Adherence to immunosuppressive therapy following liver transplantation: an integrative review

ABSTRACT Objective: to investigate the evidence available in the literature on non-adherence to immunosuppressive therapy among patients undergoing liver transplantation. Method: integrative literature review, including research whose sample consisted of patients aged over 18 years undergoing liver transplantation. It excluded those containing patients undergoing multiple organ transplants. For the selection of articles, Medline / Pubmed, CINAHL, LILACS, Scopus and Embase were searched. The search period corresponded to the initial date of indexation of different bases, up to the deadline of February 10, 2015, using controlled and uncontrolled descriptors: liver transplantation, hepatic transplantation, liver orthotopic transplantation, medication adherence, medication non-adherence, medication compliance and patient compliance. Results: were located 191 investigations, 10 of which met the objectives of the study and were grouped into four categories, namely: educational process and non-adherence; non-adherence related to the number of daily doses of immunosuppressive medications; detection methods for non-adherence and side effects of therapy. Conclusion: there were risk factors related to the health service, such as control and reduction of the number of doses; related to the individual, such as being male, divorced, alcohol or other substances user, exposed to low social support and being mentally ill.


Introduction
Liver transplantation allows the patients with terminal liver disease the opportunity to increase their quality of life, coupled with increased survival. However, the results are closely linked to the daily commitment of the patient with their immunosuppressive therapy (1)(2)(3) .
The graft receiver survival time may vary according to the initial diagnosis, ranging between 60 and 70% in the first five years, depending on the type of primary disease leading to the need of transplantation. It is worth noting that the procedure allows that approximately 80% of patients resume their work activities (4) .
It is clear that non-adherence to immunosuppressive therapy increases the risk of graft loss, in addition there is increased morbidity, represented by the presence of tremor, neurotoxicity, and acute renal failure and also the increase in mortality and re-hospitalization, raising the costs to the health system (3)(4)(5) .
Thus, adherence to the treatment plan can be defined as the patients' behavior, which meets the recommendations agreed with health professionals in relation to taking medicines, following the diet or changing their lifestyle (6)(7) .
Evaluation of adherence to drug therapy is a complex task. However, some methods have been proposed for their verification, ranging from questionnaires, measurement of serum drug dosage, or the counting of dispensed tablets; yet, it is noteworthy that none of these forms of assessment obtained greater sensitivity than 80% (8) .
The non-adherence rates to immunosuppressive medications among patients receiving solid organs can range from 36% among kidney transplant; 14.5% of heart recipients and 6.7% of liver transplant recipients.
A previous research has shown that one of every 10 deaths from liver transplant patients is related to nonadherence to immunosuppressant (8) . On the other hand, a meta-analysis including 147 studies published between 1981 and 2005 addressed the adherence to immunosuppressive therapy following solid organ transplantation, and found that only 20% of these articles were related to liver recipients (9) .
Nurse is the professional spending more time with the patient, so he is the most suitable for the development of educational activities. The result of these actions reflected in increased satisfaction and quality of life, the effective delivery of care at home, anxiety reduction, the empowerment of the individual against the disease process and an increased treatment adherence (10) .
Thus, it is of great value to research the reasons that may contribute to non-adherence to treatment in the postoperative period, in order to support nursing actions with this group of patients. Therefore, this study aimed to investigate evidence available in the literature on non-adherence to immunosuppressive therapy among patients undergoing liver transplantation.

Method
For the preparation of the integrative review (IR) the following steps were followed: identifying the topic and defining the guiding question; sampling or literature search; extraction of data from the included studies; evaluation of studies and interpretation of results, and finally, the knowledge synthesis or integrative review of the presentation itself (11) .
For preparation the guiding question of the review, we used the PICO strategy (12) , described in sequence ( Figure 1).

II
Evidences of a single cohort or case-control study.

III
Evidences of meta-synthesis of qualitative or descriptive studies.

IV
Evidences of a single qualitative or descriptive study.  The extraction of data items included was performed with the aid of a validated instrument (13) . For the analysis of the research study design and level of evidence it was used concepts proposed by Melnyk, Fineout-Overholt for clinical questions related to prognosis or prediction ( Figure 4) (14) .

