Management Trends

The introduction of effective antiretroviral therapy has resulted in dramatic clinical benefits for those persons who have access to it. Adherence to such therapy has emerged as both the major determinant and the Achilles' heel of this success. Many patients have levels of adherence too low for durable virologic control. Virologic failure from suboptimal adherence diminishes the potential for long-term clinical success, leads to the emergence of drug-resistant virus, and may undermine the dramatic benefits in health parameters seen in resource-rich countries and expected in developing countries as effective antiretroviral therapy becomes more widely available. While adherence to antiretroviral therapy is regarded as the most important determinant of clinical outcomes in HIV-positive persons, most clinicians receive little guidance on practical steps to support and improve adherence. A structured, evidence-based, 7-step approach to supporting and improving antiretroviral adherence is described here. These steps can serve as a starting point or review for care providers working to support HIV-positive patients to successfully adhere to antiretroviral therapy. [AIDS Reader. 2007;17:43-C3]

The introduction of effective antiretroviral therapy has led to dramatic clinical benefits for patients in countries fortunate enough to have access to it. HIV disease is progressing to AIDS in far fewer persons, the census in hospital AIDS wards has dramatically decreased, and the age-adjusted death rate as a result of HIV/AIDS has declined by more than 70%.^1-3 Adherence to such therapy is both the major determinant and the Achilles' heel of this success.

Adherence to effective antiretroviral therapy is widely regarded as the most important mutable determinant of clinical outcomes in HIV-positive persons.⁴ After the change in the number of CD4+ cells, antiretroviral adherence is the strongest predictor of progression to AIDS and death.^5-7

Incomplete adherence to antiretroviral therapy, however, is common in all HIV subpopulations.^8-15 For example, in a prospective study,¹⁵ 140 persons in a public hospital HIV clinic were followed for 1 year after initiation of antiretroviral therapy. The investigators assessed adherence using 3 methods: a computer chip embedded in a specially designed pill-bottle cap (microelectronic monitoring system [MEMS] cap) to record the time and duration of each bottle opening, pill count, and self-report. They calculated a composite mean adherence rate of 71% that included all 3 measures. The average rate of adherence to antiretroviral therapy reported in studies is approximately 70% (ranging from 50% to 93%).^8-16 While the exact degree of adherence necessary for durable virologic control and long-term clinical success has been shown to vary by antiretroviral class,^17-20 only 6% of HIV-infected persons reached a commonly accepted goal of greater than 95% adherence.^{8-11,13,21-24}

Virologic failure from suboptimal adherence diminishes the potential for long-term clinical success. Drug-resistant strains of HIV selected through ongoing replication in the presence of antiretroviral therapy can be transmitted to uninfected or drug-naive patients, leaving them with fewer treatment options.25 Nonadherence may eventually undermine the dramatic improvements in HIV-related health parameters seen in resource-rich countries and those expected in developing countries as effective antiretroviral therapy becomes more widely available.

Adherence is not the only determinant of antiretroviral treatment failure or success. Other factors include genetic differences in drug metabolism, prior drug resistance, severe baseline immune suppression, and concurrent opportunistic infections. Adherence to antiretroviral therapy, however, is one of few potentially alterable factors determining outcomes for patients with HIV/AIDS. Nonetheless, health care providers receive little in the way of practical guidance on how best to improve and support optimal adherence.^9,26-28 The final step toward ameliorating the impact of HIV-the actual taking of the medications-is often neglected.

Seven practical steps are presented here for HIV care providers to consider when working with patients in their difficult task of achieving and maintaining lifelong adherence to antiretroviral therapy. Each of these steps (see Box) is based on a review of the factors associated with nonadherence, emerging prospective studies that evaluate interventions to improve adherence, and our own clinical experience. We hope that these steps can serve as a starting point or review for anyone working with HIV-positive persons to support successful adherence to effective antiretroviral therapy.

