Next Generation Real-time Monitoring for PrEP Adherence in Young Kenyan Women
Phase: NA
Conditions: HIV/AIDS, Adherence
Sponsor: Massachusetts General Hospital

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Protocol 
MPYA: Monitoring Pre-exposure Prophylaxis for Young Adult women 
Mpya means “new” in Swahili 
(Official title: Next generation real-time monitoring for PrEP adherence 
in young Kenyan women) 
Version 2.8 
25 September 2020 
Funding: 
US National Institute of Mental Health (NIMH) 
(R01MH109309) 
NCT02915367

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Study team 
 
Kenyan Medical Research Institute (KEMRI)- Kisumu 
Elizabeth Bukusi, MBChB, MMed, MPH, PhD 
Zachary Kwena, PhD, MA 
George Mugendi, MPharm 
 
Massachusetts General Hospital (MGH)/Harvard Medical School 
Jessica Haberer, MD, MS 
 
KEMRI- Thika 
Nelly Mugo, MBChB, MMed, MPH 
Kenneth Ngure, PhD, MPH 
Margaret Mbuchi, PhD 
 
University of Pennsylvania (UPenn) 
Harsha Thirumurthy, PhD 
 
University of Washington (UW) 
Jared Baeten, MD, PhD 
Ruanne Barnabas, MBBS, DPhil 
 
Brigham and Women’s Hospital/Harvard Medical School 
Ingrid Katz, MD, MHSc. 
 
University of North Carolina (UNC) 
Angela Kashuba, PharmD 

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Abbreviations 
 
ADAPT 
Alternative Dosing to Augment Pre-Exposure Prophylaxis Pill Taking 
AIDS  
acquired immunodeficiency virus 
AE 
 
adverse event 
ART 
 
antiretroviral therapy 
CAG 
 
community advisory group 
CBO 
 
community based organization 
CDC 
 
Centers for Disease Control and Prevention (US) 
DAIDS  
Division of AIDS (NIH) 
DMC  
data monitoring committee 
DBS 
 
dried blood spots 
ELISA  
Enzyme-Linked Immunosorbent Assay  
FDA 
 
Food and Drug Administration (US) 
FTC 
 
emtricitabine 
FTC-TP 
emtricitabine-triphosphate  
HIV 
 
human immunodeficiency virus 
HIPAA  
Health Insurance Portability and Accountability Act 
HPTN  
HIV Prevention Trials Network 
HTTP    
hypertext transfer protocol (presentation of web data) 
iPrEx  
Pre-exposure Prophylaxis Initiative 
IQR 
 
interquartile range 
IRB 
 
institutional review board 
KEMRI  
Kenya Medical Research Institute 
MEMS  
medication event monitoring system 
MGH  
Massachusetts General Hospital 
MPYA  
monitoring pre-exposure prophylaxis for young adult women 
MSM  
men who have sex with men 
NACOSTI  
National Council of Science, Technology and Innovation  
NIH 
 
National Institutes of Health (US) 
NIMH  
National Institute of Mental Health (US) 
PEPFAR 
President’s Emergency Plan for AIDS Relief 
PIN 
 
personal identification number 
PPB 
 
Pharmacy and Poisons Board of the Ministry of Health (Kenya) 
PrEP  
pre-exposure prophylaxis 
PROUD 
PRe-exposure Option for reducing HIV 
RedCAP 
Research Electronic Data Capture 
SMS 
 
short message service (text messaging) 
STI 
 
sexually transmitted infection 
TCP/IP  
transmission control protocol/internet protocol (internet programming code) 
TDF 
 
tenofovir 
TFV-DP 
tenofovir diphosphate 
UNAIDS 
Joint United Nations Program on HIV/AIDS 
UPenn  
University of Pennsylvania  
US 
 
United States 
UTAUT 
Unified theory on acceptance and use of technology 
UW 
 
University of Washington 
VCT 
 
voluntary counseling and testing 
VOICE  
Vaginal and Oral Interventions to Control the Epidemic (study) 
WHO  
World Health Organization 
Summary 

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Real-time electronic monitoring is the optimal approach for understanding patterns of 
adherence, which is critical for determining if adherence to daily oral pre-exposure prophylaxis 
(PrEP) aligns with an individual’s risk for human immunodeficiency virus (HIV) acquisition. 
Compared with earlier adherence measurement devices, next generation Wisepill technology 
offers significant innovations in data storage and transmission reliability, cost, and usability and 
is ready for implementation in resource-limited settings. Coupling Wisepill monitoring to short 
message service (SMS) adherence reminders has great potential to support adherence at the 
precise time it is needed. Real-time strategies may be particularly important for young women- a 
population in need of self-controlled HIV prevention strategies, but one that has previously 
struggled with PrEP adherence. Triangulating weekly SMS measurement of sexual behavior 
with adherence may explain how PrEP can be used most effectively for HIV prevention (i.e., 
prevention-effective adherence).  
 
This protocol describes a longitudinal study of young Kenyan women at high risk for HIV who 
will be offered PrEP for up to two years. Adherence will be monitored in all women with the next 
generation Wisepill; half will be randomized to receive SMS reminders. The technical function, 
acceptability, cost, and validity of the next generation Wisepill device coupled to SMS reminders 
will be determined among this cohort of young Kenyan women. Additionally, SMS will be used 
for longitudinal assessment of risk perception and its alignment with PrEP adherence.  
 
Design:  Prospective study of open-label PrEP 
 
  Randomization (1:1) of SMS reminders on PrEP adherence 
  Periodic surveys of risk behavior and perception, including by weekly SMS 
 
  Two years of follow-up per participant 
 
Population: Young women at high risk for HIV infection who are interested in taking PrEP; HIV 
infected male partners of up to 30 (HIV uninfected) young women enrolled in MPYA 
 
Study sites: 
• Thika, Kenya 
• Kisumu, Kenya 
 
Approach: 
 
Overview 
We will prospectively enroll up to 380 young women who choose to initiate PrEP at two clinical 
sites in Kenya. We will also interview up to 30 male partners of study participants who report 
being in serodiscordant relationships. We will use wireless adherence monitoring to understand 
PrEP adherence behavior, as well as patterns of PrEP discontinuation (and re-initiation), in this 
cohort. We will randomize half of the women to SMS reminders to determine its impact on 
adherence. We will assess the technical function, acceptability, cost, and validity of the next 
generation Wisepill device coupled to SMS reminders, thus helping to determining the potential 
for this technology to assess and support PrEP adherence in future studies and potentially 
clinical care. Additionally, we will longitudinally assess HIV risk behaviors and perceptions using 
SMS in all women to determine how well risk for HIV infection is aligned with adherence (a 
concept called prevention-effective adherence). The study will involve a combination of 
quantitative and qualitative methods. The specific aims are as follows: 
 
Aim 1. Use the next generation Wisepill device in a cohort of young HIV-uninfected Kenyan 
women initiating PrEP to a) measure real-time adherence and b) determine the impact of 

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SMS reminders on adherence. We will monitor adherence among all women with 
Wisepill. We will randomize half to receive daily SMS reminders with the option of 
switching to SMS reminders only as triggered by missed doses; the other half will 
receive no SMS reminders. There will be two primary outcomes for this aim. First, we will 
determine enacted adherence (i.e., pill taking) and persistence (i.e., continuation of PrEP 
over time) as determined by Wisepill from initiation of PrEP use (when adherence 
patterns are often established) through 24 months of use, comparing those randomized 
or not to SMS reminders. Second, we will compare dried blood spot (DBS) tenofovir-
diphosphate levels between the two groups at multiple time points. With both outcomes, 
we will be assessing the synergy of SMS reminders coupled to real-time monitoring.  
 
Aim 2. Determine the technical function, acceptability, cost, and validity of the next generation 
Wisepill device coupled to SMS reminders. We will measure data transmission reliability, 
battery life, and other technical features through the two-year cohort study. We will 
assess acceptability and usability of our strategy via quantitative surveys in all women, 
as well as qualitative interviews in about 50 women. We will additionally assess costs 
and ease of use with a time and motion study. Using these cost estimates and adapting 
an existing mathematical model of HIV transmission, we will estimate the cost-
effectiveness of Wisepill plus the SMS reminders per HIV case averted. Adherence 
validity will be determined by comparing the Wisepill data with DBS tenofovir levels as 
measured in Aim 1. Discrepancies between the two measures will be explored through 
qualitative interviews at the conclusion of the study. 
 
Aim 3. Triangulate Wisepill adherence data with weekly assessment of HIV risk behaviors and 
perceptions, to measure prevention-effective adherence. After the first 6 months of PrEP 
use (i.e., when initial decisions about PrEP may start to change), we will send all women 
a weekly SMS survey asking about recent sexual behavior, use of alternate HIV 
prevention tools, subjective HIV risk, and perception of their PrEP adherence. We will 
explore the overlap of perceptions and behaviors and PrEP adherence, through 
quantitative surveys in all women and qualitative interviews in about 50 women. Our goal 
is to measure dynamic changes in HIV risk and perception of risk or other motivators for 
HIV prevention that may lead to PrEP discontinuation (appropriately or inappropriately). 
We will use these SMS surveys to quantify prevention-effective adherence in young 
women at risk for HIV infection (individually and for the cohort overall). At exit from the 
study, we will administer a short questionnaire to understand future plans to use PrEP 
and experiences related to PrEP during the study. 
 
Aim 4. To qualitatively determine why young women in Kenya who are at risk for HIV 
acquisition may choose not to enroll in a PrEP study or initiate PrEP as it relates to 
views on PrEP and the impact of technology on study involvement. We will interview up 
to 60 women who met eligibility criteria at screening but do not return for enrollment. We 
will also conduct at least 10 and up to 12 focus groups among five key populations 
across the two sites. These focus groups will include: key community leaders, male 
parents, female parents, young women (ages 18-24 who are not participating in the 
larger study), and young men (ages 18-24) from the community, assuming one focus 
group with each population at each site. We are allowing for one additional focus group 
per site in case of technical difficulties with the digital recorders or other data collection 
difficulties. Inquiry will be guided by domains from a prior conceptual model we have 
developed focused on understanding decision-making related to uptake of HIV treatment 
for prevention, as well as prior research on PrEP uptake and adherence. We will use an 
iterative approach over the course of data collection.  

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Aim 5. Evaluate a novel adherence measure in which the amount of emtricitabine is quantified 
along strands of hair. We will compare the emtricitabine concentration patterns in hair with other 
measures of adherence in the study, including Wisepill, dried blood spots, and self-reported 
adherence. Analysis will include correlation and categorical comparisons among the measures. 
Additionally, preliminary evidence from women who have used PrEP early in pregnancy has not 
shown risks to pregnancy or baby. Studies on breast milk exposure show that only minimal 
amount of drug is present in breast milk and even less is transmitted to the baby. We will 
therefore allow women who are breastfeeding to enroll in the study. In addition, we will offer 
participants the option to continue PrEP should they become pregnant during the course of the 
study or choose to continue PrEP while breastfeeding. Data on pregnancy outcomes will be 
added to that of other studies involving PrEP and young women, which will collectively 
contribute to understanding the safety of PrEP during pregnancy. 
 
