Alignment of PrEP Use With HIV Risk in Young Women and Men
Phase: PHASE4
Conditions: Pre-Exposure Prophylaxis, Sexually Transmitted Diseases, Bacterial, HIV Infections
Sponsor: University of Washington

Aligning PrEP and HIV Study Protocol 
Version 1.0  
23rd July 2019   
 
 
PROTOCOL: 
 
Alignment of PrEP use with HIV risk in young women and men 
 
 
 
Aligning PrEP and HIV Exposure 
 
 
Version 1.0  
July 23rd 2019  
 
 
 
Funding: 
Eunice Kennedy Shriver National Institute for Child Health and Human Development  
R21HD098923 
 
 

Aligning PrEP and HIV Study Protocol 
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23rd July 2019   
CONTENTS 
I. 
Acronyms .......................................................................................................................... 4 
II. 
Study Team ....................................................................................................................... 5 
III. Summary ........................................................................................................................... 6 
IV. Backgound ........................................................................................................................ 7 
V. Methods ............................................................................................................................11 
A. Overall Design ..............................................................................................................11 
B. Study Aims ...................................................................................................................11 
C. Primary exposure .........................................................................................................11 
D. Primary outcomes ........................................................................................................11 
E. Hypothesis ....................................................................................................................12 
F. 
Location ........................................................................................................................12 
G. Population .....................................................................................................................12 
H. Eligibility for men .........................................................................................................12 
Inclusion criteria: ................................................................................................................12 
Exclusion criteria: ...............................................................................................................12 
I. 
Eligibility for women ....................................................................................................12 
J. 
Sample size ...................................................................................................................13 
K. Study power ..................................................................................................................13 
L. 
Recruitment ..................................................................................................................13 
Overall ...............................................................................................................................13 
Talking points .....................................................................................................................13 
Recruitment brochures .......................................................................................................14 
HIV self-test kits .................................................................................................................14 
Contact with study recruitment team ..................................................................................14 
M. 
Retention ...................................................................................................................14 
N. 
General study procedures ........................................................................................14 
Informed consent ...............................................................................................................14 
Procedures for women .......................................................................................................15 
Procedures for men ...........................................................................................................15 
Screening and Enrollment ..................................................................................................15 
Follow up ...........................................................................................................................15 
Visit-specific procedural tables ...........................................................................................16 
Study exit ...........................................................................................................................17 
O. 
Special circumstances .............................................................................................17 
HIV seroconversion ............................................................................................................17 
P. Safety monitoring .........................................................................................................17 
VI. Data collection .................................................................................................................18 
VII. Linkage with data from women in the existing KWBS cohort ......................................18 

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VIII. Data analysis ....................................................................................................................18 
IX. Human Subjects considerations .....................................................................................18 
X. Clinical research site .......................................................................................................20 
XI. Data sharing and ownership ...........................................................................................21 
XII. Dissemination plan ..........................................................................................................21 
XIII. References .......................................................................................................................22 
 
 
 

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I. 
ACRONYMS  
 
AGYW  
Adolescent girls and young women 
ART 
 
Antiretroviral Treatment  
CT 
 
Chlamydia trachomatis 
DAIDS  
Division of AIDS 
DMPA  
Depo medroxyprogesterone acetate 
EC 
 
Ethics Committee  
EIA 
 
Enzyme-linked immunosorbent assay 
HBV   
Hepatitis B virus   
HIV  
 
Human Immunodeficiency Virus  
HIVST  
HIV self-test  
IDI 
 
Infectious Disease Institute  
IPV 
 
Intimate Partner Violence  
IRB 
 
Institutional Review Board  
KWBS  
Kampala Women’s Bone Study  
NG 
 
Neisseria gonorrhoeae  
PrEP   
Pre-exposure prophylaxis  
RNA 
 
Ribonucleic acid  
STI 
 
Sexually Transmitted Infection  
TFV 
 
Tenofovir  
WHO  
World Health Organization  
 
 

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II. 
STUDY TEAM  
Makerere University, Kampala, Uganda 
Andrew Mujugira, MBChB, PhD  
Timothy Muwonge, MBChB, MPH  
 
 
 
University of Washington, Seattle, USA 
Renee Heffron, PhD, MPH 
Jared Baeten, MD, PhD 
Deborah Donnell, PhD 
 
Stroger Hospital of Cook County, Chicago, USA 
Sybil Hosek, PhD   
 
 
 

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III. 
SUMMARY 
Oral pre-exposure prophylaxis (PrEP) is a recommended component of combination HIV 
prevention and its availability is rising through demonstration projects and full-scale national 
programs. In sub-Saharan Africa, young women are a priority population for HIV prevention and 
targeted to initiate PrEP, given their high HIV incidence rates and promising success from a 
strategy that can be used without the engagement of male partners. A key question in the field is 
whether young women using PrEP have ongoing HIV risk and adhere to PrEP sufficiently to have 
protection from HIV when they have condomless sex with HIV-infected partners. The only true 
way to know whether a heterosexual woman is sexually exposed to HIV or has a partner with high 
HIV risk is to test for HIV and STIs in her male partner(s) and quantify HIV viral levels, if any are 
detected. Yet engaging men in clinic-based HIV testing is challenging. More recent efforts have 
focused on using HIV self-testing kits to respond to demands on men’s time and reluctance to 
seeking preventive healthcare. The availability of PrEP also provides a new incentive for men to 
test.  
 
By leveraging an ongoing study of bone health with concurrent use of PrEP and injectable DMPA 
(often known as Depo Provera® or depot medroxyprogesterone acetate), we have opportunity to 
engage a new cohort of young men and objectively measure HIV and common STIs in these 
young men and link the results to women’s use of PrEP. The primary objective of this study is to 
determine whether young women’s adherence to PrEP aligns with the HIV status and risk of their 
male partners. To address its primary objectives, this study will leverage: 1) an ongoing study 
among young women and 2) a novel cohort of young men who are current sexual partners of the 
young women in the ongoing study to objectively measure PrEP use, HIV, and HIV factors related 
to HIV risk. This study will provide a framework for understanding how and when young women 
and men decide to take PrEP, estimate the proportion of women that are benefitting from HIV 
protection when they have male partners with or at high risk of acquiring HIV, and provide a novel 
opportunity to engage young men in PrEP delivery and as supporters of women’s PrEP use.  
 
