Medication literacy and treatment adherence in people living with human immunodeficiency virus: Mediating effects of psychosocial factors

Abstract

Treatment adherence among people living with human immunodeficiency virus (PLWH) is a critical determinant of viral suppression and improved quality of life. Medication literacy, as a key factor influencing adherence, is itself shaped by various psychosocial variables. Existing studies suggest that human immunodeficiency virus (HIV)-related stigma, self-efficacy, and trust in healthcare providers serve as significant mediators in the relationship between health literacy and treatment adherence. This review systematically explores how medication literacy affects treatment adherence in PLWH through intermediary psychosocial mechanisms such as depression, anxiety, and social support. By synthesizing current evidence, we aim to inform the development of targeted psychosocial interventions to enhance treatment outcomes and quality of life for this population. Our findings provide an evidence-based foundation for nursing practice and support innovative strategies in comprehensive HIV care.

Key Words: Anxiety; Depression; Digital health; Human immunodeficiency virus; Medication literacy; Psychosocial factors; Self-efficacy; Social support; Stigmas

Core Tip: This review highlights how medication literacy influences treatment adherence among people living with human immunodeficiency virus (HIV) through key psychosocial mediators such as stigma, self-efficacy, and social support. It integrates neurobehavioral insights and sociocultural factors, offering a multidimensional framework for understanding and improving adherence. The findings support tailored psychosocial interventions-like cognitive behavioral therapy and culturally adapted education-to enhance patient outcomes and inform holistic HIV care strategies.

INTRODUCTION

Adherence to antiretroviral therapy (ART) among people living with human immunodeficiency virus (PLWH) remains a critical global public health challenge, with complexities that extend beyond the biomedical domain. Recent epidemiological data indicate that in 2023, approximately 630000 individuals worldwide died from human immunodeficiency virus (HIV)-related complications, including 76000 children[1]. Although global viral suppression rates have significantly improved, considerable regional disparities persist[1].

Globally, ART adherence demonstrates marked spatial heterogeneity. Despite continued expansion of ART coverage in recent years, viral suppression rates remain suboptimal, reflecting systemic issues in the quality of adherence[1]. These challenges are particularly pronounced in resource-limited settings, where the gap in ART access between developing and developed countries remains substantial[2-4]. Moreover, educational attainment is closely linked to adherence outcomes, with lower educational levels associated with higher risks of treatment interruption[5].

The interaction of social determinants further compounds the difficulties in achieving sustained adherence. Economic hardship, racial inequality, and limited access to healthcare contribute to weak links in adherence among specific populations[6,7]. For instance, structural social barriers expose certain minority groups to medical discrimination, increasing the instability of their ART regimens. Gender-related factors also play a role: Women living with HIV are often at greater risk of missed doses due to caregiving responsibilities[8]. Additionally, with the rise of digital health technologies, the digital divide has emerged as a new barrier to adherence. Individuals with limited digital literacy demonstrate poorer compliance in telemedicine contexts[9].

Medication literacy, as a critical concept, refers to an individual’s ability to obtain, comprehend, and apply medication-related information[10]. Among PLWH, higher levels of medication literacy are significantly associated with better adherence outcomes[11,12]. Research shows that low medication literacy constitutes a major risk factor for poor adherence to HIV treatment, a relationship that is mediated by various psychosocial factors[11,13].

Social cognitive theory (SCT) and the health belief model (HBM) offer complementary frameworks for understanding adherence mechanisms. SCT emphasizes the central role of self-efficacy in initiating, maintaining, and preventing relapse of health behaviors, whereas HBM focuses on the perceived threat of illness and its interaction with trust in healthcare providers[14,15]. Evidence suggests that HIV-related stigma undermines adherence both directly-by increasing the likelihood of missed doses-and indirectly-by diminishing self-efficacy and reducing the likelihood of seeking social support. This underscores the limited effectiveness of single-level interventions[16]. Moreover, healthcare accessibility and service quality influence the applicability of these theoretical models. Cross-national studies indicate that patients receiving care from integrated service providers exhibit higher retention rates, suggesting that systemic factors may reshape individual psychosocial processes. Future research should thus incorporate multilevel analytical frameworks[16,17].

THEORETICAL MECHANISMS OF MEDIATION EFFECTS

Mediating pathways of stigma

External stigma → medication literacy → adherence (the impact of social exclusion on health information processing): Social exclusion restructures the pathways through which PLWH access health information, primarily via institutionalized discrimination mechanisms[18]. Studies have shown that patients often avoid reading medication inserts due to exclusionary policies in healthcare settings, resulting in a reduced accuracy in understanding drug interactions[19]. This systematic exclusion contributes to the emergence of an "information desert," where patients rely on informal social networks to exchange fragmented medical knowledge, thereby increasing the risk of dosage errors[20]. Cultural specificity further exacerbates information processing difficulties. In certain cultural contexts, traditional gender norms hinder women’s access to health information. Although encrypted social media may serve as an alternative information source, its unstructured flow of content can lead to individualized deviations in treatment strategies, especially under conditions of social exclusion and restricted information access[21,22].