Aim 6. To explore the acceptability and feasibility of assessing patterns and content of SMS 
and/or WhatsApp messages as a means of identifying risk for HIV acquisition and/or PrEP 
adherence. We are proposing a sentiment analysis (i.e., the use of language processing to 
systematically identify, quantify, and study affective states and subjective information). First, we 
will ask participants for permission to download their SMS and/or WhatsApp message history 
from the prior 90 days. We will also ask participants to identify the type of relationship (e.g., 
family member, peer, sexual partner) for up to 20 of the most commonly used numbers. We will 
then explore the number and patterns of SMS and/or WhatsApp messages sent by the 
participant to map her social networks, as well as assess for word or phrase frequency 
potentially related to HIV risk (e.g., sex, HIV) and adherence (e.g., pill, PrEP). We will 
additionally determine any correlations of this data with other reported risk and adherence 
assessments already collected in the study. All mobile communication data will be de-identified 
once it is linked to other MPYA study data to protect confidentiality. 
  
Approach: To accomplish Aim 6, we will approach participants currently enrolled in the study, 
as well as contact those who have 1) already exited the study and 2) indicated on their primary 
study consent form that they are willing to be contacted for future studies. We aim to contact as 
many participants as possible before the study ends (April 2020). Because this aim is 
exploratory, we do not have specific targets for participation.  
 
We will then obtain separate informed consent specifically for collection and analysis of mobile 
communication data. We will download this data directly from the participant’s phone. We will 
not seek any mobile communication data stored with the participant’s mobile network provider 
(e.g., Safaricom). We will use a SIM card reader to download SMS; The data will then be 
transferred to a Word document or Excel spreadsheet, which will be encrypted to ensure privacy 
using the in-built file encryption feature in Microsoft Office. WhatsApp messages (if the user has 
a smartphone) will be downloaded to a .txt file using the WhatsApp export functionality. The file 
will be converted to a Word or Excel file using Microsoft Office and encrypted, as described 
above.  
 
We will also ask participants to list their most commonly used phone numbers (up to 20) and 
describe their relationships to each number (e.g., family member, friend, sexual partner, other); 
we will not ask for that person’s name or other identifying information. We will additionally ask a 
few questions about the acceptability of accessing their mobile communication data.  
 
Analysis: The analysis of the mobile communication data is exploratory in nature and is unlikely 
to be powered for significant effects. The primary goals are therefore to determine the following: 

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• Acceptability: Acceptability will be defined by a summary of the participants’ willingness (or 
not) to provide the requested data. We will assess their level of comfort with this activity on a 
Likert scale. 
• Feasibility:  
• We will assess data availability on the participant’s phones (e.g., extent of missing or 
incomplete data). 
• We will determine our ability to map social networks from the mobile communication 
data by identifying the frequency of SMS and/or WhatsApp sent by the participant to 
each provided phone number and exploring patterns of contact (e.g., the number of 
times a participant contacts a “friend” within a given time frame). 
• We will determine the feasibility of assessing risk of HIV acquisition with the mobile 
communication data by using a combination of computational linguistic software and 
manual review of the mobile communication content. We will identify the most 
frequently used words or phrases in the SMS and/or WhatsApp messages that may be 
related to risk of HIV acquisition, accounting for the relationship of the person to whom 
the SMS and/or WhatsApp was sent (e.g., “sex” sent to a sexual partner) and potential 
use of multiple and/or mixed languages (e.g., a combination of English and Swahili 
with phonetic spelling).  
• We will use similar techniques to determine the feasibility of assessing PrEP adherence 
with the SMS and/or WhatsApp data. We will identify the most frequently used of 
words or phrases potentially related to adherence (e.g., “taking”, “PrEP”, “pill”), again 
considering use of multiple and/or mixed languages. 
• Preliminary correlations of SMS and/or WhatsApp data with other HIV risk and adherence 
data: To explore the potential for identifying individuals at risk for HIV acquisition and/or poor 
adherence, we will correlate the social networks and linguistic data with risk assessments 
obtained earlier in the study through the weekly SMS surveys or quarterly study visits (e.g., 
self-reported risk, number of sexual partners, use of alcohol), as well as overall and patterns 
of adherence as measured by pharmacy records, Wisepill data, self-reported data, and (if 
provided) hair samples. We will also consider any seroconversion events.  
• Security. Privacy is of utmost concern with these procedures. All data will be stored in an 
encrypted manner as described above. We will additionally de-identify the social media data 
as soon it is linked to the participant’s other study data (typically within one business day of 
collection). 
 
Background and rationale 
 
Real-time electronic monitoring is the optimal approach for understanding patterns of adherence 
to daily pill taking and offers novel opportunities for effective intervention.  
 
Multiple approaches have been studied to measure daily pill adherence, but few provide the 
rigor of electronic monitoring. Self-reports are often inaccurate due to social desirability and 
recall bias. Pill counts are subject to manipulation (e.g., pill dumping) and unannounced pill 
counts are costly. Pharmacy refill is feasible, but insensitive in that it provides only the maximum 
predicted adherence (i.e., individuals do not necessarily take the pills picked up from the 
pharmacy). Plasma drug levels and other biomarkers document drug ingestion yet are 
impractical for frequent collection and are expensive. None of these other measures assess 
patterns of adherence, which are critical for knowing if day-to-day adherence is adequate for 
achieving the desired clinical outcomes (e.g., viral suppression in the case of antiretroviral 
therapy [ART] [1-3] or avoidance of HIV seroconversion in the case of PrEP).  
 

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Many electronic adherence measurement tools, including the most commonly used device, the 
Medication Event Monitoring System (or MEMS), require individuals to return to the clinic for 
measurement, which may be weeks to months after adherence challenges arise. In such cases, 
the opportunity for providing adherence intervention may thus be missed, allowing clinical 
consequences to occur. Instead, monitoring with real-time measurement that can be coupled to 
real-time adherence intervention is needed [4]. In essence, good adherence measurement is 
most useful when it is timely and can be coupled to real-time interventions that address the 
contextual moment in which the adherence challenges arise. 
 
Wisepill is an electronic adherence pill container monitor that transmits the time-and-date stamp 
of each opening, using cellular technology, thus enabling real-time measurement of day-to-day 
adherence patterns. It is manufactured by Wisepill Technologies in Cape Town, South Africa.  
Because of its timely data transmission, Wisepill can be coupled to real-time interventions for 
individuals in need of support, precisely when they need them. Wisepill is discrete – 6x13 cm – 
and easy to use. Our group has extensive experience with the first generation Wisepill device, 
starting in 2009 [5]. In a pilot study among 49 adults taking ART in rural Uganda, Wisepill 
adherence was found to be 89.5% (interquartile range [IQR] 83.9–92.3%) [6]. All but two 
participants (97.9%) reported it was ‘easy/very easy’ to use, and all stated they ‘liked/really 
liked’ being monitored. Higher Wisepill adherence was significantly associated with protection 
against viral rebound (OR 0.58 for each 10% increase in adherence, 95%CI 0.34–0.98; p=0.04). 
We have used Wisepill to monitor ART adherence among >500 individuals in the same setting. 
A next generation Wisepill device has recently become available, addressing technical 
limitations of the first-generation Wisepill and readying the technology for wide-scale use 
(described below).   
 
In resource-limited settings, cell phones are common and have great potential for adherence 
intervention when coupled to real-time adherence monitoring. In Kenya, ~30 million people 
(70% of the population) own cell phones, and mobile technology for health (mHealth) is rapidly 
developing [7]. Two landmark randomized controlled trials of SMS reminders in Kenya showed 
significant increases in ART adherence and one showed an increase in viral suppression [8, 9]. 
We are studying SMS linked to Wisepill for ART adherence support in Uganda; studies 
assessing real-time adherence interventions are needed for PrEP.  
 
There is equipoise for randomization of SMS reminders, because the evidence for the 
effectiveness of SMS reminders generally is mixed and there is no evidence that reminders are 
effective for PrEP adherence. The two randomized controlled trials (RCT) noted above [8,9] did 
show improvement in antiretroviral adherence; however, another RCT did not [10]. Studies of 
SMS reminders linked to real-time adherence monitoring have similarly been mixed. Two RCTs 
found increased adherence [11,12], while a third did not [13]. The Orrell study did find a 
decrease in treatment interruptions, but none of these studies found an improvement in viral 
suppression. Importantly, these studies were all conducted within the context of HIV treatment, 
not prevention. Factors influencing adherence to HIV prevention may be quite different. 
Additionally, none of these prior studies focused on the proposed study population (young 
women) and few were conducted in recent years when individuals are inundated with social 
media, even in resource-limited settings. SMS reminders may or may not have a strong impact 
in the context of so many other electronic input. For these reasons, there is equipoise and a 
study like this will help determine the need for such an intervention, and if needed, whether daily 
or as needed messages have the better impact. 
The next generation Wisepill technology offers significant innovations compared with the first 
generation and has the potential for ready implementation in resource-limited settings, for both 
research and clinical use.  

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Wisepill (Figure 1) is a promising emerging technology poised for high 
impact in understanding adherence through real-time day-to-day 
measurements of pill taking behavior. A beta-development form of 
Wisepill has been available for several years; initial limitations 
included unreliable data transmission, limited battery life, and a 
challenging user interface in diverse settings (personal communication 
from Dr. Rivet Amico and Dr. Mirjam Kempf-Collette). Through our 
prior experience with this device, we are well positioned to test the 
newly refined next generation technology such that it is “plug and 
play” and ready for widespread use in research and potentially 
clinical care. Table 1 below presents the innovations in the Wisepill 
technology.  
 
TCP/IP=transmission control protocol/internet protocol (internet programming code) 
HTTP=hypertext transfer protocol 
 
*This feature will not be used in this study. 
Oral PrEP requires daily pill taking. Adherence is key to the effectiveness of daily oral tenofovir-
based PrEP for HIV prevention, yet has been challenging for women. Intervention through SMS 
adherence reminders may be an effective and acceptable intervention for this population.  
 
Six randomized placebo-controlled clinical trials explored the efficacy of daily oral tenofovir-
based PrEP against HIV infection [14-19], with PrEP efficacy results ranging from 0 to 75% [20].  
The variation across trials (and across individuals) in HIV protection can largely be explained by 
differences in PrEP adherence [21], with tight correlations between trial results and the levels of 
objective adherence measures in those studies and HIV protection estimates between 90-100% 
Table 1. Wisepill technology innovations 
Functionality 
First generation 
Next generation 
Battery life 
2 months 
>6 months; a new long-life mode may 
extend to 12  
Data storage capacity 
30 events 
1,000 events 
Data transmission 
2G-compatible 
2G and 3G-compatible 
Data transmission 
Simple modem that 
is required to run 
device software 
Advanced modem with separate processor 
such that device software can run 
independently (provides more powerful, 
reliable communication) 
User interface 
Oriented to 
engineers 
User friendly display and data organization 
Cost (including hosting) 
>$200 per person 
<$150 per person 
Enhanced “heartbeat” 
(positive control for device 
functionality) 
Not stored on the 
device or 
guaranteed 
Stored on the device and server; may be 
sent multiple times per day if desired 
Geo-position tracking 
N/A 
Enables device location (optional)* 
SMS packing 
Only TCP/IP 
communication 
HTTP POST allows easier integration with 
the device, enabling use of client servers 
directly 
Magnetic switch (triggered 
on device opening) 
Magnetic reed 
switch 
Chip-based solid state magnetic switch 
greatly increases reliability  
Electronic components 
Multiple 
components 
All are now solid state (no moving parts) 
and are highly reliable, especially in rugged 
environments 
Fig 1. Wisepill device  

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in individuals with high adherence [15, 22, 23]. Oral PrEP is clearly efficacious, and highly so, 
when taken.  
 