 

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IV. 
BACKGROUND 
Oral PrEP is the latest biomedical intervention to be added to a growing of body of proven HIV 
prevention strategies. Oral PrEP is recommended by the World Health Organization and many 
Ministries of Health worldwide, including in Uganda, where HIV incidence is often greatest among 
young women [1-3]. In Uganda, clinical guidelines for PrEP became available in 2016 and the 
Ministry of Health is coordinating targeted scale up of PrEP for people with greatest HIV risk [2]. 
In Kampala, the capital city, PrEP is accessible through programs for key populations (e.g. sex 
workers, men who have sex with men, adolescent girls and young women (AGYW) and negative 
members of HIV serodiscordant couples, as well as through demonstration projects and clinical 
research.  
As with any newly adopted intervention, there are key delivery questions that need to be 
understood to ensure efficient and effective scale up of PrEP on a population level. A large 
unanswered question for PrEP delivery is how well PrEP users execute daily pill taking and 
whether persistent PrEP use aligns with HIV exposure and risk. Initial demonstration projects 
among young women have found high degrees of PrEP uptake, with >80% of women offered in 
our ongoing program in western Kenya and South Africa [4]. However, programs are beginning 
to report high levels of client drop-off. Daily adherence is especially important for women to 
achieve tissue concentrations commensurate with HIV protection from PrEP [5]. Adherence may 
be greater among women who use PrEP for ≥3 months but it is not clear if adherence patterns 
and persistence align with HIV risk. Persistence with PrEP is important to provide protection 
during periods of oscillating HIV risk but PrEP could be discontinued when risk is no longer 
present (e.g. when a stable partner living with HIV is virally suppressed), thereby removing the 
low risk of medication toxicities [6]. 
PrEP adherence aligning with risk 
A large unanswered question for PrEP delivery is how well PrEP users comply with daily pill taking 
and whether PrEP use aligns with HIV exposure and risk. Daily compliance with pill-taking is 
especially important for women to achieve tissue concentrations commensurate with protection 
Table 1. Scenarios of PrEP adherence and HIV risk in 7 days prior to sample/data collection. 
Green boxes indicate scenarios where PrEP use aligns with HIV risk. 
Protection from PrEP (defined 
as TFV >40ng/ml or Wisepill 
data indicates 6-7 openings in 
the week prior to sampling) 
Low/no protection from PrEP 
(defined as TFV <40ng/ml or 
Wisepill data indicates <6 openings 
in the week prior to sampling) 
No sexual HIV risk: 
No sex in the past 
week 
PrEP not necessarily needed if 
sex is not occurring and is not 
expected to occur soon 
Lack of sufficient PrEP use aligns 
with lack of sex 
Low/No sexual HIV 
risk  
PrEP aligns with HIV risk if 
condomless sex is anticipated in 
the near future 
PrEP aligns with HIV risk if 
condomless sex is not anticipated in 
the coming week 
High sexual HIV risk 
Possible sexual exposure to HIV 
aligns with PrEP adherence 
sufficient to provide protection 
from HIV infection 
Possible sexual exposure to HIV and 
PrEP adherence insufficient to 
provide HIV protection  
TFV: tenofovir, the circulating metabolite of TDF-based medication that can be used as a marker of short-
term adherence 

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from PrEP.[5] Initial demonstration projects of PrEP focusing on young women have found high 
degrees of uptake, estimated above 80% of women offered in our ongoing program in western 
Kenya and South Africa [4]. However, a number of programs are also beginning to report high 
levels of client drop-off. Adherence may be greater among women who use PrEP for ≥3 months 
but it is not clear if adherence patterns align with HIV risk. Continuous PrEP use is important to 
provide protection during periods of oscillating HIV risk but PrEP could be discontinued when risk 
is no longer present (e.g. when a partner living with HIV is virally suppressed, when a partnership 
is stably monogamous and both partners are HIV-negative), thereby removing side effects and 
the low risk of medication toxicities (Table 1 shows how PrEP use could overlay with HIV risk) [6].  
Delivering PrEP to young women 
Young women are a focus of HIV prevention programs in many settings due to their high HIV 
incidence rates and unique vulnerability. For young people, preventive health services are viewed 
as “user-friendly” when they are efficient and offer convenient solutions to sexual and reproductive 
health problems including confidential HIV testing, contraception (including condoms), and self-
care when available [7]. In settings that follow guidelines for syndromic management of STI, 
diagnostic STI testing and treatment can be a demand-creation approach [8]. When STI testing 
is part of PrEP delivery, young people have been motivated to attend refill visits in order to receive 
STI testing and treatment and receive PrEP adherence counseling at that time [9]. Recent 
estimates of asymptomatic curable bacterial STIs – Neisseria gonorrhea (NG) and Chlamydia 
trachomatis (CT) – have been alarmingly high with prevalence estimates of 30-40% in Western 
Kenya and South Africa [9, 10] indicating high rates of condomless sex and often the presence of 
untreated infection that can compromise immune function and ease entry of HIV and other 
pathogens [9-11].  
Delivering PrEP to young men 
Momentum for the delivery of comprehensive preventive health services to young men, who are 
typically isolated from preventive health care, is growing and can be leveraged to introduce PrEP 
[12, 13]. Young men value health care services that do not interfere with paid work or compromise 
confidentiality [14]. Interventions that meet men outside of traditional facility settings and integrate 
HIV prevention with full service preventive health care, such as care for hypertension and 
diabetes, offers convenience and may increase salience of preventive behaviors yielding greater 
recruitment of young men for clinical services [15]. HIV self-testing (HIVST) is another approach 
being tested as a strategy to engage young men to know their HIV status and link them to services 
whether HIV-negative (e.g. PrEP initiation) or HIV-positive (e.g. ART initiation). Studies among 
pregnant women, men who have sex with men, and female sex workers have found that 
secondary distribution of HIVST kits can increase frequency of HIV testing among male partners 
and HIVST kits yield accurate results [16-18]. In these studies, reports of partner-perpetrated 
violence were rare, indicating that people potentially used discretion when choosing partners to 
whom to offer HIVST [17]. 
Factors influencing PrEP adherence among adolescents 
A key developmental feature of adolescence is a decreased ability to appraise risk and this may 
influence adolescent PrEP use [19]. For adolescents, risk taking provides high-level stimulation 
yielding a satisfying experience and often occurs in the presence of friends [20]. In later 
adolescence (ages 20-24 years) when self-regulatory abilities are more fully developed, risk 
appraisal and avoidance behavior emerges alongside choices and behaviors that minimize risk 
[21]. With regards to sexual behavior, adolescents may exude optimistic bias and invulnerability 
to unintended pregnancy or STIs, including HIV and often cite the pressure of social norms that 
dissuade use of condoms, especially in the context of trusting a partner [22]. With PrEP, 
adherence can be impacted by individual feelings of optimism and invulnerability which are often 

