JAIDS Journal of Acquired Immune Deficiency Syndromes:
Practical and Conceptual Challenges in Measuring Antiretroviral Adherence
Berg, Karina M MD, MS; Arnsten, Julia H MD, MPH
From the Division of General Internal Medicine, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY.
Funded partly by a Montefiore Medical Center Health Services Faculty Scholar Award to K. M. Berg and by a Center for AIDS Research grant (P30 AI51519) awarded to the Albert Einstein College of Medicine of Yeshiva University by the National Institutes of Health.
Reprints: Karina M. Berg, MD, MS, Division of General Internal Medicine, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467 (e-mail: email@example.com).
Summary: Accurate measurement of antiretroviral adherence is essential for targeting and rigorously evaluating interventions to improve adherence and prevent viral resistance. Across diseases, medication adherence is an individual, complex, and dynamic human behavior that presents unique measurement challenges. Measurement of medication adherence is further complicated by the diversity of available measures, which have different utility in clinical and research settings. Limited understanding of how to optimize existing adherence measures has hindered progress in adherence research in HIV and other diseases. Although self-report is the most widely used adherence measure and the most promising for use in clinical care and resource-limited settings, adherence researchers have yet to develop evidence-based standards for self-reported adherence. In addition, the use of objective measures, such as electronic drug monitoring or pill counts, is limited by poor understanding of the source and magnitude of error biasing these measures. To address these limitations, research is needed to evaluate methods of combining information from different measures. The goals of this review are to describe the state of the science of adherence measurement, to discuss the advantages and disadvantages of common adherence measurement methods, and to recommend directions for improving antiretroviral adherence measurement in research and clinical care.
Treatment adherence across diseases has been the focus of research for the past 4 decades, but interest in studying adherence has intensified during the era of combined antiretroviral therapy. The limitations of existing adherence measures have hindered progress in adherence research in HIV and other diseases, however.1 The use of different adherence measures can lead to discrepancies in conclusions about adherence rates and predictors of adherence. As the field of antiretroviral adherence research has evolved, the question of how to optimize adherence measurement for research and clinical care has emerged as a fundamental issue that must be addressed before potential solutions to the problem of poor antiretroviral adherence can be rigorously evaluated.
Optimizing adherence measurement in clinical and research settings is crucial for several reasons. In clinical settings, measures must be efficient, practical, and inexpensive, and precision may be less important than accurately identifying patients in need of interventions. HIV providers are urged to screen for suboptimal adherence with every patient at every visit,2 but this emphasis on adherence may have the unintended effect of promoting inaccurate self-reported adherence. Patients are most vulnerable to reporting bias, a form of social desirability bias, when they are reporting directly to health care providers from whom they may fear chastisement. Overestimated adherence rates can result in patient misclassification and lead to inaccurate targeting of adherence-improving interventions or delays in addressing adherence problems.
In addition to improving adherence reports in clinical settings, better adherence measures are needed for public health officials who rely on adherence prevalence rates and predictors of poor adherence to identify high-risk populations for adherence interventions. Better measures are also needed for the growing number of randomized trials testing the efficacy of different adherence-improving interventions. Adherence measurement challenges for investigators are different from those encountered by HIV providers. Lack of precision in adherence measures may be causing adherence differences between study arms in controlled trials to go undetected. Finally, antiretroviral adherence is crucially important in resource-limited settings, where second-line medication options are limited or virtually nonexistent and suboptimal adherence must be identified before the development of resistance.3
Commonly used methods for measuring adherence include indirect measures, such as self-reports, electronic drug monitoring (EDM), pill counts, and pharmacy refill records, and direct measures, including detection of drugs or drug metabolites in plasma. Advantages, disadvantages, and key challenges of commonly used adherence measures are listed in Table 1. Although directly observed therapy is sometimes considered a method for measuring adherence because it is primarily evaluated as an intervention, it is beyond the scope of this review. Although each method has conceptual, empiric, and logistic advantages and disadvantages, the diversity of measurement methods has contributed to the complexity of the field. The goals of this review are to describe the current state of the science of adherence measurement, to discuss the advantages and disadvantages of commonly used adherence measurement methods, and to recommend future directions for improving the measurement of antiretroviral adherence.