In the FEM-PrEP and Vaginal and Oral Interventions to Control the Epidemic (VOICE) trials 
(which involved at-risk women in Kenya, South Africa, Tanzania, Uganda, and Zimbabwe), 
<30% of participants had objective evidence of PrEP adherence, and no efficacy of PrEP 
against HIV found as a result. Those data have made some question whether PrEP works for 
women.  However, in the Partners PrEP (KNH/UoN ERC ref. # P286/05/2012 and ref. # SCC 
1336) and TDF2 (Tenofovir 2) trials (which involved serodiscordant couples in Kenya and 
Uganda and heterosexual men and women in Botswana, respectively), women did adhere well 
to PrEP, and PrEP prevented HIV in subgroups of young, high-risk women, proving that PrEP is 
efficacious for women when taken [24]. Work done after the VOICE trial suggests that multiple 
factors contributed to low adherence in that study, including complex perceptions of self-efficacy 
against HIV risk, HIV and HIV prevention stigma, and components of the clinical trial itself (e.g., 
blinding, uncertainty about efficacy).  
 
Daily oral PrEP is supported for women by US Food and Drug Administration (FDA) labelling, 
US Centers for Disease Control and Prevention (CDC) guidance, recent President’s Emergency 
Plan for AIDS Relief (PEPFAR) goals, and World Health Organization (WHO) guidelines [25-
28], and the recent Alternative Dosing to Augment Pre-exposure Prophylaxis Pill Taking 
(ADAPT) trial of multiple dosing regimens for PrEP found that women in South Africa were able 
to adhere well to a daily regimen (79% overall) [29]. For women wanting PrEP, adherence may 
be different now that efficacy is proven (unlike during the clinical trials), in an analogous way to 
the improvements in PrEP adherence and impact seen for men who have sex with men (MSM) 
between the blinded Pre-exposure Prophylaxis Initiative (iPrEx) trial (44% efficacy) and the 
open-label PRe-exposure Option for reducing HIV (PROUD) study (86% efficacy) [30, 31].  
 
As noted above, SMS reminders have been shown to be effective for ART adherence when 
sent on a scheduled basis [8, 9], as well as when tied to real-time adherence monitoring [11]; 
however, they have not yet been tested for PrEP adherence. Daily reminders may be important 
to support habit formation at PrEP initiation, given that non-adherence was already well 
established by the first quarterly tenofovir measurement in the VOICE trial [32]. Because daily 
SMS may result in habitutation (i.e., annoyance and decreased impact that may result from 
frequent reminders) with time [9], this study will test the use of daily SMS reminders, followed by 
SMS reminders only when triggered by misses doses. The approach follows a novel paradigm 
in healthcare delivery called “just-in-time”, which refers to the provision of information and/or 
services in the moment they are needed. It has been shown to be highly effective in other 
aspects of healthcare delivery, such as home health care [33-35], and has great potential to be 
applied to PrEP adherence.  
 
Risk for HIV acquisition depends, in large part, on dynamic sexual behaviors and decisions to 
use HIV prevention tools. Risk perceptions and attitudes may change over time, influencing 
PrEP adherence. Understanding the interface of dynamic risk and adherence over time is 
therefore essential for achieving prevention-effective adherence.  
 
HIV risk is dynamic over time, changing with sexual behaviors, partners, and use of prevention 
options. For instance, risk is high for a woman who has unprotected sex with an HIV-infected 
partner who is not taking ART, and risk is low for a woman who does not have sex for a 
sustained period of time. The combination of these factors at any given time may depend on 
perceptions and attitudes toward risk. Risk perception plays a central role in multiple theories of 
health behavior, with the hypothesis that individuals who perceive risk of acquiring a disease will 

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be more likely to engage in risk reducing behaviors [36, 37]. Attitudes towards risk represent the 
extent to which individuals are willing to take on risk and are considered to be an important 
predictor of behavior [38-40].  
 
Measurement of HIV risk behaviors, perceptions and attitudes has been challenging, as recall of 
behavior and perceptions is typically limited and self-report may be subject to social desirability 
bias. SMS may be an ideal means for collecting this type of data, given the ability to administer 
SMS frequently and the relative anonymity of digital data collection. Our group has used SMS to 
assess sexual behavior, as well as explored assessment of risk perception and attitude, in 
multiple projects in Kenya [41, 42]. Importantly, dynamic risk behavior and perception should be 
tracked longitudinally, as PrEP is not forever once started (unlike ART). Assessments of when 
and how it can be discontinued are needed. PrEP is not an on-and-off-again prevention strategy 
and decisions regarding its use should not be made on a daily or weekly basis (although risk 
may change this frequently), particularly for women. Pharmacokinetic studies suggest high 
adherence and weeks of lead-in may be needed for protection in vaginal tissue (in contrast 
more rapid protection rectal tissue for MSM) [43, 44]. Thus, decisions to discontinue (and 
potentially later re-initiate) PrEP should be driven by aggregated risk patterns. No such data are 
currently available, but are key for developing evidenced-based guidance. 
 
Making the best use of prevention tools during periods of high risk is the ideal– a concept we 
have termed prevention-effective adherence [3]. High PrEP adherence in the absence of risk for 
HIV acquisition is not advantageous to the PrEP user (because of potential side effects and 
other costs such as time away from work to get refills) or society (because of the cost of 
unnecessary medication, which could have gone to other HIV prevention and/or treatment 
efforts). These factors are particularly important in resource-limited settings, like Kenya. 
Moreover, PrEP non-use in the absence of risk is logical and reflects what people do; in the 
Partners PrEP Study, lack of sexual activity in a month was associated with a four-fold increase 
in PrEP non-use [23]. Concurrent weekly measurements of risk behavior, risk perception, and 
adherence over time will improve our understanding of the relationship among these factors and 
help determine when adherence interventions are needed for women relying on PrEP for HIV 
prevention.  
 
Based on the FEM-PrEP and VOICE trials, one could argue that women have trouble aligning 
their risk behaviors and perceptions with adherence to achieve HIV protection. However, 
women routinely make this type of decision in another area of health prevention - family 
planning. Women often successfully choose when to use (or not use) a given contraceptive 
option. While their choices are not always perfect, many more pregnancies have been 
prevented through family planning than would have been prevented otherwise and family 
planning is a global public health imperative. This grant proposes the foundational science 
necessary to help guide women with these vitally important choices for PrEP for HIV prevention. 
Advancement of Wisepill for PrEP adherence monitoring and intervention is needed now, as 
PrEP is being rolled out and implemented in different cultural and economic settings.  
 
Following demonstrated efficacy in PrEP clinical trials [14, 16], the US FDA approval for use of 
tenofovir/emtricitabine for HIV prevention [27], and publication of US CDC and WHO guidelines 
[25, 28], preparations to roll out PrEP have begun. More than two dozen demonstration projects 
of PrEP are planned or underway worldwide, and PrEP is being prescribed in some clinical care 
settings [45]. While adherence is known to be a critical issue for PrEP adherence, it is poorly 
understood and few tools exist to support it. This study will help fill that void. 
 
Importantly, the Kenyan Ministry of Health has included PrEP and has named young women 
 

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(among whom 20% of all new infections in Kenya occur) as a priority population in its 
Prevention Revolution Road Map 2030 [46]. Given the challenges with this population in some 
PrEP clinical trials, a better understanding of adherence and adherence support is urgently 
needed for this specific population. 
 
With the proposed administrative supplement, we will assess factors driving decision-making 
both at the point prior to PrEP uptake, and immediately after PrEP initiation, among high-risk 
young women in Kenya. In the context of this trial that is technologically intensive for 
participants, we will also seek to discern the impact of direct monitoring (using Wisepill and 
SMS feedback) on study engagement, distinguishing it from treatment-related decision-making. 
Our findings will inform messaging and other interventions to promote PrEP scale-up as a core 
component of combination prevention for this key population. These issues are critical because 
our prior research has shown that decision-making related to HIV treatment and prevention 
often reflects a tension between perceived risks and social costs incurred when taking 
medication. Specifically, adults living with HIV report that “feeling healthy” is a critical deterrent 
to ART initiation. It therefore remains unclear whether young women who are at risk for HIV 
acquisition, but are otherwise healthy, will want to initiate PrEP. 
 
Methods 
 
Overall design 
We propose a prospective study to follow up to 380 young women who choose to initiate PrEP 
at two clinical sites in Kenya; all 3 Aims will involve this cohort. Study visits will occur at 
baseline, 1 month (to address PrEP start-up symptoms and initial adherence challenges), and 
every 3 months thereafter for 24 total months per participant. At baseline, we will determine if 
PrEP is clinically safe to prescribe for each participant, confirm HIV-negative status, and 
measure socio-behavioral factors that may influence PrEP use. Longitudinal study visits will 
involve PrEP distribution (if desired), adherence counseling, clinical monitoring (including HIV 
testing), storage of dried blood spots, and (at some visits) questionnaires. SMS reminders will 
be sent to half of the participants. Additional data will be collected through the Wisepill device, 
SMS surveys, time and motion studies, and qualitative interviews. 
 
