Nonadherence has been a problem for as long as remedies for health conditions have been prescribed. The first study of adherence was published almost 60 years ago in the Journal of the American Medical Association.1 The subsequent increase in chronic illnesses, accompanied by long-term therapies, resulted in a recognition that patient nonadherence is a pervasive and costly problem. Early estimates that one half of patients do not accrue benefit from treatments because of nonadherence have continued to be cited.2,3 Although reports of empiric studies of patient adherence emerged with more regularity during the late 1960s, the field received a boost when the National Heart, Lung, and Blood Institute funded a series of grants to address nonadherence in the treatment of essential hypertension in the late 1970s. When no single intervention or optimal assessment strategy or single intervention emerged from this effort, adherence research faded from the spotlight until re-emerging in 1995 with the introduction of combination therapy for HIV/AIDS. What accounted for this attention, unfortunately, was not the fact that adherence to HIV medication was recognized as a problem. Nonadherence to HIV therapy preexisted the discovery of combination therapy.* Rather, it was the recognition that nonadherence would result in transmittable forms of drug-resistant strains of HIV that galvanized attention to the problem.4
The articles in this supplement issue bring together some of the most experienced investigators working on adherence in HIV/AIDS over the past decade. Friedland and Williams were among the first to recognize the importance of adherence in the treatment of HIV/AIDS and to advocate for interdisciplinary efforts in research to understand its dynamics and impact on care and in efforts to address the problem and maximize treatment effectiveness,5 a point that Friedland makes again in his commentary in this issue. Also in this issue, Berg and Arnsten point out that adherence measurement is needed in clinical and research settings, and call for research to evaluate methods and provide recommendations for research and clinical care. In this issue, Simoni and her associates review an impressive number of randomized controlled clinical trials (RCTs) and then point to the need for research on translating intervention strategies into clinically relevant interventions for resource-limited settings. Scholarly articles in this issue, compare theories, such as the information-motivation-behavioral skills (IMB) model of health behavior discussed by Fisher and his associates; whereas Ware and Wyatt point out the need to have processes in place to adapt theories to different cultural settings, including those that are limited in resources.
There is a wealth of perspectives in this issue, with needed attention to both resource-rich and resource-limited settings. What emerges is a recognition that adherence to HIV/AIDS treatment is more than simply remembering medications but, rather, a complex issue involving social, cultural, economic, and personal factors. Despite this complexity, this author and others working on issues of adherence are repeatedly asked for the single question that can assess adherence in all settings with reliability and validity. Similarly, this author and others are asked for the single best “tool” to increase adherence, with the implication that that there is a single strategy that would result in success regardless of the person using the tool or the setting in which it is employed.
Investigators interested in adherence research in the context of HIV/AIDS may be at risk for being trapped into debates about the “elusive gold standard,” that is, identifying the single optimal approach to the assessment of adherence and the single optimal approach to adherence intervention. When questions are raised about transporting assessment and behavior change strategies from developed countries or resource-rich settings to resource-limited settings, there is recognition that tailoring materials to different cultural contexts is essential. Similar tailoring may be equally appropriate for adherence assessment and interventions based on the environments in which the strategies are to be employed, not just abroad but in resource-rich settings as well, where patient populations, clinical structures, and disease maturity may vary greatly.
To facilitate moving beyond these debates, I propose in this article a model that could be used to guide the selection of assessment and intervention strategies for research and clinical practice. This model recognizes that any gold standard is elusive and that “one size does not fit all.” There is no single optimal assessment or intervention strategy for all situations, even within developed countries. The selection of assessment approaches and intervention strategies depends on the purpose for which each is being used. This is certainly the case when assessing or intervening in other important behaviors that have an impact on health. For example, for studies of dietary intake, some research settings call for detailed, repeated, 24-hour diet records, whereas others may be able to answer research questions using food frequency questionnaires.6 Clinicians may need quick screening questionnaires to evaluate dietary intake for specific purposes.7 Similarly, research on physical activity has numerous approaches to the assessment of diet, including physical activity logs or diaries, self-report or interviewer-administered recall of physical activity, and electronic activity monitors.8 Numerous approaches also exist for interventions to increase physical activity from a comprehensive, multisession, exercise skills-building program9 to a telephone-based walking program for clinical practice settings.10 Considering this perspective, I propose a model that could be used as a heuristic for selecting approaches to adherence assessment and intervention for research applications in diverse clinic settings in resource-rich and resource-poor settings.