Internalized stigma → self-efficacy → adherence (the impact of self-stigmatization on treatment confidence): Self-stigmatization undermines patients’ confidence in treatment through a process of cognitive fusion. Research indicates a significant positive correlation between internalized stigma and psychological inflexibility, manifesting in the pathological association of HIV status with self-worth. This often leads to a "self-punishment" tendency in treatment decisions. Neurologically, this psychological mechanism is reflected in reduced gray matter density in the anterior insula, which impairs risk perception and prompts patients to self-adjust their medication dosage in an attempt to avoid status disclosure[23,24]. A 2024 United States cross-sectional study of 208 PLWH with substance-use disorder using the A-CHESS mHealth app showed that each 1-unit increase in internalized-stigma score decreased the odds of optimal adherence by 18% (OR 0.82, 95%CI: 0.70-0.99), corroborating the "self-punishment" mechanism described above[25].

Moderating effects of stigma (divergent pathways in racial and sexual minority groups): The moderating effects of stigma exhibit distinct pathways across racial and sexual minority groups. Studies have found that African American patients facing compounded discrimination (race + HIV status) experience an elevated risk of treatment interruption. In clinical settings, this intersectionality is often embodied in a lack of trust-African American patients display greater skepticism toward prescribers’ intentions compared to White patients, leading to non-adherent dosage modifications[26,27]. Sexual minority individuals bear a unique spatiotemporal stigma burden: Men who have sex with men (MSM) report higher levels of internalized stigma within familial contexts compared to their heterosexual counterparts, although community subcultural networks may buffer external stigma[28,29]. Transgender women face a tri-layered stigma effect; the intersection of HIV stigma and gender identity discrimination significantly reduces medication storage adherence, which is markedly lower compared to cisgender patients[21,27] (Table 1).

Table 1 Distinct mediating pathways of stigma and their impact on treatment adherence.

Mediating pathway	Mechanism of action	Impact on outcomes	Group differences	Ref.
External stigma → medication literacy → adherence	Social exclusion restructures access to health information through institutional discrimination	Patients avoid reading medication inserts, leading to reduced accuracy in understanding drug interactions; an "information desert" emerges	Cultural specificity exacerbates information-processing difficulties; women may face more barriers in accessing health information	[18-20]
Internalized stigma → self-efficacy → adherence	Self-stigmatization undermines treatment confidence via cognitive fusion	Patients pathologically associate HIV status with self-worth, showing a "self-punishment" tendency in treatment decisions	Internalized stigma is positively correlated with psychological inflexibility, associated with reduced gray matter density in the anterior insula	[23,24]
Moderating effects of stigma	Multiple discrimination experiences in racial and sexual minority groups	African American patients exhibit greater distrust toward prescribing intentions; sexual minorities experience unique spatiotemporal stigma burdens	African Americans face dual discrimination (race + HIV status); men who have sex with men report higher internalized stigma in family contexts; transgender women experience a triple-layered stigma effect	[21,27]
Concealment of treatment behavior	Patients adopt systematic concealment strategies to reduce identity exposure risk	Strategies such as altering appointment times or modifying medical records increase complexity and risk in health management	Women are more likely to use "medication repackaging" due to family role conflicts; men who have sex with men build anonymous support systems through virtual networks	[62-65]

HIV: Human immunodeficiency virus.

The bidirectional role of self-efficacy

Medication literacy → self-efficacy → adherence: The Psychological Mechanism of Knowledge Translation: Medication literacy facilitates the transformation of health knowledge into treatment behavior by activating the self-regulatory system within SCT[30]. Neurobehavioral studies have shown that the effective internalization of pharmacological knowledge relies on functional coupling between the prefrontal cortex and the striatum. This neural coordination enhances the efficiency of the executive control network, thereby optimizing patients’ decision-making capabilities in managing complex medication regimens[31,32]. For example, culturally adapted health education programs that integrate traditional medical beliefs with modern biomedical knowledge can significantly improve patients’ understanding of drug interactions and boost their confidence in medication use[33-35].

Self-efficacy plays a pivotal mediating role in this process[36]. When patients are able to accurately interpret medication instructions and anticipate potential side effects, their sense of agency in disease management is substantially enhanced[36,37]. This knowledge-to-behavior translation mechanism is particularly evident in digital health interventions. AI-powered medication reminder systems, by reducing cognitive load, assist patients with low health literacy in transforming abstract information into actionable behavioral strategies-overcoming the linguistic and cognitive limitations of traditional education models[38,39].

Treatment success → enhanced self-efficacy → improved literacy (A positive feedback loop): Self-efficacy, defined as patients’ confidence in their ability to adhere to treatment, is a well-established determinant of ART adherence[40]. Crucially, self-efficacy often mediates the relationship between medication knowledge and adherence behavior. For instance, a 2023 study involving 402 Chinese patients with type 2 diabetes demonstrated that higher medication literacy significantly predicted better adherence, with self-efficacy accounting for approximately 36.7% of this effect (mediation effect size = 0.367)[41].