• 
Aim 1: Use the next generation Wisepill device in a cohort of young HIV-uninfected 
Kenyan women initiating PrEP to a) measure real-time adherence and b) determine the 
impact of SMS reminders on adherence. We will monitor adherence among all women 
with Wisepill. We will randomize half to receive daily SMS reminders with the option at 
each study visit to switch to SMS reminders only triggered by missed doses; the other 
half will receive no SMS reminders. Blood will be collected at each study visit as DBS for 
tenofovir concentration determination. 
o Outcomes:  
§ 
Wisepill adherence (enacted adherence and persistence) 
§ 
Tenofovir concentration as a marker of adherence   
 
 
• 
Aim 2: Determine the technical function, acceptability, cost, and validity of the next 
generation Wisepill device coupled to SMS reminders. Data will be collected in an on-
going manner for technical function assessment and via questionnaire for acceptability. 
Time and motion studies will gather data for ease of use and cost. Validity will be 
evaluated based on data collected in Aim 1. 
o Outcomes:  
§ 
Feasibility of Wisepill monitoring and SMS reminders 
§ 
Acceptability of Wisepill monitoring and SMS reminders 

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§ 
Ease of use, health care associated costs, and cost-effectiveness of 
Wisepill monitoring and SMS reminders 
§ 
Validity of Wisepill monitoring compared to tenofovir concentration in DBS 
 
• 
Aim 3: Triangulate Wisepill adherence data with weekly assessment of HIV risk 
behaviors and perceptions, to measure prevention-effective adherence. We will 
determine risk perception and motivations for HIV prevention through weekly SMS 
surveys, as well as through qualitative interviews. Analysis will involve the SMS data in 
comparison with Wisepill adherence data collected in Aim 1. At exit from the study, we 
will administer a short questionnaire to understand future plans to use PrEP and 
experiences related to PrEP during the study.  
o Outcome: Quantified prevention-effective adherence (defined as adherence 
during periods of risk for HIV acquisition without other forms of HIV protection) 
• 
Aim 4: To qualitatively determine why young women in Kenya who are at risk for HIV 
acquisition may choose not to enroll in a PrEP study or initiate PrEP as it relates to 
views on PrEP and the impact of technology on study involvement. We will interview up 
to 60 women who met eligibility criteria at screening but do not return for enrollment. 
o We will also conduct at least 10 and up to 12 focus groups among five key 
populations, assuming one focus group with each population at each site. We 
anticipate having 10 focus groups between the two sites, but are allowing for two 
additional focus groups if necessary due to technical difficulties, lack of data, etc. 
Inquiry will be guided by domains from a prior conceptual model we have 
developed focused on understanding decision-making related to uptake of HIV 
treatment for prevention, as well as prior research on PrEP uptake and 
adherence. We will use an iterative approach over the course of data collection.  
For the additional phase of this study, we intend to recruit five potential groups 
for focus groups: 
1) Key community leaders  
2) Male parents 
3) Female parents 
4) Young women (18-24 years) but are not otherwise participating in the 
study  
5) Young men (18-24 years) from the community 
All potential participants must be adults, but otherwise, there are no additional 
exclusion criteria other than those previously noted. 
o Outcomes:  
§ 
Understanding of decision-making in the uptake of PrEP and impact of 
technology in this study (total n=60 semi-structured interviews and up to 
n=120 across the anticipated 10 focus groups) 
• 
Aim 5. Evaluate a novel adherence measure in which the amount of emtricitabine 
is quantified along strands of hair. We will compare the emtricitabine concentration 
patterns in hair with other measures of adherence in the study, including Wisepill, dried 
blood spots, and self-reported adherence. Analysis will include correlation and 
categorical comparisons among the measures. 
• 
Aim 6. To explore the acceptability and feasibility of assessing patterns and 
content of SMS and/or WhatsApp messages as a means of identifying risk for HIV 
acquisition and/or PrEP adherence. We will download this data in a secure manner 
and then perform a sentiment analysis. Data will also be compared with other reported 
risk and adherence assessments in the study.  
o Outcomes:  

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§ 
Acceptability 
§ 
Feasibility 
§ 
Preliminary correlations 
 
Population 
This study will enroll young Kenyan women in the communities near the study sites who are 
at high risk for HIV infection who are interested in taking PrEP. For women not known to be 
in an HIV serodiscordant relationship, we define high risk according to the following risk 
score (Table 2), which was developed from women enrolled into several prior prospective 
studies (VOICE, HIV Prevention Trials Network [HPTN] 035 and FEM-PrEP [47]. A score >5 
was associated with HIV incidence >5 per 100 person-years and will therefore be used for 
an enrollment criteria for this study. Alternatively, a woman will be considered as high risk if 
she is in a known serodiscordant relationship (i.e., she has a sexual partner with known HIV 
infection); in these cases, the risk score will not be used.  
 
Table 2. HIV risk score 
Participant age 
Less than 25 years 
2 X* 
25 years or more 
0  
Married or living with husband /primary partner 
No 
2  
Yes 
0  
Partner provides financial/material support 
No 
1  
Yes 
0  
Partner has other partners 
Yes 
2  
Don’t know 
2  
No 
0  
Any alcohol use in the past 3 months 
Yes 
1  
No 
0  
Total score 
 
 
*For this study everyone will be <25 years 
 
PrEP counseling 
We will provide PrEP to all participants in accordance with CDC and WHO guidance [25, 
28]. At enrollment, participants will be fully informed of the benefits and risks of PrEP, as 
well as the need for daily adherence to achieve maximal protection against HIV acquisition. 
Adherence strategies will be discussed as recommended by the CDC guidelines (e.g., 
tailoring doses to daily routines) by trained counseling staff. Brief follow-up adherence 
counseling will be offered at each visit and may be intensified if requested by the participant 
or deemed necessary by the study staff. Additionally, starting at the 6-month follow-up visit, 
we will reassess each participant’s risk for HIV during counseling sessions per the above 
criteria. If she is no longer at high risk for HIV acquisition, we will discuss whether PrEP 
continues to be a good prevention option for her; this strategy is consistent with the goal 
prevention-effective adherence. Participants will be able to access PrEP throughout the 24-
month study period, if desired, and will be offered guidance in making this decision during 
the counseling sessions. Participants will be encouraged to only consider PrEP 
discontinuation during these sessions and not in between visits. They will, however, be 

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offered the option of returning to the study site off schedule if they are considering PrEP 
discontinuation. PrEP re-initiation will similarly be offered at study visits following 
discontinuation or in between visits if desired by the participant. Staff providing counseling 
will be distinct from those assessing adherence or dispensing PrEP to limit potential 
manipulation of the Wisepill device (e.g., opening the device without dosing to increase the 
appearance of adherence). 
 
PrEP delivery 
Tenofovir disoproxil fumarate (or TDF) and emtricitabine (or FTC) are reverse transcriptase 
inhibitors that have been approved for the treatment of HIV infection in humans in Kenya 
and the United States, among other settings. A fixed-dose, oral co-formulation of FTC/TDF 
(Truvada®) will be used in this study. PrEP will be prescribed for once-daily use. PrEP 
medication will be obtained through a donation from Gilead Sciences. 
 
Participants will receive PrEP through prescription by clinician and distribution through the 
study pharmacy. PrEP will be provided in the context of a comprehensive HIV prevention 
package, including treatment for sexually transmitted infections, offer of HIV testing for 
sexual partners, and provisions of condoms.  
 
Eligibility criteria 
The following inclusion and exclusion criteria will be used to identify potential study 
participants. These criteria reflect the target population, as well as the availability of a cell 
phone, which is critical to the adherence monitoring and intervention strategy under 
evaluation. 
 
Inclusion 
 
 
 
 
 
• Female 
• HIV-uninfected (as determined by Kenya national testing algorithms) 
• Age 18-24 years 
• Wanting to start PrEP with an initial recommendation of 6 months of use 
• Clinically safe to receive PrEP, in accordance with CDC guidelines: 
§ 
Creatinine clearance >60 mL/min 
§ 
Not infected with hepatitis B 
§ 
No other medical condition that in the discretion of the site investigator 
would make participation unsafe or complicate the goals of the study 
• Sexually active (defined as vaginal or anal sex) within the last 3 months 
• At high risk for HIV infection based on a score of >5 [47] or being in an HIV 
serodiscordant relationship (each site will enroll at least 15 young women in HIV 
serodiscordant partnerships) 
• Not pregnant  
• Owns a personal cell phone (not shared) compatible with the technology used in 
the study and the ability to charge it 
• Ability to send a text message 
• Intending to stay in the area for at least the next year 
• Willing to use study technology  
• Up to 30 HIV-infected male partners (whose HIV uninfected female partners have 
been enrolled in MPYA study) for the qualitative study 
 
Exclusion 
• 
Unable to provide consent 

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• 
Concurrent or prior participation in another research study that may influence 
adherence to PrEP and/or interfere with the procedures of this study. 
Sample size 
The study will enroll up to 380 women. The following assumptions were made in determining 
the sample size for this study:  
o An anticipated increase in executed adherence of 10% (e.g., from 70% in those 
without to 80% in those with reminders) as a result of SMS,  
o A standard deviation in adherence of 30%   
o Power=80% 
o A two-sided alpha=0.05 
o 10% loss-to-follow-up 
Under these assumptions, each randomized arm for Aim 1 should contain a minimum of 157 
women (314 total). This sample size should also be sufficient for reasonable point estimates 
for Aims 2 and 3.  
 
Recruitment 
We will use a community-based recruitment strategy for young women at risk for HIV, 
drawing from nearby organizations that provide primary health services. At the time of 
recruitment, participants will be informed about the study and given general information 
about what PrEP is and for whom it is intended (e.g., high risk of HIV acquisition). While 
study staff will attempt to identify areas where the technology doesn’t function prior to 
recruitment, if a participant does not have mobile phone reception, we will allow them to 
participate, but would not enroll them in the randomization aspect of the study.  
Thika site 
Prior to commencing this study, the Thika team will go through a process of community 
entry. The first steps of community entry will involve discussions with the community 
advisory group (CAG) to whom the protocol will be presented. The CAG for this study 
will include community stakeholders who are involved with this age group as well as at 
least 2 young women from the community aged 18-24. The CAG will advise on Thika 
site’s recruitment strategies as well as review recruitment materials. After approval by 
the relevant institutional review boards (IRBs), Thika site will sensitize the National AIDS 
&STI Control Program (NASCOP) and the County Health Departments about the 
proposed study and the catchment areas. This will ensure that the community will be 
engaged and fully informed of this proposed study. This engagement process has been 
used successfully in previous research projects funded by the National Institutes of 
Health (NIH) and Bill and Melinda Gates Foundation. 
 
Thika site will recruit the young women through community-based recruitment strategy. 
Specifically for this study, Thika site plans to recruit young women from the following 
areas:  
• Informal settlements 
• Farming communities 
• HIV clinics (for young HIV- women in serodiscordant relationships) 
• Vocational institutions – these institutions target women who have dropped out of 
school 
• Local organizations working with women at higher risk of HIV such as those 
involved in sex work  
• Organizations that provide primary health care services 
 

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Through this study, Thika site shall have an opportunity to educate the community about 
HIV, other sexually transmitted infections and PrEP. Educational messaging will be done 
in a culturally sensitive way with initial approval sought from community opinion leaders. 
 
Kisumu site 
The CAG will facilitate entry into the community. The CAG is comprised of seven 
members who will help us identify the potential study participant. Kisumu site will employ 
the following recruitment strategies: 
1.  Liaison with Voluntary Counseling and Testing (VCT)/ Sexually Transmitted 
Infection (STI) clinics 
We will collaborate with the VCT counselors and STI clinics and distribute study 
referral forms to refer HIV negative women to the study for pre-screening. We will 
also identify and encourage those who have referrals from post-test clubs, HIV 
care and various STI clinics within the seven sub-counties in Kisumu County. 
 
    The study will also focus on support and promotion from important opinion 
leaders in the community, such as Sub-County Health Management Team and 
the Medical Officers of Health, the Provincial and Hospital Superintendents, and 
other Heads of Departments in both the County and National Government. These 
links will be used to demystify the study and help arrest any rumors and bad 
publicity that may arise in the course of the study. 
 
2. Referrals 
The study staff will keep a log of key contacts and partners within the catchment 
area. HIV Testing and Counseling counselors will refer potential participants to 
our clinic for screening and possible enrolment. They will also rely on word-of-
mouth of participants enrolled in the study to widen our scope of coverage. 
 
