Since the introduction of HAART, HIV- and AIDS-related mortality has declined tremendously [1,2]. The continuous, lifelong treatment with antiretroviral therapy has significantly improved life expectancy and turned HIV from a terminal infection into a chronic disease. In HAART, adherence is of utmost importance. Poor adherence, indeed, may lead to medication failure, viral mutations and development of drug resistance [3,4]. Future treatment options become limited because of cross-resistance . The risk of transmission of resistant viruses makes adherence a public health concern [6,7]. Research and daily practice have shown that strict adherence is difficult to achieve for many of the HIV-infected patients treated with antiretroviral therapy [8,9]. Adherence to HAART requires patients to behave in a way that cannot easily be incorporated into daily life.
On the basis of earlier studies on adherence, a level of 95% or more seems to be required to prevent the development of resistant viruses [10–12]. In more recent studies, it has been shown that durable viral suppression can be achieved by using HAART regimens that require lower adherence than 95% [13,14]. Other studies suggest that the relationship between adherence and the development of resistance differs by drug class. The prevalence of resistance to non-nucleoside reverse transcriptase inhibitors is significantly higher at low levels of adherence than that to protease inhibitors [15,16].
To attain the benefits of HAART, there is a strong need for effective adherence interventions in the care of HIV-infected patients. In the process of developing patient-tailored intervention procedures, a literature study was carried out to examine what is known about the problem from the patient's perspective . This article reports the results of this review.
Quantitative studies identify factors related to or predicting adherence. Three reviews of these studies have been published in recent years [18–20]. The present review focuses on qualitative studies. Qualitative studies are conducted to explore the meaning people give to situations and are helpful in laying bare the processes that are at play in adherence . To develop an intervention tailored to the individual situation, it is necessary to understand the way people manage their daily lives when taking HAART and the interaction of this process with adherence [17,22].
Before discussing the findings from the qualitative studies, those of the quantitative reviews are summarized. The factors are grouped into the same dimensions and reported in the same sequence as used by the World Health Organization : socioeconomic factors, healthcare team and system-related factors, condition-related factors, therapy-related factors and patient-related factors. Against this background, the findings of our own review are reported.
Summary of factors related to adherence derived in quantitative studies
Socioeconomic factors such as age, gender, race, educational level and income level are inconsistent in influencing adherence [18,19]. Women who live together with children tend to have a lower level of adherence. . Social support from family and friends affects adherence positively [18,20].
Healthcare team and system-related factors related to adherence include clear instructions, providing adequate knowledge about the relationship between adherence and resistance and better medical follow-up. Support from nurses and pharmacists positively influences adherence . However, Ammassari et al.  concluded that satisfaction with healthcare and the patient–provider relationship are inconsistent factors in affecting adherence.
Condition-related factors such as CD4 cell count, viral load and time living with HIV do not significantly correlate with non-adherence in all studies [18,19]. Having HIV-related symptoms is positively associated with non-adherence .
Therapy-related factors are seen as significantly associated with non-adherence [18,19]. The antiretroviral regimen is complex: number of pills, number of daily doses, food restrictions and fitting the regimen into daily living. Side effects related to HAART are strongly associated with non-adherence, especially in persons who started treatment in an asymptomatic phase [18,19].
Patient-related factors associated with non-adherence include low patient self-efficacy, psychological distress and depression [18,19]. Mixed results were found for anxiety and depressive symptoms [18,19]. Forgetfulness is a reason for non-adherence [18,19]. Furthermore, inadequate confidence in treatment effectiveness and poor understanding of the relation between adherence and the development of resistance influence non-adherence . Knowledge and beliefs about treatment are inconsistent factors in affecting adherence . Substance abuse is a determinant of non-adherence  but seems not to be a consistent factor across studies .
Qualitative studies published from 1996 through April of 2005 were selected for this review if they focused on the patients' perspectives, barriers, facilitators and the process of adherence to HAART.
