnant women enrolled in ANC care, the percent who were retested for HIV between 32-36 weeks 
will be recorded and monitored over the course of the study. 
 
Rates of linkage to care among HIV-positive post-partum women will be reported. Once discharged 
from ANC care, HIV-positive post-partum women will be given appointments at the local IDCC. Those 
who kept the appointments and registered at the clinic as recorded in the electronic patient 
management system will be “linked” to care. Those who were previously registered patients in the 
IDCC who re-link to care will be considered re-linked. Predictors of linkage to care among HIV-positive 
post-partum women will be examined including but not limited to, demographics, time since diagnosis, 
CD4 count, viral load, and time since delivery. In addition, rates of linkage to care will be compared 
among participants who received intervention services and those who did not. Retention in care 
among post-partum women will be measured the same as among all HIV-positive patients in the IDCCs 
(see above) and recorded in the electronic patient management system.  Rates of retention on ART in 
post-partum women at one year post-delivery will be described. In addition, predictors of post-partum 

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women who default from ART will be examined including demographics, time since diagnosis, time 
since delivery, CD4 count, and viral load.     
 
Tracing activities with HIV-positive post-partum women referred to the HIV care and treatment clinic 
will be recorded on the Participant Tracing Log. The MOH patient management system will be used to 
verify registration of post-partum women in the IDCC. In addition, the Ministry of Health’s Central Data 
Warehouse will be queried to identify women who temporarily access care and treatment services 
outside of the local study community during their period of postpartum confinement.  
 
9.4 Male Circumcision 
Through linkage to MC services, the MC program aims to maximize coverage of circumcision among 
males, which is defined as the percentage of HIV-uninfected men (aged 16-49) residing in CPC 
communities who are circumcised.  Community-level MC uptake among all and eligible men will be 
reported.  BHS and ESS surveys will be used to obtain cross-sectional true estimates of MC coverage, 
based on self-report.  These surveys are described in the BCPP Evaluation Protocol (Protocol 1).  
Further, MC coverage will be estimated using records of MCs performed as well as the baseline MC 
prevalence reported by the HTC and BHS campaigns. MC coverage will be evaluated based on the most 
recent census estimates of the study community population as well as on the enumerated study 
population. 
 
9.5 ANALYSIS PLANS 
For the primary outcomes, uptake of the CP interventions, we will estimate the percentage of 
participants eligible for and receiving the intervention using BHS and HTC data to identify those 
eligible, and BHS, HTC and clinic data to identify those receiving interventions. Confidence limits for 
each outcome will be estimated using robust standard errors to account for within-community 
clustering. 
The first secondary objective is to examine demographic, clinical, and social/behavioral facilitators and 
barriers to uptake of CP interventions. We will fit Generalized Estimating Equations (GEE) models with 
robust standard errors to account for the clustering within communities.  Independent variables for 
these models will be chosen based on prior literature and hypotheses about how various demographic, 
clinical and social/behavioral factors impact uptake of HTC, PMTCT, ART and MC.  For MC, this type of 
analysis will only be possible for year 1 interventions because individual-level data on men obtaining 
MC will not be collected in subsequent years. Variables will be chosen a priori based on theoretical 
justification rather than statistical results and all chosen variables retained in the model to adjust for 
confounding. 
To compare clinical outcomes, including viral suppression, among HIV-positive persons in CPCs who 
initiate expanded ART to those who initiate ART according to national guidelines, we will use tests 
appropriate to clustered data and the distribution of the outcomes of interest. For example, for viral 
suppression, we will use GEE models to account for the clustering within communities and test for a 
difference between groups (those initiating expanded ART vs. those who initiate according to 
guidelines). Since each community will contain both of these groups of participants, clustering has less 
impact on statistical tests, but still should be taken into account in the analysis to provide appropriate 
effect estimates and confidence limits. 

