Impact of Side Effects on 5-Year Adherence to Adjuvant Endocrine Therapy in Women with Breast Cancer: An Integrative Review.

Introduction
The effectiveness of adjuvant endocrine therapy (AET) in the treatment of breast cancer is well established, as it reduces the recurrence rate and improves overall survival.1,2 AET, which incorporates selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), is routinely recommended for a duration of 5–10 years after primary treatments for hormone receptor-positive (HR+) breast cancer.3 Extending AET to 10 years significantly improves disease-free survival (DFS), whereas maintaining long-term adherence remains challenging for women with early-stage breast cancer.4,5
Adherence is defined as the process by which patients take their medications as prescribed, including three phases: initiation, implementation, and discontinuation.6 Persistence refers to the duration from treatment initiation to discontinuation and is captured within the broader construct of medication adherence.6 Previous research highlights that proper medication-taking behavior and uninterrupted therapy are crucial for maximizing the protective effects of AET against recurrence.7
Previous studies have indicated that 30% to 50% of women with breast cancer discontinue AET prematurely within 5 years.8,9 Non-adherence to AET is a significant barrier to achieving optimal therapeutic outcomes, leading to an increased likelihood of breast cancer recurrence,9 a 20% increase in mortality rates,10 higher healthcare expenses,11 and diminished quality of life (QoL).11,12 Factors associated with poor adherence to AET include sociodemographic, clinical, and psychosocial characteristics.8,13 Older age (≥65 years),9 switching between different AET prescriptions,14 and lack of social support15 have been identified as factors that negatively impact AET adherence. However, the most frequently cited predictor of AET adherence is the presence of side effects,16,17 which can adversely affect treatment adherence and significantly deteriorate QoL.18
Side effects are interpreted psychosocially rather than purely physiologically in the Necessity-Concerns Framework (NCF), in which adherence is determined by a dynamic assessment of the perceived need for treatment versus concerns about its potential side effects.19 Within this framework, the impact of side effects on treatment engagement evolves over the long term. The cumulative burden of side effects during the 5-year AET course often shifts the balance, as persistent QoL concerns gradually outweigh the perceived benefits of treatment.20
One systematic review included 25 quantitative studies to explore the factors influencing AET adherence.13 However, the review was broad in scope and did not specifically focus on how side effects influence adherence. Zhu et al21 conducted a scoping review of 57 studies to report the prevalence of common side effects among women undergoing AET but did not analyze their impact on adherence in detail.
To our knowledge, there is a lack of reviews identifying, assessing, and summarizing the impact of AET side effects on 5-year adherence in women with breast cancer. While quantitative studies have identified a statistically significant link between AET side effects and nonadherence, qualitative evidence is crucial for exploring women’s individual experiences. Integrating quantitative and qualitative studies should be considered to gain more comprehensive insights into the impact of side effects on adherence to AET. Additionally, medication-taking behaviors and symptom experiences vary across cultural contexts and healthcare systems.22 Given that China accounts for one-fifth of the world’s breast cancer patients,23 incorporating evidence from this population will contribute to the understanding of global breast cancer survivorship. This integrative review aimed to consolidate studies published in English or Chinese to provide a global perspective on the side effects of AET and their impact on 5-year adherence in women with breast cancer.

Materials and Methods

Design
An integrative review was conducted to synthesize quantitative and qualitative studies. This process followed Whittemore and Knafl’s five steps: problem identification, literature search, quality assessment, data analysis, and presentation.24

Search Method
The methodology for article search and selection followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Appendix 1).25 We reviewed articles from the inception of each database until February 2025. The databases included Medline, Cochrane Library, Embase, CINAHL, PsycINFO, Scopus, and China National Knowledge Infrastructure (CNKI). We developed the search terms from four core concepts (breast cancer, medication adherence, adjuvant endocrine therapy, and side effects) and included permutations of the following search terms: “breast neoplasm OR cancer* OR tumor* OR carcinoma*” AND “medication adherence OR compliance OR medication non-adherence OR medication persistence OR medication non-compliance” AND “endocrine therapy OR hormone therapy OR estrogen antagonists OR tamoxifen OR aromatase inhibitors” AND “side effects OR hot flash OR sexual dysfunction/vaginal dryness/libido OR weight gain OR musculoskeletal symptoms OR arthralgia OR joint pain OR fatigue”. For the Chinese database (CNKI), equivalent search terms were applied in Mandarin. The full English and Chinese search strategies are provided in Tables S1 and S2.

