Developing and Assessing a Male Engagement Intervention in Option B+ in Malawi: A Randomized Controlled Trial in Lilongwe
Phase: NA
Conditions: Hiv
Sponsor: University of North Carolina, Chapel Hill

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 1 of 46 
 
 
 
 
 
 
 
Official Study Protocol Title:  
Developing and Assessing a Male Engagement Intervention in Option B+ in 
Malawi: A Randomized Controlled Trial in Lilongwe 
 
 
 
NCT number NCT03477279 
Document Date 06/20/2019 
 
 
 
 
 
 
 
 
 

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 2 of 46 
 
 
 
 
 
 
UNCPM 21703 
Developing and Assessing a Male Engagement Intervention for Option B+ in 
Malawi: A Randomized Controlled Trial in Lilongwe  
 
 
 
 
For submission to NHSRC  
June 20, 2019 
 
 
 
 
 
 

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 3 of 46 
 
 
 
 
 
 
Study team  
Nora E. Rosenberg, PhD, MSPH 
Principal Investigator 
Department Health Behavior  
University of North Carolina Project Malawi 
Tidziwe Center 
Private Bag A-104  
Lilongwe, Malawi 
+265 (0)99 109 06726 
Email: Nora_Rosenberg@unc.edu 
 
Tiwonge Mtande, BSc 
Site Principal Investigator 
Study Coordinator 
University of North Carolina Project Malawi 
Tidziwe Center 
Private Bag A-104 
Lilongwe, Malawi 
Email: tmtande@unclilongwe.org  
+265 (0)99 641 1000 
 
Mitch Matoga, MBBS 
Co-Investigator 
Medical Officer 
University of North Carolina Project Malawi 
Tidziwe Center 
Private Bag A-104  
Lilongwe, Malawi 
+265 (0)99 951 1726 
Email: mmatoga@unclilongwe.org 
 
Twambilile Phanga, MSEN 
Co-Investigator 
Senior Research Officer 
University of North Carolina Project Malawi 
Tidziwe Center 
Private Bag A-104  
Lilongwe, Malawi 
Email: tphanga@unclilongwe.org 
 
Sam Phiri, PhD, MSc, Dip Clin Med 
Co-Investigator 
Executive Director 
Lighthouse Trust 
Kamuzu Central Hospital 
P. O. Box 106 
Lilongwe, Malawi 
Phone: +265 1 758 940 ext 112 
Cell: +265 8 88 892 523 
Email: samphiri@lighthouse.org.mw 
 
Rose Kolola Nyirenda, Head of HIV Unit 
Co-Investigator 
Director Department of HIV and AIDS 
Ministry of Health P. O. Box 30377,  
Lilongwe 3.Malawi 
Cell: +265 884 663 879  
email: nyirendarose@gmail.com 
 
Mina Hosseinipour, MD, PhD, MPH 
Co-Investigator  
Professor  
UNC Project-Malawi 
Division of Infectious Diseases 
CB# 7030, 2146 Bioinformatics  
Chapel Hill, NC 27599-7030, USA 
Phone: +265 (0)88 820 2153 
Email: Mina_Hosseinipour@unc.edu 
 
Suzanne Maman, PhD 
Co-Investigator  
Professor 
Department of Health Behavior 
Gillings School of Global Public Health 
Chapel Hill, NC 27599-7030, USA 
Phone: (919) 966-3901 
Fax: (919) 966-2921 
Email: maman@email.unc.edu 
 
William Miller, MD, PhD, MPH 
Co-investigator  
Chair and Professor 
Ohio State University  
1841 Neil Ave. 
302 Cunz Hall 
Columbus, OH 43210 
Phone: 614-292-2516 
Email: miller.8332@osu.edu 
Technical Advisors: Nuala McGrath, PhD Carol Golin, MD, MPH Lauren Graybill, MSc  

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 4 of 46 
 
 
 
 
 
 
Contents 
Study team ..............................................................................................................................................................3 
PROTOCOL SUMMARY ...............................................................................................................................................5 
Research Question..................................................................................................................................................5 
Rationale .................................................................................................................................................................5 
Methods .................................................................................................................................................................5 
Risks/Benefits .........................................................................................................................................................8 
Costs/Compensation ..............................................................................................................................................8 
Confidentiality Assurances .....................................................................................................................................8 
Conflict of Interest ..................................................................................................................................................9 
Collaborative Agreements ......................................................................................................................................9 
Intended use of results ...........................................................................................................................................9 
PROTOCOL ..................................................................................................................................................................9 
Title ...................................................................................................................................................................... 10 
Abstract ............................................................................................................................................................... 10 
Background and Justification .............................................................................................................................. 11 
Literature review ................................................................................................................................................. 12 
Hypotheses .......................................................................................................................................................... 13 
Specific Aims/Study Objectives ........................................................................................................................... 14 
Methodology ....................................................................................................................................................... 15 
Ethical and human subjects considerations ........................................................................................................ 21 
Dissemination of results ...................................................................................................................................... 25 
Work plan ............................................................................................................................................................ 25 
 ................................................................................................................................. Error! Bookmark not defined. 
Bibliography ......................................................................................................................................................... 27 
 
 

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 5 of 46 
 
 
 
 
 
 
PROTOCOL SUMMARY 
Research Question  
The overarching research question is whether a couple-based approach or an individual-based approach to Option B+ results 
in better maternal, paternal, and infant HIV outcomes one year after maternal enrollment. 
 
Rationale  
In sub-Saharan Africa, engaging HIV-infected men in HIV care and treatment and engaging HIV-uninfected men in prevention 
has proven challenging. Additionally, men rarely engage in the antenatal care-seeking of their female sexual partners, leading 
to worse maternal and infant outcomes. There is promising evidence that couple-based approaches within Option B+ prevention 
of mother to child transmission programs could address multiple outcomes simultaneously: poor male engagement in the HIV 
continuum of care, low male adoption of biomedical HIV prevention approaches, and poor uptake and retention in the 
continuum of care for women and infants. This is a randomized controlled trial to compare a couple-based intervention to an 
individual-based standard of care over a one year period. There are five objectives: 
Objective 1: determine whether the intervention increases continuum of care outcomes for HIV-infected men.  
Objective 2: determine whether the intervention increases prevention uptake in HIV-uninfected men.  
Objective 3: determine whether the intervention improves continuum of care outcomes for HIV-infected women. 
Objective 4: determine whether the intervention improves uptake of early infant diagnosis and explore its effects on mother-
to-child transmission and child survival. (This is a secondary objective). 
Objective 5: develop an in-depth understanding of transmission dynamics in Lilongwe.  
 
Methods 
Study design: This is a two-arm, non-blinded randomized controlled trial comparing a couple-based intervention to an 
individual standard-of-care approach to Malawi’s Option B+ program.  
 
Primary Population:  The study will be conducted at Bwaila District Hospital and may move instead to Area 18 if 
enrollment is slow or other studies are recruiting there. Women will be eligible to participate if they are: 
• 
HIV-positive and eligible for Option B+  
• 
>18 years old or 15-17 years old and married (emancipated minor) 
• 
Planning to remain in the relevant catchment area for the next year or notify the study team if they leave the area or 
change facilities 
• 
In a committed heterosexual relationship with a male partner for >3 months 
o 
The partner is expected to be in Malawi for at least one week in the next six months 
o 
Able and willing to give locator information for that male partner  
o 
Willing to have study staff conduct phone and physical tracing of that partner 
o 
Willing and able to engage in a couple-based intervention with that partner 
• 
Able and willing to provide informed consent  
 
Enrolling pregnant women is essential as this is the primary population eligible for Option B+. The target sample size is 500 
women randomized in a 1:1 ratio to two arms (250/arm), up to 500 of their partners, and up to approximately 500 infants 
(although more are possible due to non-singleton births). It is expected that 14,000 women will present for antenatal care at 
this hospital over a 12-month period. Approximately 700 (5%) will be newly diagnosed as HIV positive and 500 (71%) will 
meet eligibility criteria. Enrollment may take longer if there are fewer pregnancies, a lower HIV prevalence, or lower 
eligibility rates. Women will be actively followed for one year and their data will be abstracted for up to three years.  
 
Male partners will be eligible if they present to the antenatal clinic, are >18 years old or 15-17 years old and married (i.e. an 
emancipated minor), and confirm that they have been in a relationship with the female partner for >3 months. They must be 
willing to undergo couple HIV testing and counseling (CHTC) with their female partner and be able and willing to provide 

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 6 of 46 
 
 
 
 
 
 
informed consent. They must believe participation will not result in intimate partner violence or abandonment. Men will be 
actively followed for one year and their data will be abstracted for up to three years.  
 
Infants (singletons and twins) will be eligible if they are born during the study period or if the mother was identified as HIV-
infected while delivering or breastfeeding that infant. Health information may be abstracted from clinic records for up to 
three years after maternal enrollment.  
 