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To estimate the percentage of participants retained on ART among HIV-positive pregnant or 
breastfeeding women who initiate Option B+ (indefinite ART post-delivery), we will determine the 
number of HIV-positive pregnant women who initiate Option B+ during the study using BHS, HTC and 
clinic data, and determine the number retained on ART using clinic data. Confidence limits will be 
estimated using robust standard errors as for the primary outcome. Three costing studies of HTC and 
LTC services are planned. First, estimates of costs of home-based testing and mobile testing during the 
community-based HTC campaigns, including the cost per person and per new HIV case identified will 
be compared. Second, incremental costs and outcomes of strengthening facility-based routine testing 
relative to the standard of care will be estimated.  Lastly, to assess the impact of the expanded linkage 
activities, estimates of the costs and outcomes of these tracking & tracing services will be calculated. 
Outcomes are defined as the number of new or previously diagnosed HIV-infected persons not in care, 
who register at an IDCC without engaging tracking and tracing services, and who register at an IDCC 
within 90 and 180 days of their HTC encounter. 
A mixed top-down and micro-costing approach will be used to estimate costs. All relevant direct 
medical costs such as labor and materials, and direct non-medical costs such as program support and 
administrative overhead will be considered.   
Analyses will be conducted from the perspective of the health care system indicating that the costs 
included would be those typically associated with the providers and payers of care, and would exclude 
the costs and productivity losses incurred by patients and their informal caregivers. The most 
significant cost component is expected to be labor, for which the main categories include: HTC lay 
counselors and supervisors, LTC Coordinators, drivers, and community mobilizers.  
Labor time will be estimated by analyzing data records on clients seen, then confirmed through 
communication with staff and managers, and, as needed, through observation. Other cost items will be 
estimated through a combination of resource utilization and expenditure records. Any research related 
expenses will be removed in order for the resulting cost analyses to be useful for the projection of 
operational program costs. Costs of tests conducted through the baseline and annual household 
surveys administered by the Botswana Harvard Partnership will not be considered. 
Cost and outcome data will be collected, retrospectively, from routine monitoring program data stored 
in the central study database and from actual program expenditures incurred over the period 
corresponding to the HTC and LTC programmatic efforts from all BCPP communities.  The analytic 
horizon will begin in November 2013 and correspond to the period during which the HTC campaign and 
LTC program are delivered in a community. Unit costs (e.g. Cost per tested, Cost per new diagnosis, 
Cost per person linked) will estimated by dividing total costs by the relevant BCPP performance 
indicator. Where applicable any future costs will be discounted to their present value at a standard 
rate of 3%.   As needed, costs will be converted from Botswana Pula to US dollars. Costs will be 
presented in 2015 US dollars. We will conduct univariate sensitivity analysis to identify the inputs 
which most impact the results and gauge the robustness of the conclusions. Data analysis will be 
conducted using Microsoft Excel and SAS. 
 
 
10.0 ETHICAL CONSIDERATIONS  
 

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10.1 Ethical Review  
The protocol, informed consent/parental permission forms/assent forms, research participant 
education and recruitment materials, and other requested documents — and any subsequent 
modifications — will be reviewed and approved by the ethical review bodies responsible for oversight 
of research conducted at the study sites.  The Institutional Review Boards/Ethical Committees 
(IRBs/ECs) for CDC and the Health Research & Development Committee, Botswana Ministry of Health 
will review the protocol at least annually. 
 
