Leveraging infant visit PrEP screening INtegration & tasK shifting to improve post-partum HIV prevention in Malawi (LINK): a cluster-randomized trial evaluation of a postpartum HIV prevention package among breastfeeding women in Malawi

Abstract

Background

Elimination of vertical transmission of HIV remains a major global public health priority. In Malawi, more than one-third of pediatric HIV acquisitions are attributed to perinatal HIV acquisition during breastfeeding. HIV pre-exposure prophylaxis (PrEP) is a crucial biomedical tool to keep women free of HIV and eliminate vertical transmission, but effectiveness has been hampered by poor uptake and premature discontinuation. Implementation science approaches are needed to improve uptake, persistence, and adherence to PrEP among postpartum women at risk of HIV.

Methods

LINK is a type I hybrid effectiveness implementation cluster-randomized trial conducted at 12 service delivery sites within Lilongwe district, Malawi. The LINK model is a novel postpartum HIV prevention package that uses implementation strategies of integration and task-shifting/sharing and includes the following evidence-based practices: (1) maternal HIV testing integrated with Expanded Programme for Immunization (EPI) sites for infant immunizations [integration], (2) PrEP screening and referral for mothers who test HIV-negative, (3) engagement of male partner(s), and (4) community-facility linkage (CFL) peer mother model for PrEP (re)engagement [integration and task shift/share]. Clinics are randomized 1:1 to intervention or control conditions. Effectiveness outcomes include PrEP uptake, adherence, and 6-month persistence among breastfeeding women at intervention compared to control sites. Implementation outcomes assessed at intervention sites include reach, adoption, acceptability, fidelity, scalability, sustainability and cost-effectiveness. We will analyze effectiveness outcomes with routine medical records, surveys, and PrEP drug metabolites via dried blood spots which will provide additional insights into HIV risk and PrEP usage and will facilitate a “constructed cohort” of PrEP eligible postpartum women. Implementation outcomes rely on in-depth interviews, surveys, site assessments, structured observations, and other tools. Human centered design workshops prior to implementation will further inform site-specific procedures for LINK model integration and launch.

Discussion

The study establishes a simple, scalable model, building on existing HIV and maternal and child health service delivery platforms, to accelerate efforts toward eliminating vertical transmission. If the LINK model is successful at improving PrEP usage among postpartum women, feasible, and cost-effective, we will have the knowledge to support quickly sustaining and scaling the intervention in Malawi and beyond.

Trial registration

Clinicaltrials.gov NCT06506188 (registered: 2024/07/17).

Supplementary Information

The online version contains supplementary material available at 10.1186/s12913-025-13133-6.

Background

Dramatic reductions in perinatal HIV transmission have ignited calls for the elimination of mother-to-child transmission, but additional efforts are needed to decrease HIV acquisition among pregnant and breastfeeding women [1–5]. Globally, likelihood of HIV acquisition is greatest during the postpartum period [6], when HIV frequently goes undiagnosed. New postpartum acquisitions are driven by hormonally-induced alterations to the female genital tract [6–8] and norms of sex peripartum [9–12]. Acute HIV infections increase the risk of transmission to the infant through breastfeeding. In sub-Saharan Africa, nearly one-third of infant transmissions are linked to HIV acquisitions that are acquired during pregnancy or breastfeeding [13]. However, the postpartum period presents unique challenges in engaging and retaining women in HIV prevention efforts and achieving the ambitious but possible elimination of vertical transmission.

In Malawi, one-third of all new pediatric HIV acquisitions are attributed to women who acquired HIV while breastfeeding (see Fig. 1) [5]. Physiological shifts that accompany the postnatal period, including hormonal and immunological changes, increased inflammation, and alterations in the vaginal microbiome, all heighten likelihood of HIV acquisition [7, 8, 14–21]. Per-coital estimates from a cohort of HIV-serodifferent couples suggests that HIV acquisition per condomless act was fourfold higher during the postpartum period and threefold higher during pregnancy, compared to other periods [6]. After delivery, hormonal shifts increase the number of HIV receptors, and low estrogen levels during breastfeeding contribute to vaginal dryness, increasing microtrauma during sex. The combination of these biological changes and behavioral shifts [9–12], including resumption of condomless intercourse following delivery, creates a perfect storm for HIV acquisition [22–26].

Fig. 1.

