Delivering PrEP in Pregnancy
Phase: PHASE4
Conditions: HIV Infections, Pregnancy Related
Sponsor: University of Washington

 
 
 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
A Clinic-Level Cluster-Randomized Trial of Universal Availability Versus Targeted Offer of 
Oral, Daily Pre-Exposure Prophylaxis (PrEP) among Women Attending Antenatal Care Centers 
in Kenya 
 
Study Protocol 
Principal Investigator: Grace John-Stewart, Jared Baeten, John Kinuthia 
Proposal Identification Number: 1 R01 AI25498-01 
ClinicalTrials.gov Identification Number: NCT03070600 
Study Dates: 05/01/2016-04/30/2021 
Version 5.5 
May 13, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1) TITLE 
4 
2) INVESTIGATORS (ROLES AND RESPONSIBILITIES): 
4 
3) COLLABORATING INSTITUTIONS 
5 
4) LIST OF ABBREVIATIONS 
6 
5) FUNDING AGENCY 
7 
6) SUMMARY 
7 
7) BACKGROUND 
8 
A) LITERATURE REVIEW 
8 
8) RATIONALE 
12 
9) HYPOTHESIS & STUDY QUESTIONS: 
12 
A) BROAD OBJECTIVES 
12 
B) SPECIFIC OBJECTIVES 
13 
10) STUDY DESIGN AND METHODOLOGY 
13 
A) STUDY AREA DESCRIPTION: 
13 
COMPONENT 1: CLUSTER-RANDOMIZED CONTROL TRIAL 
16 
A) STUDY DESIGN 
16 
B) STUDY POPULATIONS 
16 
C) SAMPLE SIZE DETERMINATION AND FORMULAS USED 
16 
D) RECRUITMENT PROCEDURES 
17 
E) STUDY PROCEDURES 
17 
F) LABORATORY METHODS 
22 
G) DATA COLLECTION INSTRUMENTS 
23 
H) VARIABLES: OUTCOMES, INDICATORS, AND SOURCE DOCUMENTS 
24 
J) QUALITY ASSURANCE PROCEDURES 
25 
K) TRAINING PROCEDURES 
25 
COMPONENT 2: QUALITATIVE ASSESSMENT AT ORGANIZATIONAL, FACILITY AND INDIVIDUAL LEVELS
 
25 
A) STUDY DESIGN 
25 
B) STUDY POPULATION 
26 
C) SAMPLE SIZE DETERMINATION AND FORMULAS USED 
27 
D) RECRUITMENT PROCEDURES 
27 
E) DATA COLLECTION PROCEDURES 
27 
F) DATA COLLECTION INSTRUMENTS 
28 
G) TRAINING PROCEDURES 
28 
11) STUDY MATERIALS: 
28 
12) DATA MANAGEMENT AND SECURITY 
29 

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PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
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13) STUDY LIMITATIONS AND HOW TO MINIMIZE THEM: 
29 
14) HUMAN SUBJECTS 
29 
15) LIST OF APPENDICES/ATTACHMENTS 
31 
16) REFERENCES 
32 
 
 
 

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1) TITLE: PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
2) INVESTIGATORS (Roles and responsibilities): 
Grace John-Stewart, MD, PhD (MULTIPLE PRINCIPAL INVESTIGATOR) 
(Responsible for the overall project development, oversight, and science of Maternal and Child 
Health components of the project) 
Professor  
Departments of Global Health, Medicine, Epidemiology and Pediatrics, University of Washington 
Harborview Medical Center, 325 Ninth Ave., Box 359909, Seattle, WA 98104 
Tel:  +1-206-543-4278 
Fax: +1-206-543-4818 
Email:  gjohn@uw.edu 
 
Jared Baeten, MD, PhD (MULTIPLE PRINCIPAL INVESTIGATOR) 
(Responsible for the overall project development and oversight and science of PrEP components 
of the project) 
Professor, Vice Chair  
Departments of Global Health, Medicine, and Epidemiology, University of Washington 
Harborview Medical Center, 325 Ninth Ave., Box 359927, Seattle, WA 98104 
Tel:  +1-206-520-3808 
Fax: +1-206-520-3831 
Email: jbaeten@uw.edu 
 
John Kinuthia, MBChB, MMed, MPH (SITE PRINCIPAL INVESTIGATOR)  
(Responsible for the development and overall project oversight and science and overseeing all 
implementing team members in Kenya) 
Head, Department of Research & Programs, Kenyatta National Hospital 
PO Box 20723-00202, Nairobi, Kenya 
Tel: +254 0722 799-052 
Email: kinuthia@uw.edu 
 
Ruanne Barnabas, MD, DPhil (CO-INVESTIGATOR, Project Health Economist) 
(Responsible for protocol, data and analysis plan, and evaluation of the health economics, Aim 2, 
components of the study)  
Assistant Professor  
Departments of Global Health, Allergy and Infectious Diseases, University of Washington 
Harborview Medical Center, 325 Ninth Ave., Box 359927, Seattle, WA 98104 
Tel:  +1-206-520-3813 
Fax: +1-206-520-3831 
Email: rbarnaba@uw.edu 
 
Barbra Richardson, PhD (CO-INVESTIGATOR, Project Biostatistician) 
(Responsible for protocol, data and analysis plan, and evaluation of the project) 
Research Professor 
Department of Biostatistics, University of Washington 
Harborview Medical Center, 325 Ninth Ave., Box 359909, Seattle, WA 98104 
Tel:  +1-206-744-2425 
Fax: +1-206-543-4818 
Email: barbrar@u.washington.edu 
 
Gabrielle O’Malley, PhD (CO-INVESTIGATOR, Qualitative Methods lead) 

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(Responsible for protocol, data and analysis plan, and evaluation of the qualitative, Aim 3, 
components of the study)   
Associate Professor 
Department of Global Health, University of Washington  
International Training and Education Center for Health (I-TECH), 902 Boren Ave, Suite 1100, Box 
359932, Seattle, WA 98104 
Tel: +1-206-685-0775 
Email: gomalley@u.washington.edu 
 
Harsha Thirumurthy, PhD (CO-INVESTIGATOR, Self-Testing Lead) 
(Responsible for protocol, data and analysis plan, and evaluation for self-testing components of 
the study and support to health economics aspects of the study) 
Associate Professor of Health Economics 
Department of Health Policy and Management, Gillings School of Public Health 
University of North Carolina, Chapel Hill 
Tel: +1-919-966-9756 
Email: harsha@unc.edu 
 
Nancy Mwongeli (STUDY COORDINATOR) 
(Responsible for lab and site protocol development, data analysis and staff oversight) 
Kenyatta National Hospital 
Nairobi, Kenya 
Tel: +254 0713 917 226 
Email: nancym390@gmail.com 
 
Julia Dettinger, MPH (STUDY COORDINATOR) 
(Responsible for study coordination, ERC/IRB communication, protocol development, data 
collection, and analysis)  
Department of Global Health and Nursing, University of Washington 
Harborview Medical Center, 325 Ninth Ave., Box 359931, Seattle, WA 98104 
Tel:  +1-206-221-1041 
Fax: +1-206-744-3693 
Email: jcdettin@uw.edu 
 
3) COLLABORATING INSTITUTIONS 
University of Washington, Kenyatta National Hospital/University of Nairobi, University of North 
Carolina, Chapel Hill 
 
 

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4) LIST OF ABBREVIATIONS 
 
ANC 
 
 
Antenatal care 
ART 
 
 
Antiretroviral treatment 
ARVs  
 
Antiretroviral drugs 
AVAC  
 
AIDS Vaccine Advocacy Coalition 
CCC 
 
 
Comprehensive Care Clinic 
CDC   
 
Centers for Disease Control and Prevention 
CEA 
 
 
Cost effectiveness analysis 
Cr 
 
 
Creatinine 
CrCl 
 
 
Creatinine clearance 
DALY  
 
Disability-adjusted life-year 
DBS 
 
 
Dried blood spot 
DNA 
 
 
Deoxyribonucleic acid 
ERC 
 
 
Ethics Review Committee 
FGD 
 
 
Focus group discussion 
FTC 
 
 
Emtricitabine-triphosphate 
GEE 
 
 
Generalized estimating equations 
GoK 
 
 
Government of Kenya 
HBSAg 
 
Hepatitis B surface antigen 
HIV 
 
 
Human immunodeficiency virus 
HAZ 
 
 
Height-for-age z-score 
IDI 
 
 
In-depth interview 
IRB 
 
 
Institutional Review Board 
KEMRI  
 
Kenya Medical Research Institute 
KNH 
 
 
Kenyatta National Hospital 
LPV/r  
 
Lopinavir/ritonavir 
MCH  
 
Maternal and Child Health 
MOH  
 
Ministry of Health 
MSS 
 
 
Mama Salama Study 
MTCT  
 
Mother-to-child transmission 
NASCOP 
 
National AIDS and STI Control Program 
ODK 
 
 
Open Data Kit  
PMTCT 
 
Prevention of mother-to-child transmission of HIV 
PNC 
 
 
Postnatal clinic 
PP 
 
 
Postpartum 
POC 
 
 
Point-of-care 
PrEP  
 
Pre-exposure antiretroviral prophylaxis 
RCT 
 
 
Randomized controlled trial 
RNA 
 
 
Ribonucleic acid 
SSL 
 
 
Secure Socket Layer 
STI 
 
 
Sexually transmitted infection 
TDF 
 
 
Tenofovir disoproxil fumarate 
TDF/FTC 
 
Tenofovir/emtricitabine 
TDF/FTC/LPV/r 
Tenofovir/emtricitabine/lopinavir/ritonavir 
TFV-DP 
 
Tenofovir-diphosphate 
UNC 
 
 
University of North Carolina, Chapel Hill 
UON  
 
University of Nairobi 
UW 
 
 
University of Washington 
WHO  
 
World Health Organization 
 

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5) FUNDING AGENCY 
Funding type: Grant 
Name of Funding agency: National Institutes of Allergy and Infectious Disease (NIAID), National 
Institutes of Health (NIH) 
Principal Investigator on Proposal: Grace John-Stewart, Jared Baeten 
Proposal Identification Number: 1 R01 AI25498-01 
Title of Proposal:  Delivering PrEP in Pregnancy 
Dates: 05/01/2016-04/30/2021 
 
Funding type: Grant 
Name of Funding agency: The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD), National Institutes of Health (NIH) 
Principal Investigator on Proposal: Grace John-Stewart, Pamala Kohler 
Proposal Identification Number: 1 R01 HD094630-01 
Title of Proposal:  PrEP Adherence Among AGYW: A Multidimensional Evaluation 
Dates: 07/01/17-6/30/22 
 
Funding type: Grant 
Name of Funding agency: National Institute of Nursing Research (NINR), National Institutes of 
Health (NIH) 
Principal Investigator on Proposal: Jillian Pintye 
Proposal Identification Number: 1F32NR017125-01A1 
Title of Proposal:  Adherence to Pre-Exposure Prophylaxis for HIV Prevention in Pregnancy 
Dates: 08/01/17-7/31/20 
 
 
6) SUMMARY 
Women living in regions with high HIV prevalence are at high risk of HIV acquisition in pregnancy 
and postpartum because they infrequently use condoms, do not know their partner’s HIV status, 
and have biologic changes or changes in their partner’s sexual partnerships that increase 
susceptibility. Oral pre-exposure antiretroviral prophylaxis (PrEP) may be an attractive strategy 
for HIV prevention in pregnancy/postpartum; however, it is important to ensure PrEP reaches 
women who are at risk for acquiring HIV during pregnancy while avoiding unnecessary PrEP use 
during pregnancy. Clinicians and women are using PrEP in pregnancy; in qualitative studies, 
women, health workers and policy-makers support use of PrEP in pregnancy but advocate for 
models of PrEP delivery that ensure women at risk receive PrEP while minimizing unnecessary 
PrEP use in women not at risk. Targeting PrEP to women at greatest risk of HIV may maximize 
benefits, minimize potential risks, and optimize cost-effectiveness. This cluster-randomized 
clinical trial (RCT) in 20 Maternal Child Health (MCH) clinics in western Kenya (10 clinics per arm, 
at least 200 women per clinic, 4000 women overall), will compare 2 models of PrEP delivery in 
pregnancy. Clinics will offer universal availability of PrEP (and women self-select whether to use) 
or targeted offer of PrEP (i.e., offer to women identified as high risk through a standardized risk 
assessment and partner self-testing, and then women identified as high-risk select whether to 
use). Leveraging the pre-existing MCH clinic visit schedule will enable programmatically relevant 
assessment of PrEP uptake, use, and HIV incidence. The outcome of the study will be a model 
of PrEP delivery in pregnancy that optimizes effectiveness, safety, and cost-effectiveness. Our 
team has expertise in maternal-child HIV (John-Stewart, Kinuthia), PrEP clinical trials and 
implementation science (Baeten, Richardson), partner self-testing (Thirumurthy), economics and 
qualitative research (Barnabas, O’Malley).  
 

