▪ “Medicines don't work if you don't take them.”-Surgeon General Everett Koop
▪ “I'm sure people know I have AIDS when they look at my skinny face, but I have to take the meds-what choice do I have?”-Patients in New Haven, CT
▪ “I won't take these drugs. I don't have a place to keep them, they are too toxic, and they eat your methadone anyway.”-Patients in New Haven, CT
▪ “My tablets, I never forget them. They are like my underwear.”- Patients in South Africa
▪ “My family and I ran out of money, so I took the medicines every other day to make them last longer.”-Patients in South Africa
HIV/AIDS EPIDEMIC AND MEDICATION ADHERENCE
The HIV/AIDS epidemic arose within the United States in the decade of the 1980s; within 10 years, HIV/AIDS became the leading cause of death in young men and young women.1 This was followed by a stunning decline in mortality in concert with the arrival and availability of potent antiretroviral medications.2 This is among the most striking and storied events in medical and public health history. The content of this therapeutic success has required the expertise of clinical practice and biomedical, behavioral, and social science research. The power of these associated disciplines and their limitations have been part of this story. This is particularly evident in the area of HIV medication adherence, a major determinant of individual- and population-based therapeutic benefit.3-9 Biologic factors such as the characteristics of HIV itself, disease status, host immunology, and genetics as well as characteristics of medications such as drug potency and pharmacology influence adherence and therapeutic success. Behavioral factors such as knowledge, mental functioning, motivation, and skills, which predict medication acceptance and adherence, determine and are strongly associated with therapeutic success and often lie at the root of therapeutic failure.8-10 Social context such as availability of resources, access to care and treatment, race, gender, and stigma provide the background and setting in which biology and behavior operate.11-13
Figure 1 illustrates the components for HIV treatment success, influenced by biology, behavior, and social issues, and the crucial locus of adherence within the pathway to therapeutic success. To attain the desired therapeutic outcome of arrest of HIV disease progression and restoration of health, potent medications must be developed, tested, approved, and marketed, and access to them must be ensured. The former largely occurs in the biomedical and clinical context. Access is more likely a product of behavior and social context, including resources and available and appropriately configured systems of care, however. Next, medications must be accepted and properly prescribed. Proper prescription encompasses knowledge of the changing guidelines in HIV therapeutics,14 proper patient preparation, and avoidance of more common than appreciated prescription errors. The issue of medication acceptance is tied to and precedes adherence and is often neglected in studies of adherence. After acceptance has occurred, the complex behavior of adherence, which is influenced by information, motivation, behavioral skills,15 and social and cultural patient realities,13 must be successfully carried out. In our own studies, acceptance and adherence can be separated and are predicted by different but related variables. Acceptance of therapy is most strongly influenced by trust in physicians and mistrust of medications (emphasizing the central role of trust in the clinician-patient relationship and clinical care as discussed elsewhere in this article), and adherence is most strongly influenced by side effects, regimen complexity, and social support.16 Once adherence is accomplished, it is followed by an array of pharmacologic events and considerations that are more recently being appreciated as incredibly complex and are being addressed with increasing sophistication, ultimately enabling the therapeutic agent to reach its target in therapeutically efficacious amounts but still to be strongly influenced by characteristics of the host immune system and the virus. The final step, therapeutic success, requires recognition of the important need throughout this schema for separating biomedical patient-oriented behavioral and social research from the realities of clinical practice and the unique and difficult daily challenges faced by individual patients with HIV disease.
More than in most areas of health, the issue of medication adherence has been successful in bringing diverse disciplines closer together and in collaborative relations. Nevertheless, their differences and distance remain problematic, and there is a great need to construct practical models of multidisciplinary research with dissemination of results that are generalizable across a wide range of clinical settings and result in individual patient and population level effectiveness.