3. Community Based Organizations 
The Kisumu Site will inform Community Based Organizations (CBOs) within our 
catchment area about the study. There are a number of CBOs focusing on HIV-
related issues within the seven sub-counties in Kisumu. They provide a direct link 
with the community, and will serve as a liaison to our site, speaking about and 
referring participants for pre-screening, screening and possibly enrolment. 
    
4. Workplace /Education/ Social events 
The workplace will be a good opportunity to recruit potential study participants. 
Linkages will be established with the informal sector. The target sites include 
vendors in the markets, bars, and hot spots for female sex workers. Beaches and 
the fishing communities within Kisumu County will also be targeted as these 
areas are regarded high-risk spots. 
 
Study procedures 
All major study activities are summarized in Table 3. 
 
Screening- Potential participants will be consented for screening procedures, which will include 
the following: 
• 
Questions to determine the inclusion and exclusion criteria 
• 
Blood tests (HIV, creatinine, hepatitis B, hemoglobin); up to 21 ml 
• 
Urine pregnancy test 

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Participants will be invited to return to the clinic in approximately one week to obtain their 
laboratory results. This time will also allow them to carefully consider their interest in taking 
PrEP and participating in the study. Those meeting the screening criteria will be offered full 
informed consent and enrollment. Those not meeting screening criteria will be given further 
counseling on HIV prevention other than PrEP, if desired. Participants may or may not be 
informed why they did not meet the screening criteria. During the consent process, participants 
will be able to indicate whether or not it is appropriate for study staff to conduct off-site visits if 
they are unable to be reached or if there may be a problem with their Wisepill device.  
S=screening, M=month, SSV= supplemental study visit, STIs=sexually transmitted infections 
1 PrEP will be offered and dispensed (if desired) at each visit. All participants will be encouraged to take  
  PrEP for the first 6 months of the study. Subsequent decisions about continued PrEP use will take place  
Table 3. Summary of study procedures  
 
S 
M0 
M1 
M3 
M6 
M9 
M12 
M15 
M18 
M21 
M24 
SSV 
Inclusion/exclusions criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
AIM 1 
 
 
 
 
 
 
 
 
 
 
 
 
Data collection 
 
 
 
 
 
 
 
 
 
 
 
 
   Cohort/socio-behavioral data 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Wisepill adherence monitoring 
 
on-going 
 
   SMS reminders (if randomized) 
 
on-going (daily or triggered) 
 
PrEP provision 
 
 
 
 
 
 
 
 
 
 
 
 
   PrEP dispensing1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Clinical monitoring, incl STIs2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Adherence counseling 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
   Laboratory testing3 
 
 
 
 
 
 
 
 
 
 
 
 
      HIV4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
      DBS collection and storage5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
      Pregnancy evaluation6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
      Hepatitis B 
X 
 
 
 
 
 
 
 
 
 
 
 
      Creatinine 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
      Hemoglobin7 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy outcomes8 
 
 
 
 
 
 
 
 
 
 
 
X 
AIM 2 
 
 
 
 
 
 
 
 
 
 
 
 
   Time and motion studies9 
 
 
 
 
 
 
 
 
 
 
 
 
   Acceptability questionnaire 
 
X 
 
X 
 
 
X10 
 
 
 
 
 
   Qualitative interviews (young 
women) 
 
 
 
X 
 
 
X 
 
 
 
 
X11 
   Qualitative interviews with            
partners in HIV serodiscordant 
relationships12 
 
 
 
 
X 
 
 
 
 
 
 
 
AIM 3 
 
 
 
 
 
 
 
 
 
 
 
 
   Risk/motivation assessments 
 
 
 
 
on-going (weekly SMS) 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
   Process measures  
 
 
X 
 
 
 
X 
 
 
 
 
 
   Qualitative interviews  
 
 
X 
X 
 
 
X 
 
 
 
 
 
Update of phone number(s) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
X 
 
AIM 4 
 
 
 
 
 
 
 
 
 
 
 
 
   Qualitative interviews  
 
 
X13 
 
 
 
 
 
 
 
 
 
AIM 5 
 
 
 
 
 
 
 
 
 
 
 
 
Hair sample14 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Aim 6 
 
 
 
 
 
 
 
 
 
 
 
 
Social media data 
 
 
 
 
 
 
 
 
 
 
 
X 

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  in individual counseling session with consideration given to risk for HIV acquisition, experiences with  
  taking PrEP and use of alternative HIV prevention options. 
2 STIs will be evaluated based on symptoms. 
3 Blood testing will involve up to 21ml per draw.  
4 We will test for HIV at each study visit and assess any potential seroconversion using serial rapid tests 
or ELISA. During the third trimester, pregnant participants will be tested with ELISA.   
5 Blood from the venipuncture for HIV testing will be used for making the dried blood spots. For DBS 
testing, 25 μl of blood will be spotted five times onto protein saver cards (125 μl total). After spotting, the 
cards will be dried for at least 3 hours or left overnight to air-dry, and then placed in plastic bags and 
stored in a sample box with desiccant and humidity indicators at 20°C. 
6 Pregnancy assessments will include a urine pregnancy test at screening and enrollment and then as 
indicated by the WHO pregnancy symptom checklist [48], if requested by the participant, and/or at the 
discretion of the clinician. 
7 When measured with DBS, levels of tenofovir can be unreliable among individuals who are severely 
anemic. To confirm the tenofovir levels, we will conduct blood counts at screening and every six months, 
or as clinically indicated.  
8Pregnancy outcomes will be assessed up to 6 months after study completion, depending on available 
   resources. 
9 The time and motion studies will be conducted once the sites are running at full capacity (likely several  
   months into the study). 
10 This questionnaire may be given early if a participant does not take PrEP for 12 months. 
11 A subset of qualitative interviews will be performed after 24 months of follow-up if significant  
  discrepancies are seen between Wisepill and DBS adherence. 
12. A subset of qualitative interviews will be performed at month 6 with partners in serodiscordant 
relationships.  
13. These interviews will take place shortly after the screening or M1 visit, depending on when the 
participant decides not to enroll or to drop out of the study.  
14. These samples will take place during any routine study visit among participants who collected PrEP at 
the prior study visit. The time frame listed in the above table indicates that this may happen at any study 
visit based on the current progress of the study (all participants will be at M12 or later by the time of IRB 
approval).  
 
Cohort characteristics and socio-behavioral assessment- At enrollment and every 3 months 
through Month 24, we will obtain the quantitative data as listed in Table 4, which have been 
shown to impact adherence and risk assessment/decision making. Stigma and self-efficacy will 
be administered at enrollment, Month 12, and Month 24. Referenced scales (*) have been 
validated and/or used successfully in sub-Saharan African populations in prior studies. Data will 
be entered into RedCap (Research Electronic Data Capture) with ongoing quality control 
checks. RedCap is a secure web-based software program for designing clinical and 
translational research databases. It is supported by many US academic institutions, including 
the University of Washington and Massachusetts General Hospital. 
 
NB: The Thika site will use a biometric system (fingerprint scanner) to identify participants 
throughout the course of the study. Participants will be offered consent form with the option to 
decline to have their fingerprint taken. 
 
Table 4. Socio-behavioral data (descriptions listed; questionnaire submitted separately) 
Demographics and health 
Age, employment, education, marital status, residence type (e.g., with 
family), reproductive health, distance from clinic, food security, medications, 
depression* [49]  
Taking PrEP and HIV 
prevention 
Disclosure of study participation and PrEP use, belief in PrEP efficacy, 
modified Necessity and Concern questionnaire [50], time for taking PrEP, 
SMS preferences (if randomized to SMS reminder arm), help taking PrEP 
Alcohol/substance use 
Rapid Alcohol Problems Screen-4* [51], use of marijuana and other drugs 

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Adherence assessment and impact of SMS reminders (Aim 1) 
 
Wisepill monitoring- We will give all participants a next generation Wisepill device at enrollment 
and demonstrate its use, together with the participant. Participants will receive PrEP according 
to the above schedule. Because the device only holds ~1 month of PrEP medication at a time, 
participants will refill their own Wisepill as needed. We will change batteries at pharmacy visits. 
Although the battery life should last 6 months, we will change batteries and/or ask participants 
to charge their devices quarterly to avoid potential data loss. We will track battery voltage to 
model battery life (i.e., if not changed). At each visit, we will ask participants if any intentional 
periods of PrEP non-use or Wisepill device non-use occurred and the reason(s) why (e.g., lack 
of perceived risk, traveling). 
 
Randomization for SMS reminders- Enrolled participants will be randomly assigned in a 1:1 ratio 
to either SMS reminders or no SMS reminders. The code creating the random allocation order 
(“the randomization list”) will be generated and maintained by the study analyst. A variable size 
block randomization scheme, stratified by study site, will be implemented to produce the 
randomization list. The randomization will be implemented by transcribing onto paper within 
numbered envelopes. Thus, neither participants nor study staff will be blinded to each 
participant’s randomization group assignment. Fidelity of randomization will be confirmed with 
tracking in RedCap. RedCap will contain a randomization list against which we will compare the 
actual randomization of participants at the time of enrollment. This process will ensure all 
participants are randomized as planned.  
 
Provision of SMS reminders- SMS are received without charge in Kenya and cell phones with 
SMS capabilities are nearly-universally owned in the areas in which we work in Kenya. For the 
half of the cohort randomized to adherence reminders, the Wisepill server will generate an 
automated daily SMS containing a reminder of the participant’s choice and in her language of 
choice. Participants will be encouraged to choose a message that will be meaningful to her, but 
will not put her at risk for any potential social harms if someone sees the message (e.g., a 
boyfriend seeing the message and suspecting another sexual partner, or unwanted questions 
about study participation from a family member). For example, a message could refer to a 
weather report or popular radio program. The content of the message may be changed at each 
study visit, if desired. Because of the potential for SMS reminder habituation, we will offer 
participants the option of switching to SMS reminders only triggered by missed doses at each 
study visit (i.e., 2 hours after the expected dosing time). We will ask participants to keep their 
cell phones with them and charged. SMS reminders will be suspended if a participant decides 
not to take PrEP after completing a study visit counseling session; they will be reinitiated if the 
participant later chooses to start taking PrEP again. 
Assessment of the next generation 
Wisepill device (Aim 2) 
 
Technical functionality- We will 
determine the number of Wisepill 
Sexual behavior/ intimate 
partner violence 
Number, type of partners (incl. HIV status), use of condoms, transactional 
sex, abuse 
Sexual relationship power 
Sexual relationship power sub-scale [52]  
Stigma 
Perceived HIV stigma scale (modified Berger, adapted for Kenya)* [53, 54]  
Adherence 
Self-reported ability, rating, frequency of adherence, necessity and concerns 
as modified from [55] 
Self-efficacy/esteem 
Rosenberg Self-Esteem Scale* [56, 57]  
Fig 2. Unified Theory of Acceptance and Use of Technology 

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data transmission events, battery failures, other potential technical problems, and transmission 
events during two-years of follow-up. Data transmission tracking will include device hardware, 
cellular network traffic (via our collaborator, mSurvey), and the Wisepill server. In addition, we 
will measure similar information for the SMS adherence reminders component of Aim 1.   
 