Similar mechanisms have been documented in HIV populations. A recent study of 205 Yi ethnic adolescents living with HIV reported a mean adherence self-efficacy score of 73/100, with markedly higher scores among individuals exhibiting greater self-acceptance and emotional regulation. Specifically, each one-point increase in self-acceptance corresponded to a β = 0.157 increase in self-efficacy (P < 0.01)[42]. These findings highlight how cultural and socio-economic factors-such as rural residence, stigma, and social support-profoundly shape self-efficacy levels and, by extension, adherence outcomes.

Importantly, the reinforcement of self-efficacy is not solely a psychological process but also involves neurobiological mechanisms. Treatment success experiences engage the brain’s dopaminergic reward system, particularly through the activation of D2 receptors in the striatum, which strengthens neural circuits associated with positive reinforcement[43]. This neuroplastic adaptation fosters a cyclical loop whereby "successful experience → enhanced self-efficacy → deeper knowledge", gradually consolidating patients’ intrinsic motivation for sustained adherence[43].

As self-efficacy grows, patients are more likely to proactively seek structured pharmacological knowledge, such as through digital platforms, thereby further enhancing their medication literacy[44]. This synergistic interplay between behavioral reinforcement and knowledge acquisition establishes a self-sustaining positive feedback loop that ultimately improves adherence and treatment outcomes[38] (Figure 1).

Figure 1 Positive feedback loop of self-efficacy enhancement in human immunodeficiency virus treatment adherence. Self-efficacy enhancement in people living with human immunodeficiency virus follows a dynamic feedback loop that integrates behavioral, cognitive, and relational mechanisms. The process begins with micro goal achievement, such as taking medication on time for 3 consecutive days, which activates dopaminergic reward pathways and reinforces self-efficacy. This enhancement is further consolidated through learning via digital platforms, promoting structured knowledge acquisition and strengthening patients' confidence in medication management. As patients engage in proactive knowledge acquisition, their understanding of pharmacological principles deepens, leading to enhancing medication confidence and better decision-making in daily treatment adherence. These improvements contribute to adherence consolidation, which not only stabilizes behavioral patterns but also creates a virtuous cycle of successful experiences. The entire loop is sustained by social support and patient-provider trust, which modulate motivational systems and extend the effects of dopaminergic reinforcement.

Thus, interventions aimed at improving adherence should not only disseminate medication knowledge but also prioritize strategies that cultivate patients’ confidence through achievable treatment successes and psychosocial support.

The sustainability of this positive feedback loop depends on the buffering effects of social support systems. Peer support networks, particularly in virtual spaces, help reconstruct patients’ self-narratives by reframing adherence as a marker of resilience. This significantly enhances the dorsal anterior cingulate cortex’s ability to integrate feedback-related information[45-47]. Furthermore, the establishment of trust in healthcare providers can modulate the intensity of dopaminergic projections from the ventral tegmental area to the prefrontal cortex, extending the temporal window of reinforcement and maintaining the efficacy of the feedback cycle[48,49].

The role of social support networks in HIV treatment adherence

Social support networks play a vital role in treatment adherence among PLWH, influencing medication adherence through multiple dimensions, including peer support, family support, and patient–provider trust.

The mitigating effect of peer support on stigma

Peer support significantly mitigates the negative impact of HIV-related stigma on treatment adherence by providing both emotional and informational support[47]. A systematic review and meta-analysis by Berg et al[50] demonstrated strong associations between peer support and long-term retention in care, adherence, and viral suppression among PLWH. Peer support not only offers emotional reinforcement but also facilitates the exchange of experiences and medical knowledge, helping patients cope with social stigmatization while strengthening their self-efficacy and confidence in treatment. Research further indicates that peer support can reduce internalized stigma, thereby improving adherence outcomes[51].

Family support as a buffering variable between literacy and adherence

Family support, as a critical form of social support, influences both medication literacy and adherence through various mechanisms. Studies show that family support can buffer the negative effects of low medication literacy on adherence, particularly among children and adolescents. By providing emotional encouragement, medication reminders, and accompaniment to clinical visits, families help patients overcome treatment-related barriers[52,53]. Furthermore, family support can enhance self-efficacy, bolstering patients’ confidence in managing complex medication regimens and thereby improving adherence[53].

The moderating role of patient-provider trust (especially among minority populations)

Trust between patients and healthcare providers serves as a key moderating factor in ART adherence, particularly among racial and ethnic minority populations. Research has shown that African American patients tend to exhibit lower levels of trust in healthcare providers, and this distrust is associated with poorer adherence and less favorable treatment outcomes[54,55]. Enhancing patient–provider trust can be achieved through culturally responsive communication and efforts to build rapport, ultimately promoting better adherence[56]. Moreover, establishing trust helps reduce patients’ suspicion and fear of the healthcare system, encouraging them to accept and follow treatment recommendations more effectively (Tables 1 and 2).