Control population: In addition, 350 HIV-uninfected pregnant women will be enrolled and frequency matched to the HIV-
infected women based on pregnancy duration. The same eligibility criteria will be used.   
 
Procedures and Interventions:  
Study Procedures  
Upon learning that the woman is HIV-positive, she will be screened and assessed for eligibility (Screening). She will provide 
oral consent for screening. Study staff will maintain a screening log with documented reasons for non-eligibility. Women 
interested in participating will be consented into the study, administered a brief survey, provide locator information and 
randomized to one of the study arms.  
• 
Female study visit 1: Following those procedures, women will be administered a one-hour behavioral survey about 
demographics and socio-economic status, their sexual and care seeking behaviors, migration, and partnership 
characteristics. They will have a venous blood draw of approximately 20ml.  
• 
Female study visit 2: The next visit, will occur approximately six months after visit 1. At this visit, women will fill 
out a comparable behavioral survey.  
• 
Female study visit 3: The next visit, will occur approximately twelve months after visit 1. At this visit, women will 
fill out a comparable behavioral survey. They will have a venous blood draw of 20ml.  
 
Men will provide or decline oral consent for screening, then be screened for the study, assessed for eligibility and consented 
at first presentation. They can refuse to provide informed consent and this will not affect their female partner’s participation. 
For those in the couple arm, this will occur approximately one week after female study enrollment (visit 1). For those in the 
individual arm, this will occur approximately one year after female study enrollment (visit 2). For those where male partner 
consents: 
• 
Male study visit 1: Only men in the couple intervention arm will have this visit, and this will coincide with couple 
intervention visit 1. This visit will occur approximately one week after the female intervention visit 1. At this visit, 
men will fill out a behavioral survey with similar information to the female survey. They will have a venous blood 
draw of approximately 20ml.  
• 
Male study visit 2: This visit will occur approximately twelve months after the female’s visit 1. At this visit, men 
will fill out a behavioral survey with similar information to the female survey. They will have a venous blood draw 
of approximately 20ml.  
 
Standard of Care for Women, Infants, and Male Partners  
Within the Option B+ program, all women are administered ART within one week of an HIV-positive test result (and 
typically on the same day). For the first six months, they receive a monthly supply of antiretroviral therapy and attend the 
clinic monthly. After six months, if they have good adherence, they receive a three-month supply of treatment, and attend the 
clinic every three months. Women who present with male partners receive standard of care CHTC, but this occurs for a 
minority of women (approximately 10%). Men identified as HIV-positive cannot initiate treatment in Option B+ settings. 
Additionally, condoms are available through the pharmacy, but not by the HTC counselors. Women have a first viral load test 
at six months. Infants undergo early infant diagnosis with DNA PCR six weeks after delivery and an HIV rapid test at twelve 
months. Those who are HIV-infected begin antiretroviral therapy immediately. This will not be altered by the study. 
 
Study tracing procedures 
Because this is a longitudinal study with relatively few visits, efforts will be made to maintain contact with all participants 
throughout the study. A community worker will collect locator information on all participants. To verify physical locations, 
participants will use electronic or paper maps or draw maps. Community workers may accompany participants home to learn 

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 7 of 46 
 
 
 
 
 
 
their physical address. The community workers will make routine contact with all study participants on a quarterly basis to 
update locator information. They will provide study participants with study contact information and ask participants to phone 
the study staff should they transfer facilities or change their locator information.  
 
 
Individual arm (N=250) 
No intervention procedures beyond standard of care procedures will be conducted in the individual arm. Women randomized 
to the individual arm will undergo the study procedures described above. At the twelve month visit, couples in this arm who 
present together will receive standard of care CHTC. 
 
Couple arm (N=250) 
In addition to the study procedures and standard of care procedures described above, women in the intervention arm will 
undergo the following procedures: 
• 
Female intervention visit 1 and partner tracing: Women in the couple arm will be provided with study-specific 
partner referral cards and encouraged to bring male partners to antenatal care for important pregnancy information. 
The referral card will contain a specific time for male partners to present to the clinic, but note that this is flexible. 
The card will describe the purpose of the visit as pregnancy-related, not HIV-related to allow the woman the 
opportunity to disclose in the clinic if preferable. It will not contain information about the woman’s HIV status or 
HIV care-seeking. Phone and physical tracing will be conducted with utmost regard for protecting the privacy of 
enrolled women and their partners through detailed standard operating procedures. They will receive brief disclosure 
support counseling.  
• 
Couple intervention visit 1 (day 0-30+): Upon presentation, the couple will receive an enhanced CHTC 
intervention. The intervention will include pre-test counseling, return of joint results, and post-test counseling with 
differentiated messages for HIV-discordant and HIV-concordant couples. HIV-infected men can initiate cART and 
the couple will be offered condoms from the HTC counselor.  
• 
Couple intervention visit 2 (month 6): Upon presentation, the couple will receive an enhanced couple-intervention 
similar to couple visit 1. It will be similar to visit 1, but will not include testing for HIV-concordant positive couples. 
In addition, EID will be provided if the infant has not had it yet, as these visits are likely to coincide. Counselor will 
discuss the importance of birth spacing and provide or refer for contraception. A small monetary or non-monetary 
nutritional supplement (approximately $5 equivalent) will be provided. This will coincide with female study visit 2.  
• 
Couple intervention visit 3 (month 12): Upon presentation, the couple will receive an enhanced couple-
intervention similar to couple visit 2. Conduct of or reminder of infant 1-year HIV test will be conducted. This will 
coincide with the female study visit 2 and male study visit 1.  
 
Control Procedures  
The 350 HIV-uninfected women will be screened, consented, and enrolled for participation. They will answer questions to 
the same interviewer-administered survey that HIV-infected women receive at their first study visit. Control participants will 
not have any additional visits, have blood drawn or enroll male partners. Their clinical information, including syphilis rapid 
test results will be abstracted.  
 
Data collection, management, and analysis  
Study staff will be responsible for data collection. Patient health information will be collected through the Baobob electronic 
medical record, when possible, and transferred from patient to study case report forms by study staff or downloaded. Study 
consents and surveys will be stored in locked filing cabinets. Data will be entered into a password protected Open Data Kit 
(ODK) database, Access database, or similar database by a trained data entry clerk.  
• 
For objective 1, we will compare the individual to the couple arm for continuum of care outcomes for HIV-infected 
men. These outcomes include a) the proportion of HIV-infected men who learn that they are HIV-positive before the 
12 month visit, b) the proportion of HIV-infected men who begin ART within a year of the woman’s study enrollment, 
c) the proportion of HIV-infected men who remain in care one year after the woman’s study enrollment, and d) the 
proportion of HIV-infected men who are virally suppressed one year after the woman’s study enrollment. We have 
>99% power to detect a difference in the overall continuum (34% versus 73%).  

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 8 of 46 
 
 
 
 
 
 
• 
For objective 2, we will compare the individual to the couple arm for the proportion of HIV-uninfected men who a) 
are circumcised one year after study enrolment, b) had no unprotected sex with their study partner in the first six 
months after the woman initiated ART, and c) had a female partner who was virally suppressed at six and twelve 
months OR had no unprotected sex with their study partner in the second six months (7-12) after female ART 
initiation. We have 94% power to detect a risk difference of 85% in the couple intervention arm and 60% in the SOC 
arm.  
• 
For objective 3, we will compare the individual to the couple arm for a) the proportion of HIV-infected women who 
are retained in care at one year, b) the proportion of retained women who are virally suppressed at one year, and c) 
the proportion of women who are both retained and suppressed at one year. To assess outcomes on the overall 
continuum (64% versus 81%), we have 97% power. 
• 
For objective 4, we will compare the individual to the couple arm for a) the proportion of infants who had early infant 
diagnosis. To assess this outcome (0.6 versus 0.75), we have 87.5% power. We will also explore the rates of mother-
to-child transmission and child survival in the two intervention arms.  
• 
Objective 5 is exploratory and analytic. We will learn use viral genetics, and multi-assay algorithms to learn about 
the timing, direction, and bio-behavioral context of HIV transmission. We will compare HIV-infected participants 
with recent HIV infection (~50 women) to HIV-uninfected controls.  
 
For each outcome of interest, we will implement generalized linear models with an identity link and binomial distribution to 
estimate risk differences and ninety five percent confidence intervals. 
Risks/Benefits 
Risks: Participants may feel embarrassed to answer questions about sexual behavior.  They can refuse to answer any 
questions at any time. Breach of confidentiality is another risk in this study. Measures will be taken to ensure this does not 
occur. If a participant’s male partner is contacted in the community study staff will prevent other people (non-partners) from 
learning the reason for the community outreach worker visit. Once a partner is located, their identity must first be confirmed 
by the community outreach worker. The discussion with the community outreach worker must take place in a private place. 
During the blood draw or HIV test, participants may feel discomfort when blood is drawn. They may also feel dizzy or faint, 
or experience bruising or swelling at the blood drawing site.  However, risk is minimal. Participants may become worried or 
anxious while waiting for HIV test results. Trained counselors will be available to help participants deal with these feelings. 
HIV partner notification may cause social, economic, legal or physical harm but these harms are rare. Our team will do 
everything in our power to help you resolve these problems if they arise. We will also systematically ask all female 
participants if these problems have occurred.  
 