Inclusion and Exclusion Criteria
Articles had to meet the following criteria to be included in the review: 1) focused on female breast cancer survivors undergoing AET; 2) included quantitative (cohort study, cross-sectional study, randomized controlled trial), qualitative, and mixed-methods studies; 3) assessed the severity (or prevalence) or women’s lived experience of AET side effects and their impact on AET adherence; 4) measured patient adherence for 5 years or more in cohort studies or assessed medication adherence (≥5 years) in cross-sectional study; and 5) written in English or Chinese. We excluded studies that 1) did not specify the duration of patient follow-up in cohort studies and randomized controlled trials, 2) focused on interventions to improve adherence, and 3) were unavailable in full text.

Quality Appraisal
This review used the Mixed Methods Appraisal Tool (MMAT), version 2018, to appraise the quality of quantitative, qualitative, and mixed-methods studies.26 Initially, the validity of the MMAT was assessed using two screening questions (whether the article contained clear research questions and whether the data collected answered the research questions). If both answers were affirmative, the article was evaluated according to five criteria tailored to the study design. Five, four, and less than four “Yes” answers were deemed high, medium, and low quality, respectively.27 Two researchers independently assessed the 34 studies and another researcher validated the quality assessment results. The research team discussed any doubts or discrepancies to reach a final consensus. Two mixed-method studies were assessed using qualitative criteria, as only their qualitative components provided evidence on how side effects impacted medication adherence.28,29 Thus, 14 articles were appraised based on the qualitative study criteria for MMAT. Table 1 displays the quality ratings of the 34 articles. All the included studies have moderate (n=6) or high quality (n=28), and none were excluded.

Data Extraction
To complete data reduction and display, a review matrix was used to extract data from the included studies. This matrix comprised the following elements: author(s), publication year, country, study design, specific hormone medication(s), sample, measured adherence and/or persistence, reported side effects, and findings (Table 2).

Data Synthesis
Data synthesis followed the sequence outlined by Whittemore and Knafl,24 which includes data reduction, display, comparison, conclusions, and verification. Medication persistence, the duration of therapy, was included as a temporal dimension of the medication adherence process.6 The overarching concept of adherence to AET has covered different terminology, such as persistence, compliance, and adherence. Initially, subgroups were categorized according to country, target population, sample size, and medication type. Disparities and similarities between the studies were identified by analyzing and comparing the domains of the matrix. Finally, conclusions were derived from the data and validated through additional analysis.

Results

Search Selection
Initially, 1251 records were found across seven electronic databases, with an additional 16 records identified from the reference lists of reviews. After removing duplicates (n=367), 900 articles were retrieved. Two researchers independently assessed the titles and abstracts according to predefined inclusion and exclusion criteria, and 855 studies were excluded (see Appendix 2 for detailed reasons). The full text of the remaining 45 eligible studies was reviewed by three authors, and 11 studies were further excluded for the following reasons: inability to separate data on side effects across multiple influencing factors (n=5), lack of a clear link between side effects and adherence (n=4), and absence of follow-up duration (n=2). Therefore, 34 studies (33 in English and one in Chinese) were selected for the final analysis. The PRISMA flow diagram is presented in Figure 1.

Description of the Included Studies
The included studies were conducted in 11 countries: North America (n=17), Europe (n=13), and Asia (n=4). Three studies were conducted in China, among which one was written in Chinese and the other two were written in English. Notably, 13 of the 34 studies were multicentered, with seven conducted in Europe and six in North America.
In quantitative studies, participants’ ages ranged from premenopausal women (median age around 37 years) to postmenopausal women (mean age > 67 years). In qualitative studies, participants’ ages ranged from 27 to 86 years. Among the 34 studies reviewed, eight focused on postmenopausal women, while three exclusively targeted premenopausal women.41,43,44 The remaining studies (n=23) involved women of various ages, with five examining the effect of menopausal status on side effects.45,54,55,59,60 In addition, five studies discussed fertility concerns as factors related to AET non-adherence.37,38,41,43,44 The sample sizes ranged from 81 to 4645 for quantitative studies and 22 to 35 for qualitative studies.
Twenty-three studies described the side effects and medication adherence for both AIs and SERMs, of which only four distinguished the side effects of these two medications.30,45,52,54 Of the other eleven studies, four focused on AIs,29,31,47,57 six on SERMs,36,39–42,58 and one did not specify the AET type.46

Adherence to AET
Overall, five-year adherence rates to AET treatment varied across the included studies, ranging from 46% to 93.6%. The measurement methods, study settings, and medication types primarily account for this wide variability.

Measuring Adherence
Self-reported adherence was used in both qualitative (n=14) and quantitative (n=8) studies. In most qualitative studies, participants described their status of AET adherence through interviews and two studies used a visual analog scale (VAS) to assess adherence for purposive sampling.55,60 In quantitative studies, two used validated self-reported measures, including the 4-item (n=1)49 and 8-item versions (n=1)40 of the Morisky Medication Adherence Scale (MMAS), with both revealing good adherence in approximately half of the participants. Six studies employed self-designed questionnaires to measure adherence, with 5-year adherence rates ranging from 63.1% to 93.6%.30,33,39,44–46
Twelve quantitative studies utilized indirect adherence measures, including the Medication Possession Ratio (MPR) (n=3),36,37,48 pharmacy medical records (n=6),31,34,38,42,43,47 prescription databases (n=2),32,35 and electronic medical records (n=1).41 Three studies applied the MPR and used a cutoff of 80% to determine whether a patient was adherent—denoting the proportion of a specified period during which individuals were in possession of their medications. The findings showed that approximately 79% to 83% of participants maintained a high level of adherence.36,37,48 Other studies based on databases and medical records found 5-year adherence rates ranging from 46% to 89.2%, with two studies reporting higher rates of 88% and 89.2% due to their definition of adherence as the absence of discontinuation for subjective reasons.34,38

Differences in Adherence Across Countries and Medication Type
There is a large variation in adherence among women across different countries. In North America, 63.8% adherence to AIs was reported in postmenopausal women in Canada,47 while 78.7% adherence was reported in the United States.31 In Europe, the majority of studies have revealed adherence rates of approximately 80%.32,36,37,48 However, a prospective cohort study from Sweden reported 46% adherence in the fifth year.35 In Asia, studies conducted in China reported adherence rates between 61.2% and 77.4%,33,40,49 compared to 88% in Japan.38
Although most studies did not differentiate medication types when measuring adherence, five studies found significantly higher adherence rates for AIs than for SERMs.30,32,33,48,49 Two studies focusing solely on AIs reported adherence rates ranging from 63.8% to 78.7%,31,47 while studies on SERMs showed adherence rates between 51% and 71%.39–42

Long-Term Trends in Adherence
Studies reported a decrease in AET adherence over a 5-year follow-up period.35,40,43,49 One study that focused solely on SERMs found women’s adherence rates to be 89.9%, 79.4%, 74.1%, 69.6%, and 61.2% consecutively from the first to the fifth year.40 Three studies reported that AET discontinuation rates peaked during the first year,35,42,46 while another reported that the most significant decrease in adherence to AET occurred between the second and third years.49 Additionally, two studies explored adherence beyond 5 years,45,46 revealing that more women were reluctant to continue AET treatment beyond this point. Compared to 18.5% of women who discontinued treatment within the first 5 years, 65% of those who completed this period discontinued during the extended phase.46

Prevalence and Severity of AET Side Effects
Six studies measured the incidence of AET side effects,30,36,40,45,47,49 which ranged from approximately 49% to 94%. Among these, two studies compared the proportion of side effects between TAM and AIs.30,45 Eleven studies reported non-adherence rates ranging from 2.6% to 19.2% owing to side effects.30,33,34,38,40–43,45,47,49 Furthermore, one study showed that QoL and side effects were significantly worse after 1, 2, and 3 years compared to when AET was initially started.36 This review identified five major categories of AET side effects based on their high frequency across both quantitative and qualitative studies.

Musculoskeletal/Joint Pain
Twenty-four studies reported musculoskeletal side effects, specifically joint pain. Approximately 17.5% of women undergoing AET report joint pain within 1–5 years,40 with a cumulative incidence of 62.1% over five years.30 Two qualitative studies reported that women often experienced intense joint pain spreading across multiple parts of the body, which interferes with sleep and daily activities.28,56 Additionally, many women have bone and joint limitations that affect their mobility, leading to a sense of premature aging.52,53,56

Personal Images
Twenty-four studies mentioned side effects related to changes in personal image, including physical appearance and feminine identity. Specifically, about 5.9% of women reported changes in physical appearance such as weight gain and thinning hair within 1–5 years,40 with a cumulative incidence of 32.8% over five years.30 While approximately 18.5% of women experience a loss of femininity, including symptoms such as low libido and vaginal dryness within 3 years,36 reaching a cumulative incidence of 36% over five years.30 Four qualitative studies have highlighted that these changes negatively affect women’s self-esteem and daily functioning, with some women feeling inferior to their partners.50,54,55,59 This effect was particularly pronounced in the premenopausal women.

Hot Flashes
Twenty-three studies reported hot flashes, which occurred in approximately 87% of women during the first year of AET,36 and decreased to 33% after 5.5 years.45 Three qualitative studies reported that hot flashes were often accompanied by night sweats, occurring every few minutes during the day or several times throughout the night.52–54 This frequent occurrence of hot flashes interfered with sleep,52,53 caused daytime fatigue,54 and made social activities more difficult.53,54

Emotional Disturbance
Twenty studies addressed mood side effects, including depression and mood swings, with prevalence rates ranging from 28.1% at 3 months to 2.9% after 5.5 years.45,47 Two qualitative studies described depression as feeling trapped or no longer like oneself.54,58 This lowered mood is believed to result from the overall impact of side effects rather than by the direct effects of AET.58 Additionally, three qualitative studies indicated that women’s mood swings are mainly characterized by irritability and impatience, which strained their interpersonal relationships.52,54,55

Sleep Issues
Thirteen studies mentioned sleep disorders, including difficulty falling asleep and nighttime awakenings, with prevalence rates ranging from approximately 2.4% after 5.5-year to a cumulative incidence of 44.2% throughout the 5-year treatment period.30,45 A qualitative study reported that sleep disorders affect women’s ability to work during the day, making them irritable and often angry with friends and family.54 This study directly attributes sleep disorders to AET. However, four other qualitative studies have suggested that sleep disturbances are primarily the result of various serious side effects associated with AET.52,53,56,60

Impact of Side Effects on AET Adherence
This review found inconsistent results regarding the impact of adverse effects on adherence. The number or severity of side effects was negatively associated with AET adherence in twelve quantitative studies.30,31,33,35,36,39,40,44–46,48,49 Studies have found that women who experienced more side effects tended to have lower adherence rates (Hazard Ratio [HR] = 1.3, 95% CI: 1.0–1.6, p < 0.05).39 Specifically, those with two or more side effects showed a significantly greater decrease in adherence (Adjusted Odds Ratio [OR] = 4.06, 95% CI: 1.96–8.41, p < 0.001).49 Women who took symptom-relieving medications during the first year of AET were identified as predictors of treatment discontinuation in the following 4 years, with the likelihood increasing as the number of medications grew (HR = 1.83, 95% CI:1.48–2.26, p < 0.05).35 Additionally, women who experienced severe side effects were more inclined to discontinue AET because of intolerance (OR range: 2.45–4.31, p < 0.05).33,45
However, four quantitative studies showed a positive association between certain side effects and AET adherence for women using SERMs or AIs.30,32,37,44 One study found that overall side effects were linked to higher adherence (OR = 2.22; 95% CI: 1.15–4.29; p = 0.017).32 The other three studies showed that specific symptoms, such as hot flashes, vaginal problems, musculoskeletal and psychological symptoms, were positively associated with treatment adherence.30,37,44 In addition, these four studies did not evaluate how different medications (SERMs vs Als) might affect their adherence.
Different side effects may have varying impacts on AET adherence. Physically, joint pain notably affected adherence at the start of AET but stabilized over time (median OR = 1.69, p < 0.05).46 Severe vaginal dryness in the first year after treatment was also a predictor of discontinuation (HR = 3.72, 95% CI: 1.49–9.72, p = 0.006).36 Psychologically, emotional distress peaked in its impact on adherence after the second year of AET (median OR = 1.72, p < 0.001).46
Certainly, women’s perceptions of their treatment and its side effects influence their adherence, but these can change over the course of treatment. As the duration of AET treatment increased, women described their side effects with strong terms like “intense”, “excruciating”, and “unbearable”, rather than just “annoying”.55,56,60 Four qualitative studies have demonstrated that severe side effects not only diminished women’s QoL and work capacity but also negatively affected their social lives and professional roles.51,52,54,56 Additionally, these side effects harmed their mental health, causing feelings of despair, hopelessness, and even suicidal thoughts.51,53,58,60 These profound effects led them to question whether the benefits of the treatment outweigh its side effects.28,54,58 Most women reported that the decision-making process for adhering to AET became increasingly challenging over time, necessitating a trade-off between QoL and longevity.28,51,56 This depends not only on side effects but also on the patient’s beliefs about taking the medication, perceived risk of recurrence, and the ability to manage side effects.28,51,55–57 However, one qualitative study found that severe side effects did not necessarily influence adherence.53
Women also reported unmet supportive care needs. Without prior information about AET side effects, many women felt unprepared and uncertain whether the side effects were due to AET or other health issues,28,59,61 prompting them to discontinue AET in an attempt to identify the cause.51,60 Despite efforts to adjust the treatment to minimize these side effects, such attempts have often been unsuccessful, leading to discontinuation.28,54