Table 2 Key psychosocial mediating variables influencing treatment adherence in people living with human immunodeficiency virus.

Mediating variable	Definition	Mediating mechanism	Key findings	Ref.
Stigma	Social stigma and self-stigmatization related to HIV	Affects access to health information and self-efficacy through external and internal stigma pathways	Stigma leads to avoidance of medication information and increased risk of dosage errors; internalized stigma is significantly associated with psychological inflexibility	[21,22]
Self-efficacy	Patients’ belief in their ability to successfully perform treatment behaviors	Promotes translation of health knowledge into treatment behaviors via the self-regulatory system in social cognitive theory	Higher self-efficacy is significantly associated with better adherence; treatment success reinforces efficacy, forming a positive feedback loop	[31,32]
Social support	Support from peers, family, and healthcare providers	Provides emotional and informational support, buffers stigma, and enhances self-efficacy	Peer support is strongly linked to long-term retention, adherence, and viral suppression; family support buffers the negative impact of low medication literacy on adherence	[52,53]
Depression/anxiety	Mental health problems associated with HIV	Alters cognitive processing through functional decoupling of the prefrontal–limbic system	Depression reduces glucose metabolism in the prefrontal cortex, impairing working memory and executive function; anxiety heightens amygdala–insula reactivity, leading to cognitive overload	[58-61]
Patient–provider trust	Degree of trust patients have in healthcare providers	Enhances the therapeutic alliance and reduces suspicion and fear of the medical system	Lower levels of trust are linked to poorer adherence and outcomes; especially relevant among minority populations	[89]

HIV: Human immunodeficiency virus.

EMPIRICAL STUDIES ON KEY MEDIATING VARIABLES

Psychological variables

Depression/anxiety (neural circuit mechanisms of cognitive resource depletion): Depression and anxiety disrupt cognitive processing in PLWH through functional decoupling between the prefrontal and limbic systems. Longitudinal studies indicate that persistent depressive states reduce glucose metabolism in the prefrontal cortex, impairing working memory and executive function. This neural degradation is dose-responsively linked to errors in medication decision-making[57,58]. Notably, the cognitive effects of depression do not manifest immediately but accumulate over time. Research has shown that untreated chronic depression may accelerate hippocampal atrophy, damaging neural mechanisms related to learning and memory and significantly reducing the efficiency of information encoding. Magnetic resonance spectroscopy further confirms the profound structural and functional impact of depression on the brain[58]. Anxiety, on the other hand, heightens reactivity within the amygdala–insula circuit, inducing hypervigilance and cognitive overload in complex medical settings. This manifests as difficulties in prescription comprehension and confusion regarding medication dosages[59]. Cross-cultural comparative studies reveal that access to healthcare resources may partially buffer the cognitive burden of anxiety. However, in regions characterized by structural discrimination, attention dysregulation triggered by anxiety remains a primary cause of treatment discontinuation[60,61].

HIV-related shame: Dual strategies of concealed treatment behavior

HIV-related shame exerts a profound influence on patients’ behavioral decision-making patterns via neural plasticity, gradually shaping a systematic set of concealment strategies aimed at minimizing identity exposure in social and medical contexts[62]. Qualitative studies report that many individuals, in an effort to avoid stigmatization, alter clinic visit times, falsify or modify medical records, and conceal their health status[63-65]. While these strategies may temporarily reduce psychological stress and stigma-induced anxiety, over the long term, they can hinder accurate clinical assessment and compromise the scientific integrity of treatment plans, thereby increasing the complexity and potential risks of health management[66,67]. These concealment behaviors also display distinct gender differences: Women, due to conflicting family roles, are more likely to engage in practices like "repackaging medications", while MSM often establish anonymous care networks via virtual platforms[68-70]. Neuroimaging evidence shows that patients who engage in prolonged concealment strategies exhibit reduced gray matter density in the anterior insula. This structural change is closely associated with distorted risk perception, leading to biased decision-making when weighing treatment benefits against social exposure risks[36]. Importantly, the proliferation of digital health tools has created new spaces for concealment. An increasing number of patients now manage their treatment through encrypted health applications; however, this also introduces new anxieties regarding privacy breaches through digital footprints, making the balance between convenience and security particularly delicate[36,71] (Table 1). The dual-channel pathways through which external and internal shame impact treatment adherence are summarized in Figure 2.

Figure 2 Dual-channel mechanisms of human immunodeficiency virus-related shame on treatment adherence. Human immunodeficiency virus (HIV) related shame impairs treatment adherence through two complementary pathways: The external shame channel and the internal shame channel. The external shame channel follows a cascade in which social exclusion, reinforced by institutional discrimination, limits access to reliable health information, creating an information desert. This deficit increases the likelihood of medication errors, ultimately leading to adherence decline. Conversely, the internal shame channel reflects a self-directed mechanism, where self-stigmatization erodes treatment confidence, prompting self-punishment behaviors that further undermine adherence. Both pathways converge on adherence outcomes but are mediated by distinct psychosocial processes. At the foundation, the group difference layer highlights how intersecting identities-such as race, LGBTQ+ identity, and transgender status-amplify the effects of stigma through layered social disadvantages. These factors modulate the severity and progression of shame-related adherence barriers among people living with HIV. LGBTQ+: Lesbian, gay, bisexual, transgender, queer/questioning, plus.