10.2 Informed Consent 
 
a) Interventions and strengthened programs: 
HTC:  National guidelines for obtaining verbal consent prior to receiving HTC services, for adults aged 
16 or older, will be followed.  Linkage-to-care interventions  now fall under  the Ministry of Health’s 
2016 national treatment guidelines which recommend that all HIV-positive persons identified be 
referred and tracked to the HIV care and treatment clinic. Therefore, all linkage to care follow up 
tracking will now be considered standard of care and will not require permission. However, 
participants who do not link to care and receive tracking and tracing follow  up services will have the 
option to discontinue those services at any time they request.   Similarly, active retention tracing of 
participants late for appointments has been implemented in several ART clinics in Botswana with plans 
to expand the scope of this program.  For Retention Tracing, clinic patient contact information (name, 
phone number, address), OMANG (patient medical ID number) and appointment history are abstracted 
from MOH register and PIMS2 database for retention tracing of clinic patients who have missed 
scheduled clinic appointments These patients will be contacted by an MOH staff member and 
permission will be obtained to send BCPP counselors out for tracing and follow up services.  
Adherence Intervention:  Clinic patients identified as being non-adherent will be asked to consent for 
the adherence intervention (Linkage, Retention & Adherence Intervention Verbal Consent) which 
requests permission to administer the Adherence Assessment Form. 
The informed consent process will occur in the language most comfortable for participants (usually in 
Setswana) at 8.0 reading level or below. Permission/assent will be documented by having the 
participant sign the permission/assent form or make a mark if the participant is illiterate; the latter will 
be witnessed by a third party.  A copy of the informed consent/assent form will be offered to the 
participant, and if applicable, parent or legal guardian giving permission for a minor to participate.  
Staff will ensure that the participant takes a copy of a study contact card that contains study 
information and telephone numbers if the participant does not wish to take a copy of the 
permission/assent form.   
 
b) Special Populations 
Minors:  Minors (participants ages 16-17) are only enrolled with the written permission of a 
parent/legal guardian and if they provide informed assent.  
 Under circumstances where clinical or study staff suspect, or there is a reported incident of 
sexual abuse of a person under age 18, the study staff member must inform the relevant 
authorities; this is stated in the permission/assent forms.   
 Referrals will be made to youth services if needed. 
 

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c) Use of Routine Programmatic Data:  A waiver of informed consent was previously granted for the 
following activities: 
 
1) Medical record use in accordance with 45CFR 46.116 (d) to extract a limited, preselected 
dataset (Appendix P1) from MOH clinical data systems in the clinic population in Enhanced Care 
and Combination Prevention Communities.   This is done by linking BHS and HTC data with clinic 
data to monitor the care and treatment cascade from HIV testing and referral through clinic 
enrollment, ART initiation and adherence, and retention in care.  Procedures for extracting, 
matching between sources, and de-identification of this data are described in Section 8.  
Limitation of data-to-data elements based on consent/waiver-of-consent will be applied during 
the transfer of data from the clinics into the study database.  Although not all data elements are 
part of the matching algorithm, data are matched using date of birth and Omang number.  
Once match is assigned, the data retained for analysis is de-identified in accordance with the 
consent/waiver-of-consent and the stipulations of the study protocols.   
 
2) A waiver of informed consent was previously granted for the following: a) data from the HTC 
Intake questionnaire that is collected as part of HTC programmatic services in households and 
tent venues in the Combination Prevention Communities, and b) abstraction of aggregate 
program data from MC and HTC facilities. 
 
The waiver is appropriate because (1) the analysis involves no more than minimal risk to human 
subjects, and personal identifiers are encrypted for data handlers and analysts; (2) the evaluation does 
not adversely affect the rights and welfare of the subjects; (3) the evaluation cannot practicably be 
carried out without the waiver because it is not possible to obtain consent from all service recipients 
without infringing on the ability to carry out the program in an efficient manner; and (4) if consent for 
routine data use from all participants was requested, this might reasonably constitute an unnecessary 
waste of an individual’s time.  The types of consents being requested for activities in this study are 
described in Table 3. 
 
Table 3: Summary of approach to consent for various components of the study 
Project 
component 
Targeted subjects 
Activity 
Consent 
Comment 
HTC  
Persons not documented 
to be HIV-infected 
Routine HIV counseling 
and testing 
Verbal consent  
 
Programmatic 
Interventions 
Eligible residents of study 
communities 
Use of testing (rapid test) 
and intake data from HTC, 
linkage to HIV care, TB 
screening, retention 
support and PMTCT 
services 
Waiver of 
consent/assent 
granted 
45 CFR 
46.116 (d) 
Use of routine- 
clinical data 
Clinic population, all  
communities 
Use of routinely-collected, 
program data-see 
Appendix P1  
 Waiver of 
consent/assent 
granted 
45 CFR 
46.116 (d) 
Clinic Patient 
Retention and 
Adherence  
IDCC patient population in 
CPCs  
Data collection and 
permission to follow-up 
Linkage, Retention & 
Adherence Tracing 
Verbal Consent Script 
 