STEP 1: DEVELOP PATIENT-CENTERED RELATIONSHIPS
In HIV infection, there is considerable qualitative^29-33 and quantitative^34-38 evidence indicating that the clinician-patient relationship (eg, open communication, trust, feeling comfortable and well cared for, cooperation, and partnership) is an important determinant of adherence. For example, a cross-sectional study of 554 patients who received effective antiretroviral therapy demonstrated that 6 of 7 clinician-patient relationship variables studied were significantly associated with antiretroviral adherence.³⁶

These variables were patients' perceptions of communication, trust, HIV-specific information, a satisfactory dialogue about adherence, overall satisfaction with the clinician, and willingness to recommend the clinician to others (participatory decision making was the only variable not significantly associated with degree of adherence in this study). Studies in other disease states likewise demonstrate a significant link between the quality of the clinician-patient
relationship and a wide range of medication adherence and treatment outcomes.^39-43

A body of literature has emerged advocating "patient-centered relationships" as a paradigm to ameliorate the many perceived inadequacies common to clinician-patient relationships.^44-48 A patient-centered relationship seeks to understand the patient as a whole person with unique life circumstances and ideas, appreciate the experience of illness and attitudes toward treatment, and forge a partnership with the patient based on shared ideas about the priorities of care and the roles of the clinician and patient.^36,44-47

This model of care is unlike "doctor-centered care,"⁴⁶ in which the preferences and values of the doctor predominate, the patient is essentially told what to do, and opportunities to uncover and address impediments to adherence collaboratively may be missed.⁴⁹ Establishing a patient-centered relationship is also a precursor and key component of motivational interviewing (discussed in Step 2).

Because it has been shown that clinicians are capable of improving their behaviors through training,^50-53 the clinician-patient relationship is a modifiable determinant of patient adherence that deserves to be addressed. Doing so, however, requires the time, interest, and training of the clinician and, in the setting of stressful medical environments, a regular rededication to the principles of patient-centered care. These efforts will likely be rewarded with a deeper, more satisfying and effective relationship with the patient, as well as the prospect of a genuine positive impact on medication adherence.

STEP 2: USE MOTIVATIONAL INTERVIEWING
Initiating and maintaining daily adherence to antiretroviral therapy is a huge and burdensome behavioral change for patients. According to the Transtheoretical Model of Change, a widely accepted model, a change in behavior is dependent on a person's stage of readiness and motivation to make the change.⁵⁴ These stages of change are precontemplation, contemplation, preparation, action, and maintenance.

Motivational interviewing is a nonconfrontational patient-centered technique used to help persons move through these stages of change.^49,55 The spirit of motivational interviewing rests on collaboration, evocation, and autonomy; the patient's goals and readiness to change dictate the nature of the intervention. Motivational interviewing has 4 basic principles: (1) express empathy, (2) develop discrepancy (ie, change is motivated by the perceived discrepancy between present behavior and personal goals), (3) do not challenge resistance, and (4) support self-efficacy.

In general, the focus of motivational interviewing is to amplify the patient's ambivalence about the targeted behavior and elicit an argument for change from the patient. This is done by creating a judgment-free patient-centered relationship, providing appropriate information and advice, and exploring the pros and cons of change. A fuller discussion of the basis and technique of motivational interviewing can be reviewed in a number of available resources.^49,55 Motivational interviewing–related resources for clinicians and researchers, including formal in-person and video-based training, can also be found online.⁵⁶

Qualitative studies in HIV have shown motivation^57,58 and the stage of change^59,60 to be significantly associated with medication adherence. Pilot quantitative studies of motivational interviewing have shown promising positive impacts on various aspects of HIV medication adherence,^61-64 although one study showed no benefit in a cohort of HIV-positive patients with alcohol problems.⁶⁵ Quantitative studies in other disease states suggest that motivational interviewing can have a positive impact on complex long-term behaviors, such as substance abuse,^66-68 smoking cessation,⁶⁹ and attitudes about and adherence to medications.^70,71

There are many resources and strategies available to help patients succeed with the challenge of medication adherence. A patient's motivation, however, is fundamental in being able to take advantage of these resources and should be addressed by the clinician skillfully and regularly.