Self-management efficacy: A psychodynamic system of behavioral reinforcement

Self-management efficacy drives the acquisition and maintenance of treatment-adherent behaviors through positive reinforcement mechanisms in the dopaminergic reward system. A cohort study from Ethiopia found that self-efficacy levels are significantly correlated with D2 receptor density in the striatum. This neurochemical characteristic increases the rate of reinforcement learning by up to 40% among high-efficacy patients, particularly in scenarios involving medication side-effect management[36,72]. Key social moderators contribute to the enhancement of efficacy: Urban residence increases patients’ self-correction capacity by 2.1 times through improved access to real-time medical feedback, while economic empowerment reduces survival-related stress, freeing up cognitive resources for health management[72]. Cross-theoretical model research suggests that the development of self-efficacy follows a staged trajectory-during the initiation phase of behavior, trust in healthcare providers is the dominant factor, while in the maintenance phase, the influence of peer support networks becomes progressively stronger[61]. Digital interventions using virtual reality (VR) to simulate medication-taking scenarios can overcome the spatial and temporal limitations of traditional approaches, effectively enhancing the outcomes of efficacy training[59] (Table 3).

Table 3 Mechanisms through which self-efficacy mediates the relationship between medication literacy and treatment adherence.

Pathway of action	Neural mechanism	Psychological and behavioral manifestations	Influencing factors	Ref.
Medication literacy → self-efficacy → adherence	Functional coupling between the prefrontal cortex and striatum enhances executive control network efficiency	Patients accurately interpret medication instructions and anticipate side effects, strengthening their sense of agency in disease management	Culturally adapted health education integrates traditional medical beliefs with modern biomedical knowledge, enhancing confidence in medication use	[33-35]
Treatment success → reinforced self-efficacy → literacy improvement	Activation of D2 receptors in the striatum enhances neural markers of positive behavioral reinforcement	Patients consistently achieve micro-level treatment goals, forming a feedback loop of "successful experience → efficacy gain → knowledge deepening"	Peer support networks reshape patients’ self-narratives in virtual spaces; trust in healthcare providers modulates dopaminergic projections from the ventral tegmental area to the prefrontal cortex	[43-47]
Psychodynamic system of behavioral reinforcement	Positive feedback in the dopaminergic reward system drives the acquisition and maintenance of treatment-adherent behavior	High-efficacy patients exhibit a 40% increase in behavioral reinforcement learning rate, especially in managing side effects	Urban living environments offer real-time medical feedback channels; economic empowerment frees cognitive resources for health management	[59,72]
Dynamic evolution of self-efficacy	Stage-based construction of efficacy across theoretical models	In the initiation phase, trust in healthcare providers plays a central role; in the maintenance phase, the influence of peer support networks increases	Digital interventions using virtual reality simulate medication-taking scenarios, overcoming spatial and temporal limitations of traditional interventions	[61]

Modulatory mechanisms of social variables on HIV treatment adherence: Interactions among cultural adaptation, digital technology, and spatial exclusion

Research on the social determinants of HIV treatment adherence is gradually shifting from an individual-level focus to a structural-level perspective. Cultural adaptation of interventions, accessibility of digital technologies, and the spatial effects of community-level stigma together form a complex ecological system that shapes health behaviors among PLWH. This section, adopting an interdisciplinary perspective, systematically elaborates how social variables modulate adherence through pathways such as cognitive reconstruction, technological access, and geographic exclusion.

The modulating role of culturally adapted health education

Culturally adapted interventions activate collective identity networks among patients and reshape the cognitive processing of health information. A study conducted in Indonesian prisons demonstrated that integrating the Freirian dialogic education model with inmates’ daily experiences-delivered by nurses and peer educators-enhanced ART adherence and improved the feasibility and acceptability of treatment in restrictive environments[73]. The core mechanism of this modulation lies in the semantic integration of traditional medical beliefs (e.g., herbal remedies) with modern medical knowledge. For instance, involving community elders in the development of educational scripts reduces treatment resistance caused by cultural-cognitive dissonance[74]. Neuroimaging evidence indicates that culturally adapted materials enhance functional connectivity between the prefrontal cortex and temporoparietal junction, thereby improving the neural integration of cross-cultural health knowledge.

The family system also demonstrates a unique moderating value in cultural adaptation. Intervention trials in rural China found that involving family members in medication monitoring reduced dosage error rates among patients with low health literacy by 42%, primarily through the enhancement of collective family efficacy. Notably, cultural adaptation must go beyond basic linguistic translation. For example, the MASI project for South African adolescents with HIV increased intervention acceptability to 89% by integrating indigenous music and digital storytelling. The underlying mechanism involves the construction of culturally resonant digital archetypes[75].