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AIM 1a. In a cluster-RCT, compare universal PrEP (offer to all; women self-select PrEP) to 
targeted PrEP (limit the offer to women identified as high risk through a standardized risk 
assessment and partner self-testing) for outcomes reflecting the balance of PrEP effectiveness 
and avoiding unnecessary PrEP exposure to women at low or no risk of HIV: HIV incidence at 9 
months postpartum among all women (including those who did and did not receive PrEP) and 
proportion of women exposed to PrEP.  
AIM 1b. To compare trial arms for proportion of women ‘appropriately’ on PrEP (risk factors), 
PrEP adherence (drug levels) and duration, partners with known HIV status, partners on ART; 
infant outcomes (growth, birth outcomes, HIV status). 
AIM 2. To estimate the incremental cost-effectiveness of targeted PrEP compared to universal 
PrEP for women during pregnancy and postpartum, per HIV infection and disability-adjusted life-
year (DALY) averted. 
AIM 3. To qualitatively assess barriers and facilitators to uptake, adherence, acceptability, and 
feasibility in universal and targeted PrEP models at the organizational, provider, and individual 
woman level. 
 
7)  BACKGROUND 
In this study we aim to compare two models of PrEP delivery in pregnant women – universal PrEP 
(offered to all women, women self-select) or targeted PrEP (partner HIV self-test combined with 
risk score to determine whether PrEP is offered). In a cluster-RCT we will compare 10 clinics 
randomized to universal and 10 to targeted (at least 200 women per clinic) and compare HIV 
incidence among all enrolled women (including those on and not on PrEP) at 9 months postpartum 
and the proportion of women who take PrEP. We hypothesize that PrEP can be implemented in 
antenatal care clinics in way that will be acceptable and used by women at risk of HIV acquisition 
during pregnancy. Our also hypothesize is that a targeted approach will be more specific, 
effective, and cost-effective – maximizing PrEP use among pregnant women at risk and 
minimizing PrEP use for women without risk – thus providing the best balancing of effectiveness, 
cost-effectiveness, and potential for unneeded medication exposure. 
 
a) LITERATURE REVIEW 
HIV Acquisition in Pregnancy and Postpartum 
Women have persistent risk of acquiring HIV in pregnancy and postpartum and often do not 
perceive themselves to be at risk (1). In a meta- analysis of 19 studies including 22,803 person-
years, HIV incidence in pregnant/postpartum women was 3.8 per 100 p-years, 4.7/100 p-years in 
pregnancy and 2.9/100 p-years postpartum (Figure 1) (2). These HIV incidence estimates are 
particularly high given that incidence estimation was among all women (not limited to those with 
seropositive partners) and appreciable HIV infection occurred despite decreased sexual activity 
in late pregnancy and early postpartum. 
HIV 
incidence 
estimates 
in 
pregnancy/postpartum women are as 
high or higher than many ‘high risk’ 
groups, such as serodiscordant couples 
and sex workers. Given high HIV 
incidence 
in 
pregnancy/postpartum, 
there is urgent need for effective HIV 
prevention in this critical period. 
 
Pregnancy and the postpartum period 
are characterized by dramatic hormonal 
and immunologic changes, changes in genital mucosa, and epithelial disruption during delivery 
Figure 1: HIV Incidence in pregnancy (2) 

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with decreased mucosal integrity postpartum (3-6). At the same time, sexual practices change 
markedly in this period. Sexual activity declines late in pregnancy and early postpartum, and male 
partners may seek other partners, and bring HIV back to the relationship (7-9). HIV acquisition in 
pregnancy/postpartum most often occurs among women who are unaware of their partner’s HIV 
status. In Zimbabwe, among 1230 pregnant women, 239 (19%) reported their partner had been 
HIV tested, of whom 213 knew partner results, and 8 reported a HIV positive partner (0.6% of 
overall cohort). Only 1 of 14 incident HIV infections in this cohort occurred in a woman in a known 
serodiscordant partnership (10). Similarly, in a Kenyan cohort of 1310 pregnant women, only 1% 
reported knowing their partner was HIV positive, and these women had lower risk of HIV infection 
than women with unknown or reportedly HIV negative partners (11).  HIV risk may be lower among 
the select few women who report knowing their partner’s HIV-seropositive status because these 
partners are already on ART or use condoms. Many women do not know their partner’s HIV status 
or believe their partner is HIV negative (12).  
 
As prevention of mother-to-child HIV transmission (PMTCT) programs expand, women with 
chronic HIV infection are diagnosed and receive antiretrovirals (ARVs) in pregnancy, which 
decreases mother-to-child HIV transmission (MTCT) to <1% (13). In contrast, women who test 
HIV negative during pregnancy, often feel reassured that they do not have HIV or HIV risk. If these 
women acutely acquire HIV, their risk of MTCT is very high. Without ARVs, acute maternal HIV 
has a 2-fold increased risk of MTCT compared to chronic HIV maternal infection, due to higher 
viral load and absent HIV immune responses (14). With ARVs, there is >5 to 15-fold increased 
risk of MTCT among mothers with acute HIV because ARVs are started late or after transmission 
has occurred, while mothers with chronic HIV have low MTCT due to timely ARVs (Figure 2) (2). 
With global PMTCT expansion, acutely infected mothers contribute an increasing proportion of 
infant HIV infections. Over 40% of new infant 
HIV infections worldwide are estimated to be 
due to maternal HIV acquisition in pregnancy 
and postpartum (15). As a result, mothers 
may 
only 
be 
diagnosed 
when 
their 
symptomatic child is diagnosed with HIV. 
Addressing PMTCT Prong 1 (primary HIV 
prevention 
in 
women) 
during 
the 
pregnancy/postpartum period is critical for 
achieving elimination of MTCT (16). 
 
Identifying Women at Risk in Pregnancy 
Clinical prediction tools combine clinical, examination and laboratory features to identify high-risk 
groups. Using data from three cohorts of HIV serodiscordant couples, a risk score was developed 
which incorporated information regarding marital status, partner HIV RNA load, partner 
circumcision, and age (17). The risk score was useful in identifying a subset (28%) of couples 
who contributed 67% of HIV infections. Among women at risk for HIV, data from the VOICE study, 
including variables such as age, STIs, and partner characteristics or partner support, were used 
to develop a score that identified 36% of women who contributed 66% of infections (18, 19). Both 
of these scores (i.e., for serodiscordant couples and for women at risk) have been pilots as 
standardized risk assessment tools to guide initiation of PrEP for HIV prevention.   
 
For pregnant women, a risk scoring tool has also been developed to help identify those at greater 
HIV risk (20).  This tool, developed and validated using data from 1,304 women living in Kenya, 
includes the following variables: Partner HIV status unknown, number of lifetime sexual partners, 
and history of syphilis.  Women with a score >6 made up 16% of the population but accounted for 
56% of HIV acquisition events.   
Figure 2: MTCT in acute vs chronic maternal HIV (2) 

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For pregnant women, risk assessment alone may not identify all women at risk of HIV acquisition 
during pregnancy. Partner self-testing is a strategy that has been successfully used to identify 
previously unknown HIV-positive partners of pregnant women in Western Kenya. A recent study 
demonstrated high uptake of partner-testing when multiple self-tests are given distributed to 
women in antenatal care clinics along with instructions about how to use the tests and counseling 
about using discretion when determining whether to offer a self-test to sexual partners (21). Of 
women enrolled in the study, 91% (of 58 participants) reported distributing the self-test to their 
primary sexual partner and being present when their partner used the test (21). The strategy was 
also found safe for women who participated. This study did exclude a small number of women 
attending clinics who believed violence could occur from distributing the self-tests, who would 
likely benefit from PrEP given the risk of violence in their relationship. Including a self-testing 
intervention that increases partner self-testing will allow this study to identify women who may be 
categorized as low risk in the risk assessment but have a previously unknown HIV positive 
partner. 
 
Pre-Exposure Prophylaxis (PrEP) and Women 
As new studies examine topical microbicides and long-acting PrEP formulations for HIV 
prevention (22-25), oral PrEP remains a leading candidate for pregnancy given substantial 
evidence of efficacy, safety, and lack of potential for genital tract irritation that could precipitate 
preterm birth or ascending infection in pregnancy (26). Increasing partner ART use is another 
highly effective and complementary approach (27). Condoms, though effective, have not been 
widely adopted by pregnant/postpartum women, who are usually married and find it difficult to 
negotiate for condom use in the setting of a presumably stable relationship. 
 
In the Partners PrEP study, sub-group analyses demonstrated high protective efficacy of oral TDF 
(71%, p<0.002) or TDF/FTC (86%, p<0.005) in women in serodisordant partnerships (28). 
Subsequent analyses of high-risk women in Partners PrEP (>5% incidence in placebo arm), 
demonstrated similar high PrEP efficacy (64-84%) (29). An adherence substudy of Partners PrEP 
found that PrEP efficacy greater than 90% with adherence over 80% by unannounced pill count 
or electronic pill bottle monitoring (30). Some enthusiasm for PrEP use in women faltered after 
two large RCTs (FEM PrEP and VOICE) failed to demonstrate efficacy (31, 32). Failure of PrEP 
in these trials was not due to lack of 
regimen 
efficacy 
but 
to 
non-
adherence (33-35) (Figure 3). In 
both RCTs high-risk young women 
were receiving an as-yet unproven 
intervention or a placebo (36-38). In 
these 
studies, 
drug 
levels 
demonstrated low adherence, which 
differed 
from 
self-reported 
adherence.  
 
Emerging qualitative data provides insights on reasons for low adherence in some studies (37, 
39). In FEM-PrEP desire to answer research questions and belief that PrEP could decrease HIV 
incidence facilitated adherence (34, 38, 40). Side-effects influenced non-adherence, while having 
an HIV positive partner increased adherence in the Botswana TDF-2 trial (41). Analogously, 
external partnerships were associated with non-adherence in Partners PrEP, while partner 
support and desire to preserve the partnership facilitated adherence (30, 42, 43). Concerns about 
efficacy and social stigma were noted as reasons for non-adherence in VOICE (44). In an 
unblinded setting with known effectiveness, PrEP motivation may be higher than in placebo-
Figure 3: AVAC summary of PrEP efficacy and adherence 

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controlled trials and this has been shown in demonstration projects (see B7) (37). In the context 
of pregnancy, women may have higher adherence than outside of pregnancy because of 
motivation to protect themselves and their infant and health system support.  
 
In ‘real-life’ demonstration projects, participants have had high adherence and few HIV infections. 
As of June 2015, AVAC listed 37 demonstration projects on PrEP globally, including 14 that 
involve women, none of which is focused on PrEP in pregnancy. PrEP demonstration projects 
involving women have shown good adherence (>75%) in random drug level testing (Table 1). The 
Partners Demonstration project, which used PrEP as a bridge approach to ART in serodiscordant 
couples with a high risk score, observed an estimated 96% reduction in HIV transmission (45). 
The bridge approach provides dual protection to newly diagnosed serodiscordant couples with 
PrEP use until viral suppression occurs in the partner on ART. The bridge approach is ideal for 
the MCH setting, in which HIV negative women accessing pregnancy care can be the gateway to 
expedite HIV diagnosis and treatment of male partner HIV infection, which otherwise occurs late. 
For pregnant women in newly diagnosed serodiscordant couples PrEP will be essential for 
protection until partner ART is fully effective; however, prompt partner ART would shorten duration 
of PrEP with discontinuation when partners are suppressed. Sustained partner ART would 
decrease need for PrEP in subsequent pregnancies. 
 
 
Safety of PrEP in Pregnancy 
Data on PrEP safety can be extrapolated a number of studies including PMTCT and ART 
research, which includes TDF and FTC use in pregnancy (48-53). In infants of HIV-infected 
women receiving TDF and FTC there has been limited signal of fetal risk – the lack of increased 
risk in this group with concurrent exposure to other ARVs and maternal HIV is reassuring (51). 
The Antiretroviral Pregnancy Registry database includes data from 1982 infants exposed to TDF 
in first trimester in the US, without evidence of congenital anomalies (54). There has been 
evidence of small growth deficits and decreased neonatal bone mineral content (5.3 gm lower) 
among infants receiving PMTCT-TDF, but clinical relevance of these findings is unknown (53, 55). 
There is also a growing body of evidence from studies of conception among serodiscordant 
couples and PrEP RCTs that show no adverse events or difference in outcomes among infants 
born to mothers using PrEP  at conception of during pregnancy (56-60). 
 
