Adherence in AIDS clinical trials: A framework for clinical research and clinical care

J Clin Epidemiol Vol. 50, No. 4, pp. 385-391, Copyright 0 1997 Elsevier Science Inc.

1997

0895-4356/97/$17.00 PII SO895-4356(97)00041-3

ELSEVIER

Adherence in AIDS Clinical Trials: A Framework for Clinical Research and Clinical Jeannette *VA

‘DEPARTMENTS CONNECTICUT

OF INTERNAL HEALTHCARE

R. Ickowics’a* and Andrew

Care

W. Meisler’

MEDICINE AND PSYCHOLOGY, YALE UNIVERSITY, NEW HAVEN, CONNECTICUT, AND SYSTEM AND DEPARTMENT OF PSYCHIATRY, YALE UNIVERSITY, NEW HAVEN, CONNECTICUT

ABSTRACT.

Assessment of adherence within AIDS clinical trials is a critical component of the successful evaluation of therapeutic outcomes. Poor medication adherence can result in the misinterpretation of clinical trial data. Research on factors affecting adherence in AIDS clinical trials has been scarce, and few investigations have evaluated strategies for enhancing patient participation. One reason may be the absence of a conceptual framework to guide research. Consistent with previous research on medical adherence, we propose a framework whereby factors affecting adherence in AIDS clinical trials can be categorized as characteristics of the: (a) individual, (b) treatment regimen, (c) patient-provider relationship, (d) clinical setting, and (e) disease. This framework is used as a heuristic for reviewing studies that examine factors affecting adherence in AIDS clinical trials. Suggestions for future research and clinical intervention are provided. These efforts are timely because adherence is now the center of attention in discourse about the efficacy of the new class of protease inhibitor drugs; non-adherence has been linked to viral resistance and drug failure. Efforts to identify factors that influence adherence to AIDS clinical trials can inform future attempts to improve adherence and retention. Better adherence protects the scientific integrity of AIDS clinical trials, promoting more efficient and accurate evaluations of therapeutic value. Accelerated access to new treatments may follow, ultimately enhancing patient care. J CLIN EPIDEMIOL 50;4:385-391, 1997. 0 1997 Elsevier Science Inc.

KEY WORDS.

Clinical

trials,

HIV/AIDS,

adherence,

INTRODUCTION There effective

is a great therapies

sense

of urgency

for HIV-related

in the illness.

search

for safe and

Physicians,

scien-

tists, and activists agree that treatments must be identified, tested, and widely distributed as quickly as possible. Debate has emerged on how best to meet the sometimes conflicting demands between accelerated access to new drugs, protection of individuals, and scientific integrity of AIDS clinical trials. Regardless of position on this debate, there is consensus that accurate evaluation of drug efficacy and toxicity is crucial. Assessment of adherence’ within AIDS clinical trials is a critical component of the successful evaluation of therapeutic outcomes. Poor medication adherence-typically defined as taking less than 75-80% of prescribed medication-can result in the misinterpretation of clinical trial data [I]. For example, if individuals fail to adhere to a drug ‘Address reprint requests m: Jeannette R. Ickovics, Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208025, New Haven, Connecticut 06520-8025. Accepted for publication on 14 October 1996. ‘The terms adherence and compliance can be used interchangeably to reflect the extent to which an individual carries out the requirements of a clinical trial; the term adherence was selected to reflect a greater sense of patient autonomy in carrying out the prescribed behaviors.

