Sustainable East Africa Research in Community Health
Phase: NA
Conditions: HIV, Tuberculosis, Hypertension, Diabetes, Maternal Child Health, Cost Effectiveness
Sponsor: University of California, San Francisco

SEARCH Study protocol version 10.0, July 20, 2018  
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Sustainable East Africa Research in Community Health (SEARCH)
 NCT01864603 
A Study of the: 
Makerere University – University of California, San Francisco (MU-UCSF) 
Research Collaboration 
Protocol version:  10.0, July 20, 2018 
Protocol Chairs: 
Diane V. Havlir, MD 
University of California, San Francisco, USA 
Moses Kamya, MBChB, MPH, PhD 
Makerere University 
Kampala, Uganda 
Maya L. Petersen, MD, PhD 
University of California, Berkeley, USA 
Protocol Vice-Chair: 
Edwin Charlebois, MPH, PhD 
University of California, San Francisco, USA 
Study supporters and sponsors:  the Kenya Medical Research Institute (KEMRI); Infectious 
Diseases Research Collaboration (IDRC); the World Bank; National Institute of Allergy and 
Infectious Diseases (NIAID); PEPFAR; and Gilead Sciences, Inc.  

SEARCH Study protocol version 10.0, July 20, 2018                                                                      
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TABLE OF CONTENTS 
PROTOCOL TEAM ROSTER: ................................................................................................... 5 
PROTOCOL SYNOPSIS ...........................................................................................................10 
GLOSSARY……………………………………………………………………………………………...12 
1.0 STUDY CONTEXT ..............................................................................................................13 
1.1 Background .....................................................................................................................13 
1.2 Rationale .........................................................................................................................14 
1.3 Antiretroviral therapy .......................................................................................................16 
2.0 STUDY OBJECTIVES .........................................................................................................20 
2.1 Primary Study Objectives ................................................................................................20 
2.2 Secondary Objectives – Health ........................................................................................20 
2.3 Secondary Objectives – Economic and Education Outcomes ..........................................21 
2.4 Secondary Objectives – Cost and Cost-Effectiveness .....................................................22 
3.0 STUDY DESIGN .................................................................................................................22 
4.0 STUDY POPULATION ........................................................................................................24 
4.1 Community Level Inclusion Criteria ..................................................................................24 
4.2 Individual Level Inclusion Criteria ....................................................................................24 
4.3 Community Level Exclusion Criteria ................................................................................24 
5.0 STUDY INTERVENTIONS ..................................................................................................25 
5.1 Antiretroviral Therapy in a Streamlined Care Delivery (Phase I) ......................................25 
5.2 Targeted PrEP (Phase II) ................................................................................................28 
6.0 COMMUNITY LEVEL STUDY EVALUATIONS ...................................................................30 
6.1 Baseline Household Community Level Census ...............................................................30 
6.2 Community Health Campaign (CHC) ...............................................................................30 
6.3 Mortality and New Births, and HIV and TB Disease Surveillance .....................................36 
6.4 Feedback of CHC Process and Clinical Data ...................................................................38 
7.0 CLINCAL AND LAB EVALUATIONS IN PARTICIPANTS RECEIVING ART .......................39 
7.1 Recruitment, Phase I – ART Intervention .........................................................................39 
7.2 Selection of Participants in Intervention Arm, Phase I – ART Intervention .......................39 
7.3 Informed Consent and Enrollment, Phase I – ART Intervention .......................................39 
7.4 Schedule of Evaluations, Phase I – ART Intervention ......................................................40 
7.5 Timing of Evaluations, Phase I – ART Intervention ..........................................................40 

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7.6 Definitions of Evaluations, Phase I – ART Intervention ....................................................40 
7.7 Recruitment, Phase II – PrEP ..........................................................................................42 
7.8 Selection of Participants in Intervention Arm, Phase II – PrEP .........................................43 
7.9 Informed Consent and Enrollment, Phase II – PrEP ........................................................43 
7.10 Schedule of Evaluations, Phase II – PrEP .....................................................................44 
7.11 Timing of Evaluations, Phase II – PrEP .........................................................................45 
7.12 Definitions of Evaluations, Phase II – PrEP ...................................................................45 
7.13 Post-Exposure Prophylaxis (PEP) .................................................................................46 
7.14 PEP Eligibility ................................................................................................................46 
7.15 PEP Informed Consent and Enrolment ..........................................................................47 
7.16 PEP Schedule of Evaluations ........................................................................................47 
7.17 Timing and Location of Evaluations for PEP ..................................................................47 
7.18 PEP Definitions of Evaluations ......................................................................................48 
8.0 ART TOXICITY GRADING AND MANAGEMENT ...............................................................50 
8.1 Toxicity Screening ...........................................................................................................50 
8.2 Management of Laboratory Toxicities ..............................................................................50 
8.3 Management of Specific Clinical Syndromes ...................................................................50 
9.0 ECONOMIC AND EDUCATION EVALUATIONS ................................................................53 
9.1 Overview .........................................................................................................................53 
9.2 Recruitment and Enrollment of Study Participants ...........................................................53 
9.3 Procedures ......................................................................................................................53 
10.0 HEALTH CARE COSTING EVALUATIONS ......................................................................56 
10.1 Overview .......................................................................................................................56 
10.2 Recruitment and Enrollment of Study Participants .........................................................56 
10.3 Procedures ....................................................................................................................56 
11. STATISTICAL PLAN ...........................................................................................................59 
11.1 Overview of Study Design..............................................................................................59 
11.2 Primary Outcome Measurement ....................................................................................61 
11.3 Randomization of Community Pairs ...............................................................................63 
11.4 Primary Analyses ...........................................................................................................64 
11.5 Secondary Analyses ......................................................................................................69 
12. DATA COLLECTION AND MONITORING ..........................................................................75 
12.1 Data and Safety Monitoring Plan ...................................................................................75 

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12.2 Baseline Household Community Level Census ..............................................................77 
12.3 Community Health Campaign ........................................................................................77 
12.4 ART Intervention and PrEP ............................................................................................79 
12.5 Grade 3 and 4 Adverse Event and Serious Adverse Event Monitoring ..........................79 
12.6 Household Socio-Economic Survey ...............................................................................80 
12.7 Health Care Costing Evaluations ...................................................................................80 
12.8 Data Security and Integrity ............................................................................................80 
13. HUMAN SUBJECTS ...........................................................................................................82 
13.1 Ethical Considerations ...................................................................................................82 
13.2 Institutional Review Board (IRB) and Informed Consent ................................................83 
14. PUBLICATION OF RESEARCH FINDINGS ........................................................................84 
15. SUPPLEMENTAL LABORATORY EVALUATIONS .............................................................84 
REFERENCES ………………………………………………………………………………………….85 
Appendix A 
Guidelines for Adverse Event Grading – DAIDS Toxicity Table for Adults and 
Children ............................................................................................................89 
Appendix B 
Table of Study and Consent and Commitment Procedures ..............................93 
Appendix C 
Uganda Antiretroviral Therapy Guidelines ........................................................97 
Appendix D 
Kenya Antiretroviral Therapy Guidelines ...........................................................99 
Appendix E 
Sample Pediatric ART Dosing Chart ............................................................... 100 
 

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PROTOCOL TEAM ROSTER: 
 
Co-Chair: 
 
Diane Havlir, MD 
Chief, HIV, Infectious Diseases and Global 
Medicine 
San Francisco General Hospital 
University of California, San Francisco  
UCSF Box 0874 
San Francisco, CA 94143-0874, USA 
Phone: (415) 476-4082, x424 
Fax: (415) 476-6953 
Email: diane.havlir@ucsf.edu 
 
Co-Chair: 
 
Moses Kamya, MBChB, MMed, MPH, PhD 
Makerere University 
Plot 4B, Kololo Hill Drive 
P.O. Box 7972 
Kampala, Uganda 
Phone: +256-312-281479 
Fax: +256-414-540524 
Email: mkamya@infocom.co.ug 
Co-Chair and Protocol Statistician:  
 
Maya L. Petersen, MD, PhD 
Assistant Professor of Biostatistics and 
Epidemiology 
School of Public Health 
University of California, Berkeley 
Berkeley, CA 94720-7358, USA 
Phone (510) 642-0563 
Email:  mayaliv@berkeley.edu 
 
Vice-Chair: 
 
Edwin Charlebois, MPH, PhD 
Professor of Medicine  
University of California, San Francisco  
Co-Director of Prevention, AIDS Policy 
Research Center, Center for AIDS Prevention 
Studies, AIDS Research Institute 
550 16th Street, 3rd Floor   
San Francisco, CA 94143, USA  
Phone: (415) 502-1000 ext. 66241 (vm only)  
Fax: (415) 476-5348  
Email: Edwin.Charlebois@ucsf.edu 
 
Investigator: 
 
Elizabeth Bukusi, MBChB, M.Med, MPH, PhD 
Chief Research Officer and Deputy Director 
Kenya Medical Research Institute 
Co-Principal Investigator, FACES 
Box 54840 
Nairobi, Kenya 
Phone:  +254 733617503 
Fax:  +254 20 2737658 
Email: ebukusi@rctp.or.ke 
 
Protocol Virologist: 
 
Teri Liegler, PhD 
Associate Professor, Medicine-HIV/AIDS 
Director, ARI-UCSF Laboratory of Clinical 
Virology 
University of California, San Francisco 
UCSF Box 1234 
San Francisco, CA 94143-1234, USA 
Phone:  (415) 206-8929 
Email:  teri.liegler@ucsf.edu  

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Investigator - Economics: 
 
Harsha Thirumurthy, PhD 
Associate Professor 
Department of Medical Ethics and Health Policy 
University of Pennsylvania 
Philadelphia, PA 19104, USA 
Phone: (215) 746-0410 
Email: hthirumu@upenn.edu 
 
Investigator: 
 
Craig Cohen, MD, MPH 
Professor of Obstetrics, Gynecology and 
Reproductive Sciences 
University of California, San Francisco 
550 16th Street, 3rd Floor   
San Francisco, CA 94143, USA  
Phone: (415) 476-5874 
Fax: (415) 597-9300Email: 
CCohen@globalhealth.ucsf.edu 
Investigator: 
 
Tamara Clark, MPH 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA  94143-0874, USA 
Phone: (415) 206-8790 
Fax: (415) 648-8425 
Email: tamara.clark@.ucsf.edu 
 
Investigator: 
 
Elvin Geng, MD, MPH 
Associate Professor of Medicine 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA 94143-0874, USA 
Phone: (415) 476-4082, x409 
Fax: (415) 476-6953 
Email: genge@php.ucsf.edu 
 
Investigator: 
 
Gabriel Chamie, MD, MPH 
Associate Professor of Medicine 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA 94143-0874, USA 
Phone: (415) 476-4082, ext. 445 
Fax: (415) 476-6953 
Email: gabriel.chamie@ucsf.edu 
Investigator: 
 
Vivek Jain, MD, MAS 
Associate Professor of Medicine 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA 94143-0874, USA 
Phone: (415) 326-3402 
Fax: (415) 476-6953 
Email: vivek.jain@ucsf.edu 
 
Investigator: 
 
Dalsone Kwarisiima, MBChB, MPH 
SEARCH Program Manager, Uganda 
Infectious Diseases Research Collaboration 
Plot 2C Nakasero Hill Road 
Kampala, Uganda 
Phone:  +256-752-900129 
Email:  dkwarisiima@idrc-uganda.org 
 
 
Investigator – Qualitative Studies: 
 
Carol Camlin, PhD, MPH 
Associate Professor 
Department of Obstetrics, Gynecology and 
Reproductive Sciences and Center for AIDS 
Prevention Studies 
University of California, San Francisco 
550 16th Street, 3rd Floor   
San Francisco, CA 94143, USA  
Phone:  (415) 597-4998 
Email:  Carol.Camlin@ucsf.edu 
 
 

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Investigator: 
 
Zachary Kwena, MA 
Kenya Medical Research Institute 
Co-Principal Investigator, FACES 
Box 54840 
Nairobi, Kenya 
Phone: +254-733-3333005 
Email: zkwena@kemri-ucsf.org 
 
Investigator: 
 
Theodore Ruel, MD 
Associate Professor of Pediatrics 
Department of Pediatrics 
University of California, San Francisco 
UCSF Box 0136 
San Francisco, CA 94143-0136, USA 
Phone:  (415) 476-9198 
Fax:  (415) 476-1343 
Email:  Ruelt@peds.ucsf.edu 
 
Investigator: 
 
Lillian Brown, MD, PhD 
Assistant Professor of Medicine 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA  94143-0874, USA 
Phone: (415) 476-4082 ext. 122 
Fax: (415) 476-6953 
Email: lillian.brown@.ucsf.edu 
 
Investigator – Statistics and Modeling: 
 
Laura Balzer, PhD 
Assistant Professor, Biostatistics 
School of Public Health and Health Sciences 
University of Massachusetts, Amherst 
Amherst, MA, 01003-9304, USA 
Phone:  (203) 558-3804 
Email: lbalzer@umass.edu 
 
 
Investigator – Cost Effectiveness: 
 
Starley Shade, PhD 
Associate Professor of Medicine 
University of California, San Francisco 
UCSF Box 0886 
San Francisco, CA 94143-0886, USA 
Phone: (415) 476-6362 
Fax: (415) 476-5348 
Email: starley.shade@ucsf.edu 
 
 
Data Manager: 
 
Geoff Lavoy 
Data Center Manager 
Infectious Diseases Research Collaboration 
P.O. Box 7475  
Kampala, Uganda 
Phone: +256 714 964 634 
Email: glavoy@muucsf.org 
 
 
Investigator: 
 
Chi-Yuan Hsu, MD, MS 
Chief, Division of Nephrology, Medicine 
University of California, San Francisco 
UCSF Box 0532 
San Francisco, CA  94143-0874, USA 
Phone:  (415) 353-2379 
Fax:  (415) 476-2173 
Email:  chi-yuan.hsu@ucsf.edu 
 
 
Investigator: 
 
Anthony Muiru, MD 
Division of Nephrology, Medicine 
University of California, San Francisco 
UCSF Box 0532 
San Francisco, CA  94143-0874, USA 
Phone: (415) 353-2172 
Fax:  (415) 476-2173  
Email:  amuiru@gmail.com 
 

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Investigator: 
 
Martin Sirengo Wafula, MBChB, MMed 
Deputy Director of Medical Services 
Head, NASCOP 
Ministry of Health, Kenya 
P.O. Box 387-00202 
Nairobi, Kenya 
Phone:  +254-722-802140 
Fax:  +254-733-702140 
Email:  msirengo@nascop.or.ke  
 
 
 
Investigator: 
 
Carina Marquez, MD 
Assistant Professor of Medicine 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA 94143-0874 
Phone:  (415) 476-4082 ext. 331 
Fax:  (415) 476-6953 
Email:  carina.marquez@ucsf.edu  
 
 
Investigator – Statistics and Modeling: 
 
Mark van der Laan, PhD 
Professor of Biostatistics and Statistics 
School of Public Health 
University of California, Berkeley 
Berkeley, CA 94720-7358, USA 
Phone:  (510) 643-9866 
Email:  laan@stat.berkeley.edu 
 
Investigator: 
 
Catherine Koss, MD 
Assistant Professor of Medicine 
HIV, Infectious Diseases and Global Medicine 
University of California, San Francisco 
UCSF Box 0874 
San Francisco, CA  94143-0874, USA 
Phone: (415) 476-4082 ext. 441 
Fax: (415) 476-6953 
Email: catherine.koss@ucsf.edu 
 
 
 
Investigator: 
 
James Ayieko, MBChB, MPH 
Clinical Services Coordinator, SEARCH 
P.O. Box 517-20107 
Njoro, Kenya 
Phone:  +254-720-925262 
Email:  jimayieko@gmail.com 
 
 
 
 
 
Investigator – Statistics and Modeling: 
 
Yiqun Chen, BA 
Affiliate, University of California, Berkeley 
Berkeley, CA 94720-7358, USA 
Phone (510) 642-0563 
Email:  yiqunchen@berkeley.edu 
 
 
 
 
Investigator – Statistics and Modeling: 
 
Britta Jewell, PhD 
School of Public Health 
University of California, Berkeley 
50 University Hall #7360 
Berkeley, CA 94720-7360, USA 
Phone: (510) 220-0019 
Email:  bjewell@berkeley.edu  
 
 
 
 
 
Investigator 
 
Yea-Hung Chen, PhD, MS 
Epidemiologist 
San Francisco Department of Public Health 
San Francisco, CA 94102, USA 
Email: yea-hung.chen@ucsf.edu 
 
 
 
 
 
 

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Investigator 
 
Monica Gandhi, MD, MPH 
Associate Chief, HIV, Infectious Diseases and 
Global Medicine 
University of California, San Francisco  
UCSF Box 0874 
San Francisco, CA 94143-0874, USA 
Phone: (415) 476-4082, x127 
Fax: (415) 476-6953 
Email:  monica.gandhi@ucsf.edu  
Industry Representative: 
 
James F. Rooney, MD 
Gilead Sciences, Inc.  
333 Lakeside Drive  
Foster City, CA  94404, USA 
Phone: (650) 522-5708 
Email: jim_rooney@gilead.com 
 
 

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PROTOCOL SYNOPSIS  
Overall Goal:  The SEARCH study will quantify the health, economic and educational impact of 
a) early HIV diagnosis and immediate ART (antiretroviral therapy) using a streamlined care 
delivery system in rural communities in East Africa (Phase I) and b) targeted Pre-Exposure 
Prophylaxis (PrEP), targeted HIV testing and targeted care interventions on top of universal 
treatment and streamlined care ( Phase II) . The study intervention is designed to improve the 
entire continuum of care, to reduce structural barriers for all populations including those most “at 
risk” and build upon evidence based prevention interventions including adult male circumcision.    
Study Hypothesis: 1a) ART initiation at any CD4 count with streamlined delivery compared to 
CD4-driven ART initiation will reduce cumulative 3-year HIV incidence and protect and improve 
health, economic and education outcomes in communities with annual HIV testing 
campaigns.1b) Targeted PrEP, targeted HIV testing and targeted care interventions on top of 
universal treatment and streamlined care will further reduce cumulative 3 year HIV incidence.   
Study Partnerships: SEARCH is designed to inform governments and health policy makers 
and to benefit affected communities. To that end, SEARCH is a partnership with input and 
sponsorship from global and local health and development agencies, foundations, governments 
and the study communities. These include the ministries of health in Uganda and Kenya, the 
National Institutes of Health, the World Bank, and PEPFAR. 
Study Design: SEARCH is a cluster randomized community trial with 2 phases.  In Phase I, a 
hybrid model of HIV testing combining community health campaigns (CHC) and home-based 
testing for those who do not attend CHC, will be conducted in all study communities at baseline 
and will offer HIV testing and multi-disease prevention and treatment services. The intervention 
is annual and targeted HIV testing and ART independent of CD4 cell count delivered in a 
streamlined approach for all HIV infected adults and children. Components of streamlined care 
include ongoing HIV combination prevention strategies including male circumcision. Control 
communities will follow country guidelines for ART.  
In Phase II, communities will be re-randomized. A new baseline HIV negative cohort will be 
established in each community following the hybrid testing. The intervention communities will 
receive targeted PrEP, targeted HIV testing and targeted care interventions in addition to 
universal treatment and streamlined care. The control communities will receive universal 
treatment and streamlined care.  
HIV incidence will be measured using an efficient community cohort design (ECCO) comprised 
of three key elements: A) baseline household community level census, B)  community health 
campaigns (CHC) incorporating HIV testing that use unique identifiers to link individuals 
between successive waves of the intervention, and C) tracking and evaluation of individuals 
who do not participate in CHCs. HIV incidence will be measured at follow-up year 3 for Phase I, 
and at study follow-up year 6 for Phase II (3 years after the start of the new intervention in 
Phase II).  

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Study Population:  Thirty-two communities with a population of approximately 10,000 persons 
each will participate in the following three regions: A) Mbarara/Western Uganda (n=10), B) 
Tororo/Eastern Uganda (n=10), and C) Southern Nyanza Province, Kenya (n=12). 
Randomization to intervention vs. control will occur in pairs of communities matched based on 
key health, geographic and ethnographic variables including: A) geographic region B) 
population density C) number of trading centers D) transportation index, and E) occupational 
mix in Phase I. Matching of those same communities for Phase II will be based on the Phase I 
intervention arm, region, and other drivers of HIV incidence. 
Primary Endpoint: Cumulative 3 year HIV incidence in men and women ages ≥15 years after 
the start of the intervention. Both Phase I and Phase 2 periods of the study will have a primary 
endpoint measurement 3 years after start of the intervention. 
Secondary Endpoints: The health-related secondary endpoints include: 1) mortality (overall, 
maternal, and infant mortality), 2) mother-to-child HIV transmission, 3) AIDS (WHO stage 4), 4) 
tuberculosis, 5) HIV drug resistance, 6) hypertension and diabetes disease control at 3 years 
among HIV-positive and HIV-negative populations, and 7) PrEP uptake and adherence (Phase 
II only). The economic/education secondary endpoints include: 1) adult and child employment 
levels, 2) asset holdings, 3) school attendance levels, 4) programmatic costs, 5) health gains 
expressed in averted Disability Adjusted Life Years (DALY), and 6) cost effectiveness (e.g. cost 
per infection averted and per DALY averted). Other secondary endpoints include: cumulative 6-
year HIV incidence in men and women ages ≥15 years; HIV incidence rate at year 3,  
implementation of the HIV, hypertension and diabetes care cascades including testing, linkage 
and retention to care;  prevalence of complications of diabetes, hypertension and chronic kidney 
disease; and attitudes of community, patients and providers on care delivery in control and 
intervention communities.  
Study Antiretroviral Treatment Regimens: For Phase I, the study intervention is provision of 
ART for all individuals at any CD4+ cell count. ART – the regimen of efavirenz, emtricitabine 
and tenofovir disoproxil fumurate or equivalent – will be provided by the  study for those who do 
not meet in-country guidelines to start ART. These individuals will be guaranteed 3 years of 
ART. After three years, these individuals will continue uninterrupted ART provided by their 
country of residence through agreements with the Ministry of Health. For Phase II, the study 
intervention is provision of tenofovir disoproxyl fumarate and emtricitabine or equivalent for 
PrEP.          
Study Duration: The study will follow the communities for 6 years after the first community 
health campaign.   
Statistics: For both Phase I and Phase II, we  are powered to detect a 40% reduction in 3 year 
cumulative incidence in treatment versus control communities under conservative assumptions 
regarding plausible values for cumulative incidence in the control communities, baseline HIV 
prevalence, incomplete follow up, and between-community variation (matched pair coefficient of 
variation). Primary analyses will consist of estimation of cumulative incidence within each 
community and pair matched community level analysis. 

