EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words: Drug adherence, Immunosuppressive therapy, Patient education, Quality of life

Introduction
Liver transplant is a surgical treatment method known to be life-saving in cases defined as end-stage liver failure in which the liver is irreversibly and severely impaired.^1,2 In addition to an experienced transplant team and good coordination, the cooperation of the patient is also crucial and necessary for successful results in the liver transplant process. With the newly transplanted liver, patients are expected to change their lifestyle and adhere to the recommended diet and treatment regimen. In particular, adherence to immunosuppressive treatment, which prevents the body from rejecting the transplanted liver, is vital.³

Medication adherence is defined as taking the recommended medication at the right dose, at the right time, and in the right way.⁴ Medication nonadherence includes patient behaviors that may cause deterioration in the expected effects of the medication, such as missing doses or taking extra doses, interrupting medication use, discontinuing medication, variations in intake times, and incomplete medication use.^4,5 Medication adherence is critical for disease management, especially in chronic diseases, and significantly affects the achievement of targeted clinical outcomes.⁶ However, medication adherence represents a dynamic process and can be affected by several social and individual factors because it depends on the patient. Previous studies have reported that social and individual factors such as age, environment, quality of life, and depression significantly affect adherence in transplant patients.^2,5

In transplant treatment, immunosuppressive therapy suppresses the immune system, prevents the body from rejecting the transplanted organ, and helps the patient to develop tolerance to the transplanted organ.^3,5 Today, the drugs used in immunosuppressive treatment plans make it possible to raise the 1-year graft survival rate after transplant to over 90%.³ Therefore, adherence to immunosuppressive therapy is critical in transplant patients. Although patients who undergo organ transplant are informed about the importance of immunosuppressive therapy, many may not use their medications at the recommended dose and regimen.⁷ Studies have reported that the prevalence of nonadherence to the treatment in transplant patients can range from 15% to 40% depending on the transplanted organ.^1,2,5 The fact that patients who undergo solid-organ transplant have to use a large number of medications for several years may cause patients to have problems in their adherence to the medication.⁸ However, nonadherence to immunosuppressive use after transplant negatively affects the success of treatment in the short and long term and may lead to rejection, graft loss, and even death.⁶

The success of a liver transplant depends on the preservation of graft function and the prevention of posttransplant complications, especially rejection. Immunosuppressive therapy and patient adherence to the treatment regimen are important factors in the prevention of rejection and preservation of graft function. Therefore, determining the factors involved in the nonadherence to immunosuppressive drug use and implementation of interventions to prevent nonadherence are critical in the prevention of organ rejection in patients undergoing liver transplant.² In light of this information, this study aimed to determine the level of adherence to immunosuppressive therapy and the influencing factors in patients undergoing liver transplant.

Materials and Methods
Study design: We conducted a descriptive cross-sectional study to determine patient level of adherence to immunosuppressive drugs after liver transplant and the influencing factors.

Location and time period of study: We conducted the study in patients who underwent liver transplant surgery and were followed up at the organ transplant center of a university hospital (Bursa Uludag University Faculty of Medicine, Bursa, Turkey) between June 2021 and June 2022.

Study sample and the inclusion and exclusion criteria: At the organ transplant center where the study was conducted, 246 liver transplant patients were registered for follow-up during the study period. Based on the procedures for calculating the sample with a known population with a 95% CI, we aimed to include at least 150 patients. Inclusion criteria were as follows: (1) aged 18 years or older, (2) having liver transplantation, and (3) being on immunosuppressive drugs for at least 3 months posttransplant. Patients with reading or comprehension problems in Turkish and those with a diagnosis of psychiatric illness were excluded from the study.

Data collection tools and methodology: The principal investigator collected data through face-to-face interview method. Data were collected by using the “Patient Information Form” and “Immunosuppressant Therapy Adherence Scale.” The Patient Information Form was created by the investigators based on information from similar studies.^8,9 The form included questions on sociodemographic characteristics (eg, age, sex, educational status) and transplant characteristics (eg, transplantation etiology, donor type, immunosuppressive drugs used) of patients.

