Research design and search strategy

This systematic review adheres to the Cochrane Collaboration standards [28]. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to report our findings [29]. We included randomized controlled trials (RCT), or quasi-experimental studies published between January 1, 2013, and June 1, 2023. We repeated the search in May 2024 to identify any new studies. We registered this systematic review with PROSPERO (CRD42023455610). No protocol was published or amended.

We employed a comprehensive strategy to search six electronic databases: MEDLINE (PubMed), Embase, Scopus, Web of Science, CINAHL, and PsycINFO [30]. We also conducted supplementary searches through manual methods, including hand and bibliographic searches [31]. The review period was June 2023 to March 2024. We wrote the manuscript between March 2024, and July 2024.

The search strategy involved a meticulous breakdown of the research topic into three conceptual units: stigma, HIV, and adherence. Medical Subject Headings (MeSH) terms were identified for each unit, further enhancing the search efficacy within the MEDLINE database through PubMed [32]. The MeSH terms selected were: “Stigma, social stigma, internaliz(s)ed stigma and stigma reduction” [Mesh] for stigma and stigma reduction, “HIV” [Mesh], “Antiretroviral Therapy, Highly Active, ART, therapeutics” [Mesh], and “Pre-Exposure Prophylaxis, PrEP” [Mesh] for HIV, and “Medication Adherence, compliance, uptake” [Mesh] for adherence and uptake. We combined the MeSH terms with relevant keywords using Boolean connectors (AND & OR) [33]. Tailored truncators and field tags were deployed for each database, targeting titles, titles/abstracts, and full texts to improve search precision (Fatehi et al., 2014). The search strategy development was peer-reviewed by an information specialist based on the Peer Review of Electronic Search Strategies (PRESS) checklist [34]. The strategy is available in S1 File.

Study eligibility and selection process

Inclusion criteria encompassed studies published within the last decade (2013–2023) in the English language, peer-reviewed, and with accessible full-text versions. The Population-Intervention-Comparison-Outcome (PICO) framework guided the development of additional eligibility criteria [35]. Studies were eligible if the participants were 15 years old and older, either persons living with HIV on ART or at-risk populations taking PrEP. We included studies if the interventions addressed HIV- or PrEP-related stigma (intervention) and reported outcomes related to stigma reduction, ART or PrEP uptake, or adherence. Studies that addressed only stigma reduction or medication adherence but not both were not included, based on the predefined search strategy. We included only experimental RCTs or quasi-experimental studies assessing the intervention’s impact on the targeted outcomes. Exclusion criteria comprised studies with unavailable full texts, interventions not tailored to enhance ART/PrEP compliance or uptake, and lack of reported effectiveness in improving ART/PrEP adherence/uptake or stigma reduction. We also excluded studies that reported only stigma reduction without any outcome measurement for ART/PrEP adherence/uptake.

We used the online software Covidence to manage literature search. We removed duplicate entries after initial eligibility screenings based on abstracts and titles. We then evaluated the shortlisted studies. We resolved disagreements between reviewers (A.D., A.S.) through discussion to reach a consensus.

Data extraction and synthesis

Two independent reviewers (A.D., A.S.) extracted essential data points from the articles: study particulars (authors, publication year, location, study design, follow-up period, participant characteristics, and sample size), stigma-related information (stigma type, assessment method), stigma reduction interventions (intervention type, description, effectiveness), and outcomes (operationalization of ART/PrEP adherence/uptake, assessment tool used, reported results). Two authors A.D. and A.S. met to discuss the extracted data points to summarize the methodology and results of each study. These discussion notes were then used by the author A.D. to draft the tabulated findings and the manuscript. We presented the data for each study in a structured tabular format. Disagreement was settled through a collaborative discussion.

Due to notable heterogeneity in participant characteristics, intervention attributes, and measurement tools, we performed a separate synthesis for RCTs and quasi-experimental studies, aligning with recommendations from Cochrane Consumers and Communication Review Group (2013) [36]. We adopted a narrative synthesis approach, comparing disparities and commonalities in findings and contributory factors, including study design and implementation. This helped identify stigma reduction interventions that enhance ART/PrEP adherence, delineating their underlying mechanisms and pinpointing areas requiring research for deeper insights.