The impact of the digital divide on telehealth adherence

Disparities in digital literacy significantly shape patients’ ability to engage with telehealth technologies, primarily by altering neural activity patterns associated with cognitive workload and decision-making. United States-based neuroimaging research revealed that individuals with low digital literacy exhibit heightened activation in the anterior cingulate cortex when using medical apps, an indicator of cognitive overload that compromises their decision-making efficiency[76]. This neural compensation consumes limited cognitive resources, indirectly impairing medication management, particularly among elderly and rural populations.

Beyond neurocognitive mechanisms, digital literacy gaps manifest as adherence disparities in marginalized communities. In Romania, gay, bisexual, and other MSM face substantial barriers to HIV prevention services, exacerbated by the digital divide. The Prepare Romania project addressed these challenges by integrating SPARK face-to-face counseling with the Health Mpowerment mobile app, focusing on user-centered interface optimization to enhance PrEP (pre-exposure prophylaxis) adherence. Preliminary findings indicate positive impacts in reducing adherence disparities linked to digital access[77].

Cultural context further modulates the relationship between digital literacy and treatment adherence. The "privacy paradox" highlights that trust in technology is deeply embedded in cultural safety perceptions. Results from the MASI pilot study demonstrated that a culturally tailored app significantly improved ART adherence among South African adolescents and young adults living with HIV, thereby supporting sustained treatment engagement[75].

Importantly, the digital divide extends beyond mere device access to encompass generational differences in information processing styles. Younger patients often prefer fragmented, real-time push notifications, whereas older adults rely on linear, structured knowledge frameworks. This cognitive style mismatch may explain the limited efficacy-failure rate as high as 35% of remote guidance interventions in older populations[78].

Reinforcing these observations, the 17-month "Thrive With Me" RCT involving 401 sexual minority men found that high engagement with a peer-to-peer digital platform led to a +17.8% absolute increase in undetectable viral load at month 5 compared to low engagement (95%CI: 2.5-33.0), illustrating how digital literacy gradients translate into measurable virologic disparities[79].

Community-level stigma and the spatial characteristics of medication behavior

Community stigma affects not only individual psychology but also reshapes patients’ health behaviors through geographic exclusion mechanisms. Under the combined pressure of social prejudice and unequal access to healthcare resources, stigmatized groups are often compelled to adopt more complex and concealed healthcare-seeking strategies[80]. For example, in "treatment desert" regions of the United States South, the interplay of inadequate healthcare availability and social discrimination creates significant obstacles in medication access, leading to treatment delays and compromised health outcomes[81].

This form of geographic exclusion is not uniform and exhibits pronounced gendered patterns[82,83]. Female patients, in an effort to avoid societal scrutiny, often seek care at night to minimize visibility of their health status. However, this strategy introduces new risks, such as increased likelihood of medical errors due to limited night-shift resources and understaffed facilities-potentially affecting dosage accuracy. These invisible spatial barriers weaken healthcare equity and impose additional health burdens on already vulnerable populations[84,85].

The density and quality of community support networks can buffer the negative effects of spatial exclusion. Task-sharing models involving non-specialist providers have been shown to improve ART adherence and viral suppression rates among PLWH, highlighting the critical role of community health workers (CHWs) in maintaining access to ART. Their effectiveness lies in the creation of alternative healthcare channels[86]. Research by Tian et al[87] shows that adolescent HIV programs using gamified social interaction scenarios successfully build destigmatized support networks in virtual environments, accelerating treatment initiation among newly diagnosed patients. This type of digital–physical hybrid intervention provides promising new pathways for overcoming geographic stigma (Table 4).

Table 4 Mechanisms through which social support networks influence treatment adherence in people living with human immunodeficiency virus.

Type of support	Mechanism of action	Key research findings	Implications for intervention	Ref.
Peer support	Buffers HIV-related stigma through emotional and informational support	Strongly associated with long-term retention, adherence, and viral suppression among people living with HIV; reduces internalized stigma	Develop peer-based support networks, especially virtual support communities	[47,50,51]
Family support	Serves as a buffering variable between literacy and adherence, providing emotional and practical aid	Mitigates the negative effects of low medication literacy on adherence; improves adherence through medication reminders and accompaniment to care	Involve family members in medication supervision, especially for children and adolescents	[53]
Patient–provider trust	Promotes adherence by reducing patients’ suspicion and fear toward the healthcare system	Lower trust is linked to poorer adherence and treatment outcomes; particularly affects racial and ethnic minority groups	Enhance provider communication skills and adopt culturally adaptive strategies	[56]
Community support networks	Mitigate the negative effects of spatial exclusion by creating alternative healthcare pathways	Community health workers play a key role in sustaining access to antiretroviral therapy; stigma at the community level shapes care-seeking geography	Implement task-sharing interventions with lay providers; build destigmatized support networks	[87]

HIV: Human immunodeficiency virus.