The Immunosuppressant Therapy Adherence Scale (ITAS) was developed by Chisholm and colleagues (2005) to assess adherence of organ transplant recipients to immunosuppressive therapy after transplant.¹¹ The scale evaluates the adherence to posttransplant immunosuppressive therapy over the previous 3 months in 4 items (forgetting, carelessness, stopping the drug due to neglect, or stopping the drug due to feeling worse) on a 4-point Likert-type scale. The patient scores 3 points if they have not missed immunosuppressive drug treatment at all (0%) in the past 3 months, 2 points if 1% to 20% of treatment is missed, 1 point if 21% to 50% of treatment is missed, and 0 points if the patient misses treatment more than 50% of the time. The total score varies between 0 and 12. The validity and reliability of the Turkish version of the scale were demonstrated by Madran and colleagues (2016), with Cronbach alpha value reported as 0.65.⁷ In this study, we determined Cronbach alpha value as 0.73. Considering the 80% adherence level established in the literature, patients were classified as adherent if the ITAS score was ?10 points and nonadherent if the score was <10 points.^11-13

Ethical aspects of the study: We obtained approval for the study from the Ethics Committee for Clinical Studies at Bursa Uluda? University and the institution where the study was conducted (No. 2021-7/21). Before the study, each participant who met the inclusion criteria was informed about the study, and their verbal and written consent for participation was obtained. Participation was voluntary. Participants were informed that they had the right to withdraw from the study at any time without affecting their treatment or services in any way.

Statistical analyses: We analyzed obtained data obtained with SPSS version 28 (IBM, Statistical Package for Social Sciences). Before proceeding to the data analysis phase, we checked the data for conformity to a normal distribution by using skewness/kurtosis values and the Shapiro-Wilk test. We used appropriate descriptive statistics to summarize the characteristics of the participants and outcome variables. Continuous variables are expressed as means and SD, and categorical variables are expressed as frequencies and percentages. We compared data on sociodemographic and transplantation characteristics of the groups by using the chi-square test or the Mann-Whitney U test. We performed logistic regression analysis on the variables determined by the investigators to examine factors affecting compliance. The Hosmer-Lemeshow test and the Omnibus chi-square test were used to evaluate the goodness of fit of the model. P < .05 was considered significant.

Results
Sociodemographic and transplant characteristics of the patients: Relationships between the adherence level and the sociodemographic and transplant-related characteristics of the 150 patients who met the inclusion criteria are shown in Table 1. Among 150 patients, 19.3% (n = 29) were considered nonadherent based on their ITAS score. Mean age of the study patients was 50.76 ± 14.67 years, more than half (66.0%) were men, and 82% were married. Most patients had elementary school-level or high school graduate-level education (32.7% and 28.7%, respectively). Of study patients, 68.7% were unemployed and more than half reported equal income versus expenditure.

No significant difference was found between adherent and nonadherent patient groups in terms of age, sex, education status, marital status, and income (P > .05) (Table 1). However, employment rate was higher in the nonadherent group compared with the adherent group (51.7% vs 26.4%), and this difference was significant (P = .008). In our study group, mean time after transplant was 4.91 ± 3.71 years. This duration was longer in the nonadherent group than in the adherent group (5.82 ± 3.18 vs 4.69 ± 3.80 y), and this difference was significant (P = .024).

In the patient group, 84% received organs from deceased donors and the rest from living donors. All living donor transplants were transplanted from relatives. Among living donors, 5 were organs from parents, 7 were from children, 5 were from siblings, 3 were from spouses, 2 were from cousins, 1 was from an aunt, and 1 was from an uncle.