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GLOSSARY 
 
3TC 
 
 
 
Lamivudine 
ABC 
 
 
 
Abacavir 
AFB 
 
 
 
Acid-fast bacilli test 
ALT 
 
 
 
Alanine aminotransferase 
ANC 
 
 
 
Absolute neutrophil count 
ART 
 
 
 
Antiretroviral therapy 
ATV 
 
 
 
Atazanavir 
AZT 
 
 
 
Zidovudine 
BUN 
 
 
 
Blood urea nitrogen 
CBC 
 
 
 
Complete blood count 
CHC 
 
 
 
Community health campaign 
CHR 
 
 
 
Committee on Human Research, UCSF 
CI 
 
 
 
Cumulative incidence 
CK 
 
 
 
Creatine kinase 
CKD 
 
 
 
Chronic kidney disease 
CL 
 
 
 
Chloride 
CO2 
 
 
 
Bicarbonate 
DAIDS  
 
 
Division of AIDS, NIH 
DALY  
 
 
Disability Adjusted Life Years 
ECCO  
 
 
Efficient community cohort design 
EFV 
 
 
 
Efavirenz 
eGFR  
 
 
Estimated glomerular filtration rate 
FTC 
 
 
 
Emtricitabine 
GIS 
 
 
 
Geographic information system 
GPS 
 
 
 
Global positioning system 
HBV 
 
 
 
Hepatitis B 
HCG 
 
 
 
Human chorionic gonadotropin pregnancy test 
ICER 
 
 
 
Incremental Cost-Effectiveness Ratio 
IRB 
 
 
 
Institutional Review Board 
K 
 
 
 
Potassium 
 
KEMRI  
 
 
Kenya Medical Research Institute 
LPV 
 
 
 
Lopinavir 
MDRC  
 
 
Modification of Diet in Renal Disease (formula) 
MTCT  
 
 
Mother-to-child transmission 
MU 
 
 
 
Makerere University 
Na 
 
 
 
Sodium 
NCD 
 
 
 
Non-communicable disease 
NDA 
 
 
 
National Drug Authority in Uganda 
NIAID  
 
 
National Institute of Allergy and Infectious Diseases 
NNRTI  
 
 
Non-nucleoside reverse transcriptase inhibitor 
NRTI 
 
 
 
Nucleoside reverse transcriptase inhibitor 
NVP 
 
 
 
Nevirapine 
PrEP 
 
 
 
Pre-exposure prophylaxis 
RDT 
 
 
 
Rapid diagnostic test 
RNA 
 
 
 
Ribonucleic acid (e.g., HIV-1 plasma RNA) 
RTV 
 
 
 
Ritonavir 
 
SOM-REC 
 
 
MU School of Medicine - Research and Ethics Committee 
TB 
 
 
 
Tuberculosis 
TDF 
 
 
 
Tenofovir disoproxyl fumarate 
TMP/SMX 
 
 
Trimethoprim/sulfamethoxazole 
UNCST  
 
 
Uganda National Council of Science and Technology 
WHO 
 
 
 
World Health Organization 

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1.0 STUDY CONTEXT 
1.1 Background  
The SEARCH study is designed to test the impact of bold interventions in rural East Africa. In 
Phase I, SEARCH tests the effect on community health of treatment of all HIV-infected persons 
from near the onset of infection using streamlined care.  In Phase II, SEARCH tests the effect of 
targeted PrEP, targeted HIV testing and targeted care interventions on top of universal HIV 
treatment and streamlined care.  
The HIV epidemic has decimated health, education and economic gains that were made in 
Africa in the 1970s, leaving many countries with decreased life expectancy and mortality rates 
not seen in the US since the early 1900s [1]. HIV’s effects on the population level are amplified 
by disabling the work force, damaging maternal health, increasing orphans and fueling the 
overlapping epidemics of TB and malaria [2-5]. The HIV epidemic represents one of the greatest 
public health challenges of all time.  
The combination of prevention efforts and antiretroviral therapy (ART) has reduced the 
incidence of new HIV infections as well as mortality over the last decade. However, there were 
still are around 2 million new HIV infections every  year, and over 20 million individuals have 
died from HIV [1]. HIV is the leading cause of death among women of reproductive age in Sub-
Saharan Africa. At the beginning of the 21st century, global approach to deploy ART to reduce 
AIDS mortality prioritized treatment for the most ill patients based on CD4 cell count. At the start 
of SEARCH in Uganda and Kenya, ART was  generally administered in adult patients when 
their CD4 count fell  below 350 cells/mm3, or later 500 cells/mm3, and when they were  
diagnosed with a WHO Stage III or IV disease, and in other patients at high risk of HIV disease 
progression, including those with tuberculosis (TB).  Treating HIV early can prevent AIDS and 
prevent TB, a leading killer of HIV infected patients [6]. Two recent randomized trials (Temprano 
and START) demonstrate the benefit of early HIV treatment for the prevention of TB [7, 8]. Data 
also show that ART can reduce HIV transmission by 96% in HIV sero-discordant couples [9] . 
These data illustrate a dual purpose for ART – prevent AIDS (including TB) in the HIV infected 
individual and prevent HIV transmission to the uninfected partner. The identification of HIV 
infection early and initiation of treatment thus has the potential to influence the overall health of 
the community as well as its economic and educational strength and viability. After 3 years of 
SEARCH, WHO policy has changed based on the evidence cited here to recommend HIV 
treatment for all and PrEP for communities where HIV incidence exceeds 3%.  These 
recommendations are based on robust data showing that PrEP, when taken, dramatically 
reduces incident HIV infection [10, 11]. 
In Phase I of  SEARCH, we will quantify the effect of an early HIV diagnosis and ART approach 
(“test and treat”) on the health, economic productivity and educational outcomes of rural 
communities in East Africa.  There have been several mathematical models, including a 
landmark publication by Granich et al and a subsequent economic analysis, showing frequent 
HIV testing and ART will reduce overall HIV incidence over a period of 5 to 10 years, and that 
the upfront investments required for such an approach result in net savings over 13 years in 

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South Africa [12]. These models have generated heated debate within the scientific community 
based on various assumptions inherent in the models [13, 14]. These models may have also 
underestimated the benefits of ART because the evaluation framework did not include all the 
health benefits of ART, such as prevention of TB or the socioeconomic benefits of the 
preservation or return of good health afforded by ART. Thus it is time to test a population-based 
approach to  early HIV diagnosis and treatment approach and to evaluate its cost and effects 
with an evaluation framework that includes health, economic and education metrics [15-17]. 
The 2015 WHO Guidelines that recommend treatment for all and PrEP for populations with an 
incidence that exceeds 3% raise many additional questions in the field. In Phase II of SEARCH, 
we will quantify the effect of targeted PrEP, targeted HIV testing and targeted care interventions 
(linkage, retention)  based on community-level data collected in Phase I of the study, on top of 
universal treatment and streamlined care .  
Inherent to the scale up of HIV treatment including PrEP and an important part of the SEARCH 
is the need to develop new models of chronic health care delivery at the community level that 
are lower in resource needs and are sustainable. Finding patients earlier in HIV disease, 
keeping these individuals healthy with early ART, and delivering their care in a streamlined 
manner in fact may be the only viable path to deal with the health care worker shortage which is 
amplified by late HIV diagnosis, and the medical expertise and facilities needed to care for 
patients who present and are treated after HIV has significantly progressed.  Part of the 
SEARCH approach is to implement and study systems of chronic care where HIV infrastructure 
is leveraged for NCD care. To this end we will be measuring costing as well as hypertension 
and diabetes control among both HIV infected and non-infected populations. Finally, finding 
novel delivery mechanisms for PrEP and further optimizing care delivery through targeting of 
high risk populations may be the only way to truly maximize the power of treatment to shut down 
the HIV epidemic in an affordable and sustainable way.  
Also inherent to the design of the SEARCH intervention is the recognition that a “test and treat” 
approach must find an overwhelming majority of HIV infected individuals, improve upon the 
entire continuum of care including participation of the most at risk populations and build upon 
prevention interventions known to work such as male circumcision [18, 19]. The SEARCH study 
is built upon biomedical evidence that is being applied and tested in a manner which 
incorporates social science evidence and approaches.   
The SEARCH study is a multicountry collaboration built upon expertise from a broad spectrum 
of scientific disciplines. It is grounded upon partnerships with scientific, health, and development 
global agencies. SEARCH is designed to inform the health sector, finance ministries, and the 
scientific and lay communities on the medical and economic effects of early antiretroviral 
therapy (Phase I), and targeted PrEP, targeted HIV testing and targeted care interventions 
(Phase II), in rural East Africa. 
1.2 Rationale    

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There is overwhelming evidence that the benefits of ART extend well beyond those originally 
appreciated, and those that are currently measured. ART reduces mortality among persons with 
HIV. The HPTN 052 study showed that ART reduces AIDS related illness even in persons with 
CD4 cell counts above thresholds of CD4 cell counts (i.e. 350 cells/mm3)  [9]. ART also 
dramatically reduces TB risk both on the individual and the community level [6, 20, 21]; reduces 
the risk of malaria in individuals [22]; Reduces mother to child transmission (MTCT) of HIV; and 
reduces maternal and child mortality [23, 24]. Two large recently completed randomized studies 
show that ART, given early, produces superior effects compared to waiting until patients CD4 
cell counts reaches a threshold of 350 or 500 cells/mm3 [7, 8].  
ART is also a key component in a multilevel HIV prevention strategy. The HPTN 052 study 
shows definitively that ART reduces HIV transmission and preserves the health of the HIV 
infected persons receiving treatment [9]. These results build upon prior observational cohort 
studies showing reductions in HIV transmission by ART in HIV sero-discordant couples [25]. 
Biomedical interventions such as ART are likely to be highly complementary to proven 
interventions such as male circumcision and have an important role in reducing new HIV cases.   
ART and the associated restoration of health also have important effects on socio-economic 
outcomes. Studies conducted in various settings in sub-Saharan Africa and South Asia have 
documented a significant improvement in the employment outcomes of adults following the 
initiation of ART [19, 26-29]. These studies have shown a large and rapid increase in labor 
supply and labor productivity, from levels that were initially very low to levels that were similar to 
those of HIV uninfected adults. In many cases, the increase in employment outcomes took 
place within 3-6 months of ART initiation, a result that is consistent with the rapid improvement 
in health and functional capacity due to ART. Furthermore, studies have found that the treated 
patients’ family members (particularly children) also benefit substantially when a working-age 
adult becomes healthy and productive [30]. Following ART initiation in Kenya, there was a 
significant increase in the school attendance of children living with treated patients, as well as a 
reduction in child labor and improvement in nutritional status. These studies suggest that earlier 
ART initiation would prevent a decline in socio-economic status and help to protect living 
standards.  
ART can contribute to prevention of new HIV infections and prevention of AIDS and TB, 
enhance economic productivity, and improve socio-economic outcomes more generally.  A key 
question at the start of SEARCH was  why is the ART “test and treat” strategy not being 
deployed?  
First the strategy requires knowledge of HIV status, and globally, most individuals are not aware 
of their HIV status. We aim to identify HIV status throughout the community through annual 
multi-disease  community health campaigns that we have piloted and refined in western rural 
Uganda.  Our approach places HIV testing in a framework of chronic disease care vs “stand 
alone” HIV testing.that can reduce stigma associated with HIV testing and provide health 
services the communities desire. Moreover, we are interested in understanding  if and how this 
approach can improve HT/DM control among HIV infected persons  Second, there is a stigma 
for participating in care that prevents even those with known HIV infection from getting treated. 

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This study will be conducted in communities where we have established ongoing community 
engagement work, and care delivery will be adapted to the community to promote participation 
and retention.  Third, there are few data in developing nations to prove or disprove that 
asymptomatic individuals will initiate and adhere to ART. We are currently studying predictors of 
adherence in this population and will incorporate this knowledge into care delivery.  Non-
adherence to ART has serious consequences for the HIV epidemic because it means that A) 
individuals will not immediately benefit, B) HIV can become resistant requiring new and more 
expensive medications, and C) resistant HIV can spread sexually and during mother to child 
transmission.  
Community engagement strategies will be deployed in this study to maximize adherence. 
Finally, ART (despite 10-fold reductions in drug price over the last decade) is expensive to 
deliver. Providing it according to the current health delivery system might not be possible due to 
shortages in financial and human resources, particularly when doubts are expressed about the 
cost-effectiveness of such an intervention relative to many other priority health interventions. 
Thus data are needed to inform policy makers about the full range of benefits and risks of a test 
and treat ART strategy. During the course of the study, we will also use social science 
approaches to understand how the attitudes of the community, patients and providers influence 
the results of the study.  
Since the start of the SEARCH study, the policy landscape has changed in 2 major ways, 
requiring that SEARCH become a 2 phase study.  First, WHO now recommends ART for all 
persons living with HIV [31]. Second, UNAIDS has started a campaign for global programs to 
achieve “90,90,90.” This refers to 90% of persons knowing their status, 90% on ART and 90% 
suppressed [32].  Phase I of the SEARCH study will address extremely important questions for 
policy makers in this new landscape. The first question is what is the effect on population level 
new HIV infections of rolling out ART and achieving “90,90,90”? The second question is how 
can “90,90,90” be achieved? This can be accomplished in the first 3 years of the study.  
The second phase of SEARCH is predicated on the knowledge from Phase I that a) Even after 
achieving “90,90,90” there are still many new HIV infections; b) PrEP works (see above section) 
and could be utilized to further reduce new infections, but how to do this on a population level is 
not known; and c) Components in the care cascade in SEARCH have still not been fully 
optimized with our streamlined care approach and new approaches are needed to get beyond 
the “90,90,90” targets. This knowledge forms the basis for Phase II in SEARCH, where we will 
ask the following questions: 1) What is the effect of adding targeted PrEP and targeted HIV 
testing and care on top of our current testing and streamlined care model on HIV incidence? 2) 
How do we optimally implement targeted approaches to PrEP, HIV testing and care in the 
setting of universal treatment?  
1.3 Antiretroviral therapy 
The 2010 WHO Antiretroviral Treatment Guidelines recommended ART for all adults with WHO 
stage III or IV disease, tuberculosis or CD4 ≤350 cells/mm3. ART was recommended for all 
children less than 2 years of age, and subsequent ART is dependent on a variety of disease 

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and CD4 specific criteria. The WHO recommended a variety of approaches of ART for HIV+ 
pregnant women who otherwise do not meet the adult guidelines for ART.  The specific country 
guidelines for ART treatment for countries participating in SEARCH starting in October, 2011 
are summarized in Table 1 below.  

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Table 1: 2010  ART treatment guidelines 
Country 
Population  
ART initiation  
Uganda[33] 
Adults and children ≥5 years 
CD4 count ≤350 
cells/mm3 
Adults and children co-infected with 
tuberculosis (TB), co-infected with 
hepatitis B (HBV), with WHO Stage III or 
IV disease, and pregnant women 
(prophylaxis)  
Initiate ART 
irrespective of  
CD4 % or count 
Children 2 to <5 years 
CD4 % <25% or 
CD4 count <750 
cells/mm3 
Children <2 years 
Initiate ART 
irrespective of  
CD4 % or count 
Kenya[34] 
Adults and children ≥12 years 
CD4 count ≤350 
cells/mm3 
Adults and children co-infected with 
tuberculosis (TB), co-infected with 
hepatitis B (HBV) with evidence of liver 
damage, with WHO Stage III or IV 
disease, with HIV-associated 
nephropathy, and pregnant women 
(prophylaxis) 
Initiate ART 
irrespective of  
CD4 % or count 
Children 5 to 12 years 
CD4 % <20% or 
CD4 count <500 
cells/mm3 
Children 2 to <5 years 
CD4 % <25% or 
CD4 count <1000 
cells/mm3 
Children <2 years 
Initiate ART 
irrespective of  
CD4 % or count 
In 2013, the WHO revised ART initiation guidelines, recommending antiretroviral therapy for 
persons with CD4+≤500 cells/ml, all pregnant women , HIV serodiscordant couples and other 
most at risk populations.. These recommendations are summarized at 
http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf. These guidelines 
were adopted in Uganda and Kenya in 2014. In Phase I of this protocol, the intervention arm will 
provide antiretroviral therapy for all community members who otherwise do not meet the country 
criteria for ART initiation; in Phase II both study arms will provide antiretroviral therapy to all 
community members (if any) who otherwise do not meet the country criteria for ART initiation. 
The selection of antiretroviral regimen for this study was based upon the following regimen 
characteristics: antiretroviral therapy efficacy, safety profile, monitoring requirements, pill 
burden, knowledge of HIV drug resistance that emerges under the drug use, prior use and 

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experience within the study countries, consultation with in- country  advisory board, consultation 
with in -country regulatory bodies. The following regimens will be provided to the study 
populations that otherwise do not meet criteria for government supported ART.  
Table 2: Study Treatment, Phase I1 
Population 
First line regimen  
Recommended 
substitutions/second line regimens 
Adults and 
adolescents, 13 
years and above 
Emtricitabine or lamivudine, plus 
tenofovir disoproxil fumurate and 
efavirenz 
Abacavir or zidovidine plus 
lamivudine plus 
atazanavir/ritonavir or 
lopinavir/ritonavir2 
Children 3-12 
years 
Abacavir, lamivudine, and efavirenz  
Zidovudine, lamivudine and 
lopinavir/ritonavir 
Children <3 years 
Abacavir, lamivudine, and nevirapine 
Zidovudine, lamivudine and 
lopinavir/ritonavir 
Pregnant women 
and women 
attempting 
conception3   
Emtricitabine or lamivudine, plus 
tenofovir disoproxil fumurate and 
efavirenz.  
Abacavir plus lamivudine plus 
atazanavir/ritonavir or 
lopinavir/ritonavir or nevirapine 
 
1.  Exceptions to the regimens can be made in accordance with in-country treatment guidelines 
2.  Second-line therapy 
3.  Women may receive ART via in-country program (not study intervention) if ART is started 
immediately and lifelong (option B plus) 
 
In 2015, the WHO updated their guidelines and recommended HIV treatment for all and PrEP 
for populations with HIV incidence of over 3% [31]. Based on this change, SEARCH was 
modified into a 2 phase study in which Phase II incorporates universal treatment in the control 
arms. The first line regimens for adults includes an NNRTI (efavirenz) plus 2 NRTIs (TDF and 
FTC or 3TC). Details on these regimens can be found in the guidelines. 
 

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2.0 STUDY OBJECTIVES   
2.1 Primary Study Objectives 
2.1.1 To determine the effect of a strategy to start ART in HIV diagnosed persons at any CD4 
count with streamlined delivery of HIV care compared to a country based ART guidelines 
on 3 year cumulative HIV incidence in rural communities in Uganda and Kenya.   
2.1.2 To determine the effect of targeted PrEP, targeted HIV testing and targeted treatment 
interventions on top of universal HIV treatment with streamlined care on 3 year 
cumulative HIV incidence in rural communities in Uganda and Kenya.  
Unless designated otherwise, secondary objectives apply for both Phase I and Phase II.  
2.2 Secondary Objectives – Health  
2.2.1  To compare the 6 year cumulative incidence of HIV infections between the different 
treatment strategies over time. 
2.2.2 To compare time from diagnosis to AIDS between the study arms. 
2.2.3  To compare incidence of AIDS-defining events between the study arms. 
2.2.4  To compare proportion of total TB and incident TB cases associated with HIV between 
the study arms. 
2.2.5  To compare mortality between the study arms. 
2.2.6  To compare maternal and child mortality between the study arms. 
2.2.7  To compare mother to child transmission between the study arms. 
2.2.8  To compare population HIV RNA metrics between the study arms. 
2.2.9  To determine the association between population HIV RNA metrics and HIV incidence. 
2.2.10 To compare the prevalence of transmitted HIV drug-resistance mutations and 
pharmacologic measures of ART between the study arms. 
2.2.11  To compare rates of linkage to and retention in care for HIV between the study arms. 
2.2.12  To compare time to ART-initiation between the study arms. 
2.2.13 To characterize treatment outcomes in Phase I of high CD4 count individuals (CD4>350) 
including: A) CD4 cell count recovery, B) rate of virologic suppression, C) treatment-

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associated toxicities and grade 3 and 4 adverse events, and D) HIV drug resistant 
mutations after 1 and 2 years of treatment. 
2.2.14 To compare the 3 and 6 year cumulative incidence of internally derived HIV infections 
(infections genetically linked to a prior infection among members of the same 
community) between the study arms. 
2.2.15 To evaluate attitudes of community, patients and providers on care delivery in control 
and intervention communities. 
2.2.16 To evaluate implementation of other disease care cascades (hypertension, diabetes, 
women and children health services) including testing, linkage and retention to care. 
2.2.17 To compare hypertension and diabetes control between intervention and control arm 
among HIV-positive and HIV-negative adults at follow up year 3  
2.2.18 To compare HIV incidence between baseline and follow-up year 3  
2.2.19 To evaluate prevalence of complications of diabetes, hypertension and chronic kidney 
disease (CKD) and to understand the genetic susceptibility of diseases in the study 
populations in Phase II.  
2.2.20 To evaluate adherence to PrEP, the PrEP cascade, and attitudes towards PrEP in 
Phase II. 
2.2.21 To evaluate the uptake, adherence and completion of PEP in selected communities. 
2.3 Secondary Objectives – Economic and Education Outcomes 
2.3.1  To compare the trends in average levels of adults’ on- and off-farm employment 
between the study arms. 
2.3.2  To compare the trends in average levels of children’s on- and off-farm employment (child 
labor) between the study arms. 
2.3.3  To compare the trends in average levels of children’s time allocation to schooling and 
household activities between the study arms. 
2.3.4  To compare the trends in average asset holdings (durable good and livestock) between 
the study arms. 
2.3.5  To compare the trends in agricultural output and other economic production, such as 
fishing, between the study arms. 

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2.3.6  To compare the trends in average levels of cash and in-kind transfers between the study 
arms. 
2.4 Secondary Objectives – Cost and Cost-Effectiveness 
2.4.1 To compare costs of programming (campaigns, ART) and PrEP (Phase II only)  between 
the study arms: overall; per person identified, linked to care, and started on ART; and 
per ART-month, CD4 level recovered, and viral load suppressed. 
2.4.2 To compare disease burden (expressed in disability adjusted life years, DALYs) between 
the study arms, during and modelled beyond the study period. 
2.4.3 To compare the savings from averted disease associated treatment costs between the 
study arms. 
2.4.4 To compare the occurrence and consequences of false positive HIV diagnosis  
2.4.5 To calculate the incremental cost-effectiveness of the intervention, as net cost per DALY 
averted. 
2.4.6   To evaluate streamlined vs. non-streamlined care including time in motion studies for 
staff and clients (Phase I only). 
2.4.6 To evaluate cost of care for NCDs (hypertension and diabetes) in HIV-positive and HIV-
negative populations  
2.4.7 To evaluate targeted PrEP vs. country standard PrEP and targeted linkage, retention, 
and suppression interventions including time in motion studies for staff and clients 
(Phase II only). 
3.0 STUDY DESIGN  
SEARCH is a two phase cluster randomized community trial. 
The primary study hypothesis of Phase I is:  ART initiation at any CD4 count with streamlined 
delivery compared to ART initiation according to country guidelines will reduce cumulative 3 
year HIV incidence and protect and improve health, economic and education outcomes in 
communities with annual HIV testing campaigns.  The primary study endpoint is cumulative 5 
year HIV incidence in men and women ages ≥ 15 years. The study will be conducted in rural 
communities in Uganda and Kenya.  
The primary study hypothesis of Phase II is: targeted PrEP, targeted HIV testing and targeted 
care interventions on top of universal treatment and streamlined care will reduce cumulative 3 
year HIV incidence and improve other health and economic outcomes. The primary Phase II 
study endpoint is cumulative 3 year HIV incidence in men and women ages ≥ 15 years 
Community health campaigns will be conducted in all study communities at baseline and follow 
up year 3  and will offer HIV testing and multi-disease prevention and treatment services. The 

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intervention in Phase I is ART independent of CD4 cell count delivered in a streamlined 
approach for all HIV infected adults and children. This intervention will be applied in the context 
of ongoing HIV combination prevention strategies including male circumcision. In control 
communities, ART will be provided by country programs according to their guidelines. The 
intervention in Phase II is targeted PrEP, targeted HIV testing and targeted care interventions 
on top of universal HIV treatment given by streamlined care.  
HIV incidence will be measured at follow up years 3 and 6 using an efficient community cohort 
design (ECCO) comprised of three key elements: A) baseline household community level 
census, B) community health campaigns that use unique identifiers to link individuals between 
successive waves of the intervention, and C) tracking and evaluation of individuals who do not 
participate in annual CHCs. 
The schema of Phase I and Phase II of the study is shown below:  
 

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4.0 STUDY POPULATION  
4.1 Community Level Inclusion Criteria  
4.1.1 Non-adjacent geopolitical units in south-western and eastern Uganda and western Kenya. 
4.1.2 Most recent census population between 9,000 and 11,000 individuals. 
4.1.3 Served by an ART providing health center.  
4.1.4 Community leader commitment for study participation and implementation. 
4.1.5 Accessibility to health center via a maintained transportation route. 
4.1.6 Community location with sufficient distance from other potential study communities to limit 
contamination of intervention or control conditions (buffer zone) 
4.2 Individual Level Inclusion Criteria  
4.2.1 Residency of individual in community, defined as present in household for at least 6 
months of the calendar year. 
4.3 Community Level Exclusion Criteria 
4.3.1 Presence of ongoing community-based ART intervention strategies that provide treatment 
outside of the current in-country treatment guidelines. 
4.3.2 An urban setting defined as a city with a population of 100,000 or more inhabitants. 
4.3.3 Absence of a health center able to provide ART. 
 