In the Partners PrEP trial, women who became pregnant on PrEP had no evidence of adverse 
infant outcomes or long-term growth (56). Among 431 women who became pregnant, pregnancy 
outcomes were similar between placebo and PrEP arms. Among 167 infants with serial growth 
assessment, there were no differences in weight or height z-scores or head circumference during 
infancy between infants with in utero PrEP vs. placebo, However, women discontinued PrEP 
when pregnancy was diagnosed resulting in limited pregnancy time on PrEP. While safety data 
Table 1. PrEP demonstration projects in women show high effectiveness and adherence (45-47)  
Setting, study 
Number enrolled/ 
screened (%) 
PrEP 
adherence 
(method) 
# HIV infections 
# 
Infections 
expected 
without PrEP 
TDF2, Botswana; open 
label extension men and 
women 
229/335 (86%) 
93% TFV detected; 
87% TDF in women 
No HIV infections 
during 1 year 
5-6 
Partners Demonstration, 
Uganda, 
Kenya; 
Discordant couples with 
high risk score 
1013 couples 
96% uptake 
>80% 
(TFV 
detection) 
4 infections/1700 p-
years 
f/u 
(95% 
reduction) 
83 
ADAPT, South Africa  
191 
women, 
different 
PrEP 
schedules  
75% with daily PrEP  
(TFV/FTC levels) 
NA 
NA 

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are generally reassuring, there is need for continued accrual of data on growth and pregnancy 
outcomes in PrEP research studies and demonstration projects. Breastfeeding is not a 
contraindication for maternal PrEP as minimal drug is likely to pass to infants, however, there are 
scant data from infants exposed to PrEP during lactation (61-63). 
 
During the past decade, legal, ethical, and policy deliberations have informed a vision to 
accelerate access to effective interventions for pregnant women and their children (64). Pregnant 
women currently receive several preventive interventions, including anti-malarials, PMTCT, and 
TB-prevention (if HIV infected). For some interventions (malaria prophylaxis and early PMTCT), 
pregnancy implementation was informed by RCTs conducted in pregnant women and their infants 
with most benefits for the infant. For other interventions (isoniazid in HIV-infected women), 
efficacy evidence was extrapolated from non-pregnant adult studies and safety data was obtained 
from observational studies. The level of safety evidence for PrEP (no animal fetal toxicity, 
thousands of infants exposed to TDF/FTC PMTCT, hundreds to PrEP in early pregnancy) led 
WHO, CDC, and the Kenyan Ministry of Health (MoH) to permit PrEP use in pregnancy (61, 65, 
66). WHO early-release guidelines (Sept 2015) recommend PrEP for anyone at ‘substantial HIV 
risk’, and noted need for research on PrEP in pregnancy and lactation (66), and updated WHO 
guidance from 2017 recommended the use of PrEP in pregnancy and lactation, although 
important safety and implementation gaps remain. Implementation science studies can provide a 
framework to increase accrual of safety and effectiveness data of PrEP in pregnancy while 
refining programmatic strategies. 
 
8) RATIONALE 
In a region with 15-20% HIV prevalence, an estimated 20% of HIV-uninfected women could have 
HIV exposures in pregnancy. In a theoretical scenario of perfect PrEP coverage, all women at 
risk receive PrEP while no women not at HIV risk receive PrEP (Figure 4). With mandatory PrEP 
given to all women (similar to the approaches 
used for malaria prophylaxis), all women at risk 
would be covered but many women not at risk 
receive unnecessary PrEP. Our premise is that a 
targeted PrEP model may be closer to perfect 
coverage than a universal offer/self-select model. 
Implementing targeted PrEP through strategies 
that include facilitation of partner testing with self-
tests could add HIV prevention benefit by 
increasing partner HIV diagnosis and treatment 
similar to the initiation of PrEP among pregnant 
women. By implementing these strategies and 
measuring uptake, process, and HIV incidence, we can inform the best health systems model for 
PrEP delivery in pregnancy. 
 
9) HYPOTHESIS & STUDY QUESTIONS: 
In this study, we hypothesize that PrEP can be implemented in antenatal care clinics in Kenya 
such that PrEP will be acceptable and used by women at risk of HIV acquisition during pregnancy.  
a) BROAD OBJECTIVES 
The broad objective of this study is to determine the best model for optimized PrEP delivery in 
pregnancy by using existing highly accessed MCH systems as a platform for efficiently delivering 
PrEP to pregnant women. 
 
Figure 4: Potential PrEP in pregnancy delivery 
strategies 
 

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13
b) SPECIFIC OBJECTIVES 
AIM 1a. In a cluster RCT among HIV-uninfected pregnant women, to compare universal PrEP 
(offered to all; women self-select PrEP) to targeted PrEP (offered to women with a high risk score 
incorporating available partner HIV self-test data) for outcomes reflecting the balance of PrEP 
effectiveness avoiding unnecessary PrEP exposure to women at low or no risk of HIV: HIV 
incidence at 9 months postpartum among all women (including those who did and did not receive 
PrEP) and proportion of women exposed to PrEP. 
 
Hypothesis: Because of better matching of PrEP and targeted, specific PrEP counseling, 
use to HIV risk, targeted PrEP will result in lower HIV incidence and optimized proportion 
of women on PrEP. 
 
AIM 1b. To compare universal versus targeted PrEP arms for proportion of all women on PrEP, 
proportion of women ‘appropriately’ on PrEP (based on risk factors), PrEP adherence (drug 
levels), PrEP duration, partners with HIV status, partners on ART, and infant birthweight, preterm 
birth, and growth curves; to compare infant outcomes in PrEP exposed infants vs. unexposed; 
and to determine cofactors of maternal HIV incidence overall and stratified by trial arm.  
 
Hypotheses: Targeted PrEP will result in more ‘appropriate’ PrEP use, better adherence, 
shorter PrEP duration (stop after partner viral suppression), more partners on ART, and 
similar infant outcomes. 
 
AIM 2. To estimate the incremental cost-effectiveness of targeted PrEP compared to universal 
PrEP for women during pregnancy and in the postpartum period, per incident HIV infection and 
disability adjusted life year (DALY) averted.  
 
Hypothesis: Targeting PrEP to women at highest risk of HIV acquisition will be more cost-
effective than universal PrEP provision. 
 
AIM 3. To qualitatively assess barriers and facilitators to adherence, acceptability, feasibility and 
potential adaptations in all 3 RCT arms at the organizational, provider, and individual woman 
level.  
 
Hypothesis: Both models will be acceptable to women and providers; organizations will 
prefer targeted PrEP. 
 
10) STUDY DESIGN AND METHODOLOGY 
This is a mixed-methods cluster randomized study. The study has two components which will be 
rolled out with component 2 beginning once enrollment in the cluster RCT is underway: 
 
Component 1: This study is a cluster RCT, with economic and quantitative data collection, 
which will inform the identification of a cost-effective PrEP delivery approach for pregnant 
women. 
 
Component 2: Qualitative evaluation assessing barriers and facilitators to PrEP uptake 
at organizational, facility and individual women levels. 
a) STUDY AREA DESCRIPTION:  
The proposed study will be conducted in twenty health care facilities in Kisumu, Homa Bay, and/or 
Siaya Counties, Kenya. Facilities will be selected based on the HIV seroprevelance and ANC 
volume. Facilities will be selected for inclusion if they are located in a region with 15-20% HIV 
seroprevalence, have approximately 500+ HIV-negative clients receiving antenatal care at the 
facility per year, and offer postnatal care services including infant immunizations. If possible, 
facilities will also be excluded if they do not have an onsite Comprehensive Care Clinic (CCC) to 
ensure appropriate linkage to care for male partners identified as HIV-positive through partner 
testing. Facilities will also be excluded if they do not have the capability to conduct antenatal 

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PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
14
syphilis testing, either via RPR/VDRL or dual HIV/Syphilis test depending on MoH guidance. An 
overview of all enrollment procedures is shown in Figure 3 and the follow up visit schedule is 
included in Figure 4. 
 
 

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15
 
Figure 3: Overview of study procedures 
 
 

 
COMPONENT 1: CLUSTER-RANDOMIZED CONTROL TRIAL 
a) STUDY DESIGN 
 
We will select 20 clinics from Western Kenya. Ten clinics will be randomized to universal PrEP 
and ten to targeted PrEP (Table 2). To ensure balance between study arms in terms of key site 
characteristics, sites will be categorized on HIV prevalence and ANC volume, and restricted 
randomization will be used for site (cluster) allocation to intervention and control arms (67). 
Specifically, all possible randomizations that evenly distribute sites on these two specified factors 
(HIV prevalence, ANC volume) into 2 study arms will be generated, and one combination will be 
selected using a random number generator. Randomization and allocation will be performed by 
Dr. Richardson, who has no knowledge of sites other than the variables included in the restricted 
randomization process. 
Table 2: Difference between Universal and Targeted PrEP arms 
HIV self-
test for 
partners 
Risk score used 
to guide PrEP 
offer 
Universal PrEP 
Counseling 
Enhanced PrEP counseling that 
communicates individual risk 
Data on 
partner HIV 
status 
Universal 
X 
 
Targeted 
X 
X 
X 
X 
 
b) STUDY POPULATIONS 
At each clinic, enrollment will occur over an approximately 10-month period (~20 HIV negative 
women enrolled per month) with a ~1-year period of follow-up to 9 months postpartum (time of 
routine measles immunizations). Eligibility for enrollment will include age ≥15 years, pregnancy, 
and tuberculosis negative, plans to reside in area for at least one year postpartum, plans to 
receive postnatal and infant care at the study facility, and are not currently enrolled in any other 
studies.  
c) SAMPLE SIZE DETERMINATION AND FORMULAS USED 
Restricted randomization 
will be used to ensure 
that the two arms of the 
trial have balance in 
terms of prevalence of 
HIV, ANC volume, and 
rates 
of 
partner 
disclosure at included 
clinics (based on data 
from our prior CHIME 
evaluation of 141 MCH 
clinics). 
Assuming 
a 
coefficient of variation (k) of 0.2, the study has 80% power to detect a 2-fold difference in HIV 
incidence (between 4% and 2%) with 10 clinics per cluster and at least 200 women per cluster 
(Table 3). If targeted PrEP resulted in much better performance (67% decrease rather than 50%), 
6 clinics per cluster would be sufficient. Deriving our sample size from HIV incidence difference 
is conservative and will enable ample statistical power to detect effects on other outcomes (such 
as proportion on PrEP and partner characteristics). Table 4 outlines implications of potential RCT 
outcomes illustrating the value of data regarding the two PrEP delivery models in scenarios with 
Table 3: Sample size power calculations 
k 
 
HIV 
incidence 
universal 
HIV 
incidence 
targeted 
# women per 
clinic 
#clinics 
per arm 
Total 
# 
women 
0.2 
4% 
2% 
50 
27 
2700 
0.2 
4% 
2% 
100 
15 
3000 
0.2 
4% 
2% 
150 
12 
3600 
0.2 
4% 
2% 
200 
10 
4000 
0.2 
4% 
2% 
250 
9 
4500 
0.2 
4% 
2% 
300 
8 
4800 
0.2 
4% 
1.3% 
200 
6 
2400 
 

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or without a significant difference in HIV incidence. We anticipate that the targeted arm may have 
20% of women receiving PrEP (based on MSS risk score estimates) while the universal PrEP arm 
may have 5-25% of women requesting PrEP, however, these are speculative estimates. The 
study may not detect a difference in HIV incidence between PrEP delivery models because of 
appropriate PrEP uptake and use in both.  However, as outlined in the contingency table (Table 
4), for all scenarios the RCT would yield important data on viable approaches for delivering PrEP 
in pregnancy and likely reveal a superior model in terms of the balance of effectiveness, safety, 
acceptability, feasibility, and cost-effectiveness.   
 
Table 4: Contingency Table Demonstrating Implications of Potential RCT Outcomes 
Potential HIV 
incidence outcome 
Other potential results 
Impact on programs 
policy in high HIV 
prevalence regions 
Programmatically 
relevant data from 
study 
Hypothesis 
Proved 
Targeted better 
Fewer women on PrEP, 
cost-effective, safe 
Implement targeted PrEP 
Data to model and 
compare impact 
on HIV 
transmission, cost, 
and scale up.  
 
