Adherence to Potent Antiretroviral Therapy

Introduction
These Guidelines call for many people living with HIV, many of whom are asymptomatic, to be treated with highly active antiretroviral therapy (HAART) for the rest of their lives. The ability of the patient to adhere to the regimen is essential for successful treatment. Excellent adherence has been shown to increase the likelihood of sustained virologic control, which is important for reducing HIV-related morbidity and mortality. Conversely, poor adherence has been shown to increase the likelihood of virologic failure and has been associated with increased morbidity and mortality (49, 50). Poor adherence leads to the development of drug resistance, limiting the effectiveness of therapy (51). The determinants, measurements, and interventions to improve adherence to HAART are poorly characterized and understood, and more research on this critical topic is needed.

Adherence in HIV Disease
Adherence is an important determinant of both the degree and duration of virologic suppression. In addition, numerous studies have found an association between poor adherence and virologic failure. In several studies, non-adherence in patients on HAART was the strongest predictor of failure to achieve viral suppression below the level of detection (52, 53). A high degree of adherence is necessary for optimal virologic suppression with HAART; several studies have shown that 90-95% of doses must be taken for optimal suppression, and lesser degrees of adherence are more often associated with virologic failure (49, 54). To date, there is no conclusive evidence that the degree of adherence required varies with different classes of agents or different specific medications in the HAART regimen.

Imperfect adherence is common. Surveys have shown that one-third of patients missed doses within 3 days of the survey (55). The reasons for missed doses were predictable and included forgetting, being too busy, being out of town, being asleep, being depressed, having adverse side effects, and being too ill (56). One fifth of HIV infected patients in one urban center never filled their prescriptions. The instability of homelessness may lead to poor adherence, but not without exception; one recent program achieved a 70% adherence rate among the homeless utilizing flexible clinic hours, accessible clinical staff, and incentives (57).

Many predictors of poor adherence to HIV medications have been identified. These include poor clinician-patient relationship, active drug and alcohol use, active mental illness, in particular depression, lack of patient education and inability of patients to identify their medications (reviewed in reference (56)), and lack of reliable access to primary medical care or medication (58). Other sources of instability that may influence adherence include domestic violence and discrimination (58). Medication side effects may also cause poor adherence (59). More recently, fear of or the experience of metabolic and morphologic side effects of HAART has been associated with poor adherence (59).

Predictors of good adherence to HIV medications have also been identified. These include: 1) availability of emotional and practical life supports; 2) the ability of patients to fit the medications into their daily routine; 3) the understanding that poor adherence leads to resistance; 4) the recognition that taking all medication doses is important; and 5) feeling comfortable taking medications in front of people (60). Importantly, optimal viral suppression is associated with keeping clinic appointments (32).

The measurement of adherence is imperfect and lacking a gold standard. Patient self-report is weakly predictive of the likelihood of adherence; however, an estimate of poor adherence by a patient has a strong predictive value and should be regarded seriously (61, 62). Physician estimation of a patient's likelihood of adherence is a poor predictor (63). Each of several aids to measure adherence, such as pill counts, pharmacy records, smart pill bottles with computer chips recording each opening (i.e. Medication Event Monitoring Systems or "MEMSCaps”), and other devices may be of use, though each requires comparison to patient self-reports (61, 64). In some studies, clinician and patient estimates of the degree of adherence have been found to exceed measures based on MEMSCaps. Due to its complexity and cost, MEMSCaps technology is best used as an adjunct to adherence research, but is not useful in most clinical settings.

Self-report should include a short term assessment of each dose that was taken over the recent past (e.g., the past 3 days), and a general inquiry regarding adherence since the last visit, with explicit attention to the circumstances of missed doses and possible measures to prevent further missed doses. It may also be helpful for patients to bring their medications and medication diary to clinic visits.

Adherence to HAART: Approach to the Patient

Patient-related strategies
Suggestions for strategies to improve adherence are noted in Tables 7, 8, and 9. The first principle is to negotiate a treatment plan that the patient understands and to which he/she commits (65, 66). Before the first prescription is written, patient "readiness" to take medication should be clearly established. Such negotiation takes time, commonly two or three office visits, and patience. Specific education should include the goals of therapy, including a review of expected outcomes based on baseline viral load and CD4⁺ T cell counts (i.e., the Multicenter AIDS Cohort Study (MACS) data from the Guidelines), the reason for the need for adherence, and the plan for and mechanics of adherence. Patients must understand that the first HAART regimen has the best chance of long-term success (1). The clinician and health team should develop a concrete plan for the specific regimen in question, including the timing of doses of medications around meals and other daily activities. Some centers offer "dry runs" with jellybeans in order to familiarize the patient with the rigors of HAART; however, there are no data to indicate whether or not this exercise improves adherence. Daily or weekly pillboxes, timers with alarms, pagers and other devices may be useful. The development of side effects can affect the ability to adhere to treatment. Clinicians should inform patients in advance about possible side effects and when they are likely to occur; treatment for likely side effects should be included with the first prescription along with instructions on the appropriate response and the possible need to contact the clinician. In some studies, low literacy has been associated with poor adherence; clinicians should take care to assess a patient’s literacy level before relying on written information, and to tailor the adherence intervention to the individual patient. Visual aids and audio or video sources of information may be useful in these patients (67).

Education of family and friends regarding the importance of adherence, as well as recruitment of family and friends to become participants in the plan for medication adherence can be invaluable. Community interventions can be of assistance, including adherence support groups, or the addition of adherence issues to regular support group interactions. Community-based case managers and peer educators can greatly assist adherence education and adherence strategies in individual patients.