Acceptability and ease of use from the participant perspective- We will use quantitative 
questionnaires to assess anticipated acceptability of the next generation Wisepill device at 
baseline, as well as experienced acceptability in all participants at 3 months (short-term) and 12 
months (long-term). If women discontinue PrEP before12 months and express no interest in 
resuming within the remainder of the study period, the long-term acceptability questionnaire 
may be given at any time after 6 months (participants will be allowed to resume PrEP if they 
change their minds after completing this questionnaire and are still within the 24-month study 
period). Additionally, we will conduct serial qualitative interviews in a subset of approximately 50 
participants (25 in each site; half randomized to the SMS arm in Aim 1) to gain an in depth 
understanding of their experience with Wisepill monitoring, SMS adherence reminders, and 
ease of use of the device from their perspective. They will take place within one week of 
enrollment and after the participants have had approximately three months and 12 months of 
experience. Random quota sampling will be used within each category (e.g., approaching every 
third participant who meets the criteria). After approximately 10 participants have been selected, 
we will check to make sure that our random sampling is allowing for a range of ages and 
adherence levels. If this is not the case, we will begin more purposive sampling. Interviews will 
be digitally recorded and conducted in the participant’s preferred language in a private setting. 
Each interview will last approximately one hour. Additional participants may be approached if 
needed for theme saturation. We will also conduct separate serial in-depth interviews with up to 
30 (15 per site) young women in HIV serodiscordant relationships and their HIV-infected male 
partners to explore PrEP adherence in the context of serodiscordance among young couples.  
 
The quantitative questions and qualitative interview guide draw from the Unified Theory of 
Acceptance and Use of Technology (UTAUT) model (see Figure 2 and Table 5) [58]. This model 
incorporates the standard issues with technology acceptance, as well as potential challenges 
seen in some settings with Wisepill, such as stigma (social influence) and device size 
(facilitating conditions).  
 
Costing and ease of use from the provider perspective- Time and motion studies will determine 
the time necessary to procure, configure, and manage the Wisepill device, including participant 
interactions. Time and motion studies will be conducted over a two-week period at one or both 
sites when the study is running at full capacity. We will collect data on the time required to 
complete each step of the Wisepill monitoring and SMS reminders process. Results from initial 
time and motion studies will be shared with the teams and strategies for efficiency shared to 
reduce the time needed for monitoring and intervention. Observing multiple visits will allow 
estimation of the average time taken for each step; the time taken for research purposes (e.g., 
data collection) will be noted separately from the estimated time needed for implementation. 
Multiple staff will be observed and interviewed to capture the range of time and extent of effort 
required for each step. Interviews may also reflect on the initial stages of technology 
implementation. Through time and motion studies the number of participants who could be 
supported by a clinic will be estimated. Together the micro-costing data, time and motion 
studies, and clinical outcomes will be used to estimate the average cost and effort of real-time 
adherence monitoring with SMS reminders. Using the estimates of cost and data from Aim 2, 
we will adapt an existing PrEP mathematical model [59] to estimate the cost-effectiveness of 
Wisepill, with and without SMS reminders, per incident HIV case averted. These data will be key 
for decision makers considering implementation of adherence interventions. 

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Discrepancies in Wisepill and tenofovir concentrations- Participants with clinically significant 
differences between Wisepill and DBS adherence (who also provide consent to be contacted 
after the completion of the study) will be approached within six months of study completion for 
qualitative interviews to determine potential causes of the discrepancies. Both adherence 
patterns and drug levels will be shared with participants. Up to 50 such interviews will be 
conducted. 
 
Prevention-effective adherence (Aim 3) 
 
Risk attitude assessment- At enrollment and months 12 and 24, we will measure each 
participant’s risk attitude with questions concerning their perceived chance of engaging in high 
risk behaviors and acquiring HIV, as adapted from Weber [36] (e.g., “Rate from 1 [very unlikely] 
to 5 [very likely] the likelihood of engaging in unprotected sex with someone whose HIV status 
you do not know”.) We will also assess participants risk-seeking attitudes by administering a 
simple scale containing lottery-based choice tasks-- a standard approach developed by 
economists [38, 60] and widely used, including by our team in previous studies in Kenya (see 
the participant-based data collection materials). Participants will be asked to choose between 
pairs of lotteries that vary in risk and reward; a preference for certain rewards over probabilistic 
rewards will serve as an indication of risk averse attitudes. 
 
Risk behavior assessments- Following the Month 6 study visit, we will initiate weekly SMS 
surveys for all participants. The survey will be sent on the participant’s preferred date and time 
and using her preferred language. The initial SMS will consist of a message of the participant’s 
choice that will be meaningful to her, but will not put her at risk for any potential social harms if 
someone sees the message (as described above). The surveys will be sent through a secure, 
password-protected, cloud-based data management system at mSurvey that is compliant with 
all Health Insurance Portability and Accountability Act (HIPAA) data security requirements. 
These procedures will help safeguard the privacy of our participants. All data will be stored and 
backed up via Amazon services. Participants will receive approximately $0.50 for each 
completed survey. The survey questions will ask about sexual behavior, sexual partners, risk 
perception, and PrEP use in the past week (survey submitted separately). To avoid participants 
modifying their responses to shorten the survey, those reporting no sexual activity in the past 
week will be asked “filler questions” (e.g., exercise or work for pay in the past week). The filler 
questions will not inform primary study aims. SMS survey questions will be sent to all active 
study participants, regardless of their decision to take PrEP. 
 
 
Qualitative interviews- During the same serial qualitative interviews described in Aim 2 
(approximately 50 women, multiple subsets), we will ask participants about their understanding 
Table 5. Questions to be used in assessing Wisepill acceptability 
Model component 
Question description (questionnaire submitted separately)  
Performance expectancy 
Perceived usefulness, extrinsic motivations, personal 
outcome expectations 
Effort expectancy 
Perceived effort needed to use the device, complexity 
Social influence 
Perceived norms and stigma 
Facilitating conditions/barriers Presence of storage space, impact of travel, perceived 
benefits 
Behavioral intention to use 
Attitude, frequency of anticipated non-use 
Actual use 
Wisepill opening events while using PrEP 

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of PrEP adherence, including barriers and facilitators, as well as their understanding of HIV risk 
behavior, risk perceptions, motivation for HIV prevention, and how these factors relate to PrEP 
use. Specific topics will include 1) pleasure [61], 2) future orientation [62], 3) comparative risk 
[63], and 4) affect [64].These areas have been associated with risk taking for HIV and other 
conditions and may impact motivations to take PrEP. Interviews will be done at baseline (within 
1 week of PrEP initiation), 3 months and 12 months. Similar topics will be explored with up to 30 
young women and their male partners in HIV serodiscordant couples. The one-time interviews 
will be conducted around month 6. The partners will be interviewed separately.  
 
The qualitative interviews and focus group discussions described in Aim 4 (approximately 60 
women and 10-12 focus group discussions), will seek to understand their decision-making 
around participation in the study, PrEP, and their beliefs about HIV and technology.  
 
Cell phone-related concerns and study contact 
 
We will ask all participants for phone number updates at each study visit. A dedicated line will 
be established for participants to text or call with any questions about Wisepill, SMS reminders 
or surveys, or PrEP use, as well as to report any phone number changes. We will call them 
back so as to minimize any costs incurred by the participant. Participants who lose their phone 
during the course of the study and do not replace it may be offered use of an inexpensive study 
phone.  
 
Participant retention and withdrawal 
 
Participants will be tracked through study visits, as well as through their Wisepill device. 
Individuals missing scheduled appointments will be contacted through study retention teams. 
They will also be contacted for any non-functional devices, but not because of non-adherence. 
Participants will have the option of continuing, discontinuing, or reinitiating PrEP at any time for 
the two years of the study follow-up. We will encourage participants to continue to attend study 
visits even if they elect not to take PrEP for HIV testing and socio-behavioral questionnaires 
(months 6 and 12), as well as to facilitate retention. 
 
Safety 
Use of PrEP- We will employ clinical monitoring as noted above (Table 3). Creatinine will be 
tested every 6 months. If the creatinine clearance declines to <60 mL/min, PrEP will be held and 
a repeat creatinine will be drawn. If renal insufficiency is confirmed, PrEP will be permanently 
discontinued. Clinical symptoms will be systematically assessed in a structured medical history 
administered to participants. Clinical side effects of TDF and FTC/TDF that have been reported 
are primarily gastrointestinal, including nausea, vomiting, and flatulence. Serious adverse 
events will be documented and reported to all involved ethical review boards per their 
regulations. Serious adverse events (SAEs) felt to be related to PrEP will result in temporary 
hold of PrEP.  In the case of temporary holds, the hold will continue until the event is stabilized 
or resolved.  If the event resolves, PrEP may be reinitiated at the discretion of the Investigator, 
resuming safety monitoring.  The severity of clinical symptoms will be scored using the Division 
of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading the Severity of Adult and 
Pediatric AEs [65]. Decisions to hold PrEP due to clinical and/or other laboratory safety reasons, 
or in the event of overdose, will be at the discretion of the Site Investigator, in consultation with 
the Principal Investigators.  
 
HIV infection- Participants will be tested at enrollment and every 3 months for HIV as noted 
above. If found to be positive, the HIV test will be confirmed per Kenya national guidelines. 

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PrEP will be stopped, counseling will be provided, and participants will be actively linked to HIV 
care. 
 
Pregnancy- If a woman becomes pregnant during the study, PrEP will continue to be offered, in 
line with FDA labeling; indeed, the FDA is actively seeking data on TDF/FTC use in HIV-
negative women during pregnancy [66] and pregnant women have taken PrEP as part of the 
Partners Demonstration Project. We will seek additional consent for continued participation and 
ensure she understands the risks and benefits of continued PrEP use. Monthly visits will be 
added in between the usual 3-monthly visits for additional side effect monitoring. Pregnancy and 
infant outcomes will be assessed after study completion pending available resources. 
Specifically, we will contact all participants who become pregnant 6 months after their due date 
or as close to that time as possible if the study has already completed. We will ask the 
participant to attend one additional study visit with her baby (if alive) to determine the baby’s 
vital status, birth weight, and presence/absence of abnormalities as detected through clinical 
care. 
 
Breastfeeding: According to the Kenyan Ministry of Health guidelines, PrEP may be offered to 
women who are breastfeeding [67]. In addition, even though PrEP is passed on through breast 
milk, the exposure to infants is minimal and does not pose substantial risk to infants [68]. 
 
Protection against disclosure- Given the sensitive nature of the questions asked by SMS in a 
potentially vulnerable population, we will conduct process measures at Month 1 and Month 12. 
Any concerns will be assessed on an individual basis and referrals to counseling will be made 
as needed. Any harms will be reported to the ethical review boards. If multiple harms are 
detected, study procedures and SMS content will be reviewed by the community advisory 
boards associated with the study.  
 
Other factors- Throughout the study, participants will be asked a variety of questions including 
ones around depression and intimate partner violence (IPV). RedCap has been coded 
appropriately to flag a participant if they present characteristics or describe instances of one of 
these factors. Participants will be referred to the appropriate mental health provider or social 
service agency when necessary.  
 