Benefits: The benefits to females from being in this study are to help notify sexual partners that they may have been exposed 
to HIV and to get couples HIV counseling and testing (either right away or one year later) and remain in care. This study may 
help male participants learn their HIV status. It will help couples learn each other’s HIV status. If the male partner is HIV-
infected, he may be able to start HIV care or treatment. If the couple is HIV-discordant, they may be able to use behavioral or 
biomedical prevention measures to remain HIV-uninfected.  Female and infant Option B+ outcomes may improve. Malawi 
may benefit from the results of this research by learning new knowledge about partner notification and understanding of 
partner notification within the Option B+ program.  
 
Costs/Compensation 
Study and intervention visits will be compensated up to $5 per visit in Malawi kwacha or in kind equivalent.  
 
Confidentiality Assurances 
Sensitive information will be collected from male and female participants. Measures will be taken to ensure this information 
is not shared between partners. Community outreach workers will not disclose the HIV status of the female partners. They 
will simply suggest male partners report to the clinic for health information with female partners.  
 

UNCPM 21703, Protocol Version 3.0, 20 June 2019, page 9 of 46 
 
 
 
 
 
 
Both male and female participants will be assigned a study ID number. This number will be linked to the participant name 
and medical record at the antenatal clinic only through a separate log book that will be kept in a separate locked file. Data 
will be double-entered into a password protected Access database or uploaded to ODK by a trained data entry clerk. Only the 
study staff will be able to link the medical record that has the participant name on it with study information that has the study 
ID number on it. At the conclusion of the study, this link between the name and number will be destroyed.  
 
No subjects will be identified in any report or publication about this study.  In some cases, information in this research study 
could be reviewed by representatives of the University of North Carolina, research sponsors, or Malawi government agencies 
for purposes such as quality control or safety. We may present de-identified data for open access publications.  
 
All electronic data will be collected on encrypted, password-protected devices and stored on encrypted, password- protected 
servers. All paper-based data will be stored in locked filing cabinets in locked rooms. Data will be stored following the 
termination of study completion and then destroyed.  
 
Conflict of Interest 
There are no conflicts of interest.  
 
Collaborative Agreements  
This is a single-site study. We will also seek approval from the University of North Carolina at Chapel Hill Institutional 
Review Board.  
 
Intended use of results 
The results of the study will be presented at international and local scientific meetings and published in scientific journals. 
The results will also be submitted to the NHSRC. The information collected in this study may lead to larger cluster 
randomized trials that will allow further evaluation of the impact of male participation on maternal, /infant, and male partner 
outcomes.  
 
 
 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 10 of 46 
 
PROTOCOL  
Title 
 
Developing and Assessing a Male Engagement Intervention for Option B+ in Malawi:                      
A Randomized Controlled Trial in Lilongwe 
 
Abstract            
In sub-Saharan Africa, engaging HIV-infected men in HIV care and treatment and engaging HIV-uninfected men 
in prevention has proven challenging. Additionally, men rarely engage in the antenatal care-seeking of their 
female sexual partners, leading to worse maternal and infant outcomes. There is promising evidence that couple-
based approaches within Malawi’s Option B+ prevention of mother to child transmission program could address 
all of these challenges: poor male engagement in the HIV continuum of care, low male adoption of biomedical 
HIV prevention approaches, sub-optimal female engagement in the continuum of care, and poor or uncertain 
infant outcomes. Our team has developed an intervention to address these challenges, and will conduct a 
randomized controlled trial (N=500 couples) to assess intervention effectiveness at one year. Through this work 
we aim to achieve four objectives: determine whether the intervention increases continuum of care outcomes for 
HIV-infected men (Aim 1); determine whether the intervention decreases the likelihood of male exposure to HIV 
over a one-year period (Aim 2); determine whether the intervention improves continuum of care outcomes for 
HIV-infected women (Aim 3) and their infants (Aim 4). Finally, we will develop an in-depth understanding of 
transmission dynamics in Lilongwe. Results are expected to inform how best to address family outcomes in an 
Option B+ program.   
  
                          

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 11 of 46 
 
Background and Justification 
 
In sub-Saharan Africa, engaging HIV-infected men in HIV care and treatment has proven challenging. Along all 
steps of the HIV care-seeking cascade, men exhibit worse care-seeking behaviors. They are less likely to seek HIV 
testing and counseling (HTC),1-4 initiate combination antiretroviral therapy (cART),5-8 and be retained in cART 
care.9 Poor care-seeking has resulted in a lower prevalence of viral suppression10 and earlier mortality.9,11,12 
Strategies to diagnose HIV-infected men earlier and improve their HIV care-seeking and adherence behaviors are 
urgently needed.  
 
Similarly, HIV-uninfected men in HIV-discordant couples face challenges with HIV prevention. Without adopting 
any HIV prevention behaviors they are at very high risk for HIV infection.13 Consistent condom use is one option, 
but new biomedical prevention options are also available, including medical male circumcision,14-16 and “treatment-
as-prevention” (having an HIV-infected sexual partner adhere to cART for viral suppression).17,18 Helping men in 
HIV-discordant couples navigate this new HIV prevention environment is essential.  
 
Additionally, men rarely engage in the antenatal care-seeking of their female sexual partners,19 even though male 
engagement is associated with marked improvements in maternal and infant outcomes.20-22 This low level of 
engagement has been noted in Malawi’s Option B+ prevention of mother to child transmission (PMTCT) program, 
which provides all HIV-infected pregnant and lactating women with lifelong cART at the time of HIV diagnosis, 
regardless of CD4 count or clinical stage.23,24 However, low levels of male engagement have been a critical barrier 
to female Option B+ uptake and retention,19,20 and a missed opportunity for engaging men.  
 
Couple-based approaches within Option B+ could address all of these challenges: poor male engagement in the 
HIV continuum of care, low male adoption of biomedical HIV prevention, sub-optimal female and engagement in 
the continuum of care, and poor or uncertain infant outcomes. Couple-based, approaches, especially couple HTC, 
have been encouraged by the World Health Organization (WHO), but implementation questions remain: 1) 
assessing strategies for recruiting couples, and 2) understanding the impacts of couple-based strategies on HIV 
treatment and treatment as prevention.25 This proposal directly addresses both of these research areas.  
 
In previous protocols our group has conducted formative work to guide the development of a couple-based 
intervention package for HIV-infected pregnant women and their male partners. Several key findings have emerged 
from this body of work that directly inform future interventions. First, it is feasible for three quarters of newly 
diagnosed HIV-infected pregnant women to recruit male partners for couple HTC using a combination of a written 
invitation, partner tracing, and a small incentive. Second, couple HTC identifies a substantial number of HIV-
infected men who are not engaged in care, but additional approaches are required to support male care-seeking 
behaviors. Third, the majority of HIV-discordant couples initiate consistent condom use following couple HTC, but 
do not understand newer HIV prevention modalities. Fourth, couple HTC is associated with better CART uptake, 
but long-term retention has not been assessed. Within the framework of interdependence theory, these findings have 
informed a couple-based intervention to be assessed through a two-arm randomized controlled trial (N= 500 HIV-
infected women and their partners). 
 
 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 12 of 46 
 
Literature review 
UNAIDS has recently set forth global “90-90-90” targets for control of the HIV epidemic. These targets refer to 
three HIV continuum of care indicators: 90% of HIV-infected persons tested and aware of their HIV status, 90% of 
these persons retained in care at one year, and 90% of these persons virally suppressed.26 Some epidemic models 
have suggested that this level of suppression is needed to slow the spread of the HIV epidemic.27 Couple-based 
approaches for achieving 90-90-90 targets are promising for Malawi where marriage occurs early and is nearly 
universal,28 and a large share of transmission occurs within marriages.29 Couple-based approaches have been used 
in a variety of settings to address HIV-related testing, prevention, and treatment behaviors.22,30-33 Such approaches 
typically incorporate several effective elements: couple communication, joint problem solving and goal-setting;34,35 
sessions for individual couples rather than groups; and >1 intervention session.35 In formative work, we have gained 
additional insight into how to implement couple-based approaches in an Option B+ setting.  
 