Although long appreciated and studied by medical, behavioral, and social scientists in many other diseases,17-19 it has taken time for biomedical researchers and the medical community providing treatment to people with HIV/AIDS to recognize and fully appreciate the importance of adherence and its wide variability among different patients and populations. Early in HIV treatment, with drugs of limited potency, it may have seemed that adherence was of minor importance, because little was expected from available drugs. As treatment advances resulted in the availability of dramatically potent combination therapy, the requirement for excellent adherence became more apparent. Even then, however, most HIV biomedical researchers, focused on the biologic aspects of therapeutics, neglected behavioral issues and dismissed the importance of collaboration with those interested and expert in medication-taking behavior. Initially, mention of adherence at scientifically oriented HIV meetings was typically greeted by biomedical researchers with disdainful rolling of eyes. After 5 years of antiretroviral therapy, adherence appeared on most lists of causes of therapeutic failure but usually at the bottom, without much comment and well behind antiretroviral potency and pharmacology.
Even among experienced practitioners, the great excitement about therapeutic success in early clinical trials of antiretroviral therapy raced past their ability to incorporate medication adherence into the antiretroviral therapeutic paradigm. Further, in the complex world of medical care, attention to adherence was often neglected in the context of real and perceived medical exigencies and, often, by the fiscal realities and time constraints of clinical practice.20 For infectious disease-trained clinicians, representing most of those engaged in HIV treatment, there had never been another infectious disease with the therapeutic requirements of lifelong therapy. For many other clinicians, HIV therapeutics seemed too complicated, even if they were familiar with adherence support strategies. For most clinicians and researchers, regardless of specialty and training, the realities of HIV disease and issues of demographics, unfamiliar and/or disparaged risk behaviors and social circumstances, secrecy, and stigma often blunted therapeutic efforts. Often practicing closer to patients and their personal and social needs, nurses have been more aware of the need for medication adherence than physicians but were often without training and well-developed skills to evaluate and enhance medication adherence. For most biomedical researchers, although adherence became accepted as an explanatory variable for treatment failure, little interest or expertise in its characteristics emerged. Finally, with notable exceptions,8,21 relatively few behavioral scientists working with HIV disease were initially focused on therapeutic behavior, concentrating their efforts mostly on HIV prevention.12
There is now increasing appreciation of the critical role of adherence in HIV therapeutics.22 Patients, clinicians, and researchers have come to understand the importance and difficult complexities of medication adherence. This became inescapable as regimens began to fail, higher levels of adherence seemed to be necessary compared with other diseases,23 and it became apparent that therapy was likely to be lifelong. Further, with the urging of patients and their advocates, it became clearer that the complicated schedules and array of side effects and toxicities required of patients were often overwhelming and that the behavioral and social complexities of patients' life circumstances conspired to reduce therapeutic success. In retrospect, the lack of appreciation of these challenges by scientists and clinicians was naive and perhaps even arrogant.
The need for adherence support has now been integrated into consensus guidelines for the use of antiretroviral therapy,14 most antiretroviral clinical trials incorporate adherence measures, and analyses include adherence at least as an explanatory variable. Acceptance of its importance has slowly made its way toward the mainstream of HIV medical therapeutic research. In the past 5 years, a growing cadre of clinicians and researchers have come together to address the multifaceted and challenging issues of enhancing HIV medication adherence, and the present issue represents the ensuing successes and continuing unresolved issues.
To appreciate the issues in integration of the various needed research and clinical skills to address HIV medication adherence, and with the risk of overgeneralization, it may be of use to explore the similarities and differences in biologic, behavioral, and social science research and to contrast these with the tenets and realities of clinical care and practice. The intention is to illustrate why a single approach or set of expertise is not sufficient, that individual disciplines all bring value to the mix, and that none alone is likely to address needed issues of medication adherence and its enhancement fully. The intention is also to illustrate that implementation of collaboration across disciplines presents substantial challenges. The perspective is that of an HIV clinician and clinical researcher with a strong leaning toward behavioral and social sciences.