Proportion of HIV acquisitions of children in Malawi by timing of perinatal acquisition and transmission in 2020

Pie chart of proportion of HIV acquisitions of children under 5 in Malawi attributable to missed opportunity to intervene on elimination of vertical transmission

HIV pre-exposure prophylaxis (PrEP) effectively prevents HIV when taken consistently [27–30]. The World Health Organization (WHO) recommends PrEP for postpartum women who are likely exposed to HIV. Malawi Ministry of Health (MoH) recommends PrEP for breastfeeding women who meet criteria: partner living with unsuppressed HIV, sexually transmitted infections within the previous six months, having exchanged sex for money or goods, injection drug use, sex with partner of known HIV positive status without viral suppression, or sex with partner of unknown HIV status [31–33]. Daily oral PrEP with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or lamivudine (3TC), effectively prevents HIV [27–30, 34, 35] and is safe during pregnancy [36] and breastfeeding [37]. However, due to barriers of stigma, limited disclosure of PrEP use, side effects, and pill fatigue, particularly alongside other tablets used postpartum [38], oral PrEP uptake and adherence among postpartum women in sub-Saharan Africa is poor [39–41]. Longer acting PrEP may help address some of these concerns. The injectable agent long-acting cabotegravir (CAB-LA) is more discrete and less frequently dosed (every 8 weeks). CAB-LA has superior HIV prevention efficacy versus daily oral TDF/FTC in both men [42] and women [43]. Further, the infrequent dosing may be particularly appealing for women managing complexities of early infancy. CAB-LA has now been approved for use in Malawi and implementation is underway [44]. To maximize the prevention potential of any PrEP modality, injectable, oral, or other, HIV prevention service delivery programs must address shortfalls across the prevention cascade (see Fig. 2) [45].

Fig. 2.

Modified unifying HIV prevention cascade, the LINK postpartum prevention package strategy

HIV prevention cascade across motivation, access, and effective use

In Malawi, prevention-effective PrEP use among breastfeeding women is hampered by inadequate postpartum maternal HIV testing, infrequent male partner testing, fragmented PrEP service delivery, and premature PrEP discontinuations despite persistent HIV risk [46, 47]. Improving screening for potential PrEP eligibility among breastfeeding women is crucial to engage women without HIV who may benefit from PrEP. Despite national and international recommendations for postpartum testing, HIV testing of mothers after delivery is inconsistently implemented [48, 49], frustrated by insufficient provider capacity and fragmented care pathways [50–55]. An integrated testing model, where women and their male partners are offered testing alongside other postpartum services, could improve testing uptake and status awareness. Task-shifting to lower-cadre healthcare workers (i.e. HIV diagnostic assistants [HDAs]) is an effective strategy to increase access to HIV testing [58, 59], particularly in resource-constrained settings such as Malawi, efficiency is paramount [56, 57]. An integrated approach that leverages the early infant vaccination visit, the first of which occurs 6 weeks postpartum and is attended by > 95% of mother-infant pairs in Malawi [60], to offer HDA-based HIV testing and PrEP eligibility screening could increase timely PrEP initiation.

Once high-risk HIV-negative women are linked to PrEP via testing and partner screening, retention on PrEP is essential to maximize prevention. Community-facility linkage (CFL) models are an effective approach for connecting health facilities with surrounding communities [59, 61]. The model may facilitate PrEP counseling and tracing for mothers who disengage from PrEP. Strengthening the connection between health facilities and communities [62], CFL models have successfully addressed multiple barriers to maternal retention in HIV care. For pregnant or breastfeeding women living with HIV, these programs mobilize peers or lay health providers to engage in community-based services like health education, support for ART appointment adherence, and tracing mother-infant pairs who disengage from care [62, 63]. The CFL model successfully promotes ART retention among pregnant and breastfeeding women (PBFW) in Malawi [59, 64]. These models have not been deployed for retention in PrEP care among postpartum women but are a compelling opportunity to improve PrEP persistence for postpartum women.

In Malawi and elsewhere in the region, achieving elimination of vertical transmission will require closing the gaps in PrEP uptake, adherence, and persistent use among postpartum women with HIV exposure. We posit all tools (HIV testing, partner testing and notification, and PrEP) required to address incident maternal acquisition during breastfeeding exist, but implementation has been limited by scarce resources. In our study, Leveraging infant visit PrEP screening INtegration & tasK shifting to improve post-partum HIV prevention in Malawi (LINK), we will use a hybrid effectiveness-implementation [65, 66] trial design to test the effectiveness of implementation strategies of integration, changing service-delivery site, and task shifting/sharing [67–69] to overcome existing barriers to PrEP use among breastfeeding women. Leveraging maternal attendance at early infant vaccination visits, our intervention package consists of integrating HIV testing for breastfeeding mothers and their male partners via HDAs within early infant vaccine visits, and task-shares efforts to engage and retain women on PrEP via an expanded CFL model that includes peer-delivered PrEP follow-up services. Together, this package deploys effective strategies to increase HIV testing, promote partner engagement, enhance access to oral or injectable PrEP, and retain women in PrEP care.

