Rethinking Nonadherence: Historical Perspectives on Triple-Drug Therapy for HIV Disease

By decreasing viral loads to undetectable levels and restoring health to persons infected with HIV [1], the triple-drug HIV cocktail has received considerable attention. Yet the complexity of the new therapy, coupled with the fact that patients may need to take it for life, has raised concerns about nonadherence [2-9]. Fearing the possible development of untreatable, drug-resistant HIV strains in nonadherent patients, some practitioners have advised withholding triple-drug therapy in certain cases [2, 4]. Other commentators have objected, arguing that this would unfairly penalize patients whose personal characteristics-such as race, ethnicity, or history of substance abuse-are often viewed as predictive of nonadherence. This debate has major implications for both public health and patient-centered care. Physicians and health officials have long noted nonadherence to treatment among patients with such diseases as tuberculosis, diabetes, and hypertension. They have called patients who are unable or unwilling to follow prescribed regimens ignorant, vicious, recalcitrant, and noncompliant. Meanwhile, researchers have regularly tried to correlate nonadherence with specific patient characteristics. We argue that history provides two major lessons for clinicians struggling with triple-drug therapy and nonadherence. First, labels such as nonadherent overemphasize the practitioner's role in determining who should receive treatment and how it should be administered. Second, the ability to predict nonadherence in individual patients remains elusive. Given these findings, we advocate revisiting the longstanding tendency to reflexively categorize patients as either adherent or nonadherent. Although it remains essential to know who is taking triple-drug therapy properly, an approach that discourages labeling and emphasizes active patient participation in therapy will avoid judgmental and inaccurate assessments of patient behavior and may help HIV-positive patients take medications more successfully. A Historical Perspective Health officials first became concerned about uncooperative patients with tuberculosis in the 1890s, shortly after Robert Koch proved that the disease (also known as consumption) was communicable. Officials implemented numerous policies to prevent the spread of tuberculosis, including those about coughing into handkerchiefs, proper sputum disposal, and isolation of actively infected persons [10]. Although persons from all social classes violated these directives, health departments specifically targeted single, alcoholic men from rundown skid row areas [11]. These men received little tolerance when they disobeyed regulations. In 1903, New York tuberculosis control pioneer Hermann Biggs opened a facility, Riverside Hospital, to isolate such men forcibly. Riverside, he wrote, was designed for [h]omeless, friendless, dependent, dissipated and vicious consumptives [who] are likely to be most dangerous to the community [12]. Such derogatory language was common. A contemporary of Biggs advocated detention institutes for ignorant and vicious consumptives [13]. The label of nonadherence in the early 1900s thus reflected both the actual conduct of patients and judgmental assumptions about the behavior of certain populations [14]. The introduction of curative antibiotics for tuberculosis after 1945 increased concerns about nonadherence. Streptomycin and isoniazid revolutionized tuberculosis therapy, but many patients did not take their antibiotics after they were discharged from sanatoriums. Not only did these patients spread infection, but their erratic compliance produced drug resistance. Again, attention was focused on the most obviously nonadherent patients: skid row alcoholics, who were often mentally ill [15, 16]. Health officials of this era carefully eschewed the derisive language of earlier times, calling such alcoholics recalcitrant [17-19]. Yet the term recalcitrant, defined as stubbornly resistant to authority [20], implied that physicians imposed regimens that patients were to obey. Not surprisingly, writers associated recalcitrance with the alcoholic, drug addict, skid-row derelict and others with personality defects [21-23], blaming the victim for complex behaviors and conditions that were often unmanageable [24]. Assuming that such persons were inevitably nonadherent, tuberculosis officials often confined them inappropriately; nonadherent middle-class patients were rarely detained [15]. The Era of Noncompliance The introduction of multiple new antibiotics in the 1950s led to studies of nonadherence in patients with infections other than tuberculosis. For example, it was found that adults and children with streptococcal pharyngitis rarely completed 10-day courses of penicillin [25]. In one study [26], only 19% of patients took four pills daily for 10 days. Moreover, nonadherence to penicillin occurred both in public hospitals and in private practice [27]. This finding-that nonadherence was prevalent throughout the population-contradicted earlier assumptions that only poor patients or alcoholics disregarded medical recommendations. Additional data were generated in the 1970s when Sackett and Haynes and their colleagues published books on compliance and noncompliance [28, 29]. Earlier commentators had used the term noncompliant and had studied the complex relation between patients' beliefs about health and their ingestion of medication [30-32], but these authors popularized the concept of noncompliance. Even though Sackett and Haynes tried to make noncompliance a nonjudgmental term, recent authors have criticized it. As a result, the terms adherent and nonadherent-which seek to emphasize patient participation in decision making-are now preferred [33]. The work of Sackett and Haynes and their colleagues spawned thousands of studies that examined the causes of nonadherence and proposed solutions for it. Suggested corrective strategies include educating patients, modifying patient behaviors, and altering the organizational setting of the clinician-patient encounter. Specific interventions include simplified drug regimens; pill-dispensing systems; user-friendly clinics; and, for tuberculosis, directly observed therapy [34-40]. The literature on nonadherence has generated many important findings. At least 40% to 50% of patients do not adhere to either short-term antibiotic regimens or long-term therapies for asthma, diabetes, or hypertension [28, 41, 42]. Nonadherence is not an all-or-none phenomenon but is rather a dynamic set of behaviors. For example, patients may adhere to treatment with some medications but not others. Even supposedly adherent patients are usually only partially adherent [43, 44]. Indeed, some studies suggest that 80% adherence yields good clinical outcomes and is a realistic goal [45]. The degree of adherence needed for triple-drug therapy is still unknown. Research has consistently failed to identify demographic variables that predict whether patients will follow the advice of physicians. In other words, nonadherence occurs regardless of class, ethnicity, or extent of education [9, 28, 41, 42]. Certain patient characteristics-such as homelessness, mental illness, substance abuse, and previous nonadherence-may help to predict future nonadherence [46-48]. Yet none of these factors, with the possible exception of psychiatric illness [8, 42], is reliably associated with nonadherence across studies [36]. Most important, predictions about specific risk groups do not apply to all persons in such groups. For example, in one recent study that found an association between injection drug use and nonadherence to tuberculosis therapy [48], 40% of all drug users completed treatment-without directly observed therapy. Thus, it is difficult to predict nonadherence in individual patients at a rate better than that achieved with chance alone [9, 36, 41, 49-51]. Nonadherence and HIV Disease Although triple-drug therapy has highlighted the subject of nonadherence, this issue is not new to HIV disease [9]. For example, nonadherence to zidovudine monotherapy has been well described. As is true with other diseases, demographic factors have not predicted the individual behavior of HIV-infected patients. Some researchers have concluded that certain patient characteristics, such as injection drug use, are associated with greater nonadherence [7, 52-54], but others have found that HIV-positive drug users are reliable if given social supports [55-57]. The triple-drug HIV cocktail greatly magnifies earlier concerns about nonadherence. When all of their medications are included, HIV-positive patients receiving therapy with zidovudine, lamivudine, and a protease inhibitor may take 20 or more pills each day. These drugs, moreover, must be taken two or three times daily and at strict intervals. Some must be taken while patients are fasting; others must be taken with a high-fat, high-protein meal. Because the pills may cause side effects, frequent modifications of therapy may be necessary [58, 59]. Triple-drug therapy also raises concerns about drug resistance, both for individual persons and for the community. In the case of tuberculosis, erratic adherence led to the emergence of multidrug-resistant strains [46, 60]. Early data suggest that patients taking the triple-drug cocktail sporadically or at a reduced dose will probably develop drug resistance [61-66]. Moreover, resistance to one drug may produce cross-resistance within the same class, jeopardizing future treatment options for individual patients. Because multidrug-resistant strains may be transmissible, the public health consequences of nonadherence are potentially alarming [9]. Physicians prescribing triple-drug therapy have drawn on well-established adherence strategies, such as educational support and enhanced social services. They are also using newer approaches, including financial incentives, outreach workers, pharmacist counselors, and beeper and te