compliance,

medication

regimen because of intolerable side effects, there may be an underestimate of toxicity. If individuals terminate drug use because they feel that they are not getting better or they are indeed getting sicker, drug effectiveness may be underor overestimated. Poor adherence that results in an underestimate of the treatment effect may lead to a concurrent overestimate of the drug dosage required to achieve clinical benefit. Poor adherence within clinical trials may also reduce the ability to detect treatment effects when they do occur, resulting in failure to identify a potentially effective drug. Because dose delays and dose omissions are the most common forms of non-adherence, statistical power is affected by lowering the average response and adding variance to the

outcome

[2]. To

enhance

statistical

power,

the

sam-

ple size in clinical trials must be increased, resulting in longer and more expensive trials. Rates of non-adherence with medical regimens range from 15-93%, with average rates of non-adherence estimated to be 50% (e.g., [3-51). The costs of non-adherence may

be substantial

in terms

of illness,

relapse

and

recovery

[6]. Most relevant to a discussion of HIV/AIDS is the reemergence of multi-drug resistant tuberculosis (MDR-TB); the MDR-TB epidemic in the 1990s evolved, in part, because of patients’ failure to adhere to medication regimens for

prevention

or treatment

[7,8].

J. R. Ickovics and A. W. Meisler

386

Concepts

rs Subslance

Characteristics of the Trial and Treatment

Patient-Provider

Clinical

Use

Measures

Setting

::: Trial phase Assignment Regimen duration l Regimen complexity ’ Side Effects

‘Patient perceptions of HCP’s technical skill ‘Affective tone of relationship l Communication * Overall satisfaction

l l

l

Transportation ’ Childcare l Clinical environment l Scheduling l Confidentiality

* Symptomatology ’ Immunologic Status

l

L

Sociodemographics

Psychosocial

Factors

* Perceived efficacy of treatment * Knowledge 01 trial regimen l Intent to adhere and pas1 adherence * Perceived cost and benefits of regimen l Social support

FIGURE

1. Model

or recruitment,

adherence,

Adherence in clinical trials may be at least as variable as that observed in clinical practice [9]. Patient adherence may be a more important source of variability in clinical trial outcomes than the drug formulation itself. Peck [lo] suggested that drug formulation may account for 20% of variability in drug response, whereas adherence may account for 50% of the variability. In a review of six randomized, placebo-controlled studies, three of six studies demonstrated a main effect of drug versus placebo, whereas five of six studies demonstrated a main effect for adherence to treatment (even if that treatment was placebo) [ 111. Adherence is an important predictor of morbidity and mortality in clinical trials of drugs for cancer [12] and coronary heart disease [13,14]. Despite the critical importance of adherence for successful treatment as well as for research integrity, there has been limited information about predictors of adherence in AIDS clinical trials [15]. A FRAMEWORK APPLICATION

FOR

RESB4RCH

and

retention

in AIDS

clinical

trials.

is proposed. Factors affecting adherence can be categorized as characteristics of the: (a) patient, (b) treatment regimen, (c) patient-provider relationship, (d) clinical setting, and (e) disease. This framework can be used as a heuristic for reviewing extant studies and to guide future research on factors affecting adherence in AIDS clinical trials (see Fig. 1). Based on this framework, we suggest research and intervention strategies designed to better understand and enhance patient adherence to AIDS clinical trials. We will focus primarily on medication adherence over the course of a clinical trial (i.e., taking the study drugs in the correct dose at the correct time) and continuation of therapy for the length of the trial. Adherence to AIDS clinical trials also includes attending scheduled appointments, examinations and lab tests for evaluation, following prohibitions on taking other medications or substances while enrolled in the trial, and clinical follow-up that may range from 3 months to 3 years or longer [16].

AND

Drawing on previous theory and research (e.g., [3,4]), a multifactorial framework for adherence in AIDS clinical trials

Patient

Characteristics

Patient characteristics medication adherence

or individual factors associated with include patient knowledge [ 171, be-

Adherence

in AIDS Clinical

387

Trials

liefs about the disease and satisfaction with treatment [18], and social support [19]. Among patients enrolled in an AIDS clinical trial, those who were most adherent to treatment regimens reported greater social, emotional and economic support from study staff and significant others [20]. Client-centered factors associated with extreme adversity have had a negative impact on clinical trial participation: unemployment, homelessness, incarceration, being the victim of a violent crime, and hospitalization for mental illness or substance abuse [21,22]. Once enrolled, however, there were no significant differences in retention and adherence to follow-up appointments between those with and without a history of injection drug use [22-241. However, those who are actively using drugs may have more difficulty adhering to treatment regimens and attending clinic appointments [22]. Demographic factors such as patient sex and race appear unrelated to adherence in AIDS clinical trials.