STEP 3: ADDRESS KNOWN IMPEDIMENTS TO ADHERENCE
A number of potentially alterable factors have been associated with nonadherence to antiretroviral therapy. These factors should be screened for and addressed before starting antiretroviral therapy, if possible, and regularly over the course of treatment. Some of these factors are more difficult than others to deal with
effectively; antiretroviral treatment may need to proceed during this process. We acknowledge that these factors, while potentially alterable, are often very complex and require the dedication of both the patient and clinician to overcome. Identifying these factors is the first step in addressing these barriers and also helps distinguish those patients at high risk for nonadherence so that they can receive the most intensive adherence support. Several excellent reviews addressing the predictors of adherence have been published.^23,72-75

• Alcohol and drug use are common among HIV-positive persons.^76-79 For example, a national study of 2864 HIV-positive persons found that almost 20% had consumed heavy amounts of alcohol, 40% had used an illicit substance other than marijuana, and more than 12% screened positive for drug dependence over the preceding 12 months.⁷⁷ Both alcohol and active drug use have been consistently associated with nonadherence.^{15,22,76,80-85}
• A study of 85 HIV-positive persons found that cocaine use was the single factor most strongly associated with nonadherence: overall adherence to antiretroviral therapy among active cocaine users was 27%, compared with 68% among those who reported no cocaine use during the 6-month study period. Consequently, 13% of active cocaine users maintained viral suppression, compared with 46% of nonusers.⁸¹ While active drug use has been associated with nonadherence, former drug use has not, suggesting that treatment of drug addiction may have a significant impact on adherence behavior.^14,86
• Depression is very common among HIV-positive persons.^{9,77,80,81,87-89} Persons with HIV infection have at least twice the risk of depression as do HIV-negative matched controls^87,89; among HIV-positive women, the increased risk is approximately 4-fold.^88,89 Depression has been associated with nonadherence in multiple studies.^9,80,81,90
• Regimen complexity and adverse side effects are clearly associated with nonadherence.^{9,15,21,35,91-95} The aspects of regimen complexity that impact adherence principally include dosing frequency,^{9,35,91,93,95} food restrictions,⁹¹ and whether the regimen is a "fit" with the patient's routine.²¹ While reducing dosing frequency to once-daily is obviously desirable-and early studies suggest equivalent or improved adherence^96,97-the impact of once-daily antiretroviral therapy on adherence behavior has yet to be adequately evaluated. Medication side effects that affect adherence include both short-^35,92,94 and long-term^94,98 complications of therapy, including self-perceived lipoatrophy syndromes.
• Lack of social support and unstable housing are both associated with nonadherence.^{21,35,80,84,99,100} Increased support from a relationship partner was shown to improve antiretroviral adherence in a randomized study.¹⁰¹ In this study, HIV-positive persons randomized to receive 4 sessions of relationship-based adherence support significantly improved their short-term medication adherence. The improvement, however, disappeared over time, suggesting that such social support would need to be maintained for long-term antiretroviral adherence to be affected.
• Poor clinician-patient relationships are strongly associated with nonadherence.^29-38 As described in Steps 1 and 2, a successful relationship provides an opportunity to collaboratively uncover and address impediments to adherence and may help the patient develop the motivation and skills necessary for optimal adherence. Such a relationship may also facilitate the patient's development of self-efficacy, ie, one's perception of his or her ability to take medications and manage illness, which has also been linked to adherence behavior.^35,80,95

STEP 4: SCREEN REGULARLY FOR NONADHERENCE
Eliciting an adherence self-report is a relatively simple and efficient method of assessing adherence in clinical practice and has been significantly associated with viral suppression; self-reported nonadherence is likewise significantly associated with virologic failure.^14,21,22 The main task of the clinician is to elicit the self-report in a manner that maximizes its likelihood of revealing nonadherence. Otherwise, the patient will simply tell the clinician what the clinician wants to hear: that he or she has been perfectly adherent.

Adherence assessments now commonly include questions about adherence during more recent periods (eg, the past 3 days and/or past 7 days) and over longer time (eg, the past month). Both time frames have been validated against MEMS caps, and both are commonly addressed to maximize the sensitivity of the self-report.¹⁰² It also has been recognized that personal adherence behavior can vary during a given period and usually deteriorates over time.^11,13 It is therefore important to reassess adherence periodically and, if problems have been identified, as frequently as each visit (see Box).

Addressing nonadherence can seem like a daunting task to the busy clinician. Do not worry if the problem cannot be solved immediately; uncovering a problem with adherence is an important accomplishment, and solutions to it can evolve in subsequent visits.