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positioned 
within 
the 
broader 
context 
of 
family/peer, community and 
structural factors outlined in 
the social-ecological model 
[23]. This framework has 
been applied in numerous 
studies seeking to identify 
novel delivery approaches 
for 
HIV 
prevention 
interventions 
for 
young 
women and has drawn 
attention to the role that 
male partners may play to 
support or undermine PrEP 
use by young women [8, 24-
26].  
Summary of unaddressed 
questions 
In summary, PrEP is being 
scaled up nationally in 
Uganda and young people 
are an important target 
when they have substantial 
HIV risk. The question of 
whether young people align 
PrEP 
use 
and 
high 
adherence to PrEP with 
actual 
HIV 
risk 
and 
exposure is not yet fully 
addressed. We hypothesize 
that this alignment in the 
context of oscillating HIV 
risk may be challenging for 
young 
people 
and 
counselors can assist if we 
gain better understanding 
of the underlying alignment 
of risk and PrEP use and 
reasons for mal-alignment.  
Overall goal for this protocol 
This 
protocol 
describes 
methods and procedures 
for enrolling a new cohort of 
young men in order to 
provide testing for HIV and 
common curable STIs and 
offer men PrEP. Data from 
Table 2. Objective measures of HIV risk and PrEP use collected 
through the parent Kampala Women’s Bone Study and Kampala Men’s 
Study  
Kampala Women’s Bone 
Study (KWBS) 
• HIV  
• PrEP execution:  
o Tenofovir concentration in 
blood/urine 
o Daily pillbox openings 
(Wisepill™) 
o Self-report 
• PrEP persistence: 
o Pharmacy dispensation 
records 
• HIV risk 
o 
Yc DNA (marker of 
semen 
exposure/condomless 
sex) 
o 
C. trachomatis 
o 
N. gonorrhoeae 
Young male partners of KWBS 
women joining the novel 
cohort established by the 
“Aligning PrEP and HIV 
exposure” protocol 
• HIV 
• HIV risk 
o 
C. trachomatis 
o 
N. gonorrhoeae 
• PrEP execution:  
o Tenofovir concentration in 
urine 
• 
Self-report 
Figure 1. The social-ecological model that can be applied to 
understand factors influencing adolescent PrEP use 
 

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the men enrolling will be linked to data being collected among their young female sex partners in 
the Kampala Women’s Bone Study, including women’s adherence to PrEP, HIV status and STI 
diagnoses. The anonymous linkage of data between male and female sex partners will permit us 
to answer questions about HIV risk and exposure and how this aligns with PrEP use by each 
sexual partner.  
Our parent study, the Kampala Women’s Bone Study (KWBS) 
We are currently conducting a longitudinal observational study of bone health among 500  women 
ages 16-25 who initiate PrEP concurrently with the common injectable contraceptive, depot 
medroxyprogesterone acetate (DMPA, R01HD089843 PI: Heffron). In this study, we aim to 
determine whether young women using DMPA and PrEP will experience greater decreases in 
bone mineral density and markers of bone turnover and resorption relative to women using only 
one of the products (i.e. DMPA but not PrEP, PrEP but not DMPA) or neither. This clinically-driven 
parent study objectively measures bone health, PrEP adherence, and infection common curable 
STIs (Table 2). By anonymously linking data from the women in KWBS with data from their male 
partners, we can objectively measure alignment of PrEP use and HIV risk and exposure. 
Recruitment for KWBS began in May 2018, 304 (60%) have been enrolled as of July 2019, and 
retention is high: only 5.2% of expected month-1, 2.2% of month-3, and 3.3% of month-6 visits 
have been missed to date. The cohort has self-reported high behavioral risk for HIV (Table 3), 
22% were treated for a genital infection at enrollment (syndromically diagnosed), and 91% 
initiated 
PrEP 
at 
enrollment. Through 
our 
counseling, 
women 
are 
encouraged to use 
PrEP 
with 
high 
adherence 
and 
to 
discontinue 
PrEP 
during 
sustained 
periods with little risk. 
We are beginning to 
observe some PrEP 
discontinuations and 
some early decliners 
have initiated PrEP, 
indicating 
the 
potential 
for 
fluctuating risk and 
desire for PrEP.  
Impact 
By leveraging data 
already collected from 
young women in our 
ongoing study, the Kampala Women’s Bone Study, and engaging a new cohort of young men for 
this protocol, we have an ideal platform to study whether PrEP use aligns with HIV exposure and 
sexual HIV risk among young women and their male sex partners, using objective measurement 
of HIV risk, PrEP adherence, and sexual behavior. An additional high impact result is an 
opportunity to identify strategies to engage young men in HIV prevention services through a novel 
cohort study. Findings demonstrating alignment of PrEP use and HIV risk will strengthen 
Table 3. Characteristics of young women ages 16-25 enrolled in KWBS 
Number enrolled (as of 15 April 2019) 
240 
Initiating PrEP at enrollment 
91% 
% expected M6 study visits not attended 
3.3% 
% accrued person time among women initiating PrEP at 
enrollment when PrEP was not dispensed (women switching 
onoff PrEP) 
10% 
% accrued person time among women non initiating PrEP at 
enrollment when PrEP was dispensed (women switching off 
on PrEP) 
17% 
% aged 16-20 
61% 
Number of sex acts, past 3 months, median (IQR) 
24 (9-72) 
% sex acts, past 3 months, that were condomless 
35% 
Number of male sex partners, past 3 months, median (IQR) 
2 (1-5) 
% male partners that were new, past 3 months 
40% 
Treated for syndromically-diagnosed STI at enrollment visit* 
22% 
*Primary STI symptom was vaginitis or vaginal discharge. 