Couple-based approaches for 90-90-90 targets in men: In SSA, the proportion of women who know their HIV status 
is higher than men, in part due to high rates of antenatal testing. Because nearly all HIV-infected pregnant women 
have an HIV-infected male partner, recruiting the partners of HIV-infected pregnant women is an appealing 
approach to achieving the first “90%” target. However, antenatal recruitment of male partners for couple HTC has 
proven challenging. In studies with patient-led approaches, male partner recruitment is typically <30%36-38 
However, health-sector led approaches or incentives typically lead to >50% uptake of couple HTC.39-41 In a pilot 
assessment at Bwaila District Hospital, providing HIV-infected pregnant women with an invitation, clinic-led phone 
and physical tracing, and a research incentive led to 74% of couples seeking couple HTC.42 Seventy-one percent 
were HIV-infected and 47% received an HIV-positive diagnosis for the first time. Although couple HTC was 
effective for identifying HIV-infected men, it was not sufficient for linking HIV-infected men to care. Busy 
schedules accounted for a large share of non-linkage and loss, and men indicated that availability of cART at the 
time of couple HTC would have led to initiation. Additionally, having partners pick up cART would alleviate care-
seeking challenges. Thus, initiating both couple members in the antenatal setting, synchronizing their ART pickup, 
and allowing them to pick up drugs for one another is a promising strategy for improving the second “90%” target. 
For the third 90% target, adherent persons indicated that daily partner reminders, and synchronized pill-taking 
facilitate adherence, strategies that will be incorporated into the couple intervention.   
 
Prevention behaviors for men in HIV-discordant couples: Couple HTC has been associated with consistent condom 
use in this population, as well as others throughout the region.43-45 However, in our population there was confusion 
surrounding biomedical prevention approaches. Ensuring that couple-based approaches more clearly explain 
different HIV prevention options is important for helping couples remain protected. Through formative  work, we 
have developed a greater understanding of the dyadic context in which condom use is occurring. Interdependence 
Theory, a dyadic model, identifies a combination of actor, partner, and joint effects for behavior change. Each 
person’s behavior can be affected by that person (actor effects), his or her partner (partner effects), or a combination 
of both together (joint effects). The relationship context (i.e. commitment, intimacy, satisfaction, trust, 
communication, HIV communication, and sexual power) could account for these joint effects,46-51 but varies by 
setting. 47,52-55 In this setting, we found that couple communication and social support improved following CHTC. 
 
Couple-based approaches for 90-90-90 targets in women and infants: In ANC settings in Malawi, HIV testing and 
immediate ART initiation are nearly universal, but retention and adherence remain challenging.56,57 Failure to 
disclose one’s HIV status to a male partner is one key barrier to ART initiation.58 In Bwaila District Hospital, we 
have found that women who received couple HTC are more likely to return for a first ART refill visit compared to 
those who do not receive couple HTC. Disclosure made it easier for some women to take pills openly and enabled 
social and financial support from partners. This support included couple-based routines, synchronized pill-taking, 
and daily reminders. These components have bene incorporated into the enhanced couple HTC intervention. 
 
In summary, an emerging body of evidence in the region overall, and in our setting specifically, suggests that 
couple-based approaches could support a range of HIV testing, prevention, and treatment behaviors for HIV-
infected pregnant women and their male partners. However, well-designed research is needed to determine the 
effect of couple-based approaches.  

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 13 of 46 
 
Rationale for enrolling HIV-uninfected women  
HIV acquisition during pregnancy and breastfeeding leads to maternal morbidity and mortality and threatens to 
undermine elimination of mother to child transmission (eMTCT) efforts. This is due to the majority of pregnant 
women being HIV-negative,59 high rates of maternal HIV acquisition during pregnancy and postpartum,60,61 and 
elevated rates of vertical transmission at the time of maternal HIV acquisition. 62-66 As Option B+ test-and-treat 
programs have become more successful at reaching HIV-positive women at their first antenatal visit, a larger share 
of vertical transmissions will stem from maternal HIV acquisition after the first antenatal visit.67,68 These elevated 
risks have been observed in Malawi where one third of vertical transmissions among infants <3 months stem from 
new undiagnosed maternal HIV infections during pregnancy.69 Understanding the bio-behavioral characteristics of 
women most at risk for HIV acquisition and the male partners who transmit to them is critical for preventing 
maternal HIV acquisition and ultimately realizing eMTCT.  
 
 Initiating biomedical prevention, such as tenofovir-based oral pre-exposure prophylaxis (PrEP), during pregnancy 
is a promising approach for reducing maternal HIV acquisition.70-72 Daily oral PrEP, in the form of tenofovir-
emtricitabine (TDF-FTC), is safe in pregnancy70 and highly effective for preventing HIV when adherence is high.70-
72 In Malawi, the provision of PrEP in antenatal settings is appealing due to high fertility (4.4 births per woman) 
and near-universal antenatal attendance.59 However, offering PrEP to all HIV-uninfected Malawian pregnant 
women is not feasible or cost-effective73 and, as such, is not supported by the Malawi Ministry of Health. PrEP is 
recommended for populations with annual HIV incidence above 3%,74 but Malawi’s estimated HIV incidence in 
young pregnant women is only 0.6%.75,76 Thus, identifying a subset of pregnant women with HIV incidence above 
3%, such as HIV-discordant couples, women with multiple sexual partners, or women with sexually transmitted 
infections, who would benefit most from PrEP, is a critical component of implementation. Such risk targeting is 
promoted by the World Health Organization as part of a comprehensive PMTCT package.74  
 
Clinical risk scores are prediction tools for identifying sub-populations at higher risk for specific outcomes.77-80  
Recently, a risk score was developed to identify Kenyan pregnant and postpartum women with elevated risk for 
HIV acquisition.81 When the score was restricted to clinically available information (Table 1), the area under the 
receiver operating characteristic curve (AUC) was 0.76 (95% CI: 0.67-0.85), moderate predictive ability. This study 
demonstrated that risk targeting was possible in this single setting, but with moderate performance—external 
validation and possibly updating are next steps. Geographical validation examines the transportability of an existing 
risk assessment tool to a new setting.80 If the Kenyan model performs well in Malawi, this will enhance the 
generalizability of the tool. However, if it performs poorly, model updating may be needed. Updating can take 
several forms, including re-weighting the same variables, adding or removing variables, or developing a new tool. 
We have identified several variables that may be appropriate for consideration. In formative work in the antenatal 
setting (K99 MH104154),82 comparing HIV-infected pregnant women and their primary sexual partners to HIV-
uninfected women and their primary sexual partners, we identified three sets of risk factors associated with 
prevalent HIV-infection in pregnancy: 1) an HIV-positive primary sexual partner, 2) a primary sexual partner 
outside of Lilongwe for an extended period, and 3) male or female report of ≥2 lifetime marriages or ≥3 lifetime 
sexual partners (Table 1).83 In Girl Power-Malawi, a cohort study among non-pregnant young women 15-24 years 
old (UK Aid),84 we identified 11 female-reported individual, partner, and dyadic factors associated with HIV 
infection (Table 1).85 Young women with >3 of these factors had a 4% annual HIV incidence rate, fourteen-times 
higher than those with <1 factor. Differences in these different approaches reinforce the need for external validation. 
By enrolling HIV-uninfected pregnant women and comparing them to recently HIV-infected pregnant women , we 
will validate and, if needed, update a risk assessment tool for Malawian pregnant women.  
 
Hypotheses  
The overarching hypothesis of this study is that a couple-based approach is superior to an individual-approach 
(standard of care) for achieving a range of maternal, male partner and infant outcomes within Malawi’s Option B+ 
program.  
Table 1. Risk factors of interest 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 14 of 46 
 
 
Specific Aims/Study Objectives 
This study has five sets of specific aims (study objectives), which relate to HIV-infected male partners, HIV-
uninfected male partners, HIV-infected pregnant and breastfeeding women, and HIV-exposed infants. These are 
described below: 
Aim 1: Determine whether the couple-based intervention increases new HIV-positive diagnoses among HIV-
infected male sex partners, helps HIV-infected men engage and remain in care, and contributes to male viral 
suppression compared to individual standard of care. We will compare the couple-based intervention to standard 
of care for increasing the proportion of men who are aware of being HIV-infected, the proportion of these men who 
initiate and remain in cART care, and the proportion of these men with viral suppression at one year.  
 
Aim 2: Determine whether the couple-based intervention identifies HIV-discordant couples and decreases 
the likelihood of male exposure to HIV compared to individual standard of care. We will compare the 
intervention to standard of care for increasing the number of men with non-HIV exposure from their female partner 
through consistent condom use, viral suppression, abstinence, or a combination of these methods over one year.  
 
Aim 3: Determine whether the couple-based intervention improves female cART retention and viral 
suppression compared to individual standard of care. We will compare the intervention to standard of care for 
female cART retention and viral suppression at one year.  
 
Aim 4: Determine whether the couple-based intervention improves infant early infant diagnosis uptake 
compared to individual standard of care. Explore uptake of early infant diagnosis and rates of mother-to-child 
transmission and child survival in the two intervention arms. 
Aim 5: Develop an in-depth understanding of HIV transmission dynamics in Lilongwe. Using the biomarkers 
and behavioral survey, we will seek to understand transmission timing, direction, and context in Lilongwe. We will 
compare women with recent HIV infection to a population of HIV-uninfected controls to understand predictors of 
HIV acquisition in pregnancy in Malawi.  
 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 15 of 46 
 
Methodology 
Study Design:  
A couple-based intervention will be compared to individual standard of care (SOC) in an un-blinded randomized 
controlled trial (RCT) (N=500 women) to assess identification of HIV-infected men, their one-year retention in 
care, and viral suppression (Aim 1); identification of HIV-discordant couples and adoption of non-exposure to HIV 
(Aim 2), female one-year retention in care and viral suppression (Aim 3), and infant ED (Aim 4). The trial will also 
compare the two arms for social harms. Additionally, the HIV-infected women with recent HIV infection will be 
compared to a control population of HIV-uninfected women.  
 