Pharmacy refill behavior can be an important and objective indicator of who may be having difficulty taking their medications. Patients who pick up a 30-day supply of medications 3 days late could have missed 10% of their medication, unless they had a supply of additional medications from previous refills. Pharmacy dispensing and refill information is used to calculate the drug possession ratio (number of covered days dispensed/number of days between refills) and is associated with viral suppression,¹⁰³ drug resistance,¹⁰⁴ and mortality.⁴ Monitoring for late refills over time can also predict virologic failure before it happens.¹⁰⁵ Persons who are refilling their medications late should receive more intensive adherence evaluation and be considered candidates for adherence support.

STEP 5: UTILIZE ADHERENCE AIDS
A variety of devices are available that may help patients better adhere to their treatment regimens. Most of these devices are simple, inexpensive, and easy to integrate into the routine care of patients receiving effective antiretroviral therapy. Because these devices are often inexpensive or provided free of charge by pharmacies or pharmaceutical companies, it is usually possible for clinicians to provide them directly to patients as an integral part of medication counseling. These devices can help patients integrate medication taking into their daily routine in ways that minimize the need to think constantly about and remember to take their medication.

• Medication organizers (eg, pillboxes, medisets [customized patient medication packages]) are readily available and come in many different shapes and sizes appropriate to the needs of individual patients. They allow patients to organize their weekly doses of medication in one convenient location (instead of carrying multiple pill bottles) and to verify later whether they have taken the prescribed doses. Patients bringing pillboxes to appointments may help clinicians monitor for recent nonadherence. When a new regimen is prescribed, clinicians can supervise patients as they set up their first medication organizer. Some pharmacies also provide medications prefilled into weekly organizers. Medication organizers are a staple of adherence programs for HIV infection and other diseases.
• Reminder devices are particularly important given that patients cite ÒI simply forgotÓ as a primary reason for missed doses.85 Common devices include alarms on watches, beepers, or other electronic items that allow for single or multiple daily reminders. Paper or electronic calendars and diaries allow patients to document scheduled doses and note when they have been taken; these can be particularly effective in patients with cognitive impairments.106
• Visual medication schedules (VMS) show pictures of prescribed medications superimposed on a weekly calendar. Images of many prescribed medications are available in sticker sets provided by drug makers or in computer programs. It is also possible to create a VMS by affixing actual pills to a paper calendar. A VMS can help ensure that the patient understands the prescribed regimen and can help other caregivers assist in medication adherence. A VMS provided at each clinic visit has been shown to improve outcomes in patients who received anticoagulation therapy, another situation requiring chronic treatment and exact adherence.107,108
• Other helpful hints include taking medication along with another entrenched regular activity (eg, eating breakfast, brushing teeth); planning ahead for weekends, trips, or other changes in schedule; placing extra doses of medication in places frequented by the patient (eg, car, purse, knapsack, at work); and hiding medication in generic or unmarked bottles if greater confidentiality is required.

STEP 6: CONSIDER EXPANDED PHARMACY SERVICES or DIRECTLY OBSERVED THERAPY
Expanded pharmacy services are an increasingly common aspect of HIV adherence support and have been shown to be effective in improving adherence.¹⁰⁹ These services include the preparation of prefilled medication organizers, which patients can pick up at the pharmacy or which can be delivered by mail or messenger to the patient's home. Alternatively, the medication can be delivered to the patient's primary clinic or adherence support center and dispensed at regular intervals (eg, weekly or monthly). This system is a form of modified–directly observed therapy (mDOT) and allows for regular medication adherence assessments and counseling; it may be particularly helpful for those whose living situation is unstable.

Directly observed therapy (DOT) and mDOT have been identified as possible means of helping patients with severe adherence barriers improve adherence to antiretroviral therapy. Enthusiasm for DOT in HIV disease is based on its successful use in treating nonadherent patients with tuberculosis and on results from emerging studies suggesting that DOT in HIV infection is feasible. For example, a prospective nonrandomized study of mDOT was performed in a methadone clinic with 82 HIV-positive drug users.¹¹⁰ Participants ingested antiretroviral medications under direct supervision on the days they attended the clinic; evening doses and doses on "methadone take-home days" were self-administered.

