This Trial Aims to Evaluate the Effect of Two HIV Stigma Reduction Interventions at the Health Facility Level and the Individual Level for People Struggling to Access and Remain in Care in Uganda.

SCIENTIFIC PREMISE AND THEORETICAL MODEL This study is based on scientific and programmatic evidence that stigma occurring at multiple social-ecological levels hampers access to and motivation for HIV prevention and treatment. It highlights the need for multilevel, evidence-based interventions that use HIV status-neutral approaches. Guided by the social-ecological model, Logie's adaptation for stigma, previous research, and, most critically, input from people affected by HIV in Uganda on prioritizing intervention levels, we propose adapting and combining interventions at the individual and health facility levels. Specifically, at the macro/institutional level, we will focus on healthcare facilities (HCF) and adapt the Health Policy Plus Total Facility Approach for Stigma Reduction \[HP+\]. At the intrapersonal/individual level, we will adapt the HIV Empathy, Education \& Empowerment (HIVE3) intervention. HCFs in Uganda are central to the delivery of HIV prevention and treatment services, and stigma within them impedes access for people affected by HIV. Also, they face ongoing stigma in all dimensions of their lives, fueling internalized, perceived, and anticipated stigma, which can undermine HIV prevention and treatment service engagement. OVERALL DESIGN The overall goal of the Ssinga Nze study is to address HIV-related stigma and improve access to HIV care, including ART and PrEP uptake and linkage to care among people affected by HIV in Uganda. Specifically, we will adapt (Aim 1) and pilot test Ssinga Nze through a hybrid type 1 effectiveness-implementation trial of the HP+ intervention at the healthcare facility (HCF) level (organizational) and HIVE3 at the individual (intrapersonal) level (Aim 2) to (1) change stigmatizing interactions between HCF staff and people affected by HIV and create more welcoming health facilities by working at multiple levels within the health facility to reduce stigma; (2) offer peer support to individuals to help them cope with and challenge stigma and reduce internalized stigma; (3) develop skills, agency, and social assets among peers and within HCF staff to address stigma; and (4) strengthen partnerships between HCF and civil society organizations through joint intervention design and implementation. FACILITY-LEVEL INTERVENTION - HP+ HIV stigma-reduction "Total Facility" Approach (TFA) In the PRISM-Ghana study, the original HP+ HIV stigma reduction TFA approach was adapted as part of a multilevel intervention to address HIV-related stigma at the healthcare level by changing drivers of stigma and discrimination among all facility staff, including clinical and nonclinical staff. Grounded in behavior change informed by social cognitive theory principles, the approach focuses on creating space for interpersonal interactions (contact strategies), creating empathy, and building efficacy for stigma reduction through awareness, skills, knowledge building, action planning, and design and implementation of stigma-reduction activities. Consequently, the intervention focuses on improving HCF staff capacity through participatory stigma-reduction training workshops for all staff and integrating a stigma-reduction focus into institutional processes and structures. HP+ addresses immediately actionable drivers of HIV-related stigma in health facilities, including lack of awareness of stigma, fear, attitudes, beliefs, and myths and misconceptions, through participatory training and facility-developed stigma-reduction activities. Doing so catalyzes tangible action because it makes HCF staff realize they can cause meaningful change, produce immediately visible results, and institute long-term changes to permanently reduce HIV-related stigma for people affected by HIV. Recognizing HCF staff as leaders within and beyond the facility helps them effectively use their new understanding of what HIV-related stigma is, why they should address it, and what they need to do to reduce it. Partnerships are built between HCF staff and people affected by HIV through joint training and stigma-reduction intervention implementation teams. Selected HCF staff (from intervention facilities) and clients (usually not from intervention clinics) form joint intervention teams to deliver the participatory training to HFS and lead other stigma-reduction interventions at the facility. They receive a 5-day training-of-trainers workshop followed by on-site mentoring as they deliver the first round of participatory training to their peers at the HCF level. Each session includes a mix of selected clinical and nonclinical staff from across departments, with numbers, times, and dates determined by facility schedules. The modular training format and the mix of staff across levels and departments allow for flexibility in delivery to accommodate facility schedules and reduce disruption of service delivery. Stigma-reduction leaders, also called champions, are organically identified and supported by HCF management, and are provided with a small grant to develop and implement follow-up in-service stigma-reduction activities - such as a complaint system, staff