BIOMEDICAL, BEHAVIORAL, AND SOCIAL SCIENCE RESEARCH
Biomedical, behavioral, and social science research has much in common as scientific and research arenas, but false dichotomies among them have often been established and perpetuated. Integration and collaboration suffer from the familiar compartmentalization and vertical organization of academic disciplines. It is important to distinguish among them in areas of interest, techniques, and expertise, but each uses the scientific method to seek broad truths that are reproducible and generalizable as distinguished from clinical practice, which addresses the special circumstance of the individual patient.
For HIV/AIDS, biologic and clinical science have provided the technical armamentarium to treat the disease processes and require a fundamental understanding of disease pathogenesis and therapeutic tools such as pharmacologic agents. Without this information and its appropriate application, therapeutic agents would not have become available and success would not have been possible. Although many therapeutic discoveries are serendipitous, progress in biologic and clinical research is more commonly the result of the deductive scientific process of hypothesis generation, rigorous testing by observation or experimentation, and establishment and confirmation of acceptable levels of proof. Within the area of medication adherence, and specifically in HIV/AIDS, biologic and clinical research has largely focused on the characteristics of drugs, virus and immunology, and virologic and immunologic outcomes (eg, achieving a nondetectable viral load and increasing the CD4 cell count) as well as, more recently and increasingly, on clinical outcomes. Biomedical scientists are generally unfamiliar with the strategies and systems of analysis of behavioral and social science research. Behavioral and social science research has often been characterized as “soft” science and not possessing the rigor or certainty thought to be associated with “hard” biologic science (even though the most “hardened” biomedical scientist would have to accept uncertainty and changing research concepts and results). Still, among many biomedical scientists, adherence is seen as a delivery system for the more interesting issue of antiretroviral resistance and the study of adherence is still viewed as soft.
Behavioral science research follows the scientific paradigm and aims to provide for new knowledge with the ultimate goal of improving patient outcomes in the aggregate. In these activities, as is the case with biologic and clinical research, the mission of creating new knowledge that might benefit large populations predominates. Similar to biomedical research, behavioral science uses the scientific method and strives to be rigorously constructed and adhere to scientific standards of proof. The process, however, tends to be inductive and often within the framework of predetermined theoretic models of behavior. These can sometimes be rigorously tested, and their utility in specific settings can be convincingly demonstrated. They have particular applicability to clinical settings in which technical mastery of biologic issues must be wedded to patient behavior. Models of behavior and behavior change have been developed to guide strategies to promote healthy behaviors such as reduction of HIV transmission risk and medication adherence and to facilitate effective adaptation to and coping with patients' illness and disease.24 In my own experience and that of my clinical colleagues, these models are extremely useful constructs for thinking about behavioral change and designing interventions. There is a wide and overlapping array of models, however, and each model has its own advocates, tends to focus on specific behavioral attributes, and carries its own set of limitations.25
The clinical care setting is a site of particular relevance for issues relating to medication adherence. Behavioral scientists possess behavioral expertise in assessing and enhancing adherence that is often lacking among clinicians, yet behavioral scientists are not likely to appreciate fully the complexities of the clinical care environment and, most importantly, the special bond between patient and clinician. As is the case regarding the lack of organized understanding and appreciation of behavior among biomedical counterparts, behavioral scientists attempting to carry out research in the clinical care setting are usually, at least initially, unschooled in the biologic and clinical issues and strategies of clinical diagnosis and treatment as well as in clinical reasoning. These, however, might be crucial in understanding, measuring, and enhancing medication adherence. Assessment or measure of successful outcomes in HIV therapy illustrates this well. Among behavioral scientists, most measurements focus on behavioral practices such as the number or proportion of pills taken or missed and physical and mental symptoms of behavioral and social functioning. Among biomedical researchers and clinicians, “objective” and biologic measures such as virologic suppression, generation of resistant mutations, immunologic recovery, cessation of disease progression, and decrease in mortality are seen as most important, with adherence as a means to these ends. Although behavioral outcomes are themselves valued, an emerging consensus indicates that behavioral outcomes must be integrated with these final biologic and clinical products of adherence behavioral practice.