HIV incidence/CI, 
cost-effectiveness, 
safety, feasibility, 
process 
Hypothesis 
opposed 
Universal better 
Fewer women on PrEP, 
cost-effective, safe 
Implement universal 
PrEP 
Mixed 
benefits 
Universal better 
Universal too many 
women on PrEP not cost 
effective 
Refine universal strategy 
to decrease cost and 
unnecessary PrEP 
exposure 
Mixed 
findings 
Incidence low in 
both, no difference 
Targeted more cost-
effective results in few 
on PrEP 
Implement targeted PrEP 
HIV incidence 
estimate/CI, cost-
effectiveness, 
safety, process 
University more cost-
effective and fewer 
women on PrEP 
Implement universal 
PrEP 
 
d) RECRUITMENT PROCEDURES 
Following routine antenatal HIV testing during an antenatal care (ANC) visit, the study nurse will 
recruit HIV seronegative women and determine eligibility. Following screening consent, a brief 
screening form will capture age, gestational age, and eligibility characteristics. For women 
identified as eligible for the study, we will obtain written informed consent for participation and the 
women will be enrolled. The informed consent will emphasize that participation in this study is 
completely voluntary and will not affect their ability to receive antenatal, delivery or postnatal care 
at this or any other facility. This study will utilize two versions of the consent form, one used in 
universal PrEP counseling facilities and one used in targeted PrEP counseling facilities to 
explicitly describe the facility-specific procedures participants will undergo. A screening & 
enrollment log will capture the proportion of women screened, deemed to be eligible, and 
eventually enrolled, to determine the ratios of clinic attendees:screened and eligible:enrolled, 
which will aid in estimates of generalizability. We will also collect data from each facility on the 
total number of ANC attendees per month. 
e) STUDY PROCEDURES  
Enrollment data collection:  
Enrollment for all study participants will include a detailed questionnaire, including assessment of 
demographics, mental health, social support systems, drug and alcohol use, risk perception, risk 
score, partner HIV status, education, prior obstetric history, education, marital status and income. 
Data from the MCH card will be abstracted, including confirmation of HIV results as well as results 

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18
of antenatal syphilis testing. As is standard of care in MCH clinics, in both trial arms a referral 
letter encouraging HIV testing will be provided for women to give to partners and clinic-based HIV 
testing will be available for any male partner seeking testing. 
 
Universal PrEP Clinics, Enrollment Visit (N=10):  
Counseling at universal sites, will use a standardized counseling script to state that PrEP is 
available for women at risk for HIV, explain that HIV prevalence in the region is high, and will note 
that women with HIV positive partners or who don’t know their partner’s status may be at risk. 
Counseling will specify that women may have their own reasons to feel at risk or to want PrEP. 
Following standardized counseling, women will select PrEP at the same visit or will be allowed to 
deliberate on the decision and come back at the next visit with a decision. Women will be informed 
that it is advisable to use PrEP if they know their partner is HIV positive or if they do not know 
their partner’s status and will be encouraged to bring untested partners to clinic if status is 
unknown. Women who select PrEP will be welcome to involve their partners in counseling 
regarding PrEP and those with recently diagnosed HIV positive male partners (via the clinic 
referral system) will linked to care following the facilities standard linkage to care procedures. 
 
Targeted PrEP Clinics, Enrollment Visit 
(N=10):  
Following 
informed 
consent 
and 
enrollment data collection, the targeted 
PrEP clinics will provide two inter-
related innovations: risk assessment-
informed PrEP counselling and partner 
HIV Self-Test counselling.  
 
Risk 
Assessment 
and 
PrEP 
Counselling: 
The 
results 
of 
the 
PrEP 
risk 
assessment will be used to guide PrEP 
counselling and the offer of proceeding 
to the PrEP card-based eligibility 
assessment. Participants who score 
greater than 6 on the risk assessment 
will receive additional PrEP counselling 
that includes information about specific 
risk factors tailored to the participant 
(Table 5). These participants will then 
elect whether to proceed to the PrEP 
card eligibility assessment. Women 
who score 6 or less will not be individually counseled about PrEP. However, if they ask for PrEP 
they will enter the clinical assessment pathway and can be prescribed PrEP if found to be clinically 
eligible. We anticipate that participants with known HIV-positive partners will self-select for the 
PrEP eligibility assessment. Women who request PrEP despite not meeting the targeted PrEP 
criteria will be identified and approached for in-depth interviews to better understand their choices 
in Component 2 of the study. 
 
Partner HIV Self-Testing: 
Women will be offered HIV self-test kits to take to their partner for HIV testing. This will be used 
to provide further information on partner HIV-status: either initiate women in previously 
unidentified serodiscordant couples on PrEP at subsequent study visits, or to discontinue PrEP 
Table 5: Risk Score Card for HIV acquisition 
in pregnancy 
Risk factor 
Value per factor 
Score 
No. of lifetime sexual partner  
 
1 point per sexual partner 
Enter at least 1  
 
Male partner HIV status 
 
Male partner HIV status 
known or no male partner 
0 
 
 
Male partner HIV status 
unknown 
6 
 
Syphilis 
 
nonreactive  
0 
 
 
reactive 
5 
 
Total risk score 
 
 

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for women who are able to confirm their partner’s HIV-negative status. All women will be offered 
two self-tests so that they can take the test at the same time as their partner, if they chose to do 
so. If a woman does not receive the self-test counseling during the first study visit, they will receive 
self-testing counseling during their next study visit. 
 
Trained program staff will counsel study participants in the use of self-testing kits including. First, 
they will assess whether the women believe violence could occur when providing the self-testing 
kit to their partner.  If a woman declines the self-testing kit or fears violence, they will not receive 
the testing kit and this information will be included in the targeted PrEP administration algorithm.. 
Women who are comfortable providing a self-test to their sexual partner(s) will be instructed by 
study staff on the use of an oral fluid based rapid HIV test (OraQuick Rapid HIV-1/2 antibody test, 
OraSure Technologies, Bethlehem, PA, USA). Study staff will demonstrate how to use the oral 
self-testing including opening the package, collection of fluid samples, waiting 20-minutes before 
reading the test, and reading test results. Women will be counseled that it is entirely their choice 
as to whether to offer a self-test to their partner. Participants will be provided with a one-page 
summary document that describes the self-testing methods and provided information on receiving 
confirmation testing and linkages to care in the event their partner(s) test positive. Women will be 
asked to return to the clinic at their next antenatal care visit to report on the results of their partner’s 
self-test. 
 
DBS collection for confirmatory HIV testing 
DBS will be collected using a finger stick from all participants at enrollment and stored for future 
confirmatory HIV testing should a client seroconvert while in the study. Blood from the finger stick 
will be placed onto five circles on labeled DBS card and allowed to dry between 2-hours and 
overnight before storing in a low gas permeability plastic bag with a humidity indicator and stored 
in a freezer between -20 and -80 degrees at CDC KEMRI laboratory for future assessment. 
 
 
Targeted PrEP Clinic, Visit 2 (next scheduled antenatal care visit):  
During the second study visit, participants will report the results of their partner’s self-test. 
Partners who are identified as HIV-positive through the self-testing will be referred for HIV 
confirmatory testing and treatment at the nearest CCC, ideally located in the same facility if 
possible. Women who report that their partners refused the self-test, did not share the results of 
their self-test, or were unable to take the test will receive additional PrEP counseling during the 
second study visit, using the same standardized script as high-risk women identified in the first 
study visit. Women who do not return for the scheduled study visits or to obtain test results will be 
contacted by study staff.  
 
PrEP Initiation, Universal and Targeted Arms  
Women who elect to start PrEP will receive point of care hepatitis B (HBsAg) and creatinine (Cr) 
testing.  Women who are HBsAg positive or who have estimated creatinine clearance (CrCl) 50 
ml/min will be medically ineligible to initiate PrEP per  NASCOP guidelines below. 
 
PrEP Medications 
PrEP medication and dosing will follow the 2016 Guidelines on Use of Antiretroviral Drugs for 
Treating and Preventing HIV Infections in Kenya using the preferred oral TDF/FTC 
(300mg/200mg) once per day (66). 
 
Follow Up Visits, Universal and Targeted Arms 
All participants:  

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20
Women will follow the MCH schedule for their routine ANC and postpartum/immunization clinic 
visits. Study visits will be performed at all subsequent ANC visits and the 6-week, 14-week, 6-
month, and 9-month postpartum visits, the visit schedule is outlined in table 4. All women will 
receive HIV rapid test at follow up visits. The study visits are designed to meet MOH guidelines 
for PrEP users to receive HIV testing and adherence counselling every three months. Data on 
risk assessment, partnership characteristics, sexual activity and contraception use, and 
sociobehavioral factors may be collected at all study visits. Additional data will be collected on 
infant growth, birth weight and estimated gestation at birth or diagnosed preterm birth (for women 
who deliver at facilities) and serial growth will be abstracted from MCH cards; z-scores will be 
calculated using WHO Anthro-Plus. Data on birth outcomes (stillbirth, miscarriage, mortality, 
congenital anomalies) and birth length will be abstracted from MCH card or interview. We may 
also collect a small amount of hair from participants and their babies (50 strands).  
 
Follow up Adherence Counseling at both universal and targeting PrEP counseling sites:  
Among women who start PrEP, instructions on use of drug and counseling to optimize adherence 
will be identical between targeted and universal clinics. Experienced counselors from Partners 
PrEP demonstration projects will provide training and feedback to nurses at study sites prior to 
initiation of RCT. Maternal creatinine will be obtained annually and CrCl estimated. PrEP will be 
discontinued if estimated CrCl is 50 ml/min. Any drug-related reactions or adverse events will be 
documented and summarized in weekly meetings (pooled). 
 
PrEP Adherence:  
We will use a combination of self-report and tenofovir-diphosphate (TFV-DP) and emtricitabine-
triphosphate (FTC-TP) in red blood cells from dried blood spots to assess PrEP adherence. DBS 
will be collected from all women on PrEP at all subsequent antenatal visits and at weeks 6, 14, 
and 6 and 9 months postpartum (Table 6). DBS will be collected using a finger stick. Blood from 
the finger stick will be placed onto five circles on labeled DBS card and allowed to dry between 
2-hours and overnight before storing in a low gas permeability plastic bag with a humidity indicator 
and stored in a freezer between -20 and -80 degrees at CDC KEMRI laboratory for future 
assessment of TFV-DP and FTC-TP in red blood cells (Standard Operating Procedure from the 
Anderson Lab attached).  
 
We may also collect a small amount of hair from participants and their babies (approximately 50 
strand) to measure long-term adherence to PrEP at the same follow up time points as DBS. This 
will let us know whether a mother has been taking PrEP for the past few months. Hair will be sent 
to the University of California, San Francisco (UCSF) Hair Analytical Laboratory to perform this 
assay as it is one of the only labs available who perform this test.  This test is not yet available in 
Kenya. 
 
These measures of adherence will be helpful in analyzing short-term (DBS, currently 
approved) and long-term (hair) PrEP adherence. 
 
 
Seroconversion 
Women who seroconvert will be managed according to NASCOP guidelines. Point-of-care PCR 
testing may be used where available to investigate potential seroconversions. 
PrEP Discontinuation:  
PrEP will be discontinued if (1) participant seroconverts during the study; (2) participants risk 
status changes (e.g. a partner who previously refused or was unable to take the self-test tests 
negative); (3) renal dysfunction with creatinine clearance <50ml/min; (4) client requests to stop; 
(5) sustained non-adherence; or (6) participant reports their HIV-positive partner has achieved 

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21
sustained viral suppression. Reasons for discontinuation will be documented, participants will be 
requested to return for 6-week, 6-month, and 9-month postpartum HIV testing, and counseled on 
other risk reduction strategies. If a participant seroconverts during the study period, they will be 
linked with care at the nearest CCC. 
 
Compensation: 
Compensation schedule will be dependent on number of required study visits. All study 
participants will receive Ksh 300 at all study visits to compensate for their time and transportation 
expenses to participate in the study.  
 