Study Setting 
The study will be conducted at Bwaila District Hospital and/or Area 18 Health Centre if enrollment is slow or other 
challenges arise. Bwaila District Hospital is a large maternity hospital serving the greater Lilongwe catchment area. 
Within Bwaila antenatal clinic (ANC) and labor and delivery (L&D), women are routinely screened for HIV 
infection using opt-out individual HTC, and immediately eligible for cART through Option B+ if found to be HIV-
infected. Similar procedures are planned for Bwaila’s immunization clinic which sees breastfeeding women. 
Women who are initiated on cART are seen monthly for the first six months and then every three months thereafter. 
Malawi has adopted a test-and-start model of care of all adults, but men cannot initiate cART in these Option B+ 
settings even though they can test there.   
 
Study Population 
The study will be conducted at Bwaila District Hospital and moved to Area 18 Health Center if needed. Women 
will be eligible to participate if they meet the following criteria: 
Primary Population Inclusion Criteria  
• 
HIV-infected and eligible for Option B+  
• 
>18 years old or 15-17 years old and married (emancipated minors per Malawi law)  
• 
Planning to remain in the Bwaila catchment area for the next year or notify the study team if they leave 
the area or change facilities 
• 
Part of a heterosexual relationship for >3 months  
o Expects the partner to be in the relevant catchment area for at least one week in the next six months.  
o Able and willing to give locator information for this partner  
o Willing to have study staff conduct phone and physical tracing of that partner   
o Willing to undergo a couple-based intervention with this partner  
• 
Able and willing to provide informed consent 
 
Exclusion criteria 
• 
Any condition that in the opinion of the study investigator would compromise the ability of the 
prospective participant to provide informed consent, undergo study procedures safely, or would prevent 
proper conduct of the study. 
 
Enrolling pregnant women is essential as this is the primary population eligible for Option B+. The target sample 
size is 500 women randomized in a 1:1 ratio to two arms (250/arm), up to 500 of their partners, and up to 
approximately 500 infants (although more are possible due to non-singleton births). It is expected that 14,000 
women will present for antenatal care at this hospital over a 12-month period. Approximately 700 (5%) will be 
newly diagnosed as HIV positive and 500 (71%) will meet eligibility criteria. Enrollment may take longer if there 
are fewer pregnancies, a lower HIV prevalence, or lower eligibility rates. The participant will be followed for one 
year and data may be abstracted from clinic records over a three year period. 
 
Male partners will be eligible if they present to the antenatal clinic, are >18 years old or 15-17 years old and 
married (i.e. an emancipated minor), and confirm that they have been in a relationship with the female partner for 
>3 months. They must be willing to undergo CHTC with their female partner and be able and willing to provide 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 16 of 46 
 
informed consent. They must believe participation will not result in intimate partner violence or abandonment. 
Men will be actively followed for one year and their data will be abstracted for up to three years.  
 
Infants (singletons and twins) will be eligible if they are born during the study period or if the mother was 
identified as HIV-infected while delivering or breastfeeding that infant. The participant will be followed for one 
year and data may be abstracted from clinic records over a three year period from maternal enrollment. 
 
Control population  
HIV-uninfected women (N=350) will be enrolled as a control population using comparable inclusion criteria. 
These women will be enrolled for participation in a survey at their first antenatal visit. They will not have any 
additional visits or enroll male partners.  
 
Randomization 
Women will be randomized to Standard of Care (SOC), a predominantly individualized approach to Option B+, or 
to a couple intervention, a predominantly couple-based approach to Option B+. Permuted block randomization with 
block sizes of 2, 4 and 6 will be used to ensure approximately equal groups and mask the assignment procedures to 
the study staff. The allocation list will be generated using a random number generator in Stata or comparable 
program.  
 
Schedule of visits  
 
 
 
 
 
 
 
 
 
 
 
 
Mo. 0 
Wk 0-4 
Mo. 1 
Mo. 2 
Mo. 3 
Mo. 4 
Mo. 5 
Mo. 6 
Mo. 9 
Mo. 12 
Pregnancy 
(pg)/ 
postpartum (pp) 
(Medians) 
5 mo   
pg 
5 mo 
pg 
6 mo  
pg 
7 mo  
pg 
8 mo  
Pg 
9 mo  
pg 
1 mo  
pp 
2 mo  
pp 
5 mo  
pp 
8 mo  
pp 
Female standard of 
care 
ART 
 
ART 
ART 
ART 
ART 
ART 
ART/VL 
ART 
ART 
Female 
study 
activities 
Female 
study visit1 
 
 
 
 
 
 
Female 
study visit2 
 
Female 
study visit3 
Screening  
x 
 
 
 
 
 
 
 
 
 
Enrollment 
x 
 
 
 
 
 
 
 
 
 
Locator info 
x 
 
 
 
 
 
 
 
 
 
Behavioral Survey 
x 
 
 
 
 
 
 
x 
 
x 
Blood collection 
x 
 
 
 
 
 
 
x 
 
x 
Locator 
info. 
Verification 
 
x 
 
 
X 
 
 
x 
 
x 
Male study 
activities 
 
M. study  
visit 1 
 
 
 
 
 
 
 
M. study 
visit 2 
Screening 
 
x (C) 
 
 
 
 
 
 
 
x (I) 
Enrollment  
 
x (C) 
 
 
 
 
 
 
 
x (I) 
Behavioral Survey 
 
x (C) 
 
 
 
 
 
 
 
x 
Blood collection 
 
x (C) 
 
 
 
 
 
 
 
x 
Couple Intervention 
Activities  
 
 
Couple 
interv’n 
visit 1 
 
 
 
 
Couple 
interv’n 
visit 2 
 
Couple 
interv’n 
visit 3 
Disclosure/invitation 
support to woman 
x 
 
 
 
 
 
 
 
 
 
Phone/physical 
Tracing 
 
x 
 
 
 
 
 
 
 
 
Couple 
counseling 
(and testing)  
 
x 
 
 
 
 
 
x 
 
x 
Provide condoms 
 
x 
 
 
 
 
 
x 
 
x 
Dispense ART to men 
 
x (C) 
x (C) 
x (C) 
x (C) 
x (C) 
x (C) 
x (C) 
x (C) 
x (C) 
Infant activities  
EID conduct 
 
 
 
 
 
 
 
x 
 
 
Rapid test 
 
 
 
 
 
 
 
 
(x) 
 
(C)=Couple arm only; (I)=Individual arm only  
 
 
 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 17 of 46 
 
 
Study Procedures  
Upon learning that the woman is HIV-positive, she will be screened and assessed for eligibility (Screening) after 
providing oral consent. Study staff will maintain a screening log with documented reasons for non-eligibility. 
Women interested in participating will be consented into the study, administered a brief survey, provide locator 
information and randomized to one of the study arms.  
 
• 
Female study visit 1 (baseline): Following those procedures, women will be administered a one-hour 
behavioral survey about demographics and socio-economic status, their sexual and care seeking 
behaviors, migration, and partnership characteristics. They will have a venous blood draw of 
approximately 20ml.  
 
• 
Female study visit 2 (midline): The next visit, will occur approximately six months after visit 1. At this 
visit, women will fill out a comparable behavioral survey.  
 
• 
Female study visit 3 (endline): The next visit, will occur approximately twelve months after visit 1. At 
this visit, women will fill out a comparable behavioral survey. They will have a venous blood draw of 
20ml. Patient materials will be provided on family health information.  
 
Men will be screened for the study and assessed for eligibility and consented. For those in the couple arm, this 
will occur upon first presentation (typically approximately one week after female study enrollment). For those in 
the individual arm, this will also occur upon first presentation (typically one year after female study enrollment).  
 
• 
Male study visit 1 (baseline): Only men in the couple intervention arm will have this visit, and this will 
coincide with intervention visit 1. This visit will occur approximately one week after the female 
intervention visit 1. At this visit, men will fill out a behavioral survey with similar information to the 
female survey. They will have a venous blood draw of approximately 20 ml.  
 
• 
Male study visit 2 (endline): This visit will occur approximately twelve months after the female’s visit 1. 
At this visit, men will fill out a behavioral survey with similar information to the female survey. They will 
have a venous blood draw of approximately 20ml.  
 