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confidence in programmatic PrEP delivery to young people. Findings demonstrating mis-
alignment will be dissected to understand circumstances leading to over- or under-use of PrEP 
and opportunities for PrEP programs to improve alignment. All findings will be relevant for oral 
PrEP programs as well as novel PrEP strategies that are in the development pipeline, such as 
intravaginal rings and injectable PrEP. 
V. 
METHODS 
A. 
Overall Design  
The proposed research will engage a new cohort of young men, whose female partners are 
already engaged in the Kampala Women’s Bone Study. Women in the Kampala Women’s  Bone 
Study will be invited to engage in this novel study to recruit their male partners. Women’s HIV risk 
is directly related to the HIV status and risk of their male sexual partners and thus, we will leverage 
our ongoing cohort of KWBS young women to recruit their male sexual partners for a new men’s 
study. Men will be offered PrEP, diagnostic STI testing and treatment, and followed for 6 months 
to assess PrEP continuation and STIs. Men’s data will be linked to data from their female sex 
partners in the parallel KWBS study to determine whether women’s PrEP use aligns with HIV risk 
and exposure.  
B. 
Study Aims  
Aim 1. To determine whether young women’s adherence to PrEP aligns with the HIV status 
of their male partners 
Men engaging in this study will have HIV testing at enrollment, month 1 and quarterly for up to 6 
months. Results from this testing will be linked to data from the participant’s female sex partner 
that characterize her PrEP use to determine whether her PrEP use aligns with his HIV status. 
Aim 2. To determine whether young women’s adherence to PrEP aligns with the HIV risk 
of their male partners 
Men engaging in this study will have testing for common curable STIs (Chlamydia trachomatis 
and Neisseria gonorrhoeae) at enrollment, month 1 and quarterly for up to 6 months. Results from 
this testing will be linked to data from the participant’s female sex partner that characterize her 
PrEP use to determine whether her PrEP use aligns with his HIV risk (defined by the results from 
his STI testing). 
Aim 3. To determine whether young men’s adherence to PrEP aligns with the HIV status 
and risk of their female partners 
We will offer PrEP to HIV-negative men enrolled in this study and track PrEP initiation, refills, and 
adherence to PrEP (based on self-report and drug levels). The frequency of high PrEP adherence 
will be compared among men with female partners infected and uninfected with HIV or another 
STI. 
 
C. 
Primary exposure  
The primary exposure is male infection with HIV (Aim 1), NG or CT (Aim 2) and female infection 
with HIV, NG, or CT (Aim 3). 
D. 
Primary outcomes 
The primary outcome will be PrEP used by women with sufficient daily adherence to confer HIV 

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protection (6-7 doses in the past week or TFV ≥40ng/mL) for periods when women are dispensed 
PrEP. When PrEP is not dispensed, the TFV level will be assigned as 0 ng/mL. 
 
For Aim 3, the primary outcome will be PrEP used by men with sufficient daily adherence to confer 
HIV protection (4 doses in the past week), measured by self-report or objective measures (daily 
monitoring or drug levels). 
E. 
Hypothesis 
Women and men will continue to use PrEP when their partners refuse HIV testing or disclose STI 
infections.  
F. 
Location  
This study will take place at the Infectious Diseases  Institute (IDI)-Kasangati research clinic, 
located in the Kasangati area of Kampala in close proximity of several public health care facilities. 
G. 
Population 
The proposed study will enroll 200 young men who are male sexual partners of women in the 
current KWBS parent study. This demographic has a high risk for HIV acquisition thus it is ideal 
to provide them with diagnostic testing, prevention and treatment services for HIV and STIs, and 
prevent transmission to their female partners. Women from KWBS will also be engaged to discuss 
the study with their male partners and to have their data anonymously linked to their male partners 
who join this study.  
H. 
Eligibility for men 
Inclusion criteria:  
- 
Men ages ≥18  
- 
Has a female sexual partner enrolled in the Kampala Women’s Bone Study  
- 
Willing and able to provide informed consent  
Exclusion criteria:  
- Has any other condition that would preclude the ability to provide informed consent, make 
study participation unsafe, complicate the interpretation of study findings or otherwise 
interfere with achievement of the study objectives, in the investigator’s discretion. 
 
I. 
Eligibility for women 
Inclusion criteria: 
− 
Participating in the Kampala Women’s Bone Study 
− 
Willing to talk with male sex partners about the new study for men and refer men for 
study recruitment 
Exclusion criteria: 
− 
Has concerns about potential social harm stemming from anticipated conversations 
with male sex partners about the new study for men such that study staff would 
discourage the women from participation 
− 
Investigator discretion 