PURPOSE: RESEARCH PROJECT VERSUS CLINICAL PRACTICE?
The model presented in Figure 1 draws a broad distinction between research projects and clinical practice. Adherence is highly relevant in both of these settings. A wide range of research projects on persons living with HIV/AIDS include assessments of adherence to HIV medications. This is particularly important in RCTs of medication regimens, or of interventions to increase adherence to medication. Alternatively, practitioners working in HIV clinical practice settings need assessments that can be used to determine whether increasing viral load is attributable to problems with adherence to the regimen or to the effectiveness of the regimen per se.
ASSESSMENT IN RESEARCH: FOCUS ON GENERAL HIV/AIDS OR ADHERENCE
In the proposed model, a further distinction is drawn within research projects, based on the extent to which the focus of the research is on adherence. Turning first to assessment in research projects, there are those projects that are focused on HIV/AIDS in general, where the assessment of adherence is of secondary importance. Such might be the case when the adherence assessment is needed to measure the level of adherence among a group of newly diagnosed patients being treated in an RCT comparing 2 new HIV/AIDS medication regimens, with each containing a number of different agents. Although adherence is important in such trials, the precision or detail in the assessment of adherence needed to answer the primary research question of medication is less than that needed for other research projects. Alternatively, the adherence assessment needed in a prospective study of an adherence intervention designed to address environmental, social, and personal barriers to adherence among HIV/AIDS patients at different times since diagnosis would need to provide far more detailed information about adherence.
The recommended assessment for the RCT of an HIV/AIDS regimen might be a brief self-report scale. If details were needed regarding specific adherence to the various medications within the trial, the self-report assessment would need to assess adherence to each medication.11 Alternatively, if details about the individual medications were not needed, simpler self-report measures would suffice, such as a single-item visual analogue scale (VAS).12
For the RCT of the adherence intervention, more precise assessments might be needed. These measures include electronic monitoring devices (EMD) like that provided by the medication event monitoring system (MEMS) caps equipped with microprocessors that record the time and date of bottle openings, or more detailed self-administered questionnaires informed by cognitive interviewing, as discussed by Berg and Arnsten12a in this issue. Cognitive interviewing provides insight into how people with different cultural and educational backgrounds interpret questions and mentally process and report answers to questions that require, for example, recall, calculation of percentages, or reporting responses that are not socially desirable. Such interviewing can be used to enhance the reliability and validity of self-reported information.13 Research projects that focus on adherence or the role of cognitions, motivations, and expectancy might want to use composites of self-report measures, including qualitative methods. As described by Sankar and his colleagues in this issue,13a qualitative methods can provide detailed in-depth information about how a patient's beliefs about medication and reasons for nonadherence, including problems with access and stigma as well as attitudes about health, wellness, and life, can influence adherence-information that would be missed by most other assessment strategies.
ASSESSMENT IN CLINICAL PRACTICE: FOCUS ON GENERAL HIV/AIDS OR ADHERENCE
When considering the assessment of adherence within clinical practice, again, the precision of measurement should depend on the objectives of the assessment. In many HIV practices, the focus is often on treating HIV/AIDS generally and not specifically on adherence to medication. The practicing clinicians may want to have a simple measure of adherence that they could administer to patients or have patients complete in waiting rooms so as to be in a position to provide some brief counseling for adherence, as recommended by Fisher and his colleagues in this issue.13b There are also larger clinical practices and HIV clinics where patients are seen by persons, who, in addition to the prescribing clinician, provide adherence counseling. These persons could be nurse practitioners, as described elsewhere in this issue in the successful intervention by Remien and his associates,13c or medication managers, as described in the successful intervention by Mannheimer and her associates.13d Assessments for these adherence-focused interventions include detailed assessment of potential barriers to adherence relating to misunderstanding of the regimen and level of understanding, motivation, and adherence skills as well as detailed assessments of actual adherence by self-report or EMD. It might also be in adherence-focused clinical practice settings that computer-based self-report assessments could be completed by patients in waiting rooms. These assessments use pictures of each medication, allowing each patient to identify his or her exact regimen and to report levels of adherence in the recent past on a touch screen.14 Results can be printed for the patient and the adherence counselor before the visit. These assessment procedures are particularly helpful in identifying patients who do not fully understand the regimen to which they should be adhering.