V Evidences elicited from specialists opinions
Oliveira RA, Turrini RNT, Poveda VB. All included investigations were published in the English language, nine of them (90%), written by medical professionals. As for the origin, five of them (50%) were produced in North America and five (50%)

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in European countries.
As for the strength of the evidence of the studies revealed that nine (90%) articles were classified as level two evidence, that is, cohort studies and one of the researches (10%) was considered at the level four evidence, a cross-sectional study.
In order to facilitate the understanding of the highlighted results, the investigations included in this review were grouped together into categories, namely: educational process and the occurrence of noncompliance; non-adherence related to the number of daily doses of immunosuppressive medications; detection methods of non-adherence to immunosuppressive therapy and medication side effects related to nonadherence to immunosuppressive therapy ( Figure 5). The authors verified the fact that male subjects with unstable social support and mood disturbs may have more trouble in adhere to therapeutic regime. The lack of lists of patients with recurrent adhesion problems was also considered a risk factor.  (15) Prospective cohort (20) To compare the impact of the presence of a care coordinator during transitioning between a pediatric to an adult service of two recipients of liver transplant vs. an historic group.
The group that had all the information to access the care coordinator, as well as the one that received the standard information, had higher serum level of the drug when compared with those that were transferred using a conventional routine In this respect, the authors suggest that using a reference person during transfers may raise the adherence to immunosuppressant therapy. To identify patients with higher risk of non-adherence among subjects having liver transplant.
The study detected a rate of 9,2 cases of non-adherence/100 transplants. Reasons for non-adherence: lack of information and diversity of used drugs. Risk subgroups for non-adherence: divorced, mental illness, alcohol and other substance users. To compare the adherence rates between liver transplanted patients when they changed posology of Tacrolimus from twice a day to once a day.
The adherence rate did not change significantly in time after transplantation however the adherence was higher with the single dose.  (18) Prospective cohort (125) To determine the efficacy, safety and adherence to It was confirmed that the non-adhesion went from 66,4% down to 30,9% when posology changed from twice a day to a single daily dose. Serum levels of the drug were stabilized at the initial weeks of treatment without renal, liver or cardiac complications. II (the Figure 5 continue in the next (17) Prospective cohort (187) To evaluate safety and efficacy in conversion from Tacrolimus twice a day to a single daily dose in adults undergoing liver transplant.
The study corroborates that this model is safe, as six months after posology change, reducing from two doses a day to a single dose, the serum level of the drug was stable at the same level as previous without hepatic or renal function alterations. To compare the performance of three different methods of verification of non-adherence.
The largest rate of non-adherence was measured by a self-responded questionnaire; however, the authors suggest that the serum level dosage of Tacrolimus is a useful test for detection of non-adherence. Patients with software follow-up had less rejection events and toxicity to Tacrolimus. The recurring costs of the computational system was ten times less than the wages of the staff needed to fill out the follow-up forms. The use of a clinical management system showed a lower rate of non-adherence and organ rejection.  (21) Prospective cohort (108) To evaluate the nonadherence to prednisolone among 108 adults receiving a liver graft, through electronic monitoring of the event.
Roll out of an electronic system in the medicine's cap recording date, opening and closing time of a group of patients. It was proved that adherence was higher with this system and patients over 40 years had more risks in delaying medication intake. To evaluate the long-term symptoms experienced by adults undergoing liver transplant.
No correlation was found between the symptoms experienced by transplanted patients and non-adherence to treatment. The side effects were more serious for women than for men, e.g. widespread pain. Men referred sexual malfunction. Regarding the methodological design, the majority of the sample consisted of cohort studies, a design that leads to difficulties in controlling bias (22) .