MULTIDIMENSIONAL PATHWAYS OF PSYCHOSOCIAL INTERVENTIONS IN HIV TREATMENT

Psychosocial intervention strategies that integrate cognitive restructuring, behavioral reinforcement, and relational repair offer a systematic solution to improving treatment adherence among PLWH. This section, grounded in SCT and informed by advances in cultural adaptation and neuroplasticity research, explores the synergistic effects of cognitive behavioral therapy (CBT), self-efficacy training, and patient–provider communication skills in clinical interventions.

CBT for stigma reduction

CBT effectively disrupts the internalization of HIV-related stigma by reconstructing patients’ cognitive frameworks. In an intervention targeting MSM and transgender women in Nigeria, a four-session group-based CBT program guided participants in identifying automatic stigmatizing thought patterns and developing alternative self-narratives[88]. Cultural adaptation was essential to the success of this approach-for instance, incorporating collective storytelling practices from tribal rituals into cognitive restructuring helped align the intervention with indigenous values[89]. Neurobehavioral studies have shown that CBT enhances functional connectivity between the prefrontal cortex and the limbic system, improving emotional regulation and thereby reducing avoidance behaviors triggered by stigma exposure[90].

An innovative aspect of this therapy lies in its integration with digital technologies to overcome geographical barriers and expand accessibility to mental health support. In Lagos, a CBT intervention utilized VR to simulate everyday social interactions, enabling participants to rehearse stigma-coping and self-advocacy skills within a safe, immersive environment. Feedback from the program revealed that interactive training significantly reduced situational anxiety and increased participants’ confidence and willingness to seek care openly in real-life contexts[88].

Self-efficacy enhancement programs

Self-efficacy training reshapes patients’ motivational systems for health behavior through a positive feedback loop of "successful experiences → perceived competence". Interventions based on SCT often employ a three-phase progression: The initial stage emphasizes micro-goal setting (e.g., taking medication on time for 3 consecutive days) to build behavioral success; the intermediate stage incorporates peer mentoring to reinforce efficacy through observational learning; the final stage uses digital platforms to visualize behavioral data, translating abstract self-efficacy into a trackable trajectory of growth[47,91-93].

Research in cultural neuroscience indicates that efficacy training activates the dopaminergic reward pathway in the striatum, accelerating reinforcement learning. In a randomized controlled trial in Pakistan, an 8-week individualized CBT program significantly improved the mental health of patients with HIV/AIDS. Through cognitive restructuring and stress management modules, participants’ agency in managing side effects was enhanced, stigma was reduced, and perceived social support increased-likely associated with enhanced plasticity in cognitive control networks[90]. Further findings demonstrated that CBT alleviated depressive symptoms (P < 0.000, η² = 0.599) and significantly increased treatment adherence (P < 0.000, η² = 0.503). These psychological and social improvements not only elevated overall quality of life (P < 0.000, η² = 0.837) but also indirectly boosted the effectiveness of efficacy training by reducing emotional burden and freeing cognitive resources[90].

Specialized training in patient-provider communication skills

Rebuilding patient-provider trust depends heavily on clinicians’ mastery of culturally responsive communication skills. In Botswana, an intervention targeting pregnant women living with HIV introduced the "Dignity Dialogues" model to enhance healthcare workers’ communicative competence. This model integrates local cultural elements with modern medical approaches: Clinicians are trained to use traditional proverbs to deliver medical messages, making health education more relatable to patients’ language and values; narrative medicine techniques are also employed, encouraging clinicians to document patients’ illness experiences to deepen emotional connections. Preliminary evidence suggests that this dual approach strengthens the therapeutic alliance and reduces the risk of ART discontinuation caused by communication breakdowns, thereby improving adherence and health outcomes[89].

Structured training programs should go beyond superficial techniques and address underlying cognitive biases in healthcare systems to effectively reduce discriminatory practices. In Nigeria, studies have revealed significant stigmatizing attitudes and behaviors among healthcare workers toward patients with HIV/AIDS, including refusal of care and isolation in separate wards. Such actions not only violate medical ethics but also hinder patients’ access to essential services[88].

To address these challenges, CHWs have been integrated into intervention strategies, receiving training in HIV/AIDS clinical management, health education, and attitude transformation. CHWs play a vital role in delivering basic healthcare and reducing HIV-related stigma through community education and support[94]. However, they face numerous practical challenges, including limited scope of practice, insufficient training, and inadequate supervision-highlighting the need for systemic investment in resources and support[94].

Digital technologies offer new opportunities for enhancing culturally competent communication among healthcare providers. VR-based simulation systems recreate realistic patient–provider interactions, allowing clinicians to safely practice and improve cross-cultural communication skills[95,96]. Additionally, virtual patient simulations are increasingly used in medical education, particularly in psychiatry and geriatric care, to help students engage with patients who exhibit social communication difficulties[96-98]. These simulation tools provide immediate feedback, facilitating the transfer of learned skills into real clinical practice.