Methods/design

Study objectives

The LINK study has five objectives. Objectives 1, 2, and 4 focus on evaluating the effectiveness of the intervention in preventing postpartum acquisition of HIV via PrEP. Objectives 3 and 5 focus on assessing factors related to implementation, so that the intervention package that may be scaled locally or regionally if found to be effective. Specific objectives include:

1. To estimate the effect of the LINK model, compared to the standard of care (SOC), on PrEP persistence among postpartum women initiating on long acting injectable or oral PrEP while breastfeeding at 6 and 12 months post PrEP initiation.

2. To estimate the effect of the LINK model, compared to SOC, on PrEP uptake among postpartum women who do not have HIV at delivery.

3. To evaluate implementation outcomes, including reach, adoption, acceptability, fidelity, scalability, and sustainability for the LINK model among postpartum women, clinic staff, and key clinic decision-makers.

4. To assess oral PrEP adherence at 6 and 12 months using PrEP metabolites among a subset of postpartum women initiating PrEP while breastfeeding.

5. To estimate the cost-effectiveness and budget impact of the LINK model as a strategy to improve PrEP persistence among postpartum women in Malawi.

Study design

The LINK study is a type I hybrid effectiveness-implementation cluster-randomized trial that will be conducted at 12 Ministry of Health (MoH) health facilities in Lilongwe district, Malawi [65, 66]. Facilities are randomized to the LINK model or SoC, with data collection and follow-up proceeding for approximately three years.

LINK model

The LINK model’s postpartum prevention package includes four evidence-based components: (1) HIV testing via HDA offered to postpartum women receiving services at Expanded Program on Immunization (EPI) service delivery points, (2) PrEP screening and referral for postpartum women who test negative for HIV in said EPI settings, (3) invitations for health screening for male partner engagement among women receiving testing, and (4) CFL peer mother engagement during PrEP care and field-based tracing (per patient preference) in the event of any interruption in PrEP care. The control group will continue to operate under the SOC for screening for and provision of PrEP. We will use routinely collected medical records, surveys, in-depth interviews (IDIs), dried blood spot (DBS) tests, and structured observations of the clinic environment to assess study outcomes. The study data collection will use a “constructed cohort” model, where collated medical records of deliveries, HIV tests, PrEP care, and well-child visits synthesize a cohort of breastfeeding women. We will supplement medical records with surveys, randomly approaching women with an infant under two from queues at under-five clinics and PrEP clinics.

Study setting

The study will take place in twelve MoH health facilities in the Lilongwe District, Malawi. Lilongwe is the capital of Malawi, with a population of 989,000 in 2018 [70]. We selected the 12 sites based on availability and volume of services – including HIV treatment, PrEP, EPI, and maternity – and in coordination with local implementing partners and MoH. Prior to enrollment, each site will receive a site-specific training to establish LINK study data collection processes (intervention and control). Sites randomized to the intervention will receive additional workshops to facilitate integration of LINK study HDAs and CFL peer mothers into existing EPI and PrEP clinic operations, with longitudinal supervision and workshops guided by need.

Study procedures, interventions and comparisons

Randomization

All 12 sites will be randomized 1:1 intervention:control (see Fig. 3), where six sites will rece ive the LINK model (intervention) and six sites will receive existing standard HIV prevention services (control). To achieve balance in key characteristics, we implemented a constrained randomization plan based on the up-to-date counts of deliveries from women without HIV in the most recent year and breastfeeding PrEP patients in the most recent quarter. The study randomization will be conducted using StataSE 18.0 (StataCorp 2023), using the ccvrand command. Since we will work with sites to integrate the LINK model into clinical flow, sites will not be blinded to their intervention or control assignment.

Fig. 3.

LINK study process diagram

LINK study preparation and implementation for intervention and control sites

Human-centered design workshop

Human-Centered Design (HCD) is an emerging problem-solving approach that can support the development of innovative, effective, and person-centered solutions to health challenges by placing people at the center of the design process [57]. Given the diversity of interested parties relevant to successful implementation and sustainability of LINK, pre-data collection workshops will engage representatives from local implementing partners involved in: EPI programming and program development, HIV testing service delivery, PrEP service delivery and policy making/programming, and use of peer-models for health promotion services.

HCD workshops facilitate greater understanding of the needs, aspirations, behaviors, of intervention implementers. Workshops assess structural, programmatic, and site-specific context relevant to implementing proposed activities at the six intervention study sites [58]. By placing implementers at the center of the process for integrating LINK, we will identify site-level solutions to make the introduction of LINK more feasible and sustainable, and maximize its fit to the local practice setting at each facility [59]. This approach not only ensures that interventions meet the needs of end users, but also encourages ownership and buy-in from the sites [60].