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5.0 STUDY INTERVENTIONS  
5.1 Antiretroviral Therapy in a Streamlined Care Delivery (Phase I) 
Streamlined care is part of the study intervention arm only in Phase I. In Phase II, streamlined 
care will be provided through country delivery and be “standard of care” in both arms.  If 
updated treatment guidelines based on WHO recommendations are not yet implemented in 
country by the beginning of Phase II, participants in both the control and intervention arms may 
receive care through the ART delivery procedures described in Sections 7.1-7.6 until universal 
treatment is made available. 
5.1.1 Streamlined ART Delivery 
In Phase I of this study, all HIV+ participants in intervention communities will be offered HIV 
therapy at ART providing health centers via “streamlined care,” in order to maximize efficiency 
and clinic throughput, and engender the smallest impact of expanded ART access on current 
clinical sites, while maintaining treatment efficacy and safety. “Streamlined care” is defined as a 
method of enrolling ART-naïve participants, and initiating, monitoring, and sustaining ART 
delivery, in a manner consistent with the principles of care outlined in Table 3, recognizing that 
both facilities and patterns of care will vary somewhat between sites[48]. In addition, 
intervention sites will employ enhanced services for linkage and retention. These include 
provision of provider cell phone number for referral clinic; cell phone reminder before 
appointments; standardized tracking for linkage from CHC to clinic and missed visits; and 
accelerated ART start for patients not on treatment.  For participating health centers that do not 
currently offer ART in this streamlined fashion, study investigators will work with clinic staff to 
design and adapt existing procedures to this approach. During the course of the study, we will 
evaluate provider and patient attitudes and the implementation of streamlined and routine care.  
Table 3. 
           Features of “Streamlined” ART Delivery Model 
ART Clinic 
       Healthcare Team 
       ART Monitoring 
 
• 
Rapid ART initiation available 
with expedited counseling# 
• 
Short throughput* for patients 
with no active issues 
• 
Targeted adherence support 
• 
Convenient ART refill process 
 
 
 
*Throughput: time spent from 
clinic check-in to completion of 
visit 
#ART initiation may begin at CHC 
 
• 
For stable, high CD4 
patients, non-MD health 
care worker responsible for: 
1. Screening for ART-related 
adverse events and 
toxicities 
2. Dispensing, managing and 
altering ART regimens 
3. Maintaining patient and 
drug accountability records 
 
• 
Back-up support for care 
and consultation by 
physician 
 
• 
Streamlined visit schedule 
conducted by non-MD health 
care workers 
• 
Targeted laboratory 
evaluation schedule 
• 
Viral load monitoring at 6 
months after ART start and 
then at least yearly. Provider 
counseling with client on all 
viral load results.  Back-up 
support by physician 

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Study investigators and staff may provide additional support to ART providing health centers 
where needed. This may include assistance with staffing, training on good clinical practices and 
HIV care and non-communicable disease management, operation of linkage to care 
procedures, and or oversight of study drug accountability.  An anonymous patient satisfaction 
survey will be offered to a random subset of HIV-positive patients during the implementation of 
Phase II to assess streamlined care provision for quality assurance purposes.  In addition, a 
subset of HIV-positive adolescents and young adults will receive intensive viral load monitoring 
and counselling and a life-stage assessment in order to improve youth engagement and 
understand treatment barriers. 
5.1.2 Provision of ART to persons who do not qualify for treatment by country guidelines 
ART study medication will be provided to participants in communities randomized to intervention 
who do not meet in-country treatment guidelines. The study treatment will consist of a 3-drug 
ART regimen that will be provided to participants by the study (Table 2). 
5.1.2.1 Regimen and Administration 
Adults and adolescents, 13 years and above 
First Line Regimen:  
Tenofovir disoproxil fumurate (TDF) 300mg, PLUS 
 
Efavirenz (EFV) 600mg, PLUS EITHER 
 
Emtricitabine (FTC) 200mg, OR 
 
Lamivudine (3TC) 150mg 
Recommended Second Abacavir (ABC) 300mg, PLUS 
Line Regimen: 
 
Lamivudine (3TC) 150mg, PLUS EITHER 
Atazanavir (ATV) 300mg and ritonavir (RTV) 100mg, OR 
Lopinavir/ritonavir (LPV/RTV) 200mg/50mg, administered as a fixed-
dose combination 
Children 3 – 12 years   
First Line Regimen:  
Abacavir, PLUS 
 
Lamivudine, PLUS  

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Efavirenz 
Recommended Second Zidovudine (AZT), PLUS 
Line Regimen: 
 
Lamivudine, PLUS 
Lopinavir/ritonavir, administered as a fixed-dose combination 
Individual dosing information by weight can be found in Appendix E. 
Children < 3 years  
First Line Regimen:  
Abacavir, PLUS 
 
Lamivudine, PLUS  
 
Nevirapine (NVP) 
Recommended Second Zidovudine, PLUS 
Line Regimen: 
 
Lamivudine, PLUS 
Lopinavir/ritonavir, administered as a fixed-dose combination 
Individual dosing recommendations by weight can be found in Appendix E. 
Pregnant women and women attempting conception* 
First Line Regimen:   
Tenofovir disoproxil fumurate (TDF) 300mg, PLUS 
Efavirenz (EFV) 600mg, PLUS EITHER 
Emtricitabine (FTC) 200mg, OR 
Lamivudine (3TC) 150mg 
Or if patient provider desire: Tenofovir disproxil fumerate, PLUS 
EITHER 
Emtricitabine (FTC) OR Lamivudine (3TC), 
PLUS 
Lopinavir/ritonavir 200mg/50mg, two tablets PO twice daily, 
administered as a fixed-dose combination. After the first trimester, 
women may switch to efavirenz 600mg, as described above. 

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* Women may receive ART via in-country program (not study intervention) if ART is started 
immediately and lifelong (option Bplus) 
 
Recommended Second  Abacavir 300mg, two tablets PO daily, PLUS 
Line Regimen: 
 
 
 
 
Lamivudine 150mg, one tablet PO twice daily, PLUS EITHER 
 
Atazanavir 300mg and ritonavir 100mg, once PO daily, OR 
 
Nevirapine 200mg, one tablet PO daily for first 2 weeks, then one 
tablet PO twice daily 
Based on variations of standard first- and second-line ART regimens suggested among in-
country treatment guidelines, substitutions to the above can be made at the investigators’ 
discretion. 
5.1.2.2 Product Supply and Accountability 
Supply 
Each participant will be provided with ART treatment over the course of his or her participation.  
Truvada® and efavirenz, if prescribed, will be provided by the study; other medications will be 
provided by their country of residence through agreements with the Ministry of Health. 
Accountability 
Staff will maintain records of study drugs distributed according to standard guidelines.  At most 
sites, lot number and the number of pills given to each participant at each visit will be recorded.  
For Gilead-provided study medications, current product labels, Certificates of Analysis, date 
received, lot number, expiration date, and date used will be maintained for the study.  Monthly 
inventory will be conducted. 
5.2 Targeted PrEP (Phase II)  
PrEP will be provided to high risk populations defined by data collected in Phase I and by 
enhanced self-risk assessment in the intervention arms.  The populations will be identified 
through examination of sero-incidence data. Populations with new infections who do not fall into 
WHO high risks groups will be offered PrEP if they meet a risk threshold from SEARCH data or 
if they self identify as at risk for infection.  Enhanced self-risk assessment approaches will be 
developed at the community level, with community leaders that have been engaged throughout 
the study providing input into appropriate approaches for education and outreach. Treatment 
delivery models will be tailored to the population insuring that the safety monitoring is in line with 
standards identified in the protocol.  
5.2.1 Regimen and Administration 

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Adults, 15 years and above 
Tenofovir disoproxil fumurate (TDF) 300mg, PLUS EITHER 
Emtricitabine (FTC) 200mg, OR 
Lamivudine (3TC) 150mg. 
If country guidelines recommend TDF only, this will also be used as an option. 
5.2.2 Product Supply and Accountability 
Supply 
Each participant will be provided with PrEP either through the study or through the country of 
residence through agreements with the Ministry of Health. Truvada® may be provided through 
the study.  
Accountability 
Staff will maintain records of study drugs distributed according to standard guidelines.  At most 
sites, lot number and the number of pills given to each participant at each visit will be recorded.  
For Gilead-provided study medications, current product labels, Certificates of Analysis, date 
received, lot number, expiration date, and date used will be maintained for the study.  Monthly 
inventory will be conducted. 
5.2.3 Targeted Linkage, Retention and Suppression 
Community specific interventions will be designed to prevent high risk populations from not 
linking to care or not retaining in care or achieving viral suppression. The approach to designing 
these interventions will be to utilize the data collected in Phase I to identify characteristics at the 
community level of persons fitting in these categories. A menu of evidence-based interventions 
can be adapted and evaluated in the intervention communities.  
 

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6.0 COMMUNITY LEVEL STUDY EVALUATIONS 
6.1 Baseline Household Community Level Census 
Prior to the start of the study, study team members will meet with local officials and community 
representatives to discuss the study and plans for the census. Using a map of the boundaries of 
the selected communities, study staff will systematically cover the entire area within the 
boundaries to identify and enumerate all households. A head of the household will provide 
informed consent for the following information to be collected about household members:   
• 
Name 
• 
Relationship to head of household 
• 
Mobile phone number 
• 
Demographic information such as age, gender, occupation and marital status.   
• 
A fingerprint of each household member will be collected with the use of a fingerprint 
biometric device. 
• 
The household’s location relative to the local health center will be mapped using hand-
held GPS receivers. 
At the time of the census, household members will be consented verbally for participation in the 
community health campaign and for the census itself. Household members not present at the 
time of the census will not be excluded from participation in community health campaigns.    
6.2 Community Health Campaign (CHC)  
6.2.1 Overview 
A baseline community health campaign  for Phase I and Phase II will be conducted in all study 
communities and will offer A) HIV testing, and B) multi-disease diagnostic, prevention, 
treatment, and referral services (such as malaria, deworming), tailored to the community. The 
CHCs will serve two primary purposes. First, the campaigns will allow for community-wide HIV 
testing and prompt linkage to HIV care – a critical aspect of care delivery for both intervention 
and control communities. Multi-disease service delivery in the context of a community health fair 
will encourage broad communication across all demographic groups and encourage HIV testing 
as a routine part of health care. Second, the campaigns will provide an evaluation framework for 
multiple study outcomes, including health, economic and education outcomes, such as HIV 
incidence, community HIV viral load, interval vital status and AIDS assessments for efficient 
community cohort participants.  CHCs will be conducted annually in the intervention 
communities until follow up year 3, in a targeted form in follow up years 4 and 5 and full service 
at follow up year 6. Full service CHCs will be conducted at baseline and at 3 and 6 years of 
follow up in the control communities. Adults who do not attend the campaigns may have follow 
up “tracking” visits to ascertain HIV status and offer ART start for infected persons. 
6.2.2 CHC Procedures 

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Each community will have a baseline campaign performed within 4 months after the census and 
performed up to annually (Phase I). Roving CHC teams assigned to specific study communities 
will conduct the campaigns. Campaign training will be performed at the start of the SEARCH 
study, and updated as needed. 
6.2.2.1 Community mobilization 
The primary goal of community mobilization will be to maximize CHC participation and linkage 
to care by informing the community of the purpose, dates and locations of the community health 
campaign days, and of the services that will be available. These activities will include meetings 
with village leaders throughout each study community, and may include poster and leaflet 
advertising, radio advertising and enlisting community-based volunteers to describe campaign 
activities and encourage participation in the CHCs and linkage to care. Community mobilization 
will incorporate the principles of a study community engagement plan which may include 
incentives at the CHC, such as a raffle for prizes, supported by the community.  
6.2.2.2 CHC Services  
The campaign will consist of a series of stations arranged so as to maximize participant privacy 
and flow through the campaign. Participants will proceed through stations such as those 
described below, but which could be adapted to the services provided in the individual 
communities. Examples of other activities that could be included are: vaccines, referral stations 
for adult male circumcision, women and children health services, tuberculin skin testing, urgent 
care station, men’s health services, PrEP counselling,  and dermatological screening and 
services. 
Welcome Station 
At the start of each campaign, participants will review the services offered at the campaign with 
campaign staff.  If participants have not taken part in census activities prior to the campaign, 
informed verbal consent will be obtained from all adults for themselves and their children to 
participate in the campaign and to take part in census activities.  The verbal consent form will be 
read to them in the local language, and their fingerprint biometric will be recorded on tablet 
computers as affirmation of their agreement to participate.  Identifying information will be 
collected from each community member.  Identification of participants will be based on the 
following: name, village of residence, age, gender, and fingerprint biometric. Campaign staff will 
provide each participant with a campaign results card to record their screening results. 
Participants will then initiate campaign activities. 
Health and Socioeconomic Interview Station 
Health and socioeconomic questionnaires will be performed for each participant, in order to 
collect updated information about health and economic status, including interim births, illnesses, 
hospitalizations; changes in employment or educational attainment over the past year; and 

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migration patterns and social network.  Staff will interview women of child-bearing age regarding 
any births and deaths of children over the past year. 
Pre-test Counselling Station 
Prior to undergoing diagnostic testing in the campaign field laboratory, group pre-test 
counselling will take place to inform and update participants on the diagnostic services offered 
and answer questions. 
Campaign Field Laboratory  
Multiple diagnostic services will be offered in the field laboratory.  Some will be offered at all 
campaigns, and others will be recommended but not required, depending on country guidelines 
and local resources.  
a. All participants:  
i. HIV Antibody testing for all participants >9 months (Kenya) or >18 months 
(Uganda) according to country policy at the baseline CHC. In subsequent 
years, HIV testing will be optional for persons ≤10 years of age, 
depending on epidemiology of region:   
1. Initial rapid HIV test 
2. Participants with a negative result will be informed that they are 
HIV-negative 
3. Participants with an initial positive result will undergo a second 
rapid HIV test.  If the result is positive, participants will be informed 
of their HIV-positive status. 
4. Participants with discordant rapid test results (first test positive, 
second test negative) will undergo a third “tie-breaker” HIV test.  
Participants with a positive “tie-breaker” test will be informed that 
they are HIV positive. Participants with a negative “tie-breaker” 
test will be informed that they are HIV-negative.  
5. At follow up years 3 and 6 additional confirmatory HIV testing will 
be performed for research measurement confirmation of HIV 
infection and not for clinical management. At follow up year 2, this 
test will also be performed for a subset of communities in Uganda 
and Kenya for quality control of the confirmatory assay. 
ii. Dried Blood Spot on filter paper for all HIV-positive participants  
iii. At the baseline CHC, HIV testing (for HIV DNA) on Dried Blood Spots 
may be performed on either: 
a) all infants ≤9 months (Kenya) or ≤18 months (Uganda) of HIV positive 
or HIV status unknown mothers; or 
b) on infants of ≤18 months old who test rapid HIV Antibody positive,    
according to routine country policy. 

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iv. At follow up years 3 and 6, HIV testing (for HIV DNA) on Dried Blood 
Spots may be performed on infants ≤18 months of HIV positive or 
deceased mothers 
v. At follow up years 3 and 6, HIV Antibody testing may be performed on 
children 18 months to 4 years of age of HIV positive or deceased mothers 
vi. Optional: Malaria rapid diagnostic test (RDT) for participants with a 
temperature taken at the CHC of >38oC  
vii. Recommended:  Finger-stick blood random plasma glucose measure for 
all participants ≥13 years and/or HB A1c screening when available 
viii. Recommended:  Syphilis screening (RPR) for all >15 years 
ix. Recommended:  Blood pressure measurement for all ≥18 years 
x. Optional: Tuberculosis screening: Communities may be randomized to 
receive participant TB screening as part of the CHC 
xi. Optional:  Blood collected for measurement of serum creatinine and urine 
collected for renal function in a sampled population of participants 
xii. Optional: Malaria genotyping: Communities may be randomized to collect 
filter paper blood spots for genotyping 
b. HIV-infected participants:  
i. Point-of-care CD4 cell count testing (Phase I); CD4 may be performed on 
sampled populations at follow up year 6 in Phase II  
ii. HIV RNA, by fingerprick or phlebotomy 
iii. HIV infection recency may be determined from DBS using additional 
serologic testing 
c. Children <18 years 
i. Recommended:  Anthropomorphic Measures: Height and weight 
ii. Recommended:  Malaria rapid diagnostic test (RDT) for children <10 
years old with a recorded temperature (>38oC) at the CHC 
Post-test Counselling  
All adult participants, regardless of test results, will receive standard post-test counselling per 
country guidelines, including participants newly diagnosed with HIV. For known HIV+ 
participants already engaged in care, counselling will be adapted to meet their needs. Child 
participants will receive post-test counselling with a parent or guardian. On-site malaria 
treatment will be available at this station as well. All malaria RDT positive participants will be 
offered on-site malaria treatment, according to Ugandan or Kenyan standard of care for non-
severe malaria. Cases of severe malaria will be offered transportation the nearest in-patient 
health center for hospital-based treatment. 
Linkage Station 
Post-test counsellors will direct any participants with a positive screening test (i.e. HIV, 
hypertension, diabetes, etc.) to the referral station in order to meet disease-specific clinical staff 
and to schedule intake appointments for the appropriate clinic(s). Campaign staff at the referral 
station will focus on three aspects of linkage-to-care: 

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a. Patient education: All participants will receive information regarding early 
treatment and the benefits and importance of linking to disease-specific care 
after diagnosis. 
b. Patient Navigation: A clinician will meet with each participant not already in care 
in order to introduce him or herself and answer questions regarding the referral 
clinic. Following this introduction, a study assistant will schedule an intake 
appointment, or arrange immediate linkage to the clinic if available and the 
participant agrees. Participants who tested HIV-negative at their prior CHC or 
home-based testing who are newly diagnosed with HIV may be provided with 
specialized counseling, including targeted information on the benefits of linking to 
care and addressing participants’ specific fears.  Participants may also be offered 
immediate counseling from study clinic leadership by mobile phone.  
c. Structural barrier to Linkage: Transportation costs to clinics represent a major 
barrier to linkage to care in this study population. HIV-infected participants will 
receive transportation vouchers redeemable for transportation expenses after 
linking to care for their first visit at baseline in all communities and subsequently 
in intervention communities. SEARCH linkage vouchers will be collected by a 
research assistant at the clinic to which the participant is referred at the time of 
linkage to HIV-specific care.  HIV-infected participants may also receive a one-
month supply of TMP/SMX.  Some patients may also be started on ART at the 
CHC if agreements have been arranged with the local clinic for assurance of 
continued care, and initial PrEP may be provided to some participants.  For HIV, 
hypertension and diabetes, linkage may include tracking of participants who did 
not link to care.  HIV-infected participants may also be randomized to standard 
streamlined care approaches to linkage vs. enhanced, personalized linkage 
approaches such as an appointment reminder calls from the study physician or 
flexible clinic hours for study visits. 
Distribution Station/Campaign Exit 
In the final step of each CHC, participants will have their fingernails marked with permanent 
(“voting”) ink, to prevent persons from repeating campaign activities during a CHC period, and 
receive several additional services: 
a. All children ≥12 months and ≤5 years of age will be provided with Mebendazole 
(one 500 mg tablet).   
b. All children ≥ 6 months and ≤5 years of age will be provided with Vitamin A 
supplementation (one 200,000 IU capsule) 
c. Distribution of male condoms 
Documenting Participation 
Upon completion of every campaign, each community’s baseline census enumeration will be 
compared to the list of campaign attendees using all identifying information collected at the 
Welcome Station (including electronic fingerprint). After each CHC, all community members 

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(defined by enumeration in the baseline census and including HIV-infected and uninfected 
residents) who did not attend the CHC may be tracked and evaluated.  
6.2.2.3 CHC Procedures Intervention Arm 
Participants in all communities who are newly diagnosed with HIV will be encouraged to visit 
their local health center for care.  Participants in intervention communities who do not meet 
country guidelines to start ART will be asked to visit the study supported ART providing health 
center for their community, where they will be introduced and consented to the ART Intervention 
study if universal treatment has not yet been implemented in their country of residence (Phase 
I).  Participants will receive transportation vouchers, which can be redeemed at the health 
center.  The value of the transportation voucher will depend on the distance from the 
participant’s home to the clinic. Patients may be started at ART at the CHC at the discretion of 
the local health care center.  
6.2.3 Targeted/Supplemental HIV Testing (Phase II) 
Existing testing services in intervention communities will be assessed at baseline, and SEARCH 
will partner with these services to ensure linkage to the streamlined care delivery system, 
including ART at all CD4 counts for individuals diagnosed in these locations. In addition we will 
use HIV prevalence and incidence data from CHC testing campaigns and national HIV 
information to identify important key populations (KPs) and priority populations (PPs) for 
supplemental HIV testing at time periods in between community health campaigns.  
Supplemental HIV testing for KPs and PPs will be tailored to the needs of the individual 
population and may include the following strategies: 
• 
Chain referral contact (sometimes called snowball or respondent driven sampling) to 
access hard to reach populations.  In chain referral contact “seed” members of KP & PP 
populations are used to recruit their contacts that are also members of the KP & PP risk 
groups for supplemental HIV testing and those tested persons are then asked to recruit 
their KP & PP contacts in a similar fashion.  Each successive recruit is asked to 
participate in recruiting his or her KP & PP contacts for testing.  Numbered invitation 
cards and incentives may be used to enhance recruitment and testing uptake. 
• 
Private location or home-based testing will be utilized where KP & PP populations have 
issues of confidentiality and public stigma. 
• 
Venue based recruiting (such as brothels,  bars and beaches) will be employed where 
appropriate to identify KPs & PPs for referral to supplemental testing at an offsite private 
location/home or to clinic-based or community HIV testing services. 
• 
For KP & PP populations with elevated HIV incidence we may employ rapid HIV testing 
technologies that are able to identify individuals with acute HIV infection prior to HIV 
antibody responses by testing for the presence of HIV p24 antigen. 
• 
Engagement of the leadership of social, business organizations or clubs with significant 
KP & PP membership may be used to provide access to opportunities for recruitment for 
supplemental HIV testing for the organizations’ or clubs’ members.  Recruitment may 
take the form of personal or group invitations at meetings, numbered invitation cards and 

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incentives, or co-location of mobile HIV testing services at group functions as needed.  
Mobilization to attend meetings may involve incorporating activities such as sports, 
entertainment, income-generating activities, entrepreneurship and technical capacity 
building activities, life skills, education, and other health and non-health related activities 
and services into meetings and clubs. Mobilization activities may also utilize social 
networks, health workers, and school, religious, and community leaders to recruit KP 
and PP to attend meetings where HIV testing services are offered. 
• 
Non-cash incentives may be used where appropriate to enhance recruitment and uptake 
of HIV testing among KPs & PPs.  Appropriateness of type and amount of incentive will 
be informed through discussions with the study community advisory boards and key 
informant members of KP & PP populations. Incentives may include mobile phone air 
time cards, transport reimbursement, or a liter of fuel for transport drivers, that does not 
have a value of more than $5 USD. 
6.2.4 Tracking CHC non-participants  
Tracking Procedure 
Locator information collected during the baseline census enumeration will be used to locate 
CHC non-participants.  The community tracker then records the outcome of the patient after 
tracking in the community. Data of new household members including immigrants will be 
captured as well.  
Tracking Evaluation: Evaluation will consist of at least the following:   
• 
Vital status with verbal autopsy in the event of a reported death, to capture cause 
of death (e.g. trauma, illness, suicide, childbirth) whenever possible. 
• 
Field HIV antibody rapid testing according to the testing algorithm (with 
confirmation and tie-breaker testing) used in the CHC  
• 
CD4 cell count and HIV RNA testing among HIV+ participants 
• 
A health, economic and educational interview, similar to the interview conducted 
during CHCs. 
• 
Trackers will also evaluate reasons for not coming to the recent CHC, and 
investigate incentivizes for participation in the subsequent CHC. 
• 
For people who cannot be tracked: reasons for not finding the person (e.g. 
emigration out of the study community, migration within the study community, or 
other reasons). 
• 
Recommended for consideration:  The collection of Dried Blood Spots on filter 
paper, finger-stick blood glucose measures, syphilis screening (RPR) for all 
above 15 years, blood pressure measurement for everyone 18 years and older, 
and renal function measurements. 
6.3 Mortality and New Births, and HIV and TB Disease Surveillance  

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To maximize ascertainment of SEARCH study secondary outcomes, we will conduct 
community-based surveillance for key study outcomes in the one-year period between annual 
community health campaigns (CHCs).  
6.3.1 Mortality and New Births Surveillance 
Deaths and births within each study community will be ascertained using a combination of data 
from the CHC, post-CHC tracking and local death and birth registries. Depending on the 
location, staff may also work with government sponsored village health teams, village elders or 
community leaders, or their equivalent to obtain this information. 
a) CHC data: During the CHC, research assistants may update each community’s baseline 
census to reflect interim deaths and causes of death (when known) of study community 
members. Information (including electronic fingerprint and residence information) on all 
children born to members of the study community will be added to the updated census. 
b) Post-CHC Tracking: We will update each community’s baseline census based on the 
birth and mortality data collected during post-CHC tracking (see above). 
c) Local Death Registries: Study staff may work with government officials to build capacity 
to maintain ongoing lists of deaths as they occur in their community, depending on the 
desires of the village representatives.  Study staff will review these local death registries 
periodically and incorporate the information into the study census for that community. 
Immediately prior to each CHC, study staff will produce an updated community census based 
on all birth and death data collected in the past year. The updated census will represent the 
target community, including documentation of CHC participation and tracking of CHC non-
attendees. 
6.3.2 Morbidity/Disease Surveillance, Infant Diagnosis and Care Delivery 
Health Center Surveillance: Study staff will regularly collect information available from routine 
encounters at local health centers and, where needed, hospitals within the community.  The 
following information will be collected but not limited to:  
• 
Visit date and identifying information, including name, age, gender, village of residence, 
and fingerprint, will be collected on all clinic attendees at the time of clinic visit. 
• 
Diagnosis 
• 
Laboratory results 
• 
Medications 
• 
Hospitalizations 
• 
Mortality 
Study staff will also work with implementing partners and health facilities to ascertain HIV status 
of children born to HIV+ women at the heath facility.   