Self-report is the most commonly used adherence measure in clinical and research settings because it has a low staff and respondent burden, is inexpensive and flexible, and takes little time. In clinical settings, self-report allows for a discussion of reasons for missed doses and potential solutions. The validity of self-report for antiretroviral adherence has been demonstrated in 2 recent reviews. A systematic review of 77 studies using various self-report adherence measures reported that self-reported adherence was significantly correlated with HIV viral load in 84% of recall periods.4 In a meta-analysis of 65 studies, despite significant heterogeneity in point estimates, the odds of having a detectable HIV viral load was more than double in nonadherent patients compared with adherent patients (adjusted odds ratio [ORadj] = 2.31, 95% confidence interval [CI]:1.99 to 2.68).5
Because of its numerous advantages, self-report is the most likely candidate for widespread use. There are several unresolved measurement issues regarding the psychometric characteristics of specific self-report items, however. Currently, numerous different adherence questions are used in clinical and research settings.4 Most commonly, respondents are asked to report the number of doses they missed during a specified recall period or to estimate their overall percent adherence on a visual analogue scale. Response tasks may also include qualitative estimates of overall adherence, reporting the number of days of perfect adherence in the prior week, recalling when the respondent last missed a dose, or determining the number (or proportion) of doses (or pills) missed (or taken) over a specified recall period. Substantial variation also exists in the relevant time frame, with recall periods including the past 1, 3, 7, or 30 days.4 Response options may utilize a Likert6-8 or visual analogue9-11 scale and may be close-ended or open-ended. Some self-report measures consist of a single item, some are scales,12 and some questions assist the respondent with visual aids or anchors. Data suggest poor agreement between different self-report adherence measures.10,12-15 The range of self-report items used makes it difficult to compare results even among studies that all use self-report.
Another important unresolved methodologic issue is how to mitigate the “ceiling effect,” or the tendency of self-reported adherence to be positively skewed. This bias increases the risk of patient misclassification and presents analytic challenges for investigators. Although often attributed to social desirability bias, the ceiling effect may be influenced by other factors such as question misinterpretation and poor recall.16,17 For example, if a respondent is asked about the number of missed pills but answers about the number of missed doses, adherence would be overestimated. Alternatively, because recall for events remembered is more accurate than for those forgotten,18 patients may overestimate adherence because of differential recall. Because of the ceiling effect, self-report is often considered specific but not sensitive for diagnosing poor adherence.19 Some data suggest that self-reported adherence is inaccurate even among patients who report missing doses, however, and should thus not be considered 100% specific for poor adherence.20
Several interview techniques may lessen the ceiling effect associated with self-reported adherence. It has become standard practice in clinical and research settings to introduce adherence questions with a statement that normalizes nonadherence by acknowledging the challenges of regular medication taking.21 Some research suggests that patients and research participants may be more candid about their behavior when answering questions anonymously on a computer screen instead of in a face-to-face interview. Computer-assisted self-interview (CASI), which can include an audio component that eliminates literacy requirements, has been shown to increase reporting of numerous socially undesirable or stigmatizing behaviors in various populations.22-24 Although CASI has be shown to be feasible in clinical settings25 and has become popular for measuring adherence in research settings, data examining the effects of this method on response rates or validity are lacking.
Two potential directions for future investigation may provide insight into ways to improve self-reported adherence. The first is cognitive interviewing, which was developed through collaboration between survey methodologists and cognitive psychologists. Cognitive interviewing is the study of how targeted audiences interpret, mentally process, and form responses to survey questions, with an emphasis on potential biases in this complex process.26,27 In a study by Schneider et al,28 cognitive interviews of adherence questions revealed that complex recall tasks and estimation of percentages were particularly challenging without the help of a trained interviewer. Because the investigators were planning to use a self-administered survey, the results of the cognitive interviews prompted them to change their questions to enable respondents to complete them on their own. With an enhanced understanding of how respondents interpret adherence questions and what strategies they use to recall information and formulate answers, better self-report questions that minimize response error can be developed and tested.
A second potential method for improving self-reported adherence uses item response theory to combine information from multiple questions, or items, that measure a latent trait. Unlike classic measurement theory, which relies on the demonstration of reliability and validity, item response theory does not separate sources of error and combines items to create a composite “score.” Item response theory enhances precision by finely differentiating sources of error and evaluating each item's relation to the construct of interest.29 Because of its advantages over classic measurement theory, item response theory is increasingly being applied in health research.29,30
Before the adherence research community can converge on evidence-based standards for self-reported adherence, rigorous survey development and testing are needed. Fortunately, empiric testing of adherence questions is beginning to advance the science of self-reported adherence.6,14,31-33
ELECTRONIC DRUG MONITORING