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J. 
Sample size  
We will enroll approximately 200 male and 300 female participants into this study  
K. 
Study power  
Power calculations are based on the primary aim to determine alignment of women’s PrEP use 
with male sex partner’s STI 
infection status. Using an 
estimate that 20% of men 
will be infected with STI/HIV 
at any visit and 50% of their 
female partners will have 
protective PrEP levels, we 
estimate that we will have 
≥80% power to detect a 
relative risk of ≥2.00 and 
≥90% power to detect a 
relative risk of ≥2.30 in 
comparisons 
of 
the 
proportion of female visits 
with PrEP protection between visits when male partners had HIV risk or no HIV risk (assuming 
that α=0.05). If 70% of their female partners have protective PrEP levels, power will be 80% for a 
RR of 1.57 and 90% for a RR of 1.72 (Table 4). 
L. 
Recruitment 
Overall 
Women will be recruited to join this study by outreach staff at the IDI-Kasangati facility at the 
end of routine study visits for the KWBS. 
For young men who are sex partners of women in KWBS, we will leverage women participating 
in KWBS to recruit 200 of their current male sex partners. Women will be asked to consent to 
participate in recruitment of their male sex partners and to have their data anonymously linked to 
their male partner data. This will be a separate consent form and women may decline this 
component without any change to their participation in KWBS. Women with concerns about 
potentially experiencing violence from their male partner will be discouraged from recruiting this 
or any other male partners for the study and we will have staff trained in violence prevention 
available to counsel these women. The IDIK research clinic has established relationships with 
well-known organizations that specialize in IPV prevention and counseling in the event that a 
KWBS woman needs to be referred for more in-depth care. Ultimately, each woman’s participation 
will be at her own discretion. Women engaging in this new study will be provided with multiple 
strategies to talk with male sex partners about the new study: talking points, recruitment 
brochures, HIV self-testing kits, and contact information for study recruitment staff. 
Talking points 
Women enrolled in KWBS will be provided talking points to guide them to think about how to 
recruit male partners. Talking points will include benign messages about a new research study 
for men and provide ideas about how to promote the men’s study without disclosing information 
about their own recent HIV test/status or PrEP use (see Appendix for draft talking points). 
Table 4. Aim 2 power: Proportion of women with PrEP at 
protective level needed to see significant differences by male 
partner HIV risk, with ≥80% or ≥90% power. 
Male partner HIV 
risk (HIV or STI 
infection) 
PrEP at protective level, % (RR) 
Yes, exposed, N=40 
50% 
70% 
Unexposed, N=160 
 
 
For 80% power 
24.6% (RR=2.0) 
44.6% (RR=1.5) 
For 90% power 
21.5% (RR=2.3) 
40.8% (RR=1.7) 
Power calculated by nQuery Advisor using power for Chisquared test comparing two 

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Recruitment brochures 
Women will also be given recruitment materials such as brochures, to give to their male partners 
that feature information on the benefits of STI testing and treatment, an introduction to PrEP and 
its availability for HIV-negative men through the study clinic. Recruitment materials will encourage 
men to call study recruitment officers or come to the IDIK research clinic. Draft brochures and 
other recruitment materials will be submitted to the research ethic committee for approval. 
HIV self-test kits 
HIV self-testing is being rolled out in Kampala by The President’s Emergency Plan for AIDS Relief 
(PEPFAR) partners coordinated by the Ministry of Health. To align with this strategy, the study 
will also have HIVST in stock that will be available for women to take to male partners, should 
they desire. The IDIK research clinic is already using HIVST in a number of ongoing PrEP studies, 
including with pregnant women living with HIV and women engaging in transactional sex 
(NCT03484533, NCT03426670). HIVST are accompanied by written instructions in English and 
Luganda with pictures and diagrams that explain how to use them and provide a 24-hour phone 
number in case of reactive results, questions or help with the kit. Anyone reporting reactive results 
to study staff will be encouraged to come to the research clinic and anyone who does not come 
within one week will be traced via phone or an in-person visit if possible. We will follow good 
clinical practice guidelines to ensure that all people with a reactive result are supported and 
provided with confirmatory testing, treatment and care.  
Contact with study recruitment team 
Once women have initiated conversation with their male partner, they will be encouraged to let 
the recruitment team know and arrange a time for their male partner to talk with a member of the 
recruitment team. This will be done by having the recruitment officer call the woman at a mutually-
agreeable time when she can offer her phone to her male partner, facilitating a one-on-one 
conversation with the recruitment officer. This method will maintain anonymity of the potential 
male participant and permits contact without the woman providing her partner’s phone number to 
the recruitment officer. This recruitment strategy has worked well for our ongoing study that 
recruits male partners of HIV-infected pregnant women (NCT03484533). Women can also bring 
male partners to the study clinic for him to meet a recruitment officer in person or make other 
arrangements to introduce her partner to the recruitment officer.  
M. 
Retention 
We will leverage the long-established retention strategies of the community outreach team at the 
IDIK research clinic to ensure high rates of retention among male participants. Retention 
strategies include sending participants reminders before their upcoming target visit date (via SMS 
or phone call), calling participants the first day after a missed visit date, 3 days later, 1 week later, 
and 1 month later, and visiting participants in their home or place of work, when given permission, 
to offer them a free ride to the research clinic. In addition, a recruitment/retention officer will 
coordinate with the study team to ensure that study visits can be conducted on weekends and 
evenings and that men can be given expedited services, as necessary to align with work 
schedules and other obligations. 
N. 
General study procedures  
Informed consent 
Written informed consent will be obtained from each female participant in the KWBS, and each 
male study participant prior to conducting any research procedures. Participants agreeing to 
participate will sign the informed consent form and be offered copies of the informed consent 