recognition, and posters - for the HCF. The initial development and pilot test of the HP+ approach were conducted in Ghana, in partnership with local government and civil society. It aimed to reduce HIV-related stigma in health facilities. At 6-month follow-up, there were greater reductions in intervention facilities relative to the control for most HIV-stigma drivers, such as unnecessary fear of HIV transmission (24%; p\<0.001) and preferences not to treat people affected by HIV (14.2%; p=0.001) \[50\]. Feasibility and acceptability were demonstrated through (a) management demanding that the project train more staff than initially intended, (b) the high completion rate after 2 days of training (91%), (c) the large number of staff trained (1,228) in a short period, and (d) the ability of management and trainers to schedule staff training in a manner that did not disrupt facility operations. Additionally, facilities donated space for training and staff time to attend. Under the PRISM study, which further adapted HP+ to focus on HIV-related stigma, over 1,000 staff were trained in two 4-month waves (treatment and wait-list control). All trainees who started the 2-day training completed it, for a 100% attendance rate. Preliminary difference-in-difference results (unpublished) show that intervention facilities demonstrated significant improvements relative to control facilities on a subscale measuring beliefs and attitudes about gender nonconformity and sexual diversity at both 3 months (p=0.03) and 6 months (p=0.02) post-intervention. INDIVIDUAL-LEVEL INTERVENTION - HIV empathy, empowerment, and education (HIVE3) HIVE3 uses mobile technology to provide discreet peer support for people affected by HIV to date, with a focus on stigmatizing environments. The intervention is premised on the fact that the HIV-related stigma experienced by individuals affects their emotional and mental well-being and their capacity to access HIV prevention and care services. Consequently, it is essential to leverage existing social networks through peer support to encourage the utilization of HIV services and maintain emotional well-being. The goals of HIVE3 are to (a) increase peer support, (b) decrease social isolation, and (c) reduce the effects of HIV-related stigma on self-care (such as symptom monitoring and medication adherence) and healthcare-seeking behaviors (such as HIV testing and HIV care retention). HIVE3 uses the tenets of peer support defined by the Dennis Peer Support model, which includes emotional, appraisal, and informational support. Emotional support includes discussing personal challenges and difficulties, with the peer mentor serving as a strong interpersonal resource to counteract the effects of self-esteem threats. Informational support includes providing knowledge relevant to problem-solving. It includes (a) availability of relevant resources, (b) independent assessments regarding problem etiology, (c) alternative courses of action, and (d) guidance about effectiveness. Appraisal/affirmatory support is the communication of information pertinent to self-evaluation and encompasses expressions that affirm the appropriateness of emotions, cognitions, and behaviors. Peer mentors are selected among the targeted population and receive training from HIVE3 experts on the various forms of support. The peer mentors and participants receive phones with an identified application (e.g., WhatsApp) as the communication medium between peers and mentors. Mentors and peers are encouraged to maintain anonymity to enable nonjudgmental interactions. However, if they find it comfortable enough to relate more openly, the intervention supports the organic development of such relationships. Peer mentors have the contact information for the HIVE3 expert and Co-Investigator for follow-up questions and for healthcare providers to refer peers for healthcare as needed. STUDY OBJECTIVES AIM 1: Adapt the multilevel PRISM stigma reduction intervention to address HIV-related stigma for populations struggling to access and remain in HIV prevention and treatment in Uganda. To adapt the two interventions, we will implement the first seven steps of the ADAPT-ITT framework. Step 8 (intervention testing) is Aim 2. Previous research and consultations with people affected by HIV in Kampala about this study and which interventions to select and prioritize identified the health facility and individual level as priorities. Consequently, we will conduct modified Steps 1 and 2 to collect qualitative data to inform how to adapt the PRISM intervention to become Ssinga Nze. Step 1: Assess We will conduct focus group discussions (FGDs) among HCF staff (n=5), stratified by clinical (n=4) and nonclinical (n=1) staff and people affected by HIV (n=4), to generate additional knowledge on experiences of intersectional stigma and to inform the adaptation of the two interventions to the geographical and sociocultural context of people affected by HIV and HCW in Uganda. FGDs have proven effective in our previous adaptations of the two interventions and other sexual health studies by generating in-depth and diverse conversations among respondents. We will qualitatively investigate (a) stigma drivers and manifestations toward people affected by HIV, exploring HIV-related stigma in HCF and among people affected