Clinical trial NCT02584140
Conditions: HIV Prevention
Keywords: PrEP Pre-exposure Prophylaxis HIV Prevention
Sponsor: University of California, Los Angeles
Start date: 2016-05-01; Completion date: 2019-06-14
Enrollment: 136 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test a program that uses drug level monitoring, text messaging ("iTAB") and personalized counseling with HIV prevention services, including PrEP (medicine that can help prevent HIV infection when taken daily).

Detailed description:
This is an open-label single-arm longitudinal clinical trial to estimate medication adherence and retention in a PrEP HIV prevention program that implements a combination intervention strategy that uses text-messages (iTAB) and a staged adherence counseling support strategy titrated from real-time drug levels in women at-risk for HIV acquisition.

A total of 135 participants will receive the combined intervention of text messaging adherence reminders and adherence support. The text messaging system consists of daily, personalized, automated 2-way text messages to maintain adherence and retention. Participants that have a low intracellular tenofovir diphosphate (TFV-DP) concentration will receive escalated, targeted adherence support. All participants will receive access to PrEP in accordance with standardized comprehensive methods of prescribing and clinical assessments that include safety monitoring as well as regular HIV and sexually transmitted infection (STI) screening. All participants will be followed for 48 weeks after enrollment and will receive a post study follow-up at 60 weeks. The primary endpoint will be measured at 48 weeks.

Arms: arm 1: All participants will be assigned to this arm of the study.
Interventions: intervention 1: Text Messaging intervention 2: Adherence Counseling intervention 3: Daily Oral PrEP
Intervention descriptions: intervention 1: All participants assigned to the iTAB intervention will receive daily dosing reminders that will be sent for the first 6 weeks and then continue with reminders for the duration of the study. intervention 2: All participants assigned to the counseling intervention will receive sexual health and medication adherence counseling at each study visit. Participants with suboptimal adherence (TFV-DP levels of \<1050 fmol/punch (representing fewer than mean 6-7 daily doses per week)) will trigger a targeted iNSC session. Participants with two TFV-DP levels of \<1050 fmol/punch will trigger PrEP Steps, a higher intensity adherence counseling intervention consisting of four 50-minute counseling sessions and 2 booster counseling sessions. intervention 3: All participants will be offered daily oral emtricitabine/tenofovir disoproxil fumarate for Pre-exposure Prophylaxis.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version 1.4  
PrEP Adherence Enhancement Guided by iTAB and Drug Levels for Women (AEGIS)  
 
Version 1.4 
 
A Pilot Demonstration Project to Operationalize  
Pre-exposure Prophylaxis as part of Combination HIV Prevention  
with Intensified Adherence Support Among Women in  
Los Angeles and San Diego Counties 
 
 
 
 
Sponsored by: 
  
California HIV Research Program 
Gilead Sciences (Pending) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 1.4 
July 29, 2016 
 
 
 
 


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TABLE OF CONTENTS  
 
1. PARTICIPATING SITES ................................................................................................... 5 
2. KEY PERSONNEL ........................................................................................................... 5 
3. GLOSSARY OF TERMS ................................................................................................. 10 
4. STUDY SCHEMA ......................................................................................................... 12 
5. STUDY OBJECTIVES AND HYPOTHESES ....................................................................... 14 
 
5.1. 
Study Primary Objective ................................................................................. 14 
 
5.2. 
Study Secondary Objectives ............................................................................ 14 
 
5.3. 
Exploratory Objectives .................................................................................... 15 
6. PROGRAM BACKGROUND AND RATIONALE ............................................................... 15 
7. RATIONALE FOR TREATMENT REGIMENS ................................................................... 17 
8. RATIONALE FOR DOSING STRATEGY ........................................................................... 18 
9. RATIONALE FOR CONCOMITANT SERVICES ................................................................. 18 
10. RATIONALE FOR ADHERENCE MONITORING ............................................................... 19 
11. RATIONALE FOR DEMONSTRATION PROJECT ............................................................. 20 
12. ENROLLMENT OF PARTICIPANTS ................................................................................ 22 
13. INCLUSION CRITERIA .................................................................................................. 22 
14. EXCLUSION CRITERIA ................................................................................................. 23 
15. STUDY ENROLLMENT PROCEDURES ............................................................................ 23 
 
15.1. Screening ........................................................................................................... 23 
 
15.2. Baseline Visit ..................................................................................................... 23 
16. REGIMENS, ADMINISTRATION, AND DOSING ............................................................. 24 
 
16.1. High Risk Exposures While on PrEP .................................................................... 24 
 
16.2. Missed Dose Instructions ................................................................................... 24 
 
16.3. Duration of Therapy ........................................................................................... 24 
 
16.4. Drug Supply, Distribution, and Accountability .................................................... 24 
 
16.5. Adherence Assessment and Intervention ........................................................... 25 
17. FERTILITY INTENTIONS ASSESSMENT .......................................................................... 28 
18. STUDY ASSESSMENTS ................................................................................................ 28 
19. RISK REDUCTION COUNSELING INTERVENTION .......................................................... 29 


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20. SCHEDULE OF CLINICAL AND LABORATORY EVALUATIONS ......................................... 30 
21. CLINICAL ASSESSMENTS ............................................................................................. 32 
 
21.1. Complete Physical Exam .................................................................................... 32 
 
21.2. Targeted Physical Exam ..................................................................................... 32 
 
21.3. Review of Systems ............................................................................................. 32 
 
21.4. Concomitant Medications .................................................................................. 32 
22. HIV LABORATORY TESTING ........................................................................................ 32 
23. ADDITIONAL LABORATORY TESTING .......................................................................... 33 
 
23.1. STI Screening ..................................................................................................... 33 
 
23.2. Hepatitis Testing ................................................................................................ 33 
 
23.3. Serum Creatinine ............................................................................................... 33 
 
23.4. Liver Function Tests ........................................................................................... 33 
 
23.5. Complete Blood Count ....................................................................................... 33 
 
23.6. Pregnancy testing .............................................................................................. 33 
24. PLASMA COLLECTION ................................................................................................. 33 
25. DRIED BLOOD SPOT COLLECTION ............................................................................... 34 
26. POST-TRIAL ACCESS TO PREP ..................................................................................... 34 
27. CLINICAL MANAGEMENT ISSUES ................................................................................ 34 
 
27.1. Toxicity Management ........................................................................................ 34 
 
27.2. Social Harms ...................................................................................................... 35 
 
27.3. Management of Suspected Acute Seroconversion (Primary HIV Infection - PHI) . 36 
 
27.4. Seroconversion Schedule of Events .................................................................... 37 
28. CRITERIA FOR DISCONTINUATION .............................................................................. 37 
 
28.1. Temporary Medication Interruption .................................................................. 37 
 
28.2. Permanent Medication Discontinuation ............................................................. 37 
 
28.3. Program Discontinuation ................................................................................... 38 
29. DATA COLLECTION, STORAGE, AND MONITORING ..................................................... 39 
 
29.1. Protocol ............................................................................................................. 39 
 
29.2. Secure Database ................................................................................................ 39 
 
29.3. Participant Confidentiality ................................................................................. 39 
 
29.4. Data Collection and Monitoring ......................................................................... 39 


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29.5. Clinical Site Monitoring and Record Availability ................................................. 40 
30. STATISTICAL ANALYSIS AND CONSIDERATIONS .......................................................... 40 
 
30.1. Design and Sample Size ...................................................................................... 40 
 
30.2. Statistical Analysis Plan ...................................................................................... 41 
31. INFORMED CONSENT ................................................................................................. 42 
32. EXPERTS IN HIV CLINICAL CARE .................................................................................. 43 
33. HUMAN PARTICIPANTS .............................................................................................. 43 
 
33.1. Institutional Review Board (IRB) Review and Informed Consent ........................ 43 
 
33.2. Participant Confidentiality ................................................................................. 43 
34. PUBLICATIONS AND FINDINGS ................................................................................... 43 
35. BIOHAZARD CONTAINMENT ...................................................................................... 43 
36. FUNDING ................................................................................................................... 44 
37. REFERENCES ............................................................................................................... 45 
 
 
 


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1. PARTICIPATING SITES 
 
Gleicher/Chen Health Center 
AIDS Project Los Angeles Health & Wellness 
3743 S. La Brea Ave. 
Los Angeles, CA 90016 
(323) 329-9900 
 
T.H.E. Clinic at Ruth Temple 
3834 S. Western Avenue 
Los Angeles, CA 90062 
(323) 730-1920 
 
UCSD Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103  
(619) 543-8080 
 
USC 5P21 Rand Schrader Clinic 
1300 N. Mission Road 
Los Angeles, CA 90033 
(323) 343-8255 
 
Los Angeles Biomedical Research Institute at Harbor-UCLA 
1124 W. Carson St 
Los Angeles, CA 90033 
(323) 343-8255 
 
 
2. KEY PERSONNEL 
 
CCTG 
 
Protocol Co-Chairs 
Jill Blumenthal, MD 
Assistant Clinical Professor 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St, Suite A 
San Diego, CA 92103 
(619) 543-8080 
 
Sheldon Morris, MD, MPH 
Associate Professor of Medicine 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St, Suite A 
San Diego, CA 92103 
(619) 542-8080 
shmorris@ucsd.edu 
 
Co-Investigators 
David J, Moore, PhD 
Associate Professor of Psychiatry 
University of California, San Diego 
HIV Neurobehavioral Research Program 


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220 Dickinson St, Suite B 
San Diego, CA 92103 
(619) 543-5093 
djmoore@ucsd.edu 
 
Jamila K. Stockman, PhD, MPH 
Assistant Professor of Medicine 
Division of Global Public Health  
University of California, San Diego 
9500 Gilman Dr., MC 0507 
La Jolla, CA 92093-0507 
(858) 822-4652 
jstockman@ucsd.edu 
 
Michael Dubé, MD 
Professor of Medicine 
Keck School of Medicine 
University of Southern California 
1300 N. Mission Road, Room 349 
Los Angeles, CA 90033 
(323) 343-8288 
mdube@usc.edu 
 
Joel Milam, PhD 
Assistant Professor of Preventative Medicine 
University of Southern California 
1441 Eastlake Ave. 
Los Angeles, CA 90033 
joel.milam@med.ucsd.edu 
 
Eric S. Daar, MD 
Chief, Division of HIV Medicine 
Harbor-UCLA Medical Center 
Professor of Medicine 
David Geffen School of Medicine at UCLA 
1124 W. Carson St., CDCRC 205 
Torrance, CA 90502 
(424) 201-3000 x7317 
edaar@labiomed.org 
 
Katya Corado, MD 
Health Sciences Assistant Professor  
David Geffen School of Medicine at UCLA 
Harbor-UCLA Medical Center 
1124 W. Carson St., CDCRC 205 
Torrance, CA 90502 
(310) 222-2159 
krcalvo@labiomed.org 
 
Clinical Trials Specialist 
Eric E. Ellorin 
Staff Research Associate 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 


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(619) 543-8080 
eellorin@ucsd.edu 
 
Statistician 
Sonia Jain, PhD 
Professor, Division of Biostatistics and Bioinformatics 
Director, CCTG Biostatistics Core 
Co-Director, Biostatistics Research Center (BRC) 
University of California, San Diego 
9500 Gilman Dr., MC 0725 
La Jolla, CA 92093-0725 
(858) 822-2388 
sojain@ucsd.edu 
 
Study Monitor and Data Unit 
Edward Seefried, RN 
Medical Monitor, Study Coordinator, CCTG Data Unit 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
(619) 543-8080 
eseefried@ucsd.edu 
 
Jason Young, PhD 
Assistant Professor of Medicine 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
(619) 543-8080 
jay007@ucsd.edu 
 
Protocol Pharmacist 
Leticia Muttera, PharmD 
Investigational Pharmacist 
University of California, San Diego 
Antiviral Research Center 
220 Dickinson St., Suite A 
San Diego, CA 92103 
(619) 543-8080 
lmuttera@ucsd.edu  
 
 
LAC-PATH 
 
UCLA Protocol Co-Chairs  
Raphael J. Landovitz, MD MSc 
Associate Professor of Medicine 
UCLA Center for Clinical AIDS Research & Education  
11075 Santa Monica Blvd, Suite 100 
Los Angeles, CA 90025 
(310) 825-6689 
rlandovitz@mednet.ucla.edu 
 