Quality assessment of the articles

A.D. and A.S. independently conducted and documented a rigorous quality assessment. In quasi-experimental studies, we assessed the risk of bias using the Cochrane Collaboration’s risk of bias assessment tool for non-randomized interventions [28]. To evaluate the risk of bias in RCTs, we used the Cochrane Risk of Bias (RoB 2) tool [37]. RoB2 has five domains: Domain 1(a) concerns bias arising from the randomization process, and 1(b) concerns bias arising from the recruitment of a cluster-randomized study (applicable to one study). Domain 2(a) assesses bias arising from the effect of assignment to intervention and 2(b) explores the effect of adhering to intervention. Domain 3 assesses bias due to missing outcome data; Domain 4 investigates bias in measuring the outcome; and Domain 5 is the arising from selecting the reported result. “High risk of bias” in any single domain assigns an overall high risk to the RCT.

Interventions for ART adherence

Four of the seven studies that focused on interventions intended for improved ART adherence comprised a cognitive-behavioral therapy (CBT) component delivered alongside other psychological treatment approaches, unique for each study [44,46,49,50]. Due to the unique combinations with cognitive behavioral strategies, the activities implemented in each of the four studies differed with a few areas of similarity. The most common activities implemented in the four studies included psychoeducation, skills training (e.g., coping skills), and motivational interviewing [44,46,49,50]. Abbas et al implemented 8-session blend of classic and brief CBT (b-CBT) activities to each participant individually to enhance motivation, manage stress, and provide cognitive restructuring for relapse reduction [44]. Bogart et al employed an intervention named Siempre Seguiré (Spanish for “I will always continue”), a blend of CBT and dialectical behavioral therapy (DBT) in 8 group sessions, aimed to enhance coping using intersectionality perspective, i.e., whole identity of a person, which is not just defined by their diagnosis [44,46]. In contrast, Kalichman et al employed five weekly-delivered phone-based counseling sessions for behavioral self-regulation, whereby participants would develop problem solving strategies to self-identified barriers to HIV care [49]. Wagner et al used compassion-focused therapeutic principles and CBT in six group sessions grounded in self-efficacy development through experience-sharing, support building, group problem solving, and personal goal setting [50]. While quite heterogenous, all four studies used CBT as the core intervention to enhance adherence.

Bhatta et al. implemented an empowerment intervention derived from social learning and action theories, comprising of group discussion sessions over 6 weeks [45]. Two national-level trainers with public health graduate degrees facilitated all intervention sessions, employing participatory learning activities, buzz sessions, brainstorming, lectures, and discussions. Participants were encouraged to engage and communicate with others about HIV prevention, treatment, and disclosure. These sessions focused on describing self-efficacy, self-esteem, autonomy, self-care, optimism, control over the future, stigma and discrimination issues, human and health rights, family and social relationships, and stress and righteous anger management.

Bryant et al. implemented an entertainment-education intervention where participants watched a single-session short film about HIV stigma and treatment [47]. The authors chose a film, “90 DAYS”, which focused on demonstrating the nuances of HIV stigma, such as diagnosis, disclosure, and partner rejection. The film aimed to illustrate stigma-related behavior and promote covert learning about HIV stigma.

Denison et al. implemented a peer mentoring intervention for the youth, a population distinct from adult populations described in the other included studies in this systematic review. Young individuals and adolescents living with HIV have unique requirements of support and resources to develop effective HIV self-management behaviors as they transition into adulthood. Self-management encompasses adherence to antiretroviral therapy (ART), practicing safer sex behaviors, and transitioning to adult care. In Denison’s study, the intervention arm included HIV-positive youth who had successfully transitioned to self-management. The intervention arm underwent two-week training and were assigned to be mentors to the study participants [48]. Mentorship activities entailed engaging others in group-based activities, such as discussing challenges, approaches, and ideas. Table 3 summarizes the interventions and their effectiveness in reducing HIV-related stigma and improving ART adherence.

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Table 3. Intervention characteristics and study outcomes of all the studies eligible for inclusion published between January 1, 2013 to June 1, 2023 (data extracted from June 2023 to March 2024).

https://doi.org/10.1371/journal.pgph.0004604.t003

Interventions for PrEP adherence

The singular RCT examining PrEP adherence employed a unique 45-minute session intervention called project Jumpstart [51]. The session activities included motivational interviewing, client-centered counseling, and semi-structured interviewing. Four parallel arms were studied: control group, Jumpstart group, Jumpstart group (with additional 10–15 minute text message check-in), and Jumpstart group (with additional 10–15 minute text message and phone call check-in). Check-ins involved asking participants if they required assistance in achieving their PrEP-related goals established during the counseling session.