Table 6: Study Visits and specimen collection schedule 
Pregnancy 
Postpartum 
Repeated ANC Visits 
Wk 6 Wk 14 
Mo 6 
Mo 9 
Routine MCH Schedule 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Visits- All Facilities 
X 
X 
X 
Consent for the study 
X 
CRFs administered 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV test for all participants 
X 
* 
* 
* 
X 
X 
X 
X 
X 
DBS collection for all 
participants for confirmatory 
HIV testing 
X 
 
 
 
 
 
 
 
 
DBS Collect for all participants 
on PrEP 
X 
X 
X 
X 
X 
X 
X 
X 
MCH Card data abstraction 
X 
X 
X 
X 
X 
X 
X 
Partner referral letter from 
MCH 
X 
Birth outcomes, growth 
X 
X 
X 
X 
Decision re: PrEP 
X 
X 
X 
X 
X 
X 
X 
X 
*HIV Test administered at one-month follow up visit for all participants 
 
 

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Health Economic Evaluation Activities:  
The following data will be collected for the CEA: (1) estimating the cost of the intervention; and 
(2) the number of participants initiated on PrEP, HIV incidence at 6-weeks and 9-months 
postpartum, and PrEP adherence, which will be derived from the study. In addition, the base case 
costs of facility-based care will be estimated and sensitivity analyses will be conducted. Cost data 
will include: (1) Conversion rate of local currency (Kenyan Shilling) to U.S. dollars at 6-month 
intervals over the life of the project; (2) costs of all commodities used in the intervention; (3) labor 
costs for intervention workers; (4) average time clients spent with intervention including 
transportation / staff time / time for referrals; (5) local wages of target population; (6) rent; (7) 
maintenance; (8) volunteer activities; (9) user fees; (10) value of donated goods and services; 
and (11) other relevant costs, including training of providers and mobile van, fuel costs for 
community-based delivery.  
Time and motion studies will be conducted to determine the time and resources necessary to 
provide PrEP counseling in pregnancy, monitoring, and resupply. Time and motion studies will be 
conducted over a two-week period at each site during study initiation and again when the 
intervention is running at full capacity. An experienced research assistant will collect data on the 
time required to complete each step of the intervention. Results from initial time and motion 
studies will be shared with the teams and strategies for efficiency shared to reduce the time 
needed for the intervention. Observing multiple visits will allow estimation of the average time 
taken for each step; the time take for research purposes (e.g. data collection) will be noted 
separately from the estimated time needed for clinical services. Interviews with study staff will 
also quantify the effort required for each step of community-based HIV care. Through time and 
motion studies the number of participants who could be supported by a clinic will be estimated.  
A discount rate of 3% will be used with sensitivity analysis of 0% to 5%. Additionally, for analysis 
taking the societal perspective we shall also include the cost to clients in terms of lost time, wages, 
childcare, and other relevant opportunity costs. To assess these issues, we will ask participants 
what expenses and opportunity costs they incurred to receive the interventions in the surveys 
already planned for the project. We will also collect data on the average cost of medical care in 
Kenya associated with pregnancy, postpartum, HIV infection and AIDS through literature review. 
Cost data will be used with study results and mathematical models of HIV transmission to estimate 
the population level effectiveness and cost-effectiveness of the intervention. The models will use 
de-identified study data. 
Future contact with subjects 
Participants will be asked if they would be willing to be contacted in the future about participating 
in another study about PrEP after exiting from PrIMA. Participants who agree to be contacted will 
sign a consent addendum. Women will be re-contacted via phone. 
 
f) LABORATORY METHODS 
Hepatitis B (HBSAg) and Creatinine (Cr) testing: All participants in universal and targeted PrEP 
facilities who elect to use PrEP will be tested for Hepatitis B and creatinine levels using point of 
care tests.   
PrEP Adherence Methods: A subset of DBS specimens (5-10%; estimated total 440 specimens) 
from all women on PrEP will be randomly selected for TFV-DP and FTC-TP levels. DBS TFV 
levels will be conducted at Dr. Peter Anderson’s laboratory (using liquid chromatography/tandem 
mass spectrometry) at the University of Colorado. The presence of detectable FTC-TP will be a 
proxy for recent adherence in the preceding 48 hours. Given a half-life of 17 days for TFV-DP in 
DBS, levels of TFV-DP per punch can approximate cumulative dosing (<349 fmol/punch, <2 
tab/week; 350-699 fmol/punch 2-3 tabs/week, 700-1249 fmol/punch 4-6 tabs/week, and 1250 

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23
fmol/punch (daily dosing) (69). The levels used in this analysis will be updated, as appropriate, if 
evidence emerges that other levels are more predictive.  
 
g) DATA COLLECTION INSTRUMENTS 
Paper copies of data collection tools for surveys are submitted with this application for human 
subjects review. They include: 
 
Screening Form 
o Age 
o Gestational Age 
o HIV-status 
o Plans to stay in the area for at least a year 
 
Enrollment questionnaire, including: 
o Demographic information (education, obstetric history, marital status, income) 
o Risk Perception Assessment  
o Risk Score Card 
o Partner HIV status 
o Self-Efficacy 
o Social Support and Mental Health 
o IPV assessment 
o Partner Characteristic 
o PrEP attitudes and acceptability (HIV/PrEP Stigma Assessment) 
 
ANC Card Abstraction form 
o HIV status 
o Gestational Age 
o Maternal Age 
o Syphilis 
o TB status 
 
PrEP Counseling Outcomes form 
 
Partner self-test results  
 
MCH Card Abstraction Form, including: 
o Infant length 
o Birth weight 
o Gestational age at birth 
o Serial growth  
o Stillbirth 
o Neonatal mortality 
o Miscarriage 
o Infant congenital abnormality 
 
Infant, neonatal and maternal mortality (including WHO verbal autopsy instrument) 
 
Maternal follow up 
o HIV-status 6-weeks postpartum 
o 14 weeks postpartum 
o 6-months postpartum 
o HIV-status 9 months postpartum 
o Hepatitis B Antigen test result 
o Creatinine level test result 
o Sexual activity and contraceptive use 
 
PrEP Adherence 
o Pill Count data 

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24
o Self-Assessment  
o DBS collection methods 
o Discontinuation Documentation 
 
Health Economic Evaluation 
o Incremental costs at facility level, including costs incurred and averted 
o Costs incurred at participant level interview form 
o Time and motion data collection form 
h) VARIABLES: Outcomes, indicators, and source documents 
Table 7: Variables: Outcomes, Indicators, and source documents 
Indicator 
Source 
Primary Outcomes 
Maternal HIV, 6-weeks pp 
HIV Rapid Test 
Study Visit, maternal 
specimens 
Maternal HIV, 9-months pp 
HIV Rapid Test 
Study Visit, maternal 
specimens 
PrEP Exposure 
Number received PrEP/All Participants 
PrEP Counseling outcome 
form 
Secondary Outcomes 
Appropriate PrEP Use 
Scored 1 for high risk women using PrEP and 
low risk women not using PrEP; 0 for high risk 
women NOT on PrEP and low risk women using 
PrEP 
PrEP Counseling outcome 
form 
PrEP Adherence 
TFV/DP and FTC test results from 440 
randomly selected specimens  
Dried Blood Spots 
PrEP Duration 
Number of days on PrEP 
Self-report captured on 
adherence counseling form; 
pharmacy records 
Partners HIV Self-test 
Partners Self-test result 
self-report 
Infant Birth weight 
Birth weight 
MCH card 
Preterm Birth 
Estimated gestational age at birth 
MCH card 
Infant Growth 
Infant height, weight, and age for WAZ, HAZ, 
and WHZ Z-scores 
MCH card 
Cost Effectiveness Analysis Outcomes 
Costs Incurred 
Costs for startup activities, service delivery, lab 
monitoring, PrEP support, PrEP 
Cost Collection form 
Time and Motion 
Time for counseling, clinical procedures and 
PrEP counseling 
Team and motion data 
collection form 
Other Variables 
Age 
Maternal Age 
Self-report; or MCH Card 
Age Discordance 
Age Difference between participant and partner 
self-report 
Partner HIV Status  
Positive, Negative, Unknown 
Enrollment questionnaire 
Sexual Behavior 
Number of partners 
self-report 
Hepatitis B 
Hepatitis B Antigen Negative 
POC test at enrollment 
Maternal Syphilis 
RPR Test results (nonreactive/reactive) 
MCH card; POC test 
TB Status 
TB test results 
MCH card 
 
 

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j) QUALITY ASSURANCE PROCEDURES 
 
Clinical Care: the study will adhere to Government of Kenya (GoK) guidelines for the care of 
pregnant/postpartum women and their infants; no clinical care will be provided by study staff. Data 
collected as part of the study will be abstracted from the mother’s “Mother and Child Health 
booklet” and patient file, as well as the MCH clinic’s medical records, in addition to questionnaires 
administered to participants. Counseling and testing for HIV will be performed in accordance with 
government-approved MCH guidelines. Study participants will receive their PrEP medicines in the 
MCH clinic where they receive ANC/PNC services.  
 
Adherence to protocol: Weekly reporting of enrollment, follow-up, medical complications, 
laboratory results and specimen collection will enable us to monitor that the study is running 
according to approved protocols. Frequent reporting will also enable us to respond quickly to any 
problems that arise during the study. 
 
Laboratory quality control: KEMRI/CDC Laboratory that will process specimens and conduct most 
of the laboratory tests are ISO certified, and participants in external quality control verification. 
For rapid HIV testing of study participants at enrollment and follow up, creatinine, and Hepatitis B 
testing, we will use point of care tests that have been approved by the Kenyan Ministry of Health 
(MoH). Standard laboratory QA/QC procedures will be conducted.  
 
Data Quality: A dedicated data team will be responsible for data collection using an electronic 
data collection platform, ODK.  The data team will communicate frequently with the Administrative 
and Biostatistics Cores for weekly and EAP reporting, data cleaning, study monitoring, and interim 
analyses.  
k) TRAINING PROCEDURES 
Dr. John Kinuthia will supervise training of clinical personnel and study staff in study procedures.  
This will include research ethics, HIV counseling and testing, PrEP Counseling, rapid HIV testing, 
specimen collection, and completion of surveys. Dr. Ruanne Barnabas will train study staff in 
costing methods including data collection tools, and time and motion study procedures. Dr. 
Harsha Thirumurthy will train study staff in self-testing counseling and protocols. 
 
 COMPONENT 2: Qualitative assessment at organizational, facility and 
individual levels 
a) STUDY DESIGN 
To comprehensively probe the uptake, acceptability and feasibility of universal versus targeted 
PrEP use strategies, we will use mixed methods to evaluate barriers and facilitators of PrEP 
uptake and use among women and their male partners, implementation facilitators and barriers 
among healthcare providers and community and country leaders (Table 8).  We will conduct focus 
group discussions (FGDs) with healthcare workers and individual interviews with women and 
country and community level leaders. Interviews will inform development of a structured 
questionnaire to further assess barriers and facilitators of PrEP use. Better understanding the 
personal, interpersonal, social and logistical factors influencing PrEP use decisions and behaviors 
can inform the design and implementation of PrEP programs.  
 

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Table 8: Stratified Purposive Sampling Scheme and Topics for In-Depth Interviews 
In-Depth Individual Interviews 
Women: 
high-risk; 
No PrEP 
Women: 
Low-risk; 
PrEP 
Women: High 
Adherence 
Women: high-
risk; low 
adherence 
Women: High-risk; 
high adherence 
Male 
Partners 
Community Leaders 
Up to 20 
Up to 20 
Up to 20 
Up to 20 
Up to 20 
Up to 15 
Up to 10 
Topics in interview 
 
Personal HIV risk perception 
 
Knowledge, attitudes and beliefs about PrEP 
 
Partner communication strategies and behaviors 
 
Barriers and facilitators of implementation 
 
Knowledge, attitudes and beliefs about PrEP 
 
Reasons for uptake/refusal of PrEP or HIV testing 
 
Suggestions for improved delivery 
 
Barriers and facilitators of PrEP use and adherence 
 
b) STUDY POPULATION 
Female In-Depth Interview (IDI): We will conduct IDIs with five categories of women based on 
their risk status and PrEP usage during the study: (1) high risk women who declined PrEP; (2) 
low risk women who accepted PrEP; (3) women with high adherence at ~9 months postpartum; 
(4) women with high risk but low adherence at ~9months postpartum; (5) women with high risk 
and high adherence at ~9 months postpartum. We will invite 90 women to participate in IDIs to 
understand reasons for PrEP usage during pregnancy and postpartum (Table 8). Women 
selected based on their acceptance or non-acceptance of PrEP will be recruited and interviewed 
early in the study, as close to when they made their decision about PrEP usage as logistically 
possible. For the purposes of these IDIs low risk women who accept PrEP will be defined as low-
risk women in the universal PrEP facilities who accept PrEP or women in targeted PrEP facilities 
who do not meet the requirements for PrEP counseling but request PrEP. These IDIs will be 
instrumental in understanding whether the intervention did or did not work, why it did or did not 
work, and possible recommendations for enhancement of the intervention. 
 