Cirrhosis due to chronic viral hepatitis (hepatitis B, C, D, or combination) was the leading etiology of transplant (40%) followed by cryptogenic liver cirrhosis (20.7%). The most commonly used immunosuppressive drugs were tacrolimus (80.7%) and mycophenolate mofetil (79.3%). No significant difference was shown between adherent and nonadherent patient groups in terms of the donor type, transplant etiology, or type of immunosuppressive drug (P > .05).

Factors influencing adherence to immunosuppressive therapy: Eight variables (age, sex, employment status, time since transplant and tacrolimus, mycophenolate mofetil, everolimus, and corticosteroid drug therapies) were included in the logistic regression model to determine factors influencing adherence to therapy (Table 2). The analysis identified employment status (odds ratio [OR] = 2.73, 95% CI, 1.01-7.32; P = .046) as the only risk factor to influence adherence. The regression model was significant according to the Omnibus test (P = 0.031). The value for the Hosmer-Lemeshow test was .191, indicating that the model had a good fit. The coefficient of the model (Nagelkerke R2) was 0.485. This indicated that the factors in the regression model explained 48.5% of the treatment adherence in patients (Table 3).

Discussion
The immunosuppressive treatment regimen prescribed after liver transplant is key to maintaining the function of the transplanted liver and preventing rejection.⁶ In this study, we collected self-reported data from liver transplant patients to evaluate their adherence to posttransplant immunosuppressive therapy. The study showed rate of nonadherence to immunosuppressive drug therapy of 19.3%. In a 2020 study conducted by Özdemir Köken and colleagues in another center in Turkey, the rate of treatment nonadherence in liver transplant patients was 13%.⁶ A 2019 study from Jain and colleagues found that 16.5% of liver transplant patients were not adherent to treatment.¹ In line with this information, the level of nonadherence to treatment in our study can be considered to be similar to those in other studies.

Another finding of our study was that patients who continued to work were less adherent to therapy than patients who did not work. In previous studies, similar to our study, working patients were reported to have lower levels of treatment adherence.^6,15 This may be because working patients may forget to take medication or miss the medication time because of their work schedule. Transplant centers should communicate with patients who continue to work after having a liver transplant and plan their medication times according to their work schedules. A medication box might be provided for the patient to easily carry their medications with them, and they might be recommended to use an alarm to remind them of medication times.

In our study, adherence to drug therapy decreased with the time passed after liver transplant. Similar studies in the literature have also reported that adherence to drug therapy decreases after a certain period (especially after the first 6 months).^2,10,16 This may be because patients may believe that their condition has improved, that having to take medication every day becomes routine after a while, and that taking the medication is considered less important. In addition, regular medication use every day for years may be challenging for patients, and this may lead to nonadherence to medication doses or times. Considering the findings of our study, it is critical for centers to offer education, information, and interviews to patients at regular intervals to emphasize the importance of regularity and continuity in medication use. However, patient education alone may not be sufficient to ensure adherence.² Health care professionals should be appropriately trained to address patient nonadherence to treatment and to use all available tools to improve patient adherence. Therefore, a multidisciplinary collaboration developed by professional educators, supported by psychologists, and coordinated by physicians is also recommended.¹⁸ In addition, patient-physician interactions have been shown to be effective, and frequent interactions have been shown to facilitate adherence.¹⁹ In particular, more frequent interactions with potentially nonadherent patients might be effective in boosting patient adherence.

The main limitation of our study was that it was conducted in a single center with a limited number of patients. Future multicenter studies with larger samples are therefore recommended.

This study, which was conducted to examine adherence to immunosuppressive therapy in liver transplant patients and the factors influencing adherence, showed that continuing to work and time passed after transplant negatively affected adherence. It is important for health care professionals to take these factors into account in providing appropriate cognitive and behavioral interventions that can improve adherence and to continue providing education and counseling services to transplant recipients and their relatives through posttransplant check-ups as well as through phone, online, and home visits.

Volume: 22 Issue: 12 December 2024

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