Thus, each of the major approaches to adherence assessment may have a place in the model presented here. This would include EMDs or MEMS caps, which have often been referred to as a potential gold standard for adherence assessment (as described by Berg and Arnsten in this issue12a).15 Experience has revealed potential limitations that can lead to underestimates of adherence from “pocket dosing” to overestimates from “curiosity opening,” as described by Berg and Arnsten in this issue. Additional challenges are presented by the costs of the caps and the management and interpretation of the data they yield. In this issue, Fennie and his colleagues15a describe strategies to address errors in EMDs, pointing out how various approaches can affect the validity of the adherence measurement. They propose how researchers should report more details surrounding the use of EMDs, including whether patients were asked self-report questions about such habits as pocket dosing. Despite the fact that, as Fennie and his colleagues point out, consensus has yet to be reached on optimal procedures for management, adjustment, and analysis of EMD data, EMD's are an attractive component of adherence research, given the detailed longitudinal data they can provide, they have more of a place in research and, within the research domain, in studies that are focused on adherence.
Self-report assessment, the most commonly used adherence measure, is likely to have a place in both clinical and research settings. The model proposed here suggests that rather than trying to determine the single best assessment strategy, efforts should continue to develop a portfolio of different valid and reliable self-report measures with varying strengths and weaknesses that can be optimally applied, depending on the situation. A recent systematic review16 discussed in this issue by Berg and Arnsten reports on numerous measures that have been shown to predict viral load. Included in this portfolio are measures that range from pencil and paper questionnaires to the computer-based pictorial assessments. These various measures ask about adherence, ranging from questions about different prescribed medications over the last several days to single-item questions that ask about general adherence to all medications over periods of weeks or months. Given the extensive literature on assessments, it could be recommended that investigators and clinicians consider limiting their choices to those assessment approaches that have published evidence of reliability and validity. Whenever possible, particularly in research, investigators could consider using multiple measures, which allow for continued research on varying reliability and validity and the development of composite measures, as discussed by a number of scholars (including Berg and Arnsten in this issue).17
Other adherence assessment strategies, including announced and unannounced pill counts, pharmacy refills, and perhaps even therapeutic drug monitoring, may all have a place in research or practice, depending on the purpose of the assessment and the setting in which it is used. There may also be situations in which combining multiple assessments from these diverse strategies would yield greater precision of measurement and information that would be useful to address specific research questions or needs in clinical practice settings.
INTERVENTIONS FOR RESEARCH AND PRACTICE
Interventions to enhance adherence are reviewed in a comprehensive meta-analysis by Simoni and her colleagues in this issue.17a It is apparent that participants who receive interventions for adherence are more likely to achieve higher levels of adherence and are more often able to achieve undetectable viral loads than participants in various control conditions. Again, there may be a tendency for investigators to debate which are the most efficacious intervention strategies and the optimal methods for implementing these strategies in various settings. It may be that just as there is no gold standard for assessment, there is no gold standard for interventions or best intervention for all settings. It may be that an optimal approach would be to have a menu of interventions that could be matched not only to settings but to patient needs, as suggested by Gordon in this issue.17b
INTERVENTION IN RESEARCH: FOCUS ON GENERAL HIV/AIDS OR ADHERENCE
The model proposed here suggests that interventions are needed for research that is focused on HIV/AIDS in general and for research that is more specifically focused on adherence. It is apparent that trials of HIV/AIDS medications are more likely to be successful in testing new formulations if there are high levels of adherence in the various treatment arms. Nonadherence to medication in an RCT can result in failed studies and type 1 errors, where a potentially effective intervention is incorrectly rejected because patients did not adhere at sufficient levels to provide a valid test of the treatments studied. Thus, there is a rationale for intervening to enhance adherence in general HIV/AIDS research, including medication trials.
