Adherence, often used interchangeably with compliance, is "the act, action, or quality of being consistent" [7] with administration of prescribed medications. Adherence is preferred because it affirms that patients actively participate in choosing and maintaining a medication regimen. Nonadherence may mean not taking medication at all, taking reduced amounts, not taking doses at prescribed frequencies or intervals, or not matching medication to food requirements. Typical rates of medication adherence for persons with chronic diseases are about 50%, with a range from 0% to 100% [8]. Self-reported adherence to HIV therapy ranges from 46% to 88% [9-12].

Many factors have been associated with adherence, including patient characteristics, clinician-patient relationship, type of disease, treatment regimen, and clinical setting [13]. Patient characteristics include knowledge about and belief in the medication, social support, and stable living circumstances. Altered mental states caused by substance abuse, depression, or psychological stress contribute to non-adherence. Conversely, adherence does not seem to be predicted by age, sex, race, education level, socioeconomic status, or occupation [14]. Trust in and special attributes of the clinician can positively influence adherence. Asymptomatic and chronic diseases are less likely to have high rates of adherence, and complex treatment regimens decrease adherence. The organization of clinical services can affect adherence, including availability of expertise, linkages with drug treatment and mental health services, flexibility in the hours of operation, and the presence of nonjudgmental and supportive staff [15].

In addition to encompassing all of the above features, adherence to HIV therapies presents special issues that result from the biology of HIV, the magnitude of the required therapeutic effort, and the changing demography of HIV infection. Replication of HIV is rapid and highly error-prone, resulting in great species diversity and de novo drug-resistant mutants unless replication is completely suppressed. Under the selective pressure conferred by imperfect adherence, drug-resistant mutants rapidly emerge. Cross-resistance among drugs within a therapeutic class limits future treatment options, emphasizing the importance of maximal suppression and strict adherence during the initial course of antiretroviral therapy. Thus, compared with therapies for other chronic diseases, which are often forgiving of lapses in adherence, HIV therapy is unforgiving. The development and transmission of antiretroviral-resistant species carries potentially disastrous public health consequences, further distinguishing HIV infection from many other chronic diseases [16].

The magnitude of therapeutic effort for patients receiving HIV therapy is daunting. Large numbers of medications, many pills, frequent dosing, the need to match dosage to meals, and frequent side effects characterize most regimens. For example, a commonly prescribed regimen of stavudine, lamivudine, and nelfinavir requires taking 13 pills (3 doses) per day or 4745 pills (1095 doses) per year. The shifting demography of HIV diseases raises additional concerns about adherence. Increasing numbers of ethnic minority patients, injection drug users, and women have developed AIDS. However, these groups may be difficult to engage in care and have not achieved the same decrease in AIDS incidence and survival benefit as white men have [1].

Interventions that promote adherence to anti-HIV therapies are urgently needed. Despite the limited evaluation of interventions promoting adherence for other diseases [17], the urgency of the issue requires that strategies be implemented on the basis of what little is known and what is reasonably likely to be effective. Initiation of antiretroviral therapy is rarely a medical emergency. A careful plan to maximize adherence should precede initiation of therapy. Interventions to improve adherence should target the patient, clinician, treatment regimen, and clinical setting. Patient-targeted interventions include educating patients about therapy, treating substance abuse and mental illness, strengthening support systems, and tailoring medication to daily life activities. Untested technological reminders that use telephone calls, timers, or beepers may promote adherence for some patients; however, these reminders may be irrelevant for socially marginalized populations that lack access to technological cues.

Improving adherence is not the sole responsibility of the patient. Clinicians should use the repeated encounters before initiation of therapy to provide information, promote trust, and motivate the patient. Consistency, availability, and competence are essential characteristics for the clinician. Sharing successful changes in viral load and CD4 count links adherence to therapeutic benefit and helps to motivate patients. A team approach to improve adherence by using nonphysician providers, family members, and trusted peers is useful. Simplification of regimens, elimination of unnecessary medications, repeated assessment of adherence and proactive monitoring, and management of side effects should be routine. The complexity of existing medication regimens impairs adherence. Pharmacologic improvements in existing and newer therapies should allow for twice-daily or even once-daily regimens. Clearly, the pharmaceutical industry has a key role and interest in the development of simpler and safer regimens.

Special attention to the site and organization of care is needed to reach marginalized populations. With adequate resources, prisons, jails, drug treatment programs, homeless shelters, needle-exchange sites, and other community locations can become important settings in which to implement HIV therapy. In Connecticut, up to 67% of HIV-infected prisoners first received antiretroviral therapy while in prison [10], and 84% continued HIV care through a novel transitional case-management program [18] after returning to the community. In San Francisco, effective outreach has led to successful adherence in homeless populations [19]. For injection drug users, flexibility and convenience are necessary, and for some women, provision of child care at treatment sites may enhance adherence. Directly observed therapy, which has been successful in the treatment of tuberculosis, is impractical with HIV therapeutics because current treatment regimens consist of multiple daily doses. However, modified versions could use case managers, family members, and peers. Directly observed therapy can also be implemented in prisons; at needle-exchange sites; and in drug treatment programs such as therapeutic communities, methadone maintenance programs, or heroin maintenance programs of the type that are available in Switzerland [20].

Improvement in adherence is key to preventing the emergence of drug-resistant viruses that compromise therapeutic benefit and may be transmitted to others. The cost of interventions to enhance adherence is minimal compared with the cost of the therapies themselves and should be weighed against the costs to individual patients and to society that will result if therapeutic benefit is compromised. The introduction of protease inhibitor combinations led to an era of renewed optimism in the HIV and AIDS epidemic. An "era of adherence" is now necessary to sustain and expand the benefits of these therapies.