Outcome measvurement instruments

All eight studies reported outcomes related to HIV-related stigma and ART/PrEP adherence or uptake using a wide range of measurement instruments.

For stigma reporting, three studies assessed HIV-related stigma using the Internalized AIDS-Related Stigma Scale [46,48,50]; one used the 40-item HIV Stigma Scale [44], one adopted a custom 23-item scale from previous research [45], one used the Negative Self-Image Scale [47], and others conceptualized HIV stigma based on previous research and developed custom 3-item scales, unique in each study [49,51].

Unlike HIV-related stigma, where most studies utilized previously validated measurement scales, ART/PrEP adherence outcomes were assessed using single or two-item scales formulated by the authors, lending heterogeneity in the outcome reporting (Table 3). Abbas et al. assessed ART adherence using a pre-and post-test design to evaluate the impact of cognitive behavioral therapy. Adherence was measured using the General Medication Adherence Scale (GMAS), which was originally developed in the Urdu language. The GMAS comprises 11 items, each with four possible response options, categorized into three domains: (1) non-adherence due to patient behavior (NAPB), (2) non-adherence due to other diseases and pill burdens (ADPB), and (3) non-adherence due to financial constraints (NAFC). Each item is scored on a scale from 0 to 3, with the total score determining the overall adherence level. Adherence is classified as high (30–33), good (27–29), partial (17–26), low (11–16), and poor (≤10). The GMAS demonstrates strong reliability, with an internal consistency of 0.80 and a test-retest reliability of 0.996[44]. Conversely, Bhatta and Liabsuetrakul assessed adherence to antiretroviral therapy (ART) as a dichotomous variable, categorizing participants’ responses as either “yes” or “no” based on their self-reported adherence. Participants were asked, “Have you been taking your medication?” at three key time points: baseline, three months after the first follow-up, and six months after the first follow-up. However, the study did not specify the exact criteria used to determine adherence, such as whether the classification was based on a specific number of missed doses or the participant’s subjective perception of their adherence [45].

Bogart et al. measured ART adherence using both electronic monitoring and self-report methods throughout the seven-month study. At baseline, participants completed a survey and were provided with a Medication Event Monitoring System (MEMS) bottle cap (AARDEX, Inc.), which electronically tracked adherence by recording the date and time of each bottle opening. The MEMS cap was assigned approximately two months before each cohort’s intervention start date to establish a valid pre-intervention baseline and minimize potential reactivity to the monitoring process. To ensure accurate tracking, research assistants helped participants transfer their medication into the MEMS-equipped bottle. When participants had multiple medications, the cap was used for the one with the most complex dosing schedule or, if all had the same schedule, the regimen’s base medication. Adherence data were downloaded at follow-up visits scheduled at two, four, five, and seven months post-baseline. At each follow-up visit, participants also completed a brief survey to account for instances where the MEMS cap may not have captured adherence accurately. This included reporting cases in which the bottle was opened without a dose being taken, doses were removed from an alternative source (e.g., a pillbox), or multiple doses were removed at once for later ingestion. These responses were used to adjust the MEMS data, refining the adherence assessment for greater accuracy. The primary adherence outcome derived from MEMS data was continuous adherence, calculated as the percentage of total scheduled doses taken during each one-month period of the study. In addition to electronic monitoring, self-reported adherence was assessed using a visual analog scale, where participants estimated the percentage of prescribed ART doses they had taken in the past month. This self-report measure was validated against objective indicators such as viral load and pill count, enhancing the reliability of adherence assessment [46].

Bryant et al. measured medication adherence intentions using a two-item Likert-type scale adapted from Stirratt et al. (2006). This scale assessed the likelihood of participants missing their HIV medication over the next 30 days due to nondisclosure of their HIV status. Responses ranged from “not at all likely” to “very likely,” capturing variations in adherence intentions. One of the items specifically asked, “Miss doses of your ART/ARV (HIV medication) in the next 30 days due to being with a sexual partner who does not know you are living with HIV.” The study employed a randomized controlled trial (RCT) with a pre- and post-test design to compare two conditions: (1) an active control condition, where participants received a standard-of-care brochure, and (2) the intervention condition, in which participants viewed the 90 DAYS film. Adherence intentions were measured before and after exposure to these conditions, allowing the researchers to assess the impact of the intervention on participants’ likelihood of missing doses due to nondisclosure [47].