There is evidence that sites participating in the Adult AIDS Clinical Trials Group (AACTG) in the early 2000s incorporated brief counseling for adherence in their general clinic operations. In a study reporting on an RCT to evaluate the efficacy of telephone-based counseling in protocol 388 of the AACTG, it was learned that all the participating sites indicated that “subjects who were anticipated to have problems adhering received counseling.”18 This study concluded that “because of time constraints that providers and patients have, simple interventions would be particularly helpful.”18 Thus, interventions that might be recommended for general HIV/AIDS research might include brief individual adherence counseling delivered in person or by telephone. Although behavioral scientists interested in adherence interventions might want to propose a multivisit group-based intervention, when research is focused generally on HIV/AIDS, as is the case in an RCT of a new medication, it may be that a brief pharmacist-delivered didactic intervention19 would be sufficient.
A number of the papers in this supplement report on intervention programs that resulted from research focusing specifically on increasing adherence, such as the couples intervention described by Remien and colleagues in this issue. Indeed, it is research focusing on interventions for adherence that is likely to yield new discoveries about approaches that can be streamlined for other settings such as general HIV/AIDS research and clinical practice settings. It would be in this research domain focused on enhancing adherence that new adherence strategies could be discovered. As noted by Gordon in this issue, almost all adherence strategies investigated to date have focused on the patient and have not addressed interventions to ensure or streamline access to HIV care or to enhance retention or the patient's role as a partner in that care. Moreover, research in HIV/AIDS has not yet focused on intervening to modify the stigma associated with being diagnosed with HIV, or tested community-level interventions that could be designed to increase adherence to healthy lifestyles of persons with HIV, including taking medication.
INTERVENTION IN CLINICAL PRACTICE: FOCUS ON GENERAL HIV/AIDS OR ADHERENCE
Interventions to enhance adherence are important in clinical practice settings. In addition to the evidence that adherence predicts clinical outcomes, Freedberg and his colleagues demonstrate in this issue that adherence interventions “are likely to provide long-term survival benefit to patients and to be cost-effective compared with other uses of HIV care funds.”19a For the practicing clinician who sees patients individually or in conjunction with a close family member, interventions would be brief, such as that described by Fisher and colleagues or by Remien and colleagues in this issue. As discussed with regard to adherence assessments, however, there are also larger clinical practices and HIV clinics where patients are seen by persons who provide adherence counseling, such as the medication managers described by Mannheimer and colleagues in this issue. Interventions applied by these specialized counselors are more likely to be those that can be tailored to individual patient needs as indicated by detailed assessments, and those that might be delivered in dyads or groups, as discussed by Remien and colleagues in this issue. It would be in these settings that the research conducted on adherence interventions would be translated into practice. It is also noteworthy that research can be conducted on observational data gathered in clinical settings using new analytic methods, such as those described by Petersen and colleagues in this issue.19b
AN ADDED DIMENSION: RESOURCE-RICH AND RESOURCE-LIMITED SETTINGS
The model proposed in Figure 1 discusses selecting adherence assessment and intervention approaches based on research or clinical settings in developed countries or environments that are rich in resources. Figure 2 illustrates how this model could be expanded for developing countries or resource-limited settings. In these settings, where the morbidity and mortality from HIV/AIDS is so high, research on adherence and efforts to enhance adherence in clinical practice are of utmost importance. Just as there is no gold standard for adherence assessment or intervention in resource-rich environments, there is no single optimal assessment procedure or intervention for research and clinical practice settings in resource-limited environments. This issue is enriched by a number of articles that effectively illustrate the tailoring that must undertaken to develop and test meaningful culturally appropriate adherence assessment or intervention strategies in these culturally diverse settings.