Male Partner IDI: We will conduct IDIs with partners who are referred by intervention arm study 
participants. Male partners will be identified by asking participants if they would be interested in 
referring their male partner to participate in an interview. Only women whose partners know about 
their participation in the RCT will be eligible for study participation. Up to 20 male partners will be 
interviewed. This approach will be helpful in understanding perceptions of the intervention in terms 
of benefits to care for mother and child, experiences with partner-initiated self-testing, and use of 
PrEP during pregnancy.  
 
Community Leader IDIs: After the RCT, we will also conduct IDIs with 10 community leaders to 
understand community perceptions around PrEP use during pregnancy and postpartum as well 
as understanding community sentiments of the different approaches to PrEP counseling in 
facilities.  
 
Provider Focus Group Discussion (FGD): We will conduct 4 FGDs of 7-10 participants each 
designed to capture provider perspectives on implementing targeted or universal PrEP counseling 
as part of antenatal care. We will also assess provider perspectives on partner self-testing 
counseling as part of antenatal care.  
 
Female Surveys: Upon completion of the RCT, 600 participants, 30 per facility, will be randomly 
selected to participate in a structure exit interview based on the themes identified from the 

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qualitative interviews and focus group discussions. The exit interview participants will be identified 
before their final study visit and invited to participate in the survey during their final study visit. 
This will enable a quantitative frequency assessment of the most common themes. 
 
c) SAMPLE SIZE DETERMINATION AND FORMULAS USED 
We plan to conduct up to 90 semi-structured one-on-one interviews with women (10-20 women 
per stratified sample), 15 interviews with male partners, 4 focus group discussions with healthcare 
workers (2 FGDs per study arm), and 10 interviews with organizational level experts including 
those from the MOH and leaders in the community (Table 6). Based on prior experience 
conducting similar qualitative research, we believe that this sample size will reach data saturation 
(70,71).  
d) RECRUITMENT PROCEDURES 
Female PrEP Acceptance IDI: During antenatal and early postnatal care visits, study staff will 
approach women based on their risk status and whether they accepted PrEP to describe the 
purpose of the IDIs and invite interested women to participate. Participation in qualitative 
interviews will be included during study enrollment and informed consent process. 
 
Female PrEP Adherence IDI: During the study, study staff will approach women based on their 
self-reported adherence to PrEP to describe the purpose of the IDIs and invite interested women 
to participate. Participation in qualitative interviews will be included in the during study enrollment 
and informed consent process. 
 
Male Partner IDI: During study visits, we will sample women and ask them if they would be 
interested in referring their male partner to participate in an interview about partner self-testing 
and PrEP use during pregnancy. Only women whose partners know about their participation in 
the RCT will be eligible for study participation. Interested women will be provided a “study clinic 
referral form” to give their partners (Male Partner IDI Post RCT Referral Form).  Once partners 
come for enrollment, they will be given more information on the study. It will be emphasized that 
participation is completely voluntary. If interested in participation, they will undergo the informed 
consent process. 
 
Community Leader IDI: Community leaders will be identified during project initiation through 
consultations with facility staff and facility based community units. Facility staff or community 
health volunteers will provide community leaders with the referral letter inviting them to participate 
in the IDI.  If community leaders contact study staff about participating in the IDIs, they will undergo 
the informed consent process. 
 
Provider Focus Group Discussion (FGD): We will request providers working in MCH to participate 
in a FGD. These providers will be identified and recruited from serval study facilities. The FGD 
will focus on the provider experience with the study protocols, knowledge and attitudes regarding 
PrEP administration and counseling. Those who are willing and able to participate will undergo 
the informed consent process.  
 
e) DATA COLLECTION PROCEDURES 
All In-depth interviews and Focus Group Discussions (FGD) will be performed in a private area. 
Participants will meet a trained interviewer or moderator who will ask questions and take notes. 
Consent will be obtained from participants to take notes and audio record the discussion. The 
interviewer/moderator will describe procedures and norms for discussion and participation. 

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Participants will be given a chance to ask questions regarding procedures prior to the discussion. 
The socio-demographic information will be documented on separate forms. Socio-demographic 
information for the in-depth interviews of study participants and their male partners will include: 
age, marital status, education level, employment, number of children, and partner HIV status as 
shown in the participant survey portion of the in-depth interview guide.  For Community Leaders 
and health care providers, socio-demographic information that will be captured includes age, 
education level, employment, roll in the community as show in the community leader in-depth 
interview guide. 
 
Interviews with women will focus on understanding how and why women make decisions to 
accept and adhere to PrEP and the feasibility of different PrEP use strategies. We will conduct 
focus group discussions with healthcare workers from 4 study sites (2 per arm) who are involved 
in offering PrEP to understand logistical factors influencing healthcare worker ability and 
willingness to provide PrEP. All focus group discussions and interviews will be recorded and 
transcribed verbatim. To gain generalizability of barriers and facilitators influencing PrEP use, 
structured questionnaires will be administered to 30 randomly selected women per site at study 
exit. Questionnaires will be informed by themes emerging from the qualitative data. 
 
Discussions will be guided by the interviewer or moderator using a discussion guide (attached). 
Prior to FGD, the interviewer will stress the importance of maintaining confidentiality within the 
group. Participants will receive unique identification numbers and will not be addressed by their 
real names so as to maintain confidentiality. Topics that generate the most discussion, participant 
attitudes, non-verbal gestures, and interaction dynamics among group members will be 
documented by the moderators. Discussions will be conducted in English, Kiswahili, or Luo 
depending on participant preferences. Thereafter, notes will be compared to audio-recordings to 
fill in missing information and transcribed to English (if necessary). Transcribed data will be de-
identified. Tape-recorded discussions will be destroyed no later than 6 years after conducting the 
FGD or IDI. 
 
Participants will be provided refreshments and Ksh. 500 to compensate for time and 
transportation expenses to participate in the study. We will provide this monetary compensation 
to each participant at the conclusion of each discussion. 
 
f) DATA COLLECTION INSTRUMENTS 
In-Depth Interview Guide for PrEP acceptance 
In-Depth Interview Guide for PrEP adherence 
In-Depth Interview Guide for Male Partners 
Focus Group Discussion Guide 
Exit Interview Questionnaire—This instrument will be developed following the In-Depth Interviews 
and focus Group Discussions. 
g) TRAINING PROCEDURES 
Dr. Gabrielle O’Malley will supervise training of facilitators for the qualitative components of this 
study.  Dr. John Kinuthia will oversee training of staff on the exit interview survey and procedures. 
 
11) STUDY MATERIALS: 
Equipment:  The grant award includes support to purchase 20 tablets, 4 audio recorders for 
qualitative studies, field office supplies (stationary, paper, toner), 4 desktop computers, clinic 
supplies to collect and store biological samples. 
 

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Personnel: The grant award includes support for UW, UNC, and KNH investigators, clinic 
personnel, the data team, and a study coordinator.  Study personnel working in Kenya will be 
hired through KNH according to standard procedures. 
 
12) DATA MANAGEMENT AND SECURITY 
Overall Data management systems 
Clinical and baseline data collected during the course of this study will be collected electronically 
via ODK data collection software. Data will be uploaded daily via ODK Survey from Android 
phones to the ODK Aggregate web server.  Data will be transported via secure socket layer (SSL) 
and only accessible by authenticated users. Weekly reports will be generated to monitor study 
progress and troubleshoot problems. All computers, tablets (used for primary data collection), and 
individual study databases will be encrypted and password protected. Participants will be 
assigned a non-identifiable study code upon enrollment. Study analysts will receive only coded 
data. The links to patient identifiers will be retained in a password protected file on an encrypted 
computer.  
 
External Advisory Panel 
Prior to RCT initiation, we will convene an EAP to review study aims, statistical analysis plan, and 
protocol. At annual EAP meetings enrollment, retention, and pooled outcomes will be reviewed. 
Because of the short RCT timeline and potentially imbalanced follow-up time between sites, we 
do not plan to conduct an interim comparison of outcomes.  
 
Data Ownership 
The proposed project is a collaborative effort between investigators at the UW, UNC, and KNH.  
The aforementioned institutions will jointly share ownership of the data.  Study investigators at 
the UW, UNC, and KNH will have full access to the data.  Authorship on publications, conference 
presentations, abstracts and other materials generated from this study will reflect contribution to 
design, execution and analysis of the study.  
 
Data Release/Sharing Policy 
All data collected as part of this proposed research project will be made available without cost 
after registration to access or download files on a study related website (URL to be determined) 
and agreement to the data sharing agreement after completion of primary study analyses.  The 
data sharing agreement will ensure commitments to: 
1. Using the data only for research purposes and without attempting to identify study participants 
(if applicable);  
2. Securing the data using appropriate computer technology;  
3. Destroying or returning the data after analyses are completed; 
4. Restrictions on redistribution of the data to third parties; and 
5. Proper acknowledgement of the data resource. 
 
 
13)  STUDY LIMITATIONS AND HOW TO MINIMIZE THEM: 
There may not be an HIV incidence difference between RCT arms.  To address this, we outlined 
RCT benefits for varied trial outcomes in Table 4 above.  As a programmatic RCT, 
characterization of some outcomes will be limited; the design was intentional to optimize 
program/policy relevance.  We will combine MCH data abstraction with interviews and exams to 
address this as possible.  
 
14) HUMAN SUBJECTS 
Ethical Approval 

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We will obtain ethical approval from the University of Washington (UW) Human Subjects Division 
(IRB) and the Kenyatta National Hospital-University of Nairobi Ethics and Research committee 
(ERC).   
 
Collaborating sites 
The study will be conducted in collaboration with the UW, KNH, KEMRI, and CDC.  The study will 
be reviewed by the KNH ERC and UW IRB and will not be started before approvals are obtained 
from all two organizational review boards. For this specific study, University of Washington 
investigators will not be directly involved in fieldwork, data collection, or study recruitment or 
consenting processes. Data analysis performed by investigators, co-investigators and personnel 
will be performed using only de-identified data. 
 

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15) LIST OF APPENDICES/ATTACHMENTS   
I) 
DRAFT STATISTICAL ANALYSIS PLAN 
II) 
CONSENT FORMS 
III) 
GRANT APPLICATION 
IV) 
FGD & IDI GUIDES 
V) 
STANDARD OPERATING PROCEDURE FOR DBS  
 
 

