Adhering to Complex Regimens for HIV
Since the advent of antiretroviral combination therapy, adherence has become an extremely popular subject. The term appeared no less than seven times in the 1997 Federal Guidelines for the Use of Antiretroviral Agents in HIV-infected Adolescents and Adults.1 These days, adherence is a topic that is included in virtually all HIV-related conferences, even though there is little empirical evidence about adherence to antiretroviral combination therapy to discuss.
Adherence has been described as the "Achilles heel" of combination therapy, and is seen (correctly) as playing a central role in determining the success of antiretroviral treatment. However, problems of adherence are far from restricted only to antiretroviral combination therapy, although such regimens are probably among the most demanding of oral medications ever prescribed. It has long been recognized that failures of patients to follow physicians' prescriptions (for both medications and behaviors) are common, with significant costs in terms of illness prolongation, management of negative outcomes, loss of productivity and premature mortality.
Supportive and Inhibitory Factors
Medication adherence (earlier referred to as compliance, a term now considered patronizing) has been the subject of numerous studies for over 30 years, with several comprehensive reviews available.2-5 Particular attention has been devoted to chronic diseases such as diabetes, arthritis and severe and persistent mental disorders, although acute infectious diseases such as tuberculosis also have been extensively studied with respect to rates and correlates of adherence.6
Despite several decades of research addressing adherence, "little is known about the degree of adherence necessary to effect a therapeutic outcome for known therapies."7 The general medical literature suggests that adherence is almost universally less than 100%. Most estimates fall in the range of 30% to 60%, with somewhat lower rates for prophylactic medications.8 In most studies, successful adherence is defined as more than 80% of doses taken, or more than 80% of prescriptions filled on time. These global estimates do not take into account timing between doses or dietary restrictions. While no studies have been conducted to show that 80% or better adherence is therapeutically effective for combination antiretroviral therapy, several clinical reports have shown that resistance can develop when patients miss a few days or even a few doses of medication. The 80% convention may thus not be applicable to antiretroviral therapy.
The available descriptive studies of adherence in HIV-positive patients have focused on AZT, where 80% adherence was used to define "success." Using this definition, five studies found AZT adherence rates to range from 42% using a time frame of the past month,9 to 67% in the time frame of the past week.10 These rates are consistent with findings reported in the general medical literature.
In general, sociodemographic characteristics are poor predictors of adherence. Meichenbaum and Turk11 reported that "no consistent relation with adherence has been found for such variables as age, sex, social class, marital status or personality traits." Race, religion and educational levels are not consistently useful predictors in the general medical literature nor in several studies of AZT adherence.
Beliefs and Expectations
Patients' beliefs, knowledge and expectations, sometimes shared by friends and community, strongly influence medical decision-making and willingness to begin and then adhere to prescribed treatments. Adherence is found to be greater when the person perceives the need for treatment, believes the treatment will be helpful and understands the purpose of the medications. Attitudes of friends, trust in physicians and confidence in one's own ability to follow the agreed-upon treatments are also associated with adherence.12
Lack of belief in the efficacy of treatment may lead to either treatment refusal, or inadequate adherence once initiated. It is for this reason that the initial conversations between doctors and patients about combination therapy are crucial to later success: Simply telling the patient that it's time to begin antiviral therapy, writing out prescriptions and handing them to a patient who asks no questions and expresses no opinions is likely to lead to adherence problems and treatment failure. Occasionally, well-meaning physicians urge reluctant patients to start treatment, despite the patients' reservations. The more assertive patient may state that he or she is not ready to start, but others may acquiesce to a regimen that they consider of doubtful value or not congruent with their life circumstances.
Active substance abuse is likely to interfere with combination therapy, although it is not an absolute contraindication. "Benign neglect" of the problem by the health care provider is not helpful. Issues to consider include the particular drugs used, whether there is any familial or institutional structure available and whether the patients themselves are strongly committed to treatment. Some abusive substances are used on a more regular basis than others (e.g., heroin vs. cocaine), allowing for some planning of schedules. Second, some substance abusers attend day programs on a regular basis, where their medications may be stored and dispensed to them; less demanding regimens may be managed in such settings at least five or six days a week. In these settings, weekends remain problematic, but some people can arrange for a relative or friend to fill in as helpers at such times.