Most social scientists largely view populations as the unit of study and measure, placing medication adherence in a broader social and societal construct and striving to understand behaviors in the context of even more complex social, cultural, political, and economic realities. There is recognition that medication adherence is part of the larger context of HIV infection and disease. Susceptibility to HIV infection and subsequent therapeutic outcomes is not only an issue of pathogen versus host, potent medications, and personal behavior; it is also an issue of human rights, social inequalities, cultural differences, poverty, racism, exploitation of women, and dismissal of those with substance abuse and mental illness. Each of these, individually or taken together, may powerfully influence biology and behavior and, ultimately, clinical outcomes.
Many social scientists believe that existing behavioral theory-driven research in antiretroviral therapy adherence principally describes behavior change in terms of individual level factors but assert that HIV prevention and treatment must function in a larger arena and need structural interventions with broader theoretic models that address the social and environmental context.12 This is certainly true, but focus only at this level can miss the individual nuances of behavior and biology that constitute health behavior and the clinical interaction. An exception might be in anthropologic qualitative research, in which meaning and belief are sought to help explain behavior; however, paradoxically, many clinicians might view this as too subjective and not sufficiently quantitative. In addition, as is the case with behavioral scientists, the biologic and clinical information that may have an impact on approaches and outcomes is often not within the expertise of social scientists, and proposed approaches may miss the mark. Nevertheless, the insights of social science are often crucial to the care of individual patients.11-13 This is particularly true in the complex social and cultural setting that often characterizes HIV disease. Indeed, bringing the broader assessment and attention to social and cultural issues into the evaluation and care of patients, particularly those with HIV disease, is essential and still often inadequate.13,26
CLINICAL PRACTICE AND CLINICAL JUDGMENT
Clinical practice and its associated use of clinical judgment differ from biomedical, clinical, behavioral, and social research in a fundamental way. Although scientific knowledge and the scientific method are used, clinical practice and clinical judgment are a blend of scientific information, experience, and intuition.27 Medicine is far more than a body of scientific knowledge and a collection of well-practiced skills, although both are essential. Medical care requires a complex synthesis of biologic and behavioral expertise in a social context and with a strong dose of compassion. Its central mission, and that of its practitioners, is the care and maintenance of the health of the individual patient with or at risk for disease. It is that mission which ties the practitioner and patient together through an invisible but powerful bond of trust.16,20,25 Clinicians know that each patient is different and that a standardized approach must be nuanced and flexible to accommodate and work from these differences. Central to the approach of clinicians is the deductive scientific method, in which facts are assembled and hypotheses formally or informally constructed and plans are defined, carried out, and monitored for benefit or lack thereof. Apart from broad concepts, the clinical decision-making process is empiric and pragmatic and is not constrained by theoretic constructs or broad and generalizable truths. The clinical process is learned via case method evidence from many sources (eg, historical, physical, laboratory), all resulting in a synthesis of problems into a plan of action that is tailored to each patient. With regard to antiretroviral therapy, this has been represented in the now widely held belief and practice of individualization of therapy,14,28 in which stage of disease, CD4 cell count level, underlying medical history, and “patient readiness” are all factored into the decision to start therapy and the choice of drug regimen. The danger is that such individualization may be too narrowly informed and focused and that intuition and clinical judgment may be influenced by group stereotypes and heuristics and not sufficiently wedded to sound evidence.
Clinicians learn that therapeutic success is driven by biologic factors. Although enormously appreciative of the advances in HIV therapeutics brought about by biomedical and clinical research, clinicians usually appreciate that the drug development process targets patient populations most likely to succeed by virtue of biologic and behavioral parameters and that results in clinical practice do not generally approach those in highly restrictive research studies and may not be applicable to individual patients with whom they struggle to achieve success within the clinic.