Characteristics

of the Trial

and Treatment

Regimen

Adherence to medications declines as the number of drug treatments, frequency of dosage, complexity and length of the therapeutic regimen increase [3,25,26]. Features of the medication regimen, including the medication’s taste, ease of administration, frequency of dosing, number of pills per dose per day, and averseness of side effects, can also influence adherence behavior. Adherence may also be influenced by concerns about assignment to a placebo condition, and concerns about the potential short- and long-term side effects of experimental medications. Insofar as AIDS clinical trials reflect heterogeneous treatment regimens, more information about how trial characteristics affect adherence is needed. Preliminary data from our research group indicate that adherence differs by specific treatment (i.e., adherence to dd1 < adherence to AZT or ddC), and that adherence to anti-retroviral combination therapy is better than adherence to prophylaxis for opportunistic infections (83.4% versus 68.6%) [27]. An understanding of differential adherence and retention across protocols is essential in the consideration of the design, execution, and analysis of clinical trials. Protease inhibitors, the newest class of treatments for HIV disease, appear to be a major treatment breakthrough for persons with HIV disease [28,29]. Data from ongoing clinical trials indicates that the protease inhibitors can stop HIV viral replication. The study of adherence to these new drugs will be critically important with regard to the evaluation of their long-term effectiveness. Currently, frequent dosing (i.e., 20 pills per day) is required to maintain suppression of viral replication and to prevent the development of resistance. Critical questions remain about whether the salugenic effects persist under conditions of dose omission or drug termination. And some investigators have expressed concern about viral resistance and enhanced .HIV replication if the treatment protocol is modified or terminated [30].

Documenting adherence to protease inhibitors and understanding the factors that promote or deter adherence will have a major impact on clinical trials and the future of clinical care for persons with HIV.

Patient-Provider

Relationship

Aspects of the patient-provider relationship also influence adherence behavior to a variety of medical regimens [ 18,3 I]. Patient adherence is enhanced when physicians provide clear explanations, encouragement, reassurance, support, and systematic follow-up. Initial willingness to participate in a clinical trial depends on communication about informed consent between a patient and provider [32]. Few studies have examined the role of patient-provider relationships in adherence to HIV-treatment protocols. This may be important in AIDS clinical trials where 7 1% of patients in one study cited “rapport with the study team” as a reason for remaining in the trial [33]. Clearly, more research is needed given a strong literature linking patient-provider relationship and adherence in studies in other domains.

Clinical

Setting

Features of the clinical setting are also important in patients’ adherence to prescribed regimens [34,35]. Programs that provide services and incentives, such as transportation, child care, health education, drug rehabilitation, and storage lockers, have been successful at recruiting and maintaining a diverse patient population in AIDS clinical trials [21]. Other features of the setting, including location, physical environment, flexible clinic hours, and privacy, may affect adherence in AIDS clinical trials. It is important to note that patients’ perception of the clinical setting may be more important than the objective differences between settings (e.g., perceived ease of access to clinic versus distance between home and clinic). In a study of skin testing for tuberculosis, investigators encouraged returns for readings (3 days later) by providing patients with alternative reading sites, flexible hours, travel reimbursements, and dedicated staff [36]. Improving access to clinic sites may have contributed greatly to a high patient return rate of 91% (552/607), in contrast to previously documented return rates of 20% locally. Finally, it is notable that 37% of those who returned were subsequently enrolled into clinical trial protocols.