Intervention implementation

As previously described, there are four components to the LINK postpartum intervention package (see Fig. 4). These intervention components rely on a multi-component implementation strategy including service integration, which includes changing the site of HIV testing service delivery, and task shifting/sharing aspects of PrEP care – engagement and tracing for those who disengage from PrEP care– from PrEP nurses to the CFL peer model.

Fig. 4.

LINK Model for Postpartum HIV Prevention

Four components of LINK model for postpartum HIV prevention

In Malawi, EPI services are generally co-located within the “under-five” clinics. As such, components 1, 2, and 3 are deployed within the EPI/under-five clinic context. The LINK study will hire HDAs to staff each of the six intervention sites. They will be integrated into EPI service delivery – both clinic and field-based, aligning with site-specific EPI operations. Integration and alignment/extension of existing HIV testing services will be explored in our HCD workshops. This component of the intervention involves the HDA offering HIV testing services to parents who present to the under-five clinic with their child. Persons who test positive are referred to ART care at the medical facility. For parents who test negative for HIV, the HDA will administer a short screen for HIV exposure and potential appropriateness for PrEP. The screen mirrors the clinical criteria for prescribing PrEP in Malawi, with a particular emphasis on unprotected sex with a partner whose HIV status is unknown. If the parent has one or more indications for PrEP the HDA gives them a warm handoff to the PrEP clinic/peer mom (see below) at the same health facility. The HDA will also offer invitations to health screening that postpartum women could bring to their male partners to encourage HIV testing. Although testing is offered to any parent bringing in their child, this approach specifically targets postpartum women, as they represent most parents who arrive with their infants for infant vaccinations.

The final component of our intervention (#4) is integrated within existing PrEP clinics, wherein CFL peer moms are incorporated into the care pathway for breastfeeding women who are using PrEP. Specifically, the model is designed such that CFL peer mothers can meet those referred from EPI as well as those mothers who are initiating PrEP or referred through other means, offering support and encouragement to breastfeeding women during a PrEP initiation or follow-up appointment. Additionally, CFL peer mothers ask breastfeeding women about their contact preferences for follow-up if they miss an appointment, and then trace the woman according to her previously stated preference, contacting her via text, phone, or in-person, if necessary. The goal of the CFL peer mother is to reconnect the postpartum woman to PrEP care, improving persistence on PrEP and encourage adherence to oral PrEP.

As an implementation science trial, we are focusing on approaches that maximize the use of PrEP as an evidence-based intervention. However, the study staff are not prescribing PrEP. All PrEP prescription and clinical management will proceed per the Malawi PrEP guidelines and be managed by existing MoH PrEP staff.

Data collection

As a cluster-randomized implementation science trial, our outcomes are evaluated at multiple levels, with primary and secondary outcomes evaluated at the cluster (clinic) level (see Figs. 4, 5 and Table 1).

Fig. 5.

LINK Study Data Sources by Level, Location, and Objective

LINK study data sources organized by the level of data collection on a spectrum for individual, clinic, and structural. Whether data collection will take place at intervention or control sites is marked, as well as which objectives the data source applies to

Table 1.

LINK study outcomes with description, population, and primary data sources

Objective	Outcome	Description	Primary Data Sources
• Objective 1	PrEP Persistence	- Timely attendance at PrEP appointments	- PrEP Mastercard - PrEP register
• Objective 2	PrEP Uptake	- Initiation of PrEP	- Maternity register - HDA HTS register - PrEP register - PrEP Mastercard - Health Passport review
• Objective 3	Fidelity	- Degree of adherence, competence, and differentiation with which the intervention is delivered	- Survey - In-depth interviews - CFL mom logs - Fidelity checklists
• Objective 3	Acceptability	- Perceptions, perceived fit, and experiences with intervention	- Survey - In-depth interviews - AIM - mhIST
• Objective 3	Reach	- Number of people who received the intervention and their level of engagement with the intervention	- Survey - In-depth interview - HTS register - CFL peer mom log - PrEP appropriateness checklist
• Objective 3	Adoption	- Uptake of the intervention among clinical staff and policymakers	- In-depth interview - Structured observations - CFL peer mom log - mhIST
• Objective 3	Scalability	- Ability to apply the intervention to a greater number of clinics and in more contexts	- In-depth interview
• Objective 3	Sustainability	- Percieved ability to continue offering the LINK model after the conclusion of the study	- In-depth interview - PrEP Mastercard - PSAT
• Objective 4	PrEP Adherence	- Pill-taking (for oral PrEP) or injection receipt (for CAB-LA)	- PrEP register - PrEP Mastercard - Dried blood spot tests
• Objective 5	Cost-effectiveness	- Cost-effectiveness of the intervention package, compared to SOC	- Time and motion capture - Ministry of Health price list - Project ledgers

Record abstraction

We will collect data on primary study outcomes (PrEP use) by abstracting data from health facility records into a secure LINK study REDCap system. LINK study data assistants (DAs) will visit intervention and control sites to enter medical record data stored locally on paper forms. We will verify our abstracted data with medical records shared through a Data Use Agreement (DUA) with the MoH collected via scanform.