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16)  REFERENCES 
 
 
1. 
Moodley D, Esterhuizen TM, Pather T, Chetty V, Ngaleka L. High HIV incidence during 
pregnancy: compelling reason for repeat HIV testing. AIDS. 2009;23(10):1255-9. doi: 
10.1097/QAD.0b013e32832a5934. PubMed PMID: 19455017. 
2. 
Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy 
and postpartum and risk of mother-to-child HIV transmission: a systematic review and meta-
analysis. PLoS Med. 2014;11(2):e1001608. doi: 10.1371/journal.pmed.1001608. PubMed PMID: 
24586123; PMCID: PMC3934828. 
3. 
Sheffield JS, Wendel GD, Jr., McIntire DD, Norgard MV. The effect of progesterone 
levels and pregnancy on HIV-1 coreceptor expression. Reprod Sci. 2009;16(1):20-31. doi: 
10.1177/1933719108325510. PubMed PMID: 19144888. 
4. 
Rich KC, Siegel JC, Jennings C, Rydman RJ, Landay  AL. CD4+ Lymphocytes in 
Perinatal Human Immunodeficiency Virus (HIV) Infection: Evidence for Pregnancy-Induced 
Immune Depression in Uninfected and HIV-Infected Women. The Journal of Infectious 
Diseases. 1995;172(5):1221-7. 
5. 
Truong HM, Sim MS, Dillon M, Uittenbogaart CH, Dickover R, Plaeger SF, Bryson YJ. 
Correlation of immune activation during late pregnancy and early postpartum with increases in 
plasma HIV RNA, CD4/CD8 T cells, and serum activation markers. Clin Vaccine Immunol. 
2010;17(12):2024-8. doi: 10.1128/CVI.00088-10. PubMed PMID: 20980480; PMCID: 
PMC3008186. 
6. 
Richardson K, Weinberg A. Dynamics of regulatory T-cells during pregnancy: effect of 
HIV infection and correlations with other immune parameters. PLoS One. 2011;6(11):e28172. 
doi: 10.1371/journal.pone.0028172. PubMed PMID: 22140535; PMCID: PMC3226670. 
7. 
Bartellas E, Crane JM, Daley M, Bennett KA, Hutchens D. Sexuality and sexual activity 
in pregnancy. BJOG. 2000;107(8):964-8. Epub 2000/08/24. PubMed PMID: 10955426. 
8. 
Cleland JG, Ali MM, Capo-Chichi V. Post-partum sexual abstinence in West Africa: 
implications for AIDS-control and family planning programmes. AIDS. 1999;13(1):125-31. 
Epub 1999/04/20. PubMed PMID: 10207554. 
9. 
Leeman LM, Rogers RG. Sex after childbirth: postpartum sexual function. Obstet 
Gynecol. 2012;119(3):647-55. Epub 2012/02/23. doi: 10.1097/AOG.0b013e3182479611. 
PubMed PMID: 22353966. 
10. 
De Schacht C, Hoffman HJ, Mabunda N, Lucas C, Alons CL, Madonela A, Vubil A, 
Ferreira OC, Jr., Calu N, Santos IS, Jani IV, Guay L. High rates of HIV seroconversion in 
pregnant women and low reported levels of HIV testing among male partners in Southern 
Mozambique: results from a mixed methods study. PLoS One. 2014;9(12):e115014. doi: 
10.1371/journal.pone.0115014. PubMed PMID: 25542035; PMCID: PMC4277288. 
11. 
Kinuthia J, Drake AL, Matemo D, Richardson BA, Zeh C, Osborn L, Overbaugh J, 
McClelland RS, John-Stewart G. HIV acquisition during pregnancy and postpartum is associated 
with genital infections and partnership characteristics. AIDS. 2015;29(15):2025-33. Epub 
2015/09/10. doi: 10.1097/QAD.0000000000000793. PubMed PMID: 26352880; PMCID: 
PMC4692052. 
12. 
Abdool Karim Q, Dellar RC, Bearnot B, Werner L, Frohlich JA, Kharsany AB, Abdool 
Karim SS. HIV-positive status disclosure in patients in care in rural South Africa: implications 

STUDY PROTOCOL                                                                  V5.5; 13 MAY 2019 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
33
for scaling up treatment and prevention interventions. AIDS Behav. 2015;19(2):322-9. doi: 
10.1007/s10461-014-0951-4. PubMed PMID: 25677128; PMCID: PMC4345171. 
13. 
Shapiro RL, Hughes MD, Ogwu A, Kitch D, Lockman S, Moffat C, Makhema J, Moyo 
S, Thior I, McIntosh K, van Widenfelt E, Leidner J, Powis K, Asmelash A, Tumbare E, Zwerski 
S, Sharma U, Handelsman E, Mburu K, Jayeoba O, Moko E, Souda S, Lubega E, Akhtar M, 
Wester C, Tuomola R, Snowden W, Martinez-Tristani M, Mazhani L, Essex M. Antiretroviral 
regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362(24):2282-94. 
doi: 10.1056/NEJMoa0907736. PubMed PMID: 20554983; PMCID: PMC2999916. 
14. 
Dunn DT, Newell ML, Ades AE, Peckham CS. Risk of human immunodeficiency virus 
type 1 transmission through breastfeeding. The Lancet. 1992;340(5):585-8. 
15. 
Lockman S, Creek T. Acute maternal HIV infection during pregnancy and breast-
feeding: substantial risk to infants. J Infect Dis. 2009;200(5):667-9. doi: 10.1086/605124. 
PubMed PMID: 19627246. 
16. 
UNAIDS. Global Plan Towards the Elimination of New HIV Infections Among Children 
by 2015 and Keeping Their Mothers Alive. 2011. 
17. 
Kahle EM, Hughes JP, Lingappa JR, John-Stewart G, Celum C, Nakku E, Njunga S, 
Mugo N, Bukusi E, Manong R, Baeten JM, Partners in Prevention HSVHIVTST, Team PPS. An 
empiric risk scoring tool for identifying high-risk heterosexual HIV-1 serodiscordant couples for 
targeted HIV-1 prevention. J Acquir Immune Defic Syndr. 2013;62(3):339-47. doi: 
0.1097/QAI.0b013e31827e622d. 
18. 
Balkus JE, Brown E, Palanee T, Nair G, Gafoor Z, Zhang J, Richardson BA, Chirenje 
ZM, Marrazzo JM, Baeten JM. An Empiric HIV Risk Scoring Tool to Predict HIV-1 Acquisition 
in African Women. J Acquir Immune Defic Syndr. 2016;72(3):333-43. Epub 2016/02/27. doi: 
10.1097/qai.0000000000000974. PubMed PMID: 26918545; PMCID: PMC4911322. 
19. 
Balkus JE, Nair G, Montgomery ET, Mishra A, Palanee-Phillips T, Ramjee G, Panchia R, 
Selepe P, Richardson BA, Chirenje ZM, Marrazzo JM. Age-Disparate Partnerships and Risk of 
HIV-1 Acquisition Among South African Women Participating in the VOICE Trial. J Acquir 
Immune Defic Syndr. 2015;70(2):212-7. Epub 2015/06/08. doi: 
10.1097/QAI.0000000000000715. PubMed PMID: 26049280; PMCID: PMC4573287. 
20. 
Pintye J, Drake AL, Kinuthia J, Unger JA, Matemo D, Heffron RA, Barnabas RV, Kohler 
P, McClelland RS, John-Stewart G. A Risk Assessment Tool for Identifying Pregnant and 
Postpartum Women Who May Benefit From Preexposure Prophylaxis. Clin Infect Dis. 
2017;64(6):751-8. Epub 2016/12/31. doi: 10.1093/cid/ciw850. PubMed PMID: 28034882. 
21. 
Thirumurthy H, Masters SH, Mavedzenge SN, Maman S, Omanga E, Agot K. Promoting 
male partner HIV testing and safer sexual decision making through secondary distribution of 
self-tests by HIV-negative female sex workers and women receiving antenatal and post-partum 
care in Kenya: a cohort study. The Lancet HIV. 2016;3(6):e266-e74. doi: 10.1016/s2352-
3018(16)00041-2. 
22. 
Celum CL, Delany-Moretlwe S, McConnell M, van Rooyen H, Bekker LG, Kurth A, 
Bukusi E, Desmond C, Morton J, Baeten JM. Rethinking HIV prevention to prepare for oral 
PrEP implementation for young African women. J Int AIDS Soc. 2015;18(4 Suppl 3):20227. doi: 
10.7448/IAS.18.4.20227. PubMed PMID: 26198350; PMCID: PMC4509892. 
23. 
Auerbach JD, Kinsky S, Brown G, Charles V. Knowledge, attitudes, and likelihood of 
pre-exposure prophylaxis (PrEP) use among US women at risk of acquiring HIV. AIDS Patient 
Care STDS. 2015;29(2):102-10. doi: 10.1089/apc.2014.0142. PubMed PMID: 25513954; 
PMCID: PMC4321978. 

STUDY PROTOCOL                                                                  V5.5; 13 MAY 2019 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
34
24. 
Baeten J, Celum C. Systemic and topical drugs for the prevention of HIV infection: 
antiretroviral pre-exposure prophylaxis. Annu Rev Med. 2013;64:219-32. doi: 10.1146/annurev-
med-050911-163701. PubMed PMID: 23020883; PMCID: PMC3730272. 
25. 
Doblecki-Lewis S, Cohen S, Liu A. Clinical Treatment Options Infectious Diseases: 
Update on PrEP Implementation, Adherence, and Advances in Delivery. Current Treatment 
Options in Infectious Disease. 2015;7(2):101-12. doi: 0.1007/s40506-015-0046-4. 
26. 
Simhan HN, Bodnar LM, Kim KH. Lower genital tract inflammatory milieu and the risk 
of subsequent preterm birth: an exploratory factor analysis. Paediatr Perinat Epidemiol. 
2011;25(3):277-82. doi: 10.1111/j.1365-3016.2010.01176.x. PubMed PMID: 21470267; 
PMCID: PMC3229034. 
27. 
Baggaley R, Doherty M, Ball A, Ford N, Hirnschall G. The Strategic Use of 
Antiretrovirals to Prevent HIV Infection: A Converging Agenda. Clin Infect Dis. 2015;60 Suppl 
3:S159-60. doi: 10.1093/cid/civ091. PubMed PMID: 25972496. 
28. 
Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, 
Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, 
Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, 
Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, 
Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, 
Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum 
C, Partners Pr EPST. Antiretroviral prophylaxis for HIV prevention in heterosexual men and 
women. N Engl J Med. 2012;367(5):399-410. doi: 10.1056/NEJMoa1108524. PubMed PMID: 
22784037; PMCID: PMC3770474. 
29. 
Murnane PM, Celum C, Mugo N, Campbell JD, Donnell D, Bukusi E, Mujugira A, 
Tappero J, Kahle EM, Thomas KK, Baeten JM, Partners Pr EPST. Efficacy of preexposure 
prophylaxis for HIV-1 prevention among high-risk heterosexuals: subgroup analyses from a 
randomized trial. AIDS. 2013;27(13):2155-60. doi: 10.1097/QAD.0b013e3283629037. PubMed 
PMID: 24384592; PMCID: PMC3882910. 
30. 
Haberer JE, Baeten JM, Campbell J, Wangisi J, Katabira E, Ronald A, Tumwesigye E, 
Psaros C, Safren SA, Ware NC, Thomas KK, Donnell D, Krows M, Kidoguchi L, Celum C, 
Bangsberg DR. Adherence to antiretroviral prophylaxis for HIV prevention: a substudy cohort 
within a clinical trial of serodiscordant couples in East Africa. PLoS Med. 2013;10(9):e1001511. 
doi: 10.1371/journal.pmed.1001511. PubMed PMID: 24058300; PMCID: PMC3769210. 
31. 
Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, Palanee T, 
Nakabiito C, van der Straten A, Noguchi L, Hendrix CW, Dai JY, Ganesh S, Mkhize B, Taljaard 
M, Parikh UM, Piper J, Masse B, Grossman C, Rooney J, Schwartz JL, Watts H, Marzinke MA, 
Hillier SL, McGowan IM, Chirenje ZM, Team VS. Tenofovir-based preexposure prophylaxis for 
HIV infection among African women. N Engl J Med. 2015;372(6):509-18. doi: 
10.1056/NEJMoa1402269. PubMed PMID: 25651245; PMCID: PMC4341965. 
32. 
Damme LV, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, Malahleha M, Owino 
F, Manongi R, Onyango J, Temu L, Monedi MC, Mak’Oketch P, Makanda M, Reblin I, Makatu 
SE, Saylor L, Kiernan H, Kirkendale S, Wong C, Grant R, Kashuba A, Nanda K, Mandala J, 
Frensen K, Deese J, Crucitti T, Mastro TD, Taylor D, Group F-PS. Preexposure Prophylaxis for 
HIV Infection among African Women. N Engl J Med. 2012;367(5):411-22. doi: 
0.1056/NEJMoa1202614. 