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A sample of health provider and patients will be surveyed using standard instruments on a) 
patient satisfaction, b) provider satisfaction, c) perception of empathy and respect in order to 
assess qualities of the patient-provider interaction in care delivery.  
TB Surveillance: Staff will visit all clinics providing TB therapy at regular intervals throughout the 
year. The government is the sole supplier of anti-tuberculosis antibiotics in Uganda and Kenya, 
and therefore TB therapy is only available through government-run or associated clinics and 
hospitals. All TB clinic dispensaries keep government registries with diagnostic and treatment-
related outcomes for every case, including name, age, HIV status and residence information. 
Staff will enumerate all clinics providing TB therapy at baseline. At the start of the SEARCH 
study and during regular visits to TB clinics, staff will collect the following information, as 
available: 
• 
Overall interval number of TB cases reported to the clinic, with name, age, residence, 
and acid-fast bacilli (AFB) smear results 
• 
TB treatment: Data on treatment status of each case at initiation of anti-TB therapy (new 
TB cases, retreatment TB, and TB treatment defaulters) 
• 
TB treatment completion and failure rates. 
• 
All-cause TB case fatality rates: the proportion of TB patients who died on TB treatment 
each year, excluding those cases that left the community during treatment. 
• 
TB Preventive Therapy: Data on initiation and completion of Isoniazid Preventive 
Therapy (IPT) in SEARCH clinics, starting in follow up year 3. 
• 
The proportion of children with latent TB infection as measured by a tuberculin skin test 
or interferon gamma release assays in selected schools 
A sample of patients who received IPT at SEARCH clinics or through clinic-based or 
community-based delivery methods will be surveyed to assess barriers and facilitators of 
treatment completion.  
6.4 Feedback of CHC Process and Clinical Data 
 
The CHC implementation team for each community will be provided with data on CHC 
operations, including linkage to care, determine what, if any, alterations will need to be made to 
outreach, testing, tracking and surveillance procedures to make them more effective.  In 
addition, the study team will evaluate how the intervention is affecting the community: describe 
attitudes, beliefs and social norms surrounding HIV testing, disclosure, and ART; and describe 
experiences of HIV stigma and disclosure, experiences with engagement in HIV care and ART, 
and sexual behavior, among HIV-positive individuals. These modifications will be incorporated 
into subsequent campaigns in an ongoing effort to improve community trial efforts throughout 
the six-year study period.  This will allow the CHC procedures in each community to evolve in 
response to data. Individual plasma HIV-1 RNA levels measured at the CHC as part of this 
research study will be provided to clinics for subjects on ART. 
 

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7.0 CLINCAL AND LAB EVALUATIONS IN PARTICIPANTS RECEIVING ART 
7.1 Recruitment, Phase I – ART Intervention 
At the time of first awareness of HIV infection, either during a community health campaign or 
any other location, participants in intervention communities will be asked to visit the study 
supported ART providing health center in their community, where they will be introduced to the 
study.  All patients who do not meet in-country treatment guidelines for ART will be offered to be 
screened for the study.   The remainder of this section refers only to patients who will receive 
ART from the SEARCH study because they do not meet ART guidelines.  
7.2 Selection of Participants in Intervention Arm, Phase I – ART Intervention 
7.2.1 Inclusion Criteria 
7.2.1.1 
HIV-1 infection diagnosed by a rapid HIV test or any licensed ELISA test kit.  For 
patients diagnosed in a setting other than study-conducted community health 
campaigns, HIV status will be re-verified at the time of study screening. 
7.2.1.2 
Most recent CD4+ cell count > 350 cells/uL, performed within the past 6 months. 
7.2.1.3 
Willing to initiate ART. 
7.2.1.4 
Ability to swallow oral medications. 
7.2.1.5 
Ability and willingness of participant to give informed written consent. 
7.2.2 Exclusion Criteria 
 
7.2.2.1 
Currently taking ART. 
7.2.2.2 
Allergy or sensitivity to prescribed ART. 
7.2.2.3 
Active World Health Organization (WHO) HIV stage III or IV disease. 
7.2.2.4 
Any other clinical condition that, in the opinion of the site investigator, would make the 
participant unsuitable for the study, unable to comply with dosing requirements or 
qualify the participant for ART initiation according to in-country treatment guidelines. 
 
7.3 Informed Consent and Enrollment, Phase I – ART Intervention 
Written informed consent to participate in the study will be obtained from all participants.  
Consent forms will be translated from the original English to the language(s) spoken in the 
community.  The consent form will be read to participants in their local language. 
After consent, participants will undergo screening procedures to determine eligibility by clinical 
evaluation and laboratory testing.  Once eligibility is verified, participants will undergo baseline 
procedures and to receive ART medications. Screening and baseline procedures may be done 

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on the same day. Patients may be re-screened for participation according to patient-provider 
discussions.  
7.4 Schedule of Evaluations, Phase I – ART Intervention 
Table 4:  Schedule of Evaluations 
Procedure or 
Evaluation 
Screen 
Baseline 
Study Week 
4 
12 
24 
36 
48 
Every 
12 
weeks 
144 
Demographic 
information 
X 
 
 
 
 
 
X 
 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
Targeted physical 
exam 
 
X 
 
 
 
 
 
 
 
Tuberculosis screen 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
 
X 
 
 
 
 
 
 
 
Symptom screen 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
Documentation of HIV 
infection 
X 
 
 
 
 
 
 
 
 
Pregnancy 
 
X 
 
 
X 
 
X 
X1 
X 
Hemoglobin 
 
X 
 
 
 
 
X 
 
X 
Liver function tests2 
 
X6 
 
 
X 
 
 
 
 
Creatinine 
 
X 
 
 
X 
 
X6 
X3 
X 
Glucose 
 
X 
 
 
 
 
X 
 
X 
CD4 count 
X4 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA5 
 
X4 
 
 
X 
 
X5 
X5 
X5 
HIV seroconversion 
questionnaire 
 
 
X7 
 
 
 
 
 
 
1 Repeat every 24 weeks between Week 48 and Week 144. 
2 ALT at timepoints shown above. AST, total and direct bilirubin, alkaline phosphatase as indicated. 
3 Repeat at Week 96 only. 
4Only if not available within the past 6 months. CHC viral load collection fulfils this criteria. 
5 Viral loads will be measured annually. Samples collected ruing annual CHC attendance and home-based testing 
during tracking or clinic visits will qualify for this viral load measurement. 
6As clinically indicated. 
7Optional; may be performed any time within the first 6 months of enrollment at the discretion of the clinician. 
 
7.5 Timing of Evaluations, Phase I – ART Intervention 
• 
The baseline visit must be performed within 4 weeks of screening evaluations. 
• 
Weeks 4 through 144 must occur +/- 21 days from the protocol-specified target date. 
7.6 Definitions of Evaluations, Phase I – ART Intervention 

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7.6.1 Demographic information 
The following information will be collected: date of birth, sex, clinic ID (if applicable) and place of 
residence. 
7.6.2 Medical history 
A medical history will be collected including current health complaints and allergies to 
medications. 
7.6.3 Targeted physical exam 
Participants will undergo a physical exam covering the following systems: oropharynx, heart, 
lungs, skin and abdomen. Cervical cancer screening may be done in clinics where this is part of 
standard care. 
7.6.4 Vital signs 
Weight, temperature, pulse and blood pressure (in participants ≥18 years) will be recorded. 
7.6.5 Symptom screen 
Participants will be asked whether they currently have any active symptoms. 
7.6.6 Dispense medications 
Study medications will be dispensed to participants in intervention arm. The standard interval for 
dispensing medications is 12 weeks, but this may be extended at the discretion of the 
investigator for persons whose travel makes the follow up appointment not possible. It will be 
the responsibility of the SEARCH staff to maintain and document contact with the patient at the 
routine 12 week interval.  
7.6.7 Adherence assessment 
Participants will be asked to perform a 3-day adherence recall. 
7.6.8 Documentation of HIV-1 infection 
HIV-1 infection determined by previous testing will be documented at the time of study 
screening. 
7.6.9 Pregnancy testing 
Women of child-bearing potential will be tested by urine HCG (human chorionic gonadotropin).  
This testing will be repeated every 24 weeks between Weeks 48 and 144, or sooner if clinical 
suspicion of pregnancy exists. 
7.6.10 Hemoglobin 
This will consist of a hemoglobin measurement. 
7.6.11 Liver function tests 
• 
ALT will be performed at Baseline, Week 24 and as clinically indicated. AST, total and 
direct bilirubin, alkaline phosphatase will be performed as clinically indicated. 

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7.6.12 Creatinine   
At Baseline, estimated glomerular filtration rate (eGFR) will be calculated by the Modification of 
Diet in Renal Disease (MDRD) formula, which is as follows: 
eGFR = 186 * Serum creatinine-1.154 * Age-0.203 * [1.21 if African] * [0.742 if female] 
7.6.13 Glucose 
Blood glucose will be measured. 
7.6.14 Tuberculosis 
Tuberculosis screening will be performed according to each clinic’s standard of care. 
7.6.15 CD4 counts 
CD4 counts will be measured at Screen only if a result is not available within the past 6 months.   
7.6.16 Plasma HIV-1 RNA 
This will consist of a quantitative determination of the HIV-1 plasma RNA level (in copies/mL) at 
study specified intervals or as clinically indicated.  
7.6.17 HIV seroconversion interview 
An optional interview to be completed by the study staff within the first 6 months of enrollment 
which will include questions to newly HIV infected subjects on their sexual partner history, 
prevention strategies, HIV testing experience and preferences and related issues. 
7.6.18 Pharmacokinetic evaluations   
In addition to the evaluations described in Table 4, pharmacologic measurements of ART levels 
may be performed on collected hair samples at one or more visits after Week 0. 
7.6.19 Stigma questionnaire 
A random subset of community members will be asked to complete a questionnaire related to 
HIV stigma in their community. 
7.6.20 Phylogenetics testing 
An additional blood sample may be collected from participants who recently test HIV-positive to 
perform phylogenetics analysis. 
7.7 Recruitment, Phase II – PrEP 
Persons at high risk for HIV seroconversion will be offered PrEP.  These individuals will vary by 
community.  Based on input from the community, high risk populations will be approached 
through a variety of mechanisms.  These include but are not limited to a) community health 
campaigns and home testing, b) at the ART clinic for HIV serodiscordant couples, and c) after 

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enhanced self-identification events such as the men’s health station at the CHC or at locales 
where there is STI treatment or PrEP. 
7.8 Selection of Participants in Intervention Arm, Phase II – PrEP  
7.8.1 Inclusion Criteria 
7.8.1.1 
Negative for HIV-1 infection determined by a rapid HIV test or any licensed ELISA test 
kit within 4 weeks.  
7.8.1.2 
Age ≥15 years.  
7.8.1.3 
Willing to initiate PrEP. 
7.8.1.4 
Ability to swallow oral medications. 
7.8.1.5 
Ability and willingness of participant to give informed written consent. 
7.8.2 Exclusion Criteria 
 
7.8.2.1 
Any positive test indicating HIV infection. 
7.8.2.2 
Estimated glomerular filtration rate (eGFR) of ≥ 60 mL/minute by the Modification of 
Diet in Renal Disease (MDRD) formula: 
 
eGFR = 186 * Serum creatinine-1.154 * Age-0.203 * [1.21 if African] * [0.742 if female] 
7.8.2.3 
Allergy or sensitivity to prescribed PrEP.  
7.8.2.4 
Signs or symptoms of acute HIV infection.  
7.8.2.5 
Known hepatitis B infection. 
7.8.2.6 
Any other clinical condition that, in the opinion of the site investigator, would make the 
participant unsuitable for the study or unable to comply with dosing requirements. 
 
7.9 Informed Consent and Enrollment, Phase II – PrEP  
Written informed consent to participate in the study will be obtained from all participants.  
Consent forms will be translated from the original English to the language(s) spoken in the 
community.  The consent form will be read to participants in their local language. 
After consent, participants will undergo screening procedures to determine eligibility by clinical 
evaluation and laboratory testing.  Once eligibility is verified, participants will undergo baseline 
procedures and receive ART medications. Screening and baseline procedures may be done on 
the same day. Patients may be re-screened for participation according to patient-provider 
discussions. 

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7.10 Schedule of Evaluations, Phase II – PrEP  
 
Table 5:  Schedule of Evaluations 
Procedure or 
Evaluation 
Baseline 
Study Week 
4 
12 
Every 
12 
weeks 
144 
Documentation of HIV-
negative status1 
X 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
Symptom screen 
X 
X 
X 
X 
X 
Dispense medications 
X 
X 
X 
X 
X 
Adherence 
assessment 
 
X 
X 
X 
X 
HIV serology 
 
X 
X 
X 
X 
Self-risk assessment 
X 
X 
X 
X 
X 
Creatinine 
X 
 
X 
X2 
X 
Hepatitis B surface 
antigen, if available 
X 
 
 
 
 
Hair, blood, urine 
collection for PK 
evaluations 
 
X 
X 
X 
X 
Optional STD screen3 
X 
 
X 
X 
X 
Stigma questionnaire 
X 
 
 
 
 
1Within 4 weeks of enrollment; negative status at CHC or post-CHC field testing fulfills this criteria. 
2At Weeks 24, 48, 72, 96, and 120 only. 
3Optional STD screen may include gonorrhea and chlamydia testing. 
 
Participants may choose to suspend medications for PrEP based on their self-risk assessment.  
They may resume medications at any time after repeat HIV testing confirms their HIV-negative 
status.  While medications are suspended, participants will continue to be followed according to 
the schedule described in Table 5; however only the following procedures will be offered during 
this period: 
• 
HIV serology 
• 
Self-risk assessment 
• 
Optional STD screen 
 
At the seroconversion visit, adherence assessment and sample collection for PK and 
phylogenetics may be performed. 
 
Participants that suspend PrEP medications for more than 12 weeks and then resume 
medications will continue all evaluations described in Table 5 without interruption to their study 
schedule. 

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7.11 Timing of Evaluations, Phase II – PrEP  
• 
The baseline visit must be performed within 4 weeks of confirmation of eligibility. 
• 
Weeks 4 through 144 must occur +/- 21 days from the protocol-specified target date. 
 
7.12 Definitions of Evaluations, Phase II – PrEP 
7.12.1 Documentation of HIV-negative status 
HIV-1 non-infection determined by testing within the previous 4 weeks will be documented; if no 
prior test results are available, participants may be tested by HIV serology at baseline. 
7.12.2 Demographic information 
The following information will be collected: date of birth, sex, clinic ID (if applicable) and place of 
residence. 
7.12.3 Symptom screen 
Participants will be asked about any current symptoms. 
7.12.4 Dispense medications 
PrEP medications will be dispensed to participants. The standard interval for dispensing 
medications is 12 weeks, but this may be extended at the discretion of the investigator for 
persons whose travel makes the follow up appointment not possible. It will be the responsibility 
of the SEARCH staff to maintain and document contact with the patient at the routine 12 week 
interval.  Participants in some communities will be randomized to receive medications at the 
study clinic or an offsite location. 
7.12.5 Adherence assessment 
Participants will be asked to perform a 3-day adherence recall. 
7.12.6 HIV serology 
HIV rapid serology testing according to country guidelines. 
7.12.7 Self-risk assessment 
Participants will be prompted to assess their current and future risk of HIV infection. 
7.12.8 Creatinine 
Blood creatinine will be measured.  Estimated glomerular filtration rate (eGFR) will be calculated 
by the Modification of Diet in Renal Disease (MDRD) formula, which is as follows: 
eGFR = 186 * Serum creatinine-1.154 * Age-0.203 * [1.21 if African] * [0.742 if female] 
7.12.9 Hepatitis B surface antigen serology 
Participants will be tested for Hepatitis B at the Baseline visit, where such testing is available.  If 
hepatitis B positive, participants will discontinue study medications and be removed from PrEP 
evaluations. 

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7.12.10 Pharmacokinetic evaluations   
Pharmacokinetic measurements of ART levels may be performed on collected hair samples, 
dried blood spots (DBS) on filter paper, and/or urine samples, at visits after Baseline. 
7.12.11 STD screen 
Optional screening for gonorrhoea and chlamydia. 
7.12.12 Stigma questionnaire 
A random subset of participants will be asked to complete a questionnaire related to HIV stigma 
in their community. 
7.12.13 HIV seroconversion interview 
In addition to the evaluations described in Table 5, an optional interview to be administered by 
study staff to subjects who seroconvert.  The interview, which will include questions for newly 
HIV-infected subjects on their sexual partner history, prevention strategies, HIV testing 
experience and preferences and related issues, will be performed if and when participants test 
positive for HIV. 
7.12.14 Phylogenetics testing 
An additional blood sample may be collected from participants who recently test HIV-positive to 
perform phylogenetics analysis. 
7.13 Post-Exposure Prophylaxis (PEP) 
Persons who have a recent potential exposure to HIV and who are not on PrEP will be offered 
the opportunity to participate in an observational study of post-exposure prophylaxis (PEP).    
PEP will be provided by the clinic in the community according to country guidelines. 
7.14 PEP Eligibility  
7.14.1 Inclusion Criteria 
7.14.1.1 Participants who have a recent sexual exposure to a person with known or unknown 
HIV status within 72 hours.   
7.14.1.2 Age ≥15 years.  
7.14.1.3 Willing to initiate PEP. 
7.14.1.4 Ability and willingness of participant to give informed written consent. 
7.14.2 Exclusion Criteria 
 
7.14.2.1 Any positive test indicating HIV infection. 

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7.14.2.2 Estimated glomerular filtration rate (eGFR) of ≥ 60 mL/minute by the Modification of 
Diet in Renal Disease (MDRD) formula: 
 
eGFR = 186 * Serum creatinine-1.154 * Age-0.203 * [1.21 if African] * [0.742 if female] 
7.14.2.3 Allergy or sensitivity to prescribed PEP.  
7.14.2.4 Any other clinical condition that, in the opinion of the site investigator, would make the 
participant unsuitable for the study or unable to comply with dosing requirements. 
 
7.15 PEP Informed Consent and Enrolment  
Written informed consent to participate in the study will be obtained from all participants.  
Consent forms will be translated from the original English to the language(s) spoken in the 
community. The consent form will be read to participants in their local language. 
After consent, participants will undergo screening procedures by clinical evaluation. Once 
clinical eligibility is verified, participants will undergo baseline procedures and receive PEP 
medications. Screening and baseline procedures will be done on the same day. 
7.16 PEP Schedule of Evaluations  
Table 6:  Schedule of Evaluations 
Procedure or Evaluation 
Baseline 
Day   
31 
Study Week2 
11 
21 
4 
Every 4 
weeks 
24 
Demographic information 
X 
 
 
 
 
 
 
Dispense medications 
X 
 
 
 
 
 
 
Acute HIV symptom screen 
X 
 
X 
X 
X 
X 
X 
Counseling, adherence 
assessment and support 
 
X 
X 
X 
X 
 
 
HIV serology 
X3 
 
 
 
X 
X4 
X 
Creatinine 
X3 
 
 
 
 
 
 
Pregnancy and optional STI 
testing5 
X 
 
 
 
 
 
 
1Day 3, Week 1 and Week 2 visits will be done by phone only 
2Visits at Weeks 4-24 can be done in person or by phone 
3HIV serology and creatinine testing done at Baseline or within 72 hours after Baseline 
4Week 12 only 
5Done at Baseline; testing done at subsequent visits per country guidelines 
7.17 Timing and Location of Evaluations for PEP  
• 
The Baseline visit must be performed within 72 hours of possible exposure to HIV. 
• 
The Day 3 visit can be performed 1-3 days after the Baseline visit. 
• 
Week 1 must occur +/- 3 days from the protocol-specified target date. 
• 
Week 2 must occur +/- 7 days from the protocol-specified target date. 

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• 
Weeks 4 through 24 must occur +/- 14 days from the protocol-specified target date. 
 
Visits at Day 3, Week 1 and Week 2 will be conducted by telephone for participants with access 
to a telephone. For those without telephone access, the visit will take place in participants home 
or another location of their choosing.  Visits between Week 4 and Week 24 which do not include 
HIV serology testing may also be done by telephone. 
 
7.18 PEP Definitions of Evaluations 
7.18.1 Demographic information 
Demographic information such as date of birth, sex, and place of residence and phone 
number(s) will be collected. 
7.18.2 Dispense medications 
PEP medications will be dispensed to participants for a 28-day course.  In 2018, country 
guidelines recommend TDF, 3TC and ATV/r for adults. PEP medications will be provided by the 
country’s Ministry of Health and/or supplemented by the study. 
7.18.3 Adherence assessment and support 
Participants will be asked to perform a 3-day adherence recall at the Week 2 and Week 4 visit 
and will be provided with repeat counseling and support. 
7.18.4 HIV serology 
HIV rapid serology testing according to country guidelines, performed at Baseline or within 48 
hours of Baseline, as well as Weeks 4, 12 and 24. 
7.18.5  Creatinine 
Blood creatinine will be measured, performed at Baseline or within 72 hours of Baseline. 
Estimated glomerular filtration rate (eGFR) will be calculated by the Modification of Diet in Renal 
Disease (MDRD) formula, which is as follows: 
eGFR = 186 * Serum creatinine-1.154 * Age-0.203 * [1.21 if African] * [0.742 if female] 
7.18.6 Pregnancy testing 
At Baseline, women of child-bearing potential will be tested for pregnancy by urine HCG (human 
chorionic gonadotropin) and any patients will be offered .  After Week 4, pregnancy testing will 
be performed if clinical suspicion of pregnancy exists. 
7.18.7 Optional STD testing 
Participants may be offered STD testing on urine samples at Baseline, such as chlamydia and 
gonorrhoea.  Testing may be performed at subsequent visit, as clinically indicated per country 
guidelines. 
7.18.8 Optional phylogenetics and resistance analysis 

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An optional blood sample will be collected from participants for future phylogenetics analysis 
and/or resistance testing in the event of HIV seroconversion. 
7.18.9 Food support 
Participants may be offered food support, such as meals or snacks, for the duration of their PEP 
treatment to facilitate adherence. 