DAs will enter de-identified data from on-site paper registers. Clinical staff log patient visits in registers, including relevant interventions (e.g., pills provided, vaccines administered, test results, etc.). For this study, we will abstract data capturing PrEP use and child immunization visits. In addition to registers, in Malawi, each person maintains their own health record in what is referred to as a “health passport” – a small paper booklet in which key medical interventions or outcomes are recorded. DAs will use convenience sampling approaches to anonymously record the following data from the health passports of women queueing with an infant in the line for EPI visit: date of delivery, HIV register number (if applicable), and PrEP register number (if applicable).

Data collection with postpartum study participants

Although primary outcomes for PrEP persistence and uptake are identified at the clinic level through clinic-wide data abstraction, the LINK study will also directly engage patients at service delivery points to become study participants. Postpartum participants will complete surveys (up to 5000), dried blood spot (DBS) tests (up to 1000), and in-depth interviews (IDIs) (up to 40). Surveys will also assess the acceptability of each component of the LINK model. DBS tests of PrEP metabolites for breastfeeding women on oral PrEP will inform PrEP adherence. IDIs interviews with postpartum participants will explore factors affecting acceptability, fidelity, and sustainability of the LINK model.

Surveys

Eligibility: Postpartum woman presenting with infant under two at EPI clinic OR breastfeeding woman presenting at PrEP clinic, intervention or control site, aged 15 or older, provides informed consent to participate.

Sampling and data collection: Using a convenience sampling framework, women presenting to the under-five clinic or PrEP care and who meet prespecified eligibility criteria will be invited to participate in a brief survey. Eligible and interested women will provide informed consent (see Ethics and Study Reporting & Engagement). Surveys will be conducted by study staff in a private location. A subset of women who are engaged at the PrEP clinic may also be asked to provide a fingerstick blood specimen for further testing (see DBS below). A smaller subset of women, from both the under-five clinic and from the PrEP clinic recruitment sites, will be offered an IDI (see below).

Description: Surveys elements include demographic information, behavioral and structural factors affecting potential HIV acquisition, potential PrEP usage and behaviors, perceptions of PrEP stigma, and acceptability metrics for the LINK model.

Dried blood spots

Eligibility: Breastfeeding woman presenting at 6- or 12-month oral PrEP visit at PrEP clinic, intervention or control site, aged 15 or older, provides informed consent to participate.

Sampling and data collection: Using a convenience sampling framework, study DAs will recruit breastfeeding women who meet eligibility for DBS from PrEP clinic queues. All women who complete a DBS test will also complete a survey.

Description: We will measure tenofovir metabolite levels in DBS samples to quantitatively supplement medical record data regarding PrEP refill and self-reported pill-taking behavior.

In-depth interviews

Eligibility: Postpartum woman presenting with an infant under two at EPI clinic OR breastfeeding woman presenting at PrEP clinic, intervention site, aged 15 or older, provides informed consent to participate.

Sampling and data collection: Postpartum women who consent to survey completion at intervention sites will consent to IDI. We will select a subset of women (n ~ 40), purposively sampling based on time since delivery and current or historic PrEP use as captured in surveys. DAs will be instructed on target enrollment on a weekly basis and characteristics will be examined to determine subsequent enrollment objectives. All women who complete an IDI will also complete a survey.

Description: IDIs will explore factors affecting PrEP uptake, persistence, and adherence among postpartum women, guided by key constructs and domains within the Consolidated Framework for Implementation Research [71]. They will also assess the acceptability of the LINK model, the fidelity to the model among implementers, and the potential sustainability of the model.

Data collection with clinic and policy stakeholder participants

Besides women who are seeking infant vaccine and/or PrEP services, we will also survey and interview other key informants (n ~ 28) relevant to program implementation and sustainability. These include study-specific actors, such as CFL peer mothers and HDAs; non-study actors involved in the integrated activities, such as PrEP providers and EPI clinic staff/managers; and persons involved in HIV programs and policy development and implementation, including PEPFAR implementing partners and relevant staff in the Malawi MoH.

In-depth interviews

Eligibility: Clinical stakeholder at intervention site OR HIV prevention policymaker, aged 18 or older, provides informed consent to participate.