 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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10.3 Risks 
The risks, discomforts, and inconveniences that could be posed to subjects participating in this project 
include the following: 
 
 HTC Participants: 
o Blood drawing may cause pain and bruising, and rarely, infection at the site where blood is 
drawn. Study participants may feel lightheaded or faint as a result. 
o Repeated HTC may cause stress, anxiety, or embarrassment. Participants are likely to become 
distressed if they learn they are HIV positive.  
o Participants may become embarrassed, worried, or anxious when discussing their sexual 
practices, HIV risk factors, ways to protect their partner(s) against HIV, and/or ways to prevent 
acquiring HIV infection.  
o Participants may experience discrimination as a result of being perceived by others to be HIV-
infected. 
 
 Other Strengthened Program Interventions: 
o Other strengthened interventions, including linkage for HIV care, ANC, TB screening, and 
retention support all carry very minimal risk to participants. 
 
 Persons starting ART: In addition to the risks described above for survey participants, risks for 
patients initiating ART include: 
 
Adults starting ART are at risk of ART-related adverse events (e.g., hepatitis, severe skin rash, 
renal dysfunction, drug resistance, need for regimen change, etc.).   
 
10.4 Benefits of Research Participation 
 HTC:  Potential health benefits include: earlier HTC delivered to their place of residence, earlier 
diagnosis of HIV-infection with subsequent earlier enrollment in care and treatment or PMTCT, 
earlier awareness of the importance of annual HTC and risk reduction practices for adults who test 
HIV-negative, and earlier awareness of the benefits of MC for HIV negative males.   
 
 Other Strengthened Program Interventions: Evidence for health benefits of linkage-to-care and 
adherence/ retention interventions are described in Section 6.  
 
 UTT: The benefits of earlier initiation of ART might include improved survival and reduction in 
incidence of adverse events [such as serious non-AIDS events like myocardial infarction, or AIDS-
related morbidity (e.g., a new WHO stage III/IV condition)] as well as decreased likelihood of 
transmitting HIV to others.   
 
10.5 Confidentiality 
No information concerning the study or the data will be released to any unauthorized third party, 
without prior written approval of the participant, except as necessary for monitoring by the IRBs, the 
study sponsor, OHRP, or the Botswana Ministry of Health.  No data with subject identifiers will be 
released. 

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 HTC, linkage to care, and HIV care and treatment following HIV diagnosis: 
Project staff visiting households for study visits will identify an appropriately private space to 
counsel participants, perform HIV tests, and collect individual data.  If private space is not available, 
or the participant does not wish to carry out study activities in the home, an appointment will be 
made to visit one of the mobile units or study clinics instead.  All study documents, including any 
papers or files containing personal contact information (such as telephone numbers and 
addresses), will be stored in a secure location and electronic data will be password protected. Full 
Drive Encryption will be implemented at the hardware layer of all devices storing protected health 
information.  Only designated study staff will have access to study records.   
 
 Linkage to MC and MC  
MC mobilization will be conducted according to national standards for mobilization.  These standards 
include protections for transport registers and mobilization registers with PII.  
IDCC Care and Treatment: 
Care at the clinic will be provided in adherence with MOH confidentiality guidelines.  Consultations 
between  patients and clinic/research staff will occur in a private location.  All consent forms kept by 
investigators are stored in locked steel cabinets at the clinic or on password-protected electronic 
devices (e.g., tablets).  All paper forms are stored in locked steel cabinets and transported in sealed 
boxes to Gaborone.  All data collected via MOH data systems or entered from paper questionnaires are 
kept securely on password-protected log-in screens. 
 
10.6 Protocol Compliance and Compliance with UN Convention on the Rights of the Child 
Study staff will adhere to the ethical principles that are reflected in the Declaration of Helsinki (e.g., 
ICH E6, 45 CFR 46). The study will be conducted in accordance with the Botswana and Sponsor 
regulations.  
 