Similarly, practitioners may judge that broad behavioral principles and theoretic frameworks as well as experimentation in behavioral and social science are not applicable or relevant in the clinical arena in which they work. They may believe that they do not fully capture the great individual variability and complexity in patient behavior and immediate social realities faced by patients by creating categories and frameworks that seem rigid or superficial. When behavioral science is applied to patients, many medical practitioners find it confusing, impractical, and, often, too qualitative. The multiplicity of behavioral models characteristic of behavioral science is illustrative. This, in part, may be overcome by the development and implementation of behavioral strategies and techniques that more closely fit those used in clinical care24 and improvement in training in assessing and relating social and cultural patient realities to patient care.26 Clinicians receive formal training in disease biology and diagnosis and treatment and are expert in these areas but are largely expected to acquire or to possess sufficient behavioral expertise, appreciation of social context, and compassion to carry out their clinical mission.13,26 To be fully effective in the complex world of HIV illness and disease, clinicians should receive training in areas of behavioral and social science relevant and necessary for clinical practice, including medication adherence (this has been defined as “clinical behavioral and social science”).13 From personal experience and observation, it is clear that learning from the expertise of behavioral and social scientist colleagues, formally and informally, can fill gaps in clinical training and enhance clinician and patient success in promoting medication adherence.
Finally, it is important to appreciate that clinicians are protective of their patients' health and safety. Although they understand and embrace the utility of biomedical, clinical, behavioral, and social science research and may base clinical practice on the results of such research, in the context of the relationship with an individual patient, they may be wary of any research, particularly if it does not offer a direct benefit to or may be perceived as harmful to their patient. This dichotomy is particularly felt by clinicians who care for patients and also engage in clinical research.
THE PATIENT PERSPECTIVE
HIV medication adherence and its improvement, as with so many other issues during the HIV/AIDS pandemic, requires researchers and clinicians to appreciate that the nature of HIV disease itself and needs of people living with HIV/AIDS have been the most valuable teachers. All relevant scientific disciplines and clinical practitioners receive their most important input regarding medication adherence from the details of HIV disease and the lives of people living with HIV disease and AIDS. Understanding the biology of HIV, natural history of HIV disease, and pharmacology of the drugs that inhibit viral replication has provided the keys to unlocking the doors to effective therapy. The patient and his and her life experiences, culminating in those with HIV disease and its associated illnesses, have provided the most meaningful and accurate lessons about the use of these potent therapies through medication adherence. In the midst of discussion about clinicians and researchers, the importance of eliciting patients' perspectives and designing adherence interventions reflecting patients' perceptions and circumstances cannot be overemphasized. This has been true in designing the most successful interventions to enhance adherence in the developed world over the course of HIV therapy and is a crucial lesson learned and to be applied, as illustrated in several articles in this supplement, as the massive and historic rollout of antiretroviral therapy in resource-limited settings moves forward.
ADHERENCE AND CHANGES IN REGIMEN COMPLEXITY AND RESISTANCE
Although basic principles of adherence behavior and structural and social forces affecting adherence have been elaborated, it is important to appreciate how the biologic and clinical care aspects having an impact on adherence have continued to change since the early days of success of highly active antiretroviral therapy (HAART). Understanding of adherence behavior and HIV biology and therapeutics has become increasingly complex, and simple therapeutic schema cannot capture the depth or sophistication of each. As new agents appear yearly, others develop unrecognized side effects, and regimen and treatment strategies change and sometimes return to previously held paradigms. More than 20 licensed drugs are now available in 4 classes aimed at 3 viral targets, and more drugs and new targets are in development. In the Nathan Smith Clinic at Yale-New Haven Hospital, among 800 patients, more than 100 different regimens are being prescribed (M. Kozal, MD, personal communication). Always complex and filled with barriers and impediments, HIV creates additional pitfalls.