Even with the best of intentions, patients with neurocognitive impairment are likely to have major adherence problems. Some patients may have trouble sorting their pills for the day or the week, while others may have trouble keeping track of the time, or may simply forget. While frank dementia is rare even among patients with late-stage HIV illness, memory problems are not; even among HIV-positive asymptomatic men, some deficits are often identified on neuropsychological tests. Combination therapy is more often prescribed for those with symptomatic HIV illness who may be more likely to have some cognitive changes. When memory is a significant problem, prescription of complex medical regimens is unlikely to succeed unless social (e.g., family member) or institutional (e.g., home attendant) resources are regularly available to help with the scheduling and taking of medications.
Psychiatric disorders also may constitute barriers to adherence. Even mild conditions such as depressed mood, as elicited on self-report rating scales, may be associated with medication nonadherence,13 either because of impaired concentration, which is one of the criteria for diagnosing mood disorders, or because of feelings of hopelessness and despair. Among those with chronic and severe psychiatric disorders, noncompliance with psychotropic medication often contributes to relapse. When substance abuse is also present in HIV-infected patients with severe mental illness, many of whom live alone in unstable housing, the probability of effective management of combination therapy is poor.
The complexity of the regimen and how it matches to personal life circumstances are critical elements in establishing and maintaining treatment adherence. In the general medical literature, number of times a day pills must be taken, whether with meals or not, and nature and severity of side effects have each been associated with variations in adherence. It is not clear whether adherence is enhanced or reduced when patients are already taking other medications when a new one is added. Some investigators found declining rates of adherence as the number of concomitant drugs increased,14 but some patients who have already developed the skills needed for medication-taking simply fit in a few more in their pill boxes and their days.
When prescribing combination therapy, many physicians focus on potency and efficacy, ignoring the life circumstances of the particular patient. However, the regimen really has to fit into the person's daily schedule. If someone who is prescribed indinavir, for example, is working in a setting where others present who do not know about his or her HIV status, having to regulate mealtime around pill-taking may be extremely difficult; and this person may be better off with a twice-daily schedule. Another person without access to a refrigerator will not be able to handle ritonavir. If an HIV-positive student has final examinations in two weeks, this may not be the moment to initiate combination therapy that is likely to induce significant, if transient, side effects at the outset of treatment. Overall, the match in terms of timing and lifestyle is a significant determinant of long-term adherence.
Although not invariably the case, those who live with others, who have friends and relatives who believe in and encourage medication adherence, and who have a fairly organized day are far more likely to succeed with the complex regimens that combination therapy demands. Community attitudes play an important role. For example, AZT had a negative reputation among some African-American communities, which was fueled by an early, subsequently invalidated report suggesting that AZT might be less effective in this population. Combination therapy has a better reputation in inner city neighborhoods, at least currently, as demonstrated by the high street price paid for protease inhibitors -- in New York City, a bottle of indinavir sells for $100 or more (personal communication, J. Dobkin, M.D., January, 1998).
Two-way communication between doctor and patient is critical to the success of adherence. The patient has to believe that combination therapy will make a profound difference in extending life, or else the regimen's burdens will outweigh the perceived rewards. Initiating combination therapy is not usually regarded as an immediate need. If it takes extra time, or additional visits, for the doctor to convince the patient that combination therapy should be initiated now, or for the patient to convince the doctor that his or her current life circumstances are simply not conducive to starting now, then extra time must be provided. However, there are a few urgent situations when immediate initiation may be considered imperative. One example is a patient with an essentially untreatable condition such as PML who is rapidly getting sicker. Reports indicate that combination anti-HIV therapy can lead to life-saving remission in certain cases of this sort. In less urgent situations, treatment can be safely put off while doctor-patient discussions continue.
An early concern of some community activists and health care professionals working in inner city settings was the possibility that physicians would withhold antiretroviral combination therapy from certain patients simply because of their membership in a given class -- substance abusers, for example. In reality, the converse problem was frequently seen: Because the published Public Health Service guidelines are explicit about the medical indications for combination therapy, health care providers find it difficult to let psychosocial factors override these guidelines. Less experienced physicians may proceed to prescribe complex regimens to patients who are unlikely to succeed at this time in their lives, thus losing their one best chance to benefit from the breakthroughs in antiviral treatment.15
Promoting Medication Adherence
There is a startling dearth of experimental evidence regarding effective interventions to promote medication adherence. While information from rigorously designed trials is sparse, we can nevertheless get some guidance from observational or uncontrolled studies, theories of behavior change and clinical experience. These all point to a number of interventions likely to promote the initiation and maintenance of effective medication adherence. Perhaps the most critical steps toward establishing adherence occur at the outset and include engagement of the patient by the health care provider, a sense of commitment on the patient's part and negotiation of a regimen that is both feasible and acceptable to the patient. Patients have to be able to live with their schedules of pill-taking, and while some are willing to change their lifestyle in order to accommodate the most potent and complex possible treatments (unfortunately, potency and complexity are highly associated at this time), others will not or cannot.