Features

of the Disease

The role of disease-related factors (e.g., severity, chronicity) in adherence to treatment regimens has been-wellestablished [37,38]. Previous research indicates that adherence rates are lower for patients with chronic disease, and that medication adherence significantly declines over the course of treatment.

388

J. R. Ickovics and A. W. Meisler

HIV/AIDS presents unique features likely to influence adherence in clinical trials. First, HIV presents a more imminent threat of mortality than many other diseases (e.g., diabetes, hypertension). However, persons with HIV often remain asymptomatic for years, limiting noticeable immediate gain from enrolling in a treatment protocol. Some patients may drop out of one trial to enroll in another trial of a newer, more promising drug. Concerns about patient confidentiality may be heightened by the fear of stigma; this can affect adherence if the patient does not want to be seen at an AIDS clinic, does not want to be seen taking medication, or is reluctant to take time off from work for clinic appointments [21]. Finally, persons with HIV are often taking medications to prevent or treat HIV-related illness and this may impact on adherence to the other medications taken as part of a clinical trial [39]. In one study of three large HIV clinical trials, 85% of individuals were taking one or more drugs besides those required in the protocol; the average number of concomitant drugs ranged from 3-7 per month [40]. The use of concomitant medications among patients in AIDS clinical trials may influence adherence to drugs prescribed in the trial, and must be taken into consideration when evaluating therapeutic effects. In one of the few studies of disease-related factors in adherence to HIV/AIDS treatment, adherence to antiretroviral combination therapy was significantly less among patients with lower CD4 cell counts, suggesting that as disease becomes more severe, adherence may be compromised [41]. This may be due to several factors, including physical and cognitive limitations, loss of belief in the efficacy of treatment, and loss of social support with advanced disease. Features of the disease may exert important influences on patients’ adherence in AIDS clinical trials, and merit continued investigation.

Summary Patient adherence in AIDS clinical trials has been associated with a broad array of factors, including characteristics of the patient, treatment regimen, patient-provider relationship, clinical setting and disease state. To date, empirical research in these areas has been limited, and we draw conclusions based on a small number of studies. Additional research on these factors as well as the mechanisms by which they operate to affect adherence, patient health, and clinical trial outcomes is critical. Moreover, adherence to trials, in and of itself, may be important in our understanding of clinical outcomes associated with HIV.

RECOMMENDATIONS APPLICATION

FOR CLINICAL

Based on the proposed framework and previous empirical findings, programs can be designed in an attempt to en-

hance patient adherence in AIDS clinical trials [5,42,43]. First, at the level of the individual, clinical trials staff can provide counseling for patients and their families, and can assist in obtaining needed entitlements and other services (e.g., income assistance, housing, health care, transportation). Additionally, formal support programs can be conducted to enhance patients’ feelings of self#efficacy and problem-solving abilities with regard to HIV in general or specific to adherence in clinical trials. At the level of the treatment regimen, structured educational meetings with the study nurse and pharmacist are necessary to ensure that patients understand trial demands. Patients often have difficulty recalling even simple information about medications and health recommendations [44]. Thus, particularly with more complex protocols, careful and detailed patient education is vital with regard to medication scheduling, coordination with concomitant drugs, and accommodation of meal, work and sleep schedules. Provision of pill boxes, electronic beeper-reminders, or other devices may promote adherence. Aspects of the patient-provider relationship can be critical in promoting adherence in AIDS clinical trials. At the initiation of a protocol, regular meetings among investigators, clinical trials staff and other health care providers, and between staff and patients, must convey the importance of following the protocol requirements carefully, emphasize the required behaviors with rationale for their importance, and simplify the regimen (or description of the regimen) as much as possible [45]. During the trial, systematic tracking should be used, including reminders for follow-up appointments. Active monitoring of beneficial or toxic effects should be conducted with patients. Problems or side effects should be discussed, modifications made if necessary, and adherence to the (revised) protocol addressed directly. Regular communication and aggressive follow-up are essential to promote adherence. Even brief counseling sessions can be helpful if they provide information (e.g., about diagnosis, treatment, side effects), increase motivation to adhere (e.g., by persuasion, assistance with practical problems, providing reminder cues), modify schedule (when necessary and if possible), change contingencies (e.g., attention to side effects, reinforcement, increase visit frequency), and refer patients for additional help [5]. Finally, patient confidentiality and respect for privacy must be an integral part of the patient-provider relationship. In terms of the clinic setting, access to the health clinic for clinical trials can be facilitated in a number of ways: geographic proximity to high seroprevalence areas, transportation assistance, child care facilities at or near the clinic, comfortable and private waiting and examination rooms, and expanded clinic hours 1421. Improving clinic efficiency (e.g., shorter waiting times, scheduled appointments, expedited laboratory evaluation) can also improve adherence. Interventions can also address differences in disease state

Adherence

in AIDS

Clinical

Trials

and stress the need for early intervention. Understanding the natural history of HIV (e.g., long latency phase), and an individual’s place in the disease cycle is critical. Sensitivity to differences in symptom status and immune function are important, not only because of inclusion criteria for AIDS clinical trials, but also because of the recognition of how these changes influence patient care and individual assessments of health and illness. The use of concomitant drugs must be monitored given the risks for adverse drug interactions and to assess behavioral consequences. Overall, a combination of strategies will work better than individual approaches. Proactive attempts to improve patient adherence are in the best interest of clinical research and clinical care. It must be acknowledged that we have suggested strategies for enhancing adherence in the context of AIDS clinical trials. The resources for intervention will not be broadly available during standard clinical care; here, limited adherence to clinical recommendations may more accurately reflect patient behavior. Despite the potential for reduced generalizability, we maintain that enhancing adherence in AIDS clinical trials will provide the best data for recommendations to enhance the health and health care of persons with HIV.

METHODOLOGICAL

CHALLENGES

Investigators must confront a number of challenges in the conduct of valid and reliable research on adherence in AIDS clinical trials. First, there is no standard of measurement for adherence behavior itself. Nearly all previous studies have relied on patient self-report as an index of adherence. Millennia ago Hippocrates warned that physicians “should keep aware of the fact that patients often lie when they state that they have taken certain medicines.” Patient reports may be unreliable, particularly as the number of medications increases [45]. Collateral reports of adherence by a family member, friend or physician have been used in studies; however, these are limited by the extent to which the individual can actually observe the patient taking medications as prescribed. Pill counts have often been used in clinical trials; however, they likely overestimate actual pill taking [46,47]. Patients bring their pill bottles to each appointment, with the assumption that pills not in the bottle were taken on schedule; the number of pills taken are counted and compared to the number prescribed during that time period. Drug levels (e.g., serum or urine drug assays) and the use of inert biological markers (e.g., digoxin [48], phenobarbitone [49]) are considered “more objective” measures of adherence, but are unavailable for some drugs and may be distorted by the ingestion of medication just prior to a medical visit (i.e., “white coat compliance” [50]). Drug levels at any one time do not represent long-term, steady state concentrations [5 11. In addition, clinical measures such as successful health outcomes may reflect adherence, but the use of

389

clinical or functional outcomes may confound the measure of adherence with treatment efficacy [44]. The Medication Event Monitoring System (MEMS) uses a computer chip in the cap of a vial that records the precise date and time that the vial was opened and presumably when the drug was taken. Differences between MEMS and other measures of adherence have been documented, with self-reports and pill counts exceeding MEMS measures of adherence [2,52]. MEMS can provide information about patterns of drug taking, and as such provide an important tool in advancing our understanding of adherence behavior [51]. However, the use of MEMS is not a panacea; it is expensive and “pill dumping” can still occur. Measures of adherence can be manipulated by trial participants, often in an attempt to please the investigator. Future efforts to standardize assessment procedures, use of multiple measures within studies, and the development of standardized measures across studies, will contribute to advances in this area. It is important to note that accurate detection provides no insight into factors that influence adherent or non-adherent behavior. Research designs employed in adherence investigations have been simplistic to date. The majority of studies have been cross-sectional; therefore, little is known about the temporal relationships among predictors, how these relationships may change over time, or how adherence behavior itself may change in response to disease progression, habituation to medication side effects, and other factors. Few studies have included meaningful comparison groups which could lead to better evaluation of the generalizability of trial adherence to other patient populations. Data analysis strategies to examine the relative and reciprocal influences of multiple factors on adherence and retention have rarely been used. Potential interaction effects pose important challenges, and demand a thoughtful approach to data collection and hypothesis testing. Data collection efforts must be modified to account for diverse patient populations, accommodating patients with different social, sexual, drug use and economic backgrounds. For example, based on field testing, we have found that faceto-face interviews yield higher quality data than do survey measures. Interviews should be aided by the use of response cards, specific verbal instructions, and simplified question wording. All interviews must be available in English and other languages spoken by large segments of the local population (e.g., Spanish, Haitian Creole). Ideally, native speaking interviewers should conduct patient interviews. Horwitz and Horwitz [l] raise important considerations in the analysis of data from randomized controlled trials that rely solely on intent-to-treat analysis. Post-randomization changes may represent changes in health status or prognosis that would bias group comparison as originally randomized. However, there is also danger in failing to account for changes in clinical course that may occur independently or as a result of the trial. Clinical inquiry is a novel approach

390

J. R. Ickovics

that takes into consideration not only randomized group, but also patients’ clinical state and their adherence as part of the analytic plan. Differences in adherence between placebo and treatment conditions have been documented [53]. This differential non-adherence can severely bias estimates of treatment efficacy [54]. Despite these potential critical effects, adherence has largely been ignored in analyses of clinical trials results [55,56].

CONCLUSIONS The lack of a standardized “behavioral science component” to AIDS clinical trials presents the ultimate challenge to investigators of adherence. Unlike pharmacologic treatment protocols, which are standardized and thereby allow integration of data from multiple sites, the study of factors affecting adherence has been conducted almost exclusively at individual sites. Hence, sample sizes and statistical power have been limited. Published reports of clinical trials infrequently include detailed accounts of patient adherence and its measurement [57]. However, the potential medical and economic consequences of non-adherence within AIDS clinical trials are profound. Future efforts to incorporate the systematic study of adherence are needed. Identifying correlates of early adherence in clinical trials will be important in the development of strategies to maximize adherence [52], as past adherence has frequently proven to be the best predictor of future adherence [4,30,58]. This review suggests that characteristics of the patient, trial, clinic, patient-provider relationship and disease can influence adherence in AIDS clinical trials. Relatively little is known about the complex interactions among these characteristics. Efforts to identify factors that influence adherence to AIDS clinical trials can inform future efforts to improve adherence and retention. Better adherence protects the scientific integrity of AIDS clinical trials, promoting more efficient and accurate evaluations of drug efficacy and toxicity. Accelerated access to new useful therapeutics may follow, ultimately enhancing patient care. The authors gratefully acknowledge financial support from the National Institute of Drug Abuse (DA 08143-02), the National Institute for Allergy and Infectious Diseases (5 OUI AI 32766-02)) the Office for Research on Women’s Health (supplement to NIAID 5 OUI AI 32766-02), and he American Foundation for AIDS Research (7035014-RF; Scholar Award to the first author). We exrend thanks to Judith Rodin, Kathleen Ethier, Allison Merrill and Michael Rodriguez for comments on earlier drafts of this manuscript; to Rachel Fox-Tierney for manuscript preparation and research assistance; and to Dr. Gerald Friedland and the staff of the Yule-New Haven Hospital AIDS Clinical Trials Unit and the Nathan Smith Clinic for their support and encouragement.

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