II
It is recognized that the best evidence is obtained by means of high quality methodological studies, allowing the generalization of the research results and also gathering information capable of providing support for clinical decision making, such as randomized controlled trials. However, it is noteworthy that the cohort studies are typically used to evaluate results of risk exposure (23) .
Thus, this may be one of the designs recommended for research and evaluate risk factors for non-adherence to immunosuppressive therapy. Therefore, the data found in different studies included in the present IR were synthesized into categories, the first one refers to the "Educational process and the occurrence of non-adherence" where the risk factors for non-adherence were of two kinds: related to the therapeutic process, such as lack of information on the treatment and the use of various drugs; and related to the individual, such as being male, alcohol users or other substances, exposed to Oliveira RA, Turrini RNT, Poveda VB. lower or unstable social support and those with mental illnesses (5,8,15) . The strategies adopted among the studies included in this category suggest the optimization of the teaching-learning process, through the inclusion of family members training them in the use of drugs in the preoperative period (5) . In addition, direct contact with a professional responsible for the clinical follow-up seems to have a consequence in better adherence rates (15) .
Also noteworthy are the risk factors related to the organization of health services, such as the lack of records of patients with persistent compliance problems, since the formal ignorance of these subjects may result in inadequate planning of educational activities (5) .
Another category was "non-adherence related to the number of daily doses of immunosuppressive drugs," which addressed the adherence difficulties caused by the use of several drugs simultaneously. The intervention studied in this group of papers was the change in posology, from twice a day, for a daily single dose. The three studies included, found significant reduction of non-adherence, stabilization of serum drug levels and absence of liver, renal and cardiac complications (16)(17)(18) .
In the category "Methods of detection of nonadherence to immunosuppressive therapy," it was noted that putting in place surveillance methods for adherence, interferes in patients' response to drug therapy and therefore result in better outcomes of transplantation.
However, there is no consensus regarding the best method for measurement of non-compliance; and three studies (19)(20)(21) suggest that the self-administered questionnaire resulted in the measurement of the higher rate of non-compliance; another suggested tool is the implementation of a computer program for monitoring the use of medicines (20) , when associated with the assistance of health professionals, resulted in fewer rejection and intoxication events by the immunosuppressant drug. Another suggested method is an electronic device installed on the caps of the vials of drugs that would be able to detect the time of its opening and its closing (19)(20)(21) .
The last category was composed of a single work and refers to the evaluation of side effects related to immunosuppressive therapy as a risk factor for nonadherence (3) . This study found that the most serious side effects were widespread pain among female subjects, and among men sexual dysfunction, however, there was no correlation between symptoms perceived by patients and the phenomenon of non-adherence (3) .
Patients undergoing liver transplantation are patients with chronic diseases and require the constant use of drugs, with risks and health problems, making it imperative for them to be able to understand the importance of the procedure; learn to deal with the drugs; change hygiene habits, with the aim of combating infectious processes and adapt to various changes, such as the self-image, and social issues, such as work, for instance (11) .
In this sense, and due to the complexity in the education about all aspects involved in the procedure and even on adherence to immunosuppressive medications (1) .
In the research that evaluated 370 subjects undergoing transplants in France, 135 were liver transplant recipients and among them, it was found that 51% of subjects had non-adherence to treatment. It was stated also that the simplification of drugs protocols can increase compliance, because patients have difficulties in dealing with the treatment (24) .
In research (25) , which measured knowledge before and after the educational intervention among candidates to liver graft, it was found that despite the intervention contemplated the perioperative period, the understanding of the information related to the pre-operative period was higher compared to the postoperative (25) .
Another study sought to evaluate the effectiveness answers was related to the use of immunosuppressive drugs (26) .

Several factors have been associated with behaviors
of non-compliance, ranging from health problems such as depression (27) , to questions related to social status or associated with intrinsic characteristics of patients, such as being male, with low social support (5) , or related to the health system, such as the lack or absence of available medication (9) . This last factor in particular, does not apply in theory to Brazil, since health care is provided for in the Constitution of 1988, which states that health "is everyone's right and duty of the state", therefore immunosuppressive drugs are offered by the Brazilian National Health System (SUS) (28) .
Another aspect that may contribute to nonadherence are the side effects, which seem to cause more discomfort among women than among men, Rev. Latino-Am. Enfermagem 2016;24:e2778 ranging from widespread pain, more commonly reported by women, to sexual dysfunction (in men) (3) . Studies including patients with the human immunodeficiency virus (HIV), found that the absence of side effects is a protective factor for non-adherence to medication (29)(30) .
The reduction in the dosage of immunosuppressant to a single daily dose is considered as a measure that confirms the reduction of the problem of non-compliance (17)(18)(19) , an aspect pointed out by studies, showed reduction of non-adherence to  (16,20) .
There is no consensus regarding the best method of assessment of non-compliance. Probably this actually happens since it is a multidimensional phenomenon, and for this reason should be evaluated in various ways, including the use of technology (30,(33)(34)(35) .
Therefore, it is remarked the importance of guidance, through health education in relation to adherence to immunosuppressive therapy. Thus, we highlight the role of the nurse in the development of these activities, promoting safe behavior and the use of mechanisms that favor adherence in relation to immunosuppressive drugs.
It is believed that the issues brought to light in this study are able to guide the decision making process of nurses and health professionals in order to map out and know which patients are more prone to nonadherence, suggesting strategies to better monitoring and increasing adherence to therapy, but ultimately preventing and reducing the episodes of rejection, rehospitalization and especially damage to the health and quality of life of the patients (25) .

Conclusion
It was concluded that the risk factors for non- There was also remarkable the absence of national articles on the theme, indicating a field to be explored by the Brazilian scientific literature, as it becomes interesting to know what are the factors that impact on adherence to immunosuppressive therapy among Brazilian patients since the health care organization in Brazil differs from countries whose papers were included in this review.