The relation between adherence and resistance is evolving and is another illustration of the interrelation between biology, behavior, and social context. The initial rather straightforward construct of necessity for >95% adherence to achieve acceptable levels of success of viral suppression23 is now falling away as the subtleties of biology and pharmacology uncover new realities. It is universally agreed that high levels of adherence are associated with more viral suppression and should be vigorously promoted, with systems put in place for the accomplishment of this goal. The relation between adherence and HIV drug resistance is more complicated than initially assumed, however. For individuals with remaining detectable viral loads who are not fully suppressed, resistance mutations may increase with increasing levels of adherence as a function of replication in the presence of subtherapeutic levels of drugs.29,30 Further, this may vary by the individual pharmacologic properties of different drugs in a regimen and by host pharmacogenetics. Each agent in a regimen may have different levels of vulnerability to resistance at different levels of adherence (see Fig. 2). For nonboosted protease inhibitor-based regimens, most drug resistance occurs in patients who take most of their medications, with a bell-shaped curve depicting the relation between adherence and resistance peaking at 70% to 80%. For more currently used ritonavir-boosted protease inhibitor regimens, however, more limited resistance is likely at any level of adherence. This is contrasted with nonnucleoside reverse transcriptase inhibitor regimens, where resistance mutations are uncommon in highly adherent patients but likely to be common in patients with any level of adherence, resulting in incomplete viral suppression. These differences in regimens and resistance potential may occur while on therapy or at its discontinuation, because the tail of therapeutic levels may differ, exposing some drugs with longer half-lives to the possibility of monotherapy and continued viral replication in the face of subtherapeutic or absent levels of other drugs in a regimen. Further, because of drug-drug interactions and differential adherence to individual drugs within multidrug regimens, different drug combinations may have different adherence/resistance dynamics. Finally, the nature of specific resistance mutations and their ability to produce low- or high-level resistance singly or in combination with other mutations also affect clinical outcome differently. How these new biologic and clinical insights affect behavioral and social science constructs and strategies with regard to HIV medication adherence and its enhancement is not yet clear. Such a complex changed paradigm must be incorporated accurately into clinical practice as well as into behavioral adherence assessment and enhancement strategies. The population effects of these new resistance paradigms are likely of greater importance as well, particularly in resource-limited settings, where antiretroviral rollouts are occurring on a massive scale, with resistance-prone regimens that might be quite vulnerable to adherence lapses.
Medication adherence requires expertise from all these domains and acceptance of the contribution of each. As is the case with medical care in the broadest terms and, more specifically, HIV therapeutics, adherence needs to be addressed in an expansive biopsychosocial context. No single area of expertise or discipline can independently claim to have been solely responsible for the stunning success of antiretroviral therapy or for its continuation. Appreciation of these complexities and increasing levels of interdisciplinary collaboration are essential to understand HIV/AIDS therapeutics and medication adherence and to the success of interventions for their improvement. To accomplish this, cutting across existing vertical domains of expertise and professional labels and language is essential. Maintaining professional expertise in a specific discipline and working in a multidisciplinary format with other disciplines is a considerable challenge but one that can be accomplished successfully (see Tables 1 and 2).15 For fruitful, comfortable, and productive collaborations to flourish, behavioral and social scientists need to know more about the biomedical and clinical world, and those in biomedical and clinical settings must reciprocate. Communication and language need to be free of jargon and mutually comprehensible. Behavioral and social scientists need to acquire an appropriate level of technical biomedical information about the nature of HIV disease, its natural history, clinical manifestations, and familiarity with HIV medications, not in the technical detail required by biomedical researchers and clinicians but in that required by patients (eg, how they work, when they are prescribed, how they are taken, what side effects are to be expected). Further, familiarity with and understanding of the realities of medical and clinical practice settings and strategies are necessary. Finally, understanding and appreciating how clinicians think and work are essential. Conversely, biomedical researchers and clinicians need to know and integrate with their own expertise an array of features of behavioral and social science research and expertise that can inform clinical research and clinical practice and improve the lives of people living with HIV disease. No disease better exemplifies the inextricable bonds between biology, behavior, and culture than HIV/AIDS, nor is any other more likely to break through and to transcend the boundaries that separate them.
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