Co-Investigators 


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Amy Rock Wohl, MPH PhD 
Chief Epidemiologist  
Los Angeles County Division of HIV and STD Programs 
Los Angeles County Department of Public Health 
600 S. Commonwealth Avenue, Suite 1920 
Los Angeles, CA  90005-4001 
(213) 351-8140 
awohl@ph.lacounty.gov 
 
Sonal Kulkarni, MD, MPH 
Medical Director 
Los Angeles County Division of HIV and STD Programs 
Los Angeles County Department of Public Health 
600 S. Commonwealth Avenue, Suite 1920 
Los Angeles, CA  90005-4001 
(213) 351-8003 
skulkarni@ph.lacounty.gov 
 
Risa M. Hoffman, MD, MPH 
Assistant Clinical Professor 
Center for Clinical AIDS Research and Education 
11075 Santa Monica Blvd, Suite 100 
Los Angeles, CA 90025 
(310) 825-6689 
rhoffman@mednet.ucla.edu 
 
Project Director  
Ryan Kofron, MSSA 
Biomedical HIV Prevention Programs Project Director 
UCLA Center for Clinical AIDS Research & Education  
11075 Santa Monica Blvd, Suite 100 
Los Angeles, CA 90025 
(310) 825-1949 
rkofron@mednet.ucla.edu 
 
Gleicher/Chen Health Center 
Gifty Maria Ntim, MD, MPH 
Site Medical Director 
AIDS Project Los Angles Health & Wellness 
3743 S. La Brea Ave. 
Los Angeles, CA 90016 
(323) 329-9929  
gntim@apla.org 
 
Melinda Serrano, RN, MSN, FNP, PA, PHN 
Site Provider 
AIDS Project Los Angles Health & Wellness 
3743 S. La Brea Ave. 
Los Angeles, CA 90016 
(323) 329-9925 
mserrano@apla.org 
 
Susan Alvarado, MPH 
Site Project Coordinator 
AIDS Project Los Angles Health & Wellness 
3743 S. La Brea Ave. 


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Los Angeles, CA 90016 
(323) 329-9024 
salvarado@apla.org 
 
T.H.E. (To Help Everyone) Clinic at Ruth Temple 
Derrick L. Butler, MD 
Site Medical Director 
3834 S. Western Avenue 
Los Angeles, CA 90062 
(323) 295-6571 
dbutler@tohelpeveryone.org 
 
Protocol Pharmacy 
Walgreens #16368 
3745 S. La Brea Ave suite C & D 
Los Angeles, Ca 90016 
Phone: 323-801-0261 
Fax : 323-801-0262 
Cell: 714-234-0458  
 
Other Key Personnel 
 
Adherence and Behavioral Consultant 
K. Rivet Amico, PhD 
Research Associate Professor 
University of Michigan 
Department of Health Behavior and Health Education 
(810) 360-8716 
rivetamico@comcast.net 
 
Adherence Intervention Collaborators 
Steve Safren, PhD 
Professor of Psychology, Department of Psychiatry 
Massachusetts General Hospital / Harvard Medical School 
One Bowdoin Square, 7th Floor 
Boston, MA 02114 
(617) 724-0817 
ssafren@partners.org    
  
Christina Psaros, Ph.D. 
Assistant Professor of Psychology, Department of Psychiatry 
Massachusetts General Hospital / Harvard Medical School 
One Bowdoin Square, 7th Floor 
Boston, MA 02114 
(617) 724-5600 
cpsparos@partners.org 
 
Protocol Pharmacologist 
Peter Anderson, PharmD 
Assistant Professor, School of Pharmacy 
University of Colorado 
12850 E. Montview Blvd. V20-4101  
Aurora, CO 80045 
(303) 724-6128  
peter.anderson@ucdenver.edu 
 
 


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3. GLOSSARY OF TERMS 
 
AE 
Adverse Event 
AEGIS 
Adherence Enhancement Guided by iTAB and Drug Levels for 
Women 
ALERT 
Active Linkage, Engagement, and Retention to Treatment 
ALT (SGPT) 
Alanine Aminotransferase 
ART 
Antiretroviral Therapy 
AST (SGOT) 
Aspartate Aminotransferase 
CASI 
Computer Assisted Self-Interviewing 
CBC 
Complete Blood Count 
CBT 
Cognitive Behavioral Therapy 
CCTG 
California Collaborative Treatment Group 
CD4 
CD4 Lymphocytes 
CDC 
Centers for Disease Control and Prevention 
CHRP 
California HIV/AIDS Research Program 
CRF 
Case Report Form 
CM  
Contingency Management 
CT 
Chlamydia 
D/C 
Discontinue 
DHHS 
Department of Health and Human Services 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety and Monitoring Board 
ELISA 
Enzyme-linked Immunosorbent Assay 
FDA 
Food and Drug Administration 
FTC 
Emtricitabine 
GC 
Gonorrhea 
HAART 
Highly Active Antiretroviral Therapy 
HBsAg/Ab 
Hepatitis B surface Antigen/Antibody 
HCG 
Human Chorionic Gonadotropin  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV-1 
Human Immunodeficiency Virus – 1 
IDU 
Intravenous Drug Use 
IRB 
Institutional Review Board 
iTAB 
Individualized Texting for Adherence Building 
LAC 
Los Angeles County 
LFT 
Liver Function Test 
MFM 
Maternal Fetal Medicine 
mITT 
Modified Intention to Treat 
MSM 
Men who have Sex with Men 
NAAT 
Nucleic Acid Amplification Test 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
OB/GYN 
Obstetrics and Gynecology 
PBMC 
Peripheral Blood Mononuclear Cells 
PEP 
Post-Exposure Prophylaxis 
PI 
Protease Inhibitor 
PLWH 
Persons Living With HIV/AIDS 
PHI 
Primary HIV Infection 
PID 
Patient Identification Number 
PK-PD 
Pharmacokinetic-Pharmacodynamic 
PrEP 
Pre-Exposure Prophylaxis 


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QA/QC 
Quality Assurance/Quality Control 
RNA 
Ribonucleic Acid 
RPR  
Rapid Plasmin Reagin 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SoC 
Standard of Care 
SOE 
Schedule of Events 
SOP 
Standard Operating Procedure 
STI 
Sexually Transmitted Infection 
TBIL 
Total Bilirubin 
TDF 
Tenofovir Disproxil Fumarate 
TPB  
Theory of Planned Behavior 
TPPA 
Treponema Pallidum Particle Agglutination Assay 
VAS 
Visual Analog Scale 
VDRL  
Venereal Disease Research Laboratory 
 
 


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4. STUDY SCHEMA 
 
Design: 
AEGIS is an open-label single-arm longitudinal clinical trial to estimate 
medication adherence and retention in a PrEP HIV prevention 
program that implements a combination intervention strategy that 
uses text-messages (iTAB) and a staged adherence counseling 
support strategy titrated from real-time drug levels in women at-risk for 
HIV acquisition. 
 
Duration: 
Each participant will be on PrEP with medication adherence support 
for 48 weeks after enrollment with a post study follow-up at 60 weeks. 
The primary endpoint will be measured at 48 weeks. 
 
Sample Size: 
A total of 135 participants will be enrolled (50 at CCTG sites and 85 at 
the LAC-PATH site). 
 
Study Population: 
Eligible participants will include HIV-uninfected cis-gender women at 
least 18 years of age and who are at risk for HIV acquisition. 
 
Intervention: 
All participants will be given PrEP with tenofovir disoproxil fumarate 
(TDF) + emtricitabine (FTC) fixed dose combination prescribed to be 
taken once daily. All participants will receive the combined 
intervention of iTAB text messaging adherence reminders and 
intensive Next Step Counseling (iNSC). The iTAB system consists of 
daily, personalized, automated 2-way text messages to maintain 
adherence and retention, and iNSC is a brief, strengths-based 
discussion initiated at each clinic visit, typically with delivery of 
negative HIV-test results, focused on promotion of sexual health 
protection through behavioral and biomedical (adherence) strategies. 
Participants that have a low intracellular tenofovir diphosphate (TFV-
DP) concentration will receive escalated, targeted adherence support 
(see study schema). All participants will receive access to PrEP in 
accordance with standardized comprehensive methods of prescribing 
and clinical assessments that include safety monitoring as well as 
regular HIV and sexually transmitted infection (STI) screening. 
 
Regimen: 
TDF 300 mg + FTC 200 mg fixed dose combination will be given 
orally once daily starting at the baseline visit (month 0) and continued 
throughout the study.   
 
Outcomes: 
The primary outcome is adherence defined as the mean of 
quantitative intracellular TVF-DP in dried blood spots (DBS) at 4, 12, 
24, 36 and 48 weeks on study. The proportion of women achieving 
TFV-DP concentrations > 1050 fmol/punch, thought to be reflective of 
protective levels of PrEP, will be characterized. Self-reported 
adherence as indicated by responses to the iTAB texting system will 
be compared to TFV-DP levels.   
 
 


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5. STUDY OBJECTIVES AND HYPOTHESES 
 
5.1. 
Study Primary Objective 
To measure adherence to oral tenofovir disoproxil fumarate/emtricitabine 
(TDF/FTC) at weeks 4, 12, 24, 36, and 48 using both biological (dried blood 
spots) and self reported measures through daily text messaging (iTAB). 
 
5.1.1. 
Hypothesis I 
Drug levels will be high among those who persist with PrEP over time, as 
measured by tenofovir-diphosphate (TFV-DP) levels > 1050 fmol/punch at 
weeks 4, 12, 24, 36 and 48. 
 
5.1.2. 
Hypothesis II 
Intracellular TFV-DP concentrations levels will correlate with self-reported 
adherence as measured by responses to daily iTAB text messages. 
 
5.2. 
Study Secondary Objectives 
 
5.2.1. 
To describe the characteristics including demographics, social 
characteristics, and risk behaviors of women seeking PrEP. 
 
5.2.2. 
To describe PrEP awareness and acceptability prior to study enrollment 
among women.  
 
5.2.3. 
To describe perceived barriers and facilitators to PrEP use among 
women.  
 
5.2.4. 
To describe acceptability and feasibility of an HIV prevention program 
with a multimodal, intensive adherence package for PrEP delivery among 
women. 
 
5.2.5. 
To describe retention among women in an HIV prevention program that 
includes PrEP. 
 
5.2.6. 
To describe the safety and tolerability of daily TDF/FTC given for PrEP 
including discontinuation for any adverse event, serious adverse events 
and adverse events (grade 2 or higher). 
 
5.2.7. 
To describe the factors associated with discontinuation of TDF/FTC at 
any time point including change in perceived and actual risk of HIV 
acquisition, fear of disclosure, demographics, socioeconomic status, 
social characteristics (e.g., medical mistrust, non-English language, 
cultural factors), co-occurring health problems or issues (e.g., untreated 
mental illness, ongoing substance use, violence, trauma), and low 
health/HIV and system literacy. 
 
5.2.8. 
To estimate the HIV incidence in the observed cohort of female PrEP 
users. 
 


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5.2.9. 
To determine frequency of clinically significant resistance among 
seroconverters. 
 
5.2.10. 
To estimate the baseline prevalence and incidence of non-HIV sexually 
transmitted infections (STIs) including chlamydia, gonorrhea, and syphilis. 
 