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forms to take home. The informed consent forms will describe the purpose of the study, the 
procedures to be followed, the voluntary nature of the study, and the risks and benefits of 
participation, in accordance with all applicable regulations. The forms will be translated into 
Luganda and participants will select the language of their choice (either Luganda or English) for 
the informed consent process. Informed consent will be conducted in a quite space in the research 
clinic by a study staff member trained in human subjects and good clinical practice. 
Procedures for women 
Women enrolled in the KWBS will be asked by the study recruitment officers if they would be 
interested in recruiting their male partner for this new study. Recruitment officers will ensure that 
women understand fully their role, discuss and consider potential benefits and risks, such as 
inadvertent disclosure of HIV status, PrEP use, study participation, and intimate partner violence 
(IPV) and how to avoid them. Women with concerns about IPV will be discouraged from recruiting 
potential male perpetrators for the study and we will have staff trained in IPV prevention available 
to counsel these women. Women who are interested in recruiting their male partners will sign an 
informed consent form specific to partner recruitment and linkage of their male partners data, to 
their KWBS data.  
Following informed consent, the study staff will provide counseling messages and talking points 
for women to help them with the recruitment process and initiate the discussion with their male 
partner.  
Women will receive a recruitment brochure to give to their male partners. These brochures will 
include benign information on STI testing and health services available at the clinic, as well as 
contact information of study staff, whom they can call if they are interested in joining the study or 
have additional questions.  
Study staff will also provide women an HIVST kit, if they choose to deliver one to their male 
partner. To ensure that women feel comfortable with the recruitment process, study staff may also 
assist with role playing to act out talking points and delivery of the recruitment brochure and/or 
HIVST kit. 
Procedures for men 
Screening and Enrollment 
Following informed consent, men will be screened for their willingness to comply with study 
procedures, complete locator information, and assigned a unique ID. Eligible men will be enrolled 
into the study, on the same day if possible. Procedures on the day of enrollment will include: 1) 
HIV testing with PrEP dispensation or active referral to ART and HIV care depending on the 
results, 3) Hepatitis B and creatinine testing for men starting PrEP, 2) completion of 
questionnaires to assess demographic information, recent sexual behavior, partnership status, 
HIV risk perception, alcohol and drug use, mental health, and adherence to ART/PrEP, 4) 
diagnostic testing for N. gonorrhoeae and C. trachomatis using rapid tests with real time results. 
Results from creatinine testing will be available within 3-5 days from the laboratory. Any 
participants with abnormal creatinine/creatinine clearance will be contacted by the study clinician 
and asked to return for confirmatory testing. PrEP will be discontinued for any men with confirmed 
abnormal creatinine/creatinine clearance levels according to national guidelines.  
Follow up 
Follow up visits will be conducted 1, 3 and 6 months after enrollment. Procedures at each visit 
will include: 1) HIV testing with PrEP dispensation or referral to ART and HIV care depending on 
the results, 2) completion of questionnaires to assess recent sexual behavior, partnership status, 
HIV risk perception, and adherence to ART/PrEP, and 3) diagnostic testing and treatment for N. 

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gonorrhoeae and C. trachomatis. PrEP use will be objectively measured by point-of-care urine 
tests, if kits become available during the study, and real time monitoring of PrEP adherence will 
be conducted using an electronic monitoring system that captures a date-time stamp each time 
the pill container is opened, if devices become available.[27] Participants using PrEP will have a 
creatinine test at the 6-month/study exit visit which aligns with Uganda national PrEP guidelines. 
For men who test HIV-positive, confirmatory HIV testing will be conducted according to Uganda 
national guidelines and PrEP will be discontinued. HIV-positive men will continue to be engaged 
until the end of their follow up time to collect sexual behavior data, but HIV testing will not be 
conducted once HIV-positive status is confirmed. Men will be counseled about ART initiation and 
ART adherence and HIV viral load testing will be conducted when HIV is first detected and 3 
months after ART initiation. IDIK is situated next to a public health facility that provides ART and 
is often a close collaborator to receive referred research participants for HIV care. 
Visit-specific procedural tables 
 
 
SCR 
ENR 
M1 
M3  
M6 & 
EXIT  
ADMINISTRATIVE & REGULATORY PROCEDURES 
Obtain informed consent 
X 
X 
 
 
 
Collect/update locator information 
X 
X 
X 
X 
X 
Collect/update demographic information 
X 
X 
 
 
 
CLINICAL & COUNSELING PROCEDURES 
HIV pre and post-test counseling 
X 
X 
X 
X 
X 
Risk reduction counseling & condom provision 
X 
X 
X 
X 
X 
If HIV negative: PrEP counseling, including 
adherence counseling 
X 
X 
X 
X 
X 
If HIV negative: PrEP provision, if desired 
X 
X 
X 
X 
X 
If HIV negative: PrEP pill count, if using PrEP 
 
 
X 
X 
X 
If HIV negative: Urine TFV testing (when kits are 
available), download of electronic monitoring data 
(if devices are available) 
 
 
X 
X 
X 
If HIV positive: ART referral  
X 
X 
X 
X 
X 
If HIV positive: ART counseling  
X 
X 
X 
X 
X 
Diagnostic testing and/or syndromic management 
of STIs 
X 
X 
X 
X 
X 
STI treatment  
[X] 
[X] 
[X] 
[X] 
[X] 
LABORATORY PROCEDURES  
If HIV negative: Creatinine testing when using 
PrEP 
X 
 
 
 
X  
If HIV negative: HBV surface antigen 
X 
 
 
 
 
HIV rapid test  
X 
X 
X 
X 
X 

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Study exit  
Approximately 6 months after enrolling, men will complete their last study visit. At this visit, men 
will be provided with referrals to clinics of their choice to continue receiving PrEP and any other 
clinical services needed.  
O. 
Special circumstances 
HIV seroconversion 
HIV rapid testing will be conducted quarterly during follow up. We expect the rate of HIV 
seroconversion to be very low, due to the use of PrEP and repeated counseling about HIV 
prevention and PrEP. However, in the event of HIV positive rapid test results, PrEP will be stopped 
immediately, and additional blood samples will be drawn for confirmatory HIV testing according 
to national guidelines. Men with confirmed HIV seroconversion will be extensively counseled and 
referred to local clinics providing antiretroviral medications and HIV care. Seroconverting men will 
remain in the study until their follow up period has ended and can continue to receive counseling 
services from study counselors as part of good clinical care. 
Partner Notification 
Research staff will follow national guidelines for assisted partner notification (APN) in the event 
of positive HIV diagnostic tests and take precautions to avoid safety problems. Modalities in the 
existing programmatic approach of APN include self-disclosure, assisted disclosure, or facilitated 
disclosure. Staff are well trained in counseling messages regarding the benefits of APN and are 
able to conduct APN activities depending on the participant’s preferences. Staff are also very 
experienced with counseling couples’ on issues of sexual health if couples choose to attend visits 
together.   
 