Sampling and data collection: Clinical and policy stakeholders will be selected purposively based on their role in clinic and familiarity with the LINK prevention package. Study DAs will contact selected participants for an interview.

Description: IDIs will be preceded by a brief survey, which includes role and affiliation, a short version of the Program Sustainability Assessment Tool (PSAT) [72] and a Mental Health Implementation Science Tool (mhIST) [73]. IDIs will explore acceptability, fidelity, adoption, sustainability, and scalability for the LINK model with the appropriate stakeholders.

Data collection on implementation, clinic environment, and structural factors

Implementation outcomes including acceptability, fidelity and adoption will be evaluated using study records, initial site assessments, fidelity checklists, and structured observations (see Table 1). These observations will be used to characterize intervention site activities, including availability of services within the LINK package. We will review LINK study HDA PrEP appropriateness screenings for count completed and proportion completed in full. We will also review CFL peer mom logs to assess fidelity to peer support, including count and proportion of breastfeeding women with interruption in PrEP treatment. Cost outcomes will be captured using an ingredients-based approach via Malawi MoH price lists, CFL peer mom logs, study receipts (for salaries and other related consumables) and time-and-motion as appropriate.

Study monitoring and adverse event reporting

Study monitoring will verify that human subjects’ rights are protected, that data are accurate and complete, and that the trial complies with the currently approved protocol and regulatory requirements.

Data monitoring

Ongoing monitoring will be conducted by the project lead and PI throughout the study. We will conduct regular reviews of study protocols, changes in study protocols, and adherence to protocols in the field. As an implementation science intervention without an investigational drug, device, or therapy, we will not conduct standard adverse event (AE) reporting for the LINK study or explicit stopping guidelines for the trial. Instead, the study team will track and document AEs and severe adverse events (SAEs) possibly related to study activities or interventions. The project lead will report any unexpected study-related AEs/SAEs to the UNC Institutional Review Board (IRB), National Health Science Research Committee (NHSRC), and NIH. We will convene a Study Monitoring Committee (SMC) as part of the larger parent study – a three-study P01 (5P01HD112215). The SMC will be comprised of at least four members including two content experts (HIV and implementation science), a community representative, and a biostatistician. We will approach persons with clear expertise in the substantive area and appropriate cultural understanding. The SMC will meet by telephone at the outset of the study, at 12-month intervals, and as necessary. Additional meetings of the SMC can be scheduled, as needed, to discuss and resolve AE issues. The SMC will review all accrued data to assess if the study objectives were met, and to ensure that benefit exceeded harm. Interval statistical analyses will not be performed, except in descriptive form. The SMC, and all IRBs overseeing this study, will receive all reports of adverse events. Related and unexpected SAEs will trigger a special meeting of the SMC.

Ethics and study reporting & engagement

The UNC IRB (24–0323) and the Malawi NHSRC (24/02/4368) have approved the protocol, informed consent forms, and participant-facing materials. Both the UNC IRB and NHSRC will review and approve any modifications to protocol or other documents prior to implementation.

Informed consent forms will be available in both Chichewa and English. Study DAs trained in human subject research will read informed consent forms aloud and answer any questions about the study or participation. To confirm comprehension, study DAs will administer a checklist for understanding. Literate participants will be able to sign the informed consent forms, and illiterate participants will make a mark or fingerprint with a literate witness signature. All participants will be provided with a copy of the informed consent form.

Effective communication of study results to HIV prevention stakeholders in Malawi is a crucial piece of the methodology for this implementation-focused study [74]. We will present study results to study partners with interactive presentations, creating opportunities for dialogue about barriers and facilitators to implementation. We will also write up study results into accessible infographics and short-form reports for participating communities and broader audiences.

We will disseminate the study results to the scientific community through peer-reviewed journals and conference presentations. The protocol is available for review in clinicaltrials.gov (NCT06506188).

Data analysis

The LINK study relies on medical records, surveys, and DBS tests to construct a synthetic cohort to estimate results for its first, second, and fourth objectives (see Fig. 5 and Fig. 6). Its third objective is multifactorial and relies on quantitative and qualitative data. See Table 1 for a definition and data source for each measure for the study organized by objective.

Fig. 6.

LINK Study Constructed Cohort for Objective 1: PrEP persistence & Objective 4: PrEP adherence

LINK Study Constructed Cohort for Objectives 1 and 4

Effectiveness outcomes (Objectives 1, 2, and 4) will be conducted at the clinic level with an intention-to-treat analysis. We will use generalized estimating equations (GEEs) to estimate effect sizes. Using GEEs, we will condition on the clinic level variables used to perform constrained randomization: up-to-date counts of deliveries from women without HIV in the most recent year and breastfeeding PrEP patients in the most recent quarter. We will use survey results to inform adjusted measures of sensitivity analyses for persistence, uptake, and prevention-effective PrEP use for PrEP adherence among study participants (Fig. 7).