5.2.11. 
To examine changes in sexual risk behavior over time in women. 
 
5.2.12 
To determine the ability to obtain and barriers to acquiring PrEP after 
discontinuation of study among women.  
 
5.3. 
Exploratory Objectives 
 
5.3.1. 
To explore patterns of adherence among women using iTAB responses 
as predictors of biologic outcomes. 
 
5.3.2. 
To describe changes over time of self-reported adherence in real time by 
texting. 
 
6. PROGRAM BACKGROUND AND RATIONALE 
 
Women make up half of all persons living with HIV/AIDS (PLWHA) worldwide (1). In the 
United States, approximately 20% of the estimated 47,500 new infections in 2010 occurred 
in women according to the most recent CDC surveillance data (2). Two-thirds of the twenty-
five percent of those infected through heterosexual contact were women. Racial and ethnic 
minorities are disproportionately represented amongst new HIV infections in US women. In 
spite of a declining trend, black women continue to be severely overrepresented with new 
infection rate 20 times that of white women and nearly 5 times that of Hispanic women (3). 
The HIV/AIDS epidemic among women in Southern California exemplifies this national trend 
in racial and ethnic disparities. Based on the California HIV/AIDS surveillance semi-annual 
report in June 2014, Los Angeles (LAC) and San Diego (SD) counties represent two of the 
top three counties in California with regards to number of reported HIV/AIDS cases, which in 
combination, total over half of the number of HIV cases in the state (4).  
LAC alone is home to 5% of the total number of PLWHA in the US as of 2010. 
Approximately 10% of all HIV/AIDS cases in each of these counties occurred in women, of 
which heterosexual contact (69% SD and 70% LAC) is the primary mode of transmission (5, 
6).  By race/ethnicity, the highest proportion of prevalent HIV/AIDS cases in women in both 
counties was among Latinas. At the end of 2014, there were 1,332 women living with 
HIV/AIDS in SD County. Of the female HIV cases from 2007-2011 in SD, 38% were 
Hispanic and 35% White. Further, Black females make up 23% of all female HIV cases 
despite only being 5% of the county population (6). The AIDS rate in SD was almost 8 times 
higher among African American women and 2 times higher among Latina women as 
compared to White Women (6). Among female PLWHA in LAC, 45% were Hispanic, 35% 
Black, and 15% White as of December 2013; however, African-American women showed 
the highest rate of new HIV infection in 2012 (5). The known HIV-infected partners of female 
HIV patients may be intravenous drug users (IDU), men who have sex with men and women 
or have other risks and, importantly, may not disclose these risks to their female partners. 
The persistence of new cases supports the assertion that new prevention strategies are 
needed to inhibit ongoing spread of HIV infection.  
Pre-Exposure Prophylaxis (PrEP) is the use of specific antiretroviral medications (ARV) 
in HIV-uninfected persons to augment protection against HIV acquisition in the event of 


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exposure to HIV infection. Presently, TDF/FTC is the only ARV approved for daily use 
indication for HIV prevention in the US. While no single prevention modality will realistically 
confer 100% protection against HIV infection, a combination of behavioral risk-reduction 
programming, social services, mental health and substance abuse referral services with 
novel biomedical technologies, such as PrEP, is an attractive multidisciplinary programmatic 
approach to HIV prevention. 
In the iPrEx study (n=2499), an estimate of 42% [95% CI: 18-60%] protection against 
HIV infection was demonstrated in men who have sex with men (MSM) using orally 
administered TDF/FTC (7, 8). It is clear that adherence to daily PrEP was extremely 
challenging for many study participants, and that efficacy was strongly correlated with 
adherence to daily dosing. It is critical to note that in this study, efficacy was demonstrated 
in the context of monthly HIV testing, adherence counseling, sexual risk reduction 
counseling, condom provision, and regular sexually-transmitted disease (STD) testing and 
treatment. TDF/FTC for PrEP was generally well tolerated, with a statistically significant 
excess of nausea and weight loss in the treatment arm compared to placebo, which 
resolved by week 8 of the study. Other important safety issues were a non-statistically 
significant trend toward increased creatinine elevation (which resolved with medication 
discontinuation), and approximately 1% loss in bone mineral density over one year of 
treatment. M184V resistance was found among participants (n=2) who were in the “window 
period” of acute HIV seroconversion at study entry and who were treated with active 
TDF/FTC.  
Data for the effectiveness of oral PrEP in clinical trials of heterosexual women has been 
conflicting.  The Partners PrEP study and CDC’s TDF2 trial, found efficacy for oral TDF/FTC 
(63% [95% CI: 22-83%] and 75% [95% CI: 55-87%] efficacy) and Tenofovir (67% [95% CI: 
44-81%] efficacy)-based PrEP in both men and women in heterosexual partnerships (9, 10).  
By contrast, two trials examining oral PrEP in African women alone-- Fem-PrEP and VOICE-
- failed to confirm its efficacy.  Both of these trials were stopped prematurely for statistical 
futility by their Data Safety Monitoring Board (DSMB), which found no benefit to oral PrEP 
compared to placebo. In Fem-PrEP, self-reported adherence to the TDF/FTC was 95% in 
both arms, but serum TFV levels suggested adherence rates between 15 and 38% (11). An 
excess of pregnancies was noted in the TDF/FTC arm, perhaps suggesting more general 
non-adherence in that arm, both to ART and to condom use. The VOICE [MTN-003] Trial 
demonstrated no efficacy of daily Tenofovir (alone), TDF/FTC, or a daily 1% Tenofovir 
vaginal gel in a population of heterosexual women in sub-Saharan Africa—likely due to 
extremely low rates of PrEP adherence as demonstrated on plasma drug level testing (12). 
Additionally, those at highest risk were less likely to use the study product than those 
actually at lower risk. Furthermore, recent data on tissue pharmacokinetics, as discussed 
further in the next section, suggest that women may require closer to perfect adherence to 
achieve higher levels of protection from HIV infection. Therefore, demonstrating 
maintenance of high PrEP adherence in women will be critical to both optimizing the 
protective efficacy of PrEP in women and informing implementation strategies for women 
(13, 14). 
Notably, none of the published efficacy trials of PrEP to date have included US women, 
even though the FDA approved TDF/FTC for use in women at-risk for HIV acquisition. In the 
US, only data from focus groups have been published on PrEP for women (15, 16). A recent 
study further demonstrated existing interest by US women in potential PrEP use through 
qualitative analysis of data from focus groups in six US cities involving 144 at-risk women, of 
which 92%, were African-American and 10% Latino women. Less than 10% of the women 
had ever heard of PrEP prior to the study; however, upon being educated about PrEP as 
part of study conduct, participants recognized the importance of PrEP as an HIV prevention 
method and expressed willingness to try PrEP. When questioned regarding an acceptable 


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level of protection for use, women reported ideally desiring 99% efficacy but finding 50% 
sufficient and viewed PrEP as ancillary rather than a replacement for other prevention 
methods, such as condoms (17). Partial pharmacy-based prescription data compiled by 
Gilead (representing approximately 39% of retail pharmacies and <20% of Medicaid 
prescription) for individuals who started TDF/FTC for PrEP between January 2012 and 
March 2014 revealed that 42% of PrEP users were women. The overall proportion of female 
users decreased between 2012 and 2014, suggesting the need for more robust data and 
experience with US-based women in PrEP to support efforts to augment education and 
outreach efforts targeting at-risk US-based women (18). By exploring motivations for PrEP 
use and characterizing adherence patterns, behaviors, acceptability, safety and fertility 
goals in these women, we aim to expand the data set of oral PrEP in women to include US-
based women and inform decisions and policy around further implementation and scale-up. 
 
7. RATIONALE FOR TREATMENT REGIMENS 
 
PrEP strategies that have been evaluated for efficacy have used the nucleos(t)ide  
reverse transcriptase inhibitor (NRTI) TDF alone or in combination with FTC, including a co-
formulation of TDF/FTC in a once-daily pill (19). Agents active at the pre-integration stage of 
viral replication that may prevent the establishment of HIV-infected cells are thought to be 
more suitable than post-integration drugs like protease inhibitors (PI), although data to 
support this supposition are limited (20). In contrast to NRTIs, non-nucleoside reverse 
transcriptase inhibitors (NNRTIs) and PIs generally achieve lower drug concentrations in the 
genital tracts of males and females as compared to blood plasma; a potential liability when 
attempting to reduce genital tissue susceptibility to infection (21). The availability of new 
drugs such as those that block viral DNA integration or entry through CCR5 are 
mechanistically attractive; however, comparative trials of different agents for PrEP have yet 
to be performed, and the optimal correlates of protection in all populations have yet to be 
defined (22). To date, only TDF/FTC with daily dosing has been FDA approved for HIV 
prevention among at-risk populations in the US. 
A comprehensive understanding of the pharmacology of antiretroviral drugs in genital 
secretions and tissues is essential to define the most appropriate drug candidates and 
dosing strategies for PrEP. Correlating drug levels, drug dosing (including route and dose 
amount), and viral protection are critical parameters that are still being defined. Early 
findings from animal studies suggested that the high level of protection by pre-exposure 
dosing strategies may be related to the long persistence of TFV-DP and emtricitabine 
triphosphate (FTC-TP) in mononuclear cells. Rapid FTC distribution in tissues and long 
intracellular TFV persistence complement each other to maximize PrEP efficacy (23). The 
intracellular assay used in the iPrEx study was sensitive enough to detect drug for 
approximately 14 days after the last dose taken, based on TFV-DP half-life extrapolation, 
assuming the half-lives of 39 hours and 150 hours for FTC-TP and TFV-DP, respectively 
(24). Detectable (at the 10 ng/mL level) plasma concentrations of FTC and TFV, with half-
lives of 10 to 14 hours, would be expected to last for approximately 2-3 days after dosing 
(25).   
Estimates of TDF exposure from dried blood spots were further validated in the iPrEx 
open-label extension (26) and used in modeling studies to assess correlates of protection. 
Data from these modeling studies suggest that even imperfect daily adherence (as few as 4 
doses per week) in MSM as assessed by dried blood spots can provide high-level protection 
against rectal exposures (26).  Similar studies have not been performed in women, and 
given the two to three order-of-magnitude lower levels of TFV and TFV-DP that has been 
measured in cervicovaginal tissues compared to rectal tissues (27), this threshold may not 
translate over to women, and similar modeling has not been performed in women. Although 


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vaginal and cervical tissue concentrations of FTC have been shown to be 10- to 15-fold 
higher than in rectal tissue after single dose TDF/FTC, it is unclear if this is sufficient to 
compensate for reduced TFV to provide protection against vaginal exposures. Patterson et 
al. postulate that the active metabolite FTC-TP may have a shorter tissue half-life than TFV-
DP, potentially attenuating the more robust concentration’s effect on protection against 
vaginal exposures and making adherence a more critical component (27). Additionally, a 
recent Pharmacokinetic-Pharmacodynamic (PK-PD) modeling plus in vitro efficacy target 
study predicted that even with consistent daily TDF/FTC dosing, only 80% of women would 
reach protective target tissue levels of TDF (28). Data from this project may further inform 
field of PrEP pharmacokinetics in women. 
A sample of whole blood will be stored (frozen at –70 C) for future pharamacogenomic 
analyses. Polymorphisms in genes responsible for drug metabolism have been 
demonstrated in HIV-infected patients to correlate with altered pharmacokinetics, AE 
profiles, and safety and efficacy outcomes (29).  Participants who grant permission for 
storage of genetic material will have one tube of blood stored for future correlation of genetic 
haplotypes with toxicity and/or other medical outcomes in the study. Such analyses are 
planned to be combined with other CHRP-funded PrEP demonstration project datasets, but 
will utilize a distinct funding mechanism for assay and analysis. 
 
8. RATIONALE FOR DOSING STRATEGY 
 
This protocol will use a daily dosing of TDF/FTC. To date, only daily oral administration of 
TDF/FTC is FDA approved and CDC recommended in clinical practice for having 
prophylactic efficacy against HIV acquisition in at-risk populations. Although intermittent 
dosing is attractive, and the rationale is supported by the high FTC and TFV concentrations 
achieved in the male and female genital tract after oral administration (21), their long 
intracellular half-lives in humans (30), and the relatively small size of founder virus 
populations that initiate an HIV infection in the mucosa after sexual or trans-mucosal 
exposures(31) (although perhaps less so in MSM(32)), limited data exist to support the use 
of event-driven or intermittent PrEP (the non-daily dosing of ART as prevention in HIV sero-
negative patients), and moreover, there is no clinical trial data in women to support this 
practice. Data from animal models support the efficacy of intermittent drug dosing with TDF 
or TDF/FTC where an extended window of protection was attributed to the long intracellular 
persistence of FTC-TP and TFV-DP in Peripheral Blood Mononuclear Cells (PBMCs). In 
human studies, it was additionally shown that some protection could be achieved with only 
pre- and post-coital dosing of a TFV 1% vaginal gel in women but this is not as good as oral 
daily dosing (33). Demonstrating oral daily dosing effectiveness is a priority for PrEP in 
women in the United States given the inconsistent data on women taking PrEP overall and 
almost no data among women taking PrEP in the US. In addition, daily dosing in women 
may be necessary to achieve protection in vaginal exposures comparable to that in rectal 
exposure at fewer doses based on PK-PD modeling (28).  
 