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8.0 ART TOXICITY GRADING AND MANAGEMENT 
8.1 Toxicity Screening 
At each follow-up study visit in Phase 1 and Phase 2, staff will ask participants about any new 
symptoms.  Depending on the results of this screen, staff may refer the participant to a clinician 
for further evaluation.  Laboratory testing will be done according to the Schedule of Evaluations 
(Section 7.1 in Phase I, Section 7.10 in Phase II) and results will be assessed for evidence of 
laboratory values indicating possible grade 3 or 4 toxicity according to the DAIDS Toxicity Table, 
November 2014. 
8.2 Management of Laboratory Toxicities 
8.2.1 Grade 1 or 2 Toxicities 
Participants who develop grade 1 or 2 adverse events or toxicities may continue study 
medications without alteration of dosage.  Participants experiencing such events will be 
managed at the discretion of the site investigator and staff. 
8.2.2 Grade 3 Toxicities 
Clinicians will evaluate all grade 3 toxicities at the time of awareness.  If there is evidence that 
the adverse event or toxicity is NOT associated with the study drug, dosing may continue. If 
adverse event/toxicity IS thought to be related to study drug, ART may be withheld or switched 
at the clinician’s discretion. Participants should be re-evaluated every 1-2 weeks if possible and 
if patient is able to return for follow-up on that schedule, until the adverse event returns to ≤ 
grade 2 or until stabilized and no longer in need of frequent monitoring, to be determined by the 
site investigator.  ART, if withheld, may be re-introduced anytime at the discretion of the site 
investigator. 
8.2.3 Grade 4 Toxicities 
If a symptomatic grade 4 adverse event or toxicity develops, ART should be withheld or 
switched at the discretion of the site investigator, and the patient should be monitored frequently 
until the adverse event returns to ≤ grade 2 or until stabilized and no longer in need of frequent 
monitoring, to be determined by the site investigator. 
If an asymptomatic grade 4 adverse event or toxicity develops, ART may be continued or 
discontinued or switched at the discretion of the site investigator. 
8.3 Management of Specific Clinical Syndromes 
Patients will be managed according to local standard care general guidelines, including use of 
the targeted management described below.  
8.3.1 Rash 
In general: 

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Patients will be evaluated for the severity, location, and characteristics of any rash. If any 
concern exists about serious medical conditions that feature a rash, such as Stevens-Johnson 
syndrome, clinicians will consult with the site investigator to determine the best course of action. 
Issues related to EFV: 
Any rash while on efavirenz (EFV) should prompt suspicion and evaluation for non-nucleoside 
reverse transcriptase inhibitor (NNRTI) hypersensitivity rash. This should include clinical 
evaluation for systemic symptoms (fever, arthralgias, myalgias), and laboratory evaluation for 
suggestive findings (AST/ALT >2x upper limit of normal, peripheral eosinophilia). 
Participants felt to be experiencing an NNRTI hypersensitivity reaction should not be 
rechallenged with the suspected causal agent. 
An isolated rash while taking EFV does not constitute and should not raise concern for NNRTI 
hypersensitivity. 
For any serious rash (e.g., exfoliation, mucosal involvement, target lesions [erythema 
multiforme] or evidence of Stevens-Johnson syndrome): 
Participants should discontinue all ART, and staff will confer with investigators as to proper 
management. Upon resolution to grade 1 or resolved, rechallenge with EFV ART versus 
restarting with a different ART can occur at the discretion of site investigator. 
Issues related to ABC: 
Abacavir (ABC) hypersensitivity is characterized by symptoms of rash (maculopapular or 
urticarial, but sometimes absent), fever, gastrointestinal symptoms, respiratory symptoms, and 
malaise.  If ABC hypersensitivity is suspected, participants should undergo a clinical and 
laboratory evaluation.  Elevated AST/ALT, CK or creatinine, or decreased lymphocytes, are 
often present. 
Participants felt to be experiencing ABC hypersensitivity reaction should stop ABC immediately.  
They should not be rechallenged and should instead restart ART with an alternate NRTI. 
8.3.2 Nausea and Diarrhea 
Nausea and diarrhea are fairly common side effects patients experience during the first few 
weeks of ART, but usually subside and resolve promptly. Participants can be encouraged to 
take medicines with food, or to take anti-emetic symptomatic therapy. For diarrhea, unless an 
infectious cause is suspected, antidiarrheal agents may be used for symptomatic relief. 
8.3.3 AST/ALT Elevation 
If a participant’s AST and/or ALT are elevated >5x the upper limit of normal, including the 
baseline measurement, they will be referred to a clinician for immediate evaluation.  Toxicity 
management will proceed according to the plan for grade 3 or 4 events. 
 

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8.3.4 Creatinine Increase and/or Creatinine Clearance Decrease 
If a participant’s glomerular filtration rate is found to be <60 mL/minute by the MDRD formula, 
including the baseline measurement, they will be referred to a clinician for evaluation for the 
need to switch ART regimen (Phase I). In Phase II, participants with a glomerular filtration rate 
that is found to be <60 mL/minute by the MDRD formula will have PrEP discontinued, while 
evaluation for underlying renal insufficiency is performed. If the participant has a reversible 
cause of renal insufficiency that resolves, PrEP may be reinstituted with careful monitoring and 
oversight by the SEARCH clinical management team. 
8.3.5 Hyperbilirubinemia 
For isolated grade 3 or 4 unconjugated hyperbilirubinemia attributed to atazanavir (ATV), the 
drug should be continued unless associated with jaundice or scleral icterus that presents an 
intolerable cosmetic concern to the participant.  For events that cannot be attributed to ATV or a 
non-study drug-related cause, clinicians will consult with the site investigator and all study 
medications will be held pending evaluation of etiology. 
8.3.6 Management of Pregnancy 
For women who become pregnant in Phase I, EFV will be continued in accordance with country 
guidelines. EFV may also be discontinued and replaced with lopinavir/ritonavir (LPV/RTV). EFV 
can replace LPV/RTV after the first trimester of pregnancy is complete at the discretion of the 
site investigator. 
8.3.7 ART Substitutions 
 
Recommendations for alternative ART regimens in Phase I are outlined in Table 2. 

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9.0 ECONOMIC AND EDUCATION EVALUATIONS 
9.1 Overview 
A longitudinal household survey will be conducted among a random sample of adult participants 
in order to record information about the socio-economic status of participants and their 
households. These surveys will provide information needed to assess the effects of the 
intervention on a number of outcomes related to the economic and educational status of 
community members. 
9.2 Recruitment and Enrollment of Study Participants 
9.2.1. Recruitment   
Participants will be recruited after the community health campaigns, no more than annually.  In 
each of the 32 communities, 100 HIV-positive campaign participants and 100 randomly selected 
HIV-negative participants will take part in the household survey from both campaign attenders 
and non-attenders. Selected participants’ homes will be visited after the campaign using 
geographic data collected during the baseline household census.  Participants will be asked 
whether they would be willing to take part in a household socio-economic survey and their 
identity will be confirmed by name and electronic fingerprint. 
9.2.2. Informed Consent and Enrollment 
Informed consent for participation in the Household Socio-Economic Survey will be conducted 
the participant’s home shortly after the health campaign.  Consent will be conducted in the 
appropriate language with the study candidates; translators will be used if necessary. The 
informed consent will be available in local languages and will be read aloud to the study 
candidates. Enrollment will be limited to adult participants in the community health campaigns. 
9.3 Procedures 
9.3.1 Household Survey 
Participants will be visited at their homes by trained interviewers and consent will be obtained 
from those agreeing to take part. Community elders and local chiefs will be informed about the 
survey prior before interviewers begin visiting households. The interviewers will begin by 
locating the participant at the location described in the baseline household survey.  We will 
attempt to arrange for respondents to be interviewed by somebody of the same sex.  If the 
participant is not present, one additional re-visit to the household will be conducted at a later 
time. The household survey questionnaire will have a modular format, with each module 
covering a different topic. SOPs will be developed to provide further instructions on how the 
surveys will be administered. Quantitative information will be collected on various topics, such 
as: 
• 
Demographic characteristics of households, such as age and sex of household 
members 

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• 
Health and education of household members 
• 
Marital characteristics of household members 
• 
Income and employment of household members  
• 
Housing characteristics and asset ownership of households 
• 
Transfers, gifts, and loans to and from the household 
• 
Subjective expectations about future health and income 
• 
Food insecurity 
• 
Consumption and spending patterns 
• 
Health care utilization 
• 
HIV RNA testing (if not done within the past 3 months) and HIV drug resistance 
testing will be performed on persons identified as HIV+  
• 
Anthropometric measurements may be collected as performed in the baseline 
CHC 
• 
CD4 testing (optional)  
 
The household survey will be administered in a private area so that the respondent can answer 
questions freely.  Information about the schooling, employment and income will be collected 
from a knowledgeable household member in cases where the respondent is not able to provide 
accurate information. We will also offer tuberculin skin testing to measure latent tuberculosis 
infection on a population level at sites in Uganda as agreed upon with National TB Control 
programs and, for a subset of these participants, will measure air quality and ventilation in 
indoor locations they frequent and administer a separate questionnaire on social mixing patterns 
among 5-25 year olds. Renal function testing in a sampled population of participants will be 
performed, with optional samples collected for genetic testing related to kidney disease. These 
tuberculosis and renal measurements will be voluntary tests that individuals may choose to opt 
out of. Compensation for time to participate in the HSE survey will be made up to the amount of 
$10 USD per household and paid directly to the participant being interviewed. 
9.3.2 Duration of Survey 
The household survey will last approximately 2.0 hours, as is standard for comprehensive 
household surveys that contain multiple modules.  The questionnaire on social mixing patterns 
administered to a subset of participants will last approximately 1 hour. 
9.3.3 Follow-up Visits 
Households that participate in the annual community health campaigns will be revisited at least 
at years 3 and 6, and up to annually, in order to measure changes in socio-economic outcomes. 
A similar household survey questionnaire will be used during each visit, with additional modules 
that will record changes in household composition. Reasons for entry and exit of household 
members will be recorded.  The questionnaire on social mixing patterns will be administered in 
follow up year 3 and up to annually. 
9.3.4 Linkage to Community Health Campaign Data 
Information collected in the household socio-economic survey will be linked to the data from the 
community health campaign by the CHC ID number of the participant who was recruited for the 
household survey. The linked community health campaign data will provide information on the 

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HIV status of the participant as well as measures of the CD4 cell count and viral load of HIV-
positive participants.  

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10.0 HEALTH CARE COSTING EVALUATIONS 
10.1 Overview 
We will undertake a micro-costing of the resources needed to carry out the activities 
contemplated in achieving this project’s primary objectives. Activities to be costed include both 
the community health campaigns, and the provision of ART including pMTCT to both the 
intervention and control communities.  PrEP will be costed in Phase II of the study. The unit 
costs of the full range of services provided will be calculated. When combined with incidence 
data for HIV, as well as all-cause mortality and morbidity, these data will be used to estimate the 
incremental cost-effectiveness of the intervention. 
10.2 Recruitment and Enrollment of Study Participants 
As described in section 7.1, either during a community health campaign or upon testing at a 
health care facility, participants in intervention communities will be asked to visit the ART 
distributor main facility for their community where they will be introduced and enrolled into the 
study. The medical care resources required by each enrolled patient will be assessed as 
follows. A cost analysis will be carried out at each of the participating government health 
facilities that provides ART to enrolled patients and at that and other facilities that provide non-
ART care to study patients for malaria, TB and the chronic diseases that the community 
campaigns seek to mitigate. We expect to complete the cost analysis at the health facilities 
providing ART within the study communities. 
10.3 Procedures 
To assess the costs of the additional activities assessed in this study, we will conduct 
incremental unit cost analyses using standard micro-costing techniques [35]. Incremental unit 
cost comparisons will be completed, based on the costs of implementing the community 
campaigns, ART with and without streamlined care, and PrEP. This will also include time in 
motion studies for ART, PrEP and NCDs. 
10.3.1 Cost Data Teams 
Incremental costs of the interventions will be assessed using a uniform cost data collection 
protocol for gathering expenditure data at each of the study sites. We will work in close 
consultation with staff at each site to complete this protocol retrospectively over the 6 years of 
follow-up. Following training and instrument piloting to be conducted prior to study initiation, the 
data collection effort will carried out by three teams, one in each study area. Each team will 
consist of a medically trained person coupled with a person trained in finance, economics or 
accounting. They will be supervised by a senior in-country expert who will coordinate and 
communicate with the SEARCH economics team. We anticipate that the initial visit to each site 
will require 5 days to complete the cost instruments but that this will drop to 2-3 days during the 
subsequent visits.  

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10.3.2 Organization of Cost Data 
Expenditures will be classified in one of four categories; (i) personnel (including fringe benefits); 
(ii) recurring supplies and services; (iii) capital and equipment; and (iv) facility space (as 
appropriate). We will also collect retrospective expenditure data to document program start-up 
costs. The costs of each program activity will be identified through interviews with 
administrative, finance and human resources officers, supplemented by direct observation in a 
limited number of formal time and motion studies. The costing approach will emphasize 
resources utilized, rather than out-of-pocket costs. For example, where expenditures do not fully 
reflect the opportunity cost of the resources used (e.g., donations or transfer payments), we will 
adjust the valuations accordingly. Costs for capital items will be amortized on a straight-line 
basis over their expected useful life, and assuming no salvage value. Facility space required by 
the interventions will be valued at the market rental rate. Following assignment of expenditures 
to these four broad categories, we will further allocate each expenditure item across three 
areas, (i) service delivery; (ii) staff training directly related to service delivery; (iii) indirect costs 
consisting of intervention overhead and administration.  
10.3.3 Personnel Costs and the Allocation of Overhead Across Activities 
Overhead and administrative costs will be allocated to the programs in proportion to the full-time 
equivalent staff (FTEs) that study intervention service providers constitute of all service provider 
FTEs at the study sites [36]. We expect that the preponderance of intervention costs will be 
personnel time. The appropriate approach to measuring personnel time will depend upon the 
way services are organized at the study sites. For example, if dedicated staff is hired specifically 
for these interventions, costs can be obtained directly from compensation data. In the more 
likely case that service providers have multiple responsibilities, the time dedicated to these 
interventions can be obtained via interviews supplemented by direct “time and motion” 
observations, including completion by staff of logs recording major activities, for one week 
periods approximately six months apart.  
10.3.4 Measuring Unit Costs 
Outputs (denominator of the unit cost) include the numbers of patients receiving each type of 
study-supported services. Unit costs are defined as the relevant program costs divided by each 
of these outputs, respectively. To supplement this information, we will also collect information on 
patient-level contact hours, to allow us to examine the importance of participant and 
intervention-level factors related to variation in unit cost. We will also assess the variation in unit 
costs across the study sites and identify the major determinants of that variation. If possible, we 
will document changes in unit cost over time as programs potential achieve greater scale and 
administrative efficiency. These findings are intended to provide program managers with 
insights into costs structures that may be used to enhance program efficiency. We will calculate 
the cost per added person receiving ART, NCD, pMTCT and PrEP interventions, based on other 
study findings. 
10.3.5 Health Care Utilization and Spending by Households 

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The household survey mentioned in section 9.3.1 will include a section on health care utilization, 
using short term (1 month) recall for care sought for illness episodes and longer term (6 months) 
for inpatient hospital care. These questions will identify the range of health care providers used, 
the frequency, and family expenditures. 

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11. STATISTICAL PLAN 
11.1 Overview of Study Design  
This is a community-level cluster randomized controlled trial, in which 32 communities in three 
sites in East Africa (two in Uganda and one in Kenya) will be randomized in Phase I to either an 
intervention arm, consisting of annual community-health campaigns including voluntary 
counseling and testing for HIV along with a strategy of HIV antiretroviral therapy for all HIV 
infected persons regardless of CD4 cell count (Universal ART) coupled with a streamlined ART 
delivery system, or to a control arm, consisting of baseline community-health campaigns 
including voluntary counseling and testing for HIV and the current country standard guidelines 
for the initiation of HIV antiretroviral therapy for HIV infected persons (Standard ART). In Phase 
II, the same 32 communities will be re-randomized to either an intervention arm, consisting of 
targeted PrEP, targeted testing and targeted care services on top of universal streamlined ART, 
or to a control arm, consisting of universal streamlined ART. As the study is testing a 
community-level strategy, communities – rather than individuals – are the unit of randomization.  
An individually randomized trial could be used to study the effect of standard ART compared to 
ART at all CD4 counts on individual outcomes. In contrast, our interest is in the impact of a 
community-wide universal ART strategy, as compared to a standard ART strategy in Phase I, 
and the impact on a community-wide targeted PrEP and care strategy, as compared to 
universal streamlined care in Phase II, on HIV incidence and a range of secondary community 
level health, economic, and educational outcomes.  
Randomization will take place within pair-matched communities. Communities will be matched 
on site region and major factors influencing HIV transmission dynamics and health care delivery 
system structure.  The primary outcome measure for both phases is cumulative HIV incidence 
three years after start of the intervention. This will be measured for each community using an 
efficient community cohort design, in which a) community members are enumerated using a 
baseline household based census; b) individuals are serially assessed for HIV status at 
community health campaigns; and, c) individuals failing to participate in each community health 
campaign are tracked and receive home-based HIV testing.  Community-level cumulative HIV 
incidence, together with all secondary outcomes for which sufficient data are available, will be 
evaluated 3 and 6 years after the first community health campaign.  
a. Target Population of Communities 
The target population that we wish to generalize the results of this research to are rural 
and semi-rural African communities with moderate levels of HIV prevalence and 
incidence and served by health centers within or adjacent to the community.  We are 
targeting communities of approximately 10,000 persons, a size which fosters social 
familiarity and connectedness, and which are organized as one or two adjacent 
geopolitical units served by a common health center.  Community has in past work been 
defined as groups of individuals who live next to one another and participate in common 
practices; depend on one another; make decisions together; identify themselves as part 
of something larger than the sum of their individual relationships; and commit 
themselves to the group's well-being [37, 38]. Our target communities for this study 
represent units of organization that reflect these dimensions of communality. 

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b. Selection of Countries 
The two countries participating in this study (Uganda and Kenya) were chosen to meet 
the criterion that HIV incidence could be used as the primary endpoint, and that shared 
common features of HIV/TB co-infection, and general levels of maternal and child 
mortality and economic and educational structure and productivity. 
 
c. Selection of Site Regions 
We determined, on the basis of the power analysis, that 32 communities were needed to 
test the primary study hypothesis for Phase I (see Section 11.5.5). The study is 
conducted within three site regions in two countries, in an effort to balance feasibility and 
cost concerns with generalizability and protection against potential regional instability.  
We have chosen two site regions in Uganda – Western Uganda centered on the 
Mbarara District, Eastern Uganda centered on the Tororo District and in Kenya – 
Western Kenya centered on southern Nyanza Province.  Each of the two Uganda site 
regions (Western, Eastern) have 10 study communities each and within Kenya, the 
Nyanza Province have 12 study communities.  With 10-12 study communities per site, a 
central study operations center may efficiently serve these widely separated rural study 
communities. 
 
d. Selection of communities from target population   
We identified a subset of 54 candidate communities from the target population based on 
the following criteria:  
 
i. 
Inclusion criteria: 
1) Most recent census population between 9,000 and 11,000 individuals. 
2) Served by a government health center already providing ART or a highly 
functioning health center at one organizational level below those 
generally providing ART 
3) Community leaders’ consent to ethnographic mapping. 
4) Accessibility to health center via a maintained transportation route 
5) Community location with sufficient distance from other potential study 
communities to limit contamination of intervention or control conditions 
(buffer zone). 
 
ii. 
 Exclusion Criteria: 
1) Presence of ongoing community-based ART intervention strategies that 
provide treatment outside of the current in-country treatment guidelines.  
2) An urban setting defined as a city with a population of 100,000 or more 
inhabitants. 
3) National government not willing or opposed to support commodities 
needed for Community Health Campaign, if provided by an outside 
organization. 
 
e. Rationale for Selection of Study Communities and Use of Matched Pairs 

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Fifty-four communities were chosen using the systematic selection criteria listed in 
section 11.1.d.  Our study design calls for the creation of 16 matched community pairs 
within which intervention randomization will take place in Phase I and Phase II.  The 
rationale for matching in this setting is three-fold: 1) matching can increase study power 
and the precision of effect estimates if communities are matched well on factors closely 
associated with the study outcome of interest; 2) we propose to match on more 
community level drivers of HIV transmission than can be accommodated by the 
alternative approach of stratified randomization (given the sample size of 32 
communities); and, 3) prior experience from HPTN-043 has shown a high community 
acceptability of the matched pair design and allows for the utilization of validated 
procedures and community preparedness protocols from Project Accept. 
 
f. Criteria for Community Pair Matching 
In Phase I, communities were matched based on the following criteria: 1) site region, 2) 
population density, 3) number of trading centers in the community, 4) major occupational 
mix category (mixed agricultural, mining, tea plantation, fishing), and 5) migration index 
(measure of mixture with outside communities).  The top 16 pairs of matched 
communities were selected. In Phase II, these 32 communities will be re-matched based 
on Phase I allocation (intervention vs. control) and region, as well as key drivers of HIV 
incidence and potential Phase II intervention impact (e.g. baseline HIV prevalence). 
11.2 Primary Outcome Measurement  
The primary outcome measure for each phase of this community cluster-randomized trial is 
community specific 3-year HIV cumulative incidence (CI).  The general framework for measuring 
cumulative incidence is a community cohort of HIV uninfected persons identified at baseline (for 
Phase I) and at follow up year 3 (for Phase II) in each community.  Community membership will 
be identified through a community-wide, brief household enumeration done at baseline; in 
migrants to the community may be added in year 3. HIV status of individuals in the cohort will be 
assessed at baseline and after 3 and 6 years of follow up through HIV testing at a community 
health campaign with tracking and home-based HIV testing for individuals failing to participate in 
the community health campaign.  Each of these steps is described in greater detail below. 
a. Baseline Household Enumeration 
At baseline in each community we will perform a simplified community-wide, brief 
household enumeration to identify community members.  Staff in cooperation with 
community volunteers will conduct an enumeration of households in the community and 
GPS coordinates will be recorded. Each household will be approached, and a head of 
the household will be provided with an explanation of the study. A minimum of 2 repeat 
visits to the household will be made until contact with a head of the household is made. 
An enumeration of the members of the household will be conducted with a head of 
household listing the names, age, sex, relationship to head of household, occupation, 
length of residence, and general travel history/frequency for each household occupant.  
Inclusion and exclusion criteria for eligible participants in the community cohort are: 
 

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i. 
Inclusion Criteria:  
 
1) Stable residency of individual in community, defined as present in 
household for at least 6 months of the calendar year  
2) Able and willing to provide verbal informed consent. 
3) For legal minors and children-consent of legal parent or guardian. 
 
b. Cohort Participant Identification 
To aid in the identification of community participants over time, eligible persons in the 
household will be approached for consent to participate in the community health 
campaign and tracking activities.  Information to be collected includes names, alternate 
contact information such as nearby relatives or mobile phone numbers, and a unique 
biometric identifier generated electronically from the individual’s fingerprint using a 
portable computer. 
 
c. HIV Testing in Community Health Campaign 
HIV testing for community cohort participants will be conducted as follows: Identity 
confirmation using biometric fingerprint identifier will be conducted for all subjects.  For 
those who have not participated in biometric identification, consent and fingerprint ID will 
be performed along with collection of tracking information as in the baseline household 
census.  All participants will answer a brief questionnaire regarding prior HIV testing. HIV 
infection status will be determined by rapid antibody testing using a serial testing 
algorithm following country-specific guidelines.  Participants with non-reactive results will 
be informed of their HIV-negative status. An initial reactive result will be followed with a 
second rapid antibody test. Participants with repeat reactive tests will be informed 
of their HIV-positive stats. Participants with discordant results (first test reactive, second 
test non-reactive) will undergo a third “tie-breaker” HIV rapid test.  Those with a reactive 
“tie-breaker” test will be informed that they are HIV positive. Participants with a non-
reactive “tie-breaker” test will be informed that they are HIV-negative. For primary study 
endpoint measurements in follow-up years 3 and 6, confirmatory testing for HIV infection 
will be performed on rapid antibody positive Incidence Cohort members using the 
Geenius HIV-1/2 Confirmatory Assay (Bio-Rad) or Western Blot testing. A study 
endpoint (HIV infection) requires HIV positive outcomes by both rapid antibody and 
confirmatory testing.  
 