EDM has been used over the past several years to measure adherence in several diseases34-37 and is frequently used by HIV researchers.38-40 EDM use monitoring devices, such as the medication event monitoring system (MEMS) cap, which is a pill bottle cap embedded with a microprocessor that records the time and date of each bottle opening as a presumptive dose. The cap stores the information until it is downloaded. Benefits of EDM include the ability to examine patterns of adherence and detailed aspects of medication taking, such as dose interval adherence.39,41-43 EDM is often treated as the adherence “gold standard” because it produces adherence rates with lower central tendencies and more variance than other measures and correlates more closely with HIV viral load than other individual measures.19,44
As the use of EDM has increased, several potential limitations have been characterized.45 Underestimated adherence can result from not using the cap consistently, which was reported by 36% of respondents in a sample.46 “Pocket dosing,” or the act of removing more than 1 dose for each bottle opening and pocketing the extra doses to ingest at a later time, can also underestimate adherence. This has been documented in a substantial minority (37% and 41%) of participants in 2 studies.46,47 In contrast, “curiosity opening,” referring to participants opening the monitored pill bottle without removing any pills, can lead to overestimates of adherence and was reported by 26% of participants in a study.46
For some participants, the monitor itself is an adherence-improving intervention.48 Recently presented data suggest that EDM induces an improvement in adherence, or “Hawthorne effect,” that is self-limiting after 40 days, even among those participants who report no such effect.49 If these data are replicated in other populations, solutions to the Hawthorne effect may lie in study design (a phase-in period to control for the 40-day effect) or data analysis (excluding the period of initial use). Finally, concerns about selection bias have been raised because MEMS caps are large, bulky, preclude flexibility in medication taking, and are not appropriate for those who use adherence aids such as pillboxes. Studies that exclude pill box users may be biased toward persons who are less comfortable taking medications in public, less adherent, and less resourceful regarding medication adherence.50
In addition to these participant-level variables, procedural, quality control, and data management issues can have profound implications on EDM adherence estimates. Examples of important procedural decisions include the optimal interval between study visits when data are downloaded and the best way to keep track of medication changes between appointments.51 The most vexing data management challenge is correctly identifying periods of nonuse that do not represent periods of nonadherence. These can include hospitalizations, incarcerations, periods of substance abuse treatment, times when someone else's pills are taken, or times when pills are taken from a different container. To aid in data management decisions, it is recommended to “modify” downloaded EDM data using responses to survey questions or by information from daily diaries kept by participants.47,52 In a study by Bova et al,46 the investigators report the numerous procedural, data management, and analytic challenges faced by the research team. Subjects' concerns about the accuracy of the electronic data led these investigators to conduct a small-scale quality-control check demonstrating that MEMS caps did not record every bottle opening. Finally, the high cost per person has made EDM feasible primarily for use in funded investigations.
Because of the high correlation between EDM adherence estimates and viral load and the ability to examine patterns of adherence over time and dose-interval adherence, EDM is currently the most promising objective adherence measure. Continued research on strategies to minimize measurement error should inform the establishment of empirically based guidelines for the use of electronic monitors to measure adherence.
Two pill-counting techniques for measuring adherence have been described. Announced pill counts take place at clinical appointments or scheduled research visits to which the patient brings his or her medication bottles. With the correct start date for the prescription, an adherence rate is simple to calculate, and these adherence rates have been shown to have moderate correlations with EDM and HIV viral load.19,53 Announced pill counts can be inaccurate if patients empty pill containers without ingesting any pills (“pill dumping”), if the accurate start date for the pill supply cannot be determined, or if patients use multiple pill containers, however. These participant-level and methodologic sources of error often lead pill counts to overestimate adherence.54,55 In contrast, unannounced pill counts used in research settings minimize the risk of pill dumping and have been shown in some studies to predict viral load slightly better than EDM.56,57
Because of the associated methodologic challenges and potential impact on the patient-provider relationship, pill counting is poorly suited to assessing adherence in clinical settings. Logistically, pill counting requires that the patient bring the pill bottle to the visit and that there is sufficient time to count the pills. The social desirability of the clinical interaction, combined with the foreknowledge of when the appointment is going to occur, may increase the risk of pill dumping. Most importantly, patients may perceive pill counting as threatening and suggestive of lack of trust in their self-reported adherence. An adherence measure that promotes an adversarial dynamic between the provider and patient should be viewed as counterproductive.58,59
PHARMACY REFILL RECORDS
Using pharmacy refill records to measure antiretroviral adherence is common among investigators in settings in which medications are likely to be covered by a single payer, such as Medicaid, the Veterans Administration, a universal health care system, or managed care organizations.60-63 Using pharmacy refill data in community-based settings with multiple payers is more labor-intensive but has been done successfully.64 Data from population-based pharmacy refill studies were instrumental in demonstrating the relation between antiretroviral adherence and important HIV-related clinical outcomes such as disease progression, hospitalization, and mortality.65,66
The underlying premise of this method is that if patients do not receive timely refills from the pharmacy, they are missing doses (as measured by prolonged periods between refills) or not taking the medication at all. This premise is invalid if patients are obtaining medications in alternate ways (eg, free samples, family members, friends) or from other pharmacies, however. Adherence rates from pharmacy refill records are determined by comparing actual with expected refill dates67 or by identifying “medication gaps,” defined as periods during which the patient's supply of medication is assumed to have been exhausted.64