Discussion
This review collated data on 5-year AET adherence, patients’ personal experiences with AET side effects, and the impact of these on their adherence decisions. The 5-year adherence ranges from 46% to 93.6%, and there was a consistent trend of declining adherence over the 5-year treatment period. Although the number and severity of adverse effects have been identified as critical factors affecting adherence, the impact of side effects on AET adherence has been inconsistent across studies.
Most studies (30/34) were conducted in North America and Europe, while only four originated from Asia.33,38,40,49 Notably, all 13 multicenter studies were conducted in western regions.32,35,36,39,42–44,47,48,51–53,56 Multicenter studies not only facilitate participant recruitment but also improve the applicability of results.62 It is essential to conduct more multicenter studies in diverse healthcare systems and cultural backgrounds to better understand the impact of side effects on AET adherence from a global perspective.
Five studies explored the different experiences of side effects between premenopausal and postmenopausal women,45,54,55,59,60 revealing that premenopausal women are more susceptible to AET side effects and often feel inadequately supported by healthcare providers.45,54,59 As the incidence of breast cancer increasingly affects younger women,63 the limited attention paid to premenopausal women underscores the need for further research to explore the impact of AET on their specific needs.
In this review, fertility concerns were identified as a key barrier to AET adherence among younger women.37,38,41,43,44 For this group, fertility anxiety was identified as the only significant predictor of both treatment non-initiation and early discontinuation.41,64 This may be explained by the fact that the 5–10-year duration of AET often coincides with the critical period of declining fertility, creating a difficult choice between continuing treatment and pursuing motherhood.41 Therefore, early fertility counseling and clear communication about reproductive planning are essential to help women make informed decisions and maintain adherence.41,43
Among the included studies, the majority (23/34) involved both SERMs and AIs, with only four studies distinguishing between their side effects.30,45,52,54 Clinical observations suggest that different medications have distinct side effects, though some overlap may exist.65 Furthermore, recognizing these differences is key to assessing treatment tolerability and adherence.2 Thus, the lack of differentiation (SERMs vs AIs) in our review limits cross-study comparisons and makes it impossible to further explain the inconsistent findings regarding the impact of side effects on adherence.66 Future research is needed to compare the side effects of different AETs and assess their impact on adherence, ultimately enabling more personalized treatment decisions to improve treatment outcomes.
Different measures of adherence were utilized in the reviewed studies, including validated self-reports instruments (eg, MMAS), self-designed questionnaires, and indirect measures (eg, MPR and pharmacy medical records). Self-reported adherence may be influenced by memory bias and social desirability, potentially leading to inflated adherence rates.67 Additionally, indirect measures may not fully capture patients’ actual medication behaviors.68 A comprehensive, multi-method adherence instrument for AET should be explored to include objective measures, such as possession patterns to track persistence and treatment gaps (eg, “drug holidays”), as well as subjective assessments to capture intentional or unintentional non-adherence.
Among the studies reviewed, only two specifically reported adherence after 5 years.45,46 These studies found a significant decrease in AET adherence beyond 5 years compared with that within 5 years.45,46 Updated clinical practice guidelines recommend extending AET from 5 years to 10 years, with a 10-year duration showing significant benefits in reducing breast cancer recurrence.5,69 Further research is needed to accurately assess adherence during these extended treatment periods, which will provide valuable insights for improving clinical practice.
The impact of side effects on AET adherence is inconsistent across studies. This inconsistency may be interpreted through the Necessity-Concerns Framework,19 reflecting the different weights of the necessity and concerns of AET from the patients’ perspectives. When side effects are perceived as intolerable, difficult to manage,33,45 or as barriers outweighing the perceived benefits of AET,31,33,39 patients are more likely to discontinue treatment to preserve their QoL.47 When patients prioritize the goals of AET over its adverse effects, the presence of side effects may act as signals of efficacy,30 heightening treatment awareness and improving adherence.53,57