P. 
Safety monitoring  
Kidney function will be monitored at PrEP initiation and 6 months later, in accordance with 
Ugandan guidelines, using creatinine clearance calculated by Cockroft–Gault equation. The 
investigators will be responsible for continuous close monitoring of all adverse events that occur 
among study participants. For the purposes of this study, only serious adverse events (SAEs) and 
adverse events felt related to PrEP will be documented on case report forms.  Adverse events 
and the severity of clinical symptoms will be scored using the DAIDS Table for Grading the 
Severity of Adult and Pediatric AEs.[28] The study safety monitor will review clinical and laboratory 
SAEs in real time as they are reported by the site clinicians on CRFs and through email within 48 
hours of occurrence. As needed, the safety monitor will work to provide rapid consultation with 
clinicians regarding the management of toxicities. A Safety Review Team comprised of the study 
investigators and lead clinicians will review clinical and laboratory safety reports summarizing 
SAEs via conference call on an approximately quarterly basis. 
If rapid test positive: Confirmatory HIV testing and 
RNA quantification  
[X] 
[X] 
[X] 
[X] 
[X] 
BEHAVIORAL DATA COLLECTION   
Questionnaire completion 
 
X 
X 
X 
X 
Medical History questionnaire  
X 
X 
X 
X 
X 
X required procedure; [X] if clinically indicated  

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VI. 
DATA COLLECTION  
Demographic, behavioral and clinical data including STIs symptoms, sexual activity and PrEP 
adherence will be recorded electronically on case report forms (CRFs) directly entered by 
research staff into a secure web-based data management program. Results from off-site 
laboratory testing will be returned to the IDI research clinic and also entered into this system. 
Automated legal range checks will be programmed to reduce data entry errors and internal quality 
control reports will be run on a monthly basis. Paper backup forms will be available in the case of 
power or internet outages with online data entry once restored. On a weekly basis, the University 
of Washington data manager will archive a backup copy of the master dataset on secure servers 
at the University of Washington. 
VII. 
LINKAGE WITH DATA FROM WOMEN IN THE EXISTING KWBS COHORT 
Men in this study will receive a study brochure from their female partner who is participating in 
the KWBS study. The brochure will have a label affixed to it with a code that is anonymously 
linked to the study ID of the woman recruiting him. At the time of presenting to the IDIK research 
clinic, potential male participants will be asked to bring their brochure so that the code can be 
scanned, and a male ID can also be linked to the same code. Using the code will enable women’s 
ID to be linked to men’s ID(s). If an enrolling participant does not have a coded brochure, we will 
create a link to a woman’s ID by asking for the name of the woman who recruited him and 
accessing our link logs that are stored in a secure room with biometric access control.  
VIII. 
DATA ANALYSIS  
Data from each man and his female KWBS partner who recruits him will be longitudinally aligned 
using study visit dates. The primary exposure is male infection with HIV (Aim 1), NG, or CT (Aim 
2), or female infection with HIV, NG, or CT (Aim 3) and the primary outcome will be PrEP used 
by women/men with sufficient daily adherence to confer HIV protection for periods when PrEP is 
dispensed. When PrEP is not dispensed, we will assign a TFV level of 0 ng/mL. We will estimate 
the association between HIV risk and use of PrEP using GEE to account for repeated 
measurements. Models will adjust for key confounding factors (demographic, sexual behavior, 
clinical).  
IX. 
HUMAN SUBJECTS CONSIDERATIONS 
The protocol, informed consent forms (for cohort participation and for interviews of providers), 
and patient education and recruitment materials will be reviewed and approved by the IRBs/ECs 
responsible for oversight.  Subsequent to initial review and approval, the responsible IRBs/ECs 
will review the study at least annually. 
A. 
Study oversight  
The protocol study team will review a comprehensive set of safety and study operational data 
every 6 months to ensure that timelines are being met and the study will be able to answer its 
primary research questions. 
B. 
Informed consent  
We will perform paper-based consenting of participants in their preferred language.  After we have 
ensured that participants have read and understood the consent forms, we will ask them to 

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append their signature on paper. Any participant who wants their consent form to take home will 
be given a copy.   
C. 
Risks  
Risks for this cohort include side effects from PrEP provided to the young men through the study 
clinic, and discomfort associated with blood draws, interviews, and STI and HIV counseling and 
testing. Intensive and ongoing counseling and monitoring of side effects and adverse events limit 
the risk for participants from the direct study procedures.  
For clinical data collection, standardized surveys will be used that will include questions on 
sensitive topics, such as sexual behavior. All participants will be extensively counseled about the 
risk and prevention of STIs, as well as the risk for HIV transmission with sex unprotected by a 
condom and/or PrEP and the importance of using condoms consistently and correctly. We expect 
that the risk of HIV transmission will actually be lower in this cohort than the general population 
of young men due to the careful attention that will be given to counseling about HIV risk and the 
provision of PrEP. Study staff will be aware of the potential for confidentiality issues with regards 
to test results from HIV testing that are part of a participant’s study documents.  
There is the potential for confidentiality issues with regards to study data. Although the study site 
will make every effort to protect participant privacy and confidentiality, it is possible that 
participants' involvement in the study could become known to others, and that social harms may 
result. However, the research staff has extensive experience in both individual and couples 
counseling, particularly on the topics of serodiscordance and HIV status disclosure. The research 
staff will provide couples counseling if the male participant chooses to involve their study partner, 
or individual counseling if the male participant chooses to keep his STI/HIV results confidential.  
D. 
Benefits  
Participants will receive individualized HIV and STI risk-reduction counseling and testing, access 
to PrEP medication, and free condoms. In addition, participants may benefit in the future from 
information learned from this study. 
E. 
Care for persons identified as HIV positive 
Men who test positive for HIV at enrollment or become infected with HIV later in the study will be 
referred immediately to HIV care centers and encouraged to initiate antiretrovirals in line with 
Ugandan national antiretroviral guidelines.   
F. 
Treatment for injury  
Participants will be asked to inform the clinic staff if they feel they have been injured because of 
taking part in the study. Injuries may also be identified during laboratory testing, and medical 
histories. Treatment for adverse events related to study participation will be provided by the 
research clinic. If treatment is required that is beyond the capacity of the clinic, the clinic staff will 
refer the participant to appropriate services or organizations that can provide care for the injury. 
The study based at IDI will cover the costs of the referral and treatment costs up to the time the 
participant is stable, or injury is resolved.  
F. 
Study records  
Complete, accurate, and current study records will be maintained and stored in a secure manner 
throughout the study. Study records include administrative documentation and regulatory 
documentation as well as documentation related to each participant enrolled in the cohort, 
including informed consent forms, chart notes, case report forms, laboratory requisitions, 
notations of all contacts with the participant, and all other source documents.   