At participating sites, we will obtain from participants with positive rapid HIV antibody test 
results 1) a rapid CD4+ T-cell count test, 2) dried blood spots, and 3) blood plasma. 
   
d. Definition of HIV Uninfected Community Cohort (Incidence Cohort) 
Individuals who are 15 years of age or older, have HIV tested HIV seronegative and are 
eligible per inclusion criteria (stable residency and informed consent) at baseline and 
year 3 will be considered to be part of the Incidence Cohorts for Phase I and Phase II, 
respectively.  Persons who migrate into the community following the baseline 
enumeration will have data collected but not be considered as part of the Incidence 
Cohort for purposes of measurement of community specific HIV cumulative incidence for 
Phase I (although data on these individuals will still be collected and can be used in 

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secondary analyses).  If they meet eligibility criteria, such in-migrants may contribute to 
the Incidence Cohort for Phase II. Participants with evidence of HIV care (as recorded 
on Ministry of Health records) prior to the date of the baseline CHC (for Phase I) or 
follow up Year 3 CHC (for Phase II) will be excluded from the incidence cohorts. In order 
to ensure non-differential application of this exclusion criteria, enumeration data from all 
SEARCH participants (including name, sex, age, and parish/sub-county) may be 
matched to existing data from all primary SEARCH clinics (Uganda) and the FACES 
OpenMRS system (Kenya). 
e. Tracking and HIV Testing for CHC Non-Participants 
Biometric identifiers will be used to identify those community members enumerated 
during the baseline census who fail to attend the baseline CHC. These individuals will be 
tracked by the community tracker using locator information collected during the baseline 
census enumeration. 
 
When located, if alive an HIV antibody rapid test will be performed, and if positive the 
individual will be referred to care in accordance with treatment arm. At following 
subsequent CHCs, the identical procedures will be performed among all enumerated 
community members who fail to attend the CHC.  
 
11.3 Randomization of Community Pairs 
11.3.1 Randomization Strategy 
We will utilize an established randomization strategy that is both scientifically valid and 
transparent to the community stakeholders and uses local idioms to make the concept of 
randomization easily understood by traditional leaders and community members [39].   
Community randomization is conceptualized as an ongoing part of the community preparedness 
process in partnership with the community leaders and community individuals. An example of 
this strategy is described below:   
To explain the concept of a randomized controlled trial (RCT) to community groups such as  
Community Advisory Board (CAB) members, we may use a supplementary feeding analogy that 
the communities are already familiar with, likening randomizing each matched pair of 
communities to a set of twins from one family who end up attending two different schools, only 
one of which offers an indigenous energy drink during the morning break to supplement the 
child’s lunch box from home. To explain the random allocation of communities, we will also use 
local language idioms that would resonate with traditional leaders, such as words meaning ‘by 
chance’, ‘luck of the draw’, and ‘lottery’.   
For the random assignment within matched pairs of each site’s communities to intervention or 
control status we could employ a public lottery of community names to achieve maximum public 
acceptance of the randomization results by enhancing transparency and spreading ownership of 
the process. For each study site area, the computer will randomly designate the randomization 
status for each pair of study communities only as the community name that would be ‘picked up’ 

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or ‘not picked up’ in the public lottery (see sample randomization scheme in Table 6.) 
Table 7: Sample Study Site Community Pair Lottery Randomization Scheme 
Matched Pair # 
Community Names 
Picked-Up at Public Lottery 
Picked-Up 
Not Picked-Up 
1 
Atiri  
Mukuju 
Intervention 
Control 
2 
Malaba 
Koitangiro 
Control 
Intervention 
3 
Paya  
Nawire 
Control 
Intervention 
4 
Mulanda 
Mwello 
Control 
Intervention 
5 
Nabuyoga 
Pawanga 
Intervention 
Control 
 
The lottery could be a public event with members of the CAB and local leadership present along 
with guests from other community-based organizations and the general public to witness the 
lottery conducted by local chiefs or leaders.  
The lottery could be conducted in a series of draws, one for each of the matched pairs of 
communities by their local chiefs or community leaders. For each drawing, the two community 
names are written on a separate piece of paper or card and folded in half to obscure the name 
from view. For the draw, the names of each matched pair could be placed in a sealed box with a 
hand hole cut out of the top of the box. A flip of a coin could be used to decide which of the two 
community leaders will pick the community name from the box.  The unselected leader would be 
responsible for holding and shaking the selection box.  The selected chief or leader will then 
draw a paper from the box without looking into the box and the picked-up community name was 
read aloud by both of the community leaders in turn. If the randomization protocol indicated that 
the “picked-up” community was to receive the intervention (i.e., community health campaigns 
and ART initiation regardless of CD4 cell count), then the host country Principal Investigator (PI) 
would announce the drawn community as an intervention community. If the protocol called for 
the “picked-up” community to be the control (i.e., community health campaigns and standard 
ART initiation), then the host-country PI would announce it as a comparison community. This 
process would assure equal chance of being randomized to the intervention or comparison arm, 
and eliminates any residual fears of bias or rigging. 
We will use the same randomization procedures in Phase I and Phase II. 
11.4 Primary Analyses 
11.4.1 Overview of Analyses for HIV Incidence Outcomes 
 
For each phase of the study, estimation of the impact of the intervention on three year 
cumulative incidence will be based on a two stage analysis. In the first stage, we will estimate 

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cumulative incidence of HIV for each community. The community level cumulative incidence will 
then be compared between treatment and control arms, adjusting using a pre-specified 
algorithm, and accounting for the pair matched design.  
 
In our primary analysis death and outmigration from the community will be treated as right 
censoring events. In the estimation of the community specific three year cumulative incidence in 
secondary analyses we will adjust in the first stage to allow for potentially informative incomplete 
tracking success and right censoring.  
 
 
11.4.2 Data Structure 
a. Baseline Community-Level Data 
For each community in the sample, baseline variables will be measured by the census 
(including population size, summaries of demographic data such as age and sex 
distribution, and occupational mix), and in ethnographic mapping.  
 
b. Longitudinal Individual Data 
For each community in the sample, the J stable adult members of the community will be 
enumerated at baseline. We define stable as subjects who spent at least 6 months of the 
previous year in that community. At year 3, the enumeration will be updated to J* stable 
adult residents to reflect deaths, in-migrations, and outmigrations during Phase I.  Note 
that number of stable residents J is itself a community level random variable. We 
measure individual level data at time of census (t=0), including age, sex, occupation, 
location of residence, and marital status.  
 
In addition, we measure on each individual an indicator of whether he or she attended 
each CHC and indicator of whether he or she was tracked. We will aim to track all stable 
community residents included in the baseline enumeration who do not attend the each 
CHC and have not already been documented to have died. 
 
For individuals who come to the CHC, we measure HIV status, and individual –specific 
covariates, including changes in any of the baseline enumeration variables (residence, 
occupation, marital status) and secondary outcomes as specified elsewhere in the 
protocol.  For subjects who are tracked, we ascertain their vital status and if alive 
measure HIV status and the individual-specific variables measured at the CHC.  
 
c. Observed data 
For Phase I, the observed data for a given community consist of baseline community 
level covariates, Phase I intervention assignment, and J copies of the individual level 
data structure above. For Phase II, the observed data for a given community consist of 
baseline community-level covariates, Phase I intervention assignment, community-level 
outcomes and covariates measured at year 3, and J* copies of the individual level data 
structure above. For Phase I and Phase II, we observe this community level data 

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structure on 32 pair matched communities, where one community in each pair receives 
the treatment and one community the control level of the intervention.  
 
11.4.3 Estimation of Community Specific Cumulative Incidence. 
a. First Stage Target Parameter 
In our primary analysis, we define our HIV negative cohort as those individuals who are 
alive, stable residents, ≥ 15 years of age, and HIV negative at the time of baseline 
CHC/Tracking (for Phase I) or at the time of follow up year 3 CHC/Tracking (for Phase 
II). As we aim to track and test 100% of CHC non-attendees at baseline, this cohort 
should be highly representative.  
 
b. Estimation 
The outcome of interest, HIV status at follow up years 3 (for Phase I) and 6 (For Phase 
II), is not observed for all subjects in our negative cohort due to incomplete CHC 
attendance with partial tracking of non-attendees, and due to right censoring. In the 
control arm there is an increased potential for informative missingness due to the longer 
intervals between serial testing during Phase I. To address the potential bias from 
differential measurement of HIV between the study arms, in Phase I we will use baseline 
and year three data for estimation of the three year cumulative incidence in both study 
arms. In Phase II, we will use follow up year three and year 6 data for estimation of the 
three year cumulative incidence in both study arms. By using equivalent data in 
intervention and control communities, under plausible scenarios this approach reduces 
bias and in simulations results in close to nominal confidence interval coverage and type 
I error control.  
 
In secondary analyses we will adjust for potentially informative missingness in both arms 
to the extent possible given measured individual level covariates using a targeted 
maximum likelihood estimator [40].s 
 
11.4.4 Estimation of Intervention Effect. 
a. Second Stage Target Parameter.  
For Phase I and Phase II, we will evaluate the effect of the intervention on HIV 
cumulative incidence, defined as the ratio of the cumulative incidence of HIV if all 
communities in the sample had received the intervention versus all communities in the 
sample had not received the intervention (relative risk). We will also report the protective 
efficacy: (1-relative risk)x100%. This definition provides inference for the study 
communities. 
 
b. Accounting for the Matched Design 
Under the matched design used in SEARCH, the intervention is randomly allocated 
within matched pairs of communities, where the matched pairs themselves are 
generated based on applying an algorithm to a set of candidate communities. The 
experiment is thus complicated by the fact that the strata (matched pairs) within which 

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the intervention is randomized are a function of the entire sample (in particular, of the 
baseline community characteristics to which the matching algorithm is applied). As a 
result, dependence is introduced by the matching process and the observed data on the 
32 communities in the sample do not correspond to 32 i.i.d copies of a random variable; 
nor do they correspond to 16 i.i.d. copies of a random variable. To address this 
challenge, we propose to apply recent work that investigates this dependence and 
develops estimators under this design [41]. 
 
c. Adjusted Analysis 
Randomization of the intervention ensures that an unadjusted estimator will be unbiased 
for the causal effect of interest. However, imbalances between treatment and control 
communities may occur by chance, and adjustment for baseline community level 
covariates, which include aggregates of baseline individual level covariates, can improve 
efficiency and confidence interval coverage without jeopardizing unbiased estimation 
[41]. In particular, both baseline prevalence and male circumcision coverage will be 
measured on each community at the time of the first CHC and are known to affect 
incidence, but are not available for matching during Phase I, and while available at 
Phase II, residual imbalances are expected. The limited number of communities restricts 
the size of the possible adjustment set, and it is not known a priori which baseline 
covariates will result in the greatest efficiency gain. In our primary analysis for each 
Phase, we will therefore use leave-one-out cross-validation to select  the adjustment set. 
Our primary analysis will adjust for the selected covariate(s) using a targeted maximum 
likelihood estimator. Inference will be based on the estimated paired influence curve [42] 
and the Student’s t distribution with 15 degrees of freedom. We will test the null 
hypothesis of no difference in cumulative incidence between the treatment and control 
communities. This approach has been shown in simulations to result in excellent 
confidence interval coverage and type I error control while resulting in potentially 
substantial increases in power for testing the null hypothesis of no intervention effect. 
 
d. Unadjusted Analysis 
As a secondary analysis, we will obtain an unadjusted estimate as the ratio of the mean  
the community level outcomes in the treatment versus the control communities. 
Inference will be based on the estimated paired influence curve [42] and the Student's t-
distribution with15 degrees of freedom. We will test the null hypothesis of no difference 
in cumulative incidence in the treatment and control communities. 
11.4.4 Power and Sample Size 
 
The trial is being conducted in 20 community pairs in Uganda and 12 community pairs in Kenya, 
each with a population of approximately 5000 stable adult residents. In Phase I, we assume a 
baseline HIV prevalence of 10%, HIV status measured at baseline among 80% of residents, and 
75% of the approximately 3600 of those HIV negative at baseline with an outcome observed at 
year 3. This yields approximately 2700 residents per community who are HIV negative at 
baseline and have their HIV status known at year 3. We make analogous assumptions for 
Phase II, noting that the number of adult stable residents who are HIV negative at follow up year 

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3 will be depleted by incident infections occurring between baseline and year three, deaths, and 
outmigration, but replenished by both in-migrants and adolescents aging into the adult cohort. 
We note that the exact number of residents per community will vary; if the actual sample size 
per community is at least 2700 individuals then the following calculations can be considered 
conservative. We further note that moderate deviations from this number of individuals are not 
expected to have a strong effect on power (Figures 1 and 2). 
 
Figure 1:  Power for Phase I 
 
 
 
Figure 2:  Power for Phase II 
 
 
 
For Phase I, we calculated the number of matched pairs of communities needed to provide at 
least 80% power to detect a 40% reduction in 3 year cumulative incidence of HIV infection in the 
treatment versus control communities, using a two sided test at a 5% level of significance. We 

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based our sample size calculations on the simple unadjusted effect estimator; this approach 
should provide a conservative effect estimate given the potential for covariate adjustment to 
improve precision. Sample size calculations were thus based on the formula in Hayes and 
Bennet for an unadjusted comparison of proportions in a matched trial [43]. 
 
Our initial sample size calculations for Phase I assumed a 1% three year cumulative incidence 
in the control communities. This estimate was conservative based on the available literature, 
which suggested that HIV transmission rates were approximately 0.5 to 2% [44-46]. For 
example, assuming a current incidence density of 0.5 cases per 100 person years, and allowing 
for a 10% decline in transmission rate per year in the absence of the intervention (due to 
concurrent prevention activities would suggest a three year cumulative incidence of 
approximately 1.3%. Figure 1 shows the effect size we are powered to detect in Phase I when 
the control proportion is 1.25-1.55%, informed by mathematical modeling-based projections of 
three year incidence under evolving treatment guidelines. Figure 2 shows analogous estimates 
for Phase II, assuming a three year cumulative incidence, based on mathematical modeling 
projections, of 0.9% or 1.0%. 
 
We further assumed a matched pair coefficient of variation (km) of no greater than 0.4. We note 
that, while ideally external data would be available to inform choice of km, 1) km values depend 
(among other things) on which covariates are matched on, how close a match is achieved, and 
the strength of association between these covariates and the outcome, limiting generalizability 
between studies; and 2) recent work has demonstrated the instability of estimates of km based 
on empirical data [38]. We note that prior studies performed in similar settings have assumed a 
km of closer to 0.25 (Project ACCEPT, Mwanza Trial as discussed in Hayes and Moulton 1999 
[37]); in the case that this more optimistic km holds we will be powered to detect a smaller 
(approximately 30%) reduction in cumulative incidence. Figure 1 and 2 show graphs of the 
percent reduction we will be powered at 80% to detect under a range of deviations from the 
assumptions above, including variation in the number of individuals per community who are HIV 
negative at baseline/year 3 and have known HIV status at year year 3/year 6 (for Phase I and II, 
respectively), a range of three year cumulative incidence values, and a range of kmvalues (for 
16 matched pairs, and correcting for the loss of degrees of freedom when using a paired t-test 
[37]). 
 
11.5 Secondary Analyses 
11.5.1. Secondary Health Outcomes 
a. Overview.  
In addition to estimating the impact of the treatment on expected 3 year cumulative 
incidence of HIV among adults, we will also estimate the treatment effect at 3 and 6 
years follow up for the set of secondary outcomes detailed in section 2.2 for which data 
are available. Key secondary outcomes include: vertical transmission; adult, maternal 
and pediatric mortality; plasma HIV RNA levels; antiretroviral resistance; AIDS; 
tuberculosis and opportunistic infections; and, linkage, time to ART initiation, retention in 

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care for HIV-infected subjects. Given a community level estimate for each of these 
secondary outcomes, statistical analysis to evaluate the intervention’s effect on each of 
these outcomes will follow the general approach described for evaluation of the primary 
outcome, based on unadjusted and adjusted comparison of treatment and control 
communities. In the following subsections we outline the data that will be collected to 
estimate each secondary outcome.  
b. Mortality  
Deaths and births within each study community will be ascertained using a combination 
of data from the CHC and  post-CHC tracking, We will estimate all-cause mortality 
among adults, children < 1 year of age (infant mortality), children < 5 years of age 
(pediatric mortality),  
c. Mother to Child Transmission of HIV 
We will evaluate the effect of the intervention on the proportion of live births still alive 
and HIV uninfected at three  years, among all births and among births to HIV-infected 
mothers. We focus on the outcome among infants three  years after birth to capture the 
interventions effect on transmission prenatally, during birth, and during breastfeeding. 
Data from implementing partners on the HIV status of children born to HIV+ women at 
health facilities will be assessed throughout the study. In addition, estimation of 3 year 
HIV free survival rates for each community will be performed based on CHCs, combined 
with tracking of non-attendees.  This will provide us with a birth cohort that is 
representative of the entire community (and not only of those mothers who engage with 
antenatal care). Specifically, an infant will enter the cohort when his or her mother is 
seen at the CHC or tracked and the birth reported.  
d. Plasma HIV RNA levels, CD4 Cell Count, and Antiretroviral Resistance 
Quantitative HIV-1 RNA PCR testing will be used for HIV RNA level metrics, including 
proportion with HIV RNA level below the limit of detection among all HIV-infected 
individuals. In addition, HIV RNA will be measured from all HIV+ members of the 
household socioeconomic survey, providing annual data from both control and 
intervention communities. 
Drug resistance among HIV-infected individuals will be measured during the CHC, HSE 
and at tracking We will estimate proportion of treatment naive individuals with each and 
with any of these three mutations as a marker of transmitted resistance in each 
community. As markers of acquired resistance, we will also estimate proportion of HIV 
infected individuals with resistance mutations among those individuals who initiated 
treatment. 
Finally, point of care CD4 cell count testing at the CHC and among tracked subjects will 
allow us to estimate CD4 cell count recovery rates annually in the intervention arm and 
will provide population based data after 3 and 6 years of follow up in both arms.  

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Importantly, the use of the CHC plus tracking will provide us with estimates of each of 
these metrics among all HIV-infected individuals, regardless of whether they are retained 
in care. In addition to comparing these community level metrics between treatment and 
control communities, we will also assess how these outcomes vary as a function of CD4 
at antiretroviral initiation. Supplemental data on HIV+ patients in care will also be 
obtained from clinic records. 
e. Linkage, Retention, and Time to ART Initiation  
Use of the CHC combined with tracking of non-returnees (irrespective of HIV status), 
and linkage of resulting data to clinic records will allow us to generate estimates of 
linkage and retention rates among all HIV infected individuals. Specifically, we will 
estimate for each community over time the proportion of newly diagnosed HIV infected 
individuals who successfully link to care (defined as any visit to clinic), as well as the 
proportion retained in care.  In addition, we will estimate the average time from first HIV 
diagnosis to ART initiation for each community. 
f. Internally Derived HIV Infections 
 
Viral consensus sequences will be used to estimate phylogenetic relationships and 
genetic distances between HIV viruses sampled during the study. These data, together 
with additional reference sequences, will be used to classify incident HIV infections 
among community cohort members as linked or not linked to previously documented 
infections among community members [47]. 
Internally derived incident HIV infection will be defined as an incident HIV infection in a 
study participant classified, based on sequence analysis, as linked to a virus previously 
measured from a member of the same community.  Externally derived incident HIV 
infection will be defined as infection with a virus classified as unlinked to a previously 
measured virus in a member of the same community.  
The community specific outcome for this secondary analysis will be the probability of 
becoming infected over the course of the study by an internally derived virus. 
g. Additional Health Outcomes  
Measurement of AIDS-defining events, TB, and treatment-associated toxicities and 
adverse events will include passive surveillance systems and secondary data sources, 
as described in section 6.3.2 and 7.4, with analytic methods used whenever possible to 
reduce bias in estimates of the underlying population parameters. 
Confirmed active TB cases will be identified using existing registries. HIV status of 
confirmed cases will be based on a) HIV status as recorded in the registry and b) linkage 
with SEARCH study based on name and demographic information (following an initial 
feasibility study). 

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Prevalent hypertension and diabetes as well as prior diagnosis and treatment will be 
ascertained at CHC. Information on treatment and disease control will be obtained from 
CHC measurements and clinical records.  
HIV incidence will be measured with an HIV recent  infection testing algorithm among 
HIV infected individuals at Year 3.  
AIDS-defining events among HIV-infected individuals will be measured by obtaining 
WHO Stage IV diagnoses recorded in clinic.  Other information may be obtained from 
community health campaigns, tracking or hospital records. Note that measurement at 
the clinic will rely on linkage and retention of HIV infected patient in care. The resulting 
outcome data will thus be subject to both selection bias and potentially informative 
interval censoring under a non-monotone missingness pattern (i.e. patient will be seen at 
clinic intermittently, some not for long intervals, and detection of these outcomes will only 
be possible when they are seen). 
11.5.2 Supplementary Analyses 
a. Analysis of Process Outcomes 
For each step of the care cascade (testing update, linkage, and retention) we will report 
basic descriptive statistics, including unadjusted and adjusted associations between 
individual level characteristics and retention in the cascade. 
b. Effect Modification and Mediation 
Community level and pooled individual analysis will be applied to investigate how 
individual level characteristics modify the effect of the intervention, and the extent to 
which the intervention effect is mediated by update of specific intervention components. 
Secondary analyses may also include pooled individual level analyses. 
11.5.3 Economic and Education Evaluations 
The objective of our analyses will be to determine the causal effect of early ART initiation on 
several socio-economic and education outcomes. The outcomes will have a different data 
structure than the health outcomes described above, with annual longitudinal data being 
obtained for a sample of baseline CHC participants and baseline non-participants and their 
households. For the entire sample of household socio-economic (HSE) survey participants and 
for the baseline CHC and non-CHC samples our analysis will assess whether changes in socio-
economic outcomes differ between intervention and comparison communities. The analysis will 
also examine the relationship between socio-economic status and HIV status of respondents. 
For the sample of HIV-positive study participants we will analyze changes in socio-economic 
status as a function of changes in CD4 cell count and viral load. Analyses will be performed 
using STATA statistical software. 

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Sample Size    
A total of 200 participants and their household will be recruited for the HSE in each of the study 
communities. This will include 100 HIV-infected individuals and their households and 100 HIV-
uninfected individuals and their households. The sample will consist of individuals who did and 
did not participate in the CHC.   
Estimation Strategy 
The study objectives will be met by comparing changes in the main outcomes between 
intervention and comparison communities. The following outcome variables will be studied: 
adults’ on- and off-farm employment; children’s on- and off-farm employment (child labor); 
children’s time allocation to schooling and household activities; asset holdings (durable good 
and livestock); agricultural output; cash and in-kind transfers. 
For each outcome, a mixed effects regression model will be estimated in order to determine 
whether there are significant differences between intervention and control communities over 
time. Standard errors will be clustered at the community level in regressions that include 
individual- or household-level observations. A limited set of household-level characteristics will 
be included as covariates in the model. Differences between Phase I and II intervention and 
control communities will be examined at years 3, 6,  and at each of the follow-up periods during 
which the HSE is conducted in order to identify short- and long-term effects of ART. Analyses 
will be conducted separately for baseline CHC participants and non-participants. For children’s 
education and labour supply outcomes, the analyses will test for different effects on young and 
old children due to variation in the ways in which households adjust time allocation of household 
members. Effects of ART on the labour supply of adults will also be allowed to vary for men and 
women. In the models that are estimated, trends in the outcome variable that are not due to 
ART will be identified by including controls for the month during which the HSE was conducted.   
11.5.4 Health Care Costing Evaluations 
Costs 
Costs will be assessed both from the health care system analytic perspective, and from the 
patient’s perspective. During the  six years of cost data collection, costs will be measured using 
empirical data as described in section 10.3 above. However, because important health effects of 
ART and the treatment of other chronic disease extends beyond this period, we will model the 
consequences of early versus later ART initiation using the best available data on disease 
progression and the health states and associated medical care costs.  
Unit Cost Measures 
We will calculate several measures of the cost per programmatic goal achieved, from proximate 
to distal. The proximate measures will be cost per HIV+ person identified, linked to care, and 
started on ART. The intermediate measure will be cost per ART-month (person on ART for a 
month). The distal efficiency measures will focus on surrogate biological markers of ART 

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success: cost per CD4 level recovered and viral load suppressed. Costs of PrEP per HIV case 
averted will also be calculated.  
Health Status 
We will translate observed and projected health events into a standard metric of disease 
burden, Disability Adjusted Life Years (DALYs). The calculated DALYs occurring will reflect 
health benefits (e.g., added years of life from ART) estimated from the morbidity and mortality 
measured during the study, plus future health effects of HIV incidence measured during the trial, 
using our published methods to project future health burden of HIV adjusted for ART access. 
Cost-Effectiveness 
Finally we will estimate incremental cost-effectiveness. This is the net added cost per health 
outcome, e.g., per DALY averted. Both the numerator and the denominator represent the 
difference between study arms. Thus, the numerator will reflect differences in the cost of ART  
use and in savings from averted disease. (Both arms have a community testing campaign.). The 
denominator will represent the difference in DALYs due to the clinical benefits of ART, HIV 
infections averted, and any other observed disease effects. The ratio is the ICER (incremental 
cost-effectiveness ratio), in dollars per DALY averted. If the intervention saves money and 
improves health (“dominant” in cost-effectiveness parlance), no ICER will be calculated (since 
there is no cost-health tradeoff); results will be expressed as economic savings and health 
gains. In Phase II, the incremental cost of PrEP will be calculated.  
Sensitivity Analyses 
To estimate the impact of uncertainty in inputs, we will conduct extensive one-way and two-way 
sensitivity analyses. We will also using Monte Carlo multi-variable simulations to estimate the 
confidence intervals associated with the base-case incremental cost-effectiveness ratios. 
 

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12. DATA COLLECTION AND MONITORING 
12.1 Data and Safety Monitoring Plan    
The SEARCH project will employ a multi-tiered approach to monitoring the progress of the trial 
for ethics, safety, efficacy, and futility.  Monitoring will take place at the levels of the community, 
the host country, and study-wide through defined groups and processes (see Table 7).  
Table 8: SEARCH Trial Monitoring Information Sources and Responsibilities 
Information Tier 
Organization Unit  
Responsibilities 
Community 
Community Advisory 
Boards (CAB) 
Experiences and concerns of 
community members of the study 
communities and agencies. 
Host Country 
Local Advisory Boards 
(LAB) 
Ethical and policy issues and 
developments potentially 
impacting the conduct and 
rationale of the trial within the host 
country. 
Science & Ethics 
Scientific Advisory Board 
(SAB) 
Scientific and ethical issues and 
potentially impacting the conduct 
and rationale of the trial. 
Study Data 
Data Safety Monitoring 
Board (DSMB) 
Study progress including 
incidence of significant adverse 
events, interim efficacy and futility 
analyses, and issues from 
community and scientific advisory 
boards. 
 
Information on the conduct and acceptance of the study will be obtained at the community level 
through the local Community Advisory Boards who are charged with representing the 
experiences and concerns of community members of the study communities.  Issues and 
concerns about the conduct and impact of the trial on the community will be communicated in 
writing from local CAB to study investigators and presented in summaries to the study Data 
Safety Monitoring Board (DSMB).  Likewise, scientific and policy issues and developments 
potentially impacting the conduct and rationale of the trial at the host country level will be 
assessed by the study-wide and host-country site Scientific Advisory Boards and communicated 
in writing to study investigators and presented in summaries to the study DSMB.   Finally, study 
progress including incidence of significant adverse events and interim analyses will be 
presented to the study DSMB and study statisticians in written form and in person at annual or 
ad-hoc DSMB meetings. 
12.1.1 Data and Safety Monitoring Board  
 

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Pursuant to the NIH policy for Data and Safety Monitoring: a Data Safety and Monitoring Board 
will be convened to provide oversight of the SEARCH trial.  The role of the DSMB will be to 
review implementation and progress of the trial and to review the accumulating data from the 
study to detect early, significant benefit or harm for communities and persons while the trial is in 
progress.  The DMSB will consist of three main categories of Members: 1) Voting members, 2) 
Advisors, and 3) Observers. Voting Members will consist of 5 individuals, including a Chair, who 
will be nominated by the protocol Principal Investigators and approved by the Executive 
Steering Committee for the study. At least one of the voting members will be a national of the 
host site countries.  Voting Members are appointed for the duration of the study and participate 
in all closed-session meetings and votes. The voting membership will possess expertise in 
medicine, epidemiology/trials, statistics, and ethics/participant advocacy.   Advisor members will 
consist of 3-5 individuals nominated by Voting Members who provide & exchange knowledge, 
context and advice, and are approved by the Executive Steering Committee for the study.  
Advisors do not participate in DSMB voting activities.  Observer members are board members 
that support operations and functions of the DSMB and its participant members but do not 
directly participate in discussions as representatives of areas of expertise or outside agencies.  
The DSMB will convene to review study progress and safety and may be called into ad hoc 
sessions as the Board sees fit or at the request of the study Principal Investigator.  At the 
meeting, the study Statistician and Principal Investigator will present summaries of issues and 
concerns from the local and study-wide advisory boards and the trial progress and safety and 
efficacy data, including the results of any planned interim analyses, to the DSMB for 
consideration.  Following its meetings, the DSMB will act in an advisory capacity to the 
investigators to monitor study participant safety and data quality and evaluate progress of the 
study and present its recommendations in writing to NIH, study sponsors and the study Principal 
Investigator. 
12.1.2 DSMB Meetings and Interim Reports 
 
Early in the first year the DSMB shall meet to review the DSMB Charter and its guiding 
principles and to familiarize itself with the study protocol, the primary statistical analysis plan, 
and the trial safety stopping rules. The first DSMB data review will occur after all 32 
communities have completed their first community health campaign and subsequent tracking 
and a period of 60 days has elapsed to allow for referral patient linkage-to-care. The DSMB will 
meet annually thereafter. 
Primary analysis for Phase I will be performed when all 32 communities have completed 
collecting 3 years of incidence data. Analysis of HIV incidence and of all secondary outcomes 
for which data are available will be completed as described in the statistical plan (Section 11). At 
the time of completion of Phase I, a meeting of the DSMB will be convened and the study team 
will present information on study progress and the results of analyses. An analogous report to 
the DSMB will occur at the time of completion of Phase II analyses. Should event triggers such 
as an unanticipated serious adverse event, series of unanticipated adverse events, or significant 
developments in the field indicate to the DSMB Chair and the Principal Investigator that the 
DSMB should meet, an ad hoc review will be scheduled as soon as possible.  

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DSMB reports will contain information on community and advisory board issues and concerns 
and on study progress and data quality (including community health campaign testing, ART 
initiation and distribution) and safety data (serious adverse events and deaths). For stopping 
guidelines in Phase I, the protocol team recommends that an excess of deaths or HIV infections 
in the intervention arm at follow up year 3 (demonstrated in the primary analysis for Phase I) 
could justify termination of the study. An excess of deaths or HIV infections observed in the 
Phase I control arm at follow up year 3 should not trigger study termination, as all study 
communities will receive universal treatment and streamlined care during Phase II. Failure to 
demonstrate an impact of Phase I intervention on HIV incidence should also not trigger 
stopping, as Phase II is designed to evaluate impact of a targeted strategy in the context of 
achieving the UN AIDS 90-90-90 target.  
12.2 Baseline Household Community Level Census 
Household Census data will be collected by teams using hand-held computers (tablets).  Prior 
to conducting the census, the census questionnaire will be programmed into the hand-held 
computers. Programming will include range checks, structure checks and internal consistency 
checks.  Before leaving the household, the completed questionnaire will be checked for 
mistakes and completeness, ensuring each household has a unique identifier.  Data from these 
devices will be transferred daily via a secure electronic transfer to our data center facility in 
Kampala and stored on a secure server.  
Each household location will be mapped using a hand-held GPS receiver. Readings will be 
taken from the door of the household, if possible, or from a point that is most representative of 
the household.  The GPS coordinates for each household will also be recorded in the tablet 
computer at the time of administering the census questionnaire.  GPS data will be synchronized 
from the GPS to a Microsoft Access database daily and then transferred via a secure electronic 
transfer to the data center facility in Kampala and stored on a secure server. 
A digital biometric identifier based on an electronic fingerprint of each household member will be 
captured in an electronic database on the hand-held computer and linked to the household 
member name.  A portable fingerprint reader will be connected to the tablet computer via a USB 
port and the biometric identifier will be saved into the electronic database on the tablet.  The 
database will be transferred daily via a secure electronic transfer to the data center facility in 
Kampala and stored on a secure server. 
12.3 Community Health Campaign 
12.3.1 Welcome Station 
The first stop for participants during most Community Health Campaign will be the Welcome 
Station.  There will be an electronic database of all the biometric identifiers collected during the 
Census Survey available at the Welcome Station.  Staff members will verify participant’s 
fingerprint biometric identifier against the database to ensure they have a biometric identifier in 
the system.  If a participant did not have a biometric identifier taken during the Census Survey, a 
biometric identifier based on his or her digital fingerprint will be taken at the Welcome Station 

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and added to the database.  Once the participant’s biometric identifier is verified, the participant 
will be given a bracelet with a unique identifier on it.  The unique identifier will be added to the 
biometric identifier database and linked to the participant’s biometric identifier.  The participant 
will then be tracked through the Community Health Campaign with the unique identifier on the 
bracelet. 
12.3.2 Health and Socioeconomic Interview Station 
During most campaigns, health and socio-economic data will be collected by trained staff 
members electronically using tablet computers.  Prior to conducting the Health and 
Socioeconomic Interview, the interview will be programmed into the tablet computers. 
Programming will include range checks, structure checks and internal consistency checks.  The 
unique identifier on the participant’s bracelet will be used to link the participant to their interview 
data.  Data from the tablet computers will be transferred daily via a secure electronic transfer to 
our data center facility in Kampala and stored on a secure server. 
12.3.3 Other CHC Stations 
During the campaign, all information recorded at each of the stations will be recorded in Log 
Books by staff members.  The unique identifier on the participant’s bracelet will be used to link 
the participant to their data in the Log Books.  Afterwards, the Log Books will be entered directly 
into an electronic database.  Data Integrity checks will be written into the database to limit the 
entry of incorrect data and ensure entry of data into required fields.  All data will be double 
entered to verify accuracy of entry.  The database will be transferred regularly via a secure 
electronic transfer to the data center facility in Kampala and stored on a secure server. 
12.3.4 Tracking CHC Non-Participants 
Apart from the verbal autopsy questionnaire, data collected during evaluation of non-participants 
will be collected using hand-held computers (tablets).  Prior to conducting the evaluation, the 
questionnaire will be programmed into the hand-held computers. Programming will include 
range checks, structure checks and internal consistency checks.  Data from these devices will 
be transferred daily via a secure electronic transfer to our data center facility in Kampala and 
stored on a secure server. 
12.3.5 Morbidity/Disease Surveillance 
Study staff will regularly collect information available from routine encounters at local health 
centers and, where needed, hospitals within the community. This information will be available in 
the clinic’s standard visit forms and recorded by staff for data entry. 
Afterwards, the surveillance forms will be entered directly into an electronic database.  Data 
Integrity checks will be written into the database to limit the entry of incorrect data and ensure 
entry of data into required fields.  All data will be double entered to verify accuracy of entry.  The 
database will be transferred regularly via a secure electronic transfer to the data center facility in 
Kampala and stored on a secure server. 

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12.4 ART Intervention and PrEP 
All data will be obtained from encounter forms at local health centers and recorded onto 
standardized case record forms by study staff.  Afterwards, the forms will be entered directly 
into an electronic database.  Data Integrity checks will be written into the database to limit the 
entry of incorrect data and ensure entry of data into required fields.  All data will be double 
entered to verify accuracy of entry.  The database will be transferred regularly via a secure 
electronic transfer to the data center facility in Kampala and stored on a secure server.  
12.5 Grade 3 and 4 Adverse Event and Serious Adverse Event Monitoring 
Grade 3 and 4 adverse events (AEs) and serious adverse events (SAEs) will be monitored in all 
sentinel cohorts in Phase I.  We will utilize the DAIDS Toxicity Table for Adults and Children 
grading scale (Appendix A) for reported symptoms and laboratory monitoring.  The sentinel 
cohorts will be composed of persons in the intervention arm with CD4 >350 cells.  These 
individuals will be matched on CD4 to individuals not receiving ART and evaluated semi-
annually through chart review supplemented by tracking visits. 
In Phase II, participants receiving PrEP will be monitored for grade 3 and 4 AEs and SAEs 
according to the DAIDS Toxicity Table. 
The following definitions for serious or unexpected adverse events will be followed: 
A Serious Adverse Event (SAE) is any AE that results in any of the following outcomes: 
• 
Death, 
• 
Life-threatening adverse experience, 
• 
Inpatient hospitalization or prolongation of existing hospitalization, 
• 
Persistent or significant disability/incapacity, 
• 
Congenital anomaly/birth defect, or cancer, or 
• 
Any other experience that suggests a significant hazard, contraindication, side effect or 
precaution that may require medical or surgical intervention to prevent one of the 
outcomes listed above, 
• 
Event occurring in a gene therapy study 
• 
Event that changes the risk/benefit ratio of the study. 
An Unexpected Adverse Event is defined as being unexpected if the event exceeds the nature, 
severity, or frequency described in the protocol, consent form and investigator brochure (when 
applicable). An unexpected AE also includes any AE that meets any of the following criteria: 
• 
Results in subject withdrawal from study participation, 
• 
Due to an overdose of study medication, or 
• 
Due to a deviation from the study protocol 
Adverse events in sentinel sites will be reported to individual IRBs according to the table below: 

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Table 9: Adverse Events 
Institution 
Type of Adverse Events 
When to Report 
UCSF-CHR 
• 
External [off-site] adverse event that 
UCSF PI determines changes the 
study risks or benefits, OR 
necessitates modification to the CHR-
approved consent document(s) and/or 
the CHR-approved 
application/protocol 
• 
Within 10-working days of PI’s 
awareness 
SOMREC 
• 
All Serious or Unexpected events 
irrespective of relationship 
• 
Fatal or life-threatening events 
within 3 working days of 
awareness  
• 
All other SAEs within 7 
calendar days 
NDA 
• 
All serious and Unexpected events 
irrespective of relationship 
• 
Within 7-calendar days of 
awareness 
KEMRI 
SERU 
• 
All Serious or Unexpected events 
irrespective of relationship  
• 
Study-related events within 24 
hours of awareness 
• 
Unrelated events within 10 
working days of awareness 
Gilead 
Sciences 
• 
Definitely, Probably, or Possibly 
related to Gilead-supplied Truvada 
AND Serious or Unexpected 
• 
Within 15-calendar days of 
awareness 
 
12.6 Household Socio-Economic Survey 
Household Socio-Economic Survey data will be collected by teams using hand-held computers 
(tablets).  Prior to conducting the survey, the questionnaire will be programmed into the hand-
held computers. Programming will include range checks, structure checks and internal 
consistency checks.  Before leaving the household, the completed questionnaire will be 
checked for mistakes and completeness, ensuring each household has a unique identifier.  Data 
from these devices will be transferred daily via a secure electronic transfer to our data center 
facility in Kampala and stored on a secure server. 
12.7 Health Care Costing Evaluations 
Each health facility will be identified using a code. Health facility time in motion data will be 
recorded on paper and transferred to a database by study staff.  Cost data will be collected in 
Microsoft Excel and imported to a database (Microsoft Access or FileMaker) for storage and 
manipulation. Although there is no confidential patient information in the cost data, it will be 
integrated with standard secure methods used for other data in the study. The data files will be 
regularly backed up on secure servers 
12.8 Data Security and Integrity 
In order to ensure data security and integrity, the following measures will be implemented: 

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• 
All members of the study team will be educated in the study protocol prior to the onset of 
the study. 
• 
Detailed Standard Operating Procedures (SOPs) will be written for all project activities 
and be provided to relevant team members. 
• 
Team members will be thoroughly trained on the SOP’s. 
• 
Where applicable, team members will receive additional training on the use of GPS 
devices. 
• 
Where applicable, team members will receive additional training on the use of tablet 
computers. 
• 
All data transcribed from paper will be double data entered or verified. 
• 
All electronic data will be backed up on a daily basis. 
• 
All data will be transferred to the main Data Center in Kampala to the secure server.  
This sever is backed up on a daily basis and a monthly backup is stored off-site. 
• 
All computers, including the tablets, will be password protected. 
• 
All computers, including tablets, will be locked in a secure room each night. 
• 
All Log Books and CRF’s will be locked in a secure room each night. 

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13. HUMAN SUBJECTS 
13.1 Ethical Considerations 
13.1.1 ART Intervention in Phase I 
In Phase I of this study, ART will be initiated at CD4+ thresholds higher than the national 
guidelines defining standard of care. We must therefore consider the potential benefits and risks 
of ART at higher CD4 counts to ensure that the key intervention of this study (ART initiation) 
meets the strictest ethical guidelines. We submit that initiation of ART at all CD4 thresholds 
meets and exceeds ethical standards by several criteria: 
1)  ART is routinely initiated in all HIV-positive patients throughout many countries. 
2)  ART initiation for all CD4 thresholds is now recommended by many professional HIV 
medicine societies. For example, ARTs are now formally recommended by the United States 
Department of Health and Human Services for all patients.  
3)  Accumulating evidence indicates that there may be substantial clinical benefit to initiating 
ART as soon as a person is HIV infected. This benefit may accrue from reductions in 
immune activation and systemic inflammation, as well as limitation of the size of the latent 
reservoir of HIV. These pathophysiologic discoveries have been partially responsible for the 
changes in clinical practice guidelines detailed above. 
4)  The additional amount of time a patient will take ART if initiated at any CD4 threshold vs. 
country-specific guidelines is relatively small. Accumulated data on the speed of HIV 
progression (i.e., the time taken for CD4 to decline to 350 cells/uL from the time of infection) 
indicates that this may take, on average, 2-3 years in most patients. This time is even 
shorter when starting at a threshold below 500 cells/uL. This study, therefore, will bridge this 
length of treatment administration, after which point participants will be allowed to continue 
ART provided by the local government’s country-specific guidelines. 
13.1.2 ART Intervention and PrEP in Phase II 
1)  In accordance with the 2015 WHO guidelines. All study participants will receive ART in 
Phase I when the country adapts the WHO policy 
2)  In Phase II of SEARCH, all HIV+ persons will receive ART, and the dispensation of ART will 
not be considered a study intervention.  
3)  PrEP is  recommended by the WHO  for high risk populations (e.g sex workers) and is being 
rolled out in Kenya and Uganda. Because the SEARCH approach offers PrEP to persons  
not only in these risk groups but also to those persons at high risk based on self assessment 

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and a risk score,  our SEARCH approach will be considered as an intervention requiring 
informed consent to participate in this study.   
 
13.2 Institutional Review Board (IRB) and Informed Consent 
13.2.1 Obtaining Consent 
This protocol, all procedures and consent forms, and any subsequent modifications must be 
reviewed and approved by the IRBs of all the participating institutions in the U.S., Uganda and 
Kenya. This includes the UCSF Committee on Human Research (CHR), the Makerere 
University School of Medicine - Research and Ethics Committee (SOM-REC), the Uganda 
National Council of Science and Technology (UNCST), the Uganda National Drug Authority 
(NDA), and the Kenya Medical Research Institute (KEMRI) Scientific and Ethics Review Unit. 
The Kenya Pharmacy and Poisons Board (PPB) will be notified of any modifications to the 
protocol and consent forms as well. 
All consent forms will be translated into the local language and back-translated into English to 
ensure correct use of language. Consent forms will be read aloud to participants or their parents 
by trained staff. The informed consent will describe the purpose of the study, all the procedures 
involved, and the risks and benefits of participation. Interviewers will ask participants or their 
parents/guardians to summarize the study and explain the reasons why they want to participate. 
Either a signature or a thumbprint (for those who cannot read) will be acceptable to confirm 
informed consent for participation in the study, in the case of written consent forms. 
See Appendix B for further details on individual consenting procedures. 

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14. PUBLICATION OF RESEARCH FINDINGS 
The findings from this study may be published in a medical journal.  No individual identities will 
be used in any reports or publications resulting from the study. The researchers will publish 
results of the study in accordance with NIAID, UCSF, UNCST, KEMRI and Makerere University 
guidelines. 
15. SUPPLEMENTAL LABORATORY EVALUATIONS 
Laboratory testing shall take place using accredited local laboratories. In the event that local 
capacity is not available for specialized testing, reasonable efforts will be made to build local 
capacity. In the event that local capacity is not warranted, samples will be exported with all 
required permissions and permits to external testing laboratories. Table 9 lists examples of  
specialized testing, laboratories and rationale required to meet study aims. 
Table 9: Laboratory Evaluations Requiring Sample Export 
Evaluation 
Testing Laboratory  
Rationale 
Pharmacokinetic 
evaluation of ARV 
levels (hair and 
blood samples) 
UCSF Hair Analytical Laboratory (HAL) 
Monica Gandhi, MD, MPH  
University of California, San Francisco 
Department of Medicine, Division of 
HIV, ID and Global Medicine 
San Francisco, USA 
Measure ARV concentrations in 
small hair samples and DBS 
samples using validated 
methods involving liquid 
chromatography/ tandem mass 
spectrometry. (LC/MS-MS). 
Testing equipment and 
expertise not available in-
country. 
APOL1 gene 
testing and future 
testing on 
characteristics of 
kidney disease 
(DBS, blood and 
urine) 
Division of Nephrology 
Chi-Yuan Hsu, MD, MS 
University of California, San Francisco 
Division of Nephrology 
San Francisco, USA 
Testing equipment and 
expertise not available in-
country for APOL1 testing and 
other complex assays. 
HIV-1 sequencing 
for drug resistance 
mutations and 
phylogenetic 
analyses (DBS, 
blood); HIV-1 LAg-
Avidity EIA 
MRC/UVRI Uganda Research Unit on 
AIDS 
Dr. Deogratius Ssemwanga 
Uganda Virus Research Institute 
Entebbe, Uganda 
 
The UVRI is a fully accredited 
WHO reference laboratory for 
high-throughput HIV incidence, 
drug resistance genotyping and 
phylogenetic analyses with 
extensive experience in 
sequencing multi-clade HIV-1 
from DBS. Equivalent technical 
expertise is not currently 
available in Kenya. 
Western blot HIV 
testing (blood 
samples) 
Laboratory led by Monica Gandhi, MD, 
MPH 
University of California, San Francisco 
Department of Medicine, Division of 
HIV, ID and Global Medicine 
San Francisco, USA 
Assay resources for Western 
blot testing are not currently 
available in Uganda or Kenya 

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men. N Engl J Med, 2010. 363(27): p. 2587-2599. 
12. 
Granich, R.M., et al., Universal voluntary HIV testing with immediate antiretroviral therapy as a 
strategy for elimination of HIV transmission: a mathematical model. Lancet, 2009. 373(9657): p. 
48-57. 
13. 
Wagner, B. and S. Blower, Costs of eliminating HIV in South Africa have been underestimated. 
Lancet, 2010. 376(9745): p. 953-4. 
14. 
Wagner, B.G., J.S. Kahn, and S. Blower, Should we try to eliminate HIV epidemics by using a 
'Test and Treat' strategy? Aids, 2010. 24(5): p. 775-6. 
15. 
Dieffenbach, C.W. and A.S. Fauci, Thirty years of HIV and AIDS: future challenges and 
opportunities. Ann Intern Med, 2011. 154(11): p. 766-71. 

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16. 
Weber, J., R. Tatoud, and S. Fidler, Postexposure prophylaxis, preexposure prophylaxis or 
universal test and treat: the strategic use of antiretroviral drugs to prevent HIV acquisition and 
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17. 
Dodd, P.J., G.P. Garnett, and T.B. Hallett, Examining the promise of HIV elimination by 'test and 
treat' in hyperendemic settings. Aids, 2010. 24(5): p. 729-35. 
18. 
Wawer, M.J., et al., Circumcision in HIV-infected men and its effect on HIV transmission to 
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19. 
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Middelkoop, K., et al., Antiretroviral therapy and TB notification rates in a high HIV prevalence 
South African community. J Acquir Immune Defic Syndr, 2011. 56(3): p. 263-9. 
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Zachariah, R., et al., Reduced tuberculosis case notification associated with scaling up 
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22. 
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therapeutic implications: a systematic review. Lancet Infect Dis, 2011. 11(7): p. 541-56. 
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Fowler, M.G., et al., Perinatal HIV and its prevention: progress toward an HIV-free generation. 
Clin Perinatol, 2010. 37(4): p. 699-719, vii. 
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Schouten, E.J., et al., Prevention of mother-to-child transmission of HIV and the health-related 
Millennium Development Goals: time for a public health approach. Lancet, 2011. 378(9787): p. 
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25. 
Donnell, D., et al., Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a 
prospective cohort analysis. Lancet, 2010. 375(9731): p. 2092-8. 
26. 
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Pagel, C., et al., Intracluster correlation coefficients and coefficients of variation for perinatal 
outcomes from  five cluster-randomized controlled trials in low and middle-income countries; 
results and methodological implications. Trials, 2011. 12: p. 151. 
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Chingono, A., et al., Balancing science and community concerns in resource-limited settings: 
Project Accept in rural Zimbabwe. Clin Trials, 2008. 5(3): p. 273-6. 
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experimental data. Springer series in statistics,. 2011, New York: Springer. lxxi, 626 p. 
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L. Balzer, M. van der Laan, M.L. Petersen and the SEARCH Collaboration. Adaptive pre-
specification in randomized trials with and without pair-matching.  Statistics in Medicine, 
35(25):4528–4545, 2016. 
42. 
Balzer, L.B., M.L. Petersen, and M. Van der Laan, Adaptive pair-matching in the SEARCH trial 
and estimation of the intervention effect. U.C. Berkeley Division of Biostatistics Working Paper 
Series, 2014. 320. 
43. 
Hayes, R.J. and S. Bennett, Simple sample size calculation for cluster-randomized trials. Int J 
Epidemiol, 1999. Apr; 28(2): p. 319-26. 
44. 
Guwatudde, D., et al., Relatively Low HIV Infection Rates in Rural Uganda, but with High 
Potential for a Rise: A Cohort Study in Kayunga District, Uganda. PloS One, 2009. 4(1): p. 
e4145. 
45. 
Shafer, L.A., et al., HIV prevalence and incidence are no longer falling in southwest Uganda: 
evidence from a rural population cohort 1989-2005. AIDS, 2008. 22: p. 1641-49. 

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46. 
Gray, R.H., et al., Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised 
trial. Lancet, 2007. 369: p. 657-66. 
47. 
Campbell, M.S., et al., Viral linkage in HIV-1 seroconverters and their partners in an HIV-1 
prevention clinical trial. PLoS One, 2011. 6(3): p. e16986. 
48. 
Kwarisiima, D, et al., High rates of viral suppression in adults and children with high CD4+ 
counts using a streamlined ART delivery model in the SEARCH trial and rural Uganda and 
Kenya. JAIDS, 2017. 20(Suppl 4): p. 58-67.   
 

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Appendix A Guidelines for Adverse Event Grading – DAIDS Toxicity Table for Adults 
and Children 
Selected portion of the of Division of AIDS [DAIDS] Table for Grading the Severity of Adult and 
Pediatric Adverse Events, version July 2017. 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse 
event NOT identified 
elsewhere in this 
DAIDS AE grading 
table  
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities with 
intervention indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions with 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death 
SYSTEMIC 
Acute allergic 
reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
medical intervention 
indicated OR 
Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Fatigue or Malaise 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6 to < 39.3°C or ≥ 
101.5 to < 102.7°F 
≥ 39.3 to < 40.0°C or ≥ 
102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain 
(not associated with study 
agent injections and not 
specified elsewhere)  
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Pain causing inability to 
perform usual social & 
functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Unintentional Weight 
Loss  
(excludes postpartum 
weight loss) 
NA 
5 to < 9% loss in body 
weight from baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 

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CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
DERMATOLOGIC 
Rash  
Specify type, if 
applicable 
Localized rash 
Diffuse rash OR Target 
lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations of 
mucous membrane 
limited to one site 
Extensive or 
generalized bullous 
lesions OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis 
Pruritus 
(without skin lesions) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Itching causing inability 
to perform usual social & 
functional activities  
NA 
 
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss  
 
Loss of appetite 
associated with 
significant weight loss  
Life-threatening 
consequences OR 
Aggressive 
intervention indicated 
(e.g., tube feeding, 
total parenteral 
nutrition) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 4 
to 6 stools over 
baseline per 24-hour 
period 
Increase of ≥ 7 stools per 
24-hour period OR IV 
fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Nausea  
Transient (< 24 
hours) or intermittent 
AND No or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Vomiting 
Transient or 
intermittent AND No 
or minimal 
interference with oral 
intake 
Frequent episodes with 
no or mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 

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CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
RESPIRATORY 
Dyspnea or 
respiratory distress 
Report only one 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities OR 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to < 95% 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure 
with ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3 ; cells/L)  
> 7 days of age 
800 to 1,000  
0.800 x 109 to 1.000 x 
109 
600 to 799 
0.600 x 109 to 0.799 x 
109 
400 to 599  
0.400 x 109 to 0.599 x 
109 
< 400  
< 0.400 x 109 
Hemoglobin, Low  
(g/dL; mmol/L)  
≥ 13 years of age (male 
only) 
10.0 to 10.9  
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0  
4.34 to < 5.57 
< 7.0  
< 4.34 
Hemoglobin, Low  
(g/dL; mmol/L)  
≥ 13 years of age 
(female only) 
9.5 to 10.4  
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5  
4.03 to < 5.25 
< 6.5  
< 4.03 
Platelets, decreased 
(cells/mm3 ; cells/L) 
100,000 to  
< 125,000 
100.000 x 109 to 
< 125.000 x 109 
50,000 to < 100,000 
50.000 x 109 to          
< 100.000 x 109 
25,000 to < 50,000 
25.000 x 109 to          
< 50.000 x 109 
< 25,000 
< 25.000 x 109 
WBC, decreased 
(cells/mm3 ; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 x 
109 
1,500 to 1,999  
1.500 x 109 to 1.999 x 
109 
1,000 to 1,499  
1.000 x 109 to 1.499 x 
109 
< 1,000 
< 1.000 x 109 
CHEMISTRIES  
ALT or SGPT, High 
Report only one 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
AST or SGOT, High 
Report only one 
1.25 to < 2.5 x ULN 
2.5 to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 

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LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Bilirubin (Total), High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN  
OR Increase of > 0.3 
to < 1.5 x participant’s 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x participant’s 
baseline 
≥ 3.5 x ULN              
OR Increase of ≥ 2.0 x 
participant’s baseline 
Potassium, High 
(mEq/L; mmol/L) 
5.6 to < 6.0  
5.6 to < 6.0 
6.0 to < 6.5  
6.0 to < 6.5 
6.5 to < 7.0  
6.5 to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0 to < 3.4  
3.0 to < 3.4 
2.5 to < 3.0 
2.5 to < 3.0 
2.0 to < 2.5  
2.0 to < 2.5 
< 2.0  
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146 to < 150  
146 to < 150 
150 to < 154  
150 to < 154 
154 to < 160  
154 to < 160 
≥ 160  
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130 to < 135  
130 to < 135 
125 to < 130  
125 to < 130 
121 to < 125  
121 to < 125 
≤ 120  
≤ 120 
Glucose, High  
 
Nonfasting 
(mg/dL; mmol/L) 
116 to 160  
6.44 to < 8.89 
> 160 to 250 
 8.89 to < 13.89 
> 250 to 500  
13.89 to < 27.75 
> 500  
≥ 27.75 
   Fasting 
(mq/dL; mmol/L) 
110 to 125  
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500  
13.89 to < 27.75 
> 500  
≥ 27.75 
Glucose, serum, low 
(mq/dL; mmol/L) 
≥ 1 month of age 
55 to 64  
3.05 to 3.55 
40 to < 55  
2.22 to < 3.05 
30 to < 40  
1.67 to < 2.22 
< 30  
< 1.67 
 
 
 

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Appendix B Table of Study and Consent and Commitment Procedures 
Study 
component 
No. of 
participants in 
Mbarara district, 
Uganda 
No. of 
participants in 
Tororo district, 
Uganda 
No. of 
participants in 
Kenya 
Procedures 
Timeline 
Consent or commitment 
process 
Community 
Leader 
10 
10 
12 
Meet with local community 
leaders representing each of the 
32 selected communities 
Prior to the first 
Household Census and 
CHC in each selected 
community 
Obtain letter of commitment 
from leader of each selected 
community 
Baseline 
Household 
Community Level 
Census 
All individuals in 
selected 
communities 
All individuals in 
selected 
communities 
All individuals in 
selected 
communities 
Census of all community 
members to collect identifier and 
location information 
Prior to first 
Community Health 
Campaign in each 
selected community; 
also at Campaign for 
those not previously 
consented 
Verbal consent of head of 
household for themselves 
and other household 
members*; fingerprint 
biometric will be recorded as 
consent documentation 
Community Health 
Campaign 
All individuals in 
selected 
communities 
All individuals in 
selected 
communities 
All individuals in 
selected 
communities 
• Tests and measurements 
including rapid HIV testing, 
malaria testing on children and 
other health evaluations 
• Education and referral to local 
health services 
• Distribution of anti-malaria 
medications and vitamin A in 
children, and male condoms 
Prior to first 
Community Health 
Campaign in each 
selected community; 
also at Campaign for 
those not previously 
consented 
Verbal adult consent for 
themselves and their 
children to participate in 
Campaign*; fingerprint 
biometric will be recorded as 
consent documentation 
Targeted/Key 
Population 
Testing 
Any individuals in 
selected key 
population groups 
Any individuals in 
selected key 
population groups 
Any individuals in 
selected key 
population groups 
• Rapid HIV testing 
• CD4 testing, if HIV-positive 
• An optional survey on 
background and sexual history 
Any time after initial 
Community Health 
Campaign in each 
selected community 
Verbal consent of 
participating adult, age ≥15 
years 
Household Socio-
Economic Survey 
200 x 10 
communities, 
100 HIV+ & 100 
HIV- (n = 2,000) 
200 x 10 
communities,  
100 HIV+ & 100 
HIV- (n = 2,000) 
200 x 12 
communities, 100 
HIV+ & 100 HIV- (n 
= 2,400) 
A survey to collect demographic, 
health and education information 
and to perform additional health 
testing 
2-4 weeks after each 
Campaign 
Written consent, adults, 
conducted at Community 
Health Campaign or at their 
home 
Photography/ 
filming at 
Community Health 
Campaigns 
Any participants at 
selected 
Community Health 
Campaigns 
Any participants at 
selected 
Community Health 
Campaigns 
Any participants at 
selected 
Community Health 
Campaigns 
Taking photographs or filming 
participants at selected 
Campaigns 
At selected Community 
Health Campaigns 
Written consent of adults and 
their children at Campaigns 
Photography for 
dermatologic 
evaluations 
Eligible participants  
in selected 
communities 
Eligible participants 
in selected 
communities 
Eligible participants 
in selected 
communities 
De-identified photography of skin 
conditions at selected Campaigns 
At selected Community 
Health Campaigns 
Verbal consent of adults at 
Campaigns 
*Per the National Implementation Guidelines for HIV Counselling and Testing in Uganda and the Guidelines on Use of Antiretroviral Drugs for Treating and 
Preventing Infection in Kenya, adolescents 15 years and older may self-consent for testing procedures 
 

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Study 
component 
No. of 
participants in 
Mbarara district, 
Uganda 
No. of 
participants in 
Tororo district, 
Uganda 
No. of 
participants in 
Kenya 
Procedures 
Timeline 
• Consent or 
commitment process 
ART Intervention 
All HIV+ individuals 
who do not meet in-
country treatment 
guidelines 
All HIV+ individuals 
who do not meet in-
country treatment 
guidelines 
All HIV+ individuals 
who do not meet in-
country treatment 
guidelines 
Distribution of ART and routine 
testing in a streamlined model of 
care 
Up to 144 weeks from 
ART initiation for each 
participant 
• Written consent, adults 
• Parental written consent, 
children <8 years 
• Written assent, children 8-
12 years, with parental 
written consent 
• Written consent, children 
≥13 years, parental co-sign 
PrEP Intervention 
High risk persons in 
each intervention 
community 
High risk persons in 
each intervention 
community 
High risk persons in 
each intervention 
community 
Distribution of PrEP and routine 
testing 
Up to 144 weeks from 
PrEP initiation for each 
participant 
• Written consent, adults 
and independent minors, 
age ≥ 15 years 
• Parental co-consent, 
minors age 15-17 years 
PEP Evaluation 
Persons with a 
recent possible 
exposure to HIV 
Persons with a 
recent possible 
exposure to HIV 
Persons with a 
recent possible 
exposure to HIV 
Collect data and support PEP use 
among persons provided PEP 
through health center 
Up to 36 weeks from 
PEP initiation for each 
participant 
• Written consent, adults 
and independent minors, 
age ≥ 15 years 
• Parental co-consent, 
minors age 15-17 years 
PrEP-specific  
qualitative and 
quantitative 
evaluations 
a.) 3-6 service 
providers in 1 
community 
b.) HIV+ and HIV- 
persons in 1 
community 
c.) 4 linked/ 
declined PrEP 
participants in 1 
community 
d.) High risk 
persons in 
intervention 
communities 
e.) PrEP 
participants 
retained in the 
PrEP program  
a.)  3-6 service 
providers in 1 
community 
b.) N/A 
 
 
c.) 4 linked/ 
declined PrEP 
participants in 2 
communities each 
d.) High risk 
persons in 
intervention 
communities 
e.) PrEP 
participants 
retained in the 
PrEP program 
a.) 3-6 service 
providers in 1 
community 
b.) HIV+ and HIV- 
persons in 2 
communities 
c.) 4 linked/ 
declined PrEP 
participants in 2 
communities each 
d.) High risk 
persons in 
intervention 
communities 
e.) PrEP 
participants 
retained in the 
PrEP program 
a.) In-depth interview on PrEP 
implementation 
 
b.) Focus group discussion for 
HIV+ & HIV- adolescents (15-24) 
and discordant couples on PrEP 
c.) In-depth interviews on PrEP 
 
 
 
d.) Survey for CHC attendees 
who accept/decline PrEP 
 
 
e.) Surveys and in-depth 
interviews on PrEP retention and 
adherence 
a.) After 
implementation of 
PrEP in the community 
b.) During and after 
CHC in selected 
communities 
c.) During Phase II 
 
 
 
d.) During CHCs in 
selected communities 
 
 
e.) Surveys during 
FUY3-FUY6, in-depth 
interviews during 
FUY5-FUY6 
a.) Written consent, adults  
 
 
b.) Written consent, adults; 
parental co-signature for 
participants 15-17 years 
c.) Written consent, adults 
consented by CHC verbal 
consent 
 
d.) Consented by CHC 
verbal consent 
 
 
e.) Written consent, adults; 
parental co-signature for 
participants 15-17 years 
New infection 
qualitative cohort 
A subset of 
participants 
enrolled in the ART 
Intervention arm in 
selected 
communities 
A subset of 
participants 
enrolled in the ART 
Intervention arm in 
selected 
communities 
A subset of 
participants 
enrolled in the ART 
Intervention arm in 
selected 
communities 
A survey on experiences related 
to new HIV infection 
Within 6 months of 
enrollment in ART 
Delivery arm 
Written consent, adults 
Stigma 
A random subset of 
A random subset of 
A random subset of 
A questionnaire on stigma issues 
Any time at CHCs, 
Written consent, adults 

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95 
 
questionnaire 
HIV- and HIV+ 
community 
members 
HIV- and HIV+ 
community 
members 
HIV- and HIV+ 
community 
members 
related to HIV 
participant homes or 
work places, or at 
health clinics in 
selected communities 
Study 
component 
No. of 
participants in 
Mbarara district, 
Uganda 
No. of 
participants in 
Tororo district, 
Uganda 
No. of 
participants in 
Kenya 
Procedures 
Timeline 
Consent or commitment 
process 
Qualitative 
evaluation 
 
e.) 2-4 
Communi
ty leaders 
in 2 
communit
ies 
 
b.) 24-30 
Community Health 
Campaign 
participants in 
communities 
conducting CHCs  
 
c.) 10 randomly 
selected service 
providers in 2 
communities (5 per 
community) 
 
d.) Sub-sample of 
Household Socio-
Economic Survey 
in 2 communities: 
14 x 2 
communities, 
9 HIV+ & 5 HIV- (n 
= 28) 
 
e.) 18-24 HIV+ 
suppressed, 
unsuppressed and 
out of care subjects 
in 2 communities 
each 
a.) 2-4 Community 
leaders in 2 
communities 
 
b.) 24-30 
Community Health 
Campaign 
participants in 
communities 
conducting CHCs 
 
c.) 10 randomly 
selected service 
providers in 2 
communities (5 per 
community) 
 
d.) Sub-sample of 
Household Socio-
Economic Survey 
in 2 communities: 
14 x 2 
communities, 
9 HIV+ & 5 HIV- (n 
= 28) 
 
e.) 18-24 HIV+ 
suppressed, 
unsuppressed and 
out of care subjects 
in 2 communities 
each 
a.) 22-4 Community 
leaders in 4 
communities 
 
b.) 24-30 
Community Health 
Campaign 
participants in 
communities 
conducting CHCs  
 
c.) 10 randomly 
selected service 
providers in 4 
communities (5 per 
community) 
 
d.) Sub-sample of 
Household Socio-
Economic Survey 
in 4 communities: 
14 x 4 
communities, 
9 HIV+ & 5 HIV- (n 
= 56) 
 
e.) 18-24 HIV+ 
suppressed, 
unsuppressed and 
out of care subjects 
in 4 communities 
each 
a.) In-depth semi-structured 
interviews 
 
 
b.) Focus group discussions 
(1 for women, 1 for men, and 1 
mixed gender group per 
community; 8-10 individuals in 
each group) 
 
 
c.) In-depth semi-structured 
interviews 
  
 
 
 
d.) In-depth semi-structured 
interviews 
 
 
 
 
 
 
 
e.) In-depth semi-structured 
interviews 
 
 
 
e.) 1-2 weeks 
after each 
Community 
Health 
Campaign 
 
b.) Within 1-2 weeks 
after each Community 
Health Campaign 
 
 
 
 
c.) 2-4 weeks after 
each Household Socio-
Economic Survey 
 
 
 
d.) 2-4 weeks after 
each Household Socio-
Economic Survey 
 
 
 
 
 
 
e.) During Phase II 
 
 
 
 
 
For all research activities 
related to qualitative 
evaluation of SEARCH: 
Written consent, adults 
TB IPT survey 
N/A 
A subset of patients 
at SEARCH clinics  
N/A 
Survey on barriers/facilitators of 
treatment completion 
During Phase II 
Written consent, adults 
Social mixing 
questionnaire 
N/A 
A subset 
participants of 5-25 
years who took part 
N/A 
Survey on social mixing patterns 
During Phase II 
Written consent, adults; 
assent, children 8-17 years, 
with additional parental 

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96 
 
in TST testing 
during HSE survey 
consent 
Youth 
engagement 
A subset of HIV+ 
youth in one or 
more SW Uganda 
communities 
N/A 
N/A 
Intensive VL counseling and 
monitoring and life-stage 
assessment 
During Phase II 
Consented by CHC verbal 
consent 

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97 
 
Appendix C Uganda Antiretroviral Therapy Guidelines 
Selected portion of The Integrated National Guidelines on Antiretroviral Therapy, Prevention of 
Mother to Child Transmission of HIV and Infant & Young Child Feeding, Ministry of Health, 
Uganda. 
ART Initiation in Adults 
The current MoH guidelines are as summarized in a table bellow  
Including HIV positive Partner in a discordant relationship irrespective of CD4 count 
Category  
Recommendation  
First line treatment  
All children 
<15years  
Start ART 
irrespective of CD4 
count 
 <3yrs  
ABC/3TC/NVP 
3-9.9yrs ABC/3TC/EFV 
10-14.9 
<35kg 
ABC/3TC/EFV 
>35KG 
TDF/3TC/EFV 
15> 
TDF/3TC/EFV 
 
Pregnant women 
Start ART 
irrespective of CD4 
OptionB+ 
TDF/3TC/EFV 
Adults  
With CD4 less ≤ than 
500 
Stage 3and 4, TB , 
Hep B, HepC , TB co-
infection 
irrespective of CD4 
TDF/3TC/EFV 
Most at risk 
populations 
(fisher folks, 
truckers, CSWs) 
Start ART 
irrespective of CD4 
TDF/3TC/EFV 
 
 

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Eligibility criteria for initiating art in infants and children 
Three parameters guide the decision making process for initiation of ART in infants and 
children; these are the age, immunological status and WHO clinical Staging. However ART can 
also be started in children under 18 months of age presumptively (as will be described in the 
next section.)   

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99 
 
Appendix D Kenya Antiretroviral Therapy Guidelines 
Selected portion of the Guidelines on Use of Antiretroviral Drugs for Treating and Preventing 
HIV Infection, 2016 Edition. 
 
Eligibility for ART 
 
All individuals with confirmed HIV infection are eligible for ART, irrespective of CD4 cell levels, 
WHO clinical stage, age, pregnancy or breastfeeding status, coinfection status, risk group, or 
any other criteria. 
 
Timing of ART Initiation 
 
ART should be started in all patients as soon as possible (preferably within 2 weeks of 
confirmation of HIV status). 
 
ART can be initiated as soon as patients meet the ART Readiness Criteria, even if it is the same 
day as enrolment into care. ART initiation on the same day as enrolment into care has 
additional benefits for HIV prevention (e.g. for pregnant and breastfeeding women, and the HIV 
positive partner in a discordant relationship), and may have additional mortality benefits for 
infants less than 12 months of age. 
 

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100 
 
 
Appendix E Sample Pediatric ART Dosing Chart 
 
 
3 - 5.9 kg 
6 - 9.9 kg 
10 - 13.9 kg 
14 - 19.9 kg 
20 - 20.9 kg 
25 - 25.9 kg 
Tablets/Capsules 
EFV 200 - 100 
- 50mg 
NR 
NR 
200mg 
daily 
300mg daily 
300mg daily 
400mg 
daily 
ABC 300mg 
NR 
NR 
NR 
0.5 BID 
1 AM/0.5 PM 
1 BID 
ABC 60mg 
1 BID 
1.5 BID 
2 BID 
2.5 BID 
3 BID 
Use adult 
3TC 150mg 
NR 
NR 
NR 
0.5 BID 
1 AM/0.5 PM 
1 BID 
LPV/r 
100/25mg 
NR 
NR 
2 AM/1 PM 
2 BID 
2 BID 
3 BID 
LPV/r 
200/50mg 
NR 
NR 
NR 
1 BID 
1 BID 
2 AM/1PM 
AZT 300mg 
NR 
NR 
NR 
0.5 BID 
1 AM/0.5 PM 
1 BID 
NVP 200mg 
NR 
NR 
NR 
1 AM/0.5 PM 
1 AM/0.5 PM 
1 BID 
NVP 50mg 
1 BID 
1.5 BID 
2 BID 
2.5 BID 
3 BID 
Use adult 
Oral Solutions 
ABC 20mg/ml 
3ml BID 
4ml BID 
6ml BID 
NR 
NR 
NR 
3TC 10mg/ml 
3ml BID 
4ML BID 
6ml BID 
NR 
NR 
NR 
LPV/r  
80/20 mg/ml 
3-3.9kg:  1ml BID 
4-5.9kg: 1.5ml BID 
1.5ml BID 
2ml BID 
2.5ml BID 
3ml BID 
3.5ml BID 
AZT 10mg/ml 
6ml BID 
9ml BID 
12ml BID 
NR 
NR 
NR 
NVP 10mg/ml 
5ml BID 
8ml BID 
10ml BID 
NR 
NR 
NR