by HIV in Uganda; (b) the impact of stigma on access to and uptake of HIV testing, PrEP and HIV treatment among people affected by HIV; and (c) insights and suggestions for dealing with or reducing stigma within HCFs and among people affected by HIV. Sampling and recruitment HCW-We will recruit a diverse cross-section of staff that people affected by HIV may encounter during an HCF visit - such as security guards, janitors, nurses, and pharmacists - by securing the list of HCF staff from the four facilities, stratifying staff by clinical and nonclinical roles, and randomly selecting a sample from each stratum. Individuals-We will use peer-led snowball sampling to identify people with HIV (n=40) who reside in the catchment areas of the study clinics to participate in FGDs (n=4). We will collaborate with community-based organizations in Uganda to recruit people with HIV for the study. They will help identify research volunteers from their networks, and initial study participants will be asked to refer their peers. Inclusion criteria HCF staff-To qualify for the study, the individual should work in a clinical or nonclinical role at one of the study sites. Individuals-Participants must be aged 18 or older, or if 14 to 17, qualified as a mature or emancipated minor due to having an STI or catering for their livelihood, and be able and willing to provide written informed consent. Data collection HCW-Social scientists with health-facility research experience will be selected and trained to facilitate FGDs for HCW in English and people affected by HIV in Luganda (local language). All FGDs will be digitally recorded (with consent) and transcribed verbatim in a secure location to ensure privacy and protection of participant information, translated, and verified for accuracy. Recordings will be encrypted and uploaded to a secure server. Individuals-Experienced social scientists and trained peers will facilitate individual FGDs. We will specifically target and train people affected by HIV, who previously participated in research studies in Uganda as facilitators. Data analysis We will conduct rapid qualitative analysis (RQA) to inform the adaptation of the interventions, building on a process we have used successfully in ongoing studies in Ghana and Tanzania. RQA methods, increasingly used in health services research when findings are needed rapidly to inform practice and policy, have produced comparative findings for applied and targeted purposes (e.g., intervention adaptation) as compared with the generally more time-consuming and resource-intensive traditional qualitative analysis (QA) method. We will retain certain core features of conventional QA, specifically verbatim transcription of interviews and a modified grounded theory approach that uses inductive and deductive content analysis; however, formal coding of transcripts with software will not be conducted. The process will begin with immersion in the interviews and the writing of summaries for each interview. The two investigators, with two trained research assistants (including peers), will independently review the transcripts and create a summary of the key findings identified. Transcripts will be reviewed to identify stigma drivers, facilitators, and manifestations, and recommendations on ways to combat HIV-related stigma at the HCF and intrapersonal (individual) levels among people affected by HIV. The group will then meet to review each other's findings. As the findings are discussed and a consensus on interpretation is reached, they will be summarized in thematic sections, tables, and diagrams to produce a combined summative report that informs the next stage of the intervention adaptation process. Step 2: Decision Based on the RQA results, the study team, together with two peers affected by HIV, will review the RQA results and the current activities in the two interventions to identify specific areas that need to be modified to align with the study's current focus in Uganda. We expect to identify findings and recommendations around ways to incorporate the unique experiences of people affected by HIV in Uganda - including how to address HIV-related stigma, potentially different drivers, and manifestations of stigma toward people affected by HIV among HFS-and components addressing PrEP adherence, as the previous intervention in Ghana did not include this component. Step 3: Administer/Adaptation Based on Step 2, we will make initial changes to the current manual of the interventions and conduct a 2-day simulation workshop of the intervention activities with 14 participants, including representatives of the community, HCF staff, and health system management from the local to the Ministry of Health, to further identify areas for intervention improvement. Participants will work through each intervention component focused on stigma-reduction content, PrEP inclusion, and stigma around PrEP. They will review approaches to addressing key issues identified in the assessment phase. The sessions will be recorded (with consent), and two study team members will take notes on participant feedback, including how participants engage with activities. A summary of feedback for each intervention activity will be produced. Step 4: Produce The study team will meet to review, compare, and discuss the