At the outset, before even beginning combination therapy, it is helpful to review anticipated problems and barriers to adherence, which then permits the patient to work out solutions on his or her own or with assistance. For this purpose, some providers give their patients a week's worth of jelly beans or M & Ms to try to follow the prescribed schedule and see where they falter. Which doses are problematic? What are the circumstances? What is the patient thinking when errors occur? What is the patient's attitude about mistakes? Does he consider a fifteen-
Some patients find it helpful to have a written treatment plan that shows the name of the medication, time of each dose, number of pills or capsules per dose and meal restrictions, if any, along with a telephone number to call with questions and for the next appointment date. Both doctor and patient should keep a copy of the plan for review at the next visit. Other techniques for promoting adherence include identifying daily activities that can be linked to pill-taking (e.g., a regular TV show), keeping a medication diary or log (preprinted forms can be prepared), preparing pills for the week at fixed times (e.g., Sunday evening), and otherwise relating pill-taking to the normal rhythms of daily life. Planning ahead for changes in routine or for weekends can forestall lapses at such times.
Mechanical aids are often useful. These range from pill boxes with dividers in which medications can be sorted by the week and time of day to timers, alarms, beepers that can be set to ring when it is time to take pills, to signs and checklists posted on refrigerators.
Social assistance can make a major difference, especially at the beginning of the regimen. Some people have a buddy who agrees to provide reminders every time medication is scheduled. Some programs have shown that providing a hotline staffed by health providers such as nurses can make a major difference in getting patients started on combination therapy. Sometimes children remind their mothers; sometimes mothers remind their adult children.
The foregoing discussion has focused on establishing adherent behavior at the outset of combination therapy. Somewhat different challenges arise with respect to maintaining adherence, which are even less well characterized. Over time, initial enthusiasm can dwindle as the incessant demands of scheduling persist. The media begin to relate stories about treatment failures and relapses. Friends taking the same medications get sick or die. New evidence suggests that combination therapy may need to be continued for years or forever, not for 24 to 36 months as earlier hoped. As people feel better and return to work, new problems arise. Among these are maintaining confidentiality, arranging schedules to accommodate pill-taking, frequent trips to the bathroom (if taking medication that requires a high liquid intake), occasional days with significant side effects such as diarrhea, the constant reminder of illness and simply the ongoing burden of the regimen. We need to know in more detail about the hurdles, questions and worries that arise over time with combination antiretroviral therapy, and we need to develop interventions to maintain adherence once therapy is established.
Adherence and Clinical Outcome
While meticulous adherence to combination antiretroviral therapy is considered essential to good clinical outcome, the parameters of adherence have not been defined experimentally. Clinical reports indicate that missing a few days or even a few consecutive doses can lead to resistant viral strains, but whether this is common or the rare unfortunate exception is unknown. How adherent must someone be to succeed?
Finally, it is necessary to recognize (and to discuss with patients) factors other than adherence that may cause treatment failure. Even in premarketing clinical trials of protease inhibitor combinations, which included the most carefully screened, dedicated, educated and conscientious participants who were closely followed in generously staffed settings, between 15% and 35% did not achieve or maintain viral loads below the standard threshold for quantification (400 copies/ml). Reasons for treatment failure include, but are not limited to, the absence of effective treatment options for an individual patient, impaired drug metabolism or absorption, very late stage illness or inability to tolerate multiple, sometimes toxic, side effects.
Some patients who persistently sought effective treatment since 1987 have a history of monotherapy with each antiviral medication as it was marketed, with consequent serial development of resistance to the individual drugs, so that there are not enough "new" agents available to put together an effective regimen. Others, with gastrointestinal disease, do not absorb enough drug to reach effective blood levels. An unknown but significant number of patients have drug-resistant viral strains before any antiviral treatment, either through spontaneous mutations or because they were infected by someone whose viral strain had developed resistance. This latter problem signifies a particularly urgent reason to promote adherence to combination therapy, since treatment failure represents not only a personal but also a public health cost.
Still a Lot to Learn
Much remains to be learned about initiating and maintaining adherence to combination antiretroviral therapy. While a wide range of enterprising efforts have been started in various health care settings to promote adherence, few have been systematically assessed. We still know little about which adherence-
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