This method of measuring adherence further relies on the major assumption that patients who receive timely pharmacy refills ingest their medications correctly. The validity of this assumption has been evaluated by examining the association between pharmacy refill adherence and biologic outcomes, and in several studies, pharmacy refill adherence has been shown to correlate significantly with HIV viral load.61,68-70 In a study by Grossberg et al,61 pharmacy data were used to examine those who self-reported 100% adherence. Forty-one percent of this population was nonadherent by pharmacy refill records. The reclassified group had significantly poorer virologic response than those who were adherent by self-report and pharmacy refill records. Another study found a significant linear trend of improved virologic response across ordered categories of pharmacy adherence. Specifically, 84% of individuals with pharmacy adherence ≥95% had an undetectable HIV viral load, whereas only 64% of individuals with pharmacy adherence between 90% and <95% achieved this clinical outcome (P = 0.001).69
The benefits of pharmacy refill records for measuring adherence are potential immunity to social desirability and reporting bias, ability to obtain population level data, and absence of patient-level burden. The major disadvantage of this method is its limited feasibility, which makes it inappropriate for adherence assessments in clinical settings. Despite their limitations, pharmacy refill records should be considered an important and valid adherence measure in population-based research.71
THERAPEUTIC DRUG MONITORING
Monitoring of drug levels has been considered a direct objective measure of medication adherence that is feasible in clinical and research settings.52,72 Low drug levels have been associated with self-reported nonadherence72,73 and virologic failure,74-77 but not all studies have shown a benefit to measuring serum drug levels. In a study by Liechty et al,75 an abnormally low drug level had a specificity of 88% for detecting adherence of 90% or less, but another study found that the addition of drug levels to a composite adherence measure did not improve the composite measure's ability to predict viral load.78
Therapeutic drug monitoring is most severely limited by a lack of technologic standardization. Procedures for sample collection, cross-validation of analytic procedures, and interpretation of results vary between settings.79-81 Further, factors other than adherence may affect drug levels, such as drug-drug interactions and diet. Finally, serum drug levels only reflect adherence over the past 24 hours, and patients who are aware of a planned visit may ingest medication in anticipation of the test.82
COMPOSITE ADHERENCE MEASURES
Several studies have shown that pharmacy refill and pill count adherence is lower than self-reported adherence and higher than adherence measured by EDM.9,19,44,53,56,83-87 This suggests that there is measurement error associated with each method and that true adherence lies somewhere between the extremes of these diverse adherence estimates. Because of the weaknesses of each measure, it is likely that the best method of assessing adherence includes multiple measures. Techniques that combine information from multiple measures reduce the error associated with any single measure. Although using multiple measures is not feasible in routine clinical practice, in research settings, investigators should be held to the most rigorous measurement standards. Although several authors have suggested that multiple adherence measures be used in research settings, data are lacking on how best to combine measures, how many measures to combine, or how many time points to include.88-90
Liu et al19 developed the first composite adherence measure in 2001. This measure involved a hierarchy of individual measures, starting with EDM data, and then filling in missing data with pill counts and, if necessary, self-reports to create a complete database. The composite score produced an adherence rate higher than that of EDM and lower than those of pill counts and self-reports. Compared with each adherence measure, the composite score was the most highly correlated with virologic response.
In contrast, in an effort to improve the sensitivity of measures to detect nonadherence, some investigators have examined composite scores based on combining information from survey questions. One study combined questions about psychosocial, clinical, and environmental characteristics that are associated with poor adherence and found that such a composite score had a sensitivity of 71% for detecting nonadherence.91 Another study found that a composite score based on questions about trust in physician, number of children, substance use, CD4+ T-cell count, and beliefs about antiretroviral medications had a much higher sensitivity for predicting nonadherence than self-report.33 With rigorous development and testing, composite measures have the potential to improve ease and accuracy of adherence measurement.
ADDITIONAL METHODOLOGIC ISSUES IN ADHERENCE MEASUREMENT RESEARCH
Types of Validity
Validity is an essential feature of psychometric instruments that is synonymous with truthfulness, authenticity, and accuracy.92 Traditionally, the major types of validity are content, criterion-related, and construct validity. Content validity evaluates how well the questions represent the domain they are intended to measure. Demonstrating content validity often involves having questions reviewed by experts and is more challenging when the construct is multifaceted or poorly defined. To have content validity, adherence measures should represent the many distinct forms of medication adherence, including refill adherence, dosing interval adherence, dietary requirements, and pill quantity adherence.93
Criterion-related validity refers to how well a measure correlates with an external criterion. Demonstrating this type of validity relies on the existence of an external criterion that accurately represents the construct of interest. Several investigators have chosen to demonstrate the validity of adherence measures by measuring the strength of their association with EDM.6,32,94 Given the numerous sources of measurement error with EDM, however, it cannot be viewed as a perfect external criterion. Efforts to minimize measurement error associated with EDM should provide a more accurate external criterion against which to compare new adherence measures. Although criterion-related validity is important, it provides limited information about how well adherence behaviors are actually being measured.