Treatment outcomes in the mDOT group were compared with outcomes in 3 other groups: patients with a history of injection drug use (IDU) who were receiving methadone during their antiretroviral therapy (IDU-methadone group, n = 75), patients with a history of IDU who were not receiving methadone during their antiretroviral therapy (IDU-nonmethadone group, n = 244), and patients with no history of IDU (the non-IDU group, = 490). At 12 months, 56% of the mDOT group acheived an HIV-1 RNA level below 400 copies/mL, compared with 32% of the participants in the IDU-methadone group (P = .009), 33% of the IDU-nonmethadone group (P = .001), and 44% of the non-IDU group (P = .077). After adjustment for other covari-ates in a logistic regression model, mDOT participants were significantly more likely to achieve viral suppression than were patients in each of the 3 comparison groups.¹¹⁰

In addition to its potential use in methadone maintenance programs,^110-112 DOT has been shown to be a successful treatment approach in correctional facilities,^113,114 for pregnant women,¹¹⁵ for hard-to-reach HIV populations through the use of mobile vans¹¹⁶ or outreach workers in the community,^117,118 and as part of broad systems of social support in developing countries.^119-121 However, in methadone maintenance studies and other studies that evaluated mDOT, dropout rates were high and adherence to nonwitnessed doses did not improve nearly as much as adherence to witnessed doses did, suggesting that the use of DOT and mDOT still requires further evaluation and may work better for those on once-daily regimens.

While intensive DOT programs may be cost-effective,¹²² patient eligibility, duration, exit strategy, and monitoring for relapse remain unresolved issues. We suggest that patients with low motivational states who have experienced failure with less intensive adherence support and have advanced HIV disease may be the best candidates for DOT.¹²³

STEP 7: CREATE AN ADHERENCE PROGRAM
The creation of a dedicated adherence program allows for a more formalized system to address the aforementioned steps to maximize adherence and serves as an acknowledgment of the crucial role of medication adherence in health outcomes. It also acknowledges that successful support requires more time than many clinicians can commit.

Effective adherence programs described in the literature take many forms but share a number of common elements. First, the program should be patient-centered, individualized, and responsive to a broad range of patient needs and impediments to adherence. Second, the program should utilize a team approach to harness the skills, knowledge, and time of available physicians, nurses, pharmacists, social workers, and treatment advocates. Third, the program should provide ongoing adherence assessment and support that is maintained over an extended period.

A prototype for such an intervention derives from a randomized controlled trial in the Netherlands of 116 people who were beginning their first or second regimen of antiretroviral therapy.¹²⁴ The intervention group received an individualized educational counseling session at baseline and at each follow-up visit (0, 4, 24, and 48 weeks), designed to increase knowledge and self-efficacy regarding treatment adherence. Specifically, information was provided about HIV infection and its treatment as well as the relevance of adherence in clinical outcomes and in preventing resistance.

In addition, a personalized dosing schedule was developed with the patient, and plans were made to manage adverse side effects. During follow-up visits, strategies for solving any encountered problems were developed. The most common strategies were to design a new drug-dosing schedule, develop habits that make remembering doses easier, and provide additional skills to manage mild adverse side effects.

The control group received standard-of-care clinical follow-up. At week 48, 94% in the intervention group versus 69% in the control group achieved a 95% or greater rate of self-reported adherence (P = .008); 89% of the intervention group versus 66% of the control group had HIV RNA levels less than 400 copies/mL (P = .026). The intervention was found to prevent the decline in adherence commonly seen over time. Both groups started with good adherence, and the intervention helped maintain it, but adherence in the control group progressively worsened.

Other randomized studies of adherence interventions have demonstrated significant impact on self-reported adherence^125-128 and modest improvement in virologic control.^125,127 The importance of maintaining this support over time is illustrated by an uncontrolled study that found a significant improvement in adherence over a 4-week study period with an intervention based on ongoing education and financial rewards for good adherence.¹²⁹ However, adherence in the intervention group returned to baseline levels 4 weeks after the intervention, suggesting that ongoing adherence support is necessary.

No potential conflict of interest was reported by the authors.

References:

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