The US government is a signatory on the UN Convention on the Rights of the Child (defined as anyone 
under the age of 18) which requires that any research study or program activity which includes 
children that are identified as engaged in sex work, trafficked or victims of violence make special 
provisions for referral of these individuals to services. BCPP will report suspected cases to designated 
service providers (local police or social workers) as outlined in the Botswana National Guidelines for 
reporting child abuse or neglect. Contact information for the local police and social workers, and 
procedures for reporting suspected cases of child abuse or neglect are described in study specific SOP 
in the BCPP Study Manual. Local police and social workers will be contacted prior to the initiation of 
study activities in the community to ensure they are aware of the study activities in the community and 
the procedures that will be followed should BCPP staff encounter suspected cases of abuse or neglect. 
As per national guidelines, reports of suspected abuse or neglect will be made to local authorities 
within 24 hours. Study personnel who may come in contact with these study participants will receive 
training on the appropriate procedures for handling these cases if they arise during the course of the 
study and training on the SOP documented in the regulatory files. The study will retain documentation 
of all reports that includes date of report, age of participant, and the name and type of service 
provider.  No identified information will be retained in the documentation; documentation will be 
retained by the study for 2 years after study close-out.   The informed consents for the study contain 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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language that makes clear to the participant what is required to be reported to authorities and the 
impact on confidentiality. 
 
11.0 
STUDY SAFETY AND MONITORING PLAN 
 
11.1 Reporting Adverse Events 
Expedited Adverse Event (EAE) Reporting Requirements for this Study:                                                       
The study team will report in real-time, to overseeing IRB's and to sponsors, any AE following any 
exposure to the study interventions that is BOTH possibly related to study intervention and 
unexpected, and which is a Serious Adverse Event (SAE).  An SAE is defined as any untoward 
occurrence that:  
 Results in death 
 Is life-threatening (grade 4) 
 Requires hospitalization or prolongation of hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 
This level of reporting is chosen to avoid real-time EAE reporting of all deaths, hospitalizations, etc. 
occurring in study communities that are definitely not related to study procedures. 
 
Study interventions are defined as: 
1. Antiretroviral therapy implemented as per BCPP protocol 
2. HIV testing as part of the HTC campaigns 
3. Any other study-related activity in which harm (including social harm) could occur.   
With regard to ART intervention, EAE reporting will be restricted to SAEs that are possibly related to 
initiating ART beyond national guidelines.   
 
Timing of EAE reporting: 
EAEs will be reported to CDC and HRDC within 2 business days of the study investigators becoming 
aware of the event.   
 
Grading Severity of Events: 
The most current Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table) dated November 2014 will be used (or more current version, if applicable), 
and is available on the RSC website ( http://rsc.tech-res.com/).   
 
Non-EAE Adverse Event and Incident Reporting: 
The risk of adverse events related to the use of ART has been established and there is no indication 
that enrollees, with intact immune systems, who are receiving ART, are likely to have a higher risk of 
adverse events.   
 

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SAEs that do not meet the criteria for EAEs (i.e. an SAE that is NOT related to the study intervention) 
will be submitted quarterly to the IRB.  A table listing all unrelated SAEs that occurred in the specified 
quarter will be submitted to the IRB along with a brief narrative of each event.  Per discussions with 
the CDC IRB, SAEs that are unrelated to the study intervention will NOT be reported using the official 
CDC forms (.1254/.1254S).  
 
Adverse Event Reporting Period: 
The expedited AE reporting period for this study is from the time of initial study contact to the last 
study contact for a participant. 
 
AE reporting process 
Reportable events will be documented by the in-country study team who will then notify the IRBs, 
MOH, CDC-Atlanta, and Harvard Chan School teams.  The incident will be discussed and a written 
action plan will be devised and implemented within 1 week of the initial report, if needed.  Written 
documentation of all events and event resolution will be retained in the study file.  Reporting of EAEs, 
SAEs and AEs to IRBs and the study sponsor will follow institutional and IRB policies.  If applicable, a 
formal report will be sent to the appropriate IRBs using the CDC’s Incident Report Form 1254.  
 