Selection of articles
Relevant articles were identified by using the electronic database indexes (CINAHL, PUBMED, and Web of Science). The search terms HIV, (non)adherence, interviews, barriers, qualitative, study, perceptions, antiretroviral and combination were combined. The search was restricted to articles written in English. Articles were excluded for different reasons. The exact way the search was done and the reasons for excluding articles are shown in Table 1. The nature of the qualitative designs was not a criterion for exclusion. Articles that used both qualitative and quantitative methods were included but only the qualitative findings were drawn upon for this review (data taken from [23–46]).
Review of methodological quality
Studies meeting the inclusion criteria were evaluated by two reviewers for methodological quality. The appraisal considered the nature of the sample, the recruitment strategy, the population and the sample size. The quality of data collection was appraised for measures taken to assure validity, quality of the data collector (interviewer), interview type, data triangulation and the likely thickness of the data (i.e., whether enough data had been collected to support the conclusions, as can be inferred from the interview guide and the number and duration of the interviews). With regard to data analysis, attention was given to coding procedures, interpretation, measures to assure validity of the analysis and triangulation in the analysis (Table 2).
Based on the appraisal, some studies were considered to be based on insufficient data to extract strong conclusions. Either their samples were too small [37,44] or the data collection methods did not allow sufficient depth [30,38]. Four studies did not describe the duration of the (focus) interviews [25,26,30,35]. The other studies which used ‘focus group’ interviews were appraised as likely to be based on thin data, given the time available for data collection [24,27,28,33].
In four articles, the coding procedure was unclear [30,32,33,37]. In some articles the interpretation process cannot be easily reconstructed [23,25–27,33,36,37,41,44,45]. Most of the studies provide limited information regarding the validity of the analysis [24–26,28–30,33,34,36,41,42,45,46]. The analysis of one study  was appraised as dubious because the authors focused on what was common among participants and did not analyse differences.
However, the findings of the studies in which the method was unclear or questionable were in most respects comparable with the findings of the other studies. Consequently, these studies were not excluded from the review.
The included publications were read several times. During this process, findings were coded inductively and interpreted; after which the articles were organized in thematic groups and compared within these groups. The main branches of the code-tree were based on earlier studies and inductively specified. This process was performed by the first researcher and controlled by the second. When their opinions diverged, the matter was discussed until consensus was reached. The analysis of the findings of the various studies led to the identification of overall categories of themes affecting adherence.
The studies used a descriptive design or appropriated parts of ‘grounded theory’ methodology. Only the article of Wilson et al.  set forth a coherent theory based on the methodology of grounded theory. This ‘theory of reconciling incompatibilities’ explains how adherence choices occur in a particular context and in the face of specific conditions. Themes and factors associated with those choices have been summarized in this review.
Three studies used a quantitative and qualitative approach [25–27]. One study  was supplementary to a study using electronic measures of adherence. Some studies [33,34] had a broader scope than adherence. Only the findings on adherence are included in this review. Except for one longitudinal study , all studies have a cross-sectional design.
The majority of the respondents were recruited through HIV/AIDS clinics, treatment centers (healthcare) and AIDS-service organizations (community). Most studies recruited in healthcare and community organizations. One study on drug users recruited through methadone posts and included patients taking part in a longitudinal cohort study . The recruitment for most studies was by flyers and posters, which can be considered a high threshold for participation. Some studies recruited respondents partly by direct invitation, which may be assumed to lead to a higher probability of participation [23,24,26–28,31,32,34,36,38,39,42,43]. Most studies included mixed populations. All studies included persons of 18 years and older, except one study , which only included patients of 50 years and older. Only three studies [28,43,44] described the nature of the HIV exposure.
Data collection varied in that in-depth interviews, (semi-)structured interviews, focus interviews and diaries were used.
When analysing the findings in detail, 13 primary themes could be identified (Table 3). These themes could easily be grouped into the main categories used in the quantitative reviews. The order has been adapted to reflect better on the process-oriented thinking of qualitative research on adherence to antiretroviral therapy. The categories are not mutually exclusive: a theme can be classified in more than one category. A theme is introduced in the category in which it has most weight.
Both the qualitative and the quantitative studies show that many patients experience side effects when taking HAART, and that these are an important reason for non-adherence [23,26–28,30,32,34–37,40–42,44–46]. Believing that the medication is too iatrogenic is also a reason for non-adherence . Patients choose to give the body time to rid itself of medicine and recover from the resulting side effects by skipping doses [32,40]. In the model produced by Wilson et al. , deviation from prescribed routine based on body-listening and gauging was described as subprocesses of self-tailoring.