9. RATIONALE FOR CONCOMITANT SERVICES 
 
The psychology of risk-taking behavior is enormously complex, and such discussion is 
outside the purview of this protocol. However, it has been noted that risk-reduction 
behavioral programming and other behavioral interventions have had mixed results in 
accomplishing long-term benefit in terms of reduced HIV and STI acquisition (34). Recent 
studies have demonstrated incremental benefit of more intensive risk-reduction 
programming compared to standard counseling for highest-risk participants (35). It has been 
noted in mathematical models that if an intervention such as PrEP were to have the effect of 


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inducing even incremental increases in high-risk sexual activity, it may be sufficient to 
entirely abrogate any intrinsic protective efficacy afforded by the medical intervention (36). 
Although such so-called “risk compensation” has largely not been observed in biomedical 
prevention trials to date (8, 37-39) (circumcision trials being notably inconsistent in this 
regard (40)), it remains unclear what the effect on behavior will be when PrEP is 
implemented in a non-study setting, without placebo-controlled randomization, and with less 
assiduous follow-up. 
The high rate of concomitant substance use associated with high-risk sexual behavior, 
makes facile referral to such services a logical partnership for appropriate participants (41). 
In addition, the need for mental health for a variety of mood and personality disorders and 
domestic/partner violence referral often parallels the need for substance abuse services, 
and referral to such services must be similarly seamless and part of any prevention package 
offered (42-44). 
Participants may be particularly interested in PrEP for so-called “PrEP-ception” – 
conception in the setting of a serodiscordant partnership in which the female partner is HIV-
uninfected and desires to accomplish conception through conventional intercourse under the 
“cover” of PrEP to prevent HIV acquisition despite the condomless intercourse required to 
achieve pregnancy. Referral to high-risk OB/GYN services (MFM, maternal-fetal medicine 
clinics) will be established and utilized to facilitate such referrals in cases of desired 
pregnancy. 
As noted above, maximizing adherence is critical to intervention efficacy, and therefore 
HIV prevention success. In addition to multi-modal adherence support, intensive and 
proactive follow-up by study staff has been shown to be paramount in achieving participant 
follow-up and retention, including letters, telephone calls, and if applicable cell-phone text 
message and email reminders (38, 45-48). 
 
10. RATIONALE FOR ADHERENCE MONITORING 
 
Real-time dried blood spot intraerythrocytic TFV-DP drug level monitoring 
 
 
In the iPrEx study, assessments of adherence both by self-report and sensitive drug 
level assays on blood plasma and PBMCs suggested a strong correlation between 
adherence to the daily intervention and efficacy (49, 50). The low overall level of adherence 
to daily pill-taking in the study was striking, with detectable drug found in 9% of 
seroconverters, and only 51% of non-seroconverters. The medication adherence data is in 
stark contrast to the overall study retention (86-88% at 48 weeks), and self-reports of 
medication adherence (95%). Analyses designed to adjust for adherence suggest that if 
TDF/FTC were taken with fidelity on a daily basis, there could be preventive efficacy of over 
90% (8). 
The STRAND study established plasma and PBMC steady-state tenofovir (TFV) 
drug levels achieved from directly observed dosing of TDF/FTC twice weekly, four-times 
weekly, and 7-times weekly. With twice-weekly dosing, mean PBMC levels were 11 fmol/mL, 
4 days per week yielded 32 fmol/mL, and 7 days per week (daily) dosing yielded 42 
fmol/mL. In iPrEx, seroconverters had PBMC drug levels on average of 11 fmol/mL, 
suggesting fewer than two doses per week on average. Non-seroconverters had mean 
PBMC levels of 16 fmol/mL. A model created from the iPrEx data calculating the protective 
efficacy which was likely at a given drug concentration in PBMCs demonstrated that the 
PBMC drug level at which 90% protection would be achieved was estimated to be 16 
fmol/mL. Correlating the iPrEx model data with the STRAND data, two doses per week 
would be estimated to result in 76% (95% CI 56-96%) efficacy; four doses per week, 96% 
(95% CI, 90- >99%); seven doses per week (daily dosing), 99% (95% CI 96- >99%) (51). 


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The Partners-PrEP study (a population of heterosexual serodiscordant men and women 
in Kenya and Uganda) also found that drug levels strongly predicted TDF/FTC and TDF 
efficacy - detectable drug (using a more sensitive assay than the primary iPrEx data) 
predicted 86% efficacy for TDF alone, and 90% efficacy for TDF/FTC (contrast 67% and 
75%, in the overall population, respectively).  The Partners-PrEP study found three distinct 
patterns of adherence: 1. Seventy percent of participants had sustained TFV drug levels >40 
ng/mL; 2. Ten percent of the population had levels that were detectable most of the time 
(10-40 ng/mL), but dipped occasionally to undetectable levels; and 3) Twenty percent of the 
population had persistently undetectable drug levels (52). It is probable that prospective, 
real-time identification of these non-adherent populations (although it remains unclear what 
percentage this would represent in iPrEx [the MSM population studied to date] – one would 
suspect the overwhelming majority) and applying intensive adherence interventions would 
be critical to the success of a PrEP effort. 
In this study we will use intracellular TFV-DP from DBS as our primary outcome 
measure of adherence. Anderson and Castillo-Mancilla have developed technology using 
LC-MS/MS to measure intra-erythrocytic TFV-DP levels, which provide a measure of 
average tenofovir exposure (adherence) over the preceding 30-90 days, not unlike a 
Hemoglobin A1C measurement (53). Such measurements can be made from DBS samples, 
which are stable over time and easy to handle. The key characteristic that enables TFV-DP 
to be used as an adherence biomarker is the 17-day half-life of TFV-DP in red blood cells.  
A similar long-term objective measure of adherence, tightly correlated with virologic 
suppression has been validated using scalp hair samples (54). However, sampling of scalp 
hair has proven variably acceptable among diverse populations (unpublished data, ACTG 
A5257). 
 
11. RATIONALE FOR DEMONSTRATION PROJECT 
 
Daily oral PrEP with TDF/FTC as part of a combination prevention package has been 
shown to be effective for HIV prevention in randomized controlled trials of MSM and 
heterosexual men and women at risk of HIV infection (55-57). However, some studies in 
African women have shown lack of efficacy that is believed in large part due to inadequate 
PrEP adherence (11, 58). In addition, pharmacokinetic studies in women suggest that near-
perfect adherence for TDF/FTC oral dosing may be more critical for protection against 
vaginal compared with rectal exposures. Taken together, these results imply that women 
may require substantially greater levels of adherence to oral TDF/FTC to effectively 
decrease HIV acquisition. Therefore, interventions to optimize adherence are particularly 
vital to maximizing the protective efficacy of PrEP for women. Although current FDA 
approval and CDC clinical guidelines for oral TDF/FTC as PrEP include at-risk women as 
candidates, limited clinical data exists on the use of PrEP in US women. Further research is 
needed to advance effective implementation, particularly taking into account the known 
challenges to achieving and maintaining high levels of adherence for women. 
This pilot demonstration project is a single-arm, open-label, longitudinal study of 
oral TDF/FTC as part of a combined prevention package in heterosexual women age 
18 years or older and are HIV-uninfected at project entry and at-risk of HIV 
acquisition. We will evaluate adherence to and acceptability of once-daily oral TDF/FTC as 
PrEP among HIV-uninfected women in Southern California who are at increased risk of HIV 
acquisition. Los Angeles and San Diego represent two of the top three counties in California 
of number of reported HIV/AIDS cases. In combination, they total half of the number of HIV 
vases in the state supporting the need for ongoing prevention efforts in all at-risk 
populations. Working in tandem, the LAC-PATH and CCTG partnership provides a unique 
opportunity to further collaborative research that has been fostered within the CHRP funding 


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21 
structure, capitalizing on the strengths of existing individual projects in MSM and 
transgender women. The LAC-PATH group will enroll 85 women and the CCTG group will 
enroll 50 women for a total of 135 participants across five clinical sites in Los Angeles and 
San Diego counties. These clinical sites currently provide services to a racially and 
ethnically diverse population and will enable outreach to potential female participants 
disproportionately affected by the HIV/AIDS epidemic, with a focus on African-American and 
Latina women. Given the centrality of adherence to PrEP efficacy in women, this protocol 
sets forth a multi-modal, intensive strategy to support PrEP delivery that involves 
innovatively combining the use of technology, therapeutic drug monitoring and behavioral 
counseling. 
Subsequent to the publication of the iPrEx results, the CDC issued clinical guidance for 
clinicians for the use of PrEP in MSM (59). These included practical guidelines for testing 
and follow-up, albeit in the absence of data for any other schedule for follow-up than the one 
used in the iPrEx study, which entailed monthly HIV-testing, laboratory monitoring, and 
adherence and risk-reduction counseling, and serve as the basis for screening and 
monitoring in this project. 
Combination prevention services must be designed to be easily accessible, non-
judgmental, community-based, culturally, ethnically, and linguistically appropriate to the 
relevant populations, and accessible regardless of ability to pay or insurance/documentation 
status.  They will also provide vital linkages to ancillary support services, sexual risk 
reduction counseling, routine HIV testing, preconception planning and primary health care. 
In its initial pilot project, five community-based sites will serve as facilities at which 
participants may present for screening for pre-exposure prophylaxis services, as well as 
sexually transmitted diseases. At the sites, eligibility criteria will be assessed, HIV, STD and 
laboratory testing will be performed, an initial 1-month supply of PrEP medication will be 
provided, and referrals will be initiated. All participants who are provided an initial 1-month 
supply will be required to return to the site for ongoing treatment, follow-up testing, 
adherence counseling, risk-reduction programming, and other appropriate referrals. Follow-
up will be on a monthly basis for the first month, and then de-escalated to an every-3-month 
follow-up interval. Follow-up with participants by phone and email will be used as 
appropriate to maximize program retention. 
 


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12. ENROLLMENT OF PARTICIPANTS 
 
Potential participants will be screened for a combination prevention intervention. After 
the participant reviews and signs the informed consent document, receives HIV testing 
(including 4th generation test or ELISA and nucleic acid amplification (NAAT) testing) to 
confirm HIV-uninfected status, and is evaluated using the inclusion and exclusion criteria, 
she will be considered enrolled in the protocol.   
 
13. INCLUSION CRITERIA 
 
(All must be satisfied) 
Individuals who will be at most benefit from PrEP are individuals who are at recurrent 
and substantial risk for acquiring HIV infection.  
 
At-Risk Criteria (at least one):   
1) Condomless sex in the last 3 months with one or more male partners of unknown 
HIV status known to be at substantial risk of HIV infection (IDU, bisexual, sex for 
goods, recently incarcerated, from a country/ region with HIV prevalence >1%, 
interpersonal Partner Violence);   


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2) STI (rectal or vaginal gonorrhea or syphilis) diagnosis during the last 6 months. 
3) Previous post-exposure prophylaxis (PEP) use during the last 12 months. 
4) Has at least one HIV-infected sexual partner for ≥4 weeks. 
5) Sex for exchange of money, goods or services 
 
Other inclusion criteria: 
Female at birth and identifies as female gender 
Age 18 years or older  
Able to understand and provide consent in English or Spanish 
HIV negative by 4th generation test (Ag/Ab test) or combination of EIA and HIV RNA 
Creatinine clearance ≥ 60 ml/min (via Cockcroft-Gault formula) 
 
14. EXCLUSION CRITERIA 
 
Pregnancy at enrollment. 
Any condition, which in the opinion of the provider, will seriously compromise the 
participant’s ability to comply with the protocol, including adherence to PrEP medication 
dosing, such as active, untreated or unstable major mental illness (i.e. untreated psychotic 
disorder). 
Use of prohibited medications, in particular, agents known to be nephrotoxic or drugs 
slow in renal excretion (as detailed in the MOPS) 
Previous participation in an HIV vaccine trial. Participants that were documented to have 
received only placebo are not excluded.  
Signs or symptoms suspicious for Primary HIV Infection (PHI). If the participant presents 
with symptoms consistent with PHI, such participants should be referred to expert HIV 
clinical care immediately for further evaluation and treatment. For management of suspected 
PHI, see Section 26.3. 
 
15. STUDY ENROLLMENT PROCEDURES 
 
 Enrollment may only be initiated in person. To enroll, a participant must present to one 
of the clinical site facilities.  
 
15.1. Screening 
 
At a screening visit, Informed Consent will be reviewed. An intake of inclusion and 
exclusion criteria will be performed by program personnel. HIV-testing (4th generation test, or 
EIA and HIV RNA) and screening laboratories as noted in the Schedule of Evaluations 
(SOE) will be performed. If all inclusion and no exclusion criteria are met, a baseline visit will 
be scheduled within 28 days. A detailed locator form will be completed including primary 
contact telephone, paper-mail, email, social-network, and emergency contact information. 
This information will be verified at each subsequent visit for changes and/or updates. At 
screening, individuals will also be asked to complete a brief computer assisted self-interview 
(CASI)-based assessment evaluating HIV risk; PrEP awareness, barriers and facilitators; 
and willingness to take PrEP.  
 
15.2. Baseline Visit 
 
 
At the baseline visit, a needs assessment, including a CASI-based sexual risk 
assessment will be conducted. Although the intent is that the CASI is entirely self-
administered, research staff will be available to assist participants who have questions about 


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operation of the CASI instrument or content. Initial STI testing and coordination of necessary 
referral services will be performed.  Fertility intentions also will be assessed. All women who 
meet criteria for use will be offered daily oral TDF/FTC as part of a combination prevention 
package. A patient identification number (PID) will be assigned to each patient screened for 
the study. PIDs will include site code and be formatted to be compatible with the YoungLabs 
data core. PIDs will not be reassigned even if the participant fails to enter the study. The PID 
must be included on every CRF and participant specimen during the study. Each site must 
maintain a master list of PIDs in a central location. The patient registration and 
inclusion/exclusion CRF must be completed on the online system. Procedures in the study 
visits are shown in the schedule of evaluations (Section 18). 
 
16. REGIMENS, ADMINISTRATION, AND DOSING 
 
The PrEP regimen to be used will be TDF/FTC, provided as a fixed-dose combination 
tablet as Truvada®. Dosing of TDF/FTC is one tablet by mouth once daily. For participants 
with creatinine clearance <60 mL/min or on hemodialysis, TDF/FTC should not be used. No 
other regimen is available or recommended in the event of intolerance or adverse events 
attributable to TDF/FTC. 
 
 
In the event of toxicity, intolerance, or allergy, see Toxicity Management, below. 
 
16.1. High Risk Exposures While on PrEP 
 
In the event of a clinical indication for 3-drug PEP participants will be referred to locally 
available PEP services and may resume protocol participation upon completion of the PEP 
medications course with documentation of HIV-uninfected status at or after 4 weeks of PEP 
provision. 
 
16.2. Missed Dose Instructions 
 
A missed dose should be taken when remembered on a given calendar day. Instructions 
to participants will be not to take more than one tablet daily regardless of missed doses. 
 
16.3. Duration of Therapy 
 
TDF/FTC should be taken daily for 48 weeks (336 days). Participants may receive study 
treatment until their last study visit.  Further plans for continued availability of TDF/FTC for 
PrEP after the first 48 weeks will be determined based on the results of the current pilot 
demonstration study. 
 
16.4. Drug Supply, Distribution, and Accountability 
 
TDF/FTC (emtricitabine 200mg/tenofovir 300mg) will be available in bottles of 30 tablets 
to be taken as one tablet by mouth daily. Site pharmacies will be responsible for dispensing 
a 4-week supply of TDF/FTC at the baseline visit, an 8-week supply of TDF/FTC at the 4-
week follow-up visit, and a 12-week supply of TDF/FTC at the 12-week, 24-week, and 36-
week follow-up visits, in appropriate packaging based on manufacturer’s instructions (USP 
equivalent tight containers). Pharmacies at sites will be responsible for documentation of all 
medication dispensation, and tracking of all program-related medications. 


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Participants must follow-up at the site of enrollment to receive the remaining treatment 
course and associated testing and services. Further supplies will not be re-dispensed in the 
event that medication is lost.  
 
16.5. Adherence Assessment and Intervention 
 
At each study visit, adherence will be assessed by self-report metrics via CASI. DBS 
specimens will be performed for real-time intraerythrocytic TFV-DP drug level assays. 
 
16.5.1. 
Real-time intraerythrocytic drug levels 
 
Blood will be collected for intraerythrocytic TFV-DP drug level assays at each follow-up 
visit.  Prior pharmacokinetic/pharmacodynamics studies have established levels for 
categorization of dosing for interpretation of DBS levels. Given the high adherence 
requirement for women to achieve protective levels, a threshold of 1050 fmol/punch 
corresponding to 6 or more doses per week will be used as the threshold for optimal 
adherence (28, 60).  Levels below this threshold will be considered to represent suboptimal 
adherence and will trigger intensification of adherence support as outlined below. 
 
16.5.2. 
iTAB System 
 
iTAB is a personalized, two-way, text-messaging intervention developed to improve 
medication adherence in diverse difficult-to-treat cohorts such as HIV-infected with comorbid 
psychiatric (i.e. bipolar disorder) and substance use disorders (i.e. methamphetamine 
dependence) and more recently for PrEP adherence (61-63).The system has several 
components identified in the broader literature as integral to long-term engagement and 
effectiveness of text messaging interventions in supporting medication adherence, including: 
1) interactive, two-way, communication; 2) individually tailored message content; and 3) 
delivery of messages to match dosage timing (64, 65). To personalize our text-messaging 
interactions, we will use a combination of focus-group derived content in certain thematic 
areas (61), as well as allow participants to create their own messages. Patients develop 
brief statements called “implementation intentions” integrated into text messages, which 
ensures personalization capitalizing on the persuasiveness of their own language and 
phrasing, “When I brush my teeth, I will take my PrEP.” 
The iTAB system builds from a variety of behavioral theories used in HIV prevention 
studies, including the Health Belief Model, Social Cognitive Theory, and the Theory of 
Planned Behavior (TPB) (66, 67). While these theories differ in some aspects, they also 
contain a number of shared underlying constructs (68). For example, interventions that 
focus on the intention to change risk behaviors via changes in self-efficacy and perceived 
behavioral control (aspects of TPB) are associated with greater condom use (69, 70). Our 
iTAB intervention primarily targets individual or intra-personal aspects of behavior and is 
directed primarily by the TPB, which suggests that behavior is driven by: i) attitudes toward 
the proposed behavior, ii) social norms/perceptions of others, and iii) beliefs that they can 
control the behavior, which feed into behavioral / implementation intentions (e.g., “I plan to 
take my PrEP). 
iTAB has found to be associated with high adherence and valid as a measure of self-
reported adherence in CCTG 595, an open-label, two-arm, controlled, randomized 1:1 
clinical trial of iTAB versus standard of care (no iTAB) as a demonstration project evaluating 
retention and adherence to PrEP in 400 MSM and transgender women over 48 weeks. In a 
preliminary analysis of intracellular TFV-DP levels in Week 12 DBS among the first 152 
participants in the iTAB arm (71), we found that adherence in the iTAB arm was high with a 


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26 
mean TFV-DP of 1352 fmol/punch, which equates to taking 6 of 7 doses of PrEP a week. 
Since CCTG 595 is an ongoing study, the comparison of iTAB to a control arm that did not 
receive iTAB text has not been performed yet.  The preliminary data also show a significant 
correlation between TFV-DP concentrations and proportion of positive (“Yes, I took my 
meds.”) iTab responses (r=0.26, p=0.01) supporting iTAB as a valid measure of adherence. 
These findings support the use of iTAB as a valid self-reported measure for adherence that 
can discriminate between adequate and inadequate PrEP adherence.  
In this study, all participants will receive text messaging through the iTAB system. At the 
baseline visit, the study coordinator will introduce the participant to the iTAB texting system 
and provide training on iTAB framework for texting supportive reminder messages and 
tracking adherence. If a participant does not have unlimited text messaging, the study will 
provide participant reimbursement to pay for unlimited text messages. In cases where a 
participant does not have a phone, an appropriate cell phone with an unlimited texting plan 
will be provided.  
Daily dosing reminders will be sent for the duration of the study. Both reminder timing 
and message content can be individualized and will be arranged at the baseline visit. The 
study coordinator will work with the participant to select and refine 10 personal reminders 
from a list of pre-determined reminders that cover various themes shown to be effective in 
improving adherence (i.e., social support, loss frame, health gain) as well as 5 categories of 
factoids (i.e., food, history, science). Participants will receive 2 personal reminders and 5 
factoids each week for the duration of the study. These themes will be developed through 
focus groups and targeted group feedback. Participants can choose to create their own 
reminders if they prefer, and messages can be modified throughout the course of the study. 
The coordinator will work with each participant individually to ensure that adherence 
reminders are programmed to be sent at times consistent with when the patient typically 
takes her medication. Reminder times can vary for different days of the week to 
accommodate for changes in schedule (e.g., 8 M-F, and 10 AM on Sat/Sun). Once the 
preferred dosing time is identified, the text reminder system is automated. Patients will 
confirm medication taking via text responses to the personalized reminders. If a participant 
does not respond on three consecutive occasions, a high alert message (chosen by the 
participant) will be sent. If the participant does not respond to this message, the study 
coordinator will initiate phone calls to contact the participant to determine reason for no-
reply. At any point, if a participant initiates a text that is not one of the expected responses, 
the study team will review that text and contact the subject if there is a concern. Participants 
will be informed not to use texting for emergencies. The content/reasons for iTAB requests 
for assistance will be documented and summarized post study, 
 
16.5.3. 
Integrated Next Step Counseling, Targeted Integrated Next Step 
Counseling and PrEP-STEPS 
 
iNSC has two yoked components- a focused discussion of all things the person is doing 
or thinking of doing to protect their sexual health besides PrEP which then turns to 
discussing continued desire for PrEP as part of one’s protection plan, and, if so, current 
approaches to ensuring dosing in the present context/demands of participant’s life. Thus, 
regardless of whether or not the participant is receiving PrEP at any clinical visit, one (just 
the non-PrEP portion) or both parts of iNSC are implemented. During the first PrEP 
dispensation visit, the focus of the discussion is on preparing participants for adherence 
through enhancing literacy around PrEP and adherence, formulating a concrete plan for 
daily dosing and brainstorming potential barriers and discussing what to do if side-effects 
are experienced. The groundwork for discussing sexual health protection and approach that 
the study will adopt with an invitation for participants to fully engage in discussions and 


Protocol Version 1.4          07-29-2016 
 
 
27 
openly share PrEP experiences and desires. Subsequent visits follow basic process where 
experiences are discussed, participants are asked about their sense of what, if anything, 
would make sexual health protection (non-PrEP strategies) easier or more manageable, 
ways to meet those needs explored, strategies discussed and a plan identified by the 
participant, which then transition to checking in with whether or not PrEP is still something 
they want as part of their plan (or if they want to add it if eligible and not on PrEP), and if so, 
PrEP dosing experiences are explored, needs identified, strategies discussed and a plan 
developed. Discourse is documented and will be summarized at the end of the study, 
The main difference between iNSC and targeted iNSC focused on exploring whether or 
not PrEP is something the participant wants to continue with (given low drug level and 
relatedly low afforded PrEP benefit), and if so a strengths-based exploration (when dosing 
did occur, what facilitated it) precedes exploration of specific barriers to dosing (what 
specifically prevented consistent dosing), needs are identified, strategies discussed and an 
adherence plan created. Because participants all engage in iTAB, plans will also emphasize 
use of iTAB to ask for help. Participants no longer interested in PrEP will be engaged in 
discussion around that decision and their plan for how to stay HIV negative using other 
strategies discussed. 
PrEP-STEPS is a four-session weekly intervention with two subsequent monthly booster 
sessions modeled after an evidence-based ART adherence intervention (LifeSteps) which is 
a Cognitive Behavioral Therapy (CBT)-based counseling approach to facilitate PrEP 
adherence. This program will be deployed at in-person sessions and is the highest intensity 
level intervention. 
The 3 interventions will be used as three “stages” or levels of intensity of adherence 
support.  One intervention is deployed for a given participant, titrated based on the history 
and chronology of real-time measured DBS TFV-DP levels. 
All participants will receive iNSC at the baseline/entry visit and at all subsequent visits 
[see the MOPS for structure of the standard iNSC intervention]). Suboptimal adherence 
(TFV-DP levels of <1050 fmol/punch (representing fewer than mean 6-7 daily doses per 
week)) will trigger “targeted iNSC” which will be implemented when drug levels are obtained 
by the site- typically about 10 days after the clinic visit (72). Participants in this sub-optimal 
range are contact by the counselor, informed of their results and asked to come in for a 
specific conversation (targeted iNSC). This first level of more intensive support may be 
deployed by telephone or in person. There will not be additional compensation for 
participating in these sessions. Details of the targeted iNSC intervention are provided in the 
MOPS. If this is a repeat sub-optimal level the counselor schedules the participant for the 
first of 4 (+2 booster) PrEP-Steps sessions.  
 
Details of the PrEP-STEPS Program with Content Optimized for Women program are 
provided in the MOPS.  
 
All sites will be trained in the standard iNSC, targeted iNSC, and PrEP-STEPS 
interventions prior to initiation of participant enrollment. A booster-training will be scheduled 
once sites are operational. Regular conference calls will be arranged between the protocol 
adherence teams and site staff, and the protocol adherence consultant will be available for 
questions and/or troubleshooting as needed during study conduct.  Participants will be 
asked for additional consent to have their adherence support sessions audio-recorded, and 
a subset of these audio recordings will be reviewed by the adherence consulting team for 
fidelity to the intervention; such audio recordings will be destroyed after review. 
Refusal to participate in adherence interventions may be sufficient reason for participant 
to be considered for PrEP medication discontinuation, at the discretion of the Protocol 
Chairs.  
 


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28 
17. FERTILITY INTENTIONS ASSESSMENT 
 
 
CDC/DHHS guidelines on use of PrEP in women include guidance on counseling 
serodiscordant couples who want to conceive a child (73, 74). Periconception use, or 
“PrEPception” (75), is a potential area in which PrEP may be beneficial in reducing risk of 
HIV acquisition. As a result, women will not be excluded based on fertility intentions.  Fertility 
intentions will be assessed as part of the initial intake at baseline, and pregnancy testing will 
be performed at follow-up visits for monitoring as outline in the schedule of events. As 
detailed in the MOPS, the study will use a designated Informed Consent for women who 
become pregnant on-protocol, and a separate complementary schedule of follow-up for 
pregnant women, who will be followed in clinical collaboration with high-risk obstetric 
(Maternal Fetal Medicine Service) providers.  
 
18. STUDY ASSESSMENTS 
 
The 10 domains to be covered include: 
a. Adherence 
b. Substance Use 
c. Sexual Behavior/Risk 
d. Psychosocial Constructs 
e. PrEP Efficacy 
f. Willingness to Take PrEP 
g. Violence and Trauma 
h. Healthcare and Referrals 
i. 
HIV Knowledge and Perception 
j. 
Family Planning 
At the screening visit, CASI-based assessments will be administered which will include 
the domains of Sexual Behavior/Risk, PrEP efficacy, Willingness to take PrEP, Violence and 
Trauma and HIV knowledge and Perception and Family Planning.  
At the baseline visit, additional CASI-based assessments will be administered which 
include Adherence, Substance Use, Psychosocial Constructs, Violence and Trauma and 
Healthcare and Referrals.  
During follow-up visits (4, 12, 24, and 36 weeks) CASI-based assessments will continue 
which will include Adherence, Substance Use, Sexual Behavior/Risk, Psychosocial 
Constructs, Violence and Trauma and Healthcare and Referrals, and Family Planning. 
At the End of Study (week 48) visit, CASI-based assessments will include, in addition to 
above, PrEP efficacy and HIV knowledge and Perception.  
Study visits will also include discussions with study staff about substance use, 
depression and domestic violence. Concern about substance abuse will trigger referral for 
substance abuse counseling. A screen for depression and/or psychological distress or any 
request for mental health services will trigger referral for appropriate mental health services.  
Any report or suspicion of domestic/partner violence will trigger referral for appropriate 
partner services. 
In terms of risk reduction counseling, all participants will be provided a sexual health 
counseling session at every study visit starting at baseline (see below). All participants will 
be counseled that condoms should be used for all forms of penetrative non-oral sexual 
contact. 
Full contents of the CASI and assessments will be specified in MOPS. 
 


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29 
19. RISK REDUCTION COUNSELING INTERVENTION 
 
As noted above, the iNSC addresses both behavioral and biomedical strategies to 
promote protection of sexual health. iNSC will be provided at each study, preferably early in 
the study visit and in conjunction with delivery of an HIV-uninfected rapid test result. The 
structure of the intervention is provided above in section 16.5.3 and detailed in the MOPS. 
 
 


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30 
20. SCHEDULE OF CLINICAL AND LABORATORY EVALUATIONS 
 
Table 1. Schedule of Evaluations 
 
Screen 
Study Weeks of Follow-up 
Interim 
Within 
28 
days 
Baseline 
Wk 
4 
Week 12 
and every 
12 weeks 
End of 
Study or 
premature 
D/C 
Suspected HIV 
or STI infection 
Interim 
for 
Missed 
Visit 
Visit Window 
 
± 14 days 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Locator Form 
X 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Limited physical exam 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment 
X 
X 
X 
X 
X 
X 
X 
Fertility intent assessment 
X 
X 
X 
X 
X 
X 
X 
Contraceptive counseling 
X 
X 
X 
X 
X 
X 
X 
Domestic/partner violence 
assessment 
X 
X 
X 
X 
X 
X 
X 
Systems review and iTAB 
setup 
 
X 
 
 
 
 
 
PrEP dispensation 
 
X 
X 
X 
 
 
 
Adherence/ risk reduction/ 
Sexual health counseling 
 
X 
X 
X 
X 
X 
X 
Self-reported tablet 
assessments1 
X 
X 
X 
X 
X 
X 
X 
PrEP adherence 
assessment 
 
 
X 
X 
X 
X 
X 
Laboratory 
HIV EIA/VL or Ag/Ab2 
X 
 
 
 
 
 
 
Rapid HIV Test 
 
X 
X 
X 
X 
X 
X 
HBsAg and HBsAb 
X 
 
 
 
 
 
 
Urine beta HCG 
X 
X 
X 
X 
X 
X 
X 
Cr and GFR 
X 
 
X 
X 
X 
X 
X 
LFT and CBC 
 
X 
 
 
 
 
 
Serum RPR 
 
X 
 
[X] 
[X] 
X 
[X] 
3-site STI Screening 
 
X 
 
[X] 
[X] 
X 
[X] 
HSV-2 Screening 
 
X 
 
 
X5 
 
 
DBS for RBC TFV-DP 
 
 
X 
X 
X 
X 
X 
Banked plasma specimen3 
 
 
X 
X 
X 
X 
X 
HIV RNA, CD4, genotype 
 
 
 
 
 
X 
 
Whole blood 
 
 
 
 
 
X 
 


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31 
Table 1. Schedule of Evaluations 
 
Screen 
Study Weeks of Follow-up 
Interim 
Within 
28 
days 
Baseline 
Wk 
4 
Week 12 
and every 
12 weeks 
End of 
Study or 
premature 
D/C 
Suspected HIV 
or STI infection 
Interim 
for 
Missed 
Visit 
1 Domains include: Adherence, Substance Use, Sexual Behavior/Risk, Psychosocial Constructs, PrEP Efficacy, 
Willingness to Take PrEP, Violence and Trauma, Healthcare and Referrals, HIV Knowledge and Perception, and 
other instruments. 
2 Positive or indeterminate rapid HIV ELISA testing will be confirmed with a viral load. If baseline occurs > 28 
days after screening, HIV EIA/VL must be repeated.  
3 Plasma will be drawn and stored at indicated time points.  If seroconversion to HIV occurs, these samples will 
be run fI or HIV-1 RNA (viral load) and genotyping. 
4 In case of seroconversion, sample to be shipped to UCSF and used for determining viral reservoir during 
hyperacute HIV infection. 
5 Repeat HSV-2 screening at Week 48 or End of Study only if negative at Baseline. 
[X] Weeks 24 and 48 months only 


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32 
21. CLINICAL ASSESSMENTS 
 
21.1. Complete Physical Exam  
 
A complete physical exam will be done at baseline and documented in the source 
documents only. A complete physical examination is to include an examination of the skin, 
head (including eyes and nose), mouth, and neck; auscultation of the chest; cardiac exam; 
abdominal exam, genital exam (as needed), skin exam, examination of the lower extremities 
for edema, and a brief neurological assessment. The complete physical exam will also 
include signs and symptoms, height in centimeters/inches, weight in kilograms/pounds, 
diagnoses, and vital signs (temperature (°C), pulse, respiration rate, and blood pressure).  
 
21.2. Targeted Physical Exam 
 
Targeted physical exam will be done at all visits subsequent to the baseline visit and 
documented in the source documents only. A targeted physical examination is to include 
height in centimeters, vital signs (temperature, pulse, respiration rate, and blood pressure) 
and is to be driven by any previously identified or new signs or symptoms including 
diagnoses that the participant has experienced since the last visit. Staff should inquire about 
symptoms, as indicated. 
 
21.3. Review of Systems  
 
A complete review of systems will be done at baseline and reviewed at all subsequent 
visits. This should be documented in the source documents only. Review of systems is to be 
driven by any previously identified or new signs or symptoms including diagnoses that the 
participant has experienced since the last visit.  
 
21.4. Concomitant Medications  
 
Concomitant medications will be assessed at initial intake, reviewed at every study visit, 
and recorded on the appropriate CRF. Include actual or estimated start and stop dates. All 
concomitant medications (prescription and non-prescription) including 
alternative/complementary medications (e.g., herbs, vitamins, etc.) taken within 30 days 
prior to enrollment and anytime thereafter during study participation will be collected in the 
study participant’s chart and recorded on the appropriate CRF. Concomitant medication lists 
will be reviewed by program pharmacy staff for potential drug interactions as appropriate. 
 
22. HIV LABORATORY TESTING 
 
Rapid or conventional ELISA testing will be used.  All positive rapid EIA results will be 
confirmed with both a conventional blood EIA test and a viral load (negative rapid tests are 
not further confirmed, except as per individual study site policy, and positive conventional 
blood EIA tests are only confirmed by viral load testing). As indicated in the protocol, 4th 
generation test (Ag/Ab), or NAAT testing in addition to EIA, will be used at screening and 
entry to exclude occult primary/acute HIV infection. 
 
 


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33 
23. ADDITIONAL LABORATORY TESTING 
 
23.1. STI Screening 
 
All participants will be screened at baseline for rectal (rectal swab), cervical (self-
collected vaginal or urine) or pharyngeal (throat swab) gonorrhea and chlamydia using a 
verified NAAT test and for T. pallidum (syphilis) by serum treponemal/RPR testing. 
Asymptomatic STI screening will be conducted at 6-month intervals while on-study. 
Serologic testing for HSV-2 will be completed at Baseline, and again at Week 48 or End of 
Study if previously negative at Baseline.  Positive results will trigger referral to appropriate 
private or SD/LA County STD program sites for treatment. Intervening signs or symptoms 
consistent with STIs should trigger referral to appropriate private or SD/LA county STD 
program services.   
 
23.2. Hepatitis Testing 
 
Treatment with TDF/FTC or its components or congeners in participants with chronic 
active hepatitis B (Hepatitis B surface antigen (HBsAg) positive) has been associated with 
flares of hepatitis upon discontinuation of treatment.  Such participants will be referred to 
appropriate medical care for monthly liver function testing subsequent to treatment 
completion and/or consideration of ongoing Hepatitis B treatment. HBsAg negative 
participants will be referred for appropriate vaccination. 
 
 
23.3. Serum Creatinine 
 
Serum creatinine will be checked at screening to determine appropriate TDF/FTC 
dosing, and then again at Weeks 4, 12, 24, 36 and 48.   
 
23.4. Liver Function Tests  
 
AST (SGOT), ALT (SGPT), Total Bilirubin (TBIL), and alkaline phosphatase will be 
checked at baseline for all participants, and in a symptom-directed fashion as needed. 
 
23.5. Complete Blood Count 
 
Hemoglobin, hematocrit, white blood cell count and platelet count will be checked at 
baseline for all participants, and in a symptom-directed fashion as needed. 
 
23.6. Pregnancy testing 
 
Urine beta HCG will be performed to assess for pregnancy at screening, baseline, 
weeks 4, 12, 24, 36, and 48, and in a symptom-directed fashion. 
 
24. PLASMA COLLECTION 
 
Plasma will be collected and stored at Weeks 4,12, 24, 36 and 48. If seroconversion to 
HIV occurs, plasma samples will be run for HIV-1 RNA (viral load) and genotyping. These 
specimens may also be used for safety labs, or for tests whose needs become apparent 
during the course of this study. Additional whole blood will be collected at the visit 
seroconversion was detect and 24 weeks post seroconversion to determine viral reservoir 
size and immune responses. 


Protocol Version 1.4          07-29-2016 
 
 
34 
 
 
25. DRIED BLOOD SPOT COLLECTION 
 
Blood will be collected for and spotted onto Whitman Protein Saver Card for DBS 
analyses. All specimens will be stored at -80C. DBS samples available from weeks 4, 12, 24 
and 36 will be sent to the University of Colorado lab once weekly for real-time analysis.  
 
26. POST-TRIAL ACCESS TO PREP 
 
During study conduct, the team will initiate discussions about continuation mechanisms 
at either the 24- or 36-week visit to prepare for the 48-week transition off study, allowing 
ample time for discussion of intentions to continue PrEP post-study, assessment of 
insurance status, choice of healthcare location and provider, and prescription benefits 
optimization. 
The team will conduct a phone call follow-up of all participants 3 months post-study 
completion to determine post-trial access to and use of PrEP. Survey content will be based 
on an instrument developed by the PrEP Demo Project based in San Francisco (77). 
Information will be collected including current medical access and care, HIV testing, interest 
in remaining on PrEP, access to and use of PrEP, gaps in PrEP coverage, monthly cost, 
barriers to getting PrEP, and changes in HIV prevention strategies. Surveys may be 
conducted in person, via internet, or over the phone.  
 
27. CLINICAL MANAGEMENT ISSUES 
 
27.1. Toxicity Management 
 
27.1.1. 
General 
 
In the event of intolerance, including but not limited to rash, nausea, vomiting, clinical 
jaundice, or abdominal pain, an “unscheduled visit” should be made in which a directed 
clinical assessment and laboratory evaluations including creatinine, liver function tests, and 
complete blood count are performed. Alternative regimens may not be substituted.   
Only toxicities related to study medication provided through this study (TDF/FTC) will be 
considered in the toxicity management section. The grading system is located in the Division 
of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 2.0, November 2014, available at the DAIDS RCC Web Site: 
http://rsc.tech-res.com. Grade 1 creatinine elevations will have an expanded definition: In 
addition to those defined as having Grade 1 creatinine elevations by DAIDS AE Table, the 
Grade 1 definition will include A) those whose creatinine increased to 1.5x the baseline 
value (baseline value will be defined as the average of screening and enrollment for the 
participant) and B) estimated creatinine clearance of <50 ml/min (calculated using 
Cockcroft- Gault).  
Adverse events will be reported for Grade 2 and above clinical and laboratory 
abnormalities. In addition, all bone fractures and all creatinine elevations will be reported. 
Serious adverse events (SAEs) will be defined in accordance with the ICH, as any untoward 
medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization, or results in persistent or 
significant disability/incapacity. 
All Grade 1 or 2 adverse events may be managed according to the discretion of the 
provider, except as noted below.   


Protocol Version 1.4          07-29-2016 
 
 
35 
Grade 3 adverse events, if asymptomatic and not thought to be attributable to study 
medication, may be managed conservatively with continuation of TDF/FTC treatment.   
All Grade 3 symptomatic and all Grade 4 (regardless of symptomatology) events should 
prompt cessation of TDF/FTC therapy, with weekly monitoring until resolution to ≤ Grade 2.  
If a clear alternative explanation for the Grade 4 adverse event exists, TDF/FTC may only be 
continued with the approval of the Protocol PI.  Once the AE has regressed to ≤ Grade 2, 
the participant may be rechallenged with TDF/FTC at the discretion of the provider.  Any 
recurrence of the AE should prompt permanent medication discontinuation. 
 
27.1.2. 
Impaired Creatinine Clearance 
 
 
Any participant with a calculated creatinine clearance (CrCl) <60 mL/min should have 
the value confirmed within 14 days.  For those participants with a confirmed (i.e. two 
consecutive) reduction in CrCl to <60 mL/min, TDF/FTC should be discontinued. If the site 
investigator determines that another condition caused the decrease in CrCl, then TDF/FTC 
may be restarted if approved by the protocol PI. Participants should be followed as 
medically indicated (at least weekly) until the serum creatinine returns to Grade ≤ 2 or 
baseline. 
27.1.3. 
Nausea (with or without vomiting) and/or Diarrhea 
 
Although common, nausea following initiation of therapy with study medications usually 
subsides or resolves during the first few weeks of treatment. 
With the onset of Grade ≥1 nausea, advise participants to take study medications with 
food.  Participants may also be treated as needed with anti-emetics given orally or by 
suppository. 
In participants with persistent nausea, consideration should be given for evaluation of 
pancreatitis, hepatitis, hyperlactatemia/lactic acidosis, or hypercalcemia with evaluation for 
each if clinically indicated. 
For Grade 1 or 2 diarrhea, therapy should be continued with symptomatic treatment with 
antimotility agents. If Grade ≥3 diarrhea occurs and is unresponsive to antimotility agents, 
and an alternative etiology (e.g., infectious diarrhea) is not established, all study medications 
should be interrupted until resolution of diarrhea to Grade ≤2 or return to baseline.  If Grade 
≥3 diarrhea recurs upon the resumption of the study medications, all study medications 
should be discontinued permanently. 
27.1.4. 
Pregnancy 
 
Any woman who should become pregnant while on study will have the option of 
remaining on TDF/FTC and follow a separate complementary schedule of follow-up in 
clinical collaboration with high-risk obstetric (MFM) providers and. Details of this follow-up 
can be found in the MOPS. All such individuals will be reported to Gilead per FDA-mandated 
post-marketing requirements and registered by Gilead in the antiretroviral pregnancy registry 
to be followed until pregnancy outcome can be determined. 
 
27.2. Social Harms 
 
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 


Protocol Version 1.4          07-29-2016 
 
 
36 
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 core investigators to be serious or 
unexpected will be reported to the IRB(s) 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. 
 
 
27.3. Management of Suspected Acute Seroconversion (Primary HIV Infection - 
PHI) 
 
Should an enrolled participant present with signs and symptoms consistent with PHI, this 
should trigger immediate HIV EIA and Viral Load (VL) or NAT testing; any positive result 
should prompt immediate resistance testing and referral to HIV specialty care. Participants 
who seroconvert within the protocol will undergo evaluation as in the schedule of events 
(see Section 19) and be provided assistance as needed to establish care. If the subject is 
currently taking TDF/FTC a third antiretroviral would be recommended as soon as possible. 
If there is a delay in obtaining care then TDF/FTC should be discontinued until an adequate 
antiretroviral regimen can be started. If the seroconverting individual is not taking TDF/FTC 
they will be advised not to take TDF/FTC until a complete regimen can be acquired. 
 
 


Protocol Version 1.4          07-29-2016 
 
 
37 
 
27.4. Seroconversion Schedule of Events 
 
Table 2: Schedule of events for 
seroconversion 
Detection of 
Seroconversion 
4-week visit1 
 
Visit Windows 
±7 days 
±7 days 
CD4 panel 
X 
X 
Viral load 
X2 
X 
Stored Plasma 
X3 
X3 
Whole Blood 
X 
 
Linkage Services Provision/Assessment 
X 
X 
Behavioral Risk and Drug and Alcohol 
Assessments4 
X 
X 
 
1If visit unobtainable, then phone call will be made to participant for follow-up on linkage to 
care. 
2Viral load will be run on blood plasma stored from seroconversion visit and all prior study 
visits, done sequentially from date of seroconversion visit until undetectable viral load in 
blood plasma. 
3If not already being done as part SOE assessments. 
4Assessments will be based on those in the main SOE, and details can be found in the 
MOPS. 
 
28. CRITERIA FOR DISCONTINUATION 
 
28.1. Temporary Medication Interruption 
 
Attempts should be made to avoid temporary interruption.   
Symptoms should be managed aggressively and proactively in an attempt to avoid 
discontinuation, provided there is no laboratory evidence of toxicity and any symptoms are 
Grade 1 or 2.  In the event of symptomatic Grade 3 or any Grade 4 toxicity, TDF/FTC should 
be discontinued immediately, the only exception being a toxicity indisputably not attributable 
to TDF/FTC administration, with the permission of the protocol PI.   
In the event of inadvertent discontinuation due to missed appointments, loss of 
medication, or other unforeseen circumstances, treatment should be resumed as rapidly as 
possible.  Treatment should ONLY be reinstituted in the absence of signs/symptoms of PHI 
(Table 1 above). 
If the amount of time since last dosing of TDF/FTC exceeds 14 days when the 
participant wishes to reinitiate PrEP, a negative rapid HIV EIA and HIV VL should be 
documented PRIOR to PrEP reinitiation.  If a serum creatinine has not been performed for 
study purposes within the past 30 days, serum creatinine too should be repeated (and 
Creatinine Clearance calculated and documented) prior to medication re-initiation.  
 
28.2. Permanent Medication Discontinuation 
 
Permanent medication discontinuation prior to 48 weeks of treatment should be limited 
to participants who withdraw consent, have laboratory evidence of acute or chronic HIV 
infection, are so advised by HIV-treatment experts, or have severe toxicity as noted above.   


Protocol Version 1.4          07-29-2016 
 
 
38 
Such participants should continue to be followed per the protocol SOE (Cohort or 
seroconversion, as appropriate), even though they are no longer taking study medication. 
Additionally, participants who have persistently low TFV-DP levels (<1050 fmol/punch), 
are referred for targeted iNSC (first instance) and PrEP-STEPS (if followed by a suboptimal 
(<1050 fmol/punch) TFV-DP level at subsequent visit(s)). Refusal/failure to participate in 
PrEP-STEP programming by attending ≥1 visit within 30 days of request by study staff may 
be considered for medication discontinuation in discussion with the Protocol Chairs. 
 
28.3. Program Discontinuation 
 
Participants should be discontinued from the program under the following 
circumstances: 
 
Request by the participant to withdraw from the program 
Participant, in the judgment of program physicians, is unable to comply with 
provisions of the protocol in such a way as to be more likely to result in harm to the 
participant 
 
*Discontinued participants should return any unused study medication to the site for 
destruction, per program SOPs. 
 
 


Protocol Version 1.4          07-29-2016 
 
 
39 
29. DATA COLLECTION, STORAGE, AND MONITORING 
 
29.1. Protocol 
 
This protocol will be available in hardcopy and PDF formats with the current version and 
date. 
 
29.2. Secure Database 
 
The study will utilize existing CCTG informatics infrastructure provided by the UCSD 
Center for AIDS Research Bioinformatics and Information Technologies (BIT) Core. The BIT 
Core will provide study staff at CCTG and LAC-PATH sites access to OCCAMS, open 
source biomedical research data platform, to manage overall study flow, including the 
collection of data between and during participant visits including self-assessment 
questionnaires, iTAB text messages, specimen, laboratories, STI results, medication use, 
reported side effects, etc. All data will be stored in the secure and redundant BIT Core 
informatics infrastructure that uses a robust security modeling consisting of a multi-level 
hardware/software firewalled network, secure hardware and software encryption, data 
auditing and access tracking procedures and completely redundant services hosted from 
two physically separated server facilities.  This infrastructure will also provide regulated 
access and reporting of study data to the biostatistics research team and relevant providers 
on a need-to-know basis. It is the responsibility of the CCTG Data Unit to assure the quality 
of computerized data for this study. 
 