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G. 
Confidentiality  
Every effort will be made to protect participant privacy and confidentiality to the extent possible.  
Personal identifying information will be retained at the local study site.  
 
X. 
CLINICAL RESEARCH SITE 
A. 
Site location 
The Infectious Diseases Institute (IDI)-Kasangati research clinic is part of the Infectious Diseases 
Institute, Makerere University College of Health Sciences. The facility is located next to Kasangati 
Health Center IV and has adequate space and equipment for ongoing and planned research 
studies. The Infectious Diseases Institute training team offers specialized courses in HIV 
management for health providers in Africa. For this study the focus of the training will be 
combination HIV prevention services including PrEP as well as STI prevention and treatment. 
B. 
Clinical facilities 
The site has a large training room that can accommodate up to 50 people, 3 clinical rooms, 6 
counseling rooms, a pharmacy, a phlebotomy room, a side lab, secure data room with data 
archive, administrative office space, wireless internet, telephone intercom system, community 
education offices, and a large waiting area which provide sufficient space for the execution of this 
study. 
C. 
Staff 
The Principal Investigator is a seasoned HIV/AIDS researcher and trainer, of local and 
international repute. He will lead the study team to maximize the scientific, ethical integrity of the 
study and ensure the training provided is of high quality.  The study employs in total  doctors,  
nurse counselors, a pharmacy technician, laboratory staff and  community educators/counselors, 
data personnel, qualitative research associates as well as support and administrative staff. The 
respective staff are overseen by a site coordinator, training coordinator and administrator. The 
study site previously implemented the Partners PrEP Study and the Partners Demonstration 
Project and is currently implementing the KWBS. The staff have substantial experience in the use 
of PrEP and its accompanying supportive services. The staff have been involved in the conduct 
of protocol specific training, development of outreach materials, and have skills in training of adult 
learners. 
D. 
Administrative procedures 
All administrative procedures regarding protocol compliance, study coordination, study activation, 
study monitoring, study records, and use of information and publications will be done according 
to good clinical practice. 
E. 
Laboratory considerations 
We will as much as possible use the public health laboratory facilities for routine laboratory 
monitoring. In situations where this is not possible, specimens will be collected and transported 
to the study collaborating laboratories. All specimen collection, transport, processing, testing, 
archiving, and results reporting will be conducted in accordance with good clinical and laboratory 
practice standards. The collaborating laboratories for the research clinic are the IDI Core 
Laboratory and the Immunology Laboratory in the Department of Medical Microbiology at 
Makerere College of Health Sciences. These are well-established labs with extensive experience 
in supporting clinical trials. External Quality Assurance (EQA) procedures will be followed 

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throughout the study and are overseen by the University of Washington International Clinical 
Research Center. 
 
XI. 
DATA SHARING AND OWNERSHIP 
During the conduct of the trial, the study database will remain confidential. After study completion, 
access to data will follow requirements of the Infectious Diseases Institute, National Institutes of 
Health and the University of Washington. The University of Washington International Clinical 
Research Center has a Manuscripts and Ancillary Studies Committee established to enable data 
and specimen collaborative work from studies conducted through the research group. Intellectual 
property and data generated under the proposed project will be administered in accordance with 
Uganda, University of Washington and NIH policies, including the National Guidelines for 
Research involving Humans as Research Participants (2014) [113] and the NIH Data Sharing 
Policy and Implementation Guidance of March 5, 2003. 
 
Materials 
generated 
under 
the 
project 
will 
be 
disseminated 
in 
accordance 
with 
University/participating institutional and NIH policies. Depending on such policies, materials may 
be transferred to others under the terms of a material transfer agreement. Access to databases 
generated under the project will be available for educational, research and non-profit purposes 
as approved by the relevant IRBs. Publication of data shall occur during the project, if appropriate, 
or at the end of the project, consistent with normal scientific practices. We will publish our findings 
in a timely fashion and will present unpublished data at appropriate research conferences. We 
are committed to collaboration in complex disease research and will participate in data-pooling 
studies as allowed by our currently established consent forms and IRBs. 
 
Data obtained from this research study are the property of the Infectious Diseases Institute of 
Makerere University and the University of Washington International Clinical Research Center. 
Local researchers shall have unrestricted access rights to datasets collected through this 
collaborative research project in accordance with Uganda guidelines. 
 
XII. 
DISSEMINATION PLAN 
 
Dissemination of study results will follow principles of good participatory practice. Study results 
will be disseminated through presentations to study participants, stakeholders and policy makers, 
and published in conference abstracts and peer-reviewed journals. Participants will be informed 
that if they so desire, they will be contacted at the end of the study for the purpose of informing 
them about study results. Trial results will also be shared with the community advisory board, the 
Ministry of Health, implementing partners and civil society groups with interest in reproductive 
health. 

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XIII. 
REFERENCES  
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3. 
Ministry of Health Uganda, et al. Uganda Population-Based HIV Impact Assessment. 
UPHIA 
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2018 
 
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4. 
Travill, D., et al., Sexual behavior and PrEP uptake among young African women in 
demonstration project about PrEP delivery. Abstract #WEPE219, in AIDS 2018. 2018: 
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5. 
Cottrell, M.L., et al., A Translational Pharmacology Approach to Predicting Outcomes of 
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6. 
Baeten, J.M., et al., Antiretroviral prophylaxis for HIV prevention in heterosexual men and 
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7. 
World Health Organization, WHO Implementation Tool for PrEP of HIV Infection. Module 
12: Adolescents and young adults, W.H. Organization, Editor. 2018: Geneva, Switzerland. 
8. 
van der Straten, A., et al., Women's experiences with oral and vaginal pre-exposure 
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9. 
Morton, J., et al., High prevalence of curable STIs among young women initiating PrEP in 
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10. 
Barnabas, S.L., et al., Converging epidemics of sexually transmitted infections and 
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Francis, S.C., et al., Prevalence of sexually transmitted infections among young people in 
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12. 
Jhpiego. Lesotho's innovative Apex Clinic encourages older men to participate in HIV 
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MenStar Coalition. Global partners pledge over $1.2 billion to launch the MenStar 
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