Fig. 7.

LINK Study Constructed Cohort for Objective 2: PrEP Uptake

LINK Study Constructed Cohort for Objective 2

PrEP persistence

Objective 1 of the LINK study measures the impact of the LINK model on 6-month (primary) and 12-month PrEP (secondary) persistence. For oral PrEP users, persistence is defined as attendance at PrEP appointments and receipt of PrEP prescriptions until a missed refill by > 14 days for any reason. Once a person is characterized as not-persistent in the first 6-months (primary) or 12-months (secondary) outcome, they are considered non-persistent for the entirety of that period. For injectable PrEP users, persistence is defined as receipt of a PrEP injection until a missed injection by > 14 days for any reason. If a provider recommends PrEP discontinuation or transfer to an outside facility, captured within the PrEP visit card (“PrEP Mastercard), or PrEP register, then we will not consider the participant to be non-persistent. If a PrEP user switches between oral and injectable, then we will consider the participant to be persistent as long as there is no lapse in expected protective PrEP in excess of 14 days. We will calculate a risk difference for the proportion of breastfeeding women who are persistent on PrEP at 6-months and 12-months in the intervention versus control sites. The risk difference will be estimated using linear models estimated with generalized estimating equations to account for clustering of study sites. We also will conduct a subgroup analysis to estimate the risk difference in persistence between intervention in control sites, stratified by PrEP modality (oral and injectable).

Power calculation

After intervention rollout, we expect PrEP persistence among breastfeeding women at intervention sites to be 15 percentage points higher than persistence at SOC sites. With 12 participating sites, an alpha of 0.05, and an intraclass correlation coefficient of 0.03 [75], we expect to have > 95% power to detect this difference at 6 and 12 months given the number of breastfeeding women expected to initiated PrEP during the study period at each site (average of 50/year for 3 years at SOC sites and 150 per year for 3 years at intervention sites). With a more conservative intraclass correlation coefficient of 0.05, we would have 80% power to detect this difference.

PrEP uptake

Objective 2 of the LINK study measures the impact of the LINK model on PrEP initiation among breastfeeding women. To account for the effect of the size of the eligible population, we will divide the count of breastfeeding women at each clinic by the number of HIV-negative deliveries at the same clinic. We consider the women who deliver without HIV at the clinic at the same time as study implementation to be the “population at risk” for initiating PrEP at that clinic. We will calculate the risk difference for PrEP initiation while breastfeeding over all HIV-negative deliveries in the intervention vs. control sites. The risk difference will be estimated using linear models estimated with generalized estimating equations with an identity link to account for clustering of study sites. We also will conduct a subgroup analysis to estimate the risk difference in uptake between intervention and control sites among oral PrEP users and injectable PrEP users.

PrEP adherence

Objective 4 of the LINK study measures the impact of the LINK model on PrEP adherence. We will use DBS tests to measure oral PrEP metabolites in the blood from our sample breastfeeding women attending their 6-month and 12-month appointments. Malawi currently uses both TDF/FTC and TDF/lamivudine (3TC) for oral PrEP. Adherence assessments will use validated assays for tenofovir metabolites, TFVdp, for women on TDF/FTC. Women who are receiving TDF/FTC will have both TFVdp and FTCtp measured [76]. By measuring both active components of the oral PrEP formulation (tenofovir/emtricitabine) (TFVdp and FTCtp) rather than TFVdp alone, we can interpret average dose taking behavior over longer periods (1–3 months for TFVdp vs 1–2 weeks for FTCtp) [77]. UNC Chapel Hill labs have calibrated the assay with a range of 100–20,000 fmol, demonstrating precision and accuracy of ± 15%.

Once all tests have been performed and results have been obtained for tests specified in the study protocol, the samples will be destroyed at the end of the study after the analysis. We will calculate the risk difference for PrEP metabolites that indicate PrEP use among breastfeeding PrEP users over all breastfeeding PrEP users at intervention vs. control sites. The risk difference will be estimated using linear models estimated with generalized estimating equations to account for clustering of study sites. We will also compare the adherence on oral PrEP to persistence on oral PrEP from Objective 1.

Additional outcome analysis

Implementation outcomes

We use Proctor’s Implementation Outcomes Framework for our implementation outcome assessments, specifically acceptability, adoption, fidelity, reach, scalability, sustainability, and cost [78, 79]. Implementation outcomes will be assessed using both quantitative and qualitative approaches (see Table 1). To assess the acceptability of the LINK model, we will use IDIs, the Acceptability of Intervention Measure (AIM) scale [80], the Program Sustainability Assessment Tool (PSAT) [72], and the Mental Health Implementation Science Tool (mhIST) [73], administered to postpartum women and appropriate clinical and policy stakeholders. We will use referral counts from study data as well as the IDIs with clinical stakeholders to describe adoption of the LINK model. To assess fidelity, we will administer IDIs with postpartum women and clinical stakeholders, fidelity checklists, structured observations, and site assessments. To quantify reach, we will count the number of postpartum women who received HIV testing, screening for PrEP appropriateness, and a male partner health screening invitation. Additionally, we will assess the count and proportion of breastfeeding PrEP users who received CFL peer mother support and follow-up. To assess scalability of the intervention, we will conduct interviews with policymakers. To assess the sustainability of the intervention, we will administer the PSAT tool and IDIs to policymaker stakeholders and examine time trends in the reach of the study.

Cost-effectiveness outcomes

We will take an ingredients-based micro-costing approach to understand the total cost of implementing the intervention. Each ingredient, including provider, HDA, and CFL peer mother time, HIV testing kits, training costs, and transportation costs, will be included and structured into a decision tree model for someone experiencing the postpartum intervention package. We will conduct a budget impact analysis of the cost of the intervention both overall and for each of its components. We will also calculate and report incremental cost effectiveness ratios for the average cost per postpartum woman persistent on PrEP at 6 months and per breastfeeding woman initiated on PrEP, attributable to the intervention.

Discussion

Importance of study

Elimination of vertical transmission is an important global public health goal, and PrEP is a critical tool to achieve that goal. While PrEP is known to be very effective clinically, PrEP is not currently reaching all breastfeeding women exposed to HIV in Malawi. The LINK model makes use of a unique opportunity in infant immunization appointments to identify women and integrate them into PrEP care. After PrEP initiation, the LINK model continues to meet postpartum women where they are by offering CFL peer support services and follow-up. We believe that the LINK model will improve PrEP persistence, uptake, and adherence for breastfeeding women.

The LINK study uses an innovative constructed cohort design, augmented through surveys and DBS tests with sampled participants. We will obtain population-level data based on patient behavior outside the context of a typical clinical trial, while maintaining the analytical benefits of a randomized intervention. Furthermore, the LINK study will extensively measure and analyze factors affecting implementation, including acceptability, fidelity, and adoption. We will also calculate and report cost-effectiveness ratios to understand the financial impact of the LINK model on patients and healthcare in Malawi. If the LINK model is successful at improving PrEP usage among postpartum women, we will have the knowledge to support sustaining and scaling the intervention in Malawi and beyond.

With the prioritization of elimination of vertical transmission and the recent approval of long-acting injectable (LAI) PrEP in Malawi, there may be other efforts to research and improve access to PrEP for postpartum women. We will routinely assess each clinic and the national environment for changes. In conducting an implementation science trial, we seek to understand the effectiveness of the LINK model robust to evolutions in the postpartum PrEP landscape.

Abbreviations

3TC

Lamivudine

AE

Adverse event

AWYG

Adolescent women and young girls

CAB-LA

Cabotegravir, long acting

CFL

Community-facility linkage

DA

Data assistants

DBS

Dried blood spot

DUA

Data use agreement

EPI

Expanded Programme on Immunization

FTC

Emtricitabine

GEE

Generalized estimating equations

HDA

HIV diagnostic assistant

HTS

HIV testing services

IDI

In-depth interview

IRB

Institutional Review Board

LAI

Long-acting injectable

LAI

Long-acting injectable

LINK

Leveraging infant visit PrEP screening INtegration & tasK shifting to improve post-partum HIV prevention in Malawi

mhIST

Mental Health Implementation Science Tool

MOH

Ministry of Health (Malawi)

NHSRC

National Health Science Research Committee (Malawi)

PEPFAR

President’s Emergency Plan for AIDS Research (United States of America)

PrEP

Pre-exposure prophylaxis

PSAT

Program sustainability assessment tool

SAE

Severe adverse event

SOC

Standard of care

TDF

Tenofovir disoproxil fumarate

Authors’ contributions

SER, MCH, FS contributed to initial study design and content. VAL drafted initial drafts of manuscript, with subsequent rounds of revision by SER. All listed authors contributed to, reviewed, and approved of manuscript as submitted.

Funding

This trial is supported entirely by funding through the National Institute of Child Health and Human Development (5P01HD112215). SER received additional support from the Doris Duke Charitable Foundation (grant #2020143). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Persons responding to all study-specific surveys, offering perspectives via in-depth interviews, and/or providing specimens for collection via dried blood spots will complete informed consent procedures prior to participation. All study activities have been reviewed and approved for implementation by local Malawi National Health Science Research Committee and the University of North Carolina institutional review boards.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.