Patients experience demands of the medication based on the strict rules and complexities of the regimen. The intake–frequency/schedule, changes in prescribed medication, the large number, the size and bad taste of pills all have a negative bearing on adherence [23–29,34–37,40–42,44,46]. Food prescriptions that need to be observed when taking HAART may make adherence more difficult [23,27,28,41]. Skipping a meal may also lead to skipping a medication dose [32,46].
Condition-related factors pertain to being HIV positive: the symptoms of the illness, the lifelong treatment, the social image of HIV and the impact of being HIV positive on daily life. These factors are psychological distress and secrecy or disclosure of the HIV diagnosis.
Psychological distress related to the condition of being HIV positive influences adherence and is related to the uncertainty of the chronic character of HIV and its lifelong treatment . Patients are worried about the toxic substances that they are ingesting. These worries can lead to the development of ambivalence based on the paradox that the medications are both life saving and toxic. Ambivalence can lead to non-adherence .
Emotional distress may also be related to having difficulties with the HIV diagnosis and the negative aspects of antiretroviral therapy [27,28]. Taking HAART confronts patients with their HIV status [27,30,36,37,42,44,45]. In the model of Wilson et al. , being HIV positive is a part of the construct self-identity that includes non-adherence caused by avoiding the confrontation with having HIV. Acceptance of HIV is seen as influencing adherence [35,36,38,45]. Competencies in handling embarrassing situations and self-control will help to prevent emotional distress and thus non-adherence .
Most HIV-infected patients do not disclose their HIV diagnosis, fearing stigmatization, discrimination and isolation. Secrecy is difficult to maintain if one has to take medication [23–26,42]. Adverse side effects can be experienced as a sign of illness and are thus a risk factor for unwanted disclosure . When it is not possible to take medicine out of sight of others, adherence is hindered and a dose is easily skipped [24–26,28,31,34,37,38,41–43,45,46]. Patients who are open about their HIV and do not mind taking their pills in public have a higher level of adherence [31,38,39]. However, disclosure can also impede adherence when it results in antagonistic reactions from others who have negative beliefs and expectations about antiretroviral medication .
Patient-related factors represent internal factors, including trust and belief in the therapy, the motivation to take therapy, knowledge of HAART and adherence, forgetting, moods and substance use.
As in the quantitative studies, we see that patients treated with HAART are motivated to be adherent by trust and belief in the benefit of antiretroviral therapy [23,24,26–28,36–38,40–43]. Visible signs proving that medication works are helpful in supporting continuing adherence [40,43]. Information patients receive from their healthcare provider and persons in their environment are an important basis of both belief and trust in (or doubt about) the effectiveness of the medication. Patients' confidence in the effectiveness can change over time, based on laboratory results, opinions of surrounding people and of others taking the same medication [23,38]. In the theory of Wilson et al. , illness ideology, representing someone's belief about treatment, was described as a factor influencing adherence choices and based on either trust or distrust in medical science.
Being aware that antiretroviral medication allows people with HIV to live longer is important in the motivation to be adherent in taking medication. Patients feel motivated because they believe in the powerful ability of the medication to keep them alive [24,25,27,39–41]. An individual's desire to stay alive is fed by the desire to take part in future events or to stay healthy to raise children, the latter being of particular importance to women [24,27,30,40].
An individual's knowledge of HAART and of the importance of taking the medication adherently seems to bear significantly on adherence behaviour [39,41,43,45,46]. Adherence behaviour is often based on personal interpretations of good practice [41,45]. Misconceptions can lead individuals to think that they are taking medication correctly, while in fact they are not properly following the instructions and are thus non-adherent [25,32,36,40,41,45,46]. Siegel et al.  considered this type of misconception to be a justification of non-adherence behaviour, based on the ‘theory of accounts’ of Scott and Lyman .