The appraisal of side effects process evolves across the trajectory of AET treatment, which partially explains the long-term adherence decline.58 Initially, longevity often dominates decisions, but the cumulative impact of chronic side effects on daily life can lead to a shift in the risk-benefit balance.58,59 Over time, the increasing importance of QoL acts as a key mediator, potentially shifting the patient’s response from active endurance to eventual non-adherence.20 Therefore, counseling approaches to manage side effects and reassess the risk-benefit balance could help recalibrate these appraisals and improve adherence.
Side effects can impact AET adherence at various stages, particularly during the early treatment phase.36,46 Three studies found higher discontinuation rates in the first year, possibly owing to initial side effects or daily medication burden.35,42,46 Another study observed a significant decrease in adherence during the second and third years, suggesting that patients’ perceptions of AET may evolve and that the initial motivation to begin treatment may diminish, making long-term challenges more apparent.49 Understanding these dynamic changes over time can guide targeted interventions, and ultimately improve patient adherence and overall treatment outcomes.
Among the twelve studies showing a negative association between side effects and adherence, most (10/12) addressed physical symptoms (eg, joint pain), while only three examined psychological symptoms.35,46,48 Physical side effects are generally more noticeable and can be alleviated with medication, whereas psychological side effects are often hidden, difficult to identify, and underappreciated in routine clinical assessments.35,48,70 However, psychological symptoms can profoundly affect patients’ daily lives and adherence decisions.71 Therefore, future research should explore both physical and psychological side effects on adherence and their interactions to provide a basis for more personalized management strategies.
Many patients reported inadequate social support and insufficient information about their medication while struggling to recognize and manage the side effects of AET.51,55,58,59,61 A lack of social support can leave patients feeling isolated, while insufficient information limits their ability to understand and address side effects, leading to distrust in healthcare providers and nonadherence.51,58,59 Thus, more comprehensive support programs are needed to educate patients on management strategies for side effects to improve AET adherence.
This study focused solely on female patients with breast cancer, excluding male patients. Considering the rising incidence of breast cancer in men,72 the delimitation of this review’s scope to women with breast cancer may restrict the generalizability of our findings. The review only included studies published in English or Chinese, potentially missing relevant research published in other languages. Future reviews should expand their scope to include male breast cancer cases and conduct research in other languages to enrich our understanding of the impact of side effects on AET adherence and potential intervention strategies.

Clinical Implications for Practice
This integrative review may inform clinical practice to enhance long-term adherence to AET among women with breast cancer. Since 5-year adherence decreases over time and the risk of early non-adherence is high, clinical practice should strengthen early follow-up and explore appropriate instruments to assess medication adherence, ensuring more accurate monitoring and timely support. Further, a significant drop in adherence between years 2 and 3 addresses the necessity of continued support for this later and critical period. Healthcare professionals should also actively assess both physical and psychological symptoms to achieve better recognition of AET-related side effects and provide targeted management. In addition, understanding patients’ perceptions and trade-offs regarding side effects helps provide personalized support to improve adherence.

Conclusion
This review showed that side effects pose a major challenge to AET adherence among women with breast cancer, although the results across studies are inconsistent. The number and severity of side effects, as well as patients’ perceptions of the benefits and risks, are key factors that influence their adherence to AET. Many women also reported a lack of understanding and strategies for managing side effects that affect their QoL and lead to early non-adherence. However, the current studies lack standardized methods for measuring adherence and clear distinctions between the side effects of different AETs, particularly beyond 5 years. Future research should explore a comprehensive, multi-method adherence instrument and account for the various side effects of different AETs. Targeted interventions are required to support patients better and improve their long-term adherence to AET.