  
Case report forms (CRFs) will be provided for each participant. Instructions concerning 
the recording of study data on CRFs will be provided by the CCTG Data Unit. Participants 
must not be identified by name on any CRFs. Participants will be identified by the PID 
provided by the CCTG Data Unit upon registration and the linkage to the PID will be kept in 
paper copy only in a locked cabinet in a secure office at the study sites available only to the 
site investigators. Participant self-reported surveys that are performed electronically will be 
automatically stored in the electronic database secured by the CFAR BIT group for the 
CCTG. 
 
29.3. Participant Confidentiality 
 
In an effort to maintain confidentiality but allow tracking of public health resources, all 
program entrants will have a unique patient identifier code based on their study site. A date 
of birth will be requested from participants to allow two methods of identification required for 
study sample identification. All obligatory laboratory specimens, evaluation forms, and other 
records will be identified by coded PID and participant date of birth (DOB). All records will be 
kept in a locked cabinet. All computer entry and networking programs will be performed with 
only PIDs. Clinical information will not be released without written permission from the 
participant, except as necessary for monitoring by protocol QA/QC, IRB, sponsor(s) or FDA. 
All participants will sign and receive a copy of HIPAA regulations prior to study 
commencement. The original will be placed in the study chart, and a copy will be given to 
the participant. 
 
29.4. Data Collection and Monitoring 
 
 


Protocol Version 1.4          07-29-2016 
 
 
40 
Close cooperation between the Protocol Chairs, study site Investigator(s), 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.  
During the course of the study, enrollment rates, with a racial/ethnic breakdown, will be 
provided to California HIV Research Program (CHRP) on a monthly basis. Study conduct (in 
terms of assessment completion, successful sample collection, and data completeness) will 
be reviewed on a quarterly basis by the protocol team. Follow-up rates for each visit as well 
as the number of screened participants versus the number of participants enrolled, including 
a tabular list of reasons for screen-failure, will be reviewed on a monthly basis by the 
Protocol Chairs.  
The study site Investigators are responsible for continuous close monitoring of all AEs 
that occur among study participants after informed consent is signed. Accrual and summary 
of all Grade ≥2 signs and symptoms and all Grade ≥3 laboratory abnormalities will be 
prepared by the study team and reviewed by the Protocol Chairs monthly. The study team 
will also prepare a quarterly report of all AEs (regardless of grade), including the number 
and percentage of adverse events, to be reviewed by the Protocol Chairs. Serious adverse 
events, Grades 3 and 4 will be tabulated separately and reviewed by the Protocol Chairs.   
 
29.5. Clinical Site Monitoring and Record Availability 
 
A clinical study monitor will perform an on-site review of individual participant records, 
including: consent forms, CRFs, and laboratory specimen records. Monitoring will ensure 
protection of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitor will also inspect regulatory files to ensure 
requirements are being met. Pharmacy drug storage and dispensing records will be 
reviewed to ensure appropriate pharmaceutical product storage and management.  
Monitoring visits will occur when 10 participants are enrolled at each site, and then at 3-6 
month intervals during the remainder of study conduct. 
 
 
30. STATISTICAL CONSIDERATIONS 
 
 
A formal Statistical Analysis Plan (SAP) will be drafted and finalized prior to database 
lock. The SAP will contain a more detailed and/or comprehensive presentation of statistical 
methods and is the final authority for all statistical analyses.  The following section briefly 
describes the planned statistical analyses. In case the language in this section differs from 
the language in the SAP, the SAP takes precedence. 
 
30.1. Sample Size Rationale 
 
The LAC-PATH group will enroll 85 women and the CCTG group will enroll 50 women 
for a total of 135 women who will start PrEP. The target goal of the multimodal triaged 
adherence intervention for women will be to achieve 90% of women with a DBS level > 1050 
fmol/punch at any given time. The proportion and 95% confidence interval will be calculated.  
If we assume 90% of women with a DBS level > 1050 fmol/punch at any given time and 100 
women enrolled in the study, then the 95% binomial distribution confidence interval around 
the estimate will be 6% (i.e., 90% ± 6%). 
 
 


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41 
 
30.2. Statistical Analysis Plan   
 
The overarching goal of this proposal is to study the implementation of PrEP combined 
with comprehensive HIV prevention services for women living in Southern California. The 
research aims are to: i) measure PrEP adherence by intracellular TFV-DP and FTC-TP, self-
report via text messages and CASI-based adherence assessments; ii) explore the 
characteristics of women seeking PrEP and assess PrEP awareness and knowledge 
including barriers and facilitators to PrEP; and iii) determine acceptability and feasibility of a 
multi-modal adherence-based HIV-prevention program.  
 
Primary Objective: To measure adherence to oral TDF/FTC at weeks 4, 12, 24, 36, and 
48 using both biological (dried blood spots) and self-reported measures through daily text 
messaging (iTAB). 
 
 
Hypothesis I 
 
Drug levels will be high among those who persist with PrEP over time, as measured by 
tenofovir-diphosphate (TFV-DP) level > 1050 fmol/punch at weeks 4, 12, 24, 36 and 48.  
 
  
Hypothesis II 
Intracellular TFV-DP concentrations levels will correlate with self-reported adherence by 
daily texting through iTAB,  
 
For the primary analysis, we will measure adherence using a drug level cutoff consistent 
with 6 or more doses per week, as measured by TFV-DP level > 1050 fmol/punch at weeks 
4, 12, 24, 36 and 48. This will be in the as-treated group who are on-PrEP (censoring those 
on permanent or temporary discontinuation). A descriptive analysis of the proportion of 
women achieving adequate adherence by week of study will be conducted.  Baseline versus 
48 weeks proportion of adherence will be compared via Fisher’s exact test.    
 
In order to examine drug adherence surrounding the implementation of intensified 
interventions specific to women receiving targeted iNSC and those receiving PrEP-
STEPS we will compare the change in levels pre- and post-intervention.  
 
Additional sensitivity analyses will be performed using alternative cutoffs of adherence. 
Intracellular FTC-TP levels will be compared to TFV-DP for discrepancy of recent dosing 
that would be reflective of the short half-life of FTC (past day) versus the past week of 
dosing that is informed by the long half-life of TDF. 
 
Subgroup analysis will compare adherence and other outcomes between risk categories of 
women (e.g. serodiscordant partnerships with and without conception intentions, partner of 
elevated HIV risk, sex worker, recent STI, injection drug use, PEP users). 
 
Adherence will be measured by self-report using daily text messaging through iTAB. We will 
validate iTAB reported adherence in women using the TFV-DP levels for correlation with the 
proportion of positive responses in the 34 days prior to the drug level (i.e. two half lives of 
TDF) in week 12, 24, 36 or 48 using the Spearman correlation coefficient.  
 
The average days of adherence per week during this time will be calculated as number of 
days reporting doses taken in past 35 days divided by 35 multiplied by 7 and rounded to the 
nearest whole number. For each number of days per week of adherence (i.e. 0, 1, 2,3, 4, 


Protocol Version 1.4          07-29-2016 
 
 
42 
5,6 and 7) the TFV-DP will be reported from mean (95% confidence interval) and median 
(IQR). 
 
Secondary Objectives: 
To describe the characteristics of women seeking PrEP, a descriptive analysis will be 
performed for the following secondary endpoints:  
• 
PrEP awareness and acceptability prior to study enrollment 
• 
Perceived barriers and facilitators to PrEP use  
• 
HIV knowledge pre- and post-study 
 
Implementation secondary outcomes will include: 
• 
Acceptability and feasibility of an HIV prevention program with a multimodal, 
intensive adherence package for PrEP delivery defined on a Likert scale 
• 
Retention in an HIV prevention program that includes PrEP defined by making study 
visit 
• 
Safety and tolerability of daily TDF/FTC given for PrEP including discontinuation for 
any adverse event, serious adverse events and adverse events (grade 2 or higher) 
• 
HIV incidence in the observed cohort of PrEP users 
• 
Frequency of clinically significant resistance among seroconverters 
 
Additional sensitivity regression modeling will be performed for the factors associated 
with loss to follow up and discontinuation of TDF/FTC. Factors will included change in 
perceived and actual risk of HIV acquisition, fear of disclosure, demographics, 
socioeconomic status, social characteristics (e.g., medical mistrust, non-English 
language, cultural factors), co-occurring health problems or issues (e.g., untreated 
mental illness, ongoing substance use, violence, trauma), and low health/HIV and 
system literacy.   
 
Risk compensation during study will be assessed by changes in the incidence of STIs 
(chlamydia, gonorrhea, HSV-2 and syphilis) during study and self reported sexual risk 
behavior over time by number of sexual partners (by HIV status) and number 
condomless sex acts. 
 
All descriptive results will be reported as point estimates (mean or odds ratios as 
appropriate) and interval estimates (95% confidence intervals, interquartile ranges). All tests 
of significance for the secondary outcomes will be 2-sided and no adjustments will be made 
for multiple comparisons.  A p-value of 0.05 will be considered statistically significant.  
Statistical analysis will be conducted using the statistical software R 3.1.1 (www.r-
project.org).  
 
31. INFORMED CONSENT 
 
The study will be overseen by the Institutional Review Boards of UCLA, UCSD, and 
participating clinical sites, and the study and all related study documents will be approved by 
all IRBs.   
Although PrEP is recommended by the CDC and TDF/FTC has received FDA approval 
for a preventive/prophylactic indication, it is important that participants accessing resources 
understand the limitations of knowledge regarding PrEP, including effectiveness estimates, 
with precise efficacy dependent on, and likely proportional to daily adherence rates.   


Protocol Version 1.4          07-29-2016 
 
 
43 
All participants will be required to sign a one-time consent for documenting 
understanding of study procedures, risks to self and intimate contacts, course of treatment 
including a behavioral risk-reduction component and adherence counseling activities, all as 
described in the informed consent and protocol. 
 
32. EXPERTS IN HIV CLINICAL CARE 
 
Numerous references are made to conditions for invoking opinion or consultation with 
experts in HIV clinical care, including: 
 
§ 
Incidental finding of HIV-positivity on rapid screening on initial intake 
§ 
Signs or symptoms consistent with PHI (Section 22.3, Table 1)  
§ 
Toxicity or intolerance to TDF/FTC requiring discontinuation  
§ 
Unclear attribution of toxicity to TDF/FTC and/or appropriate work-up 
 
The HIV Clinical Care Expert will be considered the site PI, or if unavailable the protocol 
chair or his designee.   
 
33. HUMAN PARTICIPANTS 
 
33.1. Institutional Review Board (IRB) Review and Informed Consent 
 
 
 
This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by the IRB or ethics committee responsible for the oversight 
of the study. A signed consent form will be obtained from the participant. The consent form 
will describe the purpose of the study, the procedures to be followed and the risks and 
benefits of participation. A copy of the consent form will be given to the participant. 
 
33.2. Participant Confidentiality 
 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the 
site will be stripped of any patient identifiers (name, birthdate, medical record number) and 
only identified by the coded PID in order to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only and analyzed centrally without any possibility of linking participant identity with 
participant data. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by IRB and governmental agencies. 
 
 
34. PUBLICATIONS AND FINDINGS 
 
Publication of the results of this trial will be governed by LAC-PATH/CCTG policies. Any 
presentation, abstract or manuscript will be made available for review by pharmaceutical 
supporters prior to submission. 
 
 
35. 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 


Protocol Version 1.4          07-29-2016 
 
 
44 
and handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
 
All infectious specimens will be transported using packaging mandated in the 
Federal Code of Regulations, CDC 42 CFR Part 72. Please also refer to individual carrier 
guidelines, e.g., FedEx, Airborne, for specific instructions. 
 
 
36. FUNDING 
 
California HIV Research Program  
Drug Supply from: 
Gilead Sciences  
Foster City, California 


Protocol Version 1.4          07-29-2016 
 
 
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