RQA and adaptation workshop results. Based on this analysis of data from Steps 1 and 3, we will further adapt intervention activities to produce the first draft of the Ssinga Nze implementation manual. We will focus on maintaining fidelity to the core elements of the two original interventions and their combination in the PRISM intervention, while considering the new population (people affected by HIV) and the country and cultural context (Uganda). If gaps are identified in Step 3 that require new exercises or activities, these will be developed, and feedback will be sought from a subset of the participants in Step 3. After incorporating changes, a revised manual will be created to guide study implementation. Step 5: Topic Expert We will submit the new manual, including the summary report from the assessment stage, to identified experts for review and written feedback, specifically Sue Clay, one of the developers of HP+ and then its adaptation for intersectional stigma; Dr. LaRon Nelson, HIVE3 developer, who also led adaptation for addressing stigma; and Dr. Jae Sevelius, an expert in stigma interventions. Additionally, persons with insider local knowledge and population context around people affected by HIV (e.g., peers) and HCW (e.g., MoH) in Uganda will also review. Step 6: Integration The multilevel intervention manual will be revised based on topic-expert feedback, with follow-up clarifying questions to the topic experts, as necessary. We will also produce a training manual to standardize training and enable future replication of interventions in other settings. Step 7: Training We will provide comprehensive training to all team members whose roles are dedicated to delivering the intervention. In addition to training for study staff, specific training (see Aim 2, study procedures) will be delivered to peers who will provide peer support through HIVE3 and to HFS and people affected by HIV who will deliver the adapted HP+ intervention in their facilities. We will develop the training to be multifaceted, facilitating comprehension and retention of training concepts, using strategies that Drs. Nyblade and Abu-Ba'are have successfully deployed the interventions previously implemented (1R01NR019009; 1R21TW011786). Step 8: Testing (see Aim 2) AIM 2: Conduct a pilot hybrid type 1 effectiveness-implementation trial to test the preliminary effectiveness of the adapted multilevel Ssinga Nze HIV-related stigma reduction intervention on (a) PrEP adherence or (b) viral suppression among populations at risk of HIV who struggle to access and remain in prevention or treatment using a status-neutral approach. Overview We will conduct a randomized trial of Ssinga Nze with four facilities, two with a 6-month wait-list control, and with people affected by HIV living in each HCF's catchment area. The overarching goal is to assess the impact of the multilevel stigma-reduction interventions on PrEP uptake and adherence and HIV viral suppression. A secondary goal will be to evaluate reductions in stigma among HCF staff, reductions in internalized stigma, and anticipated reductions in HCF stigma among study participants. HCFs and study participants "associated" with each HCF will be randomly assigned to the order in which they will receive the stigma-reduction interventions. All HCFs and affiliated study participants will receive the intervention for at least 3 months. Study participation will last 3 months, with assessments conducted at baseline and 3 months after intervention delivery ends. The wait-list control design avoids the carryover effects of other crossover designs because participants move unidirectionally from the control to the intervention. Recruitment and Eligibility Healthcare facility selection and health facility staff recruitment: Four health facilities will be selected based on the following criteria: PEPFAR stigma scorecard, geographical location, and clinic volume. We will implement this project at four HIV clinics and with affiliated study participants in Central Uganda, which ranked lowest on the PEPFAR Uganda scorecard for stigma: two randomly assigned to Ssinga Nze and two to a wait-list control. In 2022, PEPFAR introduced a new Minimum Program Requirement: evidence of progress toward reducing stigma and discrimination to improve HIV treatment and prevention outcomes for people affected by HIV. The IDI evaluated individual, interpersonal, and structural stigma at 21 PEPFAR-supported public-sector health facilities in Central Uganda using a scale of 1 (poor) to 10 (good). Inclusion criteria: In keeping with the HP+ total facility approach, all staff working in the facility will be recruited. Exclusion criteria: staff who anticipate temporarily (e.g., study or parental leave) or permanently (e.g., transfer to another facility) leaving work during the study period. Participant recruitment Individuals affected by HIV (n \~120) from each health facility catchment area will be recruited by peers using snowball sampling, a method successfully used in the Empower, Peer, and Tandika clinical trials at IDI. Inclusion criteria: Eligible participants must be aged 18 or older, or, if aged 14 to 17, be a mature or emancipated minor due to an STI, or be engaged in their livelihood in accordance with national guidelines. They will be initiated on ART