Study tracing procedures 
Because this is a longitudinal study with few visits, efforts will be made to maintain contact with all participants 
throughout the study. Ascertaining outcomes on the entire cohort is a challenge as many will not present to the 
clinic and this is expected to be differential by arm. Specifically, 1) male testing outcomes cannot be observed 
among men do not present to the clinic, 2) loss-to-care outcomes cannot be distinguished from informal transfer 
without review of clinic documentation, and 3) viral suppression cannot be ascertained without a blood draw. To 
address this challenge, we will collect data prospectively, when possible, and retrospectively otherwise. Rigorous 
tracing procedures will support retrospective data collection. First, at the initial visit, women will provide extensive 
phone and physical tracing information. To verify physical locations, participants will use Google Earth and draw 
maps. Community workers may accompany participants home to learn their physical address. The community 
workers will make routine contact with all study participants on a quarterly basis to update locator information. 
They will provide study participants with study contact information and ask participants to call the study staff should 
they transfer facilities or change their locator information. If one or both members of the couple does not come for 
their study visits, study procedures can be conducted in the community or by phone. Detailed standard operating 
procedures outlining such processes will be developed to protect privacy and confidentiality.  
 
 
 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 18 of 46 
 
Standard of Care for Women, Infants, and Male Partners  
Within the Option B+ program, all women are administered ART within one week of an HIV-positive test result 
(and typically on the same day). For the first six months, they receive a monthly supply of antiretroviral therapy 
and attend the clinic monthly. After six months, if they have good adherence, they receive a three-month supply 
of treatment, and attend the clinic every three months. Women who present with male partners receive standard of 
care CHTC, but this occurs for a minority of women (approximately 10%). Men identified as HIV-infected cannot 
initiate treatment in Option B+ settings. Additionally, condoms are available through the pharmacy, but not by the 
HTC counselors. Women have a first viral load test at six months. Infants undergo early infant diagnosis with 
DNA PCR six weeks after delivery and an HIV rapid test at twelve months. Those who are HIV-infected begin 
antiretroviral therapy immediately. Standard of care may evolve over the course of the study as it is being 
implemented over a 2-year period. 
 
Individual arm procedures (N=250) 
No intervention procedures beyond standard of care procedures will be conducted in the individual arm. Women 
randomized to the individual arm will undergo the study procedures described above. At the twelve month visit, 
couples in this arm who present together will receive standard of care CHTC. An intervention will be given to 
women, as needed to support inviting the male partners.  
 
Couple arm procedures (N=250) 
In addition to the study procedures and standard of care procedures described above, women in the intervention 
arm will undergo the following procedures: 
 
• 
Female intervention visit 1 and partner tracing: Women in the couple arm will then be provided with 
study-specific partner referral cards and encouraged to bring male partners to antenatal care for important 
pregnancy information. The referral card will contain a specific time for male partners to present to the 
clinic, but note that this is flexible. The card will describe the purpose of the visit as pregnancy-related, 
not HIV-related. It will not contain information about the woman’s HIV status or HIV care-seeking. 
Phone and physical tracing will be conducted with utmost regard for protecting the privacy of enrolled 
women and their partners through detailed standard operating procedures.   
 
• 
Couple intervention visit 1 (day 0-30): Upon presentation, the couple will receive an enhanced CHTC 
intervention. The intervention will include pre-test counseling, return of joint results, and post-test 
counseling with differentiated messages for HIV-discordant and HIV-concordant couples. The counselor 
will follow a structured set of procedures that promote intra-couple communication, address gendered 
power dynamics, and encourage joint decision-making and goal setting. HIV-infected men can initiate 
cART at the antenatal clinic and the couple will be offered condoms from the HTC counselor. A small 
monetary or non-monetary allowance ($5 equivalent) will be provided. 
 
• 
Couple intervention visit 2 (month 6): Upon presentation, the couple will receive an enhanced couple-
intervention similar to couple visit 1. It will be similar to visit 1, but will not include testing for HIV-
concordant positive couples. In addition, EID will be provided if the infant has not had it yet, as these 
visits are likely to coincide. Counselor will discuss the importance of birth spacing and provide or refer 
for contraception. A small monetary or non-monetary allowance ($5 equivalent) will be provided. This 
will coincide with the female visit 2.  
 
• 
Couple intervention visit 3 (month 12): Upon presentation, the couple will receive an enhanced couple-
intervention similar to couple visit 2. Conduct of or reminder of infant 1-year HIV test will be conducted. 
This will coincide with the female study visit 3 and male study visit 2.  
 
• 
Between visits: Between sessions, couple members can pick up condoms and cART for one another. 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 19 of 46 
 
 
The following graphic depicts the differences between the two interventions. The standard of care may evolve over 
the course of the study.  
 
 
Figure 1. Intervention Overview 
 
 
Behavioral Survey 
This will be administered to women and men at each study visit to assess demographics and socio-economic status, 
HIV care-seeking and prevention behaviors, sexual behavior, intimate partner violence, couple HIV 
communication, power, self-efficacy and social harms.  
 
In-depth Interviews 
In depth interviews will be conducted with a subset of the population. Up to 10% of women and their male partners 
may be selected to answer in-depth questions about their study participation at enrollment and baseline and endline. 
In-depth interview guides will be developed to support administration of these semi-structured interviews. 
 
Biomarkers 
Blood will be collected to conduct the following tests: 
• 
HIV rapid antibody tests: Determine and Unigold are used in the national HIV program. They will be 
used to detect HIV among women and men in both arms. Although we do not anticipate changes, it is 
possible that Malawi will change its testing protocol: such changes would be considered acceptable and 
adopted in this study.  
 
• 
Viral load: This will be conducted at female study visit 3 (12 months) and male study visit 1 among HIV-
infected men (12 months). These will be study-related measures that exceed standard of care. They will be 
performed by UNC Project laboratory. This laboratory participates in the Virology Quality Assurance 
Laboratory that oversees QA/QC for assay and laboratory technologist performance for the HPTN/ACTG 
laboratory network. In addition, we will abstract results from standard of care routine viral load testing 
conducted at the 6 month visit.  
 
• 
Syphilis: Point of care rapid syphilis tests will be offered to participants according to standard of care with 
results offered to participants—e.g. at the first antenatal visit. Additionally, blood specimens will be 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 20 of 46 
 
collected, stored, and run in batch mode at the end of the study. These results will not be available to 
participants. This will be collected at female study visit 3 and male study visit 2.  
 
• 
HSV-2: Blood specimens will be collected, stored, and run in batch mode at the end of the study. These 
results will not be available to participants. This will be collected at female study visit 1 and 3 and male 
study visit 1 and 2.  
 
• 
Viral genetic testing: Blood specimens will be collected, stored, and run in batch mode at the end of the 
study. These results will not be available to participants. This will be collected at female study visit 1 and 
male study visit 1 or 2 (whenever HIV diagnosis occurs). These will be used to determine phylogenetic 
linkage to the partner and estimated duration of infection. 
 
• 
Multi-assay algorithm to classify HIV recent infection: Blood specimens will be collected, stored, and 
run in batch mode at the end of the study. This will be collected at female study visit 1 and male study visit 
1 or 2 (whenever HIV diagnosis occurs). Optimal algorithms continue to evolve and we will select the 
algorithm with the best performance characteristics. This will likely consist of BED capture immunoassay, 
an avidity assay using a modified version of the Genetic Systems ½+O ELISA, CD4 count, and HIV RNA 
concentrations to identify person with recent infection.  
Testing on syphilis, HSV-2, viral genetic testing, and multi-assay algorithms are contingent on supplemental 
funding.  
HIV-uninfected women: Controls will be frequency matched based on pregnancy duration at the first antenatal 
visit, a known confounder. Eligibility criteria will be comparable to the HIV-infected women. Eligible women 
will be enrolled, consented, and administered a comparable behavioral survey as HIV-infected women.  
Primary outcomes and statistical power 
The primary outcomes are organized by aim (Table 1). Based on historical data, we expect that 70% of male partners 
to be HIV-infected (N=350/500) and 30% (N=150/500) to be HIV-uninfected.  
 
In Aim 1 the primary outcomes are the UNAIDS 
continuum of care indicators: the proportion of HIV-
infected men aware of their HIV status, the proportion 
retained in care at one year, and the proportion virally 
suppressed (<1000 copies/µl). For all three outcomes, 
we have >90% power to detect a risk difference of 90% 
in the couple intervention arm and 70% in the SOC arm 
at each step of the continuum. We have >99% power to 
detect a difference in the overall continuum (34% versus 
73%).  
 
In Aim 2 the primary outcome is the proportion of men 
without HIV exposure from their primary partner. This 
is a composite outcome based on abstinence, female 
viral suppression, and consistent condom use. Men will be considered non-exposed for one year if, during the first 
six months there are no unprotected sex acts, and, during the second six months, there are no unprotected sex acts 
or the woman is virally suppressed (<1000 copies/µl) at six and 12 months. We have 94% power to detect a risk 
difference of 85% in the couple intervention arm and 60% in the SOC arm.  
 
In Aim 3 the primary outcomes are UNAIDS continuum of care indicators: the proportion of HIV-infected women 
retained in care at one year and the proportion virally suppressed at one year (<1000 copies/µl). For both indicators, 
(n/N)
%
(n/N)
%
Power
HIV+ Men (estimated N=175/arm)
HIV+ men diagnosed + 
(123/175) 70%
(158/175) 90% >99%
HIV+ men retained for one year
(86/123) 70%
(142/158) 90%
99%
HIV+ men virologically suppressed
(60/86) 70%
(128/142) 90%
96%
Overall cascade 
(60/175) 34%
(128/175) 73% >99%
HIV- Men (estimated N=75/arm)
HIV non-exposure 
(45/75) 60%
(64/75)
85%
94%
HIV-infected women (N=250/arm)
Retained in care 
(200/250) 80%
(225/250) 90%
88%
Virlogically suppressed
(160/200) 80%
(203/225) 90%
83%
Overall cascade 
(160/250) 64%
(203/250) 81%
97%
SOC Arm
Couple Arm
Table 2. Power calculations 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 21 of 46 
 
there is >80% power to detect risk differences of 80% (SOC arm) and 90% (intervention arm) at each continuum 
step. To assess outcomes on the overall continuum (64% versus 81%), we have 97% power. For all male outcomes 
and the female overall continuum outcome, even with 10% attrition, due to couple dissolution or other factors, we 
have >80% power to detect these expected differences.  
 
In aim 4 we will compare the individual to the couple arm for a) the proportion of infants who had early infant 
diagnosis. To assess this outcome (0.6 versus 0.75 with 20% attrition), we have 87.5% power. We will also explore 
the rates of mother-to-child transmission and child survival in the two intervention arms.  
 
Aim 5 is a primarily descriptive aim and we are therefore power calculations are not needed for descriptive 
variables. To identify predictors of recent HIV infection, we conducted a power calculation appropriate for detecting 
odds ratios. If 10% of HIV-infected women (N=50) have recent HIV infection (cases), we will need to enroll 350 
controls to detect an odds ratio of 2.5, assuming an alpha level of 0.05, 80% power, and 20% prevalence of an 
exposure of interest in the control population.   
 
Data collection, management, and analysis 
All data will be collected by trained research assistants with certifications in humans subjects projections and good 
clinical practices. All female participants will be followed for one year with study assessments at baseline, 6 months, 
and 12 months.  Data will be collected from participants or clinic records in Microsoft Access or Open Data Kit 
software on Android tablets, and stored on a secure server. Additionally, clinical data from the Baobob system or 
patient records will be collected or downloaded. Intervention fidelity will be obtained using intervention checklists 
completed by those delivering the intervention and observers.   
 
The primary analysis for this study will be intention to treat. For each outcome of interest, generalized linear models 
with an identity link and binomial distribution to estimate risk differences and ninety-five percent confidence 
intervals. Per protocol analyses will also be conducted as well based on presence of at least one CHTC visit.  
 
Ethical and human subjects considerations 
Institutional Review Board oversight and informed consent 
Approval for the study will be sought from UNC’s IRB and Malawi’s National Health Sciences Research 
Committee. These two bodies will provide oversight for the study. This protocol and the informed consent 
documents and any subsequent modifications will be reviewed and approved by both bodies. All procedures 
conform to US and Malawian ethical standards regarding research involving human subjects.  
 
Written informed consent will be obtained.  All study participants will sign an informed consent prior to 
enrollment. The consent form  will describe the purpose of the study, the procedures to be followed, the contact 
information of the local study contact investigator, and the risks and benefits of participation in accordance with 
all applicable regulations. The informed consent forms will be translated into the local language (Chichewa) and 
accuracy will be confirmed. Partners will also provide informed consent prior to study participation.  
 
Literate participants will document their provision of informed consent by signing their informed consent form. 
Non-literate participants will be asked to document their informed consent by marking their informed consent form 
(e.g., with an X, thumbprint, or other mark) in the presence of a literate third-party, impartial witness. Any other 
local IRB/ethics committee requirements for obtaining informed consent from non-literate persons also will be 
followed.  
 
Participants will be provided with copies of their informed consent forms if they are willing to receive them and 
believe they will not lead to difficulties if found by partners or other persons. It will be stressed with each 
potential participant that participation in this study is completely voluntary. Potential participants will be told that 
if they choose not to participate, there will be no penalty; they can continue to participate in other research studies 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 22 of 46 
 
or programs at the site and there will be no changes in the services they may receive at the clinic where they were 
contacted about this study. The consent will also inform participants that they have the right to refuse or withdraw 
from participation at any time.  
The investigators have experience obtaining informed consent for trials in Lilongwe and thus the informed 
consent process has been designed to maximize understanding of potential risks.  
 
Potential Risks  
All potential risks for the patients must be weighed in the context of the current standard of care for patient 
management.  Encouraging male partner attendance is already part of the standard of care at Bwaila Hospital and 
Malawi’s national PMTCT program and when men do attend they are encouraged to receive couple HIV counseling 
and testing. Thus, many study procedures are consistent with clinic procedures. There are four types of potential 
risks that may occur: breach of confidentiality or privacy, reactions to sensitive topics, social harms, and physical 
harms.  
 
Breach of confidentiality may occur through the partner notification procedures if the health worker accidentally 
discloses confidential information about one partner to the other. There could also be breach of privacy if the 
community has identified the health care worker as someone who works on HIV-related issues and presumes the 
male partner has HIV. Similarly, at the initial couple counseling session, the two members of the couple may not 
know each other’s HIV status. Counselors may accidentally disclose HIV status before receiving consent to do so 
from both participants. Participants may also feel concerned that their one-on-one interview information will be 
shared with their partner.  
 
The questionnaires will assess sensitive topics, including sexual behavior and intimate partner violence. Participants 
may have strong emotional reactions to being asked about this type of information. This is also a potential source 
of risk in both phases of the study.  
 
Social harms are also a potential risk for participants in this research due to the sensitivity of these issues. Possible 
social harms include verbal or physical intimate partner violence, divorce, or abandonment, and their sequelae. In 
the Malawian context divorce or abandonment may also signify loss of income and social ostracism.  
 
The primary physical harm pertains to risk from a venous blood draw. The risk of venous blood draw may cause 
bruising, pain, or make the client feel faint. However, quantities of blood collected are minimal and in line with that 
typically collected for routine medical procedures. 
 
Adequacy of Protection against Risks 
Female participants will be recruited form Bwaila District Hospital Option B+ program following routine HIV 
counseling and testing when they become eligible for Option B+. Males will be recruited for enrollment when they 
present to the clinic either alone or with their index sex partner.  
 
Male partners may be recruited in the community by community recruiters. Standard operating procedures will be 
developed to ensure the protection of confidentiality. Community recruiters will be rigorously trained on these 
procedures. Training will include practical sessions so they not only learn what the procedures are but also how to 
appropriately operationalize them. We will apply lessons learned from the feasibility pilot assessment to both the 
procedures themselves and the training on these procedures.  
 
In all aims, eligible persons will be recruited by trained research staff fluent in their native language to initiate the 
consent process. In order to protect persons against intimate partners, we will ensure that prospective participants 
do not believe that participation will lead to intimate partner violence or abandonment. This will screen out those 
at highest risk for intimate partner violence and other social harms. Research staff will go over the entire informed 
consent with the eligible persons and describe: the purpose of the study, the detailed procedures to be followed, the 
risks and benefits of participation, the duration of participation, and the steps taken to protect the participant. The 
eligible person will be given the opportunity to ask questions. No coercion will be placed on persons to enroll in 
the study. It will be explained that declining consent will not have any impact on the care they receive. Importantly, 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 23 of 46 
 
the informed consent will detail the possible social harms that could occur as a result of the study. Trained research 
staff will be trained to discuss the pros and cons of participation with all prospective participants. They will 
discourage participation among those who anticipate a severe social harm. The consent will also inform persons 
that they can withdraw at any time should they change their mind. Written informed consent will be obtained from 
each participant and participants will be provided with a copy of their informed consent forms. Study staff will 
document the informed consent process. The entire consent process will be conducted in accordance with the 
relevant US-based institutional review board, as well as the National Health Sciences Research Committee, the 
local regulatory body.  
 
Privacy of male and female partners is of highest importance. In both the clinic and the community, all study-related 
activities will occur in private locations. Health workers in the clinic and community will follow a rigorous set of 
procedures to ensure they are not intentionally or inadvertently disclosing HIV status or any other sensitive 
information from one partner to the other or to other members of the community.  
 
 
Through the partner notification process, community health workers will not identify themselves as persons from 
an HIV-related activity. They will present themselves as general health workers or community members. 
Community health workers will not begin the notification process until they have confirmed the identity of the male 
partner. They will follow a script about why they are in the community and why they would like to recruit the men 
to the clinic.  
 
At the couple counseling sessions, the two members of the couple may not know each other’s HIV status or other 
personal information. Counselors will be trained not to disclose past HIV status or other information. 
 