Data Management 
 
Data will be entered into RedCap (Research Electronic Data Capture) with ongoing quality 
control checks. RedCap is a secure web-based software program for designing clinical and 
translational research databases. A data manager at each site will oversee all data collection by 
study staff and will conduct multiple quality control measures (e.g., assessing for missing data 
or data entry errors). The data managers will work with the principal investigators at each site to 
ensure comparable data. 
 
Data analysis 
 
Cohort characteristics and socio-behavioral data- We will use summary statistics to describe the 
cohort characteristics and socio-behavioral data per Table 3 above. Although the groups are 
expected to be similar due to randomization, we will look for differences in these characteristics 
that may affect our conclusions. 
 
Aim 1 
 

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Description of enacted adherence and persistence: We will describe adherence as determined 
by Wisepill: number of missed doses, number of consecutive missed doses, and enacted 
adherence, defined as the proportion of unadjusted Wisepill openings divided by number of 
days during periods for which PrEP was available (i.e., picked up from the pharmacy). Enacted 
adherence will secondarily be produced adjusting for reported PrEP non-use or Wisepill non-
use. We will also summarize the persistence of PrEP use, defined as time to the first period at 
which the participant purposely discontinues (as reported or based on lack of pharmacy pick up) 
or a 28-day period of no Wisepill openings.  
 
 
     enacted adherence  =   
 
 
       # of device openings    
    
 
# expected openings based on days when PrEP was available 
 
We will summarize enacted adherence and persistence measures, and use linear regression to 
quantify the effect of factors influencing adherence, and, separately, persistence, including 
whether participants receive or do not receive adherence reminders, changes within participants 
over the time, and socio-behavioral data (Table 3).  
 
 
Additionally, a random sample of DBS from all study 
visits will be selected for analysis of tenofovir 
collection. Random samples of the dried blood spots 
will be determined and sent for processing by Dr. 
Peter Anderson at the University of Colorado, whose 
laboratory specializes in this assay. The dried blood 
spots will be shipped on dry ice through an 
experienced courier service (e.g., World Courier). 
While DBS are classified as nonregulated, exempt, we will adhere to CDC DBS shipping 
guidelines. Correlates between drug concentration and adherence will be drawn from prior 
models (Table 5). This adherence measure will be summarized for the cohort using descriptive 
statistics (e.g., median doses per week, number achieving a median of 6+ doses per week). 
Persistence will be determined as the time to undetectable tenofovir-diphosphate (TFV-DP). 
NB: We recently received a new award (R21MH1211156; Protocol 2020P002658) to analyze 
approximately 500 additional DBS from the MPYA cohort. This protocol is currently under 
review with the MGB IRB.  
 
Assessment of effect of adherence reminders- Using enacted adherence and persistence, we 
will compare women randomized to SMS adherence reminders to those assigned no SMS 
reminders, using both intention-to-treat (i.e., as randomized to SMS versus no SMS) and as-
used (i.e., enacted adherence limited to months when PrEP is collected). We will conduct 
similar, but independent analyses with Wisepill and DBS data. With Wisepill data, executed 
adherence will be calculated for each month, and all months will be compared between those 
with versus without adherence reminders using a random effects model to adjust for correlation 
within repeated adherence measures per participant and adjusting for study month. TFV-DP 
concentrations will be compared between SMS reminders groups using the same modelling 
strategy. For persistence, we will compare time to discontinuation between groups with versus 
without adherence reminders using a Cox proportional hazards model.  
 
We will also perform multivariate analyses for both enacted adherence and persistence, 
measured both by Wisepill and by TFV-DP levels, in order to adjust the effect of adherence 
reminders for any baseline differences and allow us to estimate the effects of other factors 
influencing adherence, including socio-behavioral data (Table 3). Similarly, multivariate Cox 
Table 5. TFV-DP concentrations in DBS 
Doses/week 
Median fmol/punch (IQR) 
7 
1,560 (1,246-2,029) 
6 
1,332 (1,064-1,732) 
5 
1,116 (892-1,451) 
4 
900 (719-1,171) 
3 
672 (537-874) 
2 
456 (364-593) 
1 
228 (162-297) 

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regression will be performed to model the effect of SMS reminders and other factors on 
persistence. 
 
Aim 2 
 
We will use descriptive statistics to understand the quantitative assessment of acceptability. 
Digital recordings of the qualitative interviews will be transcribed (and translated into English as 
needed). We will then use an inductive, content analytic approach to analyze the qualitative 
data. Content analysis refers to systematic process for interpreting the content of textual data 
through coding and category construction [69]. We will develop a coding scheme through initial 
review of a randomly selected subset of 33% of interview transcripts. Sections of the transcripts 
that appear to address concepts of analytic interest (e.g., device design, stigma) will be 
assigned descriptive labels, or codes. Operational definitions will be developed for the codes to 
create a codebook, which will be used to code the data [70]. We will use the qualitative data 
management computer program ATLAS.ti to code the data, which will then be repeatedly sorted 
and re-reviewed to identify a broader set of concepts (i.e., UTAUT model components, such as 
social influence). The categories will be constructed from this second, more set of concepts 
through assignment of descriptive labels, formulation of operational definitions, and selection of 
illustrative citations from the data. We will review categories and posit semantic links (e.g. 
causal links, chronological links) among them in the final, interpretive step of the analysis. 
 
Analysis will follow the Joint United Nations Program on HIV/AIDS (UNAIDS) guidelines for 
costing HIV interventions [71] and will reflect the provider perspective. We will conduct activity-
based micro-costing to estimate the incremental costs of the Wisepill and SMS PrEP adherence 
intervention including start-up, personnel, communication, equipment (Wisepill devices) and 
overhead costs. Cost data will be collected from the study budget, clinic expense reports, 
published information on labor costs, and staff interviews. These data will be used to complete 
intervention cost worksheets. Costs will be categorized as fixed or variable. Variable costs 
indicate which costs could change (e.g., using free communication instead of standard 
telephone rates) and influence the estimates from the study. 
 
We will compare enacted adherence as measured by Wisepill to tenofovir levels in DBS. We will 
determine the frequency of agreement between enacted Wisepill adherence and the 
corresponding TFV-DP category as described above (including emtricitabine-triphosphate [FTC-
TP] for daily dosing). We will also explore continuous analyses with linear regression where the 
outcome is TFV-DP concentration and predictor is enacted Wisepill adherence (e.g., a 10% 
increase) for the period preceding the blood draw.  
 
Aim 3 
 
Prevention-effective adherence- We will use weekly reported risk behavior to adjust the Wisepill 
enacted adherence and persistence of PrEP adherence in Aim 1 as follows:  
 
     prevention–effective adherence (enacted) =   
 
 
 
 
# of device openings recorded    
                    # expected openings based on HIV risk during periods of intended PrEP use 
 
     prevention-effective persistence =      duration of PrEP use  (i.e., traditional persistence)          
 
    
 
 
 
 
 
     duration of HIV risk  
We will summarize prevention-effective adherence and persistence measures. We will also use 
linear regression to quantify the effect of factors influencing weekly prevention-effective 

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adherence, and, separately, prevention-effective persistence, including whether participants 
receive or do not receive adherence reminders, changes within participants over the time 
followed, and socio-behavioral data (Table 3).  
 
Correlation between risk attitudes and PrEP adherence- Based on the choices made for the 
series of pairs presented to them, participants will be coded in the data analysis as being risk 
averse or tolerant. Responses in the risk attitudes scale will also be used to construct a binary 
measure indicating whether a participant is risk averse or tolerant. We will then compare 
executed PrEP adherence and persistence, as determined by Wisepill data in Aim 1, for 
participants who were risk averse and risk tolerant. We will use linear regression to determine 
the effect of baseline risk attitude and risk perceptions over time on adherence. These models 
will control for participants’ socio-demographic characteristics and also test whether risk 
attitudes are predictive of adherence when controlling for self-reported sexual behavior. 
Random effects for participant will be included in the linear models to account for correlation in 
outcomes within the same person over time.  
 
N.B., For all analysis involving SMS data, we will assess the randomness of the missing data 
and adjust for any biases accordingly. 
 
Qualitative interviews- We will use an inductive, content analytic approach (as described in Aim 
2) to analyze the qualitative data on PrEP adherence, risk behavior, and risk perceptions. 
 
Aim 4 
 
The same inductive, content analytic approach (as described in Aim 2) will be used to analyze 
this qualitative data.  
 
Aim 5 
 
At a routine study visit, among participants who collected PrEP at the prior study visit, we will 
ask for 5 strands of hair from the occipital region of the scalp. This will be a one-time procedure 
per participant. 
The hair will be stored in a foil packet at room temperature on site until it can be sent in one 
batch for processing by Dr. Angela Kashuba at the University of North Carolina, Chapel Hill, 
USA. Processing requires specialized techniques that are only available in this lab (i.e., infrared 
matrix-assisted laser desorption electrospray ionization mass spectrometry imaging with 100 μm 
resolution; see Rosen, Anal Chem. 2016 Jan 19;88[2]:1336-44). Any hair remaining after 
processing will be destroyed at that time. 
 
Aim 6 
Dr. Mohsen Mosleh (of Massachusetts Institute of Technology, MIT) will perform a sentiment 
analysis to try and assess risk behavior from text message content. All SMS and WhatsApp 
messages will be deidentified prior to analysis. A data use agreement will be drafted before any 
data is shared.  
 
Ethical Consideration  
The study protocol, site-specific informed consent forms, questionnaires and any subsequent 
modifications will be reviewed and approved by the IRBs at KEMRI, MGH and the UW. 
Subsequent to initial review and approval, these IRBs will review the study at least annually. 
Study Oversight 

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Drs. Mugo and Bukusi will be responsible for oversight of the Thika and Kisumu sites, 
respectively. Drs. Haberer and Baeten will communicate frequently with Drs. Mugo and Bukusi, 
as well as other study staff, by email and Skype (at least weekly). Drs. Haberer and Baeten will 
also make study site visits approximately twice annually. All serious adverse events will be 
reported to the KEMRI, MGH, and UW IRBs according to their requirements (generally 7-10 
days). 
 
An independent Data Monitoring Committee (DMC) will be established to review study data 
every six months. Three areas will be reviewed in detail:  
• 
The primary outcome for this study is the impact of SMS reminders on enacted 
adherence and persistence of PrEP adherence over a 24-month period. If the DMC finds 
that participants receiving adherence reminders have significantly worse adherence than 
those not receiving reminders, we will contact the IRBs associated with this study, as 
well as the NIMH, for further guidance.  
• 
The DMC will monitor for the safety of PrEP provision individually at every clinic visit and 
collectively every six months. Particular attention will be paid to any participants 
choosing to continue PrEP during pregnancy. If serious adverse events are found to be 
associated with PrEP use, we will contact the IRBs associated with this study, as well as 
the NIMH, for further guidance. 
• 
The DMC will review the process measures and any reports of social harms related to 
Wisepill adherence monitoring and/or SMS communication with participants. If >5% of 
participants report such occurrences, we will contact the IRBs associated with this study, 
as well as the NIMH, for further guidance. 
 