Sometimes patients just forget to take their antiretroviral medication [27,29,30,32,34,38,41–46]. Forgetting has several causes. Disruption of daily routines is the main one [23,24,26,28,32,36,42]. The medication cannot be taken as usual because the activities in which it has become incorporated fail to occur. Deviations in activities may be related to being too busy (work, child care), falling asleep or disruption of daily routines (weekends, social life, partying and travelling) [23,25,26,28,29,32,34,36,41–43,45,46]. On the one hand, a medication scheme not fitting into normal daily activities or an individual leaving home without medication are causes offered for forgetting to take medication [23–25,28,30,32,43,45]. On the other, creating a routine which incorporates taking medication promotes adherence [29,35,41,44]. Patients remember more easily to take doses when the medication-scheme is linked to daily activities . Patients use practical aids as reminders, such as pill boxes, alarms and medication schedules [23,24,26–28,34,36,37,40,41,43]. The use of these reminders may be compromised when a patient wants to prevent disclosure. The situations in which reminders may be avoided are at the same time the ones in which the risk of forgetting is high because normal routine is interrupted.
Mood states not (directly) related to being HIV positive, such as concerns, stress and feelings of depression, affect adherence negatively [23,26,28–30,33,36,39,40,45]. In particular, feeling angry, depressed or sad increases non-adherence [26,30,39]. Self-respect and the ability to enjoy oneself has a positive influence on adherence [23,36].
Substance use (drugs/alcohol) is detrimental to adherence [26,27,29,32,33,36,38,40]. Apart from intravenous drug use, negative influences are reported from ‘heroin and cocaine addiction’ [27,36], ‘drinking and drugging’  and ‘substance abuse’ [27,36,40,45]. Only the daily acquisition of drugs seems important and that leads to non-adherence [29,36,39].
Healthcare team and system-related factors
Healthcare team and system-related factors include the relationship and quality of communication with healthcare providers. Having faith in the healthcare provider and the experience of a good relationship with the healthcare provider that is based on trust and professional support seem to influence adherence positively [24–27,33,36,38–41,43,45]. Characteristics of a supportive healthcare provider include a caring attitude, effective and frank communication and clear instructions, being responsive and accessible and showing respect [25,27,37]. Sufficient time for consultations and taking time to listen are considered important in increasing trust and thus adherence [25,27,36].
Socioeconomic factors encompass environmental factors and factors of economic status. Social support is also discussed in this category. Most of the reviewed studies give some data on socioeconomic variables such as income, work, disability, etc. Only one study  referred to the influence of poverty on adherence. Two studies [36,43] mentioned homelessness as negatively influencing adherence.
As in the quantitative studies, social support was found to influence adherence to antiretroviral medication. Support from family members, including children, and friends plays a role in adherence to therapy [23,25–27,29,30,36,38–41,44]. Social support has a positive influence on adherence if it is substantial and practical: reminding to take medication, actually giving out the medication and/or offering food and drink to accompany the intake of the medication [23,30,40]. By comparison, a partner who takes medication on a different schedule or who discourages the taking of medication can lead to adherence problems [23,40].
Themes specific for subgroups
The HIV population includes subgroups such as women, men who have sex with men and drug users. Most studies comprised mixed populations. Some studies distinguished different subgroups. Only Remien et al.  described not finding any consistent differences between the three subgroups. In the other studies, no subgroup analysis was carried out.
In the studies that included only women, child care was found to be a risk factor for adherence [27,37,41,42] yet the wish to raise one's children is a major motivation to stay alive and to take HAART adherently [27,30,42]. Children supporting the adherence of their mother is particularly commented on for the women in the study of Remien et al. . Weight gain as an adverse side-effect leading to non-adherence is only mentioned in studies with women [37,42].
Some factors with known influence on adherence are more pronounced in specific populations such as drug users. Generally, drug users have an irregular lifestyle . As antiretroviral treatment is extremely difficult to fit into such a lifestyle, it is obvious that the risk for reduced adherence in this subgroup of patients is much higher than in other populations.
Table 4 has an overview of subgroup-specific factors.
In this review, findings of various qualitative studies on adherence to HAART were integrated to provide an overview of the experiences of HIV-infected patients and the processes underlying the factors identified in quantitative research. The qualitative studies not only confirmed the factors found in the quantitative studies but also provided explanations as to why many of these factors influence adherence. The explanations can be used in designing interventions that are attuned to the patient's situation. This discussion will integrate the results of the quantitative and qualitative studies as recommendations for healthcare providers in the field of HIV.