RESEARCH LIMITATIONS AND FUTURE DIRECTIONS

Paradigmatic constraints due to the lack of longitudinal data

Most existing studies rely on cross-sectional designs, limiting their ability to capture the dynamic evolution of the relationship between psychosocial factors and treatment adherence[99]. For instance, studies on HIV transmission clusters are often based on molecular network cross-sectional data, lacking longitudinal tracking of the spatiotemporal trajectories of treatment behaviors. This static analytical paradigm fails to uncover the bidirectional mechanisms between self-efficacy and medication literacy and impedes the identification of critical intervention time windows[100,101]. Future research should establish longitudinal cohorts integrating biomarkers (e.g., viral load) with behavioral monitoring, leveraging mobile health technologies for real-time data collection. Additionally, mixed-method approaches such as ecological momentary assessment are needed to capture the temporal fluctuations of psychosocial mediators[101] (Table 5).

Table 5 Research limitations and future directions.

Limitation	Specific issues	Future research directions	Suggestions for innovative methods	Ref.
Lack of longitudinal data	Existing studies predominantly adopt cross-sectional designs, limiting the ability to capture dynamic relationships between psychosocial factors and treatment adherence	Establish longitudinal cohorts integrating biomarkers with behavioral monitoring	Use mobile health technologies for real-time data collection; adopt mixed-method approaches to capture dynamic fluctuations of mediating variables	[100,101]
Methodological constraints in quantifying mediation effects	The complexity of multiple mediation models challenges traditional statistical methods; failure to account for intergroup heterogeneity may bias effect estimates	Develop hybrid models integrating computational psychiatry and structural equation modeling	Use bias-corrected bootstrap methods to relax normality assumptions in mediation testing; apply Bayesian approaches to improve the accuracy of multilevel mediation models	[102-106]
Blind spots in evaluating long-term effects of digital interventions	Current digital health studies mainly focus on short-term adherence improvements, lacking exploration of behavior maintenance mechanisms	Construct a "digital intervention life-cycle" evaluation framework	Leverage blockchain technology for decentralized data tracking; include neuroplasticity markers as biomarkers of long-term intervention efficacy	[107-108]
Insufficient comparative research on cross-cultural interventions	Lack of systematic comparisons of intervention effectiveness across different cultural contexts	Develop a three-dimensional evaluation framework for cross-cultural intervention outcomes	Compare prefrontal–limbic system responses to intervention stimuli across cultural groups; analyze the impact of geographic patterns of community-level stigma on delivery efficiency; evaluate the transferability of cultural archetypes in virtual health communities	—

Methodological innovations for mediating effect quantification

The complexity of multiple mediation models presents substantial challenges for traditional statistical approaches[102,103]. Existing structural equation modeling (SEM) frameworks often yield biased effect estimates when they fail to account for intergroup heterogeneity while simultaneously modeling observed and latent variables[104,105]. Research indicates that bias-corrected bootstrap methods can effectively relax normality assumptions in mediation testing, while Bayesian approaches improve the accuracy of multilevel mediation models when prior information is available[106]. Future work should focus on developing hybrid models that integrate computational psychiatry with SEM. This includes introducing neuroimaging indicators-such as functional connectivity strength between the prefrontal cortex and striatum-as latent variables to enhance the biological validity of mediation pathway analyses.

Evaluation gaps in the long-term effectiveness of digital interventions

Current digital health intervention research tends to focus on short-term improvements in adherence, with limited exploration of behavioral maintenance mechanisms over time[107]. For example, although the differentiated digital intervention model developed by Shandong University demonstrated immediate effectiveness in randomized controlled trials, it did not assess the rate of behavioral decay after the withdrawal of the intervention[107,108]. Future studies should construct a "digital intervention life-cycle" evaluation framework, incorporating blockchain technology for decentralized data tracking and including neuroplasticity indicators-such as changes in striatal D2 receptor availability-as biomarkers of long-term intervention efficacy.

Comparative research pathways for cross-cultural interventions

Future research should establish a three-dimensional framework for evaluating cross-cultural intervention effectiveness: (1) Neurobehavioral dimension: Comparing how different cultural groups’ prefrontal-limbic systems respond to intervention stimuli; (2) Spatial behavioral dimension: Analyzing how geographic patterns of community-level stigma modulate the efficiency of intervention delivery; and (3) Digital ecological dimension: Assessing the transferability of cultural archetypes within virtual health communities.

Based on this framework, dynamic adaptation models guided by cultural neuroscience should be developed to enable precise cultural calibration of intervention strategies.

CONCLUSION

Medication literacy plays a pivotal role in promoting treatment adherence among PLWH, with psychosocial factors such as stigma, self-efficacy, and social support serving as key mediators. This review elucidates the complex interplay between cognitive, emotional, and social mechanisms underlying adherence behaviors, integrating insights from neurobehavioral and cultural adaptation research. Future interventions should adopt a multidimensional approach that not only enhances health literacy but also addresses psychosocial barriers through tailored, culturally sensitive strategies. Strengthening self-efficacy and rebuilding patient–provider trust are essential to improving adherence outcomes and achieving sustained viral suppression in this population.