Informed Consent 
Written consent will be obtained for the prospective implementation of all proposed study 
protocols. Separate informed consent will be obtained to offer enhanced follow-up for HIV 
uninfected women using PrEP at the time of pregnancy. The consenting process will take place 
in a private room and the consent form will comprehensively provide the following information:  
• 
Introduction to the consent process, explaining the consent form and compliance with 
institution policy and country laws 
• 
Emphasis that participation is voluntary 
• 
Nature and purpose of the study 
• 
Explanation of study procedures  
• 
Potential discomforts and risks, as well as plans to protect participants from these risks;  
• 
Potential benefits 
• 
Alternatives to participation in the study  
• 
Confidentiality, including how data will be used and how it will be kept private  
• 
Refusal/withdrawal, including right to withdraw consent and leave the study at any time  
• 
Rights and complaints.   
After each major section, research staff obtaining consent will pause and check for 
understanding -- for example, by asking the potential participant to repeat, in their own words, 
what "the right to refuse" means. Participants will be offered copies of the informed consent 
forms. Each study site is responsible for developing study informed consent forms for local use, 
in accordance with all applicable regulations, based on the samples provided in the Appendix. 
Each site also is responsible for translating the forms into local languages and verifying the 
accuracy of the translation by performing an independent back-translation, which will be 
reviewed and approved by the PIs. 
 

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All recruitment, consent, and enrollment procedures, as well as all study procedures, will be 
conducted in the participant’s preferred language (i.e., Swahili, Dholuo, or English). 
 
Risks 
Study participants will face the following risks: 
1.   Risk: Taking PrEP may be associated with some health risks. Mild side effects may occur in 
as many as 1 out of 10 people and include mild kidney function (only detected by laboratory 
tests), fatigue, upset stomach, vomiting, loose stools, and dizziness. More severe side 
effects are rare and may occur in less than 1 out of 100 people; these include rash, liver 
function problems, serious kidney damage and allergic reaction. Small changes in bone 
strength have been observed, but not associated with any fractures or symptoms. PrEP may 
interact with some other medications. 
Protection: Participants will be advised to call or come to the study clinic if they have 
unexplained increased or decreased urination, weight loss, cramps, muscle pain, dizziness, 
excessive fatigue, nausea, vomiting, or shortness of breath. Study staff will be available 24 
hours a day/7 days a week to evaluate potential side effects from taking PrEP. A medical 
officer from the study team will perform any necessary examinations and determine if PrEP 
should be stopped and/or if further testing and care is needed. Participants will be ineligible 
if they have baseline kidney problems or hepatitis B. Creatinine will be tested every 6 
months during PrEP use to evaluate kidney function.  
2.   Risk: Participants may feel anxious, embarrassed, and/or worried during HIV testing.  
 
Protection: Testing will be normalized as much as possible and participants will receive 
standard counseling about HIV prevention through PrEP and other means (i.e., condoms, 
sexual partner reduction, and use of ART in any sexual partners who have HIV infection). 
Condoms will be available free-of-charge. 
3.   Risk: HIV acquisition may occur during study follow-up and drug resistance may develop if a 
participant acquires HIV during a break from PrEP and thereafter resumes PrEP.  
 
Protection: We will test for HIV infection at every study visit (baseline, month 1, month 3 and 
every 3 months thereafter up to 24 months total), consistent or greater than current CDC 
guidelines. Such frequent testing will decrease the potential for drug resistance to develop in 
the setting of acute HIV infection. If HIV seroconversion does occur, we will provide 
counseling for potential emotional trauma and assist with linkage to HIV treatment and care 
programs. We will also assess CD4 count, viral load, and drug resistance. Any 
seroconverters will be exited from the study and referred to the appropriate care center.   
4.   Risk: Some participants may experience fatigue from completing study questionnaires and 
interviews and/or receiving the SMS reminders (if so randomized) and/or the SMS surveys 
 
Protection: We will keep the questionnaires and interviews as short as possible to minimize 
the risk for fatigue. We will also allow participants to take breaks when needed. Participants 
will be advised about the number and frequency of SMS to expect. SMS will be sent at the 
time and day of the week preferred by the participant, thus minimizing potential for 
inconvenience. Participants randomized to daily SMS will be able to switch to SMS only for 
missed doses. 
5.   Risk: Privacy may be lost through use of the Wisepill device and/or SMS surveys, which 
may cause discrimination and/or problems in the relationships participants have with their 
families, sexual partners, or others. 
 
Protection: We will advise participants on the potential for Wisepill to attract attention and 
devise strategies for storage. SMS reminders will not mention HIV or medication, unless 
preferred by the participant. All SMS surveys will require a PIN before any questions are 
sent. Therefore, only study participants will be able to see them.  
6.   Risk: Privacy may be lost through security breaches with data collected through the study.  

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Protection: All hard copy data will be stored in locked cabinets at the research sites. 
Electronic data includes Wisepill opening events (hosted by Wisepill Technologies), SMS 
survey data (hosted by mSurvey), and questionnaire data (hosted on RedCap/University of 
Washington). All electronic data will be stored securely on password-protected databases in 
compliance with HIPAA standards.  
7.  Risk: Physical discomfort, bleeding or infection may occur from phlebotomy related to 
laboratory testing. 
      Protection: We will only use trained nurses or phlebotomists in this study 
8.   Risk: Birth defects could potentially occur due to the use of TDF/FTC during pregnancy. 
Available human and animal data suggest that TDF/FTC does not increase the risk of major 
birth defects overall compared to the background rate. If a woman becomes pregnant during 
the study, PrEP will continue to be offered. However, we will seek additional consent for 
continued participation and ensure she understands the following risks and benefits of 
continued PrEP use. Follow-up will increase to monthly throughout the pregnancy for closer 
clinical monitoring. 
 
Protection: Women will be assessed for pregnancy at every study visit, so that any 
pregnancy will be detected early. Any woman found to be pregnant will be counseled on the 
risks and benefits of continued PrEP use during pregnancy and given the option to continue 
or discontinue use. 
9.   Risk: TDF/FTC is passed to nursing infants however these levels are below the proposed 
paediatric therapeutic doses with current evidence proposing that PrEP can be given to 
women who are breastfeeding [68]. 
 
Protection: Women will be counselled on the risk and benefits of PrEP use during 
breastfeeding 
 
Benefits 
Participants will receive TDF/FTC PrEP, which is known to help prevent HIV infection, as well as 
routine testing for HIV, renal function, and hemoglobin levels, pregnancy assessment, and 
symptomatic screening for sexually transmitted infections. Counseling for HIV prevention will be 
provided and free condoms will be available. Study staff will also facilitate treatment for any side 
effects, HIV infection, or any other medical concerns that arise during the study and both study 
sites are Government of Kenya-approved HIV treatment centers, in addition to their prevention 
and research activities. Some may benefit from the information learned in the study and/or 
personal satisfaction from being part of research on HIV. 
 
Care for Persons Identified as HIV-infected 
This study will identify persons who are infected with HIV, either as part of the study screening 
process or during follow-up of enrolled participants. Study staff will provide participants with their 
HIV test results in the context of post-test counseling. Persons identified as HIV-infected during 
the study screening process or during follow-up will be actively linked to HIV care services, 
including primary care and antiretroviral therapy, according to Kenya national guidelines.  
 
Treatment for Injury 
Participants will be asked to inform the study staff if they feel they have been injured because of 
taking part in the study. Injuries may also be identified during laboratory testing, medical 
histories, and physical examinations. Treatment for adverse events related to study participation 
will be provided by the study clinic. If treatment is required that is beyond the capacity of the 
study clinic, the study doctors will refer the participant to appropriate services or organizations 
that can provide care for the injury. The treatment costs may also be covered by the University 
of Washington’s discretionary Human Subjects Assistance Program (HSAP). 
 

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Study Records 
Site Investigators will maintain, and store in a secure manner, complete, accurate, and current 
study records throughout the study. The investigator will retain all study records for at least 
seven years after completion of the study. Study records include administrative documentation 
and regulatory documentation, as well as documentation related to each participant screened 
and/or enrolled in the study, including informed consent forms, questionnaires, notations of all 
contacts with the participant, logs linking participant name to study identification number and 
other identifying information in study files, and all other source documents. After seven years, 
these documents may be destroyed.  
 
Confidentiality 
Every effort will be made to protect participant privacy and confidentiality to the extent possible. 
Each study site will establish a standard operating procedure for confidentiality protection; the 
protections described below will be implemented at all sites. 
• 
All study-related information will be stored securely at the study site. All participant 
information will be stored in areas with limited access.  
• 
Data collection, administrative forms, laboratory specimens, and other reports will be 
identified only by a coded number to maintain participant confidentiality. All records that 
contain names or other personal identifiers, such as cell phone numbers and informed 
consent forms, will be stored separately from study records identified by code number. 
All local databases will be secured with password-protected access systems. 
• 
Forms, lists, logbooks, appointment books, and any other listings that link participant ID 
numbers to other identifying information will be stored in a separate, locked file in an 
area with limited access. 
SMS data will be stored securely (password protected and HIPAA compliant) at mSurvey, and 
Wisepill adherence data will be stored securely at Wisepill Technology. This data will only be 
linked to a code number, not individual names.  
Participants’ study information will not be released without their written permission, except as 
necessary for oversight by: 
• 
The Principal Investigator or designees 
• 
Site IRBs 
• 
Massachusetts General Hospital 
• 
University of Washington 
• 
United States National Institutes of Health (study funder) 
• 
Kenya Medical Research Institute  
• 
National Council of Science, Technology and Innovation (NACOSTI) 
• 
Pharmacy and Poisons Board of the Ministry of Health (PPB) 
 
Investigator roles 
 
Dr. Elizabeth Bukusi and Dr. Nelly Mugo will serve as the site Principal Investigators for this 
study. Dr. Bukusi will oversee the Kisumu site, whereas Dr. Mugo will oversee the Thika site. 
 
Dr. George Mugendi will manage all direct pharmacy-related issues. Dr. Zachary Kwena will 
oversee administrative aspects of the study and qualitative interviewing and analysis for the 
Kisumu site. 
 
Dr. Kenneth Ngure will manage all administrative aspects of the study at the Thika site, as well 
as oversee qualitative interviewing and analysis. 
 

MPYA Study 
Protocol 
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version 2.8 
32 
Dr. Jessica Haberer and Dr. Jared Baeten will serve as the overall multiple-Principal 
Investigators for the study and will be responsible for study oversight and coordination of project 
management. Dr. Haberer will also lead adherence measurement and analysis, as well as 
assessment of HIV risk behaviors and perceptions through the SMS surveys. Dr. Baeten will 
provide epidemiologic expertise and cross-disciplinary guidance for HIV prevention. 
 
Dr. Ruanne Barnabas will lead the cost and cost-effective analyses within this study. 
 
Dr. Harsha Thirumurthy will support the assessment and analysis of risk perception among 
participants in this study. 
 
Dr. Ingrid Katz will serve as the Principal Investigator for the proposed supplemental study 
(Aim 4) seeking to understand why eligible participants may not join the MPYA study and 
understand community-level influences that may be impacting young women’s decisions around 
PrEP.  
 
Dr. Angela Kashuba will lead the hair analysis.  
 
Dr. Mohsen Mosleh will lead the sentiment analysis for mobile communication data (Aim 6).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MPYA Study 
Protocol 
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version 2.8 
33 
 
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