As adherence is a dynamic phenomenon in which influences vary over time, the relevance of ongoing (i.e., lifelong) attention to adherence to antiretroviral therapy should have highest priority. Healthcare providers should acquire insight into possible influencing factors in each individual patient before HAART is started and during treatment. On the base of this information, a patient can be better prepared and actions can be undertaken for specific support to optimize adherence.
Adapting medication to life rather than life to medication is the first and most important strategy to promote adherence. For instance, the use of a watch or pillbox with an alarm can be helpful in reminding a patient to take medication if (unwanted) disclosure can be avoided.
When HAART is introduced, information on possible side effects and instructions on how to manage these side effects should be given. It is important that possible side effects should be explained clearly so that patients understand properly how their medications work. During every follow-up visit, any ambivalence toward the medications (they heal but are also toxic) should be discussed.
All patients who start treatment should be prepared for the possibility of unpleasant and distressing side effects and advised how to handle them.
The patient's acceptance of being HIV positive should be discussed, as acceptance improves the chances of adherence. If medically possible, it may be better to delay treatment while helping the patient to accept the disease. Furthermore, a patient should be prepared for the fact that starting HAART can renew the confrontation with being HIV positive, which can lead to psychological distress and, therefore, to non-adherence. Follow-up should be arranged to give support.
Secrecy is threatened by taking treatment. The possibility of disclosure should be discussed with the patient as openness leads to a higher level of adherence. The fact that disclosure can lead to negative comments from others, which may adversely influence adherence, should also be discussed. If disclosure is not an option, a patient can be informed how to handle taking medicine in secret to prevent skipping doses.
If HIV-related symptoms are present, actions should be taken to diminish or manage those symptoms.
Feedback about positive reactions of the body should be used to support adherence. Showing a decreasing viral load and an increasing CD4 cell count will build trust in the medication. As trust and belief can change over time with subjective experience or through information from others, it is necessary to discuss this theme during every follow-up visit.
Pointing out the value of treatment for the patient's life during follow-up visits enhances motivation.
Information appropriate to a patient's level of understanding will lead to the patient having correct knowledge of what constitutes good adherence practice. Because a patient's personal interpretation of good adherence practice may be based on misconceptions that are used to justify risky behaviour, it is important to ask patients to describe their behaviour and if necessary to repeat instructions.
Discussing details of the circumstances that lead to forgetting medication can reveal aspects that need attention in order to improve adherence. Attention should be given to personal skills, such as the capacity to organize one's life and one's activities and the ability to anticipate risk situations.
In case of depression, a patient should be advised to undergo treatment before starting HAART. In case of substance use, it is important to find a way to minimize the risk that substance use will remain the first priority in life. Professional support or daily observed therapy can be an option.
Healthcare team and system-related factors:
A trusting relationship with the healthcare provider is essential. This relationship is built on support and open communication. Providers should give clear instructions on how to take medication, explain the relationship between adherence and viral load and offer good medical follow-up.
Acquiring insight into a patient's social support systems and counselling on how to use them is a valuable strategy in optimizing adherence. Social support has to be substantial and practical, such as reminders to take medication. Attention should also be paid to possible negative influences on adherence in the patient's environment, perhaps coordinating the (medication) schedules of partners or dealing with a discouraging influence. Mothers of young children may need help to fit the medication into the family's hectic schedule.
This review intended to lay bare the processes that are at play in adherence and a number of these processes have been highlighted. Most of the included studies, however, did not uncover underlying processes. In the majority of these studies, such factors were simply enumerated. Little attention was devoted to the relationship between the identified themes and factors related to adherence. These studies, often using limited data, fall short as qualitative studies. Only one study led to the development of an integrated theory of adherence behaviour . Furthermore, subgroup factors need more attention as does the influence of hardship and vulnerability.
Further qualitative studies can make an important contribution in this field, particularly when the research approaches deal with the respondents' own perspective. Such methods are essential given the complexity of adherence.
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