or PrEP in accordance with Ugandan guidelines. Exclusion criteria: We will exclude those unwilling to provide written informed consent for study procedures or who have a physical or mental condition that prohibits informed consent and participation in study procedures. Study procedures Participants recruited by peers will undergo minimal research procedures, including informed consent, before study enrollment. As part of the screening process, we will collect basic sociodemographic data and conduct a behavioral HIV risk assessment to ascertain study eligibility, including questions about HIV testing and willingness to take ART or PrEP. In accordance with the 2022 Consolidated Guidelines for the Prevention and Treatment of HIV and AIDS in Uganda, all participants in this study will be provided with risk-reduction counselling as standard of care. These counselling sessions will address stigma and discrimination, condom use, prevention and management of sexually transmitted infections, responsible alcohol consumption, and gender-based violence. Follow-up Participants will be scheduled for visits at the health facility after 3 months, which aligns with the current schedule for people taking ART and PrEP. As part of routine public health clinic procedures, they will receive HIV prevention counseling, HIV testing, and medications offered at their clinic (ART and PrEP at clinics not yet implementing the intervention; HIVE3/HP+ and ART/PrEP at clinics that have initiated the intervention). According to Ugandan clinical guidelines for PrEP delivery, HIV-negative people will have quarterly rapid HIV tests and be assessed for acute HIV infection before PrEP dispensing. PrEP use will be suspended if HIV tests are positive or if acute HIV infection is suspected. We will also extract clinic data from regular plasma viral load testing that is done for persons with HIV according to the local standard of care. Retention Retention measures will mimic those used in clinic ART programs in accordance with the standard of care. These include an explanation of the study visit schedule, re-emphasized at each study visit; reminder phone calls and text messages, updating of locator information (including primary and alternate phone numbers), and visits to people's homes only when they have missed several scheduled visits and if there is an abnormal laboratory result that requires follow-up. Safety monitoring Given the known high safety of antiretroviral medications for both treatment and prevention and the project's focus on implementing HP+ and HIVE3, only data on serious adverse events that are unexpected and felt by treating clinicians related to study participation will be collected. Outcomes The primary outcome is PrEP adherence. Study staff will abstract baseline and follow-up questionnaires and laboratory results on study electronic forms using REDCap, a secure web-based application, on tablet computers. Oral PrEP adherence will be objectively measured using a POC urine tenofovir assay that assesses adherence over the past 48 hours (≥1500 ng/mL). Secondary outcomes are viral suppression (HIV RNA levels \<50 copies/ml) and stigma reduction in health facilities. Statistical considerations The primary analysis will be an intent-to-treat comparison of PrEP adherence by randomization arm. Assuming 94% of participants test HIV negative (11/200 had HIV in our prior work; NCT04867798), the sample size of 120 provides 81% power to detect an increase in PrEP adherence from 40% in the control group to 60% in the intervention PrEP adherence, measured by urine tenofovir detection (≥1,500 ng/ml), will be compared between intervention and wait-list control groups using a generalized estimating equations (GEE) model with identity link, exchangeable correlation structure and robust variance estimates. A GEE model with an exchangeable working correlation is a convenient analysis tool for these data, as it accounts for within-subject correlation of outcomes and allows inference regarding the differences between intervention and control over time. The main effects of group and time and the interaction effects between group and time will be examined using the GEE, using repeated measurements of intervention and control groups at baseline and 3 months post-intervention, adjusting for baseline covariates and stigma outcomes (scores). Intervention Implementation The HP+ TFA adapted intervention to address intersectional stigma in Ghana includes two main components that build on each other and address four actionable drivers of HCF stigma: (1) participatory stigma-reduction training for all staff that addresses the key drivers of awareness, fears, and attitudes; and (2) integration of stigma reduction into facility structures and processes to institutionalize and sustain change. AIM 3: Evaluate the implementation of HP+ and HIVE3 using qualitative methods. Approach. We will conduct focus groups with healthcare facility staff (clinical and non-clinical) and with HP+ trainers and HIVE3 peers, and in-depth interviews (IDIs) with study participants in the intervention arm to gain a deeper understanding of how Ssinga Nze was implemented and experienced. We will sample from the intervention arm because the goal of Aim 3 is to explain how Ssinga Nze works. We will explore these experiences