Finally, construct validity reflects how well the measure matches theoretic expectations and can be demonstrated by examining expected relations between variables or by showing that measures are reliable indicators of an underlying construct. Most adherence measurement studies demonstrate construct validity of individual measures by assessing the strength of the association between the measure and HIV viral load. Although commonly reported, the relation between adherence and viral load may be confounded by viral resistance, regimen potency, drug interactions, and individual differences in drug absorption and metabolism. Construct validity is often considered more important than criterion-related validity for complex behaviors such as medication adherence.
The 3 major types of validity were recently evaluated in a widely used measure of nicotine dependence, the Fagerstrom test for nicotine dependence.95,96 In this study, investigators examined content validity, or how well the questions represented the domain they were intended to measure, by compiling a list of published definitions of nicotine dependence and cigarette addiction and then comparing items in the Fagerstrom test against the published definitions. They found that the scale failed to assess several important domains of addictive behavior, including diminished effects with the same amount of tobacco and unsuccessful efforts to cut down. For an adherence measure, this might be analogous to capturing missed doses but not examining dosing intervals. In both examples, lack of content validity puts the measure at risk of misclassifying respondents.
Continuing to use smoking as an example, criterion-related validity can be demonstrated by examining associations between the Fagerstrom test for nicotine dependence and an external variable that reflects nicotine dependence, for example, the number of cigarettes smoked per day or nicotine dependence measured with a different instrument. These evaluations are comparable to using EDM as an external criterion for adherence measures. In both cases, choosing an appropriate external criterion is crucial.
Evaluating expected theoretic relations is the most common way to demonstrate construct validity. For the measurement of nicotine dependence, such theoretic relations might include those between nicotine dependence as measured by the Fagerstrom test and the following variables: likelihood of future abstinence, self-efficacy for quitting smoking, nicotine withdrawal symptoms, self-perceived nicotine dependence, and saliva cotinine (a nicotine metabolite). For adherence, theoretic relations might include expected associations between poor adherence and patient level variables (eg, depression, active drug use, poor self-efficacy) or biologic variables (eg, HIV viral load, development of resistance).
Although this approach may not be directly applicable to all adherence measures, it is important to consider broader measurement issues when developing and testing adherence measures.12 In particular, investigators should incorporate approaches to demonstrating the 3 major types of validity. The skillful incorporation of these concepts requires interdisciplinary collaborations with social scientists who have expertise in measuring complex behaviors.
Threats to Validity
Adherence is difficult to measure because it is composed of several distinct behaviors. Component adherence behaviors include obtaining refills, ingesting the right number of pills, ingesting pills within an effective dosing interval, and ingesting pills in accordance with dietary requirements. Often, individual measures only gauge a single aspect of adherence behavior, and this can threaten validity. This phenomenon, termed construct underrepresentation, occurs when a measure fails to assess important dimensions of the construct in question.92 Although some adherence measures, such as EDM, provide the ability to measure several aspects of adherence, the data are not generally analyzed this way.
In addition to construct underrepresentation, EDM and other measures are vulnerable to another validity threat caused by measuring unrelated constructs. The term construct-irrelevant variance is used when a measure contains excess variance attributable to unrelated constructs. For example, constructs that may be represented in adherence data but are unrelated to medication adherence include curiosity, which may cause a person for whom EDM is an adherence-improving intervention to open an MEMS cap without taking a dose, pocket dosing, and susceptibility to the Hawthorne effect. Construct-irrelevant variance can result from a measure that is too broad, the method of administration, or a deficiency in reliability. Future measurement research should address these specific threats to validity.
Although much existing research has focused on the critical issue of medication adherence, the specific field of adherence measurement is still young. In particular, the best way for health care providers to assess individual patients' adherence is unclear, and the most rigorous way for researchers to measure adherence is unknown. Research on measurement work has separate implications for investigators and clinicians. For adherence investigators, this work should inform adherence intervention trials by providing evidence on which to base key methodologic decisions, such as which adherence measures to use and how to optimize data collection. For clinicians, examination of ways to improve self-reported adherence has the potential to decrease provider frustration, minimize adherence misclassification, and promote timely adherence interventions. Rigorous adherence measurement research demands interdisciplinary collaborations between HIV researchers and social scientists. Improving measurement of antiretroviral adherence should allow the adherence community to embark on the development and evaluation of adherence-improving interventions with standardized and empirically tested adherence measures.
1. Nichol MB, Venturini F, Sung JC. A critical evaluation of the methodology of the literature on medication compliance. Ann Pharmacother
2. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Developed by the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents-A Working Group of the Office of AIDS Research Advisory Council (OARAC). Available at: http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx
?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1. 2006. Accessed October 3, 2006.
3. Gill CJ, Hamer DH, Simon JL, et al. No room for complacency about adherence to antiretroviral therapy in sub-Saharan Africa. AIDS
4. Simoni JM, Kurth AE, Pearson CR, et al. Self-report measures of antiretroviral therapy adherence: a review with recommendations for HIV research and clinical management. AIDS Behav
5. Nieuwkerk PT, Oort FJ. Self-reported adherence to antiretroviral therapy for HIV-1 infection and virologic treatment response: a meta-analysis. J Acquir Immune Defic Syndr
6. Lu M, Rogers W, Coady W, et al. What item is most accurate for self-report of 30-day antiretroviral adherence? J Int Assoc Physicians AIDS Care
7. Wagner JH, Justice AC, Chesney M, et al. Patient- and provider-reported adherence: toward a clinically useful approach to measuring antiretroviral adherence. J Clin Epidemiol
. 2001;54(Suppl 1):S91-S98.
8. Mannheimer S, Friedland G, Matts J, et al. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clin Infect Dis
9. Giordano TP, Guzman D, Clark R, et al. Measuring adherence to antiretroviral therapy in a diverse population using a visual analogue scale. HIV Clin Trials
10. Walsh JC, Mandalia S, Gazzard BG. Responses to a 1 month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome. AIDS
11. Oyugi JH, Byakika-Tusiime J, Charlebois ED, et al. Multiple validated measures of adherence indicate high levels of adherence to generic HIV antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr
12. Pratt RJ, Robinson N, Loveday HP, et al. Adherence to antiretroviral therapy: appropriate use of self-reporting in clinical practice. HIV Clin Trials
13. Gao X, Nau DP. Congruence of three self-report measures of medication adherence among HIV patients. Ann Pharmacother
14. Mannheimer S, Thackeray L, Huppler Hullsiek K, et al. A randomized comparison of two instruments for assessing self-reported antiretroviral adherence. J Int Assoc Physicians AIDS Care
15. Wiener L, Riekert K, Ryder C, et al. Assessing medication adherence in adolescents with HIV when electronic monitoring is not feasible. AIDS Patient Care STDS
16. Johnson T, Fendrich M. Modeling sources of self-report bias in a survey of drug use epidemiology. Ann Epidemiol
17. Wagner G, Miller LG. Is the influence of social desirability on patients' self-reported adherence overrated? J Acquir Immune Defic Syndr
18. Joslyn S, Loftus E, McNoughton A, et al. Memory for memory. Mem Cognit
19. Liu H, Golin CE, Miller LG, et al. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med
20. Wagner GJ, Rabkin JG. Measuring medication adherence: are missed doses reported more accurately then perfect adherence? AIDS Care
22. Johnson AM, Copas AJ, Erens B, et al. Effect of computer-assisted self-interviews on reporting of sexual HIV risk behaviours in a general population sample: a methodological experiment. AIDS
23. Macalino GE, Celentano DD, Latkin C, et al. Risk behaviors by audio computer-assisted self-interviews among HIV-seropositive and HIV-sero-negative injection drug users. AIDS Educ Prev
24. Metzger DS, Koblin B, Turner C, et al. Randomized controlled trial of audio computer-assisted self-interviewing: utility and acceptability in longitudinal studies. HIVNET Vaccine Preparedness Study Protocol Team. Am J Epidemiol
25. Bangsberg DR, Bronstone A, Hofmann R. A computer-based assessment detects regimen misunderstandings and nonadherence for patients on HIV antiretroviral therapy. AIDS Care
26. Miller K. Conducting cognitive interviews to understand question-response limitations. Am J Health Behav
. 2003;27(Suppl 3):S264-S272.
27. Jobe JB. Cognitive psychology and self-reports: models and methods. Qual Life Res
28. Schneider J, Kaplan SH, Greenfield S, et al. Better physician-patient relationships are associated with higher reported adherence to antiretroviral therapy in patients with HIV infection. J Gen Intern Med
29. Hambleton RK. Emergence of item response modeling in instrument development and data analysis. Med Care
. 2000;38(9 Suppl):II60-II65.
30. McHorney CA. Generic health measurement: past accomplishments and a measurement paradigm for the 21st century. Ann Intern Med
31. Mannheimer S, Botsko M, Hisrchorn LR, et al. The CASE adherence index: a novel method for measuring adherence to antiretroviral therapy. J Int Assoc Physicians AIDS Care
32. Lu M, Rogers W, Coady W, et al. What is the optimal recall period for self-report (SR) of antiretroviral (ARV) adherence (AHD)? Evidence from comparisons of SR and the medication event monitoring system (MEMS). Presented at: XVI International AIDS Conference; 2006; Toronto.
33. Liu H, Miller L, Hays R, et al. A comprehensive evaluation of survey questions for adherence to antiretroviral medications and exploratory analyses for identifying optimal sets of survey questions. J Int Assoc Physicians AIDS Care
34. Cramer JA. Microelectronic systems for monitoring and enhancing patient compliance with medication regimens. Drugs
35. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA
36. Diaz E, Levine HB, Sullivan MC, et al. Use of the medication event monitoring system to estimate medication compliance in patients with schizophrenia. J Psychiatry Neurosci
37. Rosen MI, Rigsby MO, Salahi JT, et al. Electronic monitoring and counseling to improve medication adherence. Behav Res Ther
38. Deschamps AE, Graeve VD, van Wijngaerden E, et al. Prevalence and correlates of nonadherence to antiretroviral therapy in a population of HIV patients using a medication event monitoring system. AIDS Patient Care STDS
39. McNabb JJ, Nicolau DP, Stoner JA, et al. Patterns of adherence to antiretroviral medications: the value of electronic monitoring. AIDS
40. van Wijngaerden E, De Saar V, De Graeve V, et al. Nonadherence to highly active antiretroviral therapy: clinically relevant patient categorization based on electronic event monitoring. AIDS Res Hum Retroviruses
41. Liu H, Miller LG, Hays RD, et al. Repeated measures longitudinal analyses of HIV virologic response as a function of percent adherence, dose timing, genotypic sensitivity, and other factors. J Acquir Immune Defic Syndr
42. Howard AA, Arnsten JH, Lo Y, et al. A prospective study of adherence and viral load in a large multi-center cohort of HIV-infected women. AIDS
43. Levine AJ, Hinkin CH, Castellon SA, et al. Variations in patterns of highly active antiretroviral therapy (HAART) adherence. AIDS Behav
44. Arnsten JH, Demas PA, Farzadegan H, et al. Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis
45. Samet JH, Sullivan LM, Traphagen ET, et al. Measuring adherence among HIV-infected persons: is MEMS consummate technology? AIDS Behav
46. Bova CA, Fennie KP, Knafl GJ, et al. Use of electronic monitoring devices to measure antiretroviral adherence: practical considerations. AIDS Behav
47. Wendel CS, Mohler MJ, Kroesen K, et al. Barriers to use of electronic adherence monitoring in an HIV clinic. Ann Pharmacother
48. Wagner GJ, Ghosh-Dastidar B. Electronic monitoring: adherence assessment or intervention? HIV Clin Trials
49. Deschamps AE, Denhaerynck K, Van Wijngearden E, et al. Use of electronic monitoring induces a 40-day intervention effect in HIV-patients. J Int Assoc Physicians AIDS Care
50. Kalichman SC, Cain D, Cherry C, et al. Pillboxes and antiretroviral adherence: prevalence of use, perceived benefits, and implications for electronic medication monitoring devices. AIDS Patient Care STDS
51. Caruthers D, Engberg R, Sereika S, et al. Tracking and assessing adherence data for a multi-center study. Presented at: Enhancing Adherence: A State of the Science Meeting on Intervention Research to Improve Anti-Retroviral Adherence; 2005; New Haven.
52. Hugen PW, Langebeek N, Burger DM, et al. Assessment of adherence to HIV protease inhibitors: comparison and combination of various methods, including MEMS (electronic monitoring), patient and nurse report, and therapeutic drug monitoring. J Acquir Immune Defic Syndr
53. Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS
54. Rudd P, Byyny RL, Zachary V, et al. The natural history of medication compliance in a drug trial: limitations of pill counts. Clin Pharmacol Ther
55. Pullar T, Kumar S, Tindall H, et al. Time to stop counting the tablets? Clin Pharmacol Ther
56. Bangsberg DR, Hecht FM, Charlebois ED, et al. Comparing objective measures of adherence to HIV antiretroviral therapy: electronic medication monitors and unannounced pill counts. AIDS Behav
57. Moss AR, Hahn JA, Perry S, et al. Adherence to highly active antiretroviral therapy in the homeless population in San Francisco: a prospective study. Clin Infect Dis
58. Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr
59. Ingersoll KS, Heckman CJ. Patient-clinician relationships and treatment system effects on HIV medication adherence. AIDS Behav
60. Delgado J, Heath KV, Yip B, et al. Highly active antiretroviral therapy: physician experience and enhanced adherence to prescription refill. Antivir Ther
61. Grossberg R, Zhang Y, Gross R. A time-to-prescription-refill measure of antiretroviral adherence predicted changes in viral load in HIV. J Clin Epidemiol
62. Turner BJ, Laine C, Cosler L, et al. Relationship of gender, depression, and health care delivery with antiretroviral adherence in HIV-infected drug users. J Gen Intern Med
63. Legorreta A, Yu A, Chernicoff H, et al. Adherence to combined lamivudine + zidovudine versus individual components: a community-based retrospective medicaid claims analysis. AIDS Care
64. Inciardi JF, Leeds AL. Assessing the utility of a community pharmacy refill record as a measure of adherence and viral load response in patients infected with human immunodeficiency virus. Pharmacotherapy
65. Wood E, Hogg RS, Yip B, et al. The impact of adherence on CD4 cell count responses among HIV-infected patients. J Acquir Immune Defic Syndr
66. Wood E, Montaner JS, Yip B, et al. Adherence and plasma HIV RNA responses to highly active antiretroviral therapy among HIV-1 infected injection drug users. CMAJ
67. Steiner JF, Koepsell TD, Fihn SD, et al. A general method of compliance assessment using centralized pharmacy records. Description and validation. Med Care
68. Fairley CK, Permana A, Read TR. Long-term utility of measuring adherence by self-report compared with pharmacy record in a routine clinic setting. HIV Med
69. Low-Beer S, Yip B, O'Shaughnessy MV, et al. Adherence to triple therapy and viral load response. J Acquir Immune Defic Syndr
70. Maher K, Klimas N, Fletcher MA, et al. Disease progression, adherence, and response to protease inhibitor therapy for HIV infection in an urban Veterans Affairs medical center. J Acquir Immune Defic Syndr
71. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: methods, validity, and applications. J Clin Epidemiol
72. Nieuwkerk PT, Sprangers MA, Burger DM, et al. Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. Arch Intern Med
73. Murri R, Ammassari A, Gallicano K, et al. Patient-reported nonadherence to HAART is related to protease inhibitor levels. J Acquir Immune Defic Syndr
74. Alexander CS, Asselin JJ, Ting LS, et al. Antiretroviral concentrations in untimed plasma samples predict therapy outcome in a population with advanced disease. J Infect Dis
75. Liechty CA, Alexander CS, Harrigan PR, et al. Are untimed antiretroviral drug levels useful predictors of adherence behavior? AIDS
76. Lorenzi P, Yerly S, Abderrakim K, et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. Swiss HIV Cohort Study. AIDS
77. Murri R, Ammassari A, De LA, et al. Definition and measurement of adherence to antiretroviral drugs in HIV-1-infected patients. Lancet
78. Alcoba M, Cuevas MJ, Perez-Simon MR, et al. Assessment of adherence to triple antiretroviral treatment including indinavir: role of the determination of plasma levels of indinavir. J Acquir Immune Defic Syndr
79. Back D, Gatti G, Fletcher C, et al. Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS
. 2002;16(Suppl 1):S5-S37.
80. Burger DM, Aarnoutse RE, Hugen PW. Pros and cons of therapeutic drug monitoring of antiretroviral agents. Curr Opin Infect Dis
81. Acosta EP, Gerber JG. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res Hum Retroviruses
82. Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med
83. Frick PA, Gal P, Lane TW, et al. Antiretroviral medication compliance in patients with AIDS. AIDS Patient Care STDS
84. Wohl DA, Stephenson BL, Golin CE, et al. Adherence to directly observed antiretroviral therapy among human immunodeficiency virus-infected prison inmates. Clin Infect Dis
85. Wagner GJ. Predictors of antiretroviral adherence as measured by self-report, electronic monitoring, and medication diaries. AIDS Patient Care STDS
86. Farley J, Hines S, Musk A, et al. Assessment of adherence to antiviral therapy in HIV-infected children using the medication event monitoring system, pharmacy refill, provider assessment, caregiver self-report, and appointment keeping. J Acquir Immune Defic Syndr
87. Melbourne KM, Geletko SM, Brown SL, et al. Medication adherence in patients with HIV infection: a comparison of two measurement methods. AIDS Read
88. DiMatteo MR, Giordani PJ, Lepper HS, et al. Patient adherence and medical treatment outcomes: a meta-analysis. Med Care
89. DiMatteo MR. Variations in patients' adherence to medical recommendations: a quantitative review of 50 years of research. Med Care
90. Paterson DL, Potoski B, Capitano B. Measurement of adherence to antiretroviral medications. J Acquir Immune Defic Syndr
. 2002;31(Suppl 3):S103-S106.
91. Wilson KJ, Doxanakis A, Fairley CK. Predictors for non-adherence to antiretroviral therapy. Sex Health
92. Hubley AM, Zumbo BD. A dialectic on validity: where we have been and where we are going. J Gen Psychol
93. Kerr T, Walsh J, Lloyd-Smith E, et al. Measuring adherence to highly active antiretroviral therapy: implications for research and practice. Curr HIV/AIDS Rep
94. Svarstad BL, Chewning BA, Sleath BL, et al. The Brief Medication Questionnaire: a tool for screening patient adherence and barriers to adherence. Patient Educ Couns
95. Etter JF, Duc TV, Perneger TV. Validity of the Fagerstrom test for nicotine dependence and of the Heaviness of Smoking Index among relatively light smokers. Addiction
96. Etter JF. A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerstrom test for nicotine dependence. Drug Alcohol Depend
adherence; antiretroviral; HIV; measurement; research methods
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