In contrast, Denison et al. assessed ART adherence by measuring the presence of a treatment gap at two time points using two self-reported questions. Participants were asked: (1) “In the past three months, did you have a day when you did not take any ART drugs?” and (2) “What were the most days in a row that you missed swallowing your drugs in the past three months?” A binary adherence outcome was generated based on participants’ responses. Participants were classified as not having a treatment gap if they reported no missed full days of ART in the past three months or if they acknowledged missing ART but for only one day. In contrast, participants were considered to have an ART adherence treatment gap if they reported missing 48 consecutive hours or more within the past three months. If responses to both questions were missing, the adherence treatment gap outcome was also considered missing. This approach provided a structured way to assess adherence while emphasizing gaps in treatment that could impact clinical outcomes [48].

Kalichman et al. assessed ART adherence at baseline and follow-up using a reliable and validated rating scale that asked participants to estimate the percentage of their HIV medication doses taken in the past month. At baseline, adherence was measured using a visual analogue scale (VAS) graded along a continuum from 0% to 100% adherence. Participants were provided with the following instructions: “We know it is common for people to miss or skip taking doses of their ARVs (antiretrovirals). Think about the past month when answering this question. Think about what has happened over the past 30 days, that is, for one month before today. Using this rating scale, how much of your ARVs have you taken? You can answer anywhere from ‘None of my ARVs’ to ‘All of my ARVs’ or anywhere between that by marking a line. I am going to ask you to make a mark to show how much you HAVE taken in the past month: 0% means you have taken NONE of your ARVs in the past month, 50% means you have taken about HALF of your ARVs, and 100% means you have taken ALL of your ARVs and never missed a dose in the past month.” Participants were then instructed to mark their adherence level on the scale and state the corresponding percentage. For follow-up assessments conducted over the phone, the same adherence rating method was used, but without the visual scale. Instead, participants verbally reported their adherence percentage based on the same instructions and response stem. This method ensured consistency across assessments while allowing for adherence measurement in remote follow-ups [49]. Wagner et al. assessed ART adherence using a single-item self-report measure, in which participants rated the percentage of prescribed ART doses they had taken in the past month on a 0–100% scale. This measure served as an indicator of positive living behavior, providing a straightforward estimate of adherence based on participant recall [50].

Eaton et al. measured PrEP uptake through a combination of biological testing and self-report from follow-up assessments. Participants who reported any PrEP use within the four months post-intervention were asked to provide a urine sample for laboratory analysis using UrSure (UrSure, Inc., Boston, MA), a validated assay that detects the presence of tenofovir, the active ingredient in PrEP. Test results were interpreted dichotomously—indicating either the presence or absence of tenofovir—to objectively confirm self-reported PrEP adherence [51].

Outcomes

Overall, of the seven studies examining ART adherence and stigma reduction in persons with HIV, three studies showed ART adherence, and five studies showed stigma reduction. The singular study that investigated PrEP adherence and stigma reduction showed significant PrEP adherence but not stigma reduction.

Quality assessment

Table 4 summarizes the quality assessment of each study. The quality of the RCTs ranged between 58.33% and 91.67%. Six of the eight RCTs had one or two domains with a high risk of bias. In these studies, Domain 2(a) (effect of assignment to intervention) and Domain 2(b) (effect of adhering to intervention) had a high risk of bias since most of the RCTs were open-label, meaning the participants, intervention deliverers, and outcome assessors were aware of the assignment of participants to control and intervention groups. However, the remaining domains, including randomization and handling of missing outcome data, had a low risk of bias.

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Table 4. Risk of bias assessment findings of all the studies eligible for inclusion published between January 1, 2013 to June 1, 2023 (data extracted from June 2023 to March 2024).

https://doi.org/10.1371/journal.pgph.0004604.t004

Limitations

Certain limitations of this study merit discussion. First, most studies were open-label which introduces bias. Second, significant heterogeneity exists in methodologies, making head-to-head comparisons challenging to isolate the most effective intervention. Future research should prioritize robust RCTs with larger, more diverse populations and standardized outcomes. Double-blinded designs with adequate sample size, participant allocation, and blinding can minimize bias. Third, the low number of studies with small sample sizes representing limited geographical cohorts makes the generalizability of the findings challenging. The socio-cultural influences that accompany geographical diversity are crucial to the understanding of multidimensional and complex nature of HIV related stigma. Hence, studies need to be conducted in more diverse regions. Fourth, six of the eight included studies had a high risk of bias. This, combined with the utilization of varied scales and methods, calls for standardized measures in assessing ART/PrEP adherence outcomes for future research to enhance comparability and interpretation of findings.