as a function of outer setting characteristics (e.g., participant needs and resources), inner setting characteristics (e.g., clinic readiness for implementation), and individuals involved (e.g., staff attitudes and beliefs). Qualitative interviews will take place at a venue of the participant's choice, where conversations can be conducted without being overheard. Study procedures We will interview participants to gain a deeper understanding of their experiences with stigma-reduction interventions. Participant interviews We will identify a random sample of 14 individuals from the intervention arm (7 per facility). Through CFIR-informed IDIs, we will assess values, preferences, perceptions, and experiences with ISD-reduction interventions and co-located HIV status-neutral PrEP/ART services. Interviews will explore individual- and HCF-level stigma and how SW adopt (or do not adopt) PrEP/ART into their everyday lives. Experienced IDI social scientists will explore preferences for service delivery, experiences at the facility and with peer support, and whether (and how) the multi-level intervention reduced stigma, empowered participants to engage in HIV prevention, and encouraged PrEP/ART adherence and persistence. Everyone in the qualitative sample will take part in an in-depth interview at least 3 months after intervention delivery. Experienced IDI social scientists will explore preferences for service delivery and if stigma-reduction empowered SW to engage in HIV prevention and encouraged ART/PrEP adherence and persistence. Sample open-ended questions include: 1. How do you feel about receiving care at this facility? 2. In what ways, if any, did the clinic environment influence your decision to engage in HIV care? 3. How do you feel about your interactions with healthcare staff at this clinic? 4. When was the most recent time you missed taking a dose of your ART or PrEP? What happened? 5. Tell me about your last study visit? Whom did you see? What did you discuss? 6. While participating in this study, a peer contacted you to support your ART or PrEP taking. How do you feel this prevention strategy has worked for you? Focus group discussions: We will conduct nine focus groups: 1. Two focus groups with HCF staff trainers, one at each intervention facility (Entebbe Regional Referral Hospital and Kisenyi Health Center IV). 2. Four focus groups with HCF staff who participated in the training (split by clinical and non-clinical staff) at Entebbe Regional Referral Hospital and Kisenyi Health Center IV (two at each facility) 3. Two focus groups with HCF peers; one at Entebbe Regional Referral Hospital and one at Kisenyi Health Center IV 4. One focus group with individuals providing peer support We will select clinic and non-clinic staff (7 per intervention facility) who have received the HP+ training to explore their experiences in implementing the intervention, including successes and challenges, suggestions for improving HP+, and the potential for nationwide scale-up. Eligible clinic staff include physicians, clinical officers, nurses, administrators, janitors, and pharmacists. We will purposively sample clinic staff to represent variation in gender (female/male) and profession (medical/nonmedical). HIVE3 Peers: A FGD with all 8 peers (4/facility) will be conducted to discuss their experience delivering the intervention, including how it may (or may not) have impacted their own lives. Data analysis The goal of the qualitative analysis is to gain knowledge and understanding of the dynamics of multilevel stigma reduction for people affected by HIV. The qualitative dataset for Aim 3 consists of approximately 20 transcripts (14 IDIs, 6 FGDs). It will enable a rich qualitative exploration in this first-ever assessment of the Ssinga Nze intervention and HIV status-neutral ART/PrEP services for African SW. We will explore whether ISD reduction affects sustained ART and PrEP use. Data will be analyzed using rapid qualitative analysis, as outlined in Aim 1. Capacity Development This project includes components for individual, community, and institutional capacity building. First, the IDI research team will receive mentoring from Nyblade and Sevelius. Second, including peers as implementation partners strengthens the community's capacity to conduct collaborative research rather than relying solely on external organizations. Third, the multinational collaboration strengthens institutional capacity for stigma research in Uganda and helps build the next generation of stigma researchers. Quantitative data collection Data will be collected using interviewer-administered questionnaires on encrypted tablets, completed in person during scheduled quarterly visits. Interviewers will ask each question with the exact same wording, in a courteous and conversational style, and in the language of the participant's choice (English or Luganda), while maintaining confidentiality. Questions will include demographics, intervention feasibility and acceptability, PrEP uptake and adherence, social harms, alcohol and drug use, depression, and stigma. Study staff will complete Case Report Forms (CRF) for each enrolled subject and report all clinical, safety, and laboratory data entered on the CRFs. Data should be Attributable, Legible, Contemporaneous, Original, and Accurate.