Temporary postponement of HAART initiation has been proposed for patients with identified risks for poor adherence (68, 69). For example, a patient with active substance abuse or mental illness may benefit from immediate psychiatric treatment or treatment for chemical dependency. Appropriate therapy during the 1-2 months needed for treatment of these conditions may be limited to opportunistic infection prophylaxis, if indicated, and therapy directed towards the symptoms of drug withdrawal and detoxification or the underlying mental illness. In addition, readiness for HAART can be assessed and adherence education can be instituted during this time. Other sources of patient instability, such as homelessness, may also be addressed during this interval. Patients should be informed and in agreement with such a plan for future treatment and time-limited treatment deferral.

Clinicians are reminded that such factors as gender, race, socio-economic status, educational level, and a past history of drug use do not reliably predict poor adherence. Conversely, a higher socio-economic status and educational levels and a lack of a history of drug abuse do not predict adequate adherence (69). No individual patient should automatically be excluded from consideration from antiretroviral therapy simply because he or she exhibits a behavior or other characteristics judged by some to lend itself to nonadherence.

Clinician and health team-related strategies

Clinician and health team-related strategies to enhance adherence are noted in Table 8. A trusting relationship is essential. The clinician should commit to a feasible mechanism for communication between clinic visits, to ongoing monitoring of adherence, and to timely and appropriate responses to adverse events or interim illness. Interim management during physician vacations or other absences must be clarified.

Adherence requires full deployment of the available health care team. Regular reinforcement by two or more team members will assist the goals of adherence. Provider attitudes and behaviors that are supportive and non-judgmental will encourage patients to be honest about their adherence and about problems they have experienced with adherence. Interventions that have been associated with improved adherence include a pharmacist-based adherence clinic (70), a street-level drop-in center with medication storage and flexible hours for the homeless (71), an adolescent-specific adherence training program (72), and medication counseling and behavioral intervention (73); these and others are noted in Table 9. For all health care team members, specific training on HAART and adherence should be offered and updated regularly.

Monitoring may identify periods of poor adherence. There is evidence that adherence wanes over time, even in highly adherent patients, a phenomenon described as “pill fatigue” or “treatment fatigue” (68, 74). Thus monitoring adherence at every clinical encounter is essential. Reasonable responses to decreasing adherence include increasing the intensity of clinical follow up, shortening the follow up interval, and recruiting additional health team members, depending on the nature of the problem (69). Intermittent drug use or emotional crisis might lead to referral for mental health or chemical dependency assessment or further recruitment and intervention with family or friends. Some patients may require ongoing assistance from support team members from the outset, including chemically dependent patients, mentally retarded patients in the care of another, children and adolescents, or patients in crisis.

New diagnoses or symptoms may influence adherence. For example, depression may require referral, management, and consideration of the short and long-term impact on adherence. Cessation of all medications at the same time may be more desirable than uncertain adherence during a 2-month exacerbation of chronic depression.

The response to the problem of adherence in special populations has not been well studied. There is evidence that programs designed specifically for adolescents, for women and families, for injection drug users, and for homeless persons increase the likelihood of medication adherence (70, 72, 75, 76). In particular, the incorporation of adherence interventions into convenient primary care settings, the training and deployment of peer educators, pharmacists, nurses, and other health care personnel in adherence interventions, and the monitoring of clinician and patient performance regarding adherence are beneficial (71, 77, 78). In the absence of data, a reasonable response is to address and monitor adherence in all HIV primary care encounters and incorporate adherence goals in all patient treatment plans and interventions. This may require the full use of a support team including bilingual providers and peer educators for non-English speaking populations, incorporation of adherence into support group agendas and community forums, and inclusion of adherence goals and interventions into the work of chemical dependency counselors and programs.

Regimen-related strategies
To the extent possible, regimens should be simplified by reducing the number of pills and the frequency of therapy, and by minimizing drug interactions and side effects. This is particularly true for patients with strong biases against many pills and frequent dosing; for some patients, these issues are of lesser importance. There is evidence that simplified regimens with reduced pill numbers and dose frequencies improve adherence (79, 80). With the numerous effective options for initial therapy noted in these Guidelines and the observed benefit of less frequent dosing on adherence, twice daily dosing of HAART regimens is feasible in most circumstances. Regimens should be chosen with review and discussion of specific food requirements in mind and patient understanding and agreement to such restrictions. Regimens requiring an empty stomach numerous times daily may be difficult for patients with wasting, just as regimens requiring high fat intake may be difficult for patients with lactose intolerance or fat aversion. Fortunately, an increasing number of effective regimens have no specific food requirements.

Directly Observed Therapy

Directly observed therapy (DOT), in which a health care provider observes the ingestion of medication, has been shown to be successful in the management of tuberculosis, specifically in patients who are poorly adherent to medications. However, it is labor-intensive, expensive, intrusive, and programmatically complex to initiate and complete and, unlike tuberculosis, HIV requires lifelong therapy.

Several pilot programs have studied DOT in HIV patients with some preliminary success (81- 84). Programs have studied once daily regimens in prisons, in methadone programs, and in other cohorts of patients with a record of repeated poor adherence. Modified DOT programs have also been studied, in which the morning dose is observed and evening and weekend doses are self-administered. The goal of these programs is to improve patient education and medication self-administration over a time-limited (i.e., 3-6 months) period. It is too early to judge the outcomes of these programs, particularly with regard to long term adherence following completion of DOT.

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