ADHERENCE ASSESSMENT IN RESOURCE-LIMITED SETTINGS
As is the case with resource-rich settings, the precision needed for adherence assessments or the complexity of interventions is likely to vary, depending on whether the research or clinical practice setting of interest is focused generally on HIV/AIDS or, more specifically, on adherence. In this issue, for example, Maneesriwongul and her colleagues described how a 30-day VAS was used to measure medication adherence in a clinic practice setting in Thailand.19c This scale, which provides a single index of adherence, has been validated in studies conducted in London12 and in Uganda.20 Although the VAS provides a self-report global estimate of doses taken in the past month, which may suffice for RCTs of medication in resource-limited settings, other research projects are likely to require more detailed culturally tailored adherence assessment strategies. Research projects that focus on adherence and explore such related factors as stigma and access to care in resource-limited settings report using focus groups and in-depth interviewer-administered questionnaires to assess adherence, as discussed by Maneesriwongul and colleagues and Nachega and colleagues in this issue.21
The numbers of patients needing care and adherence counseling in resource-limited settings present a challenge to intervention efforts. The complexity of the information that must be imparted about HIV/AIDS care, the medication regimens, and the importance of daily adherence adds to the challenge. The use of educational videotapes is an intervention strategy that may prove to be an effective tool for counseling designed to enhance adherence in clinical settings. One such videotape was developed and tested as part of a comprehensive adherence program led by full-time adherence counselors in a South African clinic who also provide counseling to patients and lead support groups that focus on medication-taking strategies, as discussed by Wong and colleagues in this issue.22
Pearson and her colleagues review the literature on the use of modified directly observed therapy (mDOT) in developing countries in this issue, they describe the use of this intervention for patients starting highly active antiretroviral therapy (HAART) in a primary HIV clinic in Beira, Mozambique that has more than 12,000 HIV-positive patients.23 The program implemented in Mozambique, also was “adherence-focused,” providing support and monitoring adherence, managing side effects, and addressing patient concerns.
The existing theoretic models and aggregate literature from the developed world are not immediately transferable to these new culturally diverse settings. In this issue, Ware et al24 provide a thoughtful heuristic model for conducting the qualitative research that is necessary to develop cross-culturally valid models for adherence assessment and intervention. These scholars point out that understanding the setting requires “first-hand experience” in the setting, “spending time, observing, participating,” and carefully interpreting results from focus groups and other qualitative research strategies. These strategies provide examples of culturally specific approaches that adherence counselors in clinics can use, such as identifying “treatment partners” for individual patients and teaching patients and partners to use cues such as radio programs as reminders to take medications.
It would be convenient if there was a gold standard for the assessment of adherence and a single optimal tool that would enhance adherence for persons living with HIV/AIDS. It is unlikely that a single optimal assessment can be found, because the reasons for measuring adherence vary based on whether the assessment is for research or clinical purposes and require further refinement based on the research questions being investigated or the clinical needs being addressed. It is similarly unlikely that a single optimal intervention can be developed, because the reasons for nonadherence are as diverse as the populations affected by HIV/AIDS, involving far more than simply failing to remember medication but rather including motivational factors associated with health and illness, and social factors such as access and stigma.
This article presents a model that may provide some guidance to investigators and clinicians for selecting from the portfolio of established valid and reliable approaches to adherence assessment those strategies that are best suited for their needs. Similarly, this article presents considerations for selecting from a growing number of promising adherence interventions those strategies that may be best suited for the adherence challenges they face. Although the model proposed here is expanded to include resource-rich and resource-limited settings, perhaps others could expand this model by considering other dimensions such as patient age (with a focus on pediatric populations), time since infection, or substance abuse and other personal conditions. Investigators can choose whether to invest additional energy in continuing to search for the elusive gold standard, or to select adherence assessment approaches and interventions strategies that are optimal for the specific adherence demands presented by the research and clinical settings in which they work.
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12a. Berg KM, Arnsten JH. Practical and conceptual challenges in measuring antiretroviral adherence. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S79-S87.
13. 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. 2004;19:1096-1103.
13a. Sankar A, Golin C. Simoni JM, et al. How qualitative methods contribute to understanding combination antiretroviral therapy adherence. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S54-S68.
13b. Fisher JD, Cornman DH, Norton WE, et al. Involving behavioral scientists, health care providers, and HIV-infected patients as collaborators in theory-based HIV prevention and antiretroviral adherence interventions. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S10-S17.
13c. Remien RH, Stirratt MJ, Dognin J, et al. Moving from theory to research to practice: implementing an effective dyadic intervention to improve antiretroviral adherence for clinic patients. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S69-S78.
13d. Mannheimer SB, Morse E, Matts JP, et al. Sustained benefit from a long-term antiretroviral adherence intervention: results of a large randