Clinical trial NCT01327651
Conditions: HIV Infections
Keywords: Drug Administration Schedule Nucleoside Reverse Transcriptase Inhibitors Pharmacokinetics
Sponsor: HIV Prevention Trials Network
Start date: 2011-08-01; Completion date: 2014-12-01
Enrollment: 622 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Pre-exposure prophylaxis (PrEP) is a method of preventing HIV infection through the use of antiretroviral (ARV) medications before exposure to HIV. This study will examine the feasibility of different methods of dosing for a PrEP regimen. Three methods of delivery will be compared: daily, time-based, and event-based.

Detailed description:
No single strategy for the prevention of HIV has emerged as consistently used and successful, so multiple strategies have been developed. PrEP involves delivering ARV medications to people before they are exposed to HIV, in order to prevent infection. The optimal method of delivering PrEP has not yet been determined. This study will examine the feasibility of delivering PrEP in three methods. Daily dosing involves receiving ARV medications every day; time-driven dosing involves receiving ARV medications twice weekly plus a post-exposure dose; and event-driven dosing involves receiving ARV medications before and after a potential exposure to HIV. The ARV medication that will be used in this study is a combination pill that contains emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). Recent research studies have shown that, if taken consistently, a daily oral dose of FTC/TDF can reduce the risk of HIV infection.

This study will enroll HIV-uninfected men who have sex with men and transgender women (MSM/TGW) and women who have sex with men (WSM). Participation will last 34 weeks. All participants will be given a combination pill that contains FTC/TDF. For the first 5 weeks, all participants will come to the study clinic weekly to receive a single dose of FTC/TDF.

At Week 6, participants will be randomly assigned to one of three groups. In the daily dosing group, participants will take FTC/TDF once a day. In the time-dosing group, participants will take FTC/TDF twice per week and another dose after sexual intercourse (a post-exposure dose). In the event-dosing group, participants will take FTC/TDF before and after sexual intercourse. During this part of the study, participants will be given FTC/TDF to take on their own. Every week, from Week 6 to Week 29, study officials will call to ask questions about how many pills participants have taken and when they have had sexual intercourse. Participants will also complete computer-assisted self-interviews (CASIs).

Study visits will occur at enrollment, once a week for the first 5 weeks, and then once a month until Week 34. Assessment will include recording of medical history, completing an interview about sexual practices and background, and collection of blood, urine, and hair samples. Select study visits will include vaginal practices assessment (including use of lubricants and vaginal cleansing practices), family planning assessments (for women), and sex hormones assessments (for men).

Participants who acquire HIV infection during the study will discontinue study product. These participants will continue to be followed after enrollment at Weeks 4, 6, 10, 14, 18, 22, 26, 30, and every 12 weeks thereafter, as appropriate, until the last study participant completes follow-up at the study site. Participants whose first reactive HIV rapid test is at Week 34 who are later confirmed to be HIV infected will also be followed every 12 weeks after their Week 30 visit until the last study participant completes follow-up at the study site. Participants who acquire HIV infection during the study will undergo select protocol procedures and will receive counseling and referrals for HIV treatment.

Arms: arm 1: Participants will receive oral FTC/TDF daily. arm 2: Participants will receive oral FTC/TDF twice weekly with a post-exposure dose. arm 3: Participants will receive oral FTC/TDF before and after a potential exposure to HIV infection.
Interventions: intervention 1: Daily dosing intervention 2: Time-driven dosing intervention 3: Event-driven dosing
Intervention descriptions: intervention 1: A fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. intervention 2: TDF/FTC twice weekly with a post-exposure dose intervention 3: TDF/FTC as needed with a post exposure dose

Protocol documents:
Prot_ICF_000.pdf: 
 
HPTN 067 
The ADAPT study: 
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate  
Pre-Exposure Prophylaxis (PrEP) 
 
A Study of the HIV Prevention Trials Network 
 
 
 
Sponsored by: 
 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases (NIAID) 
US National Institute of Mental Health (NIMH) 
US National Institutes of Health (NIH) 
 
Drug Donated by: 
Gilead Sciences, Inc. 
 
 
Protocol Chair: 
Robert M. Grant, MD, MPH 
Gladstone Institute of Virology and Immunology 
Associate Professor of Medicine, University of California, San Francisco 
 
Protocol Co-Chair: 
Frits van Griensven, PhD, MPH 
Associate Professor of Epidemiology and Biostatistics, University of California, San Francisco 
 
Final Version 5.0 
June 10, 2013 
 
IND# 71,859 (held by DAIDS) 
DAIDS Document ID#10852 
 
 
 
 
 
 
 
 
 
 
 
 
 


HPTN 067, Final Version 5.0 
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HPTN 067 
The ADAPT study:  
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate  
Pre-Exposure Prophylaxis (PrEP)  
 
 
TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................................... v 
TERMINOLOGY FOR TENOFOVIR, EMTRICITABINE, AND THEIR DERIVATIVES viii 
PROTOCOL TEAM ROSTER .................................................................................................. ix 
INVESTIGATOR SIGNATURE PAGE .................................................................................. xii 
SCHEMA  
...................................................................................................................... xiii 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME ........................... xv 
A) Randomization Scheme ....................................................................................................... xv 
B) Study Design ...................................................................................................................... xvi 
1.0 
Introduction ......................................................................................................................... 1 
1.1 
Background and prior research ............................................................................... 1 
1.2 
Animal studies of chemoprophylaxis...................................................................... 3 
1.3 
Human FTC/TDF trials ........................................................................................... 3 
1.4 
Significance of Determining Pharmacology of Intermittent PrEP ......................... 3 
1.5 
Drug Concentration as an Adherence Measure ...................................................... 4 
1.6 
Development and Validation of Tenofovir Hair Assay .......................................... 5 
1.7 
Drug Concentration Simulation Models ................................................................. 6 
1.8  
Dose-proportionality and Drug Accumulation ....................................................... 7 
1.9 
TDF and FTC drug resistance ............................................................................... 10 
1.9.1 
Patterns of drug resistance associated with TDF and FTC ................................... 10 
1.9.2 
Substantial barrier to HIV resistance to TDF and FTC ........................................ 11 
1.10 
Rationale ............................................................................................................... 11 
1.10.1 
Justification for Intermittent PrEP ........................................................................ 11 
1.10.2 
Justification for comparing event-driven dosing and time-driven dosing to daily 
dosing .................................................................................................................... 13 
1.10.3 
Theoretical basis for postulating behavioral effects of intermittent dosing .......... 14 
Figure 1-2: Adapted IMB-model of PrEP and Condom Use .................................................... 19 
1.10.4 
Rationale for drug level testing ............................................................................. 20 
1.10.5 
Relevance to the goals of the HPTN ..................................................................... 20 
1.10.6 
Design advantages ................................................................................................ 21 
2.0 
STUDY OBJECTIVES AND DESIGN ........................................................................... 22 
2.1 
Primary Objective: ................................................................................................ 22 
2.2 
Secondary Objectives: .......................................................................................... 22 
2.3 
Study Design ......................................................................................................... 22 
2.4 
Description of the intervention ............................................................................. 23 
2.4.1 
Once-a-week directly observed dosing lead-in component .................................. 23 
2.4.2 
Self-administered dosing component .................................................................... 23 
2.4.2.1 
Daily usage........................................................................................................ 26 
2.4.2.2 Time-driven usage ................................................................................................ 26 


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2.4.2.3 
Event-driven usage............................................................................................ 27 
3.0 
STUDY POPULATION ................................................................................................... 27 
3.1 
Inclusion Criteria .................................................................................................. 28 
3.1.1 
MSM/TGW ........................................................................................................... 28 
3.1.2 
WSM ..................................................................................................................... 29 
3.2 
Exclusion Criteria ................................................................................................. 29 
3.2.1  
Vulnerable Populations ......................................................................................... 29 
3.3 
Recruitment Process.............................................................................................. 30 
3.4 
Co-Enrollment Guidelines .................................................................................... 31 
3.5 
Participant Retention ............................................................................................. 31 
3.6 
Participant Withdrawal ......................................................................................... 32 
4.0 
STUDY DRUG/INTERVENTION .................................................................................. 32 
4.1 
Study Drug/Intervention Formulation/Content ..................................................... 32 
4.2 
Study Drug/Intervention Regimen(s) and Administration .................................... 32 
4.3 
Study Drug/Intervention Supply and Accountability ........................................... 33 
4.4 
Toxicity Management ........................................................................................... 34 
4.4.1 
Grading System ..................................................................................................... 34 
4.4.2 
Discontinuation of Study Drug in the Presence of Toxicity ................................. 34 
4.4.3 
General Criteria for Discontinuation of Study Drug............................................. 35 
4.5 
Management of Specific Toxicities ...................................................................... 36 
4.5.1 
Nausea, Vomiting, and Diarrhea ........................................................................... 36 
4.5.2 
AST/ALT Elevations ............................................................................................ 37 
4.5.3 
Calculated Creatinine Clearance ........................................................................... 38 
4.5.4 
Hypophosphatemia ............................................................................................... 39 
4.5.5 
Proteinuria ............................................................................................................. 40 
4.5.6 
Glycosuria ............................................................................................................. 41 
4.5.7 
HIV Infection ........................................................................................................ 41 
4.6 
Clinical Management of Pregnancy ...................................................................... 42 
4.7 
Criteria for Early Termination of Study Participation .......................................... 43 
4.8 
Concomitant Medications ..................................................................................... 44 
5.0 
STUDY PROCEDURES .................................................................................................. 44 
5.1 
Screening............................................................................................................... 45 
5.2 
Enrollment............................................................................................................. 46 
5.3 
Weeks 1-5 ............................................................................................................. 47 
5.4 
Week 6/Randomization ......................................................................................... 48 
5.5 
Weeks 7 through 29 .............................................................................................. 49 
5.6 
Week 30 ................................................................................................................ 50 
5.7 
Week 34 ................................................................................................................ 50 
5.8 
Participants who have suspected or documented HIV infection during the study 51 
5.9 
Participants Who Become Pregnant...................................................................... 52 
5.10 
Behavioral Data Collection ................................................................................... 52 
5.10.1 
Quantitative Behavioral Component..................................................................... 52 
5.10.1.1 
Coverage and Sexual Behavior ..................................................................... 52 
5.10.2 
Qualitative Behavioral Component....................................................................... 53 
5.10.2.1 
Focus groups and key informant interviews ................................................. 53 
6.0 
SAFETY MONITORING AND ADVERSE EVENT REPORTING .............................. 56 
6.1 
Safety Monitoring ................................................................................................. 56 


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6.2 
Clinical Data Safety Review ................................................................................. 56 
6.3 
Adverse Event definition and reporting to DAIDS ............................................... 57 
6.3.1 
Adverse Events ..................................................................................................... 57 
6.3.2 
Serious Adverse Events ........................................................................................ 58 
6.3.2.1 
AE Reporting to DAIDS ................................................................................... 58 
6.3.2.2 
Grading severity of adverse events ................................................................... 59 
6.3.3 
Adverse Event Relationship to Study Product ...................................................... 59 
6.4 
Pregnancy Outcomes ............................................................................................ 59 
6.5 
Regulatory Requirements...................................................................................... 59 
6.6 
Social Harms Reporting ........................................................................................ 59 
7.0 
STATISTICAL CONSIDERATIONS.............................................................................. 60 
7.1 
Review of Study Design ....................................................................................... 60 
7.2 
Study Endpoints .................................................................................................... 60 
7.2.1 
Primary Endpoints ................................................................................................ 60 
7.2.2 
Secondary Endpoints ............................................................................................ 61 
7.3 
Accrual, Follow-up, and Sample Size................................................................... 63 
7.4 
Random Assignment ............................................................................................. 67 
7.5 
Data Analysis ........................................................................................................ 67 
7.5.1 
Primary Analyses .................................................................................................. 67 
7.5.2 
Secondary analyses on coverage, pill-use and side effects/symptoms ................. 69 
7.5.3 
Secondary analyses on adherence, acceptability and sexual behavioral data ....... 69 
7.5.4 
Secondary analyses on safety outcomes ............................................................... 71 
7.5.5 
Secondary analyses on drug concentration data ................................................... 71 
7.5.6 
Qualitative behavioral data analyses ..................................................................... 72 
7.6 Safety Monitoring for HIV Seroconversions ...................................................................... 74 
8.0 
HUMAN SUBJECTS CONSIDERATIONS .................................................................... 75 
8.1 
Ethical Review ...................................................................................................... 75 
8.2 
Informed Consent.................................................................................................. 76 
8.3 
Risks ...................................................................................................................... 77 
8.4 
Benefits ................................................................................................................. 83 
8.5 
Incentives .............................................................................................................. 83 
8.6 
Confidentiality ...................................................................................................... 84 
8.7 
Communicable Disease Reporting Requirements ................................................ 84 
8.8 
Study Discontinuation ........................................................................................... 84 
9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT ........................ 84 
9.1 
Local Laboratory Specimens ................................................................................ 84 
9.2 
Network Laboratory Specimens ........................................................................... 86 
9.3 
Quality Control and Quality Assurance Procedures ............................................. 87 
9.3.1 
QC for HIV diagnostic testing .............................................................................. 88 
9.3.2 
QC for HIV RNA monitoring ............................................................................... 88 
9.3.3 
QC for CD4 cell count determination ................................................................... 88 
9.4 
Biohazard Containment ........................................................................................ 89 
9.5 
Sample storage ...................................................................................................... 89 
10.0 
ADMINISTRATIVE PROCEDURES ............................................................................. 89 
10.1 
Study Activation ................................................................................................... 89 
10.2 
Study Coordination ............................................................................................... 90 
10.3 
Study Monitoring .................................................................................................. 91 


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10.4 
Protocol Compliance ............................................................................................. 91 
10.5 
Investigator's Records ........................................................................................... 91 
10.6 
Use of Information and Publications .................................................................... 92 
11.0 
REFERENCES ................................................................................................................. 93 
APPENDICES ............................................................................................................................ 101 
Appendix I: 
Schedule of Study Visits and Procedures ....................................................... 101 
Appendix IA.  All study participants .................................................................................. 101 
Footnotes for Appendix IA ................................................................................................. 102 
Appendix IB. Additional Procedures for Participants with Confirmed HIV Infection .... 103 
Appendix II: 
Additional power calculation with a range of average coverage rates for two 
primary hypothesis tests. ..................................................................................................... 104 
Appendix III: 
SAMPLE INFORMED CONSENT FORMS ............................................. 106 
SAMPLE SCREENING AND ENROLLMENT INFORMED CONSENT FORM .......... 106 
SAMPLE FOCUS GROUP INFORMED CONSENT ....................................................... 120 
SAMPLE KEY INFORMANT INTERVIEW INFORMED CONSENT FOR SELECTED 
STUDY PARTICIPANTS .................................................................................. 125 
SAMPLE KEY INFORMANT INTERVIEW INFORMED CONSENT FOR CLINIC 
STAFF................................................................................................................. 129 


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HPTN 067 
The ADAPT study: 
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis 
(PrEP) 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
3TC 
 
 
Lamivudine 
ABV  
 
Abacavir 
ADAPT 
 
Alternative Dosing to Augment PrEP pill Taking (study) 
AE 
 
 
Adverse event 
ALT 
 
 
Alanine transaminase 
APTIMA 
 
Amplified Probe by Transcription Mediated Amplification 
ART  
 
Antiretroviral Therapy 
AST 
 
 
Aspartate transaminase 
AIDS  
 
Acquired immunodeficiency syndrome 
AZT 
 
 
Zidovudine 
CASI  
 
Computer Assisted Self Interview 
CBC  
 
Complete blood count 
CDC  
 
US Centers for Disease Control and Prevention 
CORE  
 
(HPTN) Coordinating and Operations Center 
CPQA  
 
Clinical Pharmacology Quality Assurance Committee 
CRF 
 
 
Case report form 
CRPMC  
 
(NIAID) Clinical Research Products Management Center 
CV 
 
 
Coefficient of variation 
DAIDS 
 
Division of AIDS 
DAERS 
 
DAIDS Adverse Event Reporting System 
DBS 
 
 
Dried blood spots 
DDI 
 
 
Didanosine 
DNA  
 
Deoxyribonucleic acid 
DOT  
 
Directly observed therapy 
DSMB  
 
Data and Safety Monitoring Board 
EAE 
 
 
Expedited adverse event 
EC 
 
 
Ethics Committee 
EDM  
 
Electronic drug monitoring 
EFV 
 
 
Efavirenz 
EQA  
 
External quality assurance 
FDA  
 
(United States) Food and Drug Administration 
FTC 
 
 
Emtricitabine 
FTC/TDF 
 
Emtricitabine / Tenofovir Disoproxil Fumarate 
FTC-TP 
 
Emtricitabine Triphospate 
GEE 
 
 
General Estimating Equation 
GLP 
 
 
Good Laboratory Practice 
HBsAg 
 
Hepatitis B Surface Antigen 


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HBCoreAb 
 
Hepatitis B Core Antibody 
HBsAb 
 
Hepatitis B Surface Antibody 
HBV   
 
Hepatitis B Virus 
HIV 
 
 
Human Immunodeficiency Virus 
HPTN  
 
HIV Prevention Trials Network 
IATA  
 
International Air Transport Association  
ICH 
 
 
International Conference on Harmonisation  
IoR 
 
 
Investigator of Record 
IMB 
 
 
Information Motivational Behavior 
IND 
 
 
Investigational New Drug 
IQA 
 
 
Immunology quality assurance 
IRB 
 
 
Institutional Review Board 
IUD 
 
 
Intrauterine device 
LDMS  
 
Laboratory Data Management System 
LL 
 
 
Local laboratory 
LLN 
 
 
Lower limit of normal 
LV 
 
 
Laboratory verified (adherence)  
MSM  
 
Men who have sex with men 
MSM/TGW 
 
Men who have sex with men and transgender women 
NIAID  
 
(United States) National Institute of Allergy and Infectious Diseases 
NIH 
 
 
(United States) National Institutes of Health 
NIMH  
 
National Institutes of Mental Health 
NL 
 
 
(HPTN) Network Laboratory 
NRTI  
 
Nucleoside Reverse Transcriptase Inhibitor 
NNRTI 
 
Non-Nucleoside Reverse Transcriptase Inhibitor 
OHRP  
 
Office of Human Research Protection 
PBMC  
 
Peripheral Blood Mononuclear Cell 
PD 
 
 
Pharmacodynamic 
PEP 
 
 
Post-Exposure Prophylaxis 
PK 
 
 
Pharmacokinetic 
PrEP  
 
Pre-Exposure Prophylaxis 
PRO 
 
 
(DAIDS) Protocol Registration Office 
pSMILE 
 
Patient Safety Monitoring and International Laboratory Evaluation 
PSRT   
 
Protocol Safety Review Team 
QA/QC 
 
Quality assurance/Quality control 
RE 
 
 
Regulatory entity 
RNA  
 
Ribonucleic acid 
RSC 
 
 
(DAIDS) Regulatory Support Center 
SAE 
 
 
Serious Adverse Event 
SD 
 
 
Standard deviation 
SDMC  
 
(HPTN) Statistical and Data Management Center 
SIV 
 
 
Simian immunodeficiency virus  
SMC  
 
Study Monitoring Committee 
SOP 
 
 
Standard Operating Procedure 
SRC 
 
 
Scientific Review Committee 
SR 
 
 
Self-reported (adherence)  
SSP 
 
 
Study Specific Procedure 


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STI 
 
 
Sexually transmitted infection 
TDF 
 
 
Tenofovir Disoproxil Fumarate 
TFV 
 
 
Tenofovir 
TFV-DP 
 
Tenofovir Diphosphate 
TLFB   
 
Timeline follow-back  
TUC 
Thailand Ministry of Public Health–United States (U.S.) Centers 
for Disease Control (CDC) 
UCSF  
 
University of California at San Francisco  
ULN  
 
Upper limit of normal 
USAID 
 
United States Agency for International Development 
U.S. 
 
 
United States 
VOICE 
 
Vaginal and Oral Interventions to Control the Epidemic (study) 
VQA  
 
Virology quality assurance 
WIHS  
 
Women’s Interagency HIV Study  
WSM  
 
Women who have sex with men 
ZDV  
 
Zidovudine 
 


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TERMINOLOGY FOR TENOFOVIR, EMTRICITABINE, AND THEIR 
DERIVATIVES 
 
 
Abbreviation 
Compound 
name 
Comments 
TDF 
Tenofovir 
disoproxil 
fumarate 
This is the inactive, oral formulation of tenofovir (TFV, 
trade name: Viread®).  The ester form enhances oral 
absorption and bioavailability.  TDF is rapidly metabolized 
after dosing to the de-esterified pro-drug, which is also 
inactive.   
TFV 
Tenofovir 
This is the inactive, de-esterified form of TDF.  This is the 
form of the drug that is measured in serum, blood, other 
body fluids, and non-cellular tissue samples.   
TFV-DP 
Tenofovir 
diphosphate 
This is the active, phosphorylated form of TFV that is 
generated in cells.  This is the form of the drug that is 
measured in cells (e.g., peripheral blood mononuclear cells, 
PBMCs).  It is rapidly dephosphorylated to the inactive 
form outside of cells, and has a very short half-life outside 
of cells in tissue. 
FTC 
Emtricitabine 
FTC is an inactive pro-drug that is activated in cells by 
phosphorylation.  This is the form of the drug that is 
measured in serum, blood, other body fluids, and non-
cellular tissue samples. 
FTC-TP 
Emtricitabine 
triphosphate 
This is the active form of FTC that is generated in cells.  
This is the form measured in cells (e.g., PBMCs).   
Truvada® 
FTC/TDF 
This is the trade name of a co-formulated drug produced by 
Gilead Sciences, Inc.  Each pill contains 300 mg of TDF and 
200 mg of FTC. 


HPTN 067, Final Version 5.0 
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HPTN 067 
The ADAPT study:  
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis 
(PrEP) 
PROTOCOL TEAM ROSTER 
 
Lead Investigators 
Robert M Grant, MD, MPH 
(Chair) Investigator, Gladstone 
Institute of Virology and 
Immunology Associate  
Associate Professor of Medicine, 
University of California, San 
Francisco  
San Francisco, CA 94158 
Phone: 415-734-4810 
Fax: 415-738-5384 
Email: rgrant@gladstone.ucsf.edu 
 
Frits van Griensven, PhD, MPH 
(Co-Chair) Professor, Division of 
Preventive Medicine and Public 
Health  
Department of Epidemiology and 
Biostatistics 
School of Medicine, University of 
California at San Francisco 
Box 1224, 50 Beale Street 
San Francisco, CA, 94143-1224 
Phone: 66-9-009-22908 
Email: fritsvg@gmail.com  
 
Timothy Mastro, MD  
FHI 360 
2224 E. Hwy 54 
Durham, NC 27713  
Phone: 919-544-7040, Ext. 11305 
Fax: 919-544-0207 
Email: tmastro@fhi360.org 
 
Nirupama Sista, PhD 
FHI 360 
2224 E.  Hwy 54 
Durham, NC 27713 
Phone: 919-544-7040, Ext. 11590 
Fax: 919-544-0207 
Email: nsista@fhi360.org 
 
Linda-Gail Bekker,  
MBChB, FCP (SA), PhD 
Associate Professor  
Desmond Tutu HIV Centre 
Ground Floor, Werner and 
Beit Building North 
Institute of Infectious 
Diseases and Molecular 
Medicine 
University of Cape Town 
Faculty of Health Sciences 
Anzio Road, Observatory, 
7925 
Cape Town, South Africa 
Phone: 27-21- 633-6599 
Fax: 27-021-633-0182 
Email: Linda-
Gail.Bekker@hiv-
research.org.za 
 
Gilead Sciences, Inc. 
James Rooney, MD  
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA  94404 
Phone: 650-522-5708 
Fax: 650-522-5854 
Email: 
jim_rooney@gilead.com 
 
PAB 
Ana I. Martinez, R.Ph 
Protocol Pharmacist 
Division of 
AIDS/NIAID/NIH 
6700 B Rockledge Dr, Room 
4115 
Bethesda, MD 20892  
Phone: 301-435-3734 
Fax: 301-402-1506 
Email: 
amartinez@niaid.nih.gov 
Site Investigators 
Timothy H. Holtz, MD, MPH, 
FACP, CAPT USPHS,  
Director 
HIV/STD Research Program 
Thailand MOPH - US CDC 
Collaboration (TUC)  
DDC 7 Building, 4th floor 
Ministry of Public Health, Soi 4 
Nonthaburi 11000 Thailand 
Phone: 66-2-580-0669 ext 456 
Fax: 66-2-580-0712  
E-mail: tholtz@th.cdc.gov  
 
Surita Roux, MBChB, MPH 
Desmond Tutu HIV Foundation 
14 Sonwabile Drive, Old 
Crossroads 
Nyanga 
Cape Town, South Africa 
Phone: 27-21-386-0053 
Fax: 27-21-386-0054 
Email: surita.roux@hiv-
research.org.za 
 
Sharon Mannheimer, MD 
Columbia University 
Mailman School of Public Health 
Harlem Prevention Center 
215 W. 125th Street, A-100 
New York, NY 10027 
Phone:  212-939-2940  
Fax:  212-939-2968 
Email:  sbm20@columbia.edu  


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CORE 
Bonnie J. Dye, MPH 
Clinical Research Manager 
FHI 360 
2224 E.  Hwy 54 
Durham, NC 27713 
Phone: 919-544-7040, Ext. 11379 
Fax: 919-544-0207 
Email: bdye@fhi360.org 
 
Scott Mitchell Rose, BS 
Sr. Clinical Research Manager 
FHI 360 
2224 E. Hwy 54 
Durham, NC 27713 
Phone: 919-405-1447 
Fax: 919-544-0207 
Email: srose@fhi360.org 
 
Kevin Bokoch, BA 
Prevention Research Specialist 
FHI 360 
2224 E.  Hwy 54 
Durham, NC 27713 
Phone: 919-544-7040, Ext. 11189 
Fax: 919-544-0207 
Email: kbokoch@fhi360.org 
 
Rhonda White, R. H. Ed. 
Community Program Manager 
FHI 360 
2224 E. Hwy 54 
Durham, NC 27713 
Phone: 919-544-7040, Ext. 11515 
Fax: 919-544-0207 
Email: rwhite@fhi360.org 
 
NIH 
Michael J. Stirratt, PhD 
Program Chief, HIV Treatment 
Adherence Program 
Center for Mental Health 
Research on AIDS 
National Institute of Mental 
Health 
6001 Executive Blvd, MSC-9619 
Bethesda, MD 20892 (Postal mail) 
Phone: 301-443-6802 
Fax: 301-443-9719 
Email: stirrattm@mail.nih.gov 
  
Vanessa Elharrar, MD, MPH 
Medical Officer 
Prevention Science 
Program/DAIDS/NIAID/NIH 
6700-B Rockledge Drive, 5th 
Fl. Rm. 5249 
Bethesda, MD 20892 
Phone: 301-827-0845 
Fax: 301-402-1505 
Email:elharrarva@niaid.nih.g
ov 
 
Network Laboratory 
Susan Eshleman, MD, PhD  
Johns Hopkins University 
720 Rutland Ave 
Ross Bldg., Room 646 
Baltimore, MD 21205 
Phone: 410-614-4734 
Fax: 410-502-9244 
Email: seshlem@jhmi.edu 
 
Estelle M. Piwowar-
Manning, BS, MT (ASCP), 
SI 
Johns Hopkins University  
Pathology Bldg, Room313  
600 North Wolfe Street  
Baltimore MD 21287  
Phone: 410-614-6736  
Fax: 410-614-0430 
Email: epiwowa@jhmi.edu 
 
Craig Hendrix, MD 
Johns Hopkins University  
600 N. Wolfe Street 
Harvey Bldg, Room 502 
Baltimore, MD 21287-5554 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: cwhendrix@jhmi.edu 
 
Sociologist 
John H. Gagnon, PhD 
Professor Emeritus 
State University of New York at 
Stony Brook 
Stony Brook, NY 11794 
Phone: 631- 632-7700 
Fax: 631- 632-8203 
Email: jhgagnon@gmail.com 
 
Ethicist 
Robert Klitzman, MD 
Professor of Clinical Psychiatry 
Director, Masters of Bioethics 
Program 
Director, Ethics and Policy Core, 
HIV Center Columbia  University 
1051 Riverside Dr./Unit #15 
New York, NY 10025 
Phone: 212 543-3710 
Fax: 212 543-6003 
Email: rlk2@columbia.edu 
 
Community Advisors 
Reverend David Galetta 
NY5, No. 24 Gugulethu, 7750 
Cape Town 
South Africa 
Phone: 27-21-79-079-7184 
Email: 
galetta2day@mobileemail.vodafo
nesa.co.za 
 
Ms Prempreeda Pramoj Na 
Ayutthaya 
MSM/TGW Community 
Representative 
120/118 Moo 2, Moo Baan, 
Amarinnives 3/3 Kwang Saimai, 
Khet Saimai 
Bangkok, Thailand  
Phone: 66-818-249-063 
Email: 
preedapramoj@hotmail.com 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
 
CDC 
R. Michael Hendry, D.Sc. 
DHAP/NCHHSTP/CCID/CDC 
Bldg. 18, Rm 2-134, MS G45 
1600 Clifton Rd. 
Atlanta, GA 30329 
Phone: 404-639-1033  
Fax: 404-639-1174  
Email: mph8@cdc.gov 
 
Janet M. McNicholl, MD 
DHAP- Laboratory Branch  
1600 Clifton Rd, MS A25  
Atlanta, GA 30333  
Phone: 404-639-1520  
Fax: 404-639-2108 
Email: jkm7@cdc.gov 
 
Anupong Chitwarakorn, MD 
Senior Expert in Preventive 
Medicine 
Dept. of Disease Control 
Ministry of Public Health 
Soi 4, Tivanon Road 
Nonthaburi, Thailand 11000 
Phone: 66-2590-3225 
Fax: 66-2965-9573 
Email: AnupongC@th.cdc.gov 
 
Statistics and Data 
Jim Hughes, PhD 
HPTN SDMC  
University of Washington 
Mailstop 359931 
Seattle, WA 98195 
Phone: 206-731-3633/206-
616-2721 
Fax: 206- 731-3693/206-616-
2724 
Email: 
jphughes@u.washington.edu 
 
James Y. Dai, PhD 
SCHARP-FHCRC 
1100 Fairview Avenue North, 
M2-C200 
PO Box 19024 
Seattle, WA 98109, USA 
Phone: 206-667-6364 
Fax: 206-667-4812 
Email:jdai@scharp.org 
 
Laura McKinstry, MPH 
SCHARP-FHCRC 
1100 Fairview Ave. N. 
Mailbox E3-129 
Seattle, WA 98109-1024 
Phone: 206-667-7322 
Fax: 206-667-4812 
Email: lmckinst@scharp.org 
 
Behavioral Scientist 
K. Rivet Amico, PhD 
Research Scientist  
Center for Health, 
Intervention & Prevention 
University of Connecticut 
2006 Hillside Road, Unit 
1248 
Storrs, CT 06269 
Phone: 810-360-8716 
Fax: 860-518-0243 
Email: 
rivetamico@comcast.net 
 
Hair Pharmacologist 
Albert Liu, MD, MPH 
Director, HIV Prevention 
Intervention Studies 
HIV Research Section 
San Francisco Department of 
Public Health 
25 Van Ness Avenue, Suite 500 
San Francisco, CA 94110 
Phone: 415- 554-9104 
Fax: 415- 621-0641 
Email: Albert.Liu@sfdph.org 
 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
 
INVESTIGATOR SIGNATURE PAGE 
 
HPTN 067 
The ADAPT study:  
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis 
(PrEP) 
 
Final Version 5.0 
June 10, 2013 
 
A Study of the HIV Prevention Trials Network (HPTN) 
 
Sponsored by: 
 
US National Institute of Allergy and Infectious Diseases and 
U.S.  National Institute of Mental Health 
U.S.  National Institutes of Health 
 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the provisions of 
this protocol.  I will comply with all requirements regarding the obligations of investigators as 
outlined in the Statement of Investigator (Form FDA 1572), which I have also signed.  I agree to 
maintain all study documentation for at least two years following the date of marketing approval 
for the study product for the indication in which it was studied, unless otherwise specified by the 
Division of AIDS (DAIDS), Gilead Sciences, Inc., or the HIV Prevention Trials Network 
(HPTN) Coordinating and Operations Center.  If no marketing application is filed, or if the 
application is not approved, the records will be retained for two years after the FDA is notified 
that the Investigational New Drug (IND) application is discontinued.  Publication of the results 
of this study will be governed by HPTN policies.  Any presentation, abstract, or manuscript will 
be submitted to the HPTN Manuscript Review Committee, DAIDS, and Gilead Sciences, Inc.  
for review prior to submission. 
 
I have read and understand the information in the Investigator's Brochure(s), including the 
potential risks and side effects of the products under investigation, and will ensure that all 
associates, colleagues, and employees assisting in the conduct of the study are informed about 
the obligations incurred by their contribution to the study. 
 
__________________________________ 
Name of Site Principal Investigator 
 
 
__________________________________  
_________________________________ 
Signature of Site Principal Investigator 
 
Date  


HPTN 067, Final Version 5.0 
Page xiii 
June 10, 2013 
 
HPTN 067 
The ADAPT study:  
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis 
(PrEP) 
 
SCHEMA 
 
Purpose: 
This is a behavioral study to evaluate the feasibility of intermittent dosing of a pre-exposure 
prophylaxis (PrEP) regimen.  Recommendations for intermittent usage, compared with daily 
usage, may provide comparable coverage of possible exposures with pre- and post-exposure 
dosing, decreased pill requirements, and decreased symptoms.  This study is designed to 
optimize and facilitate future efficacy research, to be proposed separately.  The study aims to 
identify dosing regimens that foster healthy sexual practices and pill-taking behavior in people at 
high risk of human immunodeficiency virus (HIV) infection.  The word ADAPT in the study title 
is an acronym for Alternative Dosing to Augment PrEP pill-Taking.   
 
Design: 
A Phase II randomized open-label clinical trial of oral Truvada® [tenofovir disoproxil fumarate 
(TDF) plus emtricitabine (FTC)] PrEP among HIV-uninfected men who have sex with men and 
transgender women (MSM/TGW) and women who have sex with men (WSM), at high risk of 
acquiring HIV infection.  The study includes a six week lead-in period which includes directly 
observed therapy (DOT) at Enrollment and Weeks 1 through 4, followed by one week without 
dosing to determine individual steady state pharmacokinetics (PK).  This will provide the 
opportunity to create a pharmacokinetic analysis of drug levels to be expected at given rates of 
intake (adherence).  Participants will then be randomly assigned to one of three dosage groups in 
a 1:1:1 ratio: daily dosing, time-driven dosing, and event-driven dosing.  After randomization, 
participants will then complete a 24-week period of self-administered dosing (Weeks 6 through 
30), with one visit four weeks after the completion of dosing (34 weeks total).  Participants who 
acquire HIV infection during the study discontinue dosing and will be followed until study 
closure and referred for post-trial care as per local regulations.  A subset of participants in each 
of the study arms will also participate in a qualitative evaluation of the social and behavioral 
aspects of differing dosing strategies utilizing focus groups after Week 34.  A subset of clinic 
staff who directly interact with participants regarding pill-taking and sexual risk behavior, as 
well as a subset of participants identified as particularly informative will participate in key-
informant interviews after Week 34.   
 
Study Population: 
HIV-uninfected MSM/TGW, WSM at high risk of acquiring HIV infection 
 
Study Size: 
540 evaluable participants, including 180 MSM/TGW in Bangkok, 180 MSM/TGW in New York 
and 180 WSM in Cape Town.  


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
Treatment Regimen: 
Oral FTC/TDF in three dosage groups: daily dosing, time-driven dosing, and event-driven 
dosing.  The time-driven dosing group will be asked to take FTC/TDF twice weekly with a post-
exposure boost.  The event-driven dosing group will be asked to take FTC/TDF before and after 
a potential exposure to HIV infection.  In all three dosing groups, dosing will not exceed two 
doses per day or seven doses per week. 
 
Study Duration: 
The total duration of the study will be less than two years.  Enrollment is planned over 8 months.  
Follow-up will include a 30-week dosing period, with a single (final) visit four weeks after 
completion of dosing.  The 30-week dosing period includes a 6-week lead-in period which 
includes once-a-week DOT administered at Enrollment and Weeks 1 through 4, followed by one 
week without dosing.  The lead-in phase will be followed by 24 weeks of self-administered use, 
a 4 week off-drug period, and a final clinic visit at Week 34. 
 
Primary Objective: 
 To test the hypothesis that recommending intermittent (non-daily) usage of 
oral FTC/TDF chemoprophylaxis, compared with recommending daily usage, 
will be associated with: 
 
 Equivalent coverage of sex events with pre- and post-exposure dosing 
 Lower number of pills needed for coverage and fewer pills used 
 Decreased self-reported symptoms/side effects (both severity and 
frequency) during 24 weeks of self-administered use 
 
Secondary Objectives:  
 Develop objective measures of drug exposure by obtaining steady state pre-
dose “trough” drug concentration in several biological matrices for 
participants during a lead-in period of weekly DOT  
 To describe safety outcomes among PrEP users including adverse events 
among all participants and drug resistance and plasma HIV ribonucleic acid 
(RNA) levels among participants who seroconvert 
 Assess differences between arms in the acceptability of different PrEP 
regimens and in perceptions of advantages and disadvantages of different 
regimens 
 Assess differences by arm in adherence 
 Evaluate the potential influence of PrEP usage on changes in sexual behavior, 
planning for sex, prediction of risky situations, and recognition of possible 
HIV exposure from baseline to final on-drug assessment in relation to PrEP 
optimism 
 
Study Sites: 
The Thailand Ministry of Public Health–United States (U.S.) Centers for Disease Control (CDC) 
collaboration (TUC) Silom Community Clinic in Bangkok, Thailand and the Harlem Prevention 
Center in New York, USA for MSM/TGW, and Emavundleni Centre, The Desmond Tutu HIV 
Foundation in Cape Town, South Africa for WSM.   
 


HPTN 067, Final Version 5.0 
Page xv 
June 10, 2013 
 
HPTN 067 
The ADAPT study: 
A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis 
(PrEP) 
 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME 
 
A) Randomization Scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
300mg TDF/ 
200 mg FTC 
Tablets  
(Truvada®)  
DOT
Week 6 
Randomization  
Arm 3 
Event-driven  
Arm 2 
Time-driven  
Arm 1 
Daily  
120 
MSM/TGW 
120 
MSM/TGW 
120 
MSM/TGW 
60 WSM 
60 WSM 
60 WSM 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
B) Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
Week  
-10 
 
0 
6 
10 
14 
18 
22 
26 
30 
34 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
 
 
 
 
 
 
 
 
 
 
 
     Day -70 to -1 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directly Observed Therapy 
 
 
 
 
 
 
 
 
 
 
 
     Day 0 (Enrollment) up to Week 6/Randomization 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self Administered Therapy 
 
 
 
 
 
 
 
 
 
 
 
     Week 6/Randomization up to Week 30 
 
 
 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Visit 
 
 
 
 
 
 
 
 
 
 
 
     Week 34 
 
 
 
 
 
 
 
 
 
 
  


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June 10, 2013 
 
1.0 
INTRODUCTION 
1.1 Background and prior research 
The HIV epidemic is continuing to grow worldwide.  Because no single 
prevention intervention is a panacea, multiple prevention strategies must be 
evaluated and made available as “combination intervention” as rapidly as possible 
for both men and women.  The “tool box” for prevention of HIV infection should 
include different strategies such as condom usage and male circumcision, as well 
as behavioral, biomedical and structural interventions for HIV-uninfected and 
HIV-infected individuals.  Daily PrEP with oral antiretroviral drugs is currently 
being evaluated in clinical trials in diverse populations and settings.  However, for 
the majority of the “at-risk” populations, the prevention method of daily PrEP 
dosing may not match patterns of HIV risk-taking, which is unlikely to occur on a 
daily basis.  Furthermore, daily dosing of PrEP was selected for on-going 
prevention trials based on dosing intervals that are approved for treatment of HIV 
infection.   
 
Less frequent dosing of PrEP may be sufficient for prevention purposes as well as 
result in decreased drug costs and potentially lower risk of toxicity which may 
increase acceptability and improve utilization.  Studying intermittent dosing can 
contribute critical information regarding behavioral effects, adherence reporting 
and counseling content.  In addition, this study will be useful even in the setting 
of negative daily dosing trials if it identifies ways to foster pill use reporting and 
active study participation.   
 
Therefore, strategies using intermittent PrEP regimens should be evaluated as an 
alternative tool for HIV prevention.  Establishing the potential benefits and 
feasibility of intermittent regimens in terms of coverage, acceptability, resistance, 
and uptake, as well as potential influence on other risk-management strategies 
(e.g., condom use) is critical in the portfolio of research that will advise the real-
world dissemination and implementation of combination interventions.   
 
In late November 2010, the iPrEx study published results which found that the 
daily use of oral Truvada® reduced the risk of HIV infection by 44 percent in 
HIV-uninfected men who have sex with men.1 Higher adherence and adherence 
sufficient to detect drug in the blood was associated with higher levels of 
protection.  In July 2011, two separate studies reported that an oral dose of 
Truvada® can provide additional protection to heterosexual men and women in 
Africa:  HIV risk was reduced by 63% in the TDF2 study and by 73% in the 
Partners PrEP study of serodiscordant heterosexual couples in Africa. 2,3These 
two trials found efficacy for Truvada® in both men and women. These results 
contrasted with the findings of the FEM-PrEP study that was discontinued after an 
interim review found that the study was unlikely to eventually find evidence of 
Truvada® PrEP efficacy in the high-risk women who had been enrolled.4  
Efficacy in serodiscordant couples, who may foster greater adherence by 


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providing social support to each other, but not in some other individuals, is 
consistent with the findings of the iPrEx study that demonstrated that adherence 
was the key determinant of PrEP efficacy.1 All studies have confirmed the safety 
of Truvada® including a lack of clinically significant effects on the kidneys and 
the liver.  The ADAPT study seeks to find alternative dosing strategies that are 
more convenient, which may increase the consistent use of PrEP.  The ADAPT 
study will also provide important new information about how tests for drug in the 
blood may be used to monitor use of PrEP, and how to improve the reliability of 
self-reporting of pill use.   
 
Oral Truvada® is used in the ADAPT study because it has demonstrated efficacy 
in the iPrEx, TDF2, and Partners PrEP trials.  Furthermore, the prophylactic 
activity of Truvada®, which contains both emtricitabine and tenofovir disoproxil 
fumarate (TDF), was higher in non-human primates than either drug alone.5  The 
Partners PrEP trial found efficacy of Truvada to be 73% while the efficacy of 
TDF alone was 62% (P=0.18 for the difference in efficacy estimates).2  The 
Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial was not 
able to show efficacy of oral TDF, oral FTC/TDF, or tenofovir vaginal gel in 
heterosexual African women, perhaps because use of the interventions was low in 
all groups.6  The FEM-PrEP trial also showed no evidence of efficacy in 
heterosexual women with low levels of uptake.7  The ADAPT trial is designed to 
evaluate whether non-daily dosing regimens are more acceptable and feasible and 
lead to greater proportions of participants with detectable drugs compared with 
daily regimens.  
 
The data from this study will provide an excellent opportunity to understand 
either a negative or positive outcome.  Equipoise is the ethical basis for all 
randomized studies and maintaining equipoise is the responsibility of 
investigators and is taken very seriously by this investigative team.  Maintaining 
equipoise is an active process, requiring first that the virtues of the “new 
approach” be highlighted to justify considering alterations to the standard of care.  
There is the potential for both negative and positive findings in this study.  
Intermittent dosing may lead to poor coverage of exposure, costs may increase 
because pills are wasted in ineffective attempts and resistance may occur in those 
who seroconvert.   
 
The primary measure of pill-taking in this study will be based on the adjusted 
Electronic Drug Monitoring (EDM) device.  The EDM data is transmitted 
electronically to a database system and this data is used by interviewers to 
improve the accuracy of self-reported pill-taking via brief weekly interviews.  
EDM has received considerable support within the antiretroviral drug adherence 
literature as an objective measure of adherence,8-11 although EDM has also been 
noted as potentially underestimating adherence.12  Accuracy of EDM is dependent 
on case-openings being indicative of (a proxy for) pill consumption.  The 
appropriateness of this assumption is increasingly suspect if participants do not 
use the EDM case for pill dispensation, or dispense pills without actually 
consuming them.  The weekly interviews were developed to address these 


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possibilities and to increase the accuracy of EDM data with appropriate 
adjustments.  Please see further information on the use of EDM data in this trial in 
Sections 2 and 5.   
1.2 
Animal studies of chemoprophylaxis  
The most encouraging data suggesting that intermittent PrEP may be a plausible 
prevention strategy comes from a recent study in which monkeys were well-
protected from simian immunodeficiency virus (SIV) infection after receiving one 
dose of TDF plus FTC at either 7 days, 3 days, or 2 hours pre-SIV exposure 
followed by a second dose 2 hours post-exposure.13  While encouraging, these 
data cannot be directly extrapolated to humans due to the differences in simian 
anatomy and pharmacokinetics, as well as differences between HIV and the SIV 
challenge strain. 
 
The coformulation of FTC/TDF is selected for this trial because it was the most 
active in pre-clinical studies of non-human primates.  While TDF or FTC alone 
had some protective activity in animal studies, the combination of both agents 
was associated with higher levels of protection.  The combination has been co-
formulated as a single pill, and is available from Gilead Sciences, Inc. under the 
trade name “Truvada®”. 
1.3 
Human FTC/TDF trials 
The nucleotide reverse transcriptase inhibitors (NRTIs) TDF and FTC were 
licensed by the U.S.  Food and Drug Administration (FDA) for treatment of HIV-l 
infection in 2001 14 and 2003 15, respectively.  In August 2004, the FDA licensed 
a fixed dose co-formulated drug containing 300 mg TDF and 200 mg FTC (trade 
name: Truvada®).16  TDF and FTC have demonstrated outstanding safety and 
efficacy in human clinical trials.17,18  TDF has characteristics that make it suitable 
for evaluation as a chemoprophylaxis agent.  These characteristics include: 
prolonged intracellular half-life that allows once-a-day dosing, high levels of 
tolerability, potent antiviral effects, and selection of drug-resistant variants that 
have mutations associated with diminished viral replication capacity.   
 
Several clinical trials evaluating the efficacy of FTC/TDF (administered daily) for 
PrEP are ongoing or recently completed.  These multi-site trials are being 
conducted in many countries and in different populations including young women 
(CDC-funded study in Botswana,19 USAID-funded FEM-PrEP,20 NIH-funded 
VOICE21), MSM (NIH and Gates funded iPrEX22), intravenous drug users (CDC 
funded study in Thailand19), and discordant heterosexual partners (Gates funded 
Partners study23).  The results from the iPrEx trial indicated that PrEP reduced the 
risk of HIV infection and had no serious safety concerns1. 
1.4 
Significance of Determining Pharmacology of Intermittent PrEP  
Assuming dose proportionality is found, this model will be used to estimate 
extracellular and intracellular drug exposure in multiple compartments for any 


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June 10, 2013 
 
dose and dosing interval combination.  This model will be critical to the following 
three areas: 1) developing an optimal pharmacology-based adherence intervention 
for future PrEP studies, 2) assessing adherence in ongoing studies with currently 
stored samples, and 3) developing a pharmacokinetic-pharmacodynamic (PK/PD) 
model to determine target intracellular drug exposures that prevent HIV infection.   
1.5 
Drug Concentration as an Adherence Measure  
In clinical trials, measurement of drug concentrations has been proposed as a 
potential quantitative measure of medication adherence.  In this protocol, we plan 
to use drug concentration of tenofovir in different biological matrices as a 
measure of adherence.  We propose the following model to quantitatively estimate 
the percent adherence to the prescribed regimen: 
 
% Adherence = 100 ● (observed concentration / expected concentration) +  +  
where  represents the sources of measurable variability (inter- and intra-
individual variability and drug assay variability) and  is the random unmeasured 
error. 
 
Pre-dose “trough” samples will be collected at Weeks 18 and 30 following 
unwitnessed doses to be used to represent the “observed” drug concentrations and 
taken to reflect two examples of concentration to assess adherence.  This will 
enable estimation of adherence at two times during the study.  (More frequent 
assessments were not planned due to financial and site specific logistical 
constraints.) The “expected” drug concentrations are based on steady-state pre-
dose drug concentrations after, so-called, “directly observed therapy” or DOT 
which is the subject specific reference for 100% adherence.  The ratio of drug 
concentrations (observed/expected) is taken as a rough estimate of the proportion 
of prescribed doses that were actually taken plus other known and unknown 
variability. Any differences between the observed and expected values are 
attributed primarily to adherence, since the expected value estimates (described 
below) control for adherence, and since other significant sources of variation 
(e.g., assay variability and environmental variables) are reasonably assumed to be 
stable over time. 
Biological matrices and analytes to be sampled include plasma tenofovir (TFVs), 
plasma emtricitabine (FTC), intracellular tenofovir diphosphate (TFV-DP), 
intracellular emtricitabine triphosphate (FTC-TP), hair tenofovir (TFV), and hair 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
emtricitabine (FTC).  Dried blood spot (DBS) samples will also be collected at 
one study site for analysis of these drugs in whole blood, which is mainly 
comprised of red blood cells (RBCs). Each of these has different assay variability 
and analyte half-life.  Tenofovir half-lives are generally longer than emtricitabine.  
The half-life of serum analytes is less than a day; the half-life of intracellular 
analytes in PBMCs can be several days to one week; the half-life of intracellular 
analytes in RBCs can be several weeks; the half-life of the analyte in hair can be 
more than a month.  It should be noted that these half-life estimates are not well 
established for intracellular phosphates (PBMCs and RBCs) and analytes in hair.  
The method for measuring these analytes in RBCs/DBS is new and further 
validation studies are needed. These characteristics are mentioned because they 
may relate directly to the limitations of drug concentration as a method of 
adherence.  For example, all things being equal, increasing variability diminishes 
the ability to discriminate between different degrees of adherence.  Due to a larger 
accumulation index, a longer drug half-life allows both greater ability to 
discriminate among adherence levels and less susceptibility to the “white coat 
effect” wherein a subject may appear to be 100% adherent after taking only one 
dose of medication immediately prior to a study visit without having taken any 
prior doses.  The long half-life can also require delays until steady-state is 
achieved (five times the drug half-life in the biological matrix) and limit the 
ability to detect poor adherence “holidays” in time frames much shorter than the 
half-life.  For example, the two long half-life measures (cells and hair) can be 
insensitive to a holiday (no drug taking for a week or a few days, respectively) 
when most of an observation period may be associated with very high adherence.  
It is anticipated that a combination of adherence measures (e.g., 
microelectromechanical systems (MEMS) devices) can help improve sensitivity 
to this type of adherence issue.  The impact of half-life, accumulation index, and 
inter- and intra-subject variability are described further below.  Finally, hair color 
and hair treatments (e.g., dye and perms) can alter assessment of drug 
concentration in hair.  A sexual event dependent drug schedule is a challenge for 
drug concentration as adherence measure, because the standard “expected” value 
is not related to DOT steady-state directly, though steady-state DOT data can be 
used to estimate single dose drug kinetics which can, in combination with sexual 
event reporting, be used to estimate expected drug concentrations.  However, this 
introduces an undesired subjective variable (sexual activity reporting) that could 
be as inaccurate as pill-taking diaries. 
1.6 
Development and Validation of Tenofovir Hair Assay 
Methods for the detecting tenofovir (TFV) in hair have been developed and 
validated by Dr. Yong Huang’s laboratory at University of California at San 
Francisco (UCSF) and a Women’s Interagency HIV Study (WIHS) investigator 


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group at UCSF.24  This method using liquid chromatography/mass 
spectroscopy/mass spectroscopy (LC/MS/MS) has been validated for the range of 
0.01 to 0.4 ng/mg hair.  Subsequently, the feasibility of hair collection and ability 
to detect TFV in hair were evaluated among HIV-uninfected MSM participating 
in a CDC-sponsored PrEP study in San Francisco.  Single samples of hair were 
collected and tested in a blinded fashion in this placebo-controlled trial.  Overall, 
hair collection was found to be feasible and acceptable among men enrolled in a 
PrEP trial, and hair analysis was highly sensitive and specific for TFV exposure in 
these participants.  Correlative studies between peripheral blood mononuclear 
cells (PBMC) and hair levels and between different directly-observed dosing 
patterns and TFV hair levels are currently in progress. 
1.7 
Drug Concentration Simulation Models 
In computer simulation models, the “expected” drug concentration is based on the 
PK characteristics of the drug and the prescribed dosing regimen of the study.  To 
facilitate these simulations, PK data are available from several reports in which 
TDF (Viread®) has been administered to human research participants.  From 
these studies, one can make some estimates of the effective intracellular half-life 
for tenofovir diphosphate (TFV-DP), the active moiety of the drug, which appears 
to be approximately ~150 hours.25-27  From these studies, however, the inter-
individual variability for half-life and peak concentration (Cmax) for TFV-DP is 
relatively large (coefficient of variation around 50% to 65%).  Accordingly, the 
best parameter estimates for such a simulation come from individual study 
participants.  To avoid intensive, frequent PK sampling, which would be 
cumbersome in a clinical trial, one can employ a combination of (1) population-
based estimates from the studies like those cited above, and (2) data from a few 
samples from each individual in a prospective study.  This approach substantially 
reduces inter-individual variation, while reducing logistical complexity of the 
study.  To remove the variable of adherence in estimation of individual PK 
parameter estimates, samples collected from the individuals tested should follow 
an observed dose.  With an observed dose, the possibility of variable adherence 
affecting subsequent drug concentrations is removed.  This leaves the following 
variables to consider: inter-individual PK variability, assay variability, and 
unknown sources of noise that may vary with time in the environment.  Examples 
of simulations of the dosing strategy of TFV-DP in PBMCs and TFV in blood 
serum (Figure 1-1) are shown below.   
 


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Figure 1-1.   
Simulation of TFV-DP concentration in PBMCs (y-axis-1) and in blood serum (y-
axis-2) versus time (x-axis) anticipated with the weekly regimen planned for this 
study: TDF 300 mg weekly; note the regimen is administered as Truvada® 
(FTC/TDF).  Note the minor increase in Ctau and Cmax between Day 28 and Day 
35 in PBMCs where intra-individual variability will be estimated.  Simulation 
parameters are based on data from previous studies.25-27  Simulations assume 
dose-proportionality and do not include intra-individual or inter-individual 
variation.  Note the wide swings in concentration in blood serum over the dosing 
interval indicating that the concentration is very sensitive to changes in time of 
the preceding dose or missing the preceding dose.  However, the concentration is 
insensitive to missed doses several days prior to the sampling time. 
 
To use the computer modeling methods described above, two key facts must be 
determined with regard to the interaction of drug, participant, and regimen: intra-
individual variability and dose-proportionality.  Knowledge of these variables is 
essential for planning future studies that use estimated PK parameters based on 
individual drug concentrations to evaluate adherence. 
1.8  
Dose-proportionality and Drug Accumulation  
In order for drug concentration to be used as an adherence measure, the dose-
proportionality must be stable at concentrations throughout the adherence range of 
interest: from concentrations associated with 100% adherence down to 


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concentrations associated with lower levels of adherence.  While dose-
proportionality is closely related to first order PK, there are other conditions that 
will cause disproportionate kinetics, even for a first order drug.  Very few drugs 
exhibit mixed or zero order PK in the clinically relevant concentration range (e.g., 
aspirin, phenytoin, and fluoxetine).  For these drugs, a proportional increase in 
dose results in a disproportionately large increase in concentration.  For other 
drugs, a proportional increase in dose may result in a disproportionately small 
increase in concentration.  This can be seen in drugs with saturable absorption, 
and with drugs that are anabolized to phosphorylated forms within cells, such as 
TFV, FTC, and zidovudine (ZDV).  For example, because phosphorylation of 
zidovudine (AZT)-monophosphate within cells is the rate-limiting step in AZT-
triphosphate anabolism, increasing the AZT dose can result in disproportionately 
small or no increase in AZT-triphosphate.  For either cause of disproportionate 
PK, the assumption of proportionate change in adherence (as with expected and 
observed drug concentrations) becomes more complex.   
 
While the dose-proportionality for both TDF and FTC are well-established 28,29 
this proportionality has not been determined for the phosphorylated moieties of 
these drugs and must be established for one to use TFV-DP or FTC-triphosphate 
(FTC-TP) as measures of adherence to a Truvada® (FTC/TDF) regimen.   
 
Other proportionality factors are dose frequency and the accumulation of drug 
concentration with time – characteristics that are unique to each drug and dosing 
regimen.  Drugs that are dosed at intervals more frequent than their half-life 
accumulate over time and achieve concentrations that are higher at steady-state 
than following a single dose.  This accumulation – the so-called “accumulation 
index” or Rac – varies with the ratio of the drug half-life to dose frequency as 
follows:  
 
Rac = 1/(1 – e-k), where k is the elimination rate constant [Ln(2)/half-life] 
and  is the dosing interval.   
 
The greater the drug half-life is, the greater the accumulation index.  The higher 
the accumulation index, the greater the magnitude by which drug accumulation 
will exceed sources of noise in drug concentration assessment (e.g., dosing time 
variation, assay variability, assay sensitivity, and inter- and intra-individual 
variability).  When measuring adherence with drug concentration, one is assessing 
the magnitude of difference between (1) the expected concentrations of drug at 
prescribed dosing intervals assuming 100% adherence, and (2) the actual drug 
concentrations from an unobserved dosing period.  The difference is attributed to 
less than 100% adherence.  A reduction in adherence has the equivalent effect on 


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concentration as a reduction in the frequency of dosing (i.e., the concentration 
falls).  Drugs with a large accumulation index provide a greater degree of 
detectable difference between 100% adherence and lesser adherence.  For drugs 
with little accumulation (dose frequency less than their half-life), it may be very 
difficult to discriminate the concentration associated with a single dose (without 
any prior doses) from perfect adherence.  Therefore, a participant with poor 
adherence can appear to a have high level of adherence with a low accumulation 
index drug and drug regimen combination.  In contrast, large accumulation index 
drug and drug regimen combination is very resistant to “white-coat adherence”, in 
which a participant takes one or several doses within the day prior to a scheduled 
research clinic visit.   
 
Table 1-1.  Accumulation index for parent and phosphorylated moieties of 
TDF and FTC dosed either weekly (168 hours) or daily (24 hours).  Drug 
moieties and regimens are ranked by accumulation index.  An index of 2 indicates 
a doubling of concentration at steady-state compared to a single dose.  An index 
of 1 indicates no accumulation at steady-state.  For example, the concentration 
observed with 100% adherence can look the same as no adherence if the non-
adherent participant takes a single dose prior to the observed blood collection 
when TDF, FTC or FTC/TDF are used with prescribed weekly dosing regimens.  
By contrast, the concentration expected with 100% adherence to FTC/TDF will be 
9.6 (TFV-DP) or 2.7 (FTC-TP) times the concentration observed if a participant 
has taken only a single dose prior to the scheduled observation.   
Table 1-1.  Accumulation index for parent and phosphorylated moieties of 
TDF and FTC dosed either weekly (168 hours) or daily (24 hours). 
Drug moiety 
Half-life 
(hours) 
Dosing 
interval 
(hours, 
tau) 
Dosing 
interval / 
half-life 
(tau/HL) 
Accumulation 
index 
(Rac) 
TFV-DP 
150 
24 
0.2 
9.5 
FTC-TP 
36 
24 
0.7 
2.7 
TFV-DP 
150 
168 
1.1 
1.9 
TFV 
17 
24 
1.4 
1.6 
FTC 
10 
24 
2.4 
1.2 
FTC-TP 
36 
168 
4.7 
1.0 
TFV 
17 
168 
9.9 
1.0 
FTC 
10 
168 
16.8 
1.0 
 
For this reason, TFV-DP (the intracellular form of TFV) is an excellent candidate 
for drug adherence monitoring, especially with daily dosing (Table 1-1).  With an 
intracellular half-life of ~150 hours, daily to weekly dosing of TDF has a TFV-DP 
accumulation index ranging from of 9.5 to 1.9, offering a great range of 
sensitivity for determining reduced adherence over a large range of dose 


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frequencies.  In contrast, TFV concentration (measured in plasma), when TDF is 
dosed daily, would be expected to perform much less well, with a small difference 
in drug accumulation at steady-state during daily dosing when compared to a 
single dose (e.g., taken on the day of observation).  When using TDF on a weekly 
dosing regimen, there is no anticipated difference between drug concentrations of 
plasma TFV compared to taking a single dose of TDF without any prior doses.  
Contrasting the two lines in Figure 1-1 illustrates this point graphically.  The 
different dose regimens are easily distinguishable in Figure 1-1 where 
intracellular TFV-DP is measured.  In contrast, the TFV plasma levels are largely 
overlapping with daily and weekly dosing at least one day per week. 
1.9 
TDF and FTC drug resistance 
If HIV infection occurs during the trial, the participant may be exposed to both 
TDF and FTC before HIV infection is diagnosed.   
 
Participants will be tested for HIV infection at Screening, Enrollment, and Weeks 
4, 6, 10, 14, 18, 22, 26, 30, and 34.  HIV RNA testing will be used in addition to 
serologic testing for HIV infection if a participant has signs or symptoms 
consistent with acute (pre-seroconversion) HIV infection, or expresses a concern 
about recent HIV acquisition.  Frequent testing for HIV acquisition during the 
study period will allow prompt cessation of study drug in an HIV-infected 
participant, minimizing the risk that resistant virus will emerge.  Recent results of 
a trial of topical Tenofovir gel were encouraging in that there was no indication of 
resistance.30 
1.9.1 Patterns of drug resistance associated with TDF and FTC 
HIV mutations associated with TDF resistance are well-defined.  TDF resistance 
usually results from selection of HIV with the K65R mutation, or with a 
combination of three or more mutations associated with resistance to thymidine 
analogue NRTIs.  Rare insertion mutations near codon 69 can also affect TDF 
susceptibility.14  Even in the presence of the K65R mutation, HIV isolates are 
partially susceptible to TDF.  The K70E mutation is also associated with TDF 
resistance. 
 
High-level resistance to FTC can develop with a single mutation, M184V or I, 
within weeks with monotherapy.31  The M184V/I mutations also confer high-level 
resistance to lamivudine (3TC), and low-level resistance to abacavir (ABV) and 
didanosine (DDI), but increase susceptibility to ZDV and TDF.16  No clinical 
studies have evaluated the timing for emergence of resistance mutations when 
TDF and FTC are used in combination. 


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1.9.2 
Substantial barrier to HIV resistance to TDF and FTC 
The accumulation of antiretroviral drug resistance mutations is usually associated 
with decreased fitness of HIV.  Viruses that only have the K65R mutation have a 
replication capacity of 53% compared to wild-type virus; replication capacity is 
further decreased to 24% when the K65R and M184V mutations are both 
present. 14   
 
Among HIV-infected individuals treated with TDF/3TC/efavirenz (EFV) 
combinations for up to three years,32 the K65R mutation occurred in 2.7% (8/299) 
of patients and the M184V mutation occurred in 6% (18/299) of patients.  In a 
study of treatment-naïve patients,33 patients received either TDF/FTC/EFV 
(n=257) or Combivir® (ZDV+3TC)/EFV (n=254) for 48 weeks.  Among the 34 
patients with virologic failure at 48 weeks, 17% (2/12) in the TDF/FTC/EFV 
group and 32% (7/22) in the Combivir/EFV group had M184V mutations.  No 
patients developed K65R mutations through 48 weeks of the study.  In a Phase III 
trial that involved adding TDF to a failing regimen, the K65R mutation occurred 
in 3% (n=183) of the patients receiving TDF, and the M184V mutation occurred 
in 1% of all patients on antiretroviral therapy including 3TC (n=274) by Week 
24.34  Taken together, these data indicate a substantial barrier to TDF resistance.  
Combined use of FTC/TDF may further increase the barrier to drug resistance. 
 
1.10 
Rationale 
1.10.1 Justification for Intermittent PrEP 
All current PrEP trials are evaluating daily dosing of antiretroviral drugs for HIV 
prevention.  The daily dosing strategy was selected for prevention trials based on 
dosing intervals that are approved for treatment of HIV infection.  The hypothesis 
for this trial is that daily dosing of FTC/TDF for prevention may be excessive.  
The rationale for this hypothesis is the following:  (a) the intracellular half-lives 
of the TFV-DP and FTC-TP are ~150 hours and ~48 hours respectively, which 
provides substantial drug concentrations to be present for several days after each 
dose,  35 (b) non-human primate models indicate that dosing once a week may be 
sufficient for protection if post-exposure dosing is also used,5,13 (c) the majority 
(>80%) of individuals at high risk of HIV infection are exposed to HIV less often 
than daily, typically only once or twice a week,36 and (d) the amount of virus 
exposing uninfected users of PrEP is substantially less than the amount of virus 
present in individuals with established HIV infection who require treatment.  
Importantly, the dosing interval for treatment has never been optimized; although 
daily dosing was found to be effective for treatment of HIV infection in clinical 
trials, less frequent dosing has not been evaluated for HIV treatment or 
prevention.  Doses of TDF higher than 300 mg per day appear to be less active in 
treatment studies than the 300 mg dose,28 which may reflect tolerance issues. 
 


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Intermittent PrEP has several potential advantages over daily dosing.  First, less 
frequent dosing is expected to decrease side-effects related to drug exposure.  
Lower doses of PrEP agents may diminish mild side effects, such as cramping, 
diarrhea, flatulence, headache, and dizziness, which could interfere with 
adherence.  Even if these side effects are rarely severe enough to require stopping 
HIV treatment for infected individuals, they may interfere with adherence when 
taken for prophylaxis.  While current PrEP trials will assess overall rates of 
adverse events (AE), little or no information is being obtained regarding 
interactions between drug dose, non-specific grade 1 symptoms, adherence, or 
actual patterns of pill-use, and drug exposure.  This gap in knowledge will persist 
even after the current generation of trials is completed, and therefore is directly 
addressed in this project. 
 
Cost reduction is another important advantage of intermittent dosing in 
intermittently exposed persons.  Exploratory analysis for PrEP in the U.S.  
indicates that cost-effective implementation would be challenging.36  Cost 
concerns suggest that interventions would have to be targeted to the highest 
incidence subgroups of the population, many of whom are difficult to identify 
because of social stigma and other factors.  Similarly, cost effectiveness of PrEP 
is expected to be marginal in Africa and Asia,37,38 where the majority of HIV 
infections occur and where the U.S. government is providing most of the funding 
for HIV treatment and HIV prevention programs.  Intermittent dosing, if shown to 
be effective, would greatly facilitate cost-effective implementation of PrEP.  The 
cost of the drug (Truvada®) is a major component of the total program cost of 
PrEP.  In HPTN 067, we will follow the number of pills required and used very 
closely.  In addition, we realize that PrEP programs involve a variety of additional 
costs (i.e.  HIV counseling and testing) in addition to pill-use.  Outside of the aims 
of this study, we will collaborate with experts in this field to inform fully 
developed cost effectiveness modeling to evaluate the cost effectiveness of the 
intervention.  We will work with staff and investigators to identify differences in 
resources associated with different usage groups in all elements including 
counseling, communications, community education, drug importation, drug 
storage, drug dispensation, drug labeling, medical evaluation, and laboratory 
testing. 
 
Further, in relation to self-administration of PrEP, there is reason to believe that 
intermittent regimens may foster higher rates of adherence if these regimens are 
perceived as being more acceptable, feasible, and responsive to one’s specific risk 
reduction needs.  These critical aspects of uptake and acceptability of PrEP are 
essential in preparing for the wide-scale availability of these prevention strategies 
and best supporting their dissemination and implementation, if found efficacious 
in ongoing studies.   
 
 
 
The decision about whether a larger efficacy trial of intermittent PrEP should go 
forward is, of course, speculative at this point and will involve results from the 
HPTN 067 trial, ongoing studies of daily oral and topical PrEP, and potentially 


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other sources as well.  In the context of HPTN 067, the conditions that would 
favor for moving either intermittent PrEP arm forward are:  
 Equivalency of coverage between daily PrEP and intermittent PrEP.  If 
coverage is significantly lower in the intermittent PrEP arm relative to the 
daily arm then this would suggest that intermittent PrEP might have lower 
efficacy for HIV prevention and should move forward only if additional 
information becomes available that the missing coverage may not be 
essential for efficacy.  If coverage in the intermittent PrEP arm is equal to 
or better than the daily arm, then this would suggest that intermittent PrEP 
might have equivalent (or better) efficacy for HIV prevention; 
 Significantly decreased drug usage in the intermittent PrEP arm.  If fewer 
pills are used in the intermittent PrEP arm relative to the daily arm then 
intermittent PrEP will be less expensive to implement.   
 Significantly decreased side effects in the intermittent PrEP arm relative to 
the daily arm.  A major reason for interest in intermittent PrEP is the 
hypothesis that fewer drug doses will result in fewer side effects.   
 An efficacy trial of intermittent PrEP versus daily PrEP will be warranted 
if current trials show that daily PrEP is sufficiently effective to be 
considered as a viable HIV prevention tool.  An efficacy trial of 
intermittent PrEP versus placebo would be warranted if daily oral PrEP 
fails to demonstrate efficacy relative to placebo, and the failure of daily 
recommendations is found to be attributable to low levels of drug 
exposure that may be improved with intermittent dosing 
recommendations. 
 
Although the results of a recent trial of intermittent topical dosing of Tenofovir 
were encouraging, the converse to all of the conditions above may also occur.30  It 
may prove challenging for participants to forecast and recognize sexual risk 
resulting in lower adherence and coverage.  Recommendations for intermittent 
dosing may complicate use such that participants elect not to use PrEP at all.  
Further, intermittent dosing may not foster daily habits that may be important for 
use.  Finally, anxiety associated with thinking about HIV exposure may form a 
barrier to PrEP use.  Although drug resistance was not observed in non-human 
primate studies of intermittent PrEP, drug resistance risk in people may be more, 
or less, likely during intermittent use of PrEP in people.   
1.10.2 Justification for comparing event-driven dosing and time-driven 
dosing to daily dosing 
Post-exposure prophylaxis (PEP) frequently fails on an intent-to-treat basis 
because individuals fail to recognize significant exposures to HIV, or fail to 
timely initiate prophylaxis after being exposed.39  Anxiety, denial, imperfect 
communication with partners, lack of information, and substance use all 
contribute to failure to initiate PEP regimens.  These factors may or may not bear 
on use of intermittent PrEP regimens.  Barriers and facilitators will be fully 
characterized and are anticipated to include unintentional factors (periodic 
forgetting, challenges in prospective memory, or planning) and more internally 


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driven factors (such as stigma, intentional avoidance, beliefs in negative outcomes 
from pill-use, inaccurate information about pill content or use) which will be 
generally organized by a theory-based approach to predicting actual patterns of 
pill-use across and within the different arms (daily, time-driven, or event-driven). 
 
Event-driven dosing will require specific communication between study 
counselors and participants to promote skills in identifying antecedents of sexual 
risk in order to prepare participants for the conditionality of taking a tablet prior to 
sexual events.  Thus, it is anticipated that participation in the event-driven arm 
may foster planning for sexual activity, and more explicit recognition of the risks 
of HIV exposure associated with sexual activity.  Such planning and recognition 
may ultimately affect partner choice, the amount and types of sexual activity, the 
patterns of PrEP use, and overall exposure to HIV.  For example, planning for 
sexual activity may include plans for using condoms, disclosure, strategic 
positioning, and other risk reduction strategies.  Pill-use is anticipated to be an 
integral part of this planning and thus across arms it is assumed that those in the 
event-driven arm will demonstrate a pattern of pill-use most consistent with 
recommendations.  Further, little is presently known about actual preferences 
from a participant or clinic staff perspective for intermittent versus daily dosing.  
End of study questionnaire items will provide information about overall 
preferences for regimens of varying kinds, and focus group data will inform 
overall perceptions of feasibility of each regimen with qualitative data.  A subset 
of study participants and clinic staff will participate in post-study focus groups 
and key-informant interviews to understand the extent and reasons for the 
development of preferences for certain regimens over others.  These multiple 
sources of data will provide much needed characterization of how intermittent 
versus daily PrEP is viewed by those assigned to different arms.   
1.10.3 Theoretical basis for postulating behavioral effects of intermittent 
dosing 
This research provides a unique opportunity for hypothesis driven, theory-based 
research on PrEP use, and risk behavior in the context of PrEP trials.  An adapted 
Information, Motivation, Behavioral skills (IMB) model of risk reduction and 
health behavior adoption is applied as an organizing explanatory framework for 
the assessment and characterization of core factors influencing both condom-use 
and PrEP use.  The IMB model was originally formulated primarily as a theory of 
risk reduction 40 and has since been articulated to a host of health promotion 
behaviors, including HIV prevention,41-46 self breast examinations,47 and 
antiretroviral medication adherence.41,42  
 
Essentially, the IMB model proposes that a health behavior is a function of one’s 
fund of accurate information about the behavior, one’s personal and social 
motivation towards the behavior, and one’s set of behavioral skills for 
implementing the behavior across various conditions and one’s associated self-
efficacy for doing so.  We position exploration of important aspects of self-
perception social roles and their impact on PrEP use and sexual and PrEP use 


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behavior in the context of PrEP as one of the factors that contribute to one’s 
overall motivation towards desired behaviors.  The core constructs and the 
structural relations among these constructs are specified such that information and 
motivation can co-vary but are not determinants of each other; information and 
motivation both relate to behavioral skills in positive directions so that the more 
informed one is about a health behavior or the greater one’s personal and social 
motivation towards the health behavior, the greater one’s set of behavioral skills 
for implementing that behavior; one’s set of behavioral skills for implementing a 
health behavior relates directly to the implementation of the health behavior in 
question.  For behaviors that have not become overly automated, this is a 
mediated model where the direct relations between information and behavior and 
between motivation and behavior are largely mediated by behavioral skills.  
Essentially, this mediation suggests that when behaviors are difficult or complex, 
being well informed or highly motivated is insufficient to impact on behavior if 
one’s skills in implementing that behavior over diverse situations and over time 
are not also well developed. 
 
The utility of the identified core constructs, as well as their structural relations, 
has been supported by numerous studies with diverse populations41 and is the 
basis for a number of risk reduction (condom use) intervention approaches, 
including prevention protocols for HIV-positive persons in care48 and ART 
adherence interventions.49  The model has also been used in other PrEP trials to 
organize barriers and facilitators to pill-taking, to providing accurate reports of 
pill-taking, and intervention approaches to support pill-taking efforts. 
 
Articulated to the behaviors of interest in the present study, an adapted IMB-
model to address condom-use and PrEP use specifically in the context of the 
proposed intermittent PrEP trial was developed (Figure 1-2).  Drawing from 
previous research, as well as an interest in providing greater specificity in 
identifying and characterizing important aspects of risk reduction behavior in 
relation to PrEP use, each of the core constructs of the IMB-model were 
elaborated to the kinds of facilitators and barriers that are anticipated to be most 
influential to the adoption of PrEP across the study arms (thus resulting in risk 
event coverage via PrEP) and the kinds of information, motivation, and 
behavioral skills for condom use in the context of PrEP that would be expected to 
predict potential changes in participants’ condom use over the course of their 
participation in the PrEP trial.   
 
Behavior-relevant information includes funds of accurate information, and also 
the extent to which participants believe common pieces of misinformation to be 
true or factual.  As indicated in Figure 1-2, where basic information about 
condoms or about PrEP, PrEP trials, and one’s assigned regimen is important, of 
equal importance is the extent to which participants believe inaccurate “facts” to 
be true (such as, ‘condoms contain HIV or other diseases,’ ‘PrEP drugs cause 
HIV,’ ‘participants are asked to leave the trial if they are not consistently adherent 
to PrEP’).  Specific to this construct, it is likely that without appropriate 
counseling support, participants in the more complex dosing arms (intermittent) 


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may have greater difficulty in reaching requisite informational levels about the 
specific requirements of their regimen.  However, given the comprehensive 
counseling approach adopted in this study, significant differences in accurate 
information for condom use or PrEP use are not anticipated.  Because of concerns 
that intermittent doses may be “too complicated” for individuals to negotiate over 
time, establishing a null difference in knowledge of regimen and regimen 
requirements is very important.  Also, differences in misinformation between 
arms are of interest. 
 
Behavior-relevant motivation houses a number of core subconstructs (Figure 1-2).  
Within this construct, personal and social beliefs and attitudes towards the 
adoption and non-adoption of the behavior are housed.  To the extent that one has 
strong positive attitudes and beliefs that adoption of the behavior will bring 
positive consequences (personal and social), and non-adoption is not viewed as 
positive, participants are expected to be in a better position to adopt the behavior 
consistently (providing requisite skills are in place).  Individuals experiencing 
personal and social barriers to behavior adoption will be less apt to develop 
requisite skills or, subsequently, practice the behavior consistently.   
 
There is an emphasis on specific variables to the traditional conceptualization of 
motivation within the IMB-model to allow for better representation of the kinds of 
attitudes and beliefs that are critical in elucidating what has been identified as risk 
compensation.  The theory of risk compensation 50 postulates that biomedical 
prevention interventions, like PrEP, could decrease perceived risk of HIV 
infection and increase risk behavior.  Positive associations between optimistic 
attitudes regarding treatment or prevention interventions and sexual behavior may 
reflect risk compensation.  Because attitudes towards PrEP and condom use are an 
essential aspect of the IMB-model, adapting the model to expand on the 
motivation construct to include detailed assessment of perceived positive 
consequences of PrEP use and of condom use (particularly in terms of potential 
changes in condom optimism that may occur as a result of PrEP trial 
involvement) and perceived vulnerability to positive consequences of PrEP and 
condom use and negative consequences of non-use (most specifically, to HIV 
infection in unprotected events), the current study will offer an examination of 
mechanisms by which risk behavior may change in participants.  Further, because 
of the comprehensive conceptualization of motivation adopted in the model, this 
study will be positioned to be able to speak to risk compensation (where 
perceived risk in the context of non-condom use would diminish through adoption 
of an alternative [PrEP use] strategy).  It is important to note, however, that the 
current study’s counseling protocol developed to support pill-taking and condom 
use will not allow for a ‘naturalistic’ characterization of either of these 
phenomenon.  However, this work would build to the growing literature 
evaluating changes in risk-behavior in the context of PrEP when appropriate 
counseling is provided.51 
 
The model has also been adapted to provide for better representation of core 
features of social theories of sexual conduct.  Social theories of decision making 


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have demonstrated explanatory and predictive power in the field of behavioral 
economics,52-54 particularly in the context of decision-making under conditions of 
uncertainty.  Presently, little is known about the role participants develop in the 
context of PrEP trials or the relation between these roles and risk-prevention 
behaviors.  The exploration of these important aspects of the “PrEP participant 
role” and their impact on PrEP use and sexual behavior in the context of PrEP is 
positioned as one of the factors that contribute to one’s overall motivation towards 
these behaviors.  Like other aspects of motivation, we anticipate that positive self-
beliefs - positive attributes one would use to describe oneself in their role in the 
trial and as a active contributor to it (prevention activist) - will contribute to 
higher motivation towards PrEP use and condom use and that this will be more 
characteristic of participants in the intermittent than the daily PrEP arm.   
  
The behavioral skills construct (Figure 1-2) includes objective and perceived 
skills in the implementation of the targeted behavior, across diverse and 
challenging circumstances, as well as one’s perceived efficacy in being able to 
implement an attained skill.  As the most proximal construct to behavior, and in 
the context of the structural relations identified by the IMB-model, skills carry the 
direct relation between lead-in (exogenous) constructs (information and 
motivation) and the behavior itself (condom use, PrEP use).  Essentially, the 
IMB-model proposes that even the highly motivated and well informed will have 
difficulty adopting a behavior if they do not develop or feel comfortable using 
requisite skills to actually perform the behavior in the situations that typify 
behavioral execution in their daily lives.  For example, a woman who is well 
informed about condom use and is highly motivated to use condoms may be 
unable to consistently adopt the behavior if she does not have the negotiation 
skills needed to convince her partner to use a condom.  A participant who requires 
privacy when taking his PrEP dose may be informed and motivated, but may lack 
the skills needed to take PrEP in privacy (e.g., planning, use of hiding strategies).  
To the extent that the targeted behavior becomes increasing difficult in the context 
of one’s life, skills play an increasingly large role in mediating the relation 
between the lead-in constructs and the outcome behavior.   
 
Because assigned PrEP arm likely will require differing sets of requisite skills for 
consistent and regimen-accurate pill-taking, the effects of being in the intermittent 
PrEP arm on the development of and changes in certain skill-sets is of a particular 
interest.  Those assigned to the event-driven arm are asked to take a pre-exposure 
dose prior to and following a sex event.  The unique requirement of pre-exposure 
dose taking is addressed in counseling support for individuals in this arm through 
guidance in the development of sexual ‘forecasting’ skills - skill sets for 
predicting when a potential event may occur.  Part of this prediction will involve 
exploration of one’s personal patterns of sexual behavior and risk exposures.  As 
such, it is possible that those assigned to this arm will increase their sexual 
planning skills, as well as their abilities to clearly identify important factors in 
sexual (and prevention-related) decision making.  While all arms participating in 
risk reduction and condom adoption counseling, the repeated cumulative 


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exposures to forecasting risk may produce unique skills acquisition and efficacy 
in the event-driven arm.   
 
Outside of the core constructs of the adapted IMB-model, an additional set of 
‘moderating’ variables are typically defined in IMB-models 41which include 
variables that are believed to alter, and at times attenuate IMB-model proposed 
relations.  Severe depression, active substance use, or homelessness were 
identified in the IMB-model of antiretroviral medication adherence as factors that 
limit IMB-model based interventions and would require resolution before changes 
in information, motivation, or behavioral skills could be promoted through 
intervention.55  The ‘moderator hypothesis’ is not adopted in the adaptation of the 
IMB-model for PrEP use.  Instead, these personal and situational variables are 
used to define the context in which PrEP use must be negotiated, and are 
incorporated in the adherence/PrEP use counseling approach.  As indicated in 
Figure 1-2, context variables include persistent negative mood,  perceived 
relationship with study staff and providers, disclosure of study participation to 
important others, active drug/alcohol use, and personal history (education, 
participation in other trials) and are used to help to define the  psychological and 
social context in which participation in the trial, experiences of negotiating trial 
participation, and one’s PrEP-related information, motivation, and behavioral 
skills are developed, experienced, and modified.  Context variables will be 
examined to assess for unique contributions in influencing PrEP adherence and 
PrEP related information, motivation, and behavioral skills areas.   
 
A specific goal of this study is also to identify potential changes in other 
prevention behaviors (condom use) and, if observed, potential correlates of 
changes in risk behavior.  If a pattern of reduced condom use is observed in the 
sample from baseline to final on-drug assessment, the data will be examined for 
attitudes, perceived vulnerability to HIV and high optimism about PrEP efficacy.  
Elucidating the relations between depression, and perceptions of relationships and 
rapport with study team and risk behavior, as well as its core determinants, is a 
unique contribution of the present research.  While depression and substance use 
have been well demonstrated in their relation to risk,56-58 the manner in which 
these factors co-exist or contextualize core facilitators and barriers to one’s funds 
of information, motivation, and behavioral skills is less well understood, but 
critical in the empirical guidance of support strategies for PrEP use. 
 
 


HPTN 067, Final Version 5.0 
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INFORMATION about 

Goals of trial 

PrEP 

Specific regimen requirements (when to use, how to use) 

Accurate information about study-drug, intentions of research, and dosing 
requirements (low level of misinformation or faulty heuristics) 

Condom Use 

Where to obtain, how to use correctly, how condoms protect from STIs 
(HIV), and low funds  of accurate information  
MOTIVATION 
Personal Motivation 

Ownership of study (positive beliefs of personal role in answering study 
question) 

Attitudes/beliefs towards target behavior (pill-taking, condom use) 

Positive consequences of pill-taking (condom use) 

Perceived vulnerability (susceptibility) to positive consequences of pill-
taking (condom use) 

Positive beliefs of regimen-daily life fit (condom use-daily life fit) 

Lower negative consequences of pill-taking (condom use) 

Ownership of regimen (positive beliefs that regimen is responsive to one’s 
personal patterns of risk), condom use adoption (positive beliefs that 
condoms are well matched to one’s personal patterns of risk) 
Social Motivation 

Commitment to goals of study at community (MSM, WSM) level 

Perceived role in study (activist vs.  patient role) 

Attitudes/beliefs that others support behavior (pill-taking, condom use) 

Positive attitudes/beliefs about pill-taking (condom use) as a ‘social’ 
contribution 

Lower levels of attributions of pill-taking (condom use) as being done or 
maintained for “others” 
BEHAVIORAL SKILLS 
PrEP-specific objective and perceived skills and 
confidence in: 

Pill-taking in diverse situations 

Requiring privacy 

When schedule changes 

When feeling depressed, hung-over, anxious 

Over time 

When not sexually active 

Following regimen requirements 

Planning for sex 

Pre-exposure pill-use 

Post-exposure pill-use 

Management of potential side-effects 

Remembering dose-times or pre/post dose 

Organizing pill-taking 

Managing social consequences (real or 
perceived) of study participation 
Condom use-specific objective and perceived skills 
and confidence in appropriate (correct) condom 
use: 

In diverse situations/contexts 

With steady partner(s) 

In casual sex or sex for barter or money 

With partners preferring not to use a condom 
(skills in negotiation of use) 

When feeling depressed, anxious, stressed 

In the context of drugs or alcohol 

Over time 

Continued use of condoms in ongoing sexual 
relationships 
 
 
BEHAVIOR 
COVERAGE 
(PILL-TAKING at 
rates that 
provide high 
coverage of risk 
events) 
RATES OF PILL-
TAKING as 
recommended  
CONDOM USE 
(continued or 
changes in) 
 
CONTEXT VARIABLES (variables that may influence levels of motivation and relations between information, motivation, behavioral skills and outcomes) 

Persistent Negative Mood States (e.g., depression); Persistent Positive Mood States (e.g., optimism) 

Perceived relationship with clinic providers and study staff 

Disclosure of study participation to important others 

Demography (income, education, previous participation in HIV prevention studies, close contact with or experience with HIV) and active alcohol or drug use 
Figure 1-2: Adapted IMB-model of PrEP and Condom Use 
INFORMATION about 

Goals of trial 

PrEP 

Specific regimen requirements (when to use, how to use) 

Accurate information about study-drug, intentions of research, and dosing 
requirements (low level of misinformation or faulty heuristics) 

Condom Use 

Where to obtain, how to use correctly, how condoms protect from STIs 
(HIV), and low funds  of accurate information  
MOTIVATION 
Personal Motivation 

Ownership of study (positive beliefs of personal role in answering study 
question) 

Attitudes/beliefs towards target behavior (pill-taking, condom use) 

Positive consequences of pill-taking (condom use) 

Perceived vulnerability (susceptibility) to positive consequences of pill-
taking (condom use) 

Positive beliefs of regimen-daily life fit (condom use-daily life fit) 

Lower negative consequences of pill-taking (condom use) 

Ownership of regimen (positive beliefs that regimen is responsive to one’s 
personal patterns of risk), condom use adoption (positive beliefs that 
condoms are well matched to one’s personal patterns of risk) 
Social Motivation 

Commitment to goals of study at community (MSM/TGW, WSM) level 

Perceived role in study (activist vs.  patient role) 

Attitudes/beliefs that others support behavior (pill-taking, condom use) 

Positive attitudes/beliefs about pill-taking (condom use) as a ‘social’ 
contribution 

Lower levels of attributions of pill-taking (condom use) as being done or 
maintained for “others” 
BEHAVIORAL SKILLS 
PrEP-specific objective and perceived skills and 
confidence in: 

Pill-taking in diverse situations 

Requiring privacy 

When schedule changes 

When feeling depressed, hung-over, anxious 

Over time 

When not sexually active 

Following regimen requirements 

Planning for sex 

Pre-exposure pill-use 

Post-exposure pill-use 

Management of potential side-effects 

Remembering dose-times or pre/post dose 

Organizing pill-taking 

Managing social consequences (real or 
perceived) of study participation 
Condom use-specific objective and perceived skills 
and confidence in appropriate (correct) condom 
use: 

In diverse situations/contexts 

With steady partner(s) 

In casual sex or sex for barter or money 

With partners preferring not to use a condom 
(skills in negotiation of use) 

When feeling depressed, anxious, stressed 

In the context of drugs or alcohol 

Over time 

Continued use of condoms in ongoing sexual 
relationships 
BEHAVIOR 
COVERAGE 
(PILL-TAKING at 
rates that 
provide high 
coverage of risk 
events) 
RATES OF PILL-
TAKING as 
recommended  
CONDOM USE 
(continued or 
changes in) 
CONTEXT VARIABLES (variables that may influence levels of motivation and relations between information, motivation, behavioral skills and outcomes) 

Persistent Negative Mood States (e.g., depression)  

Perceived relationship with clinic providers and study staff 

Disclosure of study participation to important others 

Demography (income, education, previous participation in HIV prevention studies, close contact with or experience with HIV) and active alcohol or drug use 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
1.10.4 Rationale for drug level testing 
Fostering adherence and minimizing social desirability bias in adherence 
reporting are challenges for prevention trials that are increasingly appreciated.  
For example, while reported adherence in the Carraguard microbicide trial was 
96%, adherence utilizing an objective measure of applicator use was only 44%.59  
In HPTN 039, reported adherence to acyclovir was not associated with herpes 
virus isolation in regions where high levels of adherence were reported, 
suggesting substantial over-reporting of adherence.60  All measures of adherence 
and pill-taking can be influenced by participants seeking to satisfy their roles, 
although electronic pill monitoring devices and pill counts may adjust for recall 
bias.   
 
HPTN 067 will evaluate the use of drug levels in PBMCs, hair, and DBS as 
objective measures of drug exposure and pill-use.  FTC-TP and TFV-DP have 
long intracellular half-lives (48 and 150 hours, respectively) such that 
measurements made using specimens collected at clinic visits will reflect pill-use 
over the previous days to weeks.  Such measures of long term drug exposure are 
less influenced by “white coat” effects, where pills are utilized more in the day 
immediately prior to the clinic visit.  The relationship between drug level and pill-
use is complicated by individual factors that affect absorption, distribution, and 
clearance of drugs.   
 
In this study, the relationships between drug exposure and pill-taking will be 
calibrated for each participant during a lead-in phase including DOT.  In this 
manner, the study will have an objective measure of pill-use and over-reporting of 
pill-use for Weeks 10, 18 and 30 when plasma will be evaluated for drug levels.  
This objective measure will be used to more sensitively detect participants who 
have discontinued all pill-use despite reports to the contrary, and to identify the 
extent of over-reporting of pill-use in the three usage groups for the weeks prior to 
these evaluation periods.  Recommendations for intermittent use may be 
associated with less over-reporting of pill-taking because intermittent regimens 
require more thoughtful behavior; therefore, social expectations for pill-use may 
be less.  HPTN 067 may also provide important new information regarding the 
factors that explain variance between pill-taking and drug exposure in African and 
Asian populations.  These factors may include sex, body size, age, and ethnic 
background, although this comparison may be confounded by near uniform and 
different genders in these two geographic regions. 
1.10.5 Relevance to the goals of the HPTN 
The goal of the HPTN is to identify effective methods to prevent HIV infection.  
While existing PrEP research may find that daily dosing is associated with some 
protection against HIV infection, there is little information available about how 
PrEP implementation and uptake can best be supported.  Additional information 
that can identify core facilitators and barriers to PrEP use is needed to maximize 
the availability and effectiveness of PrEP.  It is also possible that existing trials 


HPTN 067, Final Version 5.0 
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may fail to demonstrate efficacy of daily PrEP, due to dose-related intolerance or 
insufficient adherence to regimens that may be poorly matched to risk behavior or 
sexual activity.  HPTN 067 will test whether one dosing strategy is preferable to 
others for the purposes of future efficacy studies.  In doing so, the IMB-model 
used to characterize PrEP use, risk, and changes in risk allows for a detailed 
examination of which factors appear most influential of PrEP use, across and 
within study arms, and to the use of condoms.  HPTN 067 will test specific 
hypotheses regarding sexual and adherence behavior related information, 
motivation, and behavioral skills, with additional examination of the relative role 
of PrEP- and condom use-optimism, , depression, substance use, and social roles 
developed in regard to being part of this PrEP trial among participants.  Across all 
arms, participants are supported by an IMB-model based, participant-centered 
counseling protocol to promote pill-taking and continued or increased condom 
use.  The differences observed between the arms will reflect differences that 
would be anticipated to emerge in the context of PrEP when it is delivered with 
appropriate support.  HPTN 067 has direct relevance to PrEP uptake, feasibility, 
adoption and it offers to provide a level of empirical guidance to better 
understanding and promoting these factors that have not been offered to date. 
1.10.6 Design advantages 
Chemoprophylaxis is a fast moving field with multiple studies in progress.  It is 
impossible to predict with confidence the results of existing studies or when 
pivotal information will become available.  HPTN 067 is designed to address 
questions that are significant regardless of the outcome of existing PrEP trials.   
 
A key advantage of this protocol is that it brings together investigators and 
communities that are leading current pivotal studies in the PrEP field, including 
pre-clinical evaluation of dosing strategies in animal models and clinical trials of 
safety and efficacy of daily dosing in injection drug users, WSM, and MSM.  This 
assures that there will be a benefit from insights gained during the current trials, 
including both published and unpublished findings.   
 
This trial is designed to inform a larger efficacy study aimed at dose optimization.  
The efficacy study would have a non-inferiority design if daily oral TDF/FTV 
PrEP were found to be superior to standard interventions in current trials.  
Alternatively, if daily dosing is not found to be efficacious in current trials 
because of dose-related intolerance or poor adherence related to pill burden, the 
future efficacy study would have a superiority design versus standard of care, 
which would remain no use of PrEP. 
 
Regardless of eventual design, a future efficacy study of intermittent PrEP 
requires guidance in terms of patterns of pill-taking adherence and a strong signal 
for acceptability and feasibility within the targeted participant groups.  HPTN 067 
will assess the feasibility of different intermittent dosing strategies, identify 
theory-based determinants of sexual and pill-taking behavior during PrEP use, 
maintain cohorts of participants interested in intermittent PrEP, and build 


HPTN 067, Final Version 5.0 
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interagency infrastructure that is essential for efficacy evaluation, regardless of 
whether it utilizes superiority or non-inferiority designs.  Because nearly 20,000 
people are expected to finish PrEP trials in the next three years, there would be 
ample opportunity to fully power a non-inferiority study of daily versus 
intermittent PrEP.  This study would develop the information, collaborative 
relationships, and infrastructure required to develop the next generation of PrEP 
research and program development. 
2.0 
STUDY OBJECTIVES AND DESIGN 
2.1 
Primary Objective: 
To test the hypothesis that recommending intermittent (non-daily) usage of oral 
FTC/TDF chemoprophylaxis, compared with recommending daily usage, will be 
associated with:  
 Equivalent coverage of sex events with pre- and post-exposure dosing 
 Lower number of pills needed for coverage and fewer pills used 
 Decreased self-reported symptoms/side effects (both severity and 
frequency) during 24 weeks of self-administered use 
2.2 
Secondary Objectives:  
 Develop objective measures of drug exposure by obtaining steady state pre-
dose “trough” drug concentration in several biological matrices for 
participants during a lead-in period of weekly DOT  
 To describe safety outcomes among PrEP users including adverse events 
among all participants and drug resistance and plasma HIV RNA levels 
among participants who seroconvert 
 Assess differences between arms in the acceptability of different PrEP 
regimens and in perceptions of advantages and disadvantages of different 
regimens 
 Assess differences by arm in adherence  
 Evaluate the potential influence of PrEP usage on changes in sexual behavior, 
planning for sex, prediction of risky situations, and recognition of possible 
HIV exposure from baseline to final on-drug assessment in relation to PrEP 
optimism 
2.3 
Study Design 
HPTN 067 is a Phase II randomized open-label clinical trial of oral FTC/TDF 
PrEP among HIV-uninfected men who have sex with men (MSM), transgender 
women, (TGW) and women who have sex with men (WSM) at high risk of 
acquiring HIV infection.  The study includes a six weeks lead-in period including 
DOT at Enrollment and Weeks 1 through 4, followed by one week without dosing 
to determine individual steady state pharmacokinetics.  This will provide the 
opportunity to create a pharmacokinetic analysis of drug levels to be expected at 
given rates of intake (adherence) which will be analyzed as part of the secondary 


HPTN 067, Final Version 5.0 
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analysis to confirm self-reported data.  Participants will then (at Week 6) be 
randomized to one of three dosage groups in a 1:1:1 ratio: daily dosing, time-
driven dosing, and event-driven dosing.  After randomization, participants will 
complete a 24-week period of self-administered dosing, with one visit four weeks 
after the completion of dosing (34 weeks total).  Participants who acquire HIV 
infection during the study will discontinue dosing and will be followed until study 
closure and referred for post-trial care as per local regulations.  A subset of study 
participants in each of the study arms (convenience sample) and clinic staff will 
also participate in a qualitative evaluation of the social and behavioral aspects of 
differing dosing strategies, to include focus groups and key informant interviews 
after Week 34. 
2.4 
Description of the intervention 
2.4.1 Once-a-week directly observed dosing lead-in component  
A six week lead-in period consisting of DOT at Enrollment and Weeks 1 through 
4, followed by one week without dosing will be used to estimate steady-state drug 
levels and accumulation and decay constants for each individual.  The purpose of 
obtaining these estimates is to interpret adherence measurements during the 
subsequent self-administered dosing phase of the study.  During the DOT phase, 
all participants will begin the study by having weekly visits from Enrollment 
through Week 5.  During this period, participants will begin learning how to use 
the EDM device prior to beginning the self-administered phase.  At Enrollment 
through Week 4, participants will receive one directly observed dose per week of 
oral FTC/TDF (five doses total).  No drug will be administered during Week 5.  
PBMC specimens will be collected for analyses of drug levels at Weeks 4 and 5.  
These values will be used to estimate the accumulation and decay constants and 
steady state levels of TFV-DP; FTC-TP may also be measured. DBS samples will 
also be collected at one study site for exploratory studies of these analytes in 
whole blood RBCs.  Blood samples should be collected prior to dosing.  Plasma 
and hair samples will also be collected prior to dosing and stored at selected study 
visits, which may be used for comparison of PBMC drug levels to drug levels in 
those samples.  These concentrations will be evaluated to test for steady-state and 
the “expected” pre-dose concentration for each individual.  Week 4 and Week 5 
data (Week 5 alone if steady-state has not been achieved) will provide a point 
estimate for the expected concentration at steady-state and an estimate of intra-
individual variability in this pre-dose concentration.  Decay will be monitored 
from drug dose concentration data collected at Week 6.  The Study Specific 
Procedures (SSP) Manual will detail acceptable windows for the DOT phase. 
2.4.2 Self-administered dosing component  
After the 6-week lead-in period including DOT (Enrollment and Weeks 1 through 
4 followed by no dose at Week 5), participants will be randomly assigned to one 
of three unblinded PrEP usage groups at Week 6: (1) daily usage, (2) time-driven 
usage, and (3) event-driven usage, as described in the Schema.  Individuals will 
participate in theory-based, participant-centered, individual, brief (10-15 minutes) 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
counseling sessions optimized for each usage plan at study visits.  This counseling 
approach will draw from well-established models (e.g., motivational 
interviewing) and will be based on the IMB model adapted for this research.  This 
counseling will also be informed by the current literature on effective strategies 
and approaches to promoting adherence to antiretroviral therapy (ART).61,62  
 
The adherence support counseling approach used in this protocol, entitled “Next 
Step Counseling”, includes structural, cultural, and personal facilitators and 
barriers to daily, time-driven, and event-driven pill-use.  This counseling 
approach seeks to target and address adherence-related information, motivation, 
and behavioral skills required to produce optimal rates of adherence.  For 
different arms, the information and skills targeted differ slightly in content 
particularly in early sessions.  All participants will receive regimen-specific 
information during their first counseling session, which will vary between but not 
within the study arms.  Information regarding the mechanisms of FTC/TDF for 
potential HIV-prevention will be standardized across the arms, but the added 
messaging that focuses on how one’s specific assigned regimen provides 
protection against infection will be arm (regimen) specific. All participants will be 
counseled about the risks and benefits of PrEP and it will be emphasized that the 
efficacy of intermittent dosing has not been established. Therefore participants 
will be educated about the necessity to use condoms from start to finish of every 
sexual intercourse. Condoms and lubricant will be provided by the sites, as 
appropriate.  
 
Additionally, messaging for preparatory skills needed for one’s specific regimen 
schedule will be explored.  For the daily arm, this exploration includes review of 
commonly used strategies for daily pill-taking (e.g., dose timing, matching dose 
with daily event).  For the time-driven arm, strategies to remember dose-taking 
twice weekly, ways to identify risk events requiring a post exposure dose, and 
‘rules of thumb’ for when a post-exposure dose replaces a weekly dose or a 
weekly dose replaces a post-exposure dose will be discussed.  For the event 
driven arm, strategies for sexual forecasting, those strategies discussed with the 
time driven arm for post-exposure and ‘rules of thumb’ for not exceeding 
recommended doses per week will be discussed.  These issues will be re-visited as 
needed at subsequent sessions.   
 
All remaining aspects of the semi-structured counseling approach to support PrEP 
use will be administered identically to participants through targeted discussions of 
pill-taking at each study visit.  The exact content and strategies identified in each 
counseling session are individually targeted and tailored, thus the approach is 
intended to have the flexibility to identify and address specific strengths and 
weaknesses in integrating pill-taking into the ecology of one’s daily life, which 
will vary at the level of the individual participant.  While the content intentionally 
varies by participants, the discussion process of the pill-taking is standardized 
across participants and all arms.  Exceptions, previously noted, are in first session 
in terms of information-delivery and the identification and exploration of 
regimen-specific skills.   


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
 
Risk-reduction counseling for condom use will also be included, as is standard for 
PrEP trials, and will be enhanced to mobilize the participant-centered approaches 
and skills developed with trainings and implementation of the Next Step 
Counseling protocol.  All participants will be counseled about the known benefits, 
or lack thereof of PrEP, and that they should protect themselves in other ways, 
including using condoms during intercourse.  All groups will be informed that 
missed doses should be taken when the person remembers, but no more than two 
pills per 24-hour period, or seven pills per week should ever be taken.  
Counseling at each study visit will target increasing the perceived ease of pill-
taking and decreasing perceived burden of pill-taking, utilizing various client-
centered, motivational interviewing and motivation enhancement strategies.  All 
participants in each arm will receive identical counseling, although the 
informational content pertinent to pill-taking regimen will vary by arm, as will the 
relative weight of specific skills (e.g., sexual planning skills development).  All 
participants will receive a sufficient supply of study medication to last until the 
next scheduled visit, accompanied by an electronic pill monitoring system to track 
the timing and frequency of pill-use.   
 
If individuals in the time- and event-driven arms are having sex frequently and 
taking the pills as recommended, they could end up taking the pills daily.  
Although preliminary research has indicated that this behavior is likely to be rare, 
the counseling and behavioral strategies that lead to daily use would remain 
distinct, as described above.  As the participants in the time-driven arms will be 
encouraged to think about possible exposure to HIV in the context of pill taking, 
while the participant in daily arms will be encouraged to build pill taking into 
daily routines.  Migration and preferences between arms will be monitored in this 
trial.  In practice, there will undoubtedly be considerable variation in sexual 
frequency in the persons enrolled in this study and understanding the advantages 
and disadvantages of time-driven and event-driven usage strategies across the 
spectrum of sexual activity will be possible.   
 
During this period of self-administered PrEP, participants will be asked to take 
pills only from the EDM device/case.  The EDM cases electronically transmit the 
date and time of all case openings to a central server, which is then distributed to 
the interviewers conducting the weekly telephone-based assessments of pill-
taking and risk behavior.  To assess pill-taking, the EDM-collected data will serve 
as a prompt for interviewers to query participants.  For each case opening, the 
participant will be asked to describe what happened (number of pills loaded or 
dispensed (which could be zero if the case was opened with no release of tablets) 
and what happened with each dispensed tablet (taken or not taken; time/day of 
consumption if taken).  After assessing the outcomes associated with each 
documented case-opening, participants will be asked if they had any additional 
pill-events that were not discussed to capture pills that were consumed but not 
dispensed from the EDM case.  Pill-taking assessment will be followed by 
assessment of risk events (day/time and type of event) using a timeline follow-


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
back approach, when needed or when time intervals assessed extend beyond one 
week.   
 
Because the current assessment of adherence to PrEP regimens requires the 
collection of highly specific sexual and pill-taking behaviors (e.g., time of sex 
events and times of pill-taking), retrospective recall of events and pill-taking in 
traditional one-month or three-month intervals is likely to prohibit the collection 
of the information needed with a reasonable degree of accuracy.  Recent work 
suggests that shorter recall intervals produce more accurate reports of risk 
behavior,63 while daily telephone based (as well as electronic diary and web-based 
diary) assessments have a well demonstrated history.64-67  To balance potential 
sensitization with need for accurate recall, a weekly schedule of telephone-based 
interviews will provide the main vehicle for collection of time and type of sexual 
events, as well as determination of outcomes for each EDM recorded device 
opening.  Telephone interviewers will be trained in neutral assessment 
approaches, with careful messaging to participants at each call providing 
permission statements and normalization of reporting “risk” events and missed 
pills to reduce self-presentation bias.  Additionally, interviewers will be trained in 
techniques for participants who have difficulty in recalling events and for use 
when the assessment interval has for whatever reason extended beyond 
approximately the past week.  To assist participants in recall, items such as sexual 
behavior journals and small diary cards will be created for the purposes of the 
current research and offered to participants for use, although they are not required.  
Participants opting to use these memory aids will be asked to use them when 
conversing with the interviewer on weekly calls.   
 
The data collected via these weekly interviews will be used to adjust the EDM-
collected data to produce a continuous measurement of pill-taking throughout 
participation in this phase of the project.  These data will also be used to produce 
the longitudinal assessment of risk (condom use or non-use).  The adjusted EDM 
data and risk behavior data will be combined to calculate PrEP coverage of risk 
events.  Specifically, a sex act will be considered “covered” if at least one pill is 
taken during the 4 days (96 hours) before the act and at least one additional pill is 
taken within 24 hours after the act.  See Section 7.2.1 for further details. 
2.4.2.1 Daily usage 
Those randomized to the daily dosing group will receive recommendations to take 
FTC/TDF once a day regardless of sexual activity.  Details regarding pill-taking 
counseling will be provided in the counseling manual.   
 
2.4.2.2 Time-driven usage 
Those randomized to the time-driven dosing group will be asked to take 
FTC/TDF twice weekly with a post-exposure boost.  Specifically, they will 
receive recommendations to take one pill two days per week, three to four days 
apart, regardless of sexual activity.  In addition, they will be instructed to take a 
post-exposure booster dose within two hours after sexual intercourse, defined as 


HPTN 067, Final Version 5.0 
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any penile intromission, whether oral, vaginal, or anal, and whether or not 
condoms were used.  The post-exposure dose should be taken after the first penile 
insertive sex and not repeated if there are multiple penile intromissions in a day.  
The post-exposure boost will also count as one of the twice-weekly doses if it 
occurs on the prescribed day.  Pill-taking counseling in the time-driven arm will 
be the same as in the daily arm, with adjustments in education provided for the 
recommended regimen (e.g., additional information pertaining to booster doses).   
2.4.2.3 Event-driven usage  
Those randomized to the event-driven dosing group will be asked to take one 
tablet of FTC/TDF, preferably between 24 to 48 hours prior to sexual intercourse 
and a post-exposure booster dose within two hours of sexual intercourse, defined 
as any penile intromission, whether oral, vaginal, or anal, and whether or not 
condoms were used.  If the participant anticipates sexual intercourse, but did not 
take the dose 24 hours prior to the event, the participant should take the pre-
exposure dose as soon as possible before the event.  The post-exposure boost will 
also count as a pre-exposure dose for the next sex act that occurs up to 48 hours 
later.  Pill-taking counseling in the event-driven arm will be the same as in the 
daily arm, with adjustments in education and skills-building provided for the 
recommended regimen (e.g., additional information pertaining to booster doses 
and pre-exposure doses, and skills development in forecasting sexual exposures to 
facilitate appropriate pre-event dose taking).   
3.0 
STUDY POPULATION 
The study will enroll 540 evaluable HIV-uninfected volunteers: 180 MSM/TGW at the 
CDC TUC Silom Community Clinic in Bangkok, Thailand, 180 MSM/TGW at the 
Harlem Prevention Center in New York, USA and 180 WSM at Emavundleni Centre, 
The Desmond Tutu HIV Foundation in Cape Town, South Africa. Transgender women 
(male-to-female transgender or TGW) are at higher risk of HIV infection (10.5% in 
Thailand based on unpublished data from 2010, Bureau of Epidemiology, Ministry of 
Public Health).  The route of the HIV infection in this population can be from both anal 
and neovaginal sex (see definition below under section 3.1.1) as some transgender 
women stop anal intercourse after gender reassignment surgery.  The TGW population 
exhibits similar risk behavior and closely interacts with their MSM counterpart 
population therefore including them in this protocol could extend the coverage and 
benefit of this study to the whole MSM/TGW community. The efficacy of oral Truvada 
PrEPhas been demonstrated for vaginal, penile and anal exposure to HIV; separate 
assessment of efficacy for neovaginal exposure is not currently planned. 
 
Participants will be selected for the study according to the criteria in Sections 3.1 and 3.2 
(and the guidelines in Section 3.4).  They will be recruited as described in Section 3.3 
(and assigned to a study treatment group as described in Section 7.4).  Issues related to 
participant retention and withdrawal from the study are described in Sections 3.5 and 3.6, 
respectively. 


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3.1 
Inclusion Criteria 
 At least 18 years old  
 Literacy in one of the study languages (Thai, Xhosa and/or English) 
 Able to provide written informed consent  
 Able to provide weekly telephonic updates  
 Within 70 days of Enrollment: 
o serum creatinine < upper limit of normal (ULN) and calculated 
creatinine clearance of at least 70 mL/min by the Cockcroft-Gault 
formula where:  
 eCcr (female) in mL/min = [(140 – age in years) x (lean 
body weight in kg) x 0.85] / (72 x serum creatinine in 
mg/dL) 
 eCcr (male) in mL/min =  [(140 – age in years) x (lean 
body weight in kg)] / (72 x serum creatinine in mg/dL) 
o Serum phosphate > the lower limit of normal (LLN)  
o Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) < 2 x ULN  
o Hemoglobin > 10 g/dL  
o Hepatitis B surface antigen (HBsAg) negative 
o Willing and able to provide adequate locator information.   
 
Note: Participants without HBV immunity at screening will be offered vaccination as 
indicated in Section 5.1.   
3.1.1 MSM/TGW 
 Male at birth 
 Reporting anal and/or receptive neovaginal intercourse* with at least one man 
or transgender woman in the past six months  
 One or more of the following risk factors for HIV acquisition in the past six 
months according to self-report: 
 Sexual intercourse with more than one man or transgender woman 
 History of an acute sexually transmitted infection (STI)  
 Sex in exchange for money, goods or favors 
 Condomless intercourse (oral, anal, vaginal or neovaginal) with a partner 
known to be HIV-infected or of unknown HIV infection status according 
to self-report 
 
*The neovagina is the surgically constructed organ that has been made to look like a 
female vaginal sex organ.  It usually involves the removal of the male sex organ (penis) 
and surgically constructing a vagina.  The procedure is formally termed neovaginoplasty 
or sexual reassignment surgery (SRS) in cases when a vagina did not previously exist.  
Receptive neovaginal sex is the act of a male putting a penis into a transgender female's 
neovagina. 


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3.1.2 WSM  
 Female at birth or self identify as female 
 Not pregnant or breastfeeding 
 Not able or intending to become pregnant during the next year   
 If able to become pregnant, self reported use of an effective method of 
contraception at Enrollment, and intending to use an effective method for the 
next 34 weeks (refer to Section 4.6 for effective methods of contraception) 
 One or more of the following risk factors for HIV acquisition in the past six 
months according to self report: 
 Sexual intercourse with more than one man 
 History of an acute STI 
 Sex in exchange for money, goods or favors 
 Condomless intercourse (oral, anal or vaginal) with a partner known to be 
HIV-infected or of unknown HIV infection status 
3.2 
Exclusion Criteria 
 Proteinuria 2+ or greater at screening 
 Glucosuria 2+ or greater at screening 
 Serious and active medical or mental illness 
 One or both HIV rapid tests is reactive at Screening or Enrollment, regardless 
of subsequent HIV diagnostic test results 
 Signs or symptoms suggestive of acute HIV infection  
 Use of hypoglycemic agents for diabetes or agents with known nephrotoxic 
potential 
 Use of ARV therapy (e.g., for PEP or PrEP) in the 90 days prior to study entry 
 Serum phosphate level below site laboratory LLN (lower limit of normal) 
 Current participation (or participation within three months of screening) in 
any HIV prevention study.   
 Previous or current participation in the active arm of an HIV vaccine trial.   
 Acute or chronic HBV infection* 
 Participant has a psychological or social condition or an addictive disorder 
that would preclude compliance with the protocol 
 Any other reason or condition that in the opinion of the investigator would 
interfere with participation, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives 
 
* Refers to chronic active HBV infection evidenced by a positive test for hepatitis 
B surface antigen (HBsAg). 
3.2.1  Vulnerable Populations 
Persons under the age of 18 years of age will not be included since the effects of 
antiretroviral therapy on physical development and other growth parameters (e.g., 
effects on bone growth and bone mineral density) in HIV uninfected children and 


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minors have not been fully evaluated, and exploration of these safety issues is 
beyond the scope of this project.   
 
No incarcerated persons will be screened, enrolled or followed in this study due to 
logistical, technical, and ethical reasons. Participants who become incarcerated 
during the course of the study will be considered lost to follow-up. Excluding 
prisoners in all countries is due both to ethical considerations regarding 
participation in studies while incarcerated as well as logistical challenges which 
would make follow-up among prisoners infeasible.  For example, the study relies 
on an EDM device to send information about opening times and pill-taking to a 
central server for adherence and drug intake monitoring.  It is unlikely however 
that EDM signals can be sent or received from a high security prisons.  In 
addition, weekly telephone interviews about sexual and pill taking behavior will 
be conducted with all participants. These weekly interviews would be difficult to 
conduct with prisoners and confidentiality could not be guaranteed.  
 
Pregnant women will not be included or will be discontinued from study drug 
because of the potential risks to the fetus if the mother is taking Truvada®.  
Persons with mental disabilities may be included; however any person who 
cannot provide informed consent will be excluded from participation in the 
project.  Staff conducting enrollment will be trained to identify participants who 
cannot provide informed consent. These persons will be given the opportunity to 
reschedule their enrollment appointment as appropriate.  All participants will be 
afforded the same protections. 
3.3 
Recruitment Process 
Site Institutional Review Board (IRB)-approved media advertisements, telephone 
scripts, and fliers may be used by recruiters at venues of socialization, open 
houses, and public events. 
 
MSM/TGW will be recruited from both the Bangkok MSM Cohort study, an 
ongoing prospective study of HIV infection among 1,000 HIV negative 
MSM/TGW at the Silom Community Clinic and from their voluntary counseling 
and testing (VCT) population. 
 
The community education and recruitment team located at the Emavundleni 
Centre will use their extensive networks in the Nyanga District to recruit WSM to 
this study.  They will also utilize the IRB-approved pre-screening protocol at the 
Emavundleni Centre to locate potential recruits who will be invited to participate. 
 
Harlem Prevention Center CRS’ recruitment strategy will combine community-
based outreach, referral from other current and past studies conducted at the CRS, 
and venue-based outreach.  Study staff will meet with stakeholders and 
community members to develop a comprehensive educational and recruitment 
strategy that is responsive to community needs and concerns.  The resulting 
strategy will be used to create study-specific media advertisements, telephone 


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scripts, and fliers.  The materials will be reviewed by the Columbia University 
Medical Center Institutional Review Board (IRB).   IRB-approved materials will 
be used to inform community members, stakeholders, community-based 
organizations, medical providers and potential participants about the study and to 
identify MSM/TGW who may be eligible for study participation.  Harlem site 
staff will collaborate with partner organizations based in New York City’s diverse 
MSM/TGW communities to engage and recruit study participants.  Interested 
participants from completed studies at the CRS who have given permission to be 
contacted will be referred to HPTN 067 for prescreening. Similarly, targeted 
venue-based recruitment will be focused on engaging Black and Latino 
MSM/TGW of color, as well as other groups, in HPTN 067. 
 
3.4 
Co-Enrollment Guidelines 
Study participants may not enroll in other HIV vaccine or interventional 
prevention trials to reduce participant burden with study visits, to facilitate high 
levels of adherence and retention (including compliance with study medications), 
to avoid potential unblinding of HIV vaccine trials, and to avoid confounding in 
the interpretation of the primary and secondary endpoint data. 
3.5 
Participant Retention 
Once a participant enrolls in this study, the study site will make every effort to 
retain him/her for 34 weeks of follow-up in order to minimize possible bias 
associated with loss-to-follow-up.  Optimally, participant retention procedures 
will be established to achieve at least 90% retention at Week 34 (from 
randomization).  Study site staff are responsible for developing and implementing 
local standard operating procedures (SOPs) to target this goal.  Components of 
such procedures will include: 
 
 Thorough explanation of the study visit schedule and procedural requirements 
during the informed consent process and re-emphasis at each study visit 
 Thorough explanation of the importance of all three study treatment groups to 
the overall success of the study 
 Collection of detailed locator information at the Screening visit, and active 
review and updating of this information at each subsequent visit 
 Use of mapping techniques to establish the location of participant residences 
and other locator venues 
 Use of appropriate and timely visit reminder mechanisms 
 Immediate and multifaceted follow-up on missed visits 
 Mobilization of trained outreach workers or “tracers” to complete in-person 
contact with participants at their homes, other community locations, and 
friends and family 
 Regular communication with the study community at large to increase 
awareness about HIV/AIDS and explain the purpose of HIV prevention 
research and the importance of completing research study visits 


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3.6 
Participant Withdrawal 
Regardless of the participant retention methods described above, participants may 
voluntarily withdraw from the study for any reason at any time.  The IoR also 
may withdraw participants from the study in order to protect their safety and/or if 
they are unwilling or unable to comply with required study procedures after 
consultation with the Protocol Chair, Division of AIDS (DAIDS) Medical Officer, 
Statistical and Data Management Center (SDMC) Protocol Statistician, and 
Coordinating and Operations Center (CORE) Protocol Specialist.  Participants 
who withdraw prior to Randomization/Week 6 will not be randomized and will be 
replaced.   
 
Desire to stop using the study medication or to use study medication in a manner 
that differs from the recommended usage is not a reason for participant 
withdrawal from the study.  These participants should be encouraged to remain in 
the study and complete study procedures.  Participants should continue to be 
provided study medication as long as they express interest in continuing.  
Participants who report intentional overdosage of drug (more than 1 tablet in 2 
hours, more than 2 tablets in 24 hours, or more than 7 tablets in 7 days) should 
receive repeated counseling regarding pill-use and study medication should be 
withheld in consultation with the Protocol Safety Review Team (PSRT) if 
overdosage is deemed likely to occur again despite repeated counseling.   
 
Participants may be withdrawn if the study sponsor, government or regulatory 
authorities, [including the Office of Human Research Protection (OHRP) and the 
US FDA] or site IRBs/Ethics Committees (ECs) terminate the study prior to its 
planned end date.   
 
Every reasonable effort will be made to complete a final evaluation (as described 
in Section 5.6) of participants who terminate from the study prior to Week 30, and 
study staff will record the reason(s) for all withdrawals from the study in 
participants’ study records. 
4.0 
STUDY DRUG/INTERVENTION 
4.1 
Study Drug/Intervention Formulation/Content 
FTC/TDF is a fixed dose combination tablet containing 200 mg of FTC and 300 
mg of TDF. It is available as Truvada®, a medication approved by the U.S. FDA 
for treatment and prevention of HIV-1 infection.68  Further information on 
Truvada® is available in the current package insert.68 
4.2 
Study Drug/Intervention Regimen(s) and Administration 
After the 6-week lead-in period including DOT, participants will be randomly 
assigned to one of three unblinded PrEP usage groups of oral therapy:  (1) daily 
usage, (2) time-driven usage, and (3) event-driven usage.  During this period of 


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self-administered therapy, FTC/TDF tablets will be dispensed in an EDM device 
as outlined in the Study Specific Procedures. 
 
Daily Dosing 
Those randomized to the daily dosing group will receive recommendations to take 
one FTC/TDF tablet once a day with or without food regardless of sexual activity.   
 
Time-Driven Dosing 
Those randomized to the time-driven dosing group will be asked to take one 
FTC/TDF tablet twice weekly with or without food with a post-exposure boost.  
Specifically, they will receive recommendations to take one tablet two days per 
week, three to four days apart, regardless of sexual activity.  In addition, they will 
be instructed to take a post-exposure booster dose of one tablet within two hours 
after sexual intercourse, defined as any penile intromission, whether oral, vaginal, 
or anal, and whether or not condoms were used.  The post-exposure dose should 
be taken after the first penile insertive sex and not repeated if there are multiple 
penile intromissions in a day.  The post-exposure boost will also count as one of 
the twice-weekly doses if it occurs on the prescribed day. 
 
Event-Driven Dosing 
Those randomized to the event-driven dosing group will be asked to take one 
tablet of FTC/TDF with or without food, preferably between 24 to 48 hours prior 
to sexual intercourse and a second post-exposure booster dose within two hours of 
sexual intercourse, defined as any penile insertive sex, whether oral, vaginal, or 
anal, and whether or not condoms were used.  If the participant anticipates sexual 
intercourse, but did not take the dose 24 hours prior to the event, the participant 
should take the pre-exposure dose as soon as possible before the event.  The post-
exposure boost will also count as a pre-exposure dose for sex that occurs up to 48 
hours later. 
 
Note: For all arms, no more than two tablets per 24-hour period, or seven tablets 
per week should ever be taken.   
4.3 
Study Drug/Intervention Supply and Accountability 
Study Product Supply, Distribution and Accountability 
Emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg study 
product tablets are manufactured and provided by Gilead Sciences, Inc. under the 
trade name Truvada®. FTC/TDF tablets must be stored in the pharmacy in the 
original container. Each bottle contains a silica gel desiccant canister to protect 
the product from humidity. Store at 25°C. Excursions permitted between 15° to 
30°C. 
 
Study Product Acquisition 
Emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg study 
product will be supplied by the NIAID Clinical Research Products Management 
Center (CRPMC).  The study site pharmacist can obtain FTC/TDF study products 


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through the CRPMC by following the instructions in the Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trial Networks, and instructions in the SSP 
Manual. 
 
Study Product Accountability 
The site pharmacist must maintain complete records of all study products received 
from the NIAID Clinical Research Products Management Center (CRPMC) and 
subsequently dispensed to study participants.  All study products must be stored 
in the pharmacy.  At non- US sites all unused study products must be destroyed in 
accordance with the procedures outlined in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks and according to local 
procedures. For the US site any unused study products must be returned to the 
CRPMC in accordance with the procedures outlined in the manual Pharmacy 
Guidelines and Instructions for DAIDS Clinical Trials Networks.  
4.4 
Toxicity Management 
In general, the site investigator has the discretion to hold study drug at any time if 
she or he feels that continued study drug use would be harmful to the participant, 
or interfere with treatment deemed clinically necessary according to the judgment 
of the investigator.  Unless otherwise specified below, the investigator should 
immediately consult the PSRT for further guidance in restarting study drug or 
progressing to permanent discontinuation.   
4.4.1 Grading System 
The grading system is located in the Division of AIDS Table for Grading Severity 
of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, 
December 2004 (Clarification August 2009), which can be found on the 
Regulatory Support Center (RSC) Web site:  
http://rsc.tech-res.com/safetyandpharmacovigilance/. 
4.4.2 Discontinuation of Study Drug in the Presence of Toxicity 
Grades 1 or 2 
In general, participants who develop a Grade 1 or 2 AE regardless of relatedness to 
study drug, and that is not specifically addressed below, may continue use of the 
study drug per protocol.   
 
Grade 3 
Participants who develop a Grade 3 AE or toxicity that is not specifically 
addressed below and is judged to be related to study drug by the IoR/designee, 
study drug use should be temporarily discontinued in consultation with the PSRT.  
In general, and unless otherwise decided in consultation with the PSRT, the 
investigator should re-evaluate the participant at least weekly for up to 2 weeks 


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(or for 2 weeks following the receipt of the results for lab toxicities) to document 
resolution of toxicity to less than Grade 2.  The study drug should be permanently 
discontinued if improvement to severity ≤ Grade 2 cannot be documented within 
4 weeks of receipt of the initial result.  If study drug use is resumed and the same 
Grade 3 AE recurs at any time, the IoR/designee must consult the PSRT for 
further guidance on holding of study drug, frequency of reevaluation or 
progression to permanent discontinuation of the study drug. 
 
Grade 4 
Participants who develop a Grade 4 AE or toxicity that is not specifically 
addressed below (regardless of relationship to study drug) should have the study 
drug temporarily discontinued.  The IoR/designee must consult the PSRT and 
continue the temporary study drug hold until a recommendation is obtained from 
the PSRT.  In general, study drug use will not be resumed if the Grade 4 AE is 
considered related to study drug use.  If, in consultation with the PSRT, study 
drug use is resumed and the same Grade 4 AE recurs at Grade 4 level at any time, 
study drug must then be permanently discontinued. 
4.4.3 General Criteria for Discontinuation of Study Drug 
Participants may voluntarily discontinue the study drug for any reason at any 
time.  Site IoRs will permanently discontinue participants from study drug per 
protocol for any of the specific criteria below, which may be further clarified in 
the SSP Manual.  Site IoRs also may permanently discontinue participants for 
reasons not shown here or in the SSP Manual.  In such cases, the Site IoRs should 
first query the PSRT for review.  The PSRT will provide a written response to the 
site indicating their recommendation based on careful review of all relevant data. 
 
A participant will be permanently discontinued from drug use by the IoR/designee 
for any of the following reasons: 
 HIV-1 infection.  Such participants will not resume study drug use at any 
time.  Study drug will be held immediately upon recognition of the first 
reactive rapid HIV test or positive GenAptima HIV RNA assay.  The 
IoR/designee must permanently discontinue study drug if HIV infection is 
confirmed.  A decision to resume study drug in participants who are 
subsequently confirmed to be HIV-uninfected requires approval of the 
Protocol Chair, PSRT and HPTN NL. 
 Viral hepatitis.  Such participants will not resume study drug use at any time. 
 Pregnancy.  A participant who becomes pregnant must not resume study drug 
use.   
 Breastfeeding.  Study drug use may not resume for participants who report 
breastfeeding at any time after enrollment. 
 
Any participant who prematurely discontinues study drug should be followed 
according to the procedures in the Schedule of Evaluations in Appendix I, with the 


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exception of study drug dispensation, counseling, and adherence measurements.  
Weekly calls to determine sexual risk exposure should continue for all HIV 
seronegative participants.  
 
Study drug will be temporarily withheld from a participant for any of the following 
reasons: 
 Report of use of prohibited concomitant medications described in Section 4.8.  
Study drug use may resume when the participant reports that s/he is no longer 
taking the prohibited medication, provided other reasons for temporary study 
drug hold/permanent discontinuation do not apply. 
 The participant is unable or unwilling to comply with required study 
procedures, or otherwise might be put at undue risk to their safety and well-
being by continuing study drug use, according to the judgment of the 
IoR/designee.  The IoR/designee must consult the PSRT on all temporary study 
drug holds instituted for this reason for further guidance on resuming study drug 
use, continuing the temporary hold, or progressing to permanent 
discontinuation.  If study drug use is temporarily held/permanently discontinued 
for this reason, but the underlying reason for the temporary hold later resolves, 
the IoR/designee should consult the PSRT to resume study drug use at that time. 
 
Participants who temporarily or permanently discontinue study drug will be 
instructed to return all study drug as soon as possible. 
 
4.5 
Management of Specific Toxicities 
Specific guidance related to product hold is also noted here, as it pertains to the 
clinical management of toxicities. 
4.5.1 Nausea, Vomiting, and Diarrhea 
Participants with Grade 1 or 2 nausea, vomiting, or diarrhea may be treated 
symptomatically with hydration, oral antiemetic therapies or antiemetic 
suppositories at the discretion of the site investigator.  The site investigator should 
order any clinically relevant laboratory analyses (per judgment of the 
IoR/designee).   
 
Participants with Grade  3 nausea, vomiting, or diarrhea, for which an alternative 
etiology is not established, must discontinue the study drug temporarily until 
grade 2 or lower and be treated symptomatically.  Should condition(s) not 
improve to Grade <2 within 7 days, the IoR/designee should consult the PSRT for 
guidance on continuing the temporary discontinuation or progressing to 
permanent discontinuation of study drug.   
 


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Repeat episodes of these events will be handled independently, and the instruction 
above will be followed for each event. 
4.5.2 AST/ALT Elevations 
Careful assessments should be done to rule out the use of alcohol, lactic acidosis 
syndrome, non-study medication-related drug toxicity, herbal 
medications/supplements, or viral hepatitis as the cause of elevation in AST or 
ALT of any grade.  The participant must be carefully assessed for any symptoms 
or signs of hepatotoxicity, including fatigue, malaise, anorexia and nausea, 
jaundice, acholic stools, right upper quadrant pain, or hepatomegaly.  If the 
AST/ALT elevation is considered most likely to be due to concomitant illness or 
medication, standard management, including discontinuation of the likely 
causative agent, if possible, should be undertaken.  If symptoms or signs of 
clinical hepatitis are present, study drug must be held or discontinued (see below). 
 
Grade 1 
For study participants with less than Grade 1 AST and ALT at study entry, an 
increase to Grade 1 AST or ALT even in an asymptomatic participant may be of 
concern.   
 
AST and ALT must be repeated as soon as possible (at most within 1 week of the 
receipt of the results).  Study drug may be continued while repeating AST and 
ALT at the discretion of the investigator provided the participant is asymptomatic.  
Should the repeat AST and ALT testing indicate a continuation of Grade 1, the 
PSRT should be immediately consulted. 
 
In the case of symptomatic participants, study drug will be held temporarily, and 
management (including resumption of study drug) should be arranged in 
consultation with the PSRT. 
 
Grade 2 
Participants should have AST/ALT re-checked as soon as possible (at most within 
1 week of the receipt of the results) and then be followed weekly until levels are 
Grade < 1.  The frequency of follow up may be altered at the discretion of the site 
investigator following consultation with the PSRT.  Study drug may continue at 
the discretion of the investigator provided the participant is asymptomatic. 
 
In the case of symptomatic participants, study drug will be held temporarily, and 
management (including resumption of study drug) should be arranged in 
consultation with the PSRT. 


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Grade 3  
Study drug should be temporarily held for any Grade 3 AST or ALT.  Participants 
should have AST/ALT re-checked as soon as possible (at most within 1 week of 
the receipt of the results).  Participants should then be followed weekly until 
levels are Grade < 1.  Resumption of study drug should be arranged in 
consultation with the PSRT.  If improvement to Grade <1 cannot be documented 
within three weeks of receiving the Grade 3 results, study drug must be 
permanently discontinued. 
 
If following a Grade >3 event(s) the participant is permitted to resume study drug, 
but has an additional event (AST and/or ALT) at a Grade 3 level, the 
IoR/designee must temporarily hold the study drug, offer symptomatic treatment 
(if appropriate), and order any clinically relevant laboratory analyses (per 
judgment of the IoR/designee).  The PSRT should be consulted for further 
guidance on continuing the temporary hold, clinical management of the 
participants, or progressing to permanent discontinuation of the study drug. 
 
Grade 4  
Study drug should be permanently discontinued for any Grade 4 AST or ALT and 
the PSRT should be immediately notified.  Participants should have AST/ALT re-
checked as soon as possible (at most within 1 week of the receipt of the results).  
Participants should then be followed weekly until levels are Grade  1 unless 
indicated by the PSRT.   
 
Note for all Grades 
If the investigator has determined in consultation with the PSRT that the case has 
stabilized, it may be possible to decrease the frequency of follow-up laboratory 
testing in addition to resumption of study drug.   
4.5.3 Calculated Creatinine Clearance 
If the calculated creatinine clearance is <50mL/min, study drug should be 
temporarily held and it should be confirmed within 1 week of the receipt of the 
results, and the PSRT should be consulted.  If the calculated creatinine clearance is 
confirmed to be <50mL/min, the study drug must be permanently discontinued.  
Participants who fail to have a confirmed test within 7 days of receiving the initial 
result, should be permanently discontinued from use of the study drug.   
 
If re-testing yields a result >50mL/min, the IoR/designee must consult the PSRT 
for further guidance on resuming study drug use, continuing the hold temporarily, 
or progressing to permanent discontinuation. 


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By which the investigator in consultation with the PSRT has determined that the 
case has stabilized, it may be possible to decrease the frequency of follow-up 
laboratory testing in addition to resumption of study drug.   
4.5.4 Hypophosphatemia 
Grades 1 and 2 
The phosphate should be repeated within 2 weeks of the receipt of any initially 
abnormal results.  Supplemental phosphate should be given with phosphate-rich 
food or fluid with or without neutral phosphate solution.  Other causes of 
phosphate loss should be evaluated.  Unless other temporary study drug hold 
requirements apply, study drug need not be held. 
 
Grade 3  
The phosphate should be repeated within 1 week of receipt of any initially 
abnormal results, and should be accompanied by serum creatinine testing and urine 
dipstick for protein/glucose.  Supplemental phosphate should be given with 
phosphate-rich food or fluid with or without neutral phosphate solution, and other 
causes of low phosphate should be investigated.  Participants with any of the 
following results (of tests accompanying the repeat phosphate test) will have study 
drug held: 
 Proteinuria >3+ 
 Glycosuria >3+ 
 Creatinine >1.5 X ULN 
 Creatinine clearance <50 mL/min 
 
Participants may continue study drug provided that: 
 Study drug hold is not otherwise indicated (e.g., due to the results of creatinine, 
creatinine clearance, urine protein, and/or urine glucose) 
 Phosphate levels will be retested approximately weekly until return to <Grade 
2, unless other retesting schedule has been advised by the PSRT 
 
Grade 4 
The phosphate should be repeated within 1 week of the receipt of any initially 
abnormal results, and should be accompanied by serum creatinine testing and urine 
dipstick for protein/glucose.  Supplemental phosphate should be given with 
phosphate-rich food or fluid with or without neutral phosphate solution.  Other 
causes of low phosphate should be investigated. 
 


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Participants will have study drug held, and the PSRT must be immediately 
contacted.  Phosphate levels will be retested approximately weekly until return to 
<Grade 2, unless another retesting scheduled has been advised by the PSRT.  
Participants may resume study drug, provided that: 
 Study drug hold is not otherwise indicated (e.g., due to the results of serum 
creatinine, creatinine clearance, urine protein, and/or urine glucose) 
 The phosphate level has returned to <Grade 2 
 A request to resume study drug is approved by the PSRT 
 
PSRT notification should occur for any result >Grade 2 for protein or glucose 
measured by urine dipstick performed at the time of confirmatory draw for a 
phosphate level. 
4.5.5 Proteinuria 
Proteinuria will be assessed by urine dipstick.  A finding of 1+ proteinuria should 
be confirmed with a second urine dipstick performed no earlier than one week but 
no later than 2 weeks after detection of the first 1+ proteinuria.  Proteinuria of 2+ 
or greater does not need to be confirmed at a separate visit. 
 
The IoR/designee should temporarily hold study drug in the following 
circumstances: 
 Detection of 3+ or greater proteinuria at any visit.  Study drug should be held 
regardless of serum creatinine or phosphorus results obtained at the time of 
proteinuria detection.  Urine dipstick testing and serum creatinine and 
phosphate should then be performed monthly for at least three months. The 
PSRT should be consulted for permission to resume study product based on 
repeat urine dipstick testing. 
 
 Detection of 2+ proteinuria.  Study drug should be held until results of serum 
creatinine and phosphorus results obtained at the time of proteinuria detection 
are available.  Study drug hold should continue if hold criteria outlined for 
serum creatinine and/or phosphorus are met.  If neither value meets criteria for 
study product hold, study drug should be resumed. 
 
 Detection of 1+ proteinuria confirmed on two separate visits.  Study drug 
should be held only if serum creatinine or phosphorus results obtained at the 
time of detection of proteinuria meet hold criteria (Sections 4.5.3 and 4.5.4). 
 


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4.5.6 Glycosuria 
Glycosuria will be assessed by urine dipstick.  A finding of 1+ glycosuria should 
be confirmed with a second urine dipstick performed no earlier than one week but 
no later than 2 weeks after detection of the first 1+ glycosuria.  Glycosuria of 2+ or 
greater does not need to be confirmed at a separate visit.  Note:  The severity of 
glycosuria is graded using the same grading scale as for proteinuria. 
 
The IoR/designee should temporarily hold study drug in the following 
circumstances: 
 Detection of 3+ or greater glycosuria at any visit.  Study drug should be held 
regardless of serum creatinine or phosphorus results obtained at the time of 
glycosuria detection.  Urine dipstick testing and serum creatinine and 
phosphorus should then be performed monthly for at least three months. The 
PSRT should be consulted for permission to resume study product based on 
repeat urine dipstick testing. 
 
 Detection of 2+ glycosuria.  Study drug should be held until results of serum 
creatinine and phosphorus results obtained at the time of glycosuria detection 
are available.  Study drug hold should continue if hold criteria outlined for 
serum creatinine and/or phosphorus are met (Sections 4.5.3 and 4.5.4).  If 
neither of these values meets criteria for study drug hold, study drug should be 
resumed. 
 
 Detection of 1+ glycosuria confirmed on two separate visits.  Study drug 
should be held only if serum creatinine or phosphorus results obtained at the 
time of detection of glycosuria meet hold criteria. 
 
4.5.7 HIV Infection  
Frequent testing for HIV acquisition during the study period will allow prompt 
cessation of study drug in an HIV-infected participant, minimizing the risk that 
resistant virus will emerge.  Therefore, HIV testing will be performed at 
Screening, Enrollment, and Weeks 4, 6, 10, 14, 18, 22, 26, 30 and 34, and also (1) 
at any visit during which signs or symptoms of a viral syndrome are present, (2) at 
any visit where a participant expresses concerns about recent acquisition of HIV 
infection, or (3) at the discretion of the site investigator.  If a recent infection is 
suspected, a GenAptima HIV RNA test for acute HIV infection will be 
performed.  At the Screening and Enrollment visits, individuals will be deferred 
and referred for evaluation and care if they have any signs or symptoms consistent 
with acute (pre-seroconversion) HIV infection, or if they express a concern about 


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recent HIV infection.  Signs and symptoms consistent with acute HIV infection 
include fever (temperature > 38° C), pharyngitis, or a new rash.  Evaluation of 
possible acute HIV infection prior to enrollment will be performed outside of the 
study, according to local testing guidelines.  If an individual is confirmed to be 
HIV-uninfected after evaluation, they may resume the Screening and Enrollment 
process. 
 
Any enrolled participants who acquire HIV infection during the study will 
permanently discontinue study product and will be followed after Enrollment at 
Weeks 4, 6, 10, 14, 18, 22, 26, 30 and then every 12 weeks after Week 30 as 
appropriate until the last study participant completes follow-up at the study site.  
Participants whose first reactive HIV rapid test is at Week 34 who are later 
confirmed to be HIV infected will also be followed every 12 weeks after their 
Week 30 visit until the last study participant completes follow-up at the study site.  
Appendix 1B notes the additional laboratory tests to be completed at time of 
diagnosis and follow-up visits. All protocol procedures will be completed with the 
following exceptions:   
 Study drug supply and associated counseling 
 Weekly telephone or personal contact 
o Review of EDM and sexual intercourse events 
 HIV rapid testing, with confirmation if one or both HIV rapid tests is 
reactive 
 Behavioral Assessment (CASI) 
 Specimen collection related to drug tolerance (serum creatinine, serum 
phosphate, AST/ALT, protein and glucose) and/or adherence (lysed 
PMBCs, urine and hair for storage)  
 
HIV-infected participants will be followed to contribute information regarding 
HIV outcomes after PrEP exposure, to maintain confidentiality, and to comply 
with expectations of communities.  These participants will receive counseling and 
referrals for HIV treatment and care according to local guidelines.  Participants 
who test positive for HIV during the DOT phase will be replaced, but will be 
continued to be followed.   
4.6 
Clinical Management of Pregnancy 
Receipt of study medication by biologically female study participants requires use 
of an effective method of contraception, including an intrauterine device (IUD), 
hormonal contraception, or sterilization.  All participants should also use male or 
female condoms for prevention of HIV and other STIs.  As needed, study staff 
will provide contraceptive counseling to enrolled participants throughout the 
duration of study participation and will facilitate access to contraceptive services 
through direct service delivery and/or active referrals to local service providers.  


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Study staff also will provide participants with male and/or female condoms and 
counseling on use of condoms.   
 
Pregnancy testing will be performed at Screening, Enrollment and at Weeks 4, 6, 
10, 14, 18, 22, 26, and 30.  Participants will be encouraged to report all signs or 
symptoms of pregnancy to study staff.  Participants who are pregnant will stop 
study drug but will continue to be followed according to the schedule of visits.  
All protocol procedures will be completed with the following exceptions:   
 Study drug supply and associated counseling 
 Urine specimen for pregnancy testing for women with reproductive 
potential 
 Specimen collection related to drug tolerance (serum creatinine, serum 
phosphate, AST/ALT, protein and glucose) and/or adherence (lysed 
PMBCs, urine and hair for storage)  
 
Weekly interviews for participants who are on permanent product hold due to a 
positive pregnancy test may only cover sexual events.  
 
The site IoR or designee will counsel any participants who become pregnant 
regarding possible risks to the fetus according to site-specific SOPs.  Participants 
may not enroll if they are currently breastfeeding and study drug should be 
discontinued if any participant identifies that she is breastfeeding after enrollment.  
The IoR or designee also will refer the participant to all applicable services; 
however, sites will not be responsible for paying for pregnancy-related care.   
 
Participants who are pregnant at the Week 30 visit will continue to be followed 
until the pregnancy outcome is ascertained (or, in consultation with the PSRT, it 
is determined that the pregnancy outcome cannot be ascertained).  Pregnancy 
outcomes will be reported on relevant Case Report Forms (CRFs).  Outcomes 
meeting criteria for expedited adverse event reporting also will be reported. 
Participants who become pregnant during the DOT phase will be replaced, but 
will be continued to be followed.   
4.7 
Criteria for Early Termination of Study Participation 
Participants may voluntarily withdraw from the study for any reason at any time.  
Site IoR may, with the approval of the PSRT, withdraw participants before their 
scheduled termination visit to protect their safety.  Participants who withdraw 
prior to Randomization/Week 6 will not be randomized.  Participants also may be 
withdrawn if the study sponsors, government or regulatory authorities (including 
the OHRP or US FDA), or site IRBs/ECs terminate the study prior to its planned 
end date.  Site investigators are required to consult the Protocol Chair and 


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Protocol Biostatistician prior to the termination of any study participant.  Study 
staff will record the reason(s) for all withdrawals in participants’ study records. 
 
Any participant who wishes to discontinue study participation prematurely for any 
reason should undergo the evaluations regularly scheduled for Weeks 30 prior to 
discontinuation and dismissal from the study, provided that the participant is 
willing to do this.   
4.8 
Concomitant Medications 
With the exception of medications listed as prohibited (see below, this section), 
enrolled study participants may use concomitant medications during study 
participation.  All concomitant medications, including prescribed and over-the-
counter preparations, vitamins and nutritional supplements, recreational drugs, 
and herbal preparations reported within the 70 days prior to study enrollment and 
throughout the course of the study will be recorded on the Case Report Forms 
(CRF) designated for that purpose.  Medications used for the treatment of AEs 
that occur during study participation also will be recorded on applicable study 
case report forms. 
 
Should participants report use of any of the following medications, they will be 
required to discontinue use of study drug: interleukin therapy, medications with 
significant nephrotoxic potential (including but not limited to amphotericin B, 
aminoglycosides, cidofovir, foscarnet and systemic chemotherapy), and 
medications that may inhibit or compete for elimination via active renal tubular 
secretion (including but not limited to probenecid). In addition, if a participant 
requests post-exposure prophylaxis (PEP) for HIV exposure, they will be referred 
to a health care provider for evaluation. If a participant starts ARV therapy for 
PEP, they should hold study medications until completion of the course of PEP. 
 
5.0 
STUDY PROCEDURES 
An overview of the study visit and procedures schedule is presented in Appendix 
I.  Study visits will occur at Screening, Enrollment, at Weeks 1, 2, 3, 4 and 5 
during the DOT lead-in phase, at Week 6 (randomization), and at Weeks 10, 14, 
18, 22, 26, and 30 during the self-administered PrEP phase; a final visit will be 
conducted four weeks after completion of the dosing phase (at Week 34).   
Presented below is additional information on visit-specific study procedures.  
Detailed instructions to guide and standardize all study procedures across sites 
will be provided in the SSP Manual. 


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5.1 
Screening 
Screening procedures may occur over one or more visits.  All participants must 
provide written informed consent for screening before completing any other 
procedures.  Participants who fail screening for any reason may rescreen one 
additional time.   
 
The following procedures will occur as part of screening: 
 
Administrative, Behavioral, and Regulatory Procedures 
 Informed consent 
 Assign participant ID 
 Collection of locator information 
 Demographics information 
 Behavioral Assessment (Computer Assisted Self Interview [CASI]) 
 
Clinical/Counseling Procedures 
 Medical history (including concomitant medications) 
 HIV risk reduction counseling 
 
Laboratory Procedures 
 Urine specimen for pregnancy testing for women with reproductive 
potential 
 Urine dipstick for protein and glucose 
 Blood specimen for the following: 
o HIV rapid testing, with confirmatory testing if one or both tests is 
reactive 
o Complete blood count (CBC) 
o Serum creatinine (for estimated creatinine clearance)  
o Serum phosphate 
o AST/ALT 
o HepBsAg 
o HepBsAb and HepBCore Ab testing (if HepBsAg is negative) 
o Plasma for storage 
 
 
Participants who are susceptible to HBV infection will be offered HBV 
vaccination.   
 
Screening may be discontinued at any time if a participant is found to be 
ineligible.  HIV counseling and testing will be offered to everyone who consents 
to screening.  Sites will follow the HIV testing algorithm for screening included in 
the SSP Manual.  If a reactive result is obtained for one or both of the HIV rapid 
tests, the person is not eligible for the study.  Additional testing to confirm HIV 
infection will be performed in accordance with local guidelines.  If HIV infection 
is confirmed, participants will receive counseling and be referred for appropriate 
care.   


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If all laboratory tests and interview screening indicate that an individual is eligible 
for the study, s/he will be asked to return to the site to complete enrollment.  
Those who are not eligible will be informed that they do not meet the 
requirements of the study and, if necessary, will be referred for appropriate 
medical care.  There must be no more than 70 days between Screening and 
Enrollment. 
5.2 
Enrollment 
If all Inclusion/Exclusion Criteria are met, then the participant may enroll.  
Participants with one or more reactive HIV rapid test results will not be eligible 
for the study.  Final eligibility determination and enrollment must be completed 
within 70 days from the time of the first blood draw for the screening HIV test.  
The effective point of enrollment is the time of first directly observed weekly 
dosing.  The effective point of randomization is the assignment of study arm at 
the Week 6 visit.  Participants must be present at the study site for enrollment. 
 
The following procedures will occur as part of enrollment: 
 
Administrative, Behavioral, and Regulatory Procedures 
 Confirm locator information 
 Confirm eligibility 
 
Clinical/Counseling Procedures 
 Administer study drug (DOT)  
 HIV risk reduction counseling 
 Interim medical history including concomitant medications  
 Full physical examination including baseline symptoms and side effects 
assessment 
 Complete baseline family planning assessment for women and sex 
hormones assessment for men.   
 Complete vaginal practices assessment for women (including use of 
lubricants and vaginal cleansing practices) 
 Orientation to the EDM device 
 
Laboratory Procedures* 
 Urine specimen for pregnancy testing for women with reproductive 
potential 
 Blood specimen for the following: 
 
o HIV rapid testing, with confirmatory testing if one or both tests is 
reactive.  Note: if one or both HIV rapid tests are reactive, the 
participant is ineligible to enroll in this study (should not receive study 
drug).   
o Plasma for storage 
 


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*All HIV rapid testing and specimen collection should be completed prior to 
administration of study medication. 
5.3 
Weeks 1-5 
A period of DOT will be used to estimate steady-state drug levels and 
accumulation and decay constants for each individual.  During the DOT phase, all 
participants will begin the study by having weekly visits from Enrollment through 
Week 5.  At Enrollment through Week 4, participants will receive one directly 
observed dose per week of oral FTC/TDF (five doses total).  No drug will be 
administered during Week 5.     
 
The following procedures will occur during Weeks 1 through 5: 
 
Administrative, Behavioral, and Regulatory Procedures 
 Confirm locator information 
 Social Harms Assessment 
 
Clinical/Counseling Procedures 
 HIV risk reduction counseling (Week 4 only) 
 Administer study drug (DOT) at Weeks 1 through 4 
 Interim medical history including concomitant medications 
 AE Assessment 
 Complete follow-up family planning assessment for women and sex 
hormones assessment for men (Week 4 only) 
 
Laboratory Procedures* 
 Specimens collected at Week 4 only (not collected at Weeks 1, 2, 3, or 5): 
o Urine specimen for pregnancy testing for women with reproductive 
potential 
o Blood specimen for the following: 
 HIV rapid testing, with confirmatory testing if one or both tests 
is reactive 
 DBS for storage for host genetic testing** 
 AST/ALT 
 Serum Creatinine (for estimated creatinine clearance) 
 
 Specimens collected at Weeks 4 and 5 only (not collected at Weeks 1, 2, 
or 3): 
o Blood draw for the following: 
 Plasma for storage 
 Lysed PBMCs for storage 
 DBS for storage for drug levels (Harlem Only) 
o 
Hair for storage 
o 
Urine for storage 
No medication administered at Week 5. 
 


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*All HIV rapid testing and specimen collection should be completed prior to 
redosing of study medication. 
**DBS are stored for genetic testing related to drug metabolism and/or HIV 
infection, provided that the participant provided consent for this testing.  Consent 
for genetic testing is optional and will not affect study participation.  See Section 
9.5 for more details.  
5.4 
Week 6/Randomization 
After the 6-week lead-in period including DOT, participants will be randomly 
assigned to one of three unblinded PrEP usage groups:  (1) daily usage, (2) time-
driven usage, and (3) event-driven usage.  Participants will receive counseling 
optimized for each usage plan.  Participants must be present at the study site for 
randomization.   
 
The following procedures will occur during Week 6: 
 
Administrative, Behavioral, and Regulatory Procedures 
 Confirm locator information 
 Randomization  
 Social harms assessment 
 Behavioral Assessment (CASI) 
 
Clinical/Counseling Procedures 
 Adherence orientation 
 HIV risk reduction counseling 
 AE assessment 
 Study drug supply and associated counseling 
 Symptom driven physical examination including symptoms and side 
effects assessment 
 Complete follow-up family planning assessment for women 
 Interim medical history including concomitant medications 
 
Laboratory Procedures* 
 Urine specimen for pregnancy testing for women with reproductive 
potential 
 Blood specimen for the following: 
o HIV rapid testing, with confirmation if one or both HIV rapid tests is 
reactive 
o Plasma for storage 
o Lysed PBMCs for storage 
o DBS for storage for drug levels (Harlem Only) 
 Hair for storage 
 Urine for storage 
 Urine dipstick for protein and glucose 
 


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*All rapid testing and specimen collection should be completed prior to redosing 
of study medication. 
5.5 
Weeks 7 through 29 
The following procedures will occur during Weeks 7 through 29 (Visits 
conducted at Weeks 10, 14, 18, 22, and 26): 
 
Administrative, Behavioral, and Regulatory Procedures 
 Weekly telephone or personal contact 
o Review of EDM and sexual intercourse events 
 Confirm locator information 
 Social Harms Assessment 
 
The following additional procedures will occur at Week 18: 
 Behavioral Assessment (CASI) 
 
Clinical/Counseling Procedures 
 HIV risk reduction counseling 
 AE assessment 
 Study drug supply, pill counts and associated counseling 
 Symptom driven physical examination including symptoms and side 
effects assessment 
 Complete follow-up family planning assessment for women 
 Interim medical history including concomitant medications 
 
Laboratory Procedures* 
All Visits: 
 Urine specimen for pregnancy testing for women with reproductive 
potential 
 Blood specimen for the following: 
o HIV rapid testing, with confirmation if one or both tests is reactive 
o Plasma for storage 
Weeks 10 and 18 only: 
 Blood specimen for the following: 
o CBC  
o Serum creatinine (for estimated creatinine clearance) 
o Serum phosphate  
o AST/ALT 
o Lysed PBMCs for storage 
o DBS for storage for drug levels (Harlem Only) 
 Hair for storage 
 Urine for storage 
 Urine dipstick for protein and glucose 
 


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*All HIV rapid testing and specimen collection should be completed prior to 
redosing of study medication. 
5.6 
Week 30 
The following procedures will occur during Week 30: 
 
Administrative, Behavioral, and Regulatory Procedures 
 Confirm locator information 
 Social harms assessment 
 Behavioral Assessment (CASI)  
 
Clinical/Counseling Procedures 
 HIV risk reduction counseling 
 AE assessment 
 Return of EDM device and pill count 
 Symptom driven physical examination including symptoms and side 
effects assessment 
 Complete follow-up family planning assessment for women and sex 
hormones assessment for men. 
 Complete vaginal practices assessment for women (including use of 
lubricants and vaginal cleansing practices)Interim medical history 
including concomitant medications 
 
Laboratory Procedures* 
 Urine specimen for pregnancy testing for women with reproductive 
potential 
 Blood specimen for the following: 
o HIV rapid testing, with confirmation if one or both tests is reactive 
o CBC 
o Serum creatinine (for estimated creatinine clearance) 
o Serum phosphate 
o AST/ALT 
o Plasma for storage 
o Lysed PBMCs for storage 
o DBS for storage for drug levels (Harlem Only) 
 Hair for storage 
 Urine for storage 
 Urine dipstick for protein and glucose 
 
5.7 
Week 34 
The following procedures will occur during or after Week 34 (post study follow-
up visit): 
 


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Administrative, Behavioral, and Regulatory Procedures 
 Social harms assessment 
 Focus groups and key informant interviews with selected study 
participants and site staff are to be conducted after Week 34 *  
 
Clinical/Counseling Procedures 
 HIV risk reduction counseling 
 AE assessment 
 
Laboratory Procedures 
 HIV rapid testing, with confirmation if one or both tests is reactive 
o Plasma for storage if one or both HIV rapid tests is reactive 
 Urine dipstick for protein and glucose 
 
*Note:  The focus groups and key informant interviews with selected participants and site 
staff may be done at any time within a 3 month window after Week 34. 
5.8 
Participants who have suspected or documented HIV infection during the 
study 
The FDA-cleared Amplified Probe by Transcription Mediated Amplification 
(APTIMA) HIV-1 RNA Qualitative Assay (Gen-Probe, Inc, referred to as the 
GenAptima HIV RNA test) may be used to confirm HIV infection in enrolled 
participants who have one or more reactive HIV rapid tests.  This assay will also 
be used at follow-up visits to resolve the HIV infection status of participants 
whose HIV status is not clear (e.g., newly reactive HIV rapid test(s) with a 
negative or indeterminate Western blot) and to confirm or rule out acute HIV 
infection in participants who have signs or symptoms of acute HIV infection or 
express a concern that they might be newly HIV-infected.  Rapid diagnosis of 
HIV infection in participants who become HIV-infected during the study will 
allow prompt cessation of study drug (to minimize the risk of resistance) and 
appropriate counseling. 
 
If any enrolled participant has one or more reactive HIV rapid tests or a positive 
GenAptima HIV RNA test, study drug must be discontinued immediately and the 
Site IoR  and the HPTN NL must be notified.  If HIV infection is subsequently 
confirmed, the site should notify the Protocol Safety Review Team (PSRT). A 
decision to resume study drug in participants who are subsequently confirmed to 
be HIV-uninfected requires approval of the Protocol Chair, PSRT and HPTN NL. 
 
Any participant who is found to have confirmed HIV infection after Enrollment 
will be followed at all scheduled visits and also every 12 weeks after the Week 30 
visit, until the last participant at that study sites completes his or her final study 
visit.  HIV-infected participants will be followed to contribute information 
regarding HIV outcomes after PrEP exposure (including viral set point), to 
maintain confidentiality, and to comply with expectations of communities.  See 


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Section 4.5.7 for more details. Participants with confirmed HIV infection will be 
referred for HIV counseling and treatment as appropriate. 
5.9 
Participants Who Become Pregnant 
All protocol-specified study procedures will continue with the exception of 
administration of study product, instructions for study product use, and adherence 
counseling. See Section 4.6 for more details.  
5.10 
Behavioral Data Collection 
There are five primary methods used in data collection for pill-taking, risk 
behavior, core and sub-construct areas, and perceptions of acceptability; (1) EDM 
data indicating the dates/times that the EDM case was opened (adjusted by self-
report data as described below), (2) weekly incentivized telephone-based brief 
interviews to record risk events, (3) CASI collected self-report measures, (4) 
qualitative focus group and key informant interviews with study participants and 
clinic staff who directly interact with participants regarding their pill-taking and 
sexual risk behavior; and (5) data collected on CRFs during regular visits.   
5.10.1 Quantitative Behavioral Component 
 
5.10.1.1 
Coverage and Sexual Behavior  
The primary measure of pill-taking will be based on the adjusted EDM data.  The 
EDM data is transmitted electronically to a database system and this data is used 
by interviewers to improve the accuracy of self-reported pill-taking via brief 
weekly interviews, as in Section 2.4.2.  Further, several steps will be taken to 
reinforce participant use of the EDM case.  At Enrollment, all participants will be 
instructed to use the EDM case for each pill-taking event, provided with an 
explanation of why the EDM case is needed to achieve the scientific aims of the 
study, and trained on its use.  Staff will also explore any difficulties with EDM 
case use.  Finally, to minimize curiosity openings during the study, clinic staff 
will work to familiarize the participant with the EDM device, and will provide the 
participant with an EDM device and a one month supply of multivitamin pills 
during the DOT phase.   
 
Because the timing of sexual events is critical to establishing coverage in the 
intermittent arms, sexual behavior will be assessed during weekly interviews to 
minimize difficulties with recall.  During weekly telephone interviews, the 
interviewer will also ask the participant if a sex event occurred during this time 
period and the day(s) of the event(s) will be recorded.  For each event-day, the 
general start time of the event/session/or round, event type(s), and number of 
partners involved, as well as if condoms were used during all insertions for that 
round/session, will be collected.  This will be repeated until all days/events are 
characterized.  Interviewers will be staff or contractors otherwise unknown to the 
participant, and trained in neutral assessment and timeline follow-back techniques 


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to facilitate brevity and minimization of social-desirability (or self-presentation) 
bias.  In the event that a participant is not contacted for a given assessment week, 
additional attempts will be made to contact the participant with the timeframe 
adjusted to reflect the entire interval since the last contact.  Where no contact has 
been made and the participant comes to a monthly clinic visit, the telephone based 
interview data will be replaced with an in-person interview from a trained staff 
member.  Alternative data collection method will be noted in the participant’s 
data.   
 
In addition to the weekly interview risk-data collected, a more general risk 
assessment will be included as a brief measure in the CASI assessments including 
safer sexual practices such as serosorting, sexual positioning, etc..  While it is 
improbable that participants will be able to recall the timing of events occurring 
during this longer time period, the assessment of risk behavior occurring over the 
last one to three months is not uncommon.69-73  These CASI delivered items will 
be constructed with sensitivity to keeping the full CASI assessment no more than 
30 minutes in full. 
 
Participants will complete CASI based surveys at Screening, and at Weeks 6, 18, 
and 30.  CASI instruments have been selected to represent the core constructs of 
the adapted IMB-model, and the context variables identified in the present 
research.  Measures for inclusion in a particular CASI assessment are varied to 
manage participant burden so not all measures will be repeated at every 
assessment.  Some measures will need to be developed or refined to be culturally 
appropriate for the targeted groups of participants although all measures have 
versions that have been used in some manner in previous research within different 
communities.  All questionnaires will be administered via CASI in the local 
language at the study site. 
 
If a participant needs assistance with CASI, a study staff member will help him or 
her and this help will be noted in the CASI data.  The administration of 
questionnaires will take approximately thirty minutes.  Non-literate participants 
will not be eligible for this study.   
5.10.2 Qualitative Behavioral Component 
 
5.10.2.1 
Focus groups and key informant interviews 
We will explore differences between arms in the acceptability of different PrEP 
regimens using qualitative research methods, including focus groups and key 
informant interviews.  Two focus groups will be performed per study arm at each 
site.  Each focus group will include approximately 6-8 study participants per 
study arm group per site per focus group. These groups will include 
approximately 108-144 participants total.  Two key informant interviews will be 
performed per study arm per site with selected study participants identified by 
study staff for a total of 18 participant key informants.  In addition, a total of 9-12 
key informant (site staff who interacted directly with participants during the 


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study) interviews will be conducted of 3-4 staff members per site.  Key informant 
interviews will be conducted after the on-drug period (after Week 34).  
Participants who discontinue study drug early for reasons not related to AEs or 
symptoms/side effects will be specifically targeted for the focus groups and key 
informant interviews, as their participation will provide information on why some 
high-risk individuals who have access to PrEP elect not to use it.  Focus groups 
and key informant interview are each anticipated to last approximately 2 hours.   
 
Focus groups: For participant focus groups, participants will be recruited from 
clinic through advertisement of the focus groups approximately 6 weeks prior to 
conducting the groups; participants not attending the clinic during this enrollment 
period will be contacted to be made aware of these groups.  Convenience 
sampling will be used, where interested participants are enrolled until each focus 
group is “filled”.  Enrollment ends when all groups are filled.  Note that results of 
focus groups will be interpreted and presented with this limitation in mind.  
Adequate reminders will be used to ensure participants attend the event at the 
appropriate date and time.  Focus group participants will be encouraged to select a 
pseudonym or nickname to protect their confidentiality within the group.  Focus 
groups will be held in a private space in the clinic or off-site in a space where 
responses cannot be overheard by clinic attendees or staff.  Focus groups will be 
conducted by staff not directly involved with participants in the study during the 
course of the trial. All focus groups will be administered, recorded and transcribed 
in the native language of the site.  Analysis will be completed at each site and 
then transcripts will be translated.  General themes will be identified across sites.  
Recordings and transcripts will be maintained in a secure location and destroyed 
after analysis according to DAIDS guidelines for data retention.   
 
A focus group guide will be developed that has queries posed to each group 
regarding;  
 their perceptions of feasibility, acceptability and ease of uptake for their 
assigned regimen  
 if they altered the regimen to better ‘fit’ their daily life or risk behavior  
 whether they would switch to a different regimen if available  
 what the ideal regimen would be 
 common barriers and facilitators to following their regimen 
 whether important others knew the participant was enrolled in the study  
 feelings towards the project, project-staff, and how pill-taking and 
condom use was supported  
 perceptions of the support provided for pill-taking and for condom use, 
how they would change it, and what frequency or type of support would 
be most acceptable to them if they were taking PrEP outside of the 
context of research.  
 
Additionally, to further guide theory and intervention development, self-perceived 
attributes defining “PrEP participant”, “consistent PrEP user” and “consistent 
condom user” will be qualitatively explored.  Discussion from focus groups will 


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be transcribed and coding will be approached with a two-phase analytic method 
(fully detailed in Section 7.5.6), including both theory-grounded and content 
analyses.  Rigorous qualitative methods will be used to identify the emerging 
themes, primarily surrounding pill-taking and condom use in the context of PrEP.  
Coding will focus on the adapted IMB model of pill-taking and condom use 
through focused identification of content within the core determinants of the IMB 
model and content related to barriers and facilitators of each behavior that cannot 
be coded with the model constructs.  Data gathered from focus groups are 
intended to supplement and inform the quantitative results obtained regarding 
perceptions of dosing schedule, feelings about group assignment, perceptions of 
HIV risk, disclosure of study participation and pill-use to sexual partner(s), 
housemates and family, relationships with study staff, perceptions of social role, 
and factors influencing use of pills.  Data collected through qualitative focus 
groups may be combined with qualitative data collected in sub-studies targeting 
ADAPT participants and their experiences on-study if appropriate. 
 
Key informant interviews: Direct-care clinic staff will have had extended 
cumulative interactions with participants in each of the study arms by the close of 
the on-drug phase.  Therefore, each of these staff is considered to be a key 
informant with valuable knowledge of and experience with each of the regimens 
and how participants interacted with the study and the regimen demands.  
Selected study participants, such as those who crossed over study arms, 
discontinued study drug, or withdrew from the study, will also be considered key-
informants.  Semi-structured interview guides will be developed that query 
interviewees along similar themes listed above.  Because of the structured nature 
of these interviews, content analysis will be the primary analytic strategy focused 
on coding main content of responses to queries.  Data will supplement participant-
based responses to quantitatively and qualitatively assess acceptability and 
feasibility and to refine the adapted model developed for the present research.  
Key informant interviews for participants will be completed by staff not directly 
involved in the study.  Key informant interviews with staff will be completed by 
clinic staff who do not function in a supervisory role for the interviewee.  All key 
informant interviews will be held in a private space in the clinic or off-site in a 
space where responses cannot be overheard by clinic attendees or staff.  Data 
collected through qualitative interviews may be combined with qualitative data 
collected in sub-studies targeting ADAPT participants and their experiences on-
study if appropriate. 


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6.0 
SAFETY MONITORING AND ADVERSE EVENT REPORTING 
6.1 
Safety Monitoring  
Close cooperation between the Protocol Chair(s), study site Investigator(s), 
NIAID Medical/Program Officer, CORE Protocol Coordinator, SDMC 
Biostatistician, HPTN NL, and other study team members will be necessary in 
order to monitor participant safety and to respond to occurrences of toxicity in a 
timely manner.  The team will have regularly scheduled conference calls during 
the period of study implementation, and additional ad hoc calls will be convened 
if required. 
 
The study site Investigators are responsible for continuous close monitoring of all 
AEs that occur among study participants after enrollment, and for alerting the 
PSRT if unexpected concerns arise.   
 
A sub-group of the Protocol Team, including the Protocol Chair, DAIDS Medical 
Officer, one or more site clinicians, and the SDMC Clinical Affairs Safety 
Associate will serve as the PSRT to be chaired by the Protocol Chair.  The HPTN 
SDMC will prepare routine safety data reports for review by the PSRT, which 
will meet via conference call approximately once per month or as needed 
throughout the period of study implementation to review safety data, discuss 
product use management and address any potential safety concerns.  The content, 
format and frequency of safety data reports will be agreed upon by the PSRT and 
the SDMC in advance of study implementation. 
6.2 
Clinical Data Safety Review 
A multi-tiered safety review process will be followed for the duration of this 
study.  The study site investigators are responsible for the initial evaluation and 
reporting of safety information at the participant level, and for alerting the PSRT 
if unexpected concerns arise.  Participant safety is also monitored at the Network 
level through a series of routine reviews organized and led by the SDMC Clinical 
Affairs staff (Study Monitoring Committee (SMC) reviews), the PSRT and study 
sponsors.  In addition, the study will be overseen by and periodically reviewed by 
a NIAID Data and Safety Monitoring Board (DSMB). Additional reviews may be 
conducted at each of these levels as dictated by the occurrence of certain events.   
 
HPTN SDMC Clinical Affairs staff will review incoming safety data on an 
ongoing basis.  Events identified as questionable, inconsistent, or unexplained 
will be queried for verification.  AE reports submitted in an expedited manner to 


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the DAIDS Safety Office will be forwarded to the DAIDS Medical Officer for 
review. 
 
The PSRT will meet regularly via conference call to review clinical data reports 
generated by the HPTN SDMC.  The content, format and frequency of the clinical 
data reports will be agreed upon by the PSRT and the SDMC in advance of study 
implementation.  In addition to the routine safety data reviews, the PSRT will 
convene on an ad hoc basis to make decisions regarding the handling of any 
significant safety concerns.  If necessary, experts external to the HPTN 
representing expertise in the fields of ART, biostatistics, HIV transmission and 
medical ethics may be invited to join the PSRT safety review.  A recommendation 
to stop the trial may be made by the PSRT at any such time that the team agrees 
that an unacceptable type and/or frequency of AEs has been observed. 
 
Recommendations regarding permanent discontinuation of study product may 
involve sponsor consultation with the U.S. FDA. 
 
In the unlikely event that the protocol team or PSRT has serious safety concerns 
that lead to a decision to permanently discontinue the study product for all 
participants and stop accrual into the study, the protocol team or PSRT will 
request a review of the data by the HPTN SMC before recommending that the 
study be stopped.  If at any time, a decision is made to discontinue the study 
product in all participants, DAIDS will notify the U.S. FDA and the site 
Investigators of Record will notify the responsible IRBs/ECs expeditiously. 
6.3 
Adverse Event definition and reporting to DAIDS  
Requirements, definitions and methods for expedited reporting of AEs are 
outlined in Version 2.0 of the DAIDS Expedited Adverse Events (EAE) Manual, 
which is available on the Regulatory Support Center (RSC) website at  
http://rsc.tech-res.com/safetyandpharmacovigilance/.  This information is also 
available in Section 14.4 of the HPTN Manual of Operations at 
http://www.hptn.org/network_information/policy_procedure/HPTNMOP2010.ht
m. 
6.3.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical research 
participant who has been administered an investigational product and which does 
not necessarily have a causal relationship with the investigational product.  As 
such, an AE can be an unfavorable or unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with 
the use of an investigational product, whether or not considered related to the 


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product.  The term “investigational product” for this study refers to the oral 
medication Truvada® (emtricitabine/ tenofovir disoproxil fumarate). 
 
Study participants will be provided instructions for contacting the study site to 
report any untoward medical occurrences they may experience, except for 
possible life-threatening events, for which they will be instructed to seek 
immediate emergency care.  Where feasible and medically appropriate, 
participants will be encouraged to seek evaluation where a study clinician is 
based, and to request that the clinician be contacted upon their arrival.  With 
appropriate permission of the participant, whenever possible, records from all 
non-study medical providers related to untoward medical occurrences will be 
obtained, and required data elements will be recorded on study CRFs.  All 
participants reporting an untoward medical occurrence will be followed clinically 
until the occurrence resolves (returns to baseline) or stabilizes. 
 
Study site staff will document in source documents and the appropriate AE Log 
CRF all AEs reported by or observed in enrolled study participants regardless of 
severity and presumed relationship to study product.  AE severity will be graded 
per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 
1.0, December 2004 (Clarification dated August 2009). 
6.3.2 Serious Adverse Events  
Serious AEs (SAEs) will be defined per International Conference on 
Harmonisation (ICH) guidance, as specified in Version 2.0 of the Manual for 
Expedited Adverse Events to DAIDS, dated January 2010.   
6.3.2.1 AE Reporting to DAIDS 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study.    
 
According to the SAEs reporting category in the manual, all SAEs occurring 
during the study reporting period (defined below) will be reported to the DAIDS 
RSC Safety Office in an expedited manner, within three reporting days of site 
awareness of the events (see definition in Appendix D of the manual).   
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS.  In the 
event of system outages or technical difficulties, expedited AEs may be submitted 
via the DAIDS EAE Form.  For questions about DAERS, please contact DAIDS-
ES at DAIDS-ESSupport@niaid.nih.gov.  Site queries may also be sent from 
within the DAERS application itself. 
 
 
The study agent for which expedited reporting is required is Truvada® 
(emtricitabine/ tenofovir disoproxil fumarate).  For each trial participant, the AE 
reporting period begins at Enrollment and ends when the participant completes 
the Week 34 or exit Visit.  If the study is still enrolling or in follow-up when a 


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participant has completed their Week 34 or exit visit, any EAEs that study staff 
become aware of on a passive basis should be reported to DAIDS in an expedited 
manner.  
 
After study closure, only suspected, unexpected, serious adverse drug reactions 
(SUSARs; defined in Version 2.0 of the DAIDS EAE Manual) that study staff 
become aware of on a passive basis will be reported to DAIDS in an expedited 
manner. 
6.3.2.2 Grading severity of adverse events 
The severity of all AEs will be graded according to the current Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
1.0, dated December 2004 (with Clarification dated August 2009), which is 
available on the RSC website at  
http://rsc.tech-res.com/safetyandpharmacovigilance/.      
6.3.3 Adverse Event Relationship to Study Product  
Relatedness is an assessment made by a study clinician of whether or not the 
event is related to the study agent.  The relationship of all AEs to study product 
will be assessed as specified in Version 2.0 of the DAIDS EAE Reporting 
Manual.   
6.4 
Pregnancy Outcomes  
Pregnancy outcomes will be collected for all applicable study participants.  After 
the participant’s final study contact, any pregnancy outcomes that meet criteria for 
SAE reporting (e.g., congenital anomalies) occurring among participants will 
continue to be expeditiously reported. 
6.5 
Regulatory Requirements  
Information on all reported AEs will be recorded on CRFs and included in reports 
to the FDA and other applicable government and regulatory authorities.  The site 
IoR/designee will submit AE information in accordance with local regulatory 
agencies’ or other local authorities’ requirements.  The site IoR/designee also will 
submit AE information and any other relevant safety information to the 
IRB/Ethics Committee (EC) in accordance with IRB/EC requirements. 
6.6 
Social Harms Reporting 
Although study sites will make every effort to protect participant privacy and 
confidentiality, it is possible that participants' involvement in the study could 
become known to others, and that social harms may result (i.e., because 
participants could be perceived as being HIV-infected or at "high risk" for HIV 
infection).  For example, participants could be treated unfairly, or could have 
problems being accepted by their families and/or communities.  Social harms that 
are judged by the IoR/designee to be serious or unexpected will be reported to the 


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responsible site’s IRBs/ECs at least annually, or according to their individual 
requirements.  Social harms will be collected and reported on CRFs during 
regular visits.  In the event that a participant reports social harm, every effort will 
be made by study staff to provide appropriate care and counseling to the 
participant, and/or referral to appropriate resources for the safety of the 
participant.  Each site will provide such care and counseling in accordance with 
standardized guidance in the SSP Manual.  While maintaining participant 
confidentiality, study sites may engage their Community Advisory Boards in 
exploring the social context surrounding instances of social harm, to minimize the 
potential occurrence of such harm. 
 
7.0 
STATISTICAL CONSIDERATIONS 
7.1 
Review of Study Design 
This is a Phase II randomized open-label clinical trial of oral Truvada® 
(FTC/TDF) PrEP among HIV-uninfected MSM/TGW and WSM at high risk for 
acquiring HIV infection.   
 
The study will randomize 540 people, 180 MSMTGW at the TUC Silom 
Community Clinic in Bangkok, Thailand, 180 MSM/TGW at the Harlem 
Prevention Center in New York, USA and 180 WSM at Emavundleni Centre, The 
Desmond Tutu HIV Foundation in Cape Town, South Africa.  The study includes 
a lead-in period of 6 weeks including DOT to determine individual steady state 
PK, and a 24-week self-administered PrEP phase to assess adherence, sexual 
behaviors, tolerance, and acceptability.  At Week 6, participants will be 
randomized and assigned to one of three dosage groups in a 1:1:1 ratio: daily 
dosing, time-driven dosing, and event-driven dosing.  During the self-
administered PrEP phase, all participants will engage in PrEP adherence 
counseling during all study visits and once per week telephone contacts will be 
used to query each participant regarding sexual exposure and pill-use.  If a 
participant cannot be reached for a given week or weeks of telephone-based 
assessment, an interview based timeline follow-back approach administered at the 
next clinic visit will be used to complete missing information and will be denoted 
as having been collected via this alternative method.  Focus groups (selected 
participants) and key informant interviews (selected participants and clinic staff) 
will occur within three months after Week 34.   
7.2 
Study Endpoints 
7.2.1 Primary Endpoints 
Consistent with the primary study objective to test the hypothesis that 
recommending intermittent (non-daily) use of oral FTC/TDF chemoprophylaxis, 
compared with recommending daily usage, will be associated with:  
 


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o Equivalent coverage of sex events with pre- and post-exposure dosing   
o Lower number of pills needed for coverage and fewer pills used  
o Decreased self-reported symptoms/side effects (both severity and 
frequency) during 24 weeks of self-administered use, the following 
endpoint(s) will be assessed: 
 The proportion of sexual exposures covered by pre- and post-exposure dosing.  
Coverage will be determined based on the adjusted electronic and self-
reported pill-use data.  Specifically, a sex act will be considered “covered” if 
the following two conditions are met: 
i. At least one pill is taken during the 4 days (96 hours) before the act or 
prior to the act on the day of the act (e.g., if a sex act occurs on Friday, 
that act would be covered if a pill was taken on Monday, Tuesday, 
Wednesday, Thursday, or Friday prior to the act) and: 
ii. At least one additional pill is taken within 24 hours after the act (e.g., if a 
sex act occurs on Friday at 11 pm, that act would be covered if the second 
pill was taken between Friday 11 pm and Saturday 11 pm). 
Note that the same pill can cover a pre-exposure dose and a post-exposure 
dose if events are closely spaced.  At no time should a participant in the 
intermittent arm be taking more pills than the daily arm.   
 The (minimum) total number of pills needed for 100% coverage over the 
follow-up period (based on randomization arm and self-reported sexual 
history in the weekly interviews) (after Week 6 up until about the Week 30 
visit).   
 The total pills actually used over the follow-up period, based on the adjusted 
electronic and self-reported pill-use data (after Week 6 through Week 30)  
 The self-reported symptom/side effect scores (to be developed) for common 
symptoms/side effects including headache, dizziness, cramping, abdominal 
pain, and flatulence.  Collected during clinic visits.   
7.2.2 Secondary Endpoints 
Consistent with the secondary study objective to develop objective measures of 
drug exposure among PrEP users by obtaining pre-dose “trough” drug 
concentration in several biological matrices for participants enrolled during a 
lead-in period of weekly DOT, the following endpoint(s) will be assessed: 
 
 Measurement of TFV-DP in PBMCs.  Samples will also be collected and 
stored for possible future substudies comparing the level of TFV-DP in 
PBMCs to the levels of extracellular TFV in plasma, of intracellular analytes 
in whole blood (Harlem only), and of TFV- in hair.  FTC and its 
phosphorylated derivative, FTC-TP, may also be measured. 
 


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Consistent with the secondary objective to describe safety outcomes among PrEP 
users, including AEs among all participants and drug resistance, and plasma HIV 
RNA levels among participants who seroconvert, the following will be provided: 
 
 A listing of all AEs (see Sections 6.3.1 and 6.3.2) by grade, relationship to 
study product, and arm 
 A listing, by arm, of drug resistance test results and plasma HIV RNA levels 
among all participants who seroconvert while on study 
 
Consistent with the secondary study objective to assess the acceptability of 
different PrEP regimens and perceptions of advantages and disadvantages of 
different regimens, the following endpoint(s) will be assessed: 
 The proportion of participants in each of the study arms who self-report 
acceptability of assigned study arm collected on CASI assessment   
 Perceptions of advantages and disadvantages of different regimens as reported 
by participants and clinic personnel in focus groups and key informant 
interviews 
Consistent with the secondary study objective to assess differences by arm in 
adherence, PrEP use, and related information, motivation and behavioral skills, 
the following endpoints will be assessed:  
 The percentage adherence (number of pills taken/number of pills 
recommended based on regimen) and percentage of correctly timed adherence 
(number of pills taken within the recommended timeframe/number of pills 
recommended for intermittent arms) during 24 weeks of follow-up based on 
weekly interviews and adjusted EDM data 
 The percentage adherence (number of pills taken/number of pills 
recommended based on regimen) during 24 weeks of follow-up based on pill 
counts 
 The proportion of participants who discontinue all PrEP use based on self-
report via CASI or weekly interviews 
 Information related to PrEP use, motivation, and behavioral skills based on 
self-report via CASI 
Consistent with the secondary study objective to evaluate the potential influence 
of PrEP usage on changes in sexual behavior, planning for sex, prediction of risky 
situations, and recognition of possible HIV exposure in relation to PrEP optimism, 
and other demographic variables, the following endpoints will be assessed: 
 The frequency of unprotected sex acts via CASI  
 Planning for sex assessed via CASI 
 Safer sex planning survey assessed via CASI 
 Perceived vulnerability assessed via CASI 
 PrEP optimism assessed via CASI 


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 Demographic measures assessed at enrollment 
 7.3 
Accrual, Follow-up, and Sample Size 
The study is mainly powered to assess and compare the proportion of HIV 
exposures covered by pill-use (coverage) in the different populations and usage 
groups.  The study will randomize 540 people, 180 MSMTGW at the TUC 
Bangkok site, 180 MSMTGW at the Harlem Prevention Center and 180 WSM at 
Emavundleni Desmond Tutu site.  In each site, 60 participants will be randomly 
assigned to each of three study arms.  The total number of sex acts and the 
number of covered sex acts will be computed for each participant based on the 
adjusted EDM data and weekly telephone interviews.  A covered sex act is 
defined as one with pre- and post- drug use in a time period defined in Section 
7.2.1.  Further details will be provided in the statistical analysis plan.   
 
Since we anticipate that key findings may differ by site and risk group, the study 
will be powered to analyze each cohort of 180 participants separately. 
 
There are two hypotheses of interest for the coverage endpoint.  First, we are 
interested in the non-inferiority hypothesis that the selected intermittent arm is not 
markedly inferior to the daily arm in the percentage of sex acts covered by pill-
use:  
 
(1) 
Ho: pd – pi >δ 
Ha: pd – pi <δ 
 
Where pi is the average proportion of covered sex acts in the intermittent arm, pd 
is the corresponding quantity for the daily arm and δ represents an “indifference 
region” (i.e., if the average proportion of covered sex acts for the intermittent arm 
is within at least δ of the daily arm we will consider them to be equivalent).  The 
second hypothesis is that one intermittent arm has a higher proportion of covered 
sex acts compared to the other intermittent arm: 
 
(2) 
 
 
Ho: pi1= pi2 
 
 
Ha: pi1≠ pi2 
 
Where pi1 is the proportion of covered sex acts in one intermittent arm and pi2 is 
the proportion in the other intermittent arm.   
 
 
 
The following are assumed in the sample size calculations: each person will 
report, on average, 50 sex acts over the 24 week self-administered follow-up 
period.  This will vary from person to person and in the final analysis we will 
account for variable numbers of sex acts across participants.  For simplicity, we 
ignore that variability here.  It is assumed that 90% of sex acts in the daily arm 
will be covered (10% uncovered).  Further, it is assumed that the proportion of 


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uncovered acts will vary across participants with a coefficient of variation (CV) of 
40% - 80% (a relatively large variance).  The sample size calculations of Hayes 
and Bennett 74 are used directly to assess the power for the superiority hypothesis 
(2) and we adapt their approach for the non-inferiority hypothesis (1). 
 
 


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Table 7.1  Non-inferiority region (δ) for hypothesis (1) 
assuming 60 participants/arm, 50 acts per participant, α =0.05 
(one-tailed).  Power is computed against the alternative that 
coverage is exactly equal in the two arms (i.e. δ = 0). 
CV Power 
% ``uncovered’’ 
sex in daily arm 
(1 – pd) 
null δ 
  n=60 
.4 
.9 
.1 
0.031 
.4 
.95 
.1 
0.035 
.6 
.9 
.1 
0.040 
.6 
.95 
.1 
0.045 
.8 
.9 
.1 
0.049 
.8 
.95 
.1 
0.055 
 
 
 
Table 7.2  Minimum detectable difference between the rate of 
covered sex acts in one intermittent treatment arm as 
compared to the other intermittent arm (hypothesis 2), 
assuming 60 participants/arm, 50 acts per participant, α = 0.05 
(two-tailed). 
CV Power 
The rate of 
uncovered sex 
acts in 
intermittent arm 
1 (1 – pi1) 
Minimum 
detectable rate of 
uncovered sex in 
intermittent arm 
2  (1 – pi2) 
n=60 
.4 
.8 
.1 
0.134 
.4 
.9 
.1 
0.140 
.6 
.8 
.1 
0.145 
.6 
.9 
.1 
0.154 
.8 
.8 
.1 
0.160 
.8 
.9 
.1 
0.173 
 
Table 7.1 shows the equivalence region for the non-inferiority test that the rate of 
``uncovered’’ sex acts in the intermittent arm is not different from that in the daily 
arm.  The smaller the equivalence region is, the better power to test the non-
inferiority hypothesis will be achieved.  For a fairly large CV (0.4-0.6), Table 7.1 
shows that the targeted sample size provides a rather small equivalence margin,  
around 0.03-0.05, when the daily arm has 10% sex not ``covered’’ by pill-use.  
Table 7.2 shows the minimum detectable rate of covered sex in one intermittent 
arm when the other intermittent arm has 10% covered sex acts.  The closer the 
minimum detectable rate is to 0.1, the better power to detect small differences.  
For a CV between 0.4-0.6, Table 7.2 suggests the targeted sample size provides 
good power to detect a 0.03-0.06 increase from the daily arm.  This analysis 
suggests that there is good power for comparing the rates of covered sex acts 


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between the two intermittent arms.  Tables 7.1 and 7.2 are relatively insensitive to 
the number of acts per participant so deviations from the expected 50 acts per 
person or small amounts of loss to follow-up will not significantly affect power 
for the coverage endpoint.  Additional power calculations were conducted to 
examine the impact of varying rates of covered sex act (0.8~0.95) on the minimal 
detectable difference (see tables in Appendix II).  Similar power performances 
were observed for the range of rates. 
 
Table 7.3 The sample size needed to achieve a fixed power level (0.8 or 0.9) to a 
detect difference in tolerance scores (based on Vertigo symptom scale for 
dizziness) between the daily arm and one intermittent arm, given a range of CV, 
assuming tolerance scores are collected twice in the study, the average tolerance 
score in the daily arm is 15, the standard deviation within subject is 5, α = 0.05 
(two-tailed). 
CV 
Power 
The average tolerance 
scores in the intermittent 
arm  
Sample size 
needed per arm 
.4 
.8 
 10 
 26 
.4 
.9 
 10 
 34 
.6 
.8 
 10 
 46 
.6 
.9 
 10 
 61 
.8 
.8 
 10 
 75 
.8 
.9 
 10 
 99 
 
The proposed sample size of 60 per arm also provides good power to detect 
differences in the tolerance scores between the daily arm and one intermittent 
arm, corresponding to the hypotheses 
 
(3) 
 
 
Ho: ud= ui 
Ha: ud≠ ui 
 
where ud is the mean tolerance score in the daily arm and ui is the mean tolerance 
score in the intermittent arm.  The Vertigo symptom scale for dizziness is used for 
illustration.  This scale will be measured twice in this study.  Based on literature 
on validation of this scale 75 the mean of this scale in the daily arm is assumed to 
be 15, the standard deviation among two measurements within a subject is 
assumed to be 5, the required sample sizes to detect 1/3 decrease in one 
intermittent arm for various sizes of CV and power, using a two sided test (α = 
0.05) are shown in Table 7.3.  The sample size calculation is based on formula in 
Hayes and Bennett.74  For within risk group analyses, the target sample size will 
provide adequate power to detect similar decrease provided the CV is 0.6 or less 
(which we believe is likely). 
 
Table 7.4 shows the power to detect the difference of the number of pills used in 
the study between the daily arm and the intermittent arm, corresponding to the 
hypotheses 


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June 10, 2013 
 
 
(4) 
 
 
Ho: ud= ui 
Ha: ud≠ ui 
 
where ud is the mean number of pills used in the daily arm and ui is the mean 
number of pills used in the intermittent arm. The table gives the power for a range 
of differences and standard deviations, assuming the average number of pills used 
in the daily arm is 120 and a two sided test (α = 0.05).  The targeted sample size 
will provide adequate power to detect approximately 15-20% decrease in number 
of pills used.  A much larger difference is expected so the trial is very well 
powered for this endpoint.  In addition, we do not want to be powered to detect 
smaller differences in pill usage between the intermittent arm and the daily arm 
since small differences in pill-use do not represent a meaningful benefit of the 
intermittent arm.   
 
Table 7.4  The power to detect the difference of average pill-use throughout 
study period between the daily arm and one intermittent arm, given a range of 
standard deviations and the differences, assuming the average number of pills 
used in the daily arm is 120, n = 60/arm and α = 0.05 (two-tailed). 
Difference between 
Daily arm and the 
intermittent arm 
 Standard 
Deviation 
(SD) of pills 
used in the 
study 
The average number 
of pills used in the 
daily arm  
Power 
20 
20 
 120 
 0.99 
20 
40 
 120 
 0.97 
20 
60 
 120 
 0.73 
10 
20 
 120 
 0.97 
10 
40 
 120 
 0.49 
10 
60 
 120 
 0.25 
7.4 
Random Assignment 
Participants who meet the study eligibility criteria will be offered enrollment in 
the study, and those willing to take part will be assigned at random to one of three 
treatment arms.  The randomization code will be developed and maintained by 
statisticians at the HPTN SDMC.  Randomization will be stratified by site.   
7.5 
Data Analysis  
7.5.1 Primary Analyses 
Descriptive analyses will be carried out to determine if randomization has resulted 
in study arms that are similar with respect to key baseline measures.   
 


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The primary analyses will consist of a comparison of the proportion of sex acts 
covered by pill-use, percentage of pills taken among all pills that should be taken 
based on his/her assigned regimen and reported side effects/symptoms between 
the three randomization arms.  All the analyses described here will be intent-to-
treat (in this context, intent to treat means that all sex acts will be included in the 
analysis while the participant is HIV-uninfected, regardless of whether or not the 
participant is on a product-hold).  All analyses in this section will be conducted 
separately for different social groups, defined as women, Thai MSM/TGW, and 
US MSM/TGW in each risk group. Analyses involving pill-use data will be 
carried out using the adjusted electronic and self-reported pill-use data.  EDM 
pill-use data will be adjusted based on weekly interviews to take into account 
openings of the device not associated with pill consumption and pill consumption 
not associated with an opening (i.e. when more than one pill is dispensed at one 
opening, or pocket dosing).  Information collected after HIV seroconversion, if 
any, will not be included in the analyses. 
 
H1: Study-drug coverage of risk events across the 24-week monitoring period will 
be statistically equivalent between the non-daily dosing arms and the daily dosing 
arm. 
The sex and pill-use data collected weekly will be summarized for each 
participant as total number of sex acts and the total number of sex acts “covered’’ 
by pill-use during the self-administer study period.  Logistic regression will be 
used to compare the proportion of covered acts between randomized arms.  The 
standard errors of parameter estimates will be scaled by the over dispersion 
parameter to account for extra binomial variability and robust standard errors will 
be used.   
 
H2: Non-daily arms will have fewer reported side-effects. 
Symptom/Side-effects scores will be collected at regular intervals.  They will be 
treated as ordinal repeated measures, or continuous measures depending on the 
type of tolerance score.  For ordinal measures, a proportional odds model will be 
used for generalized estimating equation (GEE) analysis based on the cumulative 
logit function.  For continuous scores, a linear model will be used for GEE 
analysis.  In both cases, robust standard errors (GEE) will be used to correct for 
correlation between repeated measures on the same individual.  Pre-
randomization scores will be used as covariates in the analysis to adjust for 
heterogeneity between participants.  Pairwise comparison will be conducted for 
three randomization arms.  Nominal p-values will be provided and a permutation 
procedure will be used to provide comparisons between the arms that are 
corrected for multiple testing. 
 
H3a: Fewer total pills will be required for non-daily arms. 
The minimum total number of pills needed to cover all sex acts during the self-
administered period will be computed for each subject using the self-reported 
sexual history data.  The (mean of the) logarithm of the total numbers of pills will 
be compared between the three arms by ordinary linear regression and the log of 


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the duration of follow-up will be included in the model as an offset term to 
account for (potentially) different follow-up periods for each participant 
 
H3b: Fewer total pills will be used for non-daily arms. 
The total number of pills used during the self-administered period will be 
computed for each subject using the adjusted EDM data.  The (mean of the) 
logarithm of the total numbers of pills will be compared between the three arms 
by ordinary linear regression and the log of the duration of follow-up will be 
included in the model as an offset term to account for (potentially) different 
follow-up periods for each participant.   
7.5.2 Secondary analyses on coverage, pill-use and side effects/symptoms 
Differences in effects between the risk groups will be tested although it is 
acknowledged that tests for effect modification usually have low power. 
 
Another secondary analysis will consider 4 categories of coverage: not covered, 
pre-dose only taken, post-dose only taken, pre and post-dose taken (i.e., covered).  
A 4 x 3 contingency table will be formed to describe the category of coverage by 
arm for each sex act and will use a randomization procedure (randomizing by 
participant) to test for differences between arms. 
 
Exploratory secondary analyses using weekly collected pill use and sexual 
behavior data will examine coverage specifically for high risk events (defined as 
receptive vaginal or receptive or insertive anal intercourse events where no 
condom use was reported). Methods identical to those outlined for hypothesis H1 
in section 7.5.1 will be used. 
7.5.3 Secondary analyses on adherence, acceptability and sexual behavioral 
data 
H1: Time- and event-driven arm participants will report greater preference for their 
assigned study arm at the Week 30 assessment than those in the daily arm. 
 
The proportion of participants in each of study arms who accept the dosage 
recommendation at the Week 30 assessment will be computed and summarized.  
The rate of acceptability will be compared between arms using a chi-squared test.   
 
H2: At Week 30 assessments, participants assigned to time- and event-driven arms 
will report higher levels of PrEP use related information, motivation, and behavioral 
skills, in comparison to those in the daily arm. 
 
A score for PrEP use will be computed based on IMB (see Table 1, Section 5.10) for 
each participant and a Wilcoxon rank sum test will be used to compare the scores 
between treatment arms. 
 
H3: Across all 24 weeks of on-drug monitoring, rates of adherence to one’s assigned 
regimen will be higher in the time- and event-driven arms. 


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Self-reported adherence (SR adherence) will be calculated for each participant as 
the percentage of pills taken among all pills that should be taken based on his/her 
assigned regimen and (in the case of the intermittent arms) self-reported sex 
events.  Logistic regression will be used to compare the adherence rates between 
randomized arms.  The standard errors of parameter estimates will be scaled by 
the overdispersion parameter to account for extra binomial variability and robust 
standard errors will be used.  Analyses will be done with and without the 
unvalidated pill-use data, as described in Section 7.5.1.   
 
We will also calculate adherence by pill count for each participant for each 4 
week follow-up period.  Adherence by pill count will be descriptively compared 
to SR adherence.  A scatterplot of the two measures of adherence will be 
presented and the concordance correlation 76 will be computed for these two 
measures of adherence. 
 
H4: Across all 24 weeks of on-drug monitoring, proportion of participants requesting 
discontinuation of study drug will be lower in the time- and event-driven arms. 
The proportion of participants in each of study arms who discontinue study drug 
during follow-up will be computed.  The rate of discontinuation will be compared 
between arms using a chi-squared test.   
 
H5: PrEP use will not uniquely contribute to increases in risk (non-condom use risk 
events) from baseline to final Week 30 assessment (null disinhibition hypothesis). 
The self-reported data on sex acts will be summarized for each subject to create 
the total number of sex acts and the number of sex acts with and without condom 
use.  Rates of condom use relative to total sex acts, for those with at least one act 
reported throughout the 24 week monitoring, will be calculated based on data 
collected with CASI.  Logistic regression will be used to assess whether the rate 
of condom use is different across arms.  The standard errors of parameter 
estimates will be scaled by the estimated overdispersion parameter to account for 
extra binomial variability.   
 
H6: A relationship between intervention arm and coverage can be explained by PrEP 
optimism. 
 
Here we illustrate just one set of analyses that we will do to explore this 
hypothesis.  It is likely that additional analyses will be suggested by the results 
found in this and related analyses. 
 
Suppose we find that coverage (for example) differs significantly by intervention 
arm.  We may hypothesize that the observed effect of arm on coverage can be 
explained by changes in PrEP optimism between the intervention arms.   
 
 
Arm 
 
Coverage 
 
 
 
            PrEP Optimism 


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Where the solid arrows indicate the true causal pathway and the dashed arrow 
indicates a univariate (unadjusted) association that is not significant in the 
adjusted model.  To investigate this we would run the following models (here, Y 
is the outcome, A is intervention arm, OP is optimism about PrEP): 
 
 
Y ~ A 
 
Y ~ A + OP 
 
OP ~ A 
 
If optimism about PrEP mediates the effect of arm on the outcome, then we would 
expect to see a strong relationship between the outcome and arm in the first 
model, a weak relationship between the outcome and arm after controlling for 
PrEP optimism in the second model, and a strong relationship between optimism 
about PrEP and arm in the third model.   
 
H7: Planning for sexual events, prediction of risk events, and recognition of risk 
events will be superior at last on-drug assessment within time and event-driven arms 
compared to the daily PrEP arm. 
7.5.4 Secondary analyses on safety outcomes 
A listing of all AEs will be provided, including HIV infection, among the 
participants.  For participants who become HIV-infected, this will describe any 
drug resistance and plasma HIV RNA levels.  It is not anticipated that enough 
cases of HIV infection will be identified to make any comparative analyses 
possible. 
7.5.5 Secondary analyses on drug concentration data 
The initial 6-week lead in period including DOT will provide data for estimation 
of steady-state drug concentrations with the primary moiety of interest being 
TFV-DP.  While drug concentration data collected during this period may allow 
estimation of PK parameters (clearance, volume of distribution, half-life), the 
sparse weekly sampling and fixed pre-dose schedule of blood collection will limit 
the precision of these estimates.  The primary readout from this period is the pre-
dose drug concentration at Weeks 4 and 5.  These concentrations will be 
evaluated to test for steady-state and the “expected” pre-dose concentration for 
each individual.  Week 4 and Week 5 data (Week 5 alone if steady-state has not 
been achieved) will provide a point estimate for the expected concentration at 
steady-state and an estimate of intra-individual variability in this pre-dose 
concentration.  Decay will be monitored from drug dose concentration data 
collected at Week 6.   
 
All of the assays used will be validated and approved for use in NIH network 
studies by the Clinical Pharmacology Quality Assurance (CPQA) Program 
consistent with FDA standards for drug development.  All of these assays use 
LC/MS methods for analyte quantitation. 


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These data will be used to compute laboratory verified adherence (LV adherence) 
for participants in the unobserved dosing phase of the study.  In contrast to self-
report adjusted EDM-based adherence (defined in Section 7.5.3), LV adherence is 
computed as the ratio of observed and expected concentrations (where the 
expected concentration is based on the reported dosing) and can be greater than 
1.0 due to random variability.  Random error can be attributed to intra-individual 
variability and assay variability in the laboratory (<15% CV) with the validated 
assay used at the HPTN NL.   
 
With scheduled dosing, the expectation of drug concentration can be estimated 
based on observed drug concentrations at the end of the DOT period by a simple 
simulation of drug concentration over time according to the prescribed regimen.  
The regimen itself is simply an invariant scalar that predicts the expected 
concentration.  Event-driven dosing introduces an additional variability that 
decreases the precision of any LV adherence estimates.  With sexual event 
dependent dosing, a similar simulation can be performed, using the time of sex 
and the PK parameters derived from the DOT period.   
 
Based on available information, it is predicted that participants who take 4 or 
more pills in the previous 14 days will have detectable TFV-DP in their PBMCs, 
as measured at Weeks 10, 18 and 30.  Undetectable drug levels in persons 
reporting using 4 or more pills is an indication of over-reporting.  In a secondary, 
exploratory analysis, we will repeat the analyses of coverage (Section 7.5.1) and 
adherence (Section 7.5.3) and data from periods of over-reporting will be 
censored from the analysis.  Persons reporting use of fewer than 4 pills in the last 
2 weeks will be included in the analysis regardless of drug level.  We will 
evaluate the amount of data censored by arm and we will compare the results 
obtained in this analysis to those obtained without censoring over-reporting 
periods.  Drug levels may also be assessed in whole blood (Harlem site only). 
7.5.6 Qualitative behavioral data analyses 
Data collected via focus groups within each study arm at each site will be used 
in theory grounded and content analysis.  Key informant interviews will be 
conducted with selected participants and clinic staff at each site.  All material 
will be transcribed and results translated into English as needed.   
 
A representative portion of transcripts will be reviewed prior to coding to 
determine most appropriate unit to code (utterance, table turn, complete sentence, 
or some other integral).  Once units are defined, transcripts will undergo two 
phases of qualitative analysis.  The first phase utilizes grounded theory analysis or 
a site selected valid alternative methodology (e.g., framework analysis).77 78  
Grounded theory approaches use an iterative inductive process of reviewing 
content and identifying themes in the data that characterize, qualify, or define 
the phenomenon of interest.79  The methodology recommended for grounded 
theory includes a phase of open-coding where transcripts are iteratively 


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reviewed by individuals familiar with theories and formulations of the 
phenomenon (e.g., pill-taking, PrEP) enough to provide an adequate level of 
theoretical sensitivity in the development of coding schemes.  These reviews 
produce a set of general global categories which describe the concepts and 
properties of the phenomenon under study.  Given the intended content of the 
focus group queries, it is anticipated that a priori phenomenon will include 
pill-taking, participating in a PrEP trial, risk reduction behavior (condom use), 
PrEP regimens, and social roles.  However, additional phenomenon that 
emerge from focus group data will also be included.  Open-coding can be 
further qualified by axial coding, defined as not only a comprehensive 
description of the phenomenon but also identification of the context in which it 
occurs (moderating content), intervening conditions for it to occur (mediating 
conditions), action strategies (activities done surrounding or in response to the 
phenomenon), and consequences (outcomes of activities).  With adequate 
characterization of the data with open codes, consolidation of codes will lead 
to a final coding system that will be used to quantify the data.  It is assumed 
that using this process, the focus groups will be characterized in terms of the 
main content describing discussions of critical aspects of pill-taking and PrEP 
participation defined both a priori and through the identification of emerging 
phenomenon that may not have been anticipated.  Note that while constant 
comparison methods are used, we are also interested in applying principles of 
classic content analyses in that the relative frequencies of variable aspects of 
the axial codes are also of interest.80  Because of this, we will evaluate 
agreement on a minimum of 10% of the coded units via double-coding.   
 
Focus group data will also be used to inform the adapted IMB model employed 
in this research and to identify the relative type and frequency of theory-
related barriers and facilitators via content (structural) analysis.79  As opposed 
to grounded theory or a valid alternative method selected by the site used to 
identify core constructs relevant to the phenomenon in question, content 
analyses is theory based in identifying content categories a priori and culling 
the data into units that reflect, or do not reflect, core content categories for 
summary (e.g., frequencies, relative proportions).  It is anticipated that after 
completion of the grounded theory coding, coders will review content of the 
focus groups for references to barriers and facilitators of pill-taking and of 
prevention behaviors (e.g., condom use).  Each identified barrier and 
facilitator will be further coded for content that is informational, motivational 
or behavioral skills related.  These non-orthoganol codes will characterize the 
kinds of barriers and facilitators reported in focus group discussions.  
Importantly, any barrier or facilitator not coded by IMB model determinants 
will be identified and further analyzed for emerging themes (content) that will 
be used in future applications of the model and to provide guidance for targets 
of pill-taking and condom use support strategies.  Similar to the classical 
content analysis portion of the grounded theory approach, at least 10% of the 
units will be double coded to determine agreement.  It is anticipated that data 
from focus groups will provide nuanced information about acceptability and 
feasibility of the various PrEP regimens and will characterize the factors that 


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appear most influential to focus group participants in maintaining pill-use, as 
well as condom use in the context of PrEP.   
 
Key informant interviews: Semi-structured interviews will be conducted after 
Week 34.  The one-on-one interviews with selected participants and study staff 
will use an interview guide and responses will be recorded and transcribed.  
Responses will be reviewed by the team of interviewers and qualitative working 
group for the identification of units for coding (e.g. by specific interview item 
response, by distinct phrase or complete thought) and inductive generation of 
main content themes.  Qualitative analytic strategies similar to those used in 
analyzing focus group data will be adopted for the key informant interview data 
as well. 
Analysis for both qualitative components will be completed using CDC EZ Text 
or another similar qualitative software program.   
 
7.6 Safety Monitoring for HIV Seroconversions 
HIV seroconversions are not the primary outcome in HPTN 067 because they are 
expected to be rare.  However, if an unexpectedly large number of serconversions 
were to occur in the trial, and if these were all concentrated in one arm, then this 
information would overshadow results from the pre-specified primary outcome of 
coverage.  Therefore, it makes sense to devise a monitoring plan for HIV 
seroconversions.   
 
Daily Truvada® is the “standard of care” condition in this trial, with proven 
efficacy in MSM based on iPrEx and in WSM based on the Partners PrEP trial. 2  
The intermittent arms are the “experimental” conditions.  Thus, our concern is 
that the HIV seroconversion rate may be higher in the intermittent arms compared 
to the daily arm.  To evaluate this concern, we will compare the combined number 
of HIV events in the intermittent arms with the number of events in the daily arm. 
 
The following table gives the probability (p-value) for various distributions of 
HIV seroconversion events between the daily and intermittent arms under the null 
hypothesis assumption of no difference in HIV seroconversion rates between the 
3 arms.  Note that these probabilities have not been adjusted for multiple looks at 
the data (“multiple testing”).  Such adjustments typically require some assumption 
about the expected total number of events, which is difficult to predict here (in 
fact, in the two original HPTN 067 sites – South Africa and Thailand – we expect 
fewer than 8 total events).  This suggests, however, that one should be 
conservative in using these probabilities for modifying the trial (i.e. only stop 
when the probability is quite small).  In addition, these probabilities depend on the 
total number of events in the intermittent arms and do not distinguish between all 
events in one arm (say, event-driven) and a mix of events in the two intermittent 
arms.  The rationale for this is that we would be equally “alarmed” in either case.  
Finally, the probabilities given in the table are “one-sided” in the sense that we 
would not consider stopping the trial if all events were in the daily arm (if this 


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possibility were included, the probabilities in the table would be larger and the 
number of events to consider stopping would be greater). 
 
Number in daily arm 
Number in intermittent arms 
Probability1 
0 
3 
.30 
0 
4 
.20 
0 
5 
.13 
0 
6 
.088 
0 
7 
.059 
0 
8 
.039 
0 
9 
.026 
1 
9 
.10 
1 
10 
.075 
1 
11 
.054 
1Computed as a one-tailed p-value under the null assumption that 2/3 of the HIV events will occur 
in the intermittent arms and 1/3 will occur in the daily arm 
 
Based on this table, the earliest one could possibly reach a one sided p < 0.05 
level is when 8 events have occurred.  Thus, when 8 events have occurred, the 
data will be immediately forwarded to the DSMB for prompt consideration.  The 
DSMB and SDMC will monitor the total number of events.  The study team and 
DSMB will agree upon a monitoring plan for HIV seroconversion events. 
 
8.0 
HUMAN SUBJECTS CONSIDERATIONS 
8.1 
Ethical Review 
This protocol and the template informed consent forms contained in Appendix III 
— and any subsequent modifications — will be reviewed and approved by the 
HPTN Scientific Review Committee (SRC) and DAIDS Protocol Safety Review 
Committee (PSRC) with respect to scientific content and compliance with 
applicable research and human subjects regulations.   
 
The protocol, site-specific informed consent forms, participant education and 
recruitment materials, and other requested documents — and any subsequent 
modifications — also will be reviewed and approved by the ethical review bodies 
responsible for oversight of research conducted at the study site.  The University 
of Cape Town in Cape Town is the IRB of record for the Cape Town site. The 
Institutional Review Board, Human Research Protection Office, US Centers for 
Disease Control and Prevention and the Ethical Review Committee for Research 
in Human Subjects, Department of Medical Sciences, Ministry of Public Health, 
Thailand are the IRBs of record for the Bangkok site. Columbia University 
Medical Center Institutional Review Board in New York is the IRB of record for 
the New York site.  
 


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Subsequent to initial review and approval, the responsible IRBs/ECs will review 
the protocol at least annually.  The Investigator will make safety and progress 
reports to the IRBs/ECs at least annually, and within three months of study 
termination or completion.  These reports will include the total number of 
participants enrolled in the study, the number of participants who completed the 
study, all changes in the research activity, and all unanticipated problems 
involving risks to human subjects or others.  IRBs and participants will also be 
informed of important new findings related to the effectiveness of PrEP.  Study 
sites will submit documentation of continuing review to the DAIDS Protocol 
Registration Office, via the HPTN CORE, in accordance with the current DAIDS 
Protocol Registration Policy and Procedure Manual. 
8.2 
Informed Consent 
Written informed consent will be obtained from each study participant.  Each 
study site is responsible for developing a study informed consent form for local 
use, based on the template in Appendix III that describes the purpose of the study, 
the procedures to be followed, and the risks and benefits of participation, in 
accordance with all applicable regulations.  The study site also is responsible for 
translating the template form into local languages and verifying the accuracy of 
the translation.   
 
Participants will document their provision of informed consent by signing their 
informed consent forms.  Non-literate participants will not be eligible for the 
study.  (Further details regarding DAIDS requirements for documenting the 
informed consent process are provided in the DAIDS standard operating 
procedure (SOP) for Source Documentation.) 
 
Participants will be provided with a copy of their informed consent forms if they 
are willing to receive them. 
 
 


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8.3 
Risks 
Acute viral syndromes  
The study is designed to defer enrollment of all participants who have signs or 
symptoms of acute viral syndromes, which may reflect acute HIV infection, or 
other acute viral infections such as H1N1 influenza.  Persons with acute viral 
syndromes will not be enrolled.  They can be enrolled after signs and symptoms 
resolve if they remain eligible in all other respects, including negative HIV 
antibody status.  Persons suspected of acute HIV infection will be evaluated using 
HIV RNA testing.   
 
Phlebotomy  
Phlebotomy may lead to discomfort, feelings of dizziness or faintness, and/or 
bruising, swelling and/or infection.   
 
Confidentiality 
Although study sites make every effort to protect participant privacy and 
confidentiality, it is possible that participants' involvement in the study could 
become known to others, and that social harms may result.   
 
Study Medications 
TDF.   
More than 12,000 adult patients have been treated with Viread® alone or in 
combination with other antiretroviral medicines for 28 days to 215 weeks in 
clinical trials and expanded access studies.16 The most common side effects 
(occurring in 10% or more of patients) identified from any of the 3 large 
controlled clinical trials include rash, diarrhea, headache, pain, depression, 
asthenia (weakness) and nausea. 
 
About 5 to 10 out of 100 people with HIV taking Viread® tablets in Studies 903, 
934 and 907 (clinical studies of Viread® in combination with other antiretroviral 
agents) have experienced these side effects:   
 Headache 
 Pain, including abdominal, back or joint pain 
 Fever 
 Weakness or fatigue 
 Diarrhea 
 Nausea or vomiting 
 Depression 


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 Insomnia (inability to sleep) 
 Headache 
 Dizziness 
 Sinus inflammation, respiratory (chest) infection 
 Anxiety 
 Rash 
 Increased cholesterol 
 Increased creatine kinase (an enzyme found in tissues and cells of the body), 
which could mean muscle damage 
 Increased amylase (an enzyme made by the pancreas that helps digest food) 
 
The following additional side effects have been reported in patients taking 
Viread® outside of clinical trials. It is not always possible to estimate how 
frequently these events occur or know if they result from taking tenofovir 
disoproxil fumarate. 
 Immune system problems (allergic reaction, including swelling of face, lips 
and/or tongue) 
 Nutrition problems (buildup of lactic acidosis, low potassium in the blood, 
low phosphate levels in the blood) 
 Shortness of breath 
 Stomach problems (swelling of the pancreas, increased amylase, and stomach 
pain) 
 Liver problems (fat in the liver, swelling of the liver, increased liver enzymes) 
 Rash 
 Muscle and tissue problems (breakdown of muscle fibers, softening of the 
bones, weakness, muscle pain) 
 Kidney problems (kidney failure, decline in kidney function, increase 
creatinine [a marker of kidney function], protein in the urine, increase 
urination) 
 Weakness 
 
Viread® may cause the following serious side effects: 
 Lactic acidosis (buildup of acid in the blood)  
 Serious liver problems (hepatotoxicity) with liver enlargement 
(hepatomegaly) and fat in the liver (steatosis) 
 “Flare-ups” of hepatitis B virus (HBV) infection, in which the disease 
suddenly returns in a worse way than before, can occur if Viread® is stopped 
 Kidney problems  
 Changes in bone mineral density (thinning bones) 
 Changes in body fat  


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 Changes in the HIV-positive patient’s immune system (Immune 
Reconstitution Syndrome) 
 
The side effects listed above were reported in people with HIV infection. They 
used Viread® for HIV treatment. The side effects of Viread® when taken by 
healthy people who do not have HIV infection are currently unknown.  
 
TDF is a pregnancy category B medication.  A controlled human study of TDF 
among pregnant women has been conducted, but results are not currently 
available (HPTN 057: http://www.hptn.org/research_studies/hptn057.asp).   
 
FTC.  More than 2,000 adult patients have been treated with Emtriva® alone or 
in combination with other antiretroviral medicines for 10 days to 200 weeks in 
clinical trials.15 The most common side effects (occurring in 10% or more of 
patients) identified from any of the 3 large controlled clinical trials include 
headache, diarrhea, nausea, fatigue, dizziness, depression, insomnia, abnormal 
dreams, rash, abdominal pain, asthenia (muscle weakness), increased cough, and 
rhinitis (runny nose). Skin discoloration (darkening of the palms and/or soles) 
may also happen with Emtriva®. 
 
About 5 to 10 out of 100 people with HIV taking Emtriva® capsules in Studies 
301, 303 and 934 (clinical studies of Emtriva® in combination with other 
antiretroviral agents) have experienced these side effects:   
 Headache 
 Pain, including abdominal or joint pain 
 Weakness or fatigue 
 Paresthesia (tingling) 
 Diarrhea 
 Nausea or vomiting 
 Depression 
 Insomnia (inability to sleep) or abnormal dreams 
 Headache 
 Dizziness 
 Cough 
 Sinus inflammation, respiratory (chest) infection 
 Rash 
 Increased cholesterol or triglycerides 
 Increased creatine kinase (an enzyme found in tissues and cells of the body), 
which could mean muscle damage 
 Increased amylase (an enzyme made by the pancreas that helps digest food) 


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Emtriva® may cause the following serious side effects: 
 Lactic acidosis (buildup of acid in the blood)  
 Serious liver problems (hepatotoxicity) with liver enlargement 
(hepatomegaly) and fat in the liver (steatosis) 
 “Flare-ups” of hepatitis B virus (HBV) infection, in which the disease 
suddenly returns in a worse way than before, can occur if Emtriva® is stopped 
 Changes in body fat  
 
The side effects listed above were reported in people with HIV infection. They 
used Emtriva® for HIV treatment. The side effects of Emtriva® when taken by 
healthy people who do not have HIV infection are currently unknown.  
 
 
FTC is a pregnancy category B medication.  No controlled human studies of FTC 
among pregnant women have been conducted.   
 
FTC/TDF combination tablet.   
About 5 to 10 out of 100 people with HIV taking Truvada® tablets in Study 934, 
a clinical study of Truvada® and efavirenz, have experienced these side effects.16 
 Diarrhea or nausea 
 Fatigue or lack of energy 
 Sinus inflammation, respiratory (chest) infection 
 Dizziness or headache  
 Depression or insomnia 
 Rash  
 Increased cholesterol 
 Increased creatine phosphokinase (CPK; an enzyme found in tissues and cells 
of the body), which could mean muscle damage 
 Increased amylase (an enzyme made by the pancreas that helps digest food) 
 
Other side effects that have occurred in at least 5 out of 100 patients receiving the 
components of Truvada®, emtricitabine15 or tenofovir disoproxil fumarate14, with 
other HIV medications in clinical trials include: 
 Anxiety 
 Joint pain (arthralgia) 
 Increased cough 
 Upset stomach or indigestion (dyspepsia) 
 Fever 
 Muscle pain (myalgia) 


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 Pain  
 Abdominal pain 
 Numbness or tingling of the skin (paresthesia) 
 Problem with the nerves that can cause weakness, changes in sensation, or 
pain (peripheral neuropathy) 
 Pneumonia 
 Runny nose (rhinitis) 
 
The following additional side effects have been reported in patients taking 
tenofovir disoproxil fumarate14, a component of Truvada®, outside of clinical 
trials. It is not always possible to estimate how frequently these events occur or 
know if they result from taking tenofovir disoproxil fumarate. 
 Immune system problems (allergic reaction) 
 Nutrition problems (buildup of lactic acidosis, low potassium in the blood, 
low phosphate levels in the blood) 
 Shortness of breath 
 Stomach problems (swelling of the pancreas, increased amylase, and stomach 
pain) 
 Liver problems (fat in the liver, swelling of the liver, increased liver enzymes) 
 Rash 
 Muscle and tissue problems (breakdown of muscle fibers, softening of the 
bones, weakness, muscle pain) 
 Kidney problems (kidney failure, decline in kidney function, increase 
creatinine [a marker of kidney function], protein in the urine, increase 
urination) 
 Weakness 
 
Truvada® may cause the following serious side effects: 
 Lactic acidosis (buildup of acid in the blood)  
 Serious liver problems (hepatotoxicity) with liver enlargement 
(hepatomegaly) and fat in the liver (steatosis) 
 “Flare-ups” of hepatitis B virus (HBV) infection, in which the disease 
suddenly returns in a worse way than before, can occur if the patient stops 
taking Truvada®.   
 Kidney problems  
 Changes in bone mineral density (thinning bones) 
 
Other side effects with Truvada® when used with other anti-HIV-1 medications 
include.16 


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 Changes in body fat have been seen in some patients taking Truvada® and 
other anti-HIV-1 medicines. These changes may include increased amount of 
fat in the upper back and neck (“buffalo hump”), breast, and around the main 
part of the patient’s body (trunk). Loss of fat (wasting) from the legs, arms 
and face may also happen. 
 In some patients with advanced HIV infection (AIDS), signs and symptoms of 
inflammation from previous infections may occur soon after anti-HIV 
treatment is started. 
 
The side effects listed above were reported in people with HIV infection. They 
used Truvada® for HIV treatment. The side effects of Truvada® when taken by 
HIV uninfected people for prevention have been evaluated in the iPrEx study, 
Partners PrEP, and TDF2 studies.  Truvada® was well tolerated with no reported 
side effects by the majority of PrEP users.  Less than 1 in 10 reported nausea, 
abdominal cramping, headaches, or dizziness in one or more of these studies.  The 
side effects typically resolved within the first 4 weeks of Truvada® use.  The 
iPrEx study found that bone mineral density was less in those taking Truvada® 
compared with people taking placebo.  The difference in bone mineral density 
was less than 1% on average, and did not progress after the first 24 weeks, and 
was not associated the bone fractures.1-3_  For the daily arm, the FTC/TDF dosing 
regimens are consistent with package insert recommendations.  Most participants 
in the time-driven and event-driven arms are anticipated to utilize FTC/TDF at a 
less frequent rate than package insert recommendations. 
 
Nucleotide Analogues.  Lactic acidosis (elevated lactic acid levels in the blood) 
and severe hepatomegaly (enlarged liver) with steatosis (fatty liver) that may 
result in liver failure, other complications or death have been reported with the 
use of antiretroviral nucleoside analogues alone or in combination.  The liver 
complications and death have been seen more often in women on these drug 
regimens.  Some nonspecific symptoms that might indicate lactic acidosis 
include: unexplained weight loss, stomach discomfort, nausea, vomiting, fatigue, 
cramps, muscle pain, weakness, dizziness, and shortness of breath.  These effects 
are not expected in this study involving a brief exposure to antiretroviral drug. 
 
Antiretroviral drugs.  Redistribution/accumulation of body fat including central 
obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial 
wasting, breast enlargement, and "cushingoid appearance" have been observed in 
persons receiving antiretroviral drugs.  The mechanism and long-term 
consequences of these events are currently unknown.  A causal relationship has 
not been established.  These effects are not expected in this study involving a 
brief exposure to antiretroviral drug. 


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Drug Resistance.  Drug resistance may occur during the study if a participant 
becomes HIV-infected.  Multiple steps will be taken to minimize the risk of drug 
resistance.  Rapid HIV testing will be performed at Screening and Enrollment, 
and then approximately every 4 weeks during the trial.  Persons with acute viral 
syndromes that may reflect acute HIV infection will defer enrollment and be 
referred for evaluation of acute infection.  If acute HIV infection is suspected after 
enrollment, the participant will undergo evaluation using rapid HIV antibody 
testing and GenAptima HIV RNA testing, as indicated.  These steps should 
minimize the risk of drug resistance occurrence by identifying HIV infection in its 
early stages and stopping study drug.  If any participant in HPTN 067 becomes 
HIV-infected during the study and develops TDF or FTC resistance, an alternative 
treatment regimen could be used that includes a non-nucleoside reverse 
transcriptase inhibitor (NNRTI), a protease inhibitor, and an NRTI that is not 
affected by the M184V or K65R mutations.   
8.4 
Benefits 
Several clinical trials evaluating the efficacy of FTC/TDF (administered daily) for 
PrEP are ongoing or have already been completed as described in Section 1.3.  
The results of these studies will be shared with participants as they are made 
available.   
Participants in this study will benefit from HIV education and prevention 
messages.  They will receive free HIV and HBV serologic testing.  Participants 
found to be susceptible to HBV will be offered standard HBV vaccinations.  The 
services to be provided for HIV seroconverters include: laboratory testing for 
drug resistance, plasma HIV RNA level, and CD4 cell count.  Participants who 
acquire HIV infection during the study will be provided with referral for HIV 
services and evaluation of whether ART is needed and will continue to be 
followed in this study. 
8.5 
Incentives 
Pending IRB/EC approval, participants will be compensated for their time and 
effort in this study, and/or be reimbursed for travel to study visits and time away 
from work.  Incentives for responses to weekly telephone contacts will be 
provided via payment at the next clinic visit.  Site-specific reimbursement 
amounts will be specified in the study informed consent forms. 


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8.6 
Confidentiality 
All study-related information will be stored securely at the study site.  All 
participant information will be stored in locked file cabinets in areas with access 
limited to study staff.  All laboratory specimens, reports, study data collection, 
process, and administrative forms will be identified by a coded number only to 
maintain participant confidentiality.  Participation in clinical research includes the 
risks of loss of confidentiality and discomfort with personal nature of questions.  
During focus groups, participants will be encouraged to use a nickname or 
pseudonym to protect their identity.  All focus groups and key informant 
interviews will be recorded and transcribed by qualified personnel.  All 
participant identifiers will be removed from transcripts and the recordings, notes 
and transcripts will be destroyed according to DAIDS regulations.  All local 
databases will be secured with password-protected access systems.   
 
Participant’s study information will not be released without the written permission 
of the participant, except as necessary for monitoring by the U.S. CDC, NIAID 
and/or its contractors; Gilead Sciences, Inc. representatives of the HPTN CORE, 
SDMC, and/or NL, the U.S. FDA, other government and regulatory authorities, 
and/or site IRBs/ECs.   
8.7 
Communicable Disease Reporting Requirements 
Study staff will comply with all applicable local requirements to report 
communicable diseases identified among study participants to local health 
authorities.  Participants will be made aware of all reporting requirements during 
the study informed consent process. 
8.8 
Study Discontinuation 
The study may be discontinued at any time by NIAID, the HPTN, the National 
Institutes of Mental Health (NIMH), Gilead Sciences, Inc., OHRP, the U.S. FDA, 
the US CDC, the Thailand Ministry of Public Health, the South African 
Medicines Control Council, and/or site IRBs/ECs. 
9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
9.1 
Local Laboratory Specimens 
As described in Section 5, the following types of specimens will be collected for 
testing at the local laboratory (LL):  
 Urine specimen for the following: 
o Pregnancy testing for women with reproductive capacity 


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o Dipstick for protein and glucose 
o Storage 
 Blood specimen for the following: 
o HIV rapid testing (See SSP for protocol algorithm) 
o HIV confirmatory testing with a Western blot and/or with the 
GenAptima HIV RNA test 
o Quantitative HIV RNA testing in any participant with confirmed 
HIV infection 
o CD4 cell count in any participant with confirmed HIV infection 
o HepBsAg 
o HepBCoreAb (if the test for HepBsAg is negative) 
o HepBsAb (if the test for HepBsAg is negative) 
o CBC 
o Serum creatinine (for estimated creatinine clearance)  
o Serum phosphate 
o AST/ALT 
o Plasma for storage 
o Lysed PBMCs for storage 
o DBS for storage for host genetic testing (see section 9.5) 
o DBS for storage for drug levels (Harlem site only) 
 Hair specimen for storage 
 
Local laboratories will perform testing such as Chemistry, Hematology, and 
pregnancy tests as indicated in Appendix I.  International Laboratories performing 
these tests will be monitored by Patient Safety Monitoring and International 
Laboratory Evaluation (pSMILE) and must demonstrate successful participation 
in the relevant External Quality Assurance (EQA) programs.  US sites should 
send the tests to CLIA-certified laboratories and must participate in EQA 
programs. 
 
Local laboratories may also perform CD4 cell count testing and quantitative HIV 
RNA (viral load) testing as indicated in Appendix I.  Laboratories performing 
these tests will be monitored by the DAIDS Immunology Quality Assurance 
(IQA) and /or Virology Quality Assurance (VQA) programs and must 
demonstrate successful participation in the relevant EQA programs. US sites must 
use CLIA-certified laboratories; participation in the IQA and / or VQA program is 
recommended. 
 
Each study site will adhere to standards of good laboratory practice, the HPTN 
Network Laboratory Manual, and local SOPs for proper collection, processing, 
labeling, transport, and storage of specimens to the LL.  Specimen collection, 
testing, and storage at the LL will be documented using the HPTN Laboratory 
Data Management System (LDMS) as described in the SSP Manual. 
 
All specimens will be shipped in accordance with International Air Transport 
Association (IATA) specimen shipping regulations.  All shipments will be 
documented using the HPTN LDMS as described in the SSP Manual. 


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9.2 
Network Laboratory Specimens 
As described in Section 5, the following types of specimens will be collected for 
testing at the HPTN NL:  
 
Virology 
 
The HPTN NL will perform testing to determine HIV infection status in selected 
cases (e.g., indeterminate Western blot) and may also perform specialized assays 
to characterize HIV viruses and the immune response to HIV infection in 
participants who become HIV-infected during the study.  This may include testing 
with assays used for analysis of HIV incidence.  Additional assays may be 
performed at the HPTN NL or at an outside laboratory designated by the HPTN 
NL.  This testing may include HIV genotyping, HIV phenotyping, HIV subtyping, 
minority variants assays, or other tests to characterize HIV viruses and/or the host 
response to HIV infection.  Results from those tests will not be returned to study 
sites or study participants. 
 
Pharmacology 
 
Retrospective analysis of drug levels will provide an objective measure of 
adherence.  Estimation of PK for each participant allows for drug concentrations 
to be used as objective measures of drug exposure and allows for an estimation of 
pill-use during the self-administered dosing phase of the study. 
 
The level of TFV-DP in PBMCs will be monitored after directly observed doses 
during Weeks 4 and 5.  Decay will be monitored at Week 6.  If results from that 
testing indicate that PBMC testing will be informative (if sufficient levels of 
TFV-DP are detected in PBMCs), levels of TFV-DP will be monitored in PBMCs 
at Weeks 10, 18, and 30.  PBMC drug levels will be measured using assays that 
are validated and approved by the Clinical Pharmacology Quality Assurance 
Committee (CPQA).  FTC-TP may also be measured.  Aggregate results that do 
not identify individual study participants may be made available to study sites 
during the trial to provide information on adherence of participants to the study 
regimens.  Data from individual study participants will not be returned to study 
sites or study participants.  Stored plasma may be tested at the HPTN NL to 
measure extracellular drug levels of TFV and FTC, for comparison.  Initial 
testing  of DBS samples (Harlem site only) will be performed using a subset of 
the samples to obtain data about the accumulation of drug to steady state; results 
from that testing will be used to evaluate whether the DBS testing should be 
expanded to include additional DBS samples from that site. 
 
 
Hair will be collected and stored for possible measurement of drug levels at 
Weeks 4, 5, 6, 10, 18, and 30.  Testing of hair for drug concentrations may be 
performed either at the HPTN NL or at an outside laboratory designated by the 
HPTN NL.  If an outside laboratory is used, protocols for drug measurement must 


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first be validated, after the laboratories are enrolled in the CPQA, and the assay 
must be approved by the CPQA before HPTN 067 specimens are tested.  Hair 
samples that are not destroyed during analysis will be destroyed once all hair 
analysis is completed. 
 
Urine will be stored for possible future studies analyzing the relationship between 
TFV drug level and dose and the occurrence of renal proximal tubulopathy.  
Those laboratory studies would be funded separately if daily PrEP trials show that 
proximal tubulopathy occurs among HIV-uninfected persons at a higher rate after 
TDF exposure than among HIV-uninfected persons exposed to placebo.  The 
testing would include fractional excretion of uric acid and phosphate (involving 
parallel testing of these analytes in plasma and urine), urine protein, urine 
glucose, urine creatinine, and urine calcium. 
 