11.2  DSMB  
Proposed Schedule of DSMB Reviews and Interim Data Analysis 
The BCPP is divided into three interlocking protocols (two active protocols, after Protocol 2 was 
terminated in 2015), and the investigators expect that DSMB review will require information regarding 
interim study results and study conduct from all three.  The combination prevention package under 
study includes the following interventions that are outside of current SOC in Botswana: provision of 
ART for all HIV-infected adults regardless of WHO Stage or CD4 count and streamlined ART delivery. 
Hence, the reports will provide information needed to evaluate the adverse and favorable effects of 
such interventions on individually treated patients as well as on the communities in which they reside. 
The study will require at least 6 reviews, DSMB 1-6, proposed to take place at baseline and at the end 
of years 1, 2, 3, 4, and 5. DSMB 3 and 4 will evaluate intervention rollout and safety. At DSMB 5, the 
DSMB can recommend stopping for efficacy or extending the study by 1 year should there be low 
intervention coverage or a lower than expected incidence rate in the Enhanced Care arm. To 
demonstrate that the study has reasonable power to answer the study questions given information up 
to the time of each review, investigators will provide the DSMB with assessments of the adequacy of 
coverage of proposed interventions; estimated conditional power given available incidence 
information will be provided at DSMB 4 and all subsequent reviews.  While there will be separate 
reports for each of the protocols, each report will make use of the data available from all protocols.  
Details of the DSMB review plan for each protocol are provided in that protocol, and the full detailed 
plan is provided in Appendix C4.  
 
11.3 Protocol Violations 
The study will be conducted in full compliance with the protocol.  The research team will ensure that 
volunteers are informed of and understand the risks of their participation in research. Protocol 
violations and cases of social harm will be documented using the appropriate study forms and reported 
to IRBs and sponsors in accordance with the institutional policies.  Minor protocol violations that do 
not pose a threat to the health or welfare of participants will be compiled and reported to the IRBs at 
the time of annual IRB review.  Incident reporting is the responsibility of the Principal Investigators of 

BCPP Intervention Protocol 3_ v6.0 | September 22, 2017 
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this study.  Emergency departures from protocol that eliminate an apparent immediate hazard to 
participants and are deemed crucial for the safety and well-being of that participant may be instituted 
for that participant only.  In that case the Investigator will contact the IRBs and sponsor as soon as 
possible to document the reasons for violation and ensuing events.   
 
11.4 Monitoring Plan 
A complete monitoring plan has been developed and the site will complete a study site activation 
checklist prior to study initiation.   Internal (sponsor) and external monitors will travel to the study site 
according to a pre-determined monitoring schedule specified in the monitoring plan to conduct 
general monitoring.  The study site will maintain a monitoring log to document all monitoring visits. 
Investigators and staff will grant access to the monitors to allow inspection and review study 
documents (e.g., consent forms, data collection forms, other source documents) and pertinent clinic 
records for confirmation of the study data. Study monitors will also inspect study facilities and 
documentation and may observe the performance of study procedures. 
 
12.0 ADMINISTRATIVE PROCEDURES AND INFORMATION DISSEMINATION 
 
12.1 Study Records and Document Retention 
Complete, accurate, and current study records will be maintained and stored in a secure manner 
throughout the duration of the study and additionally for five years after study close-out. Study 
records include administrative documentation— including all reports and correspondence relating to 
the study — as well as documentation related to each participant screened 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. Necessary documents to be maintained by the 
site before, during and after the study will be in accordance with GCP regulations and guidance. A 
complete list of needed documentation will be provided prior to initiation of the study and will appear 
in the study manual. 
 
12.2 Information Dissemination and Publication Plan 
Study findings will be disseminated through presentations, reports and publication in peer-reviewed 
journals and other publications.  In-country data and country specific information will be made 
available to national policy-makers, organizational, and implementing partners.  A detailed publication 
and communication plan will be developed that describes the number and types of reports and 
manuscripts planned for the study and criteria for authorship.  Formal presentations at conferences 
and scientific publications will follow CDC, Harvard Chan School, and MOH guidelines.  A data sharing 
plan will also be developed that details the requirements and process for requesting access to stored 
data and a samples for sub-studies and future analysis. 
 
 
 
 

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