STUDY PROTOCOL                                                                  V5.5; 13 MAY 2019 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
35
33. 
Tobin SC. VOICE reveals the need to improve adherence in PrEP trials. AIDS. 
2015;29(12):N9. Epub 2015/08/06. doi: 10.1097/QAD.0000000000000693. PubMed PMID: 
26244400. 
34. 
Corneli AL, Deese J, Wang M, Taylor D, Ahmed K, Agot K, Lambaard J, Manongi R, 
Kapiga S, Kashuba A, Damme LV, Group ftF-PS. FEM-PrEP: Adherence Patterns and Factors 
Associated WIth Adherence to Daily Oral Study Product for Pre-exposure Prophylaxis. Journal 
of Aquired Immune Deficiency Syndromes. 2014;66(3):324-31. 
35. 
Thomson KA, Baeten JM, Mugo NR, Bekker L-G, Celum CL, Heffron R. Tenofovir-
based Oral PrEP Prevents HIV Infection among Women. Curr Opin HIV AIDS. 2016;11(1):18-
26. doi: 0.1097/COH.0000000000000207. 
36. 
Corneli AL, McKenna K, Perry B, Ahmed K, Agot K, Malamatsho F, Skhosana J, 
Odhiambo J, Damme LV. The Science of Being a Study Participant: FEM-PrEP Participants’ 
Explanations for Overreporting Adherence to Study Pills and for the Whereabouts of Unused 
Pills. J Acquir Immune Defic Syndr. 2015;68(5):578-84. 
37. 
Amico KR, Stirratt MJ. Adherence to preexposure prophylaxis: current, emerging, and 
anticipated bases of evidence. Clin Infect Dis. 2014;59 Suppl 1:S55-60. Epub 2014/06/14. doi: 
10.1093/cid/ciu266. PubMed PMID: 24926036; PMCID: PMC4060253. 
38. 
Corneli A, Wang M, Agot K, Ahmed K, Lombaard J, Damme LV. Preception of HIV 
Risk and Adherence to a Daily Investigational Pill for HIV Prevention in FEM-PrEP. J Acquir 
Immune Defic Syndr. 2014;67(5):555-63. 
39. 
Baeten JM. Adherence in HIV type 1 prevention trials. J Infect Dis. 2010;201(9):1279-
81. doi: 10.1086/651697. PubMed PMID: 20235837. 
40. 
Corneli A, Perry B, Agot K, Ahmed K, Malamatsho F, Van Damme L. Facilitators of 
adherence to the study pill in the FEM-PrEP clinical trial. PLoS One. 2015;10(4):e0125458. doi: 
10.1371/journal.pone.0125458. PubMed PMID: 25867624; PMCID: PMC4395082. 
41. 
Kebaabetswe PM, Stirratt MJ, McLellan-Lemal E, Henderson FL, Gray SC, Rose CE, 
Williams T, Paxton LA. Factors Associated with Adherence and Concordance Between 
Measurement Strategies in an HIV Daily Oral Tenofovir/Emtricitibine as Pre-exposure 
Prophylaxis (Prep) Clinical Trial, Botswana, 2007-2010. AIDS Behav. 2015;19(5):758-69. doi: 
10.1007/s10461-014-0891-z. PubMed PMID: 25186785; PMCID: PMC4586059. 
42. 
Kintu A, Hankinson SE, Balasubramanian R, Ertel K, Tumwesigye E, Bangsberg DR, 
Haberer JE, Partners Ancillary Adherence Study T. Sexual Relationships Outside Primary 
Partnerships and Abstinence Are Associated With Lower Adherence and Adherence Gaps: Data 
From the Partners PrEP Ancillary Adherence Study. J Acquir Immune Defic Syndr. 
2015;69(1):36-43. doi: 10.1097/QAI.0000000000000538. PubMed PMID: 25942457; PMCID: 
PMC4422183. 
43. 
Ware NC, Wyatt MA, Haberer JE, Baeten JM, Kintu A, Psaros C, Safren S, Tumwesigye 
E, Celum CL, Bangsberg DR. What's love got to do with it? Explaining adherence to oral 
antiretroviral pre-exposure prophylaxis for HIV-serodiscordant couples. J Acquir Immune Defic 
Syndr. 2012;59(5):463-8. doi: 10.1097/QAI.0b013e31824a060b. PubMed PMID: 22267018; 
PMCID: PMC3826169. 
44. 
van der Straten A, Mayo A, Brown ER, Amico KR, Cheng H, Laborde N, Marrazzo J, 
Torjesen K. Perceptions and Experiences with the VOICE Adherence Strengthening Program 
(VASP) in the MTN-003 Trial. AIDS Behav. 2015;19(5):770-83. doi: 10.1007/s10461-014-
0945-2. PubMed PMID: 25384907; PMCID: PMC4416998. 

STUDY PROTOCOL                                                                  V5.5; 13 MAY 2019 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
36
45. 
Baeten J, al e, editors. Near Elimination of HIV Transmission in a Demonstration Project 
of PrEP and ART. CROI; 2015. 
46. 
Henderson F, al e, editors. Characteristics and oral PrEP Adherence in TDF2 open-label 
extension in Botswana. Eighth IAS Conference on HIV Pathogenesis; 2015. 
47. 
Bekker LG, al e, editors. HPTN 067/ADAPT Cape Town: A Comparison of Daily and 
Nondaily PrEP Dosing in African Women. CROI; 2015. 
48. 
Zash R, Souda S, Chen JY, Binda K, Dryden-Peterson S, Lockman S, Mmalane M, 
Makhema J, Essex M, Shapiro R. Reassuring Birth Outcomes With 
Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV 
in Botswana. J Acquir Immune Defic Syndr. 2016;71(4):428-36. Epub 2015/09/18. doi: 
10.1097/QAI.0000000000000847. PubMed PMID: 26379069; PMCID: PMC4767604. 
49. 
Gibb DM, Kizito H, Russell EC, Chidziva E, Zalwango E, Nalumenya R, Spyer M, 
Tumukunde D, Nathoo K, Munderi P, Kyomugisha H, Hakim J, Grossjurth H, Gilks CF, Walker 
AS, Musoke P, team obotDt. Pregnancy and Infant Outcomes among HIV-Infected Women 
Taking Long-Term ART with and without Tenofovir in the DART Trial. PLoS Med. 
2012;9(5):e10001217. doi: 0.1371/journal.pmed.1001217. 
50. 
Chi BH, Sinkala M, Mbewe F, Cantrell RA, Kruse G, Chintu N, Aldrovandi GM, 
Stringer EM, Kankasa C, Safrit JT, Stringer JSA. Single-dose tenofovir and emtricitabine for 
reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women 
given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. The 
Lancet. 2007;370(9600):1698-705. doi: 10.1016/s0140-6736(07)61605-5. 
51. 
Ransom CE, Hou Y, Patel K, Scott GB, Watts DH, Williams P, Siberry GK, Livingston 
EG, Group PToIMPAACT. Infant Growth Outcomes After Maternal Tenofovir Disoproxil 
Fumarate Use During Pregnancy. J Acquir Immune Defic Syndr. 2013;64(1). doi: 
0.1097/QAI.0b013e3182a7adb2. 
52. 
Flanagan S, Barnes L, Anderson J, Barber T, editors. The effect of tenofovir on renal 
function in HIV-positive pregnant women. HIV Drug Therapy Glasgow Congress; 2014; 
Glasgow, Scotland: Journal of the International AIDS Society. 
53. 
Siberry GK, Williams PL, Mendez H, Seage GR, Jacobson DL, Hazra R, Rich KC, 
Griner R, Tassiopoulos K, Kacanek D, Mofenson LM, Miller T, DiMeglio LA, Watts DH, 
(PHACS) PHACS. Safety of Tenofovir Use During Pregnancy: Early Growth Outcomes in HIV-
Exposed Uninfected Infants. AIDS. 2012;26(9):1151-9. doi: 0.1097/QAD.0b013e328352d135. 
54. 
Wang L, Kourtis AP, Ellington S, Legardy-Williams J, Bulterys M. Safety of tenofovir 
during pregnancy for the mother and fetus: a systematic review. Clin Infect Dis. 
2013;57(12):1773-81. doi: 10.1093/cid/cit601. PubMed PMID: 24046310. 
55. 
Siberry GK, Jacobson DL, Kalkwarf HJ, Wu JW, DiMeglio LA, Yogev R, Knapp KM, 
Wheeler JJ, Butler L, Hazra R, Miller TL, Seage GR, 3rd, Van Dyke RB, Barr E, Davtyan M, 
Mofenson LM, Rich KC, Pediatric HIVACS. Lower Newborn Bone Mineral Content Associated 
With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy. Clin Infect Dis. 
2015;61(6):996-1003. doi: 10.1093/cid/civ437. PubMed PMID: 26060285; PMCID: 
PMC4551007. 
56. 
Mugo NR, Hong T, Celum C, Donnell D, Bukusi EA, John-Stewart G, Wangisi J, Were 
E, Heffron R, Matthews LT, Morrison S, Ngure K, Baeten JM, Partners Pr EPST. Pregnancy 
incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a 
randomized clinical trial. JAMA. 2014;312(4):362-71. doi: 10.1001/jama.2014.8735. PubMed 
PMID: 25038355; PMCID: PMC4362516. 

STUDY PROTOCOL                                                                  V5.5; 13 MAY 2019 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
37
57. 
Beigi R, Noguchi L, Parsons T, Macio I, Kunjara Na Ayudhya RP, Chen J, Hendrix CW, 
Masse B, Valentine M, Piper J, Watts DH. Pharmacokinetics and placental transfer of single-
dose tenofovir 1% vaginal gel in term pregnancy. J Infect Dis. 2011;204(10):1527-31. doi: 
10.1093/infdis/jir562. PubMed PMID: 21930612; PMCID: PMC3192189. 
58. 
Callahan R, Nanda K, Kapiga S, Malahleda M, Mandala J, Ogada T, Damme LV, Taylor 
D, Group ftF-PS. Pregnancy and Contraceptive Use Among Women Participating in the FEM-
PrEP Trial. Journal of Aquired Immune Deficiency Syndromes. 2015;68(2):196-203. 
59. 
Vernazza PL, Graf I, Sonnenberg-Schwan U, Geit M, Meurer A. Preexposure 
prophylaxis and timed intercourse for HIV-discordant couples willing to conceive a child. AIDS. 
2011;25(16):2005-8. doi: 10.1097/QAD.0b013e32834a36d0. PubMed PMID: 21716070. 
60. 
Whetham J, Taylor S, Charlwood L, Keith T, Howell R, McInnes C, Payne E, Home J, 
White D, Gilleece Y. Pre-exposure prophylaxis for conception (PrEP-C) as a risk reduction 
strategy in HIV-positive men and HIV-negative women in the UK. AIDS Care. 2014;26(3):332-
6. doi: 10.1080/09540121.2013.819406. PubMed PMID: 23876052. 
61. 
AIDSinfo. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected 
Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the 
United States. Washington, DC: National Institutes of Health, 2016. 
62. 
Benaboud S, Pruvost A, Coffie PA, Ekouevi DK, Urien S, Arrive E, Blanche S, 
Theodoro F, Avit D, Dabis F, Treluyer JM, Hirt D. Concentrations of tenofovir and emtricitabine 
in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA 
Study, Step 2. Antimicrob Agents Chemother. 2011;55(3):1315-7. doi: 10.1128/AAC.00514-10. 
PubMed PMID: 21173182; PMCID: PMC3067089. 
63. 
Mirochnick M, Best BM, Clarke DF. Antiretroviral pharmacology: special issues 
regarding pregnant women and neonates. Clin Perinatol. 2010;37(4):907-27, xi. doi: 
10.1016/j.clp.2010.08.006. PubMed PMID: 21078458. 
64. 
Blehar MC, Spong C, Grady C, Goldkind SF, Sahin L, Clayton JA. Enrolling pregnant 
women: issues in clinical research. Womens Health Issues. 2013;23(1):e39-45. doi: 
10.1016/j.whi.2012.10.003. PubMed PMID: 23312713; PMCID: PMC3547525. 
65. 
Ministry of Health NASCP. Guidelines on use of Antiretroviral Drugs for Treating and 
Preventing HIV INfection in Kenya 2016. Nairobi, Kenya: NASCOP, 2016 July 2016. Report 
No. 
66. 
WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis 
for HIV. Geneva, Switzerland: World Health Organization (WHO), 2015. 
67. 
Ivers NM, Halperin IJ, Barnsley J, Grimshaw JM, Shah BR, Tu K, Upshur R, 
Zwarenstein M. Allocation techniques for balance at baseline in cluster randomized trails: a 
methodological review. Trials. 2012;13(120):9. 
68. 
Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, Hosek S, 
Mosquera C, Casapia M, Montoya O, Buchbinder S, Veloso VG, Mayer K, Chariyalertsak S, 
Bekker L-G, Kallas EG, Schechter M, Guanira J, Bushman L, Burns DN, Rooney JF, Glidden 
DV. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and 
transgender women who have sex with men: a cohort study. The Lancet Infectious Diseases. 
2014;14(9):820-9. doi: 10.1016/s1473-3099(14)70847-3. 
69. 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic 
data capture (REDCap)--a metadata-driven methodology and workflow process for providing 
translational research informatics support. J Biomed Inform. 2009;42(2):377-81. Epub 
2008/10/22. doi: 10.1016/j.jbi.2008.08.010. PubMed PMID: 18929686; PMCID: PMC2700030. 

STUDY PROTOCOL                                                                  V5.5; 13 MAY 2019 
PrEP Implementation for Mothers in Antenatal Care (PrIMA) 
 
38
70. 
Morse J. Determining Sample Size. Qual Health Res. 2000;10:3-5. 
71. 
Marshall M. Sampling for qualitative research. Fam Pract. 1996;13(6):522-5.