Drug Resistance Testing Performed at a Commercial Laboratory 
 
Samples from participants who become HIV-infected during the study will be 
shipped to the HPTN NL.  A sample collected at the time of HIV diagnosis will 
be sent to a commercial laboratory (e.g., Monogram Biosciences, South San 
Francisco, CA) for HIV resistance testing.  Results from that testing will be made 
available to study sites at study closure.  Results may be provided to study sites 
prior to study closure upon request, with approval of the HTPN NL and the 
Protocol Chair.  Results from any other resistance testing (e.g., minority variants 
analysis, if performed, see above) will not be returned to study sites. 
9.3 
Quality Control and Quality Assurance Procedures 
The clinical sites will document that their clinical laboratories are certified under 
the Continuous Laboratory Improvement Act of 1988 (CLIA-certified) and/or 
participate in DAIDS sponsored EQA programs.  NL staff will conduct periodic 
visits to each site to assess the implementation of on-site laboratory quality 
control (QC) procedures, including proper maintenance of laboratory testing 
equipment and use of appropriate reagents.  NL staff will follow up directly with 
site staff to resolve any QC or quality assurance (QA) problems identified through 
proficiency testing and/or on-site assessments.  Throughout the course of the 
study, the HPTN NL will select a random sample of stored specimens to test for 
QA purposes.  NL staff will follow-up directly with site staff to resolve any QA 
problems identified through this process. 
 
All of the assays to be used in this study have been approved for use in HPTN 
studies by the cross-network CPQA program.  The quality of the assays is also 
continuously evaluated by a twice yearly proficiency testing program 
administered by the CPQA.  Satisfactory scores are required for the laboratory to 
be able to continue to use assays in support of HPTN studies.  The Pharmacology 
Core Lab will adhere to Good Laboratory Practice (GLP) for processing all 
samples. 


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9.3.1 QC for HIV diagnostic testing 
The HPTN NL will perform HIV diagnostic testing for QC.   
 
Before performing HIV diagnostic testing, all sites must validate their testing 
algorithm, and the validation study must be approved by the HPTN NL.  Local 
laboratories will perform testing for HIV diagnosis at Screening, Enrollment, and 
other scheduled visits.  Algorithms for HIV diagnostic testing are provided in the 
SSP Manual.   
 
Participants will be tested for HIV infection status using two HIV rapid tests. 
International sites must use one which must be an FDA-cleared rapid test and 
another locally available rapid test such as the DETERMINE assay.  The US site 
must use two FDA-cleared rapid tests.  Preference is given to FDA-cleared 
OraSure Oraquick HIV½, Clearview HIV½ Stat Pak, Clearview Complete HIV½ 
, Trinity Unigold Recombigen or OraSure Oraquick HIV 1/2 as the FDA-cleared 
rapid test. The NL must approve the testing algorithm at each site prior to study 
activation and/or when a site needs to change a kit.  Participants with one or two 
reactive HIV rapid test results at Screening or Enrollment will not be eligible for 
enrollment, regardless of subsequent test results.  In those cases, HIV infection 
status will be confirmed using local HIV testing guidelines.  Participants who 
have one or two reactive HIV rapid test results at any other study visit will be 
further tested using an FDA-cleared Western blot or the GenAptima HIV RNA 
test.  Further testing will be based on the results of the confirmatory testing, as 
described in the SSP Manual.  In addition, if a participant has signs or symptoms 
consistent with acute HIV infection, or expresses a concern about recent HIV 
acquisition, testing will be performed using the GenAptima HIV RNA test.  
Regardless of whether HIV RNA testing is used for diagnostic testing, HIV 
infection must be confirmed in all cases using two independent samples.   
 
9.3.2 QC for HIV RNA monitoring  
Quantitative HIV RNA (viral load) testing will be performed at local laboratories 
to monitor HIV infection in any subject with confirmed HIV infection.  Viral load 
testing will be performed in HIV-infected participants at the visit when HIV 
infection is confirmed, and at subsequent study visits.  Note that this is distinct 
from use of qualitative HIV RNA testing that is performed to determine HIV 
infection status (see above).  Local laboratories must participate in the DAIDS 
Virology QA (VQA) program, with EQA results that are deemed satisfactory by 
the HPTN NL. US sites must use a CLIA-certified laboratory participating in 
EQA program; VQA program participation recommended. 
9.3.3 QC for CD4 cell count determination 
For participants who become HIV-infected during the study, CD4 cell count 
testing will be performed at the time when HIV infection is confirmed and at 
subsequent study visits.  Non-U.S. laboratories performing CD4 cell count testing 


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must be enrolled in the United Kingdom National External Quality Assessment 
Service (UK NEQAS) program through the DAIDS IQA program.  US sites must 
use a CLIA-certified laboratory participating in EQA program; IQA program 
participation recommended. 
9.4 
Biohazard Containment 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of 
blood and shipping and handling of all specimens for this study, as currently 
recommended by the U.S. CDC.  All infectious specimens will be transported in 
accordance with U.S. regulations [42 Code of Federal Regulations (CFR) 72]. 
9.5 
Sample storage 
Selected samples from HIV seroconverters and other participants will be shipped 
to the HPTN NL.  At the discretion of the HPTN NL, samples may be transferred 
to a DAIDS-approved repository.  Other specimens will be stored at study sites 
and shipped to the HPTN NL upon request.   
 
Study site staff will store all PBMC, plasma, urine, and hair samples collected in 
this study until all protocol-related testing has been completed, including QC 
testing and other testing performed at or coordinated by the HPTN NL.  The study 
site will be informed by the SDMC when shipments to the NL are required, and 
will be instructed which samples to ship.  In addition, study participants will be 
asked to provide written informed consent for their blood and urine specimens to 
be stored after the end of the study for possible future testing.  The specimens of 
participants who do not consent to long-term storage and additional testing will be 
destroyed at the end of the study.  Reposited specimens may be used to analyze 
human genes that are known or thought to be involved in the transport or 
metabolism of the study agents, emtricitabine or tenofovir disoproxil fumarate.  
Genes that affect the course of HIV infection, and other viral infections, may also 
be analyzed. 
10.0 ADMINISTRATIVE PROCEDURES 
10.1 
Study Activation 
Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent form(s) 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE).  Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support 
Center (RSC).  The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all of the required documents have been received.   


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Pending successful protocol registration and submission of all required 
documents, CORE staff will “activate” the site to begin study operations.  Study 
implementation may not be initiated until a study activation notice is provided to 
the site. 
 
Site-specific informed consent forms (ICFs) will be reviewed and approved by the 
DAIDS PRO and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process.  A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an 
amendment, sites should implement the amendment immediately.  Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC.  The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) 
WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
10.2 
Study Coordination 
DAIDS holds the Investigational New Drug (IND) application for this study 
(#71,859).  Copies of all regulatory documents submitted to this IND by DAIDS 
will be forwarded to Gilead Sciences, Inc.  Assignment of all sponsor 
responsibilities for this study will be specified in a Clinical Trials Agreement 
executed by DAIDS and Gilead Sciences, Inc. 
 
Study implementation will be directed by this protocol as well as the SSP Manual.  
The SSP Manual — which will contain reference copies of the DAIDS SOPs for 
Source Documentation and Essential Documents, as well as the DAIDS Manual 
for Expedited Reporting of Adverse Events to DAIDS, Version 2.0, dated January 
2010 and the DAIDS Toxicity Tables — will outline procedures for conducting 
study visits, data and forms processing, AE assessment, management and 
reporting, dispensing study products and documenting product accountability, and 
other study operations.   
 
Study case report forms and other study instruments (e.g., CASI) will be 
developed by the study team and HPTN SDMC.  Data will be transferred to the 
HPTN SDMC, processed, and cleaned.  Quality Control reports and data queries 


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will be generated on a routine basis and distributed to the study sites for 
verification and resolution.   
 
Close coordination between protocol team members will be necessary to track 
study progress, respond to queries about proper study implementation, and 
address other issues in a timely manner.  Rates of accrual, adherence, follow-up, 
and AE incidence will be monitored closely by the team as well as the HPTN 
SMC.  The Protocol Chair, DAIDS Medical Officer, Protocol Biostatistician, and 
CORE Protocol Specialist will address issues related to study eligibility and AE 
management and reporting as needed to assure consistent case management, 
documentation, and information-sharing across sites. 
10.3 
Study Monitoring 
On-site study monitoring will be performed in accordance with DAIDS policies.  
Study monitors will visit the site to: 
 
 verify compliance with human subjects and other research regulations and 
guidelines 
 assess adherence to the study protocol, study-specific procedures manual, and 
local counseling practices 
 confirm the quality and accuracy of information collected at the study site and 
entered into the study database  
 
Site investigators will allow study monitors to inspect study facilities and 
documentation (e.g., informed consent forms, clinic and laboratory records, other 
source documents, and CRFs), as well as observe the performance of study 
procedures.  Investigators also will allow inspection of all study-related 
documentation by authorized representatives of the HPTN CORE, SDMC, NL, 
NIH, Gilead Sciences, Inc., and U.S. and in-country government and regulatory 
authorities including relevant IRBs/ECs.  A site visit log will be maintained at the 
study site to document all visits. 
10.4 
Protocol Compliance 
The study will be conducted in full compliance with the protocol.  The protocol 
will not be amended without prior written approval by the Protocol Chair and 
NIAID Medical Officer.  All protocol amendments must be submitted to and 
approved by the relevant IRB(s)/EC(s) and the DAIDS RSC prior to 
implementing the amendment. 
10.5 
Investigator's Records 
The IoR will maintain, and store in a secure manner, complete, accurate, and 
current study records throughout the study.  In accordance with Federal 
regulations, for each of the two investigational products tested, the IoR will retain 
all study records for at least two years following the date of marketing approval 
for the study product for the indication in which it was studied.  If no marketing 


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application is filed, or if the application is not approved, the records must be 
retained for two years after the FDA is notified that the IND is discontinued.  
Study records include administrative documentation — including protocol 
registration documents and all reports and correspondence relating to the study — 
as well as documentation related to each participant screened and/or enrolled in 
the study — including informed consent forms, locator forms, case report forms, 
notations of all contacts with the participant, and all other source documents. 
10.6 
Use of Information and Publications 
Publication of the results of this study will be governed by HPTN policies.  Any 
presentation, abstract, or manuscript must include acknowledgement to the HPTN 
and will be submitted by the Investigator to the HPTN Manuscript Review 
Committee, DAIDS, and Gilead Sciences, Inc. for review prior to submission. 
 


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11.0 REFERENCES 
 
1. 
Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV 
prevention in men who have sex with men. N Engl J Med. Dec 30 2010;363(27):2587-2599. 
2. 
Baeten J. Antiretroviral Pre-Exposure Prophylaxis for HIV-1 prevention among 
heterosexual African men and women: the Partners PrEP Study. 6th IAS Conference on HIV 
Pathogenesis, Treatment and Prevention (IAS 2011). Rome, Italy2011. 
3. 
Thigpen MC, Kebaabetswe PM, Smith DK, et al. Daily oral antiretroviral use for the 
prevention of HIV infection in heterosexually active young adults in Botswana: results from the 
TDF2 study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011). 
Rome, Italy2011. 
4. 
MTN Statement on Decision to Discontinue Use of Oral Tenofovir Tablets in VOICE, a 
Major HIV Prevention Study in Women. 2011; http://www.mtnstopshiv.org/node/3619. 
Accessed October 12, 2011. 
5. 
Garcia-Lerma JG, Otten RA, Qari SH, et al. Prevention of rectal SHIV transmission in 
macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. Feb 
2008;5(2):e28. 
6. 
Marrazzo J, Ramjee G, Nair G, et al. Pre-exposure Prophylaxis for HIV in Women: Daily 
Oral Tenofovir, Oral Tenofovir/Emtricitabine, or Vaginal Tenofovir Gel in the VOICE Study 
(MTN 003) Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 
3-6 March 2013; Atlanta, GA. 
7. 
Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection 
among African women. N Engl J Med. Aug 2 2012;367(5):411-422. 
8. 
Bangsberg DR, Hecht FM, Charlebois ED, Chesney M, Moss A. Comparing objective 
measures of adherence to HIV antiretroviral therapy: Electronic medication monitors and 
unannounced pill counts. AIDS & Behavior. 2001;5(3):275-281. 
9. 
Macalino GE, Celentano DD, Latkin C, Strathdee SA, Vlahov D. Risk behaviors by 
audio computer-assisted self-interviews among HIV-seropositive and HIV-seronegative 
injection drug users. AIDS Educ Prev. Oct 2002;14(5):367-378. 
10. 
Liu H, Golin CE, Miller LG, et al. A comparison study of multiple measures of 
adherence to HIV protease inhibitors. Ann Intern Med. May 15 2001;134(10):968-977. 
11. 
Berg KM, Arnsten JH. Practical and conceptual challenges in measuring antiretroviral 
adherence. J Acquir Immune Defic Syndr. Dec 1 2006;43 Suppl 1:S79-87. 


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12. 
Bova CA, Fennie KP, Knafl GJ, Dieckhaus KD, Watrous E, Williams AB. Use of 
electronic monitoring devices to measure antiretroviral adherence: practical considerations. 
AIDS Behav. Mar 2005;9(1):103-110. 
13. 
Garcia-Lerma G, Cong M-E MJ, al. e. Prevention of Rectal Simian HIV Transmission in 
Macaques by Intermittent Pre-exposure Prophylaxis with Oral Truvada. 16th Conference on Retroviruses 
and Opportunistic Infections. Montreal, Canada2009. 
14. 
Gilead Sciences. VIREAD Full Prescribing Information. 2001; 
http://www.gilead.com/pdf/viread_pi.pdf, 2009. 
15. 
Gilead Sciences. EMTRIVA Full Prescribing Information. 2005; 
http://www.gilead.com/pdf/emtriva_pi.pdf, 2009. 
16. 
Gilead Sciences. Truvada Full Prescribing Information. 2006; 
http://www.gilead.com/pdf/truvada_pi.pdf, 2009. 
17. 
Gallant J, DeJesus E, Arribas J, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, 
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APPENDICES 


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APPENDICES 
Appendix I: Schedule of Study Visits and Procedures 
 
Appendix IA.  All study participants 
 
 
 
Screening (up to 
–Day 70) 
Week 0 
Enrollment 
Weeks  1-5 
DOT 
Week 6 
Randomization 
Weeks 7-29 
Self-admin 
dosing1 
Week 30 
End of drug 
dosing 
Week 34 
Post-Study 
Follow-up Visit  
Administrative, Behavioral, and Regulatory Procedures 
 
 
 
 
 
 
 
Screening/Enrollment informed consent 
X 
 
 
 
 
 
 
Locator information 
X 
X 
X 
X 
X 
X 
X 
Demographic information 
X 
 
 
 
 
 
 
Social harms assessment 
 
 
X 
X 
X 
X 
X 
Randomization to a treatment arm 
 
 
 
X 
 
 
 
Behavioral assessment (CASI) 
X 
 
 
X 
X2 
X 
 
Adherence/ behavioral monitoring (telephonic weekly) 
 
 
 
 
X 
X 
 
Focus groups and key informant interviews 
 
 
 
 
 
 
X3 
Clinical/Counseling Procedures 
 
 
 
 
 
 
 
Adherence and EDM orientation/ counseling and pill counts 
 
X 
 
X 
X4 
X4 
 
Complete medical history including medications 
X 
 
 
 
 
 
 
Interim medical history including concomitant medications  
 
X 
X 
X 
X 
X 
 
Adverse event (AE) assessment 
 
 
X 
X 
X 
X 
X 
Vaginal practices assessment for women 
 
X 
 
 
 
X 
 
Sex hormones assessment for men 
 
X 
X6 
 
 
X 
 
Family planning assessment for women 
 
X 
X6 
X 
X 
X 
 
Full physical exam (symptoms/side effects assessment) 
 
X 
 
 
 
 
 
Symptom-driven physical exam (symptoms/side effects 
assessment) 
 
 
 
X 
X 
X 
 
Once per week directly observed dosing  
 
X 
X5 
 
 
 
 
Study drug supply and associated counseling 
 
 
 
X 
X 
 
 
HIV pre-test, risk reduction, and post-test counseling 
X 
X 
X6 
X 
X7 
X 
X 
Laboratory Procedures * 
 
 
 
 
 
 
 
Sample testing: 
 
 
 
 
 
 
 
Urine for pregnancy8 
X 
X 
X6 
X 
X 
X 
 
Urine dipstick for protein and glucose 
X 
 
 
X 
X9 
X 
X 
Blood collection for: 
 
 
 
 
 
 
 
HIV rapid testing (with confirmation if indicated)10 
X 
X 
X6 
X 
X7 
X 
X12 
Complete blood count (CBC) 
X 
 
 
 
X9 
X 
 
Serum creatinine (for estimated creatinine clearance) 
X 
 
X6 
 
X9 
X 
 
Serum phosphate 
X 
 
 
 
X9 
X 
 
AST/ALT 
X 
 
X6 
 
X9 
X 
 
Hepatitis B virus testing 13  
X 
 
 
 
 
 
 
Sample storage: 14 
 
 
 
 
 
 
 
Plasma for storage 
X 
X 
X11 
X 
X 
X 
X12 
DBS for storage for host genetic testing 
 
 
X6 
 
 
 
 
Lysed PBMCs for storage  
 
 
X11 
X 
X9 
X 
 
DBS for storage for drug levels (Harlem only) 
 
 
X11 
X 
X9 
X 
 
Hair for storage 
 
 
X11 
X 
X9 
X 
 
Urine for storage 
 
 
X11 
X 
X9 
X 
 
* All rapid testing (for HIV infection, pregnancy, and urine protein) and all sample collection for testing and for storage should be completed 
prior to dosing study medication 


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Footnotes for Appendix IA 
 
1 Visits conducted at Weeks 10, 14, 18, 22 and 26.  
2  Week 18 only. 
3 Focus group discussions and key informant interviews may be done at any time within a three 
month window after Week 34 with selected study participants and site staff.   
4 Adherence orientation if necessary.  Week 30 is the end of the self-administered dosing period 
and therefore will include pill counts only.   
5 Weeks 1-4. 
6  Week 4 only. See Section 9.5 for more details. 
7 HIV testing including pre-and post- test counseling will be performed at Weeks 10, 14, 18, 22 
and 26.   
8 Biologic females who were not found to be pregnant at a previous study visit.  Those with 
documented inability to become pregnant (tubal ligation, etc.) will not require testing. 
9 Weeks 10 and 18 only.  
10  HIV diagnostic testing must be performed at the indicated study visits according to the 
algorithms provided in the SSP Manual.  The HPTN NL should be consulted in any case where 
HIV infection status is unclear, one or both HIV rapid tests is reactive, HIV seroconversion is 
documented, or acute HIV infection is suspected.  CD4 cell count testing, viral load monitoring, 
and HIV drug resistance testing will be performed for participants with confirmed HIV infection 
only (see Appendix 1B).  Participants that are confirmed to be HIV-infected according to the 
SSP Manual will have no further HIV diagnostic testing performed at subsequent study visits. 
11 Weeks 4 and 5 only.  
12 At Week 34, plasma should be stored if one or both of the HIV rapid tests is reactive. 
13  Participants who are susceptible to HBV infection will be offered HBV vaccination.  
Participants should be retested for hepatitis at subsequent study visits if they express a concern 
about recent hepatitis acquisition, or have clinical signs/symptoms of hepatitis. 
14  Store samples on site until requested by the HPTN NL. 


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Appendix IB. Additional Procedures for Participants with Confirmed HIV Infection 
 
 
Time of 
diagnosis 
Weeks 10, 18, 
and 30  
(if after HIV 
diagnosis) 
Weeks 14, 22 
and 26  
(if after HIV 
diagnosis) 
Every 12 weeks 
after week 30 
 (until the last 
participant ends 
follow-up) 
CD4 cell count testing 
X 
X 
 
X 
HIV viral load testing 
X 
X 
 
X 
Shipment of samples to the HPTN 
NL1 
X 
X 
 
 
HIV genotyping2 
X 
 
 
 
Other testing3 
X 
X 
 
 
Additional plasma storage 
X 
X 
X 
 
Lysed PBMCs for drug levels4 
X 
 
 
 
 
1 Stored samples from HIV seroconverters will be shipped to the HPTN NL; sites should store 
samples until they receive a request for shipping from the SDMC.  At the discretion of the HPTN 
NL, samples may be transferred to a DAIDS-approved repository. 
2 The HPTN NL will coordinate HIV resistance testing using samples shipped to the HPTN NL.  
HIV genotyping results from this study visit (time of HIV diagnosis) will be provided to study 
sites at study closure.  Results from this testing may be provided to study sites prior to study 
closure with approval of the HPTN NL and the Protocol Chair.   
3 Additional testing may be performed at the HPTN NL for research purposes; at the discretion 
of the HPTN NL, additional testing for research purposes may also be performed at another 
laboratory (e.g., at one of the study sites, at the U.S. CDC, or at another laboratory with special 
expertise).  Those results will not be returned to study sites or study participants.  This testing 
may include additional HIV genotyping/sequencing assays, HIV phenotyping, HIV subtyping, 
minority variants assays, other assays to characterize HIV + viruses and/or the host response to 
HIV infection. 
4 Additional Lysed PBMCs do not need to be collected at the confirmatory blood draw 
(confirmatory diagnosis) if already drawn at a scheduled visit.  
Note: Participants with confirmed HIV infection will continue in the study, off of study drug.  
Any enrolled participants who acquire HIV infection during the study will permanently 
discontinue study product and will be followed after Enrollment at regularly scheduled monthly 
visits and then every 12 weeks after Week 30 until the last HIV uninfected participant reaches 
Week 34. 


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Appendix II: Additional power calculation with a range of average coverage rates 
for two primary hypothesis tests. 
 
Table 1  Non-inferiority region (δ) for hypothesis (1) assuming 60 participants per 
arm, 50 acts per participant, α =0.05 (one-tailed).  Power is computed against the 
alternative that coverage is exactly equal in the two arms (i.e. δ = 0). 
CV Power 
% ``uncovered’’ sex in 
daily arm (1 – pd) 
null δ 
 
.4 
.9 
.2 
0.053 
.4 
.95 
.2 
0.059 
.6 
.9 
.2 
0.071 
.6 
.95 
.2 
0.080 
.8 
.9 
.2 
0.091 
.8 
.95 
.2 
0.103 
.4 
.9 
.05 
0.020 
.4 
.95 
.05 
0.022 
.6 
.9 
.05 
0.023 
.6 
.95 
.05 
0.026 
.8 
.9 
.05 
0.027 
.8 
.95 
.05 
0.031 
 
 
 


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Table 2  Minimum detectable difference between the rate of covered sex acts in 
one intermittent treatment arm as compared to the other intermittent arm, 
assuming 60 participants per arm, 50 acts per participant, α = 0.05 (two-tailed). 
CV Power 
The rate of 
uncovered sex 
act in 
intermittent arm 
1 (1 – pi1) 
Minimum 
detectable 
rate 
of 
uncovered sex in intermittent arm 2  
(1 – pi2) 
 
.4 
.8 
.2 
0.256 
.4 
.9 
.2 
0.267 
.6 
.8 
.2 
0.282 
.6 
.9 
.2 
0.299 
.8 
.8 
.2 
0.313 
.8 
.9 
.2 
0.338 
.4 
.8 
.05 
0.072 
.4 
.9 
.05 
0.076 
.6 
.8 
.05 
0.077 
.6 
.9 
.05 
0.082 
.8 
.8 
.05 
0.084 
.8 
.9 
.05 
0.091 
 
 
 


HPTN 067, Final Version 5.0 
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Appendix III: SAMPLE INFORMED CONSENT FORMS 
 
SAMPLE SCREENING AND ENROLLMENT INFORMED CONSENT FORM 
 
 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) (HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
Study Implementers: Thailand Ministry of Public Health  - US Centers for Disease Control and 
Prevention Collaboration (TUC), Silom Community Clinic, Bangkok, Thailand; Emavundleni 
Desmond Tutu HIV Centre in Observatory, South Africa; Division of HIV/AIDS Prevention, US 
Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA; Harlem Prevention 
Center, Columbia University, New York, NY, USA; HIV Prevention Trials Network (HPTN), 
U.S. National Institutes of Health (NIH), Bethesda, MD, USA; US National Institutes of Mental 
Health (NIMH), Bethesda, MD, USA; Gladstone Institute, University of California at San 
Francisco, San Francisco, CA, USA.   
 
Study Sponsors: NIH, Division of AIDS (DAIDS), US National Institute of Allergy and 
Infectious Diseases (NIAID), and U.S. National Institute of Mental Health (NIMH).  Study drug 
is provided by Gilead Sciences, Inc. 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
 
INTRODUCTION 
You are being asked to take part in a research study.  The goal of this study is to find out more 
about whether people can take a drug that may prevent HIV infection and what that experience is 
like for them.  This drug is called Truvada®.  Truvada® is commonly used to treat HIV 
infection.  HIV is the virus that causes AIDS.  This study is being done among [men and 
transgender women who have sex with men/women who have sex with men] in your community.  
Whether you join the study or not is up to you.  If you choose to join the study, you may stop 
taking part at any time.   
 
There may be no direct benefits for you if you participate in this study.  There also may be some 
risks with taking part in the study.  Before you can make an informed decision about whether to 
take part in this study, you should understand the possible risks and potential benefits of being in 
this study.  That process is called informed consent.  This informed consent document will give 
you an idea of what will take place during the study and provides you with detailed information 
about this research study.  This consent form might contain some words that are not familiar to 
you.  Please ask us to explain anything that you do not understand before you sign this form.  If 


HPTN 067, Final Version 5.0 
Page 107 of 133 
June 10, 2013 
 
you state that you understand the study and have decided that you want to participate, you will be 
asked to read, sign, and date this form.  You will also be offered a copy of this form to keep. 
 
What happens if you do not want to take part? 
Before you learn more about the study it is important that you know the following: 
 You do not have to be in this study if you do not want to and you can stop taking part in the 
study at any time without affecting the services you get at [insert clinic]. 
 If you decide to stop taking part in the study, you may still join another study if one is available 
and you qualify. 
 
Why is this study being done? 
Truvada® is a tablet that has two drugs in it.  These drugs are called “emtricitabine” and 
“tenofovir”.  These drugs are commonly used to treat HIV infection.  Truvada® is generally safe 
when used as treatment for HIV.  Truvada® is not a cure for HIV or AIDS.  When given together 
with other drugs, Truvada® may help to prevent or delay AIDS in people with HIV.  The 
purpose of this study is to find out how different schedules of taking Truvada® affects how it 
works, whether these different schedules affects the safety of the drug and whether people like it.   
 
On July 16, 2012, the United States Food and Drug Administration’s (FDA) approved daily oral 
PrEP using Truvada® for prevention of HIV in adult men and women at high risk of getting HIV 
through sex. The daily dosing recommendation was based on published results from the iPrEx, 
TDF2, and Partner’s PrEP studies, which recommended daily use of the tablets.  Actual use 
varied among participants. 
 
Several studies have recently completed or are going on to find out whether an oral dose of 
Truvada® may help to prevent HIV infection.  They are listed as follows:  
 iPrEx: First study to demonstrate the effectiveness of a daily oral dose of  Truvada® in 
reducing the risk of HIV infections in HIV-uninfected men who have sex with men in 
Brazil, Ecuador, Peru, South Africa, Thailand and the United States.  
 Partner’s PrEP: This study of heterosexual couples in Kenya and Uganda found that a 
daily oral dose of either Tenofovir or Truvada® tablets by the HIV uninfected partner 
reduced the risk of HIV transmission from the HIV infected partner. 
 TDF2: In this study of sexually active HIV uninfected men and women (ages 18-29) in 
Botswana, a daily oral dose of Truvada® was found to reduce the risk of HIV infection.  
 FEM-PrEP: This study tested the daily oral use of Truvada® for HIV prevention among 
women in Kenya, Tanzania and South Africa. The study was stopped after a review team 
found out that it was unlikely that those who were assigned to take Truvada® were going 
to have fewer HIV infections that those who were not. The FEM-PrEP researchers looked 
more closely at their data and found that too few women had used the drug to be able to 
tell whether the drug would work to prevent HIV infection.   


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 VOICE: This study is testing different ways of preventing women in South Africa, 
Uganda and Zimbabwe from getting HIV infection. At first, the study was comparing 
people taking a daily dose of Truvada®, a daily dose of Tenofovir (another anti-AIDS 
medicine), or daily use of a Tenofovir vaginal gel with people taking a tablet that did not 
contain medication or using gel that did not have Tenofovir. Researchers found that too 
few women had used the gel or tablets to be able to tell whether they would work to 
prevent HIV infection.  
 STRAND: This was a much smaller study that examined the levels of the drug tenofovir 
in hair and blood samples when this antiretroviral was taken at different time intervals.  
Tenofovir is one of the components of Truvada®, the drug used in our HPTN 
067/ADAPT study. As expected, the STRAND study found that the amount of drug in 
the body is higher when PrEP tablets are taken more frequently.  Using PrEP seven days 
per week resulted in the highest drug levels.  Using PrEP 4 days per week resulted in 
lower levels, but when compared to data from the iPrEX study this amount appeared to 
be enough to protect against HIV infection in most men who have sex with men.  Using 
PrEP 2 days per week resulted in even lower drug levels but the iPrEx study results 
suggest that this can still reduce the risk of acquiring HIV infection to some extent. There 
was no evidence that men taking less than 2 tablets per week would have any protection.   
One clear finding from these studies is that Truvada® can only provide protection if people take 
it consistently.  Participants are reminded that it is not certain how well non-daily use of PrEP 
will work to prevent HIV infection.  It is important that all study participants try to take the 
tablets, or tell us why the tablets are not being taken. If you are having problems taking the 
tablets, or have concerns, or have decided not to take the tablets for personal reasons, please tell 
us. Telling us about your experience allows us to understand the most acceptable way to take 
PrEP regimens. The ADAPT trial aims to find ways to adapt PrEP regimens to make them easier 
to take.  All participants in this study will be updated with new information and findings that 
come out on this important issue. We encourage all participants to discuss any concerns about 
these studies, or the safety of Truvada®, with the ADAPT study staff.   
 
[For the sites in Harlem and Bangkok only: Participants who were born male but living as a 
female are eligible to enroll in this study if they are otherwise eligible. However, it should be 
noted that there have been too few transgendered women in PrEP studies to know whether PrEP 
is effective for them.]  PrEP does not prevent pregnancy or sexually transmitted infections like 
syphilis, gonorrhea, or herpes.  Using condoms for all intercourse is a good way to maintain your 
sexual health. Thus, it is important to continue using condoms from start to finish every time you 
have sex. 
 
About 540 people will take part in this study at three different study sites.  In Thailand, we will 
enroll 180 men who have sex with men and transgender women.  In the US we will enroll 180 
men who have sex with men and transgender women.  In South Africa, we will enroll 180 
women who have sex with men.  People in the study will be asked to take part for a total of 34 
weeks (approximately 8 months and 2 weeks).  Everyone will take Truvada® for the first 30 of 
these 34 weeks (approximately 7 months and 2 weeks) based on their group.   
 
In this study there are three groups based on how often they will take Truvada® 


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 Group 1 will be asked to take a pill once a day.   
 Group 2 will be asked to take a pill twice per week (every three or four days) 
and another pill after sex.   
 Group 3 will be asked to take a pill before and after sex.   
 
 
What will happen during the study visits?  
 
Screening visit: The first study visit is called the screening visit.  The screening visit will take 
about 45 minutes.  During this visit, we will ask you questions about your health, current 
medications and personal life to see if you are eligible to participate.  Study staff will ask your 
name and contact information so that we can keep in touch with you during the study.   
 
If you are eligible and willing to participate, you will be asked to complete an interview, using a 
computer, about your background and sexual practices.  We will counsel you about HIV 
infection, risks you may be taking and how to avoid getting HIV.  We will draw ~XX mL of 
blood (about X tablespoons).  This blood will be tested for HIV, hepatitis B virus, and [insert 
other local testing as applicable].  We will also ask you for a urine sample.  Your blood and urine 
will be tested to assess your overall health and whether your liver and kidneys are working 
normally.  [Insert for women- If you are pregnant or breastfeeding, you cannot join this study.  If 
you are a woman that is able to become pregnant, we will test your urine for pregnancy.]  Study 
staff will inform you of the results of all tests which affect your health.  Some people may not be 
able to join the research study because of information they provide during the screening process.   
If you are currently or have ever been part of another study to prevent HIV infection or HIV 
vaccine study, you may not be able to participate in this study.  Please also tell us if you join 
another study after agreeing to take part in this one, as this may affect your health.   
 
What if your blood shows that you have HIV? 
We will give you the results of your HIV test during this visit.  If the test shows you have an HIV 
infection, you cannot be in the study.  If you have a test result at this or any study visit that 
indicates you may have been infected with HIV, we will arrange to confirm the test result.  If the 
confirmatory tests show that you do have HIV infection, we will perform tests to see how well 
your body can fight off infections and measure the amount of virus in your blood.  If we confirm 
that you are infected with HIV later in the study, you will have to stop taking Truvada®, but we 
will ask you to continue to come to the study clinic as scheduled.  In this case, we will also test 
your blood to see if Truvada® can still be used to treat your HIV infection during these monthly 
visits.  [Insert any additional local testing that may be performed].  [Insert any local reporting 
requirements.]  We will also refer you for HIV treatment and care.   
 
What if your blood shows that you have hepatitis? 
To protect your health, everyone who takes part in the study should be vaccinated for hepatitis B 
virus infection (unless you have already had the disease or the vaccine).  This is because the 
drugs used in Truvada® can also be used to treat hepatitis B virus and taking Truvada® now 
might result in less effective treatments for hepatitis B virus if you were ever infected.  You will 
need to come back to get the results of the testing for hepatitis B virus.  If you are not immune, 
you will be offered a vaccine against the hepatitis B virus.  If you agree, we can give you the 


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first vaccination immediately. The hepatitis B follow-up visit will take about 30 minutes.  You 
will receive the second vaccination about a month later and the third one about six months later.  
If you have a hepatitis B virus infection you cannot be in the study.  If you later develop another 
form of hepatitis while in the study, you should stop taking the study drug.   
 
Enrollment visit: If you are eligible and agree to participate, you will be asked to come back to 
the clinic to start the study.  This will be your enrollment visit.  The enrollment visit will take 
about an hour.  During this visit, we will ask you questions about any changes in your health and 
medications and give you a full physical exam.  Study staff will confirm your name and update 
your contact information.  We will ask you about anything that has happened as a result of your 
study participation.  We will again counsel you about HIV infection, risks you may be taking, 
and how to avoid getting HIV.  We will draw ~XX mL of blood (about X tablespoons) and your 
blood will be tested for HIV.  [Insert for women- If you are pregnant or breastfeeding, you 
cannot join this study.  If you are a woman that is able to become pregnant, we will test your 
urine for pregnancy. We will ask you about what you use to prevent pregnancy and questions 
about use of lubricants (lubes) or things you might do to clean your vagina.]  [Insert for men- We 
will ask you about hormones that you may use to make your body bigger or more feminine.] 
Study staff will inform you of the results of all tests which affect your health.  We will give you 
an electronic pill box that sends an electronic message to our system when it is opened. We will 
explain to you how this pill box works and give you a supply of vitamins so that you can get 
used to using it.  
 
Once we have completed all of these tests, we will give you your first dose of Truvada®.  A 
nurse will observe you taking this dose and we will watch you to see how your body reacts to the 
study drug.   
 
Weeks 1-5: For the first six weeks of the study after your enrollment visit, we will ask you to come 
to the clinic once a week and take Truvada®.  A staff member will observe you doing this.  You 
will not take a dose during week 5, but we will ask you to come to the clinic.  At weeks 4 and 5, we 
will also take samples of your blood, urine and hair.  We will draw ~XX mL of blood (about X 
tablespoons) and test it for HIV.  You will be counseled about HIV and how to avoid it. [Insert for 
women- We will ask you about what you use to prevent pregnancy during the week 4 visit.]  [Insert 
for men- We will ask you about hormones that you may use to make your body bigger or more 
feminine during the week 4 visit.] As noted above, there is no evidence that once weekly Truvada® 
is protective.  Throughout this study you should use condoms and take all available precautions to 
reduce your risk of HIV infection.  Remember that no PrEP regimen is a stand-alone solution.  
ADAPT study staff will provide further guidance.  These visits will last about an hour.    
 
Weeks 6-29, 30 and 34: At the beginning of Week 6, we will use a lottery-like system to determine 
which study group you will join.  You will be given a 4-week supply of Truvada® and asked to take 
Truvada® according to the schedule in your group.  Your Truvada® will come in a pill box just like 
the one provided to you at enrollment that sends an electronic message to our system when it is 
opened.  This way we can monitor when you take Truvada®.  A nurse will explain how this pill box 
works and we will ask you to use this box every time you take a pill.  Study staff will also ask you 
to take notes in a journal about your sex life and pill-taking.  This visit will last about two hours.   
 
[For women] If you are a woman who is able to become pregnant, we will perform a pregnancy test 


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at every study visit.  If you become pregnant, you should stop taking Truvada®.  At these visits, we 
will ask you about what you use to prevent pregnancy during every visit and questions about use of 
lubricants (lubes) or things you might do to clean your vagina at the week 30 visit.]  [Insert for men- 
We will ask you about hormones that you may use to make your body bigger or more feminine 
during the week 30 visit.] 
 
After six weeks, we will ask you to come to the clinic every four weeks for approximately seven 
visits.  This visit will last about an hour.  At every visit we will confirm your contact details and ask 
you about your health and any drugs you may be currently taking.  We will ask you about any drug 
side effects you might be experiencing and discuss any health problems you might be having.  At 
these visits, we will also take samples of your blood, urine and hair. We will draw ~XX mL of 
blood (about X tablespoons) and test it for HIV.  You will be counseled about HIV and how to 
avoid it.  We will ask you to bring the pill box with you to the visit as well as any remaining pills.  
A nurse will count your leftover pills.  You will get a new supply of Truvada®.  For 24 weeks, 
(every week until about week 30) we will call you and ask you questions about the number of pills 
you have taken and when you had sex.   
 
At some of these visits (weeks 6, 18, and 30) you will be asked to complete an interview (with a 
person or by using the computer) which will take about 30 minutes.  During these interviews we 
will ask you questions about your sex life, pill-taking and whether you have side effects from taking 
Truvada®.  At weeks 10 and 18, your blood will be tested to assess your overall health, whether 
your liver and kidneys are working normally and the amount of Truvada® in your blood.  At week 
30 you will stop taking Truvada®, but we will ask you to come in for one more visit at week 34 to 
have your blood tested for HIV.  If you stop taking Truvada® before week 30, we will ask you to 
come for study visits at week 30 and 34 to complete the same procedures and we will also ask you 
why you chose to stop taking the study drug.  We will ask you to return any unused study drug as 
soon as possible after you stop taking the drug.   
 