To protect participants against risks associated with sensitive topics, they will be reminded that the answer to their 
questions will be kept confidential and that this information will not be shared with anyone, including their sex 
partner. They will be allowed the opportunity to refuse to answer certain questions.  
 
Social harms will be actively monitored in both phases of research through formal assessment. One key purpose of 
the formative work was to determine whether the prevalence for social harms is too high in this setting. This was 
not the case, so substantial modifications to the strategy have not been made. Among 300 HIV-infected women in 
this setting participating in similar studies, none reported intimate partner violence as a result of study participation 
and less than 2% reported abandonment. It is critical to monitor and appropriately address social harms. Social harm 
monitoring will occur through both routine and ad hoc screening. At all study visits, social harms will be assessed 
in both partners through a structured assessment form. This form will assess both the nature and the magnitude of 
the harm. Additionally, participants will be encouraged to come to the clinic when a social harm occurs. During 
these ad-hoc visits, the same social harm form will be filled out. When social harms do occur they will be reported 
according to ethical body regulatory procedures for adverse events. Social harms will be addressed through a set of 
standard operating procedures that includes referrals for medical, legal, or psychosocial services. We have begun a 
situational analysis that has already identified numerous resources in the catchment area. These include a special 
police unit for addressing domestic disputes, counseling on alcohol abuse, family counseling, marital counseling, 
HIV counseling, HIV support groups, rape crisis services, and inpatient and outpatient medical services. We will 
expand this situational analysis on an annual basis. Referrals will be documented and we will follow up on the 
outcomes.  Social harms will be reported as a main outcome in the primary study manuscript so harms and benefits 
can easily be considered together.  
 
The primary physical harm pertains to risk from a venous blood draw. The risk of venous blood draw may cause 
bruising, pain, or make the client feel faint. However, quantities of blood collected are minimal and in line with that 
typically collected for routine care. They will be collected in a health facility and near trained medical personnel 
should the patient become faint. 
 
Potential Benefits of the Proposed Research to the Subjects and Others 
There are potential benefits of the proposed research to the subjects themselves and to others. For HIV-infected 
women who participate in the intervention, it is possible that the involvement of their partner will lead to physical 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 24 of 46 
 
or psychosocial health benefits for themselves or their infants. In formative work, we saw improvements in social 
support and couple communication following couple counseling. For HIV-infected men, it is possible that the 
intervention may help them link to care sooner than they otherwise would or become re-linked to care if previously 
lost. For HIV-uninfected men, there is the possibility that the intervention may help them take measures to 
effectively limit their exposure to HIV and prevent transmission. For women, there is the possibility that this can 
lead to improved retention in care or adherence. For infants, there is the possibility that the research will lead to 
earlier and more thorough HIV diagnosis—this can be life-saving.  
 
This research is designed to benefit society by gaining new knowledge. Understanding how to optimize the 
implementation of Option B+ is critical given the high human and economic costs of the disease in this region. 
Research findings will be disseminated within Malawi and internationally.  
 
 
Importance of the Knowledge to be Gained 
There is considerable potential for the proposed research to generate findings of importance. Specifically, the 
activities proposed are designed to enhance the quality and effectiveness of the Malawi Option B+ program for 
women, linkage to HIV care for HIV-infected men, and prevention from HIV for men. This has implications not 
only for Malawi but also for other high prevalence countries. Results will be disseminated nationally, regionally, 
and internationally.  
 
Reportable Events 
All serious adverse events associated with the procedures will be appropriately reported to the UNC IRB and the 
Malawi NHSRC according to their reporting procedures. Field staff in Malawi will be trained to complete 
descriptions of adverse events that will then be sent electronically to both the PI and the co-PI. Thus, adverse 
events will be monitored at three levels; by the Principal Investigators, by the UNC IRB and by the NHSRC.  Of 
course, efforts will be taken to minimize the potential for adverse events. Intervention and research staff training 
will stress ensuring confidentiality and avoidance of negative events, and quality assurance/quality control 
(QA/QC) will be performed regularly to ensure adherence to proper counseling techniques. Two types of reports 
will be made involving the conduct of the study.  Adverse Events Reports will be made using standard forms 
available from the relevant IRBs for adverse events associated with the study procedures or subject 
participation.  Serious medical adverse events are unlikely as the only medical procedure that will be conducted as 
part of HIV standard of care. Incident Reports will also be made of any incidents involving the conduct of the trial 
(eg, enrolling a participant who did not meet eligibility criteria, needle stick injuries of staff, etc.) These reports 
will be made in the form of a letter or memo to the Chairs of the relevant IRBs signed by a Principal Investigator. 
All reporting form study staff to the PI or co-PI should be made in real-time whenever possible (i.e. when the 
participant is still present). However, if this is not possible, a written report must be made within 24 hours.  
 
Copies of adverse event reports will be stored at UNC and in the study offices at UNC Project-Malawi.  Adverse 
events or incident reporting in this trial has been considered in the context of several important characteristics of 
the study. First, this is a minimal-risk study as defined in federal regulations—“the probability and magnitude of 
harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical or psychological examinations or tests.”  
 
In addition we will provide contact information for participants:  We will provide participants with information on 
how to contact the local research staff to report such events as breaches of confidentiality, HIV-related disruption 
of families, acts of discrimination, and physical harm. We will ask participants to return to the research site or 
otherwise contact research staff in order to make such reports as well as receive referrals to mitigate potential 
harm. This will not include identifying information about the study or references to HIV or HIV testing, so that 
the cards will not have the potential to jeopardize the confidentiality of participants.  
 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 25 of 46 
 
Dissemination of results 
The results of the study will be presented at international scientific meetings and published in scientific journals.  
The results will also be submitted to the NHSRC. The preliminary data collected in this study may lead to larger 
longitudinal studies that will enable us to further evaluate the impact of male participation on maternal, infant, and 
male partner outcomes.  
 
Study team  
Nora E. Rosenberg, PhD, MSPH, Principal Investigator 
Dr. Rosenberg, as the Principal Investigator, is responsible for overall scientific direction and ethical conduct of 
the study.  
 
Tiwonge Mtande, BA, Site Principal Investigator  
Ms. Mtande, as the Site Principal Investigator, is responsible for overall operational function of the study. She is 
the in-country point of contact for all study activities, operations, and ethics. She will undertake study coordinator 
responsibilities. Half of her time will be dedicated to this study. She will supervise all study staff and ensure data 
integrity and ethical conduct of the study. 
 
Mitch Matoga, MBBS, Co-Investigator 
Dr. Matoga, as a Co-Investigator, is responsible for consultations on medical aspects of the study. He may use 
study data for his dissertation.  
 
Twambilile Phanga, MBBS, Co-Investigator and Senior Research Officer 
Ms. Phanga, as a Co-Investigator and Senior Research Officer will support procedures surrounding social harms 
and conduct periodic quality control activities.  
 
Sam Phiri, PhD, MSc, Dip Clin Med, Co-Investigator 
Dr. Phiri is the Director of the Lighthouse Trust, which employs many of the staff in the study clinic. He will ensure 
staff are appropriately allocated or trained.  
 
Rose Kolola Nyirenda, Co-Investigator, Director Department of HIV and AIDS 
Dr. Niyirenda is the Director of Malawi’s Department of HIV and AIDS. In this role, she will serve as a liaison 
between the study and policy. She will be the knowledge-to-practice link in the study.  
 
Mina Hosseinipour, MD, PhD, MPH, Co-Investigator  
Dr. Hosseinipour is the Scientific Director of UNC Project. In this capacity, she will provide scientific direction to 
the study.  
 
Suzanne Maman, PhD, Co-Investigator  
Dr. Maman will provide guidance on qualitative aspects of the study.  
 
William Miller, MD, PhD, MPH, Co-investigator 
Dr. Miller will provide guidance on quantitative aspects of the study.  

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 26 of 46 
 
Work plan 
 
 
The study will have a one quarter preparation phase, a two-year implementation phase, and a half-year analysis 
and publication phase. During the implementation phase, each evaluation time point (enrollment, six-month visits, 
and twelve-month visits) is expected to last one year.  
 
 
 
 
 
 
 
Quarter 
 
2017 
Q2 
2017
Q3 
2017
Q4 
2018 
Q1 
2018 
Q2 
2018
Q3 
2018 
Q4 
2019 
Q1 
2019 
Q2 
2019 
Q3 
2019 
Q4 
Study preparation 
× 
 
 
 
 
 
 
 
 
 
 
Implementation 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
Enrollment period 
 
× 
× 
× 
× 
 
 
 
 
 
 
Six month visit 
 
 
 
× 
× 
× 
× 
 
 
 
 
Twelve month visit 
 
 
 
 
 
× 
× 
× 
× 
× 
 
Analysis and publication 
 
 
 
 
 
 
 
 
 
× 
× 

UNCPM 21703, Protocol Version 3.0. 20 June 2019, page 27 of 46 
 
 
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