Some people in the study may be asked to take part in a focus group (a discussion among a small 
group of people about a specific set of topics) or a one-on-one interview with site staff after they 
stop taking Truvada®.  In these focus groups or interviews, people discuss their pill-taking and 
sexual behavior, HIV risk behavior, feelings about their group assignment, and whether they 
talked with anyone about pill-use or study participation.  If you are asked to take part in a focus 
group we will explain more about this.  In that case, you will also be asked to sign another 
informed consent form.   
 
How Will Your Samples Be Used? 
As part of the study we will collect samples of your blood, urine and hair.  These samples will be 
used for a number of laboratory tests for your safety and measurements of study drug in your 
body. Samples of your blood, hair and urine will be sent to designated laboratories in the United 
States for further testing. No hair samples will remain after testing has been completed. There 
may be some leftover samples of blood and urine samples after all of the study-related testing 
has been completed.  We would like to use these samples for future research studies to develop 
new HIV tests, HIV vaccines and treatments.  If you agree to this use of your samples, we will 
ask you to initial the end of this form.   
 


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We may also want to examine the genes in your body, called DNA, since they might affect how 
your body responds to HIV and how your body reacts to the study drug.  For instance, a person 
that is very tall probably has different genes than a person who is very short, or a person whose 
ancestors come from a certain place probably have different genes compared to the genes of a 
person from a far off land.  No two persons in the world have exactly the same genes.  That is 
what makes each of us different.  We will also be looking at your genes to study your body’s 
reaction to infections, including how genes turn on or off.  Understanding these “genetic” 
differences may help us understand how the human body responds to HIV.  These tests are being 
performed for research only and may be performed in a research laboratory that does not do 
clinical (patient care) testing.  The type of DNA tests that would be performed are unlikely to 
have any direct impact on your health or future treatments.  Some testing may be performed after 
the close of the study.  For these reasons, the results of the DNA testing will not be reported back 
to the study investigators or to you.  We will ask you at the end of this form if you agree to DNA 
testing.  You do not need to agree to DNA testing in order to be in this study.   
 
If you do not agree to have your left over samples stored you can still be in this study.  If you 
agree to store your samples but change your mind later, you can contact study staff.  We will 
then destroy your samples.  If you agree, your left over samples will be stored indefinitely [insert 
local guidelines].  Any future use or the ability to store your samples longer needs to be reviewed 
and approved by the NIH and local authorities.  If these studies involve other laboratories, we 
will need approval from your local authorities to store or transfer them elsewhere.  Your left over 
samples will not be sold or used for commercial reasons. 
 
 
What Are the Possible Risks or Discomforts? 
Study drug side effects 
 
About 5 to 10 out of 100 people with HIV taking Truvada® tablets have these occasional side 
effects which usually go away after stopping the drug   
 Upset stomach, vomiting, gas, loose or watery stools   
 Dizziness or headache  
 Abdominal pain  
 Lack of energy/general body weakness 
 Mild problems of kidney function that are only detected by laboratory tests   
 Shortness of breath or cough  
 Rash, including allergic reaction  
 Anxiety 
 Joint pain, muscle pain, or other pain syndrome 
 Fever 
 
Fewer than 5 out of 100 people with HIV taking Truvada® tablets have: 
 Skin discoloration/darkening of the palms and/or soles of the feet 
 
Rarely, people taking Truvada® also have experienced:  
 Abnormal placement of body fat  
Some of these changes may include: 


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 Increase in fat around the waist and stomach area 
 Increase in fat on the back of the neck  
 Breast enlargement  
 Weight loss (wasting) 
Some of these body changes include:  
 Thinning of the face, legs and arms 
 
Potentially serious side effects are rare, but include: 
 Liver function problems 
 Serious kidney damage or failure 
 Low phosphate levels (a chemical in the blood) or protein or sugar in the urine 
 Inflammation or swelling and possible damage to the pancreas 
 Bone pain and bone changes such as thinning and softening which may 
increase the risk of  breakage 
 Allergic reaction 
 Lactic acidosis (too much acid in the body tissues and blood) and severe 
hepatomegaly (enlarged liver) with steatosis (fatty liver) that may result in 
liver failure, other complications and death have been reported with the use of 
antiretroviral nucleoside analogues alone or in combination.  The liver 
complications and death have been seen more often in women on these drug 
regimens.  Some nonspecific symptoms that might indicate lactic acidosis 
include: unexplained weight loss, stomach discomfort, nausea, vomiting, 
fatigue, weakness, and shortness of breath. 
 If you are infected with both Hepatitis B and HIV, you should be aware that 
your liver function tests may increase, and symptoms associated with hepatitis 
(an acute inflammation of the liver) may worsen if emtricitabine or tenofovir 
is stopped. 
 
Some people taking emtricitabine, one of the ingredients in Truvada®, experienced the following 
side effects: 
 Inability to sleep, unusual dreams 
 Runny nose 
 Rash, itching, which sometimes can be a sign of an allergic reaction 
 Increases in pancreatic enzyme (substances in the blood), which could mean a 
problem with the pancreas  
 Increased triglycerides (fatty acid in the blood) 
 Increased creatine phosphokinase (CPK; an enzyme found in tissues and cells 
of the body), which could mean muscle damage 
 Skin darkening of the palms and/ or soles  
 
Some people taking tenofovir, one of the ingredients in Truvada®, experienced the following 
side effects: 
 Depression 
 Inflammation or swelling and possible damage to the pancreas and liver 
 Allergic reaction: symptoms may include fever, rash, upset stomach, 
vomiting, loose or watery stools, abdominal pain, achiness, shortness of 


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breath, a general feeling of illness or a potentially serious swelling of the face, 
lips, and/or tongue 
 
The side effects listed above were reported in people with HIV infection.  They used Truvada® 
for HIV treatment.  We do not know the side effects of Truvada® when taken by healthy people 
who do not have HIV infection.  A small number of people in this study may have these side 
effects or other side effects that we do not know about.  However, we will screen your kidney 
function and overall health before you join the study.  This will reduce the chances of having any 
side-effects.   
 
HIV resistance 
If you become infected with HIV, there is a risk that the HIV you have become infected with 
could become "resistant" to Truvada®.  This may then mean that you may not be able to be 
treated with Truvada® nor the drugs which are combined together to make Truvada® (Tenofovir 
and Emtricitabine).  Viral drug resistance to these drugs can also cause cross resistance to more 
commonly used drugs such as Lamivudine (3TC). Your doctor would need to prescribe different 
drugs which are used to treat HIV infection.  These other drugs may have more side effects or 
may be less easy to take than a treatment that has Truvada®.  Truvada® alone is never enough 
for treatment of HIV infection, so additional drugs are always needed for treatment. 
 
Sensitive questions 
The questions we will ask you about your sexual behavior or drug use may make you feel 
uneasy.  However, you do not have to answer any question that you do not want to and you can 
stop answering the questions at any time.   
 
Blood and hair samples 
Taking blood samples may cause some pain, bruise your arm, or make you feel lightheaded.  In 
rare cases, you may faint.  There is also a slight chance of infection when blood is drawn.  You 
may be nervous while you are waiting for your HIV test result.  If the tests show that you have 
HIV, you may worry about your health and future.  You will receive counseling before and after 
the test to help address your concerns.  We will make every effort to protect your confidentiality 
during the study.  However, it is possible that others may learn that you are part of this study and 
they may think that you are infected with HIV or are at high risk for infection with HIV.  
Because of this you could have trouble finding or keeping a job.  You could also have problems 
with your family, friends and community.   
 
Taking a sample of your hair may cause some discomfort.  You may worry that this is painful or 
affects how you look.  Approximately 100 strands of hair are needed for this procedure.  This is 
about the number of hairs that a person loses from their body every day.   The collection 
procedure involves cutting the shaft of the hairs near the scalp; the root of the hair will not be 
collected.  Each hair will be cut carefully and will be sampled around your scalp, this way people 
will not be able to tell that your hair has been removed.  We can also take a hair sample from 
another part of your body other than your scalp if you wish.   If you do not wish to provide a hair 
sample, you can still participate in the study and it will not affect the care you would normally 
receive.  
 
 


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Other possible risks 
We do not know of other risks if you are using any other drugs than Truvada®.  These drugs 
may include herbal or diet pills or powders.  Please tell study staff if you are using any of these.   
 
[For Women] How will the study drug affect pregnancy or breastfeeding? 
Women who join the study must agree to use effective contraception and must have pregnancy 
tests and answer questions about your current family planning method at the Enrollment Visit, 
and at other visits while in the study (about every 4 weeks).  Effective contraception includes 
barrier methods (including condoms), hormonal methods (such as the birth control pill or shot), 
intrauterine contraceptive device (IUD), and sterilization.  Condoms are the only method which 
also protect you against HIV infection and should be used from start to finish every time you 
have sex even if you are using another contraceptive method.   
 
If you are pregnant or breastfeeding, you cannot join this study.  If you become pregnant during 
the study, or within 28 days after completing the study, you should notify the study personnel 
right away for your safety.  If you are still in the study, we would like you to continue to have 
study visits.  If you become pregnant during the study, you will stop taking the pills right away.  
The study staff will refer you to available sources of medical care and other services for you or 
your baby.  The study does not pay for this care.   
 
Please tell your doctor during your pregnancy about your study participation.  Your study doctor 
will ask that you, or your doctor, provide updates on the progress of your pregnancy and its 
outcome.  The study doctor will make this information available to the study sponsor for safety 
monitoring follow-up.   
 
We do not know if Truvada® tablets have any effect on babies whose mothers take it during 
pregnancy or when breastfeeding.  Because of this, women who are pregnant or breastfeeding 
cannot participate in this study.   
 
What Are the Potential Benefits? 
At screening and other study visits we will check to see if you have HIV infection.  The 
counseling you get during this study may help you to avoid HIV and other sexually-transmitted 
infections.  If you have or become infected with HIV, this counseling may help you to learn how 
to better care for yourself and avoid passing HIV to your sexual partners.  If you become HIV 
infected, we will refer you for care and/or treatment.  At the screening visit we will also check if 
you have hepatitis B infection.  If needed, we will offer you a hepatitis B vaccination.  During 
the study you will have tests to check on the health of your blood, liver, and kidneys.  If any 
health problems are found, you will be referred for care.  At every visit you will receive condoms 
and lubricant free of charge.   
 
You may not receive any other direct benefit from being in this study however, you or others in 
your community may benefit from this study later.  The information gathered during this study 
may help to prevent HIV and other infections.  This may be beneficial to you and your 
community.   
 
 


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What are Some Reasons Why You May Be Withdrawn From the Study Without Your 
Consent? 
You may be withdrawn from the study without your consent for the following reasons: 
 The research study is stopped or canceled. 
 The study staff feels that staying in the study would be harmful to you. 
 The study investigators identify other reasons that they believe would prevent you 
from continuing in the study. 
 Finally, the study can be stopped by local authorities, such as the ethical review 
committee, or by other agencies, such as the study sponsor or other oversight 
agencies.  
 During the study, you may be told of important new information about the study that 
may affect your safety.  For example, if the study shows that you taking part in it may be 
bad for your health, we will tell you.  It will be up to you to decide if you want to 
continue in the study.  If you decide to stay in the study, we may ask you to sign an 
updated informed consent form.  You will also be told when the results of the study may 
be available, and how to learn about them.   
 If you have any major health problems during the study, the doctor may require that you 
stop taking study drug for your own safety.   
 If you or your doctor decides that you should withdraw from the study we may ask you 
to come in for a final visit.   
 
What are the alternatives to participating in this study? 
[Sites to amend as applicable]  If you choose not to take part in this study, it will have no effect 
on the regular medical care that is available to you at this clinic or elsewhere.  There may be 
other studies going on at this study clinic or in the community for which you may be eligible.  If 
you wish, we will tell you about other studies that we know about.  There may also be other 
places where you can go for HIV counseling and testing.  We will tell you about those places if 
you wish.  If you prefer to take daily Truvada® and not enroll in this study, we encourage you to 
discuss this with your primary care provider. 
 
How will your privacy be protected? 
All the information you give us as part of this study will be kept secret.  All your laboratory test 
results will also be kept secret.  You will get a unique study identification number that will be 
used instead of your name on your documents.  However, at every study visit we will ask you to 
identify yourself.  This is to make sure that it is you who provides samples and information to us.  
Also we want to make sure that no other person than you can get your confidential laboratory 
test results.  Your personal information (name, address, phone number) will be protected by the 
research clinic.  Only the study staff will be able to see records that identify you by name.  This 
information will not be shared with others.  All records will be stored in locked files at the study 
clinic.  Results of your laboratory tests will be made available only to you when you visit the 
clinic.  Your name will never be used in any publication or presentation about the study. 
 
The United States Food and Drug Administration (FDA) has been informed of this study and has 
allowed it to be done.  Your records may be reviewed by the sponsor of the study (US National Institutes 
of Health (NIH), US NIMH) and their representatives, [insert name of site] IRB/EC, study staff, study 
monitors, the FDA, the United States Office for Human Subjects Protections, Gilead Sciences and 
[insert applicable local regulatory authorities]. 


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June 10, 2013 
 
 
[For US site only: We cannot guarantee absolute confidentiality.  In addition to the efforts made 
by the study staff to help keep your personal information confidential, we have obtained a 
Certificate of Confidentiality from the U.S. Federal Government.  This certificate protects 
researchers from being forced to tell people who are not connected with this study, such as the 
court system, about your participation.  Any publication of this study will not use your name or 
identify you personally.  
  
People who may review your records include: the U.S. Food and Drug Administration (FDA), 
[insert name of site] IRB, National Institutes of Health (NIH), study staff, study monitors, and 
drug companies supporting this study.  Also, the Certificate of Confidentiality does not prevent 
you from releasing information about yourself and your participation in the study. The 
Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of Federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse 
and/or neglect or a risk of harm to you or others, we will tell the proper authorities.] 
 
What will be asked from you in this study?  
In this study you will be asked to come to the study clinic at least 13 times; every week during 
the first six weeks, and then once a month for seven months (total 34 weeks).  If you develop 
HIV during the course of the study, we will ask you to return to the clinic every 12 weeks after 
Week 30 until the study ends at this site.  If we need to do additional tests for your health, we 
may ask you to come for an additional visit.  We will ask you to take Truvada® according to the 
schedule in your group.  You will also be asked to remember every time you have sex and when 
you took Truvada®.  You will be asked to complete a phone interview every week (during 
approximately Weeks 7-30) and a computer questionnaire at Screening, Weeks 6, 18 and 30.  We 
will also take samples of your blood, urine and hair.  If you are unable to come to the clinic for 
your study visits, or if you are unable or not willing to do any of these things, you should not 
take part in this study.   
 
How will study staff keep in contact with you during the study? 
You will be asked to provide your address and phone number(s).  The staff will ask you for 
names of people who will always know how to find you and places where you can be found.  It 
is possible that the staff may visit you at your house or contact one of the people on your contact 
list if you are not able to attend your visits or if the staff have important information for you.  If 
we talk to people on this list, we will not tell them why we are trying to reach you.  If you are not 
willing to give us this information, you should not agree to be in this study.   
 
What happens if you are injured by this research? 
Taking part in this study may put you at risk for personal injury.  You may develop side effects from the 
study drug.  If such side effects happen, study staff will assist you in getting medical care.  [Sites to 
specify institutional policy:]  It is unlikely that you will be injured as a result of taking part in this study.  
If you are injured, the [institution] will give you the treatment needed for your injuries.  You [will/will 
not] have to pay for this treatment.  You will be told where you can get additional treatment for your 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
injuries.  There is no program to pay money or give other forms of compensation for such injuries.  You 
do not give up any legal rights by signing this consent form. 
 
Who can you contact if you have any questions? 
We are happy to answer any questions that you may have.  It may be that you have questions 
about your rights as a study participant or that you think you have been injured because you were 
in this study.  In this case you can contact [insert name of the investigator or other study staff] at 
[[insert telephone number and physical address].   
 
If you have any questions or concerns about whether you should join this study, or your rights as 
a research participant, you should contact [insert name ore title of person on the IRB/EC or other 
organization appropriate for the site] at [insert physical address and telephone number].     
 
What is the cost of study participation? 
There is no cost to you for being in this study.  You will receive [insert local amount] for your 
time, effort, and travel to and from the clinic for each study visit.  In addition, you will receive 
[insert local amount] for each phone call with study staff to discuss your pill-taking and sexual 
behavior.  If study staff has to call you to get this information, you will receive [insert local 
amount] for your time.  You will be given condoms and lubricants, free of charge at each visit. 


HPTN 067, Final Version 5.0 
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The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
 (HPTN 067) 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
US National Institute of Allergy and Infectious Diseases (NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
SCREENING AND ENROLLMENT INFORMED CONSENT FORM 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
SIGNATURE PAGE 
Samples Stored for Future Testing 
Blood: 
_____  My initials indicate that any left over blood samples may be stored for future  
testing after study-related testing has been completed. 
_____  I do not agree to allow left over blood samples to be saved for long-term storage  
and future testing after study-related testing has been completed. 
____  I agree to allow genetic (DNA) testing of my blood for future testing. 
____  I do not agree to allow genetic (DNA) testing of my blood. 
Urine 
____  My initials indicate that any left over urine samples may be stored for future testing after   
            study-related testing has been completed. 
____  I do not agree to allow left over urine samples to be saved for long term storage and  
future testing after study-related testing has been completed. 
 
If you have read this consent form, or had it read and explained to you, and you understand the 
information, and you voluntarily agree to join the study, please sign your name or make your mark below. 
 
____________________ 
________________________ 
______________ 
Participant Name (print) 
Participant Signature 
Date 
 
____________________ 
________________________ 
______________ 
Study Staff Conducting  
Study Staff Signature 
Date 
Consent Discussion (print) 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
SAMPLE FOCUS GROUP INFORMED CONSENT 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
 (HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
(NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
FOCUS GROUP INFORMED CONSENT FORM– STUDY PARTICIPANTS 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
 
Introduction 
You have been invited to participate in a focus group with other participants from the ADAPT 
study: A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use 
of Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis 
(PrEP) (HPTN 067).  A focus group is a discussion among a small group of people about a 
specific set of topics.  Focus groups are led by a focus group leader.  The comments made by 
focus group participants are studied by researchers to learn more about what participants believe 
concerning the topics that they discuss in the group.  The goal of this study is to find out more 
about whether people can take a drug that may prevent HIV infection and what that experience is 
like for them.  The purpose of this focus group is to help us learn more about:  
 How you feel about taking Truvada® according to the schedule in your pill-taking 
schedule group.   
 How taking part in this study made you feel about your risk for HIV.   
 Whether you told your partners, friends and families about taking part in this study.   
 How you feel about working with the staff at the study clinic.   
 
Approximately 36 to 48 participants at [insert site] will take part in these focus groups.  
Approximately 6-8 participants at [insert site] in 6 focus groups (2 focus groups per pill-taking 
schedule group).  These focus groups will take place sometime after your Week 34 study visit.  
An equal number of people will take part in focus groups at [insert other sites] for a total of 
about 108 to 144 participants at all sites.  The information from these focus groups will help us 
better understand what we learn from the rest of the study.  We hope the information we learn 
will help us reduce the number of people who become infected with HIV in the future.  The 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
information gathered from these focus groups will be combined with the rest of the information 
that is collected during this research study.   
 
Procedures 
The focus group will be led by a member of the study team that you did not work with during the 
study.  You will be asked to share your views about the use of certain drugs to prevent HIV 
infection and about how you make decisions about sex.  You will also be asked why you think 
people in the community would or would not want to take part in a study like this one in the 
future.   
 
In the focus group you will be asked to address each other by a made up name in order to ensure 
privacy and confidentiality.  If any of the questions make you upset you may choose to leave the 
focus group at any time, or in some cases, the focus group leader may ask you to take a break or 
leave the focus group altogether.  You will also be provided with contact and referral information if 
any of the questions raise issues that you would like to talk about at a later time.   
 
Your participation in this focus group is voluntary.  You are not required to participate in this 
focus group in order to remain in the rest of the study (HPTN 067).  Although we hope that you 
will be comfortable answering all of the questions openly and honestly, please keep in mind that 
you may refuse to answer any of the questions, or stop your participation completely, at any 
time.  If you choose not to participate in a focus group discussion or refuse to answer any of the 
questions, you will not lose any of the benefits of your regular medical care at [study clinic]. 
 
[To be modified to reflect site practices:  The focus group will take place in a location  that the 
study staff have determined will provide you with privacy and confidentiality such as a room at 
the clinic, or other appropriate places.  The study team will talk with you about this so you know 
where to go for the focus group.  ] 
 
Each focus group should take about 2 hours.  There will be no cost to you for participation.  You 
will receive [insert local amount] for your time and effort. 
 
To help assure that we get the best understanding possible from each focus group the participant 
answers will be recorded.  After the focus group is finished, the recording will be typed (called 
a transcript) by qualified personnel.  All identifying information will be removed from the 
transcript.  Your name will not be included on the transcript.  These recordings will be destroyed 
after all analysis is completed.   
 
What Are the Potential Benefits? 
You may not receive any other direct benefit from being in this study; however, you or others in 
your community may benefit from this study later.  The information gathered during this study 
may help to prevent HIV and other infections.  This may be beneficial to you and your 
community.   
 
What Are the Possible Risks or Discomforts? 
The questions we will ask you may make you feel uneasy.  We hope that the focus group 
procedures described above will protect your confidentiality and minimize your discomfort when 
discussing sensitive topics.  However, the greatest risk may involve your privacy and 


HPTN 067, Final Version 5.0 
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June 10, 2013 
 
confidentiality.  This is because confidentiality is limited in a focus group setting, since the other 
members of the focus groups are present during the discussion and we cannot guarantee that they 
will not discuss what you will say later.  Additional steps that the study team has taken to protect 
your privacy are described below.   
  
How Will Your Privacy Be Protected? 
Every effort will be made to keep your personal information confidential.  Your personal 
information (name, address, phone number) will be protected by the research clinic.  Your name, 
or anything else that might identify you personally, will not be used in any publication of 
information about this study.  We encourage you to make up a name or use a nickname during 
this focus group.   
 
The United States Food and Drug Administration (FDA) has been informed of this study and has 
allowed it to be done.  Your records may be reviewed by the sponsor of the study (US National Institutes 
of Health (NIH), US NIMH) and their representatives, [insert name of site] IRB/EC, study staff, study 
monitors and [insert applicable local regulatory authorities]..   
 
[For US site only: We cannot guarantee absolute confidentiality.  In addition to the efforts made 
by the study staff to help keep your personal information confidential, we have obtained a 
Certificate of Confidentiality from the U.S. Federal Government.  This certificate protects 
researchers from being forced to tell people who are not connected with this study, such as the 
court system, about your participation.  Any publication of this study will not use your name or 
identify you personally.  
  
People who may review your records include: the U.S. Food and Drug Administration (FDA), 
[insert name of site] IRB, National Institutes of Health (NIH), study staff, study monitors, and 
drug companies supporting this study.  Also, the Certificate of Confidentiality does not prevent 
you from releasing information about yourself and your participation in the study. The 
Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of Federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse 
and/or neglect or a risk of harm to you or others, we will tell the proper authorities.] 
 
 


HPTN 067, Final Version 5.0 
Page 123 of 133 
June 10, 2013 
 
Persons to Contact for Problems or Questions 
For questions about this study or a research-related injury, contact: 
 
 [site insert name of the investigator or other study staff] 
 [site insert telephone number and physical address of above] 
 
For questions about your rights as a research participant, contact: 
 
 [site insert name or title of person on the Institutional Review Board (IRB)/Ethics 
Committee (EC) or other organization appropriate for the site] 
 [site insert telephone number and physical address of above] 
 
 


HPTN 067, Final Version 5.0 
Page 124 of 133 
June 10, 2013 
 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
(HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
US National Institute of Allergy and Infectious Diseases (NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
FOCUS GROUP INFORMED CONSENT FORM – STUDY PARTICIPANTS 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
 
SIGNATURE PAGE 
 
If you have either read or have heard the information in this consent form, if all of your questions 
have been answered and if you agree to take part in the focus group, please sign your name on 
the line below. 
 
 
 
_______________________  
 
____________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
_______________________  
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
 
 
Consent Discussion (print) 
 
 
 
 


HPTN 067, Final Version 5.0 
Page 125 of 133 
June 10, 2013 
 
SAMPLE KEY INFORMANT INTERVIEW INFORMED CONSENT FOR SELECTED 
STUDY PARTICIPANTS 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
(HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
(NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
KEY INFORMANT INTERVIEW INFORMED CONSENT FORM FOR SELECTED 
STUDY PARTICIPANTS  
 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
 
Introduction 
You have been invited to participate in an interview to discuss your study participation in the 
ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of 
the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure 
Prophylaxis (PrEP) (HPTN 067).  .  A Key Informant Interview is an individual discussion about 
a specific set of topics.  The purpose of this interview is to help us learn more about:  
 
 Perceived feasibility and acceptability of each of the regimens (pill-taking schedule) 
 Facilitators and barriers to pill-taking overall and in relation to specific regimens 
 Preferred regimen 
 Best strategies to support pill-taking 
 Continued condom use in the context of PrEP trials 
 Best strategies to support staff and counselors working with PrEP users 
 
Two persons per study group at each of the three study centers will participate in key informant 
interviews after they have completed their Week 34 visit.  This means a total of six participants 
at [insert site] and an additional twelve participants at [site 2, site 3].  The information from these 
interviews will help us better understand what we learn from the rest of the study.  We hope the 


HPTN 067, Final Version 5.0 
Page 126 of 133 
June 10, 2013 
 
information we learn will help us reduce the number of people who become infected with HIV in 
the future. 
 
The information gathered from these interviews will be combined with the rest of the 
information that is collected during this research study.   
 
Procedures 
The interview will be led by a member of the research team that you did not work with during 
the study.  You will be asked to share your views about the use of certain drugs to prevent HIV 
infection and about how [insert local population] make decisions about sex.  You will also be 
asked why you think people in the community would or would not want to take part in a study 
like this one in the future.  You will be asked to share your views about the use of the study 
regimen you were assigned and the regimen demands.   
 
If any of the questions make you upset either you or the interviewer may stop the interview at any 
time.  You will also be provided with contact and referral information if any of the questions raise 
issues that you would like to talk about at a later time.   
 
Your participation in this interview is voluntary.  You are not required to participate in this 
interview in order to remain in the rest of the study (HPTN 067).  Although we hope that you 
will be comfortable answering all of the questions openly and honestly, please keep in mind that 
you may refuse to answer any of the questions, or stop your participation completely, at any time 
and you will not lose any of the regular benefits of your regular medical care at [study clinic].   
 
[To be modified to reflect site practices: The interview will take place in a location that the 
study staff have determined will provide you with privacy and confidentiality such as the clinic, 
or other appropriate places.  The study team will talk with you about this so you know where to 
go for the interview. 
 
Each interview should take about 2 hours.  There will be no cost to you for participation.  You 
will receive [insert local amount] for your time and effort. 
 
What Are the Potential Benefits? 
You may not receive any other direct benefit from being in this study; however, you or others in 
your community may benefit from this study later.  The information gathered during this study 
may help to prevent HIV and other infections.  This may be beneficial to you and your 
community.   
 
What Are the Possible Risks or Discomforts? 
To minimize any discomfort and to protect your privacy the interview will be conducted in a 
private area that will allow you to speak comfortably without being overheard.  Although we 
hope that you will be comfortable answering all of the questions openly and honestly, please 
keep in mind that you may refuse to answer any of the questions, or stop the interview 
completely, at any time.  The greatest risk may involve your privacy and confidentiality.  The 
steps that the study team has taken to protect your privacy are described below.   
  
How Will Your Privacy Be Protected? 


HPTN 067, Final Version 5.0 
Page 127 of 133 
June 10, 2013 
 
Every effort will be made to keep your personal information confidential.  Your personal 
information (name, address, phone number) will be protected by the research clinic.  Your name, 
or anything else that might identify you personally, will not be used in any publication of 
information about this study.   
 
To help assure that we get the best understanding possible from the interview your answers will 
be recorded.  After the interview is finished, the recording will be typed (called a transcript) by 
qualified personnel.  All identifying information will be removed from the transcript.  Your name 
will not be included on the transcript.  These recordings will be destroyed after all analysis is 
completed. 
 
Your records may be reviewed by the sponsor of the study (US National Institutes of Health (NIH), US 
NIMH) and their representatives, [insert name of site] IRB/EC, study staff, study monitors and [insert 
applicable local regulatory authorities]..   
 
 [For US site only: We cannot guarantee absolute confidentiality.  In addition to the efforts made 
by the study staff to help keep your personal information confidential, we have obtained a 
Certificate of Confidentiality from the U.S. Federal Government.  This certificate protects 
researchers from being forced to tell people who are not connected with this study, such as the 
court system, about your participation.  Any publication of this study will not use your name or 
identify you personally.  
  
People who may review your records include: the U.S. Food and Drug Administration (FDA), 
[insert name of site] IRB, National Institutes of Health (NIH), study staff, study monitors, and 
drug companies supporting this study.  Also, the Certificate of Confidentiality does not prevent 
you from releasing information about yourself and your participation in the study. The 
Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of Federally funded projects or for 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse 
and/or neglect or a risk of harm to you or others, we will tell the proper authorities.] 
 
Persons to Contact for Problems or Questions 
For questions about this study or a research-related injury, contact: 
 
 [site insert name of the investigator or other study staff] 
 [site insert telephone number and physical address of above] 
 
For questions about your rights as a research participant, contact: 
 
 [site insert name or title of person on the Institutional Review Board (IRB)/Ethics 
Committee (EC) or other organization appropriate for the site] 
 [site insert telephone number and physical address of above] 
 
 


HPTN 067, Final Version 5.0 
Page 128 of 133 
June 10, 2013 
 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
(HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
US National Institute of Allergy and Infectious Diseases (NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
KEY INFORMANT INTERVIEW INFORMED CONSENT FORM FOR SELECTED 
STUDY PARTICIPANTS 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
 
SIGNATURE PAGE 
 
If you have either read or have heard the information in this consent form, if all of your questions 
have been answered and if you agree to take part in the Key Informant Interview, please sign 
your name on the line below. 
 
 
 
_______________________  
 
____________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
_______________________  
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
 
 
Consent Discussion (print) 
 
 
 


HPTN 067, Final Version 5.0 
Page 129 of 133 
June 10, 2013 
 
SAMPLE KEY INFORMANT INTERVIEW INFORMED CONSENT FOR CLINIC 
STAFF 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
(HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
(NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
KEY INFORMANT INTERVIEW INFORMED CONSENT FORM FOR SELECTED 
CLINIC STAFF  
 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
 
Introduction 
You have been invited to participate in a research study which includes an interview to discuss 
your role as a provider to participants in their counseling or pill-taking in the ADAPT study: A 
Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of 
Intermittent Oral Emtricitabine/Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis (PrEP) 
(HPTN 067) study.  A Key Informant Interview is an individual discussion about a specific set of 
topics.  The purpose of this interview is to help us learn more about:  
 
 Whether you think these regimens (pill-taking schedules) will work for and are accepted 
by participants 
 What helps or prevents how well participants follow their regimens overall and in 
relation to specific regimens 
 Preferred regimen 
 Best strategies to support pill-taking 
 Continued condom use in the context of PrEP trials 
 Best strategies to support staff and counselors working with PrEP users 
 


HPTN 067, Final Version 5.0 
Page 130 of 133 
June 10, 2013 
 
Approximately 3-4 clinic staff members directly involved in counseling or pill-taking during 
HPTN 067 at each of the three study centers will participate in key informant interviews after all 
participants have completed their Week 34 visit.  This means a total of about 9-12 participants 
from all the  study centers.  The information from these interviews will help us better understand 
what we learn from the rest of the study.  We hope the information we learn will help us reduce 
the number of people who become infected with HIV in the future. 
 
Clinic Staff at [insert site] that provided care in the form of counseling or pill-taking in the 
Behavioral Aspects of PrEP Counseling for Intermittent Exposure (HPTN 067) will participate in 
these interviews after all participants have completed the Week 34 study visit.  The information 
gathered from these interviews will be combined with the rest of the information that is collected 
during this research study.   
 
Procedures 
[Sites to adjust as needed]  The interview will be led by an individual that is not directly a 
member of our research team here at [insert clinic], but is affiliated with our overall research 
organization.  The individual will not be someone who has a supervisory role for your position.  
You will be asked to share your views about the use of certain drugs to prevent HIV infection 
and about how [insert local population] make decisions about sex.  You will also be asked why 
you think people in the community would or would not want to take part in a study like this one 
in the future.  You will be asked to share your views about the use of each of the regimens and 
how participants interacted with the study and the regimen demands. 
 
If any of the questions make you upset either you or the interviewer may stop the interview at any 
time.  You will also be provided with contact and referral information if any of the questions raise 
issues that you would like to talk about at a later time.   
 
Your participation in this interview is voluntary.  You are not required to participate in this 
interview in order to remain employed at [insert site].  Although we hope that you will be 
comfortable answering all of the questions openly and honestly, please keep in mind that you 
may refuse to answer any of the questions, or stop your participation completely, at any time. 
 
[To be modified to reflect site practices]: The interview will take place in a location that the 
study team have determined will provide you with privacy and confidentiality.  The study team 
will talk with you about this so you know where to go for the interview. 
 
Each interview should take about 2 hours.  There will be no cost to you for participation.  You 
will receive [insert local amount] for your time and effort. 
 
What Are the Potential Benefits? 
You may not receive any other direct benefit from being in this study; however, you or others in 
your community may benefit from this study later.  The information gathered during this study 
may help to prevent HIV and other infections.  This may be beneficial to you and your 
community.   
 


HPTN 067, Final Version 5.0 
Page 131 of 133 
June 10, 2013 
 
What Are the Possible Risks or Discomforts? 
To minimize discomfort and to protect your privacy the interview will be conducted in a private 
area that will allow you to speak comfortably without being overheard.  Although we hope that 
you will be comfortable answering all of the questions openly and honestly, please keep in mind 
that you may refuse to answer any of the questions, or stop the interview completely, at any time.  
The greatest risk may involve your privacy and confidentiality.  The steps that the study team has 
taken to protect your privacy are described below.   
 
What are the alternatives to participating in this study? 
[Sites to amend as applicable]  If you choose not to take part in this study, it will have no effect 
on your employment at this site.  We may have other studies now or in the future at this site, 
although there are none currently planned.    
 
How Will Your Privacy Be Protected? 
Every effort will be made to keep your personal information confidential.  Your personal 
information (name, address, phone number) will be protected by the study team.  Your name, or 
anything else that might identify you personally, will not be used in any publication of 
information about this study.  You will be identified by a code number known only to you and 
the study staff.  This number – not your name – will mark all information about you.  However, 
because there are only a few staff at your site working on this study, it is likely that researchers 
will know your identity and the information you share. 
 
To help assure that we get the best understanding possible from the interview your answers will 
be recorded.  After the interview is finished, the recording will be typed (called a transcript) by 
qualified personnel.  All identifying information will be removed from the transcript.  Your name 
will not be included on the transcript.  The recording will be destroyed after all analysis is 
completed.   
 
Your records may be reviewed by the US Food and Drug Administration (FDA), Gilead Sciences, Inc, 
the OHRP and the US Centers for Disease Control and Prevention (CDC) as well as the sponsor of the 
study (US National Institutes of Health (NIH), US NIMH) and their representatives, local regulatory 
authorities, [insert name of site] IRB/EC, study staff and study monitors.   
 
[For US site only: We cannot guarantee absolute confidentiality.  In addition to the efforts made 
by the study staff to help keep your personal information confidential, we have obtained a 
Certificate of Confidentiality from the U.S. Federal Government.  This certificate protects 
researchers from being forced to tell people who are not connected with this study, such as the 
court system, about your participation.  Any publication of this study will not use your name or 
identify you personally.  
  
People who may review your records include: the U.S. Food and Drug Administration (FDA), 
[insert name of site] IRB, National Institutes of Health (NIH), study staff, study monitors, and 
drug companies supporting this study.  Also, the Certificate of Confidentiality does not prevent 
you from releasing information about yourself and your participation in the study. The 
Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of Federally funded projects or for 


HPTN 067, Final Version 5.0 
Page 132 of 133 
June 10, 2013 
 
information that must be disclosed in order to meet the requirements of the federal Food and 
Drug Administration (FDA). 
  
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse 
and/or neglect or a risk of harm to you or others, we will tell the proper authorities.] 
 
 
Persons to Contact for Problems or Questions 
For questions about this study or a research-related injury, contact: 
 
 [site insert name of the investigator or other study staff] 
 [site insert telephone number and physical address of above] 
 
For questions about your rights as a research participant, contact: 
 
 [site insert name or title of person on the Institutional Review Board (IRB)/Ethics 
Committee (EC) or other organization appropriate for the site] 
 [site insert telephone number and physical address of above] 
 
 


HPTN 067, Final Version 5.0 
Page 133 of 133 
June 10, 2013 
 
The ADAPT study: A Phase II, Randomized, Open-Label, Pharmacokinetic and 
Behavioral Study of the Use of Intermittent Oral Emtricitabine/Tenofovir Disoproxil 
Fumarate Pre-Exposure Prophylaxis (PrEP) 
(HPTN 067) 
 
Final Version 5.0 
June 10, 2013 
DAIDS Document ID: 10852 
 
US National Institute of Allergy and Infectious Diseases (NIAID) 
US National Institute of Mental Health (NIMH) 
 US National Institutes of Health (NIH) 
 
Sponsor: NIAID, NIMH, NIH 
 
KEY INFORMANT INTERVIEW INFORMED CONSENT FORM FOR CLINIC STAFF 
WHO WERE DIRECTLY INVOLVED WITH PARTICIPANTS IN COUNSELING OR 
PILL-TAKING 
 
INVESTIGATOR OF RECORD: [insert name] 
PHONE: 
[insert number] 
 
 
SIGNATURE PAGE 
 
If you have either read or have heard the information in this consent form, if all of your questions 
have been answered and if you agree to take part in the Key Informant Interview, please sign 
your name on the line below. 
 
 
 
_______________________  
 
____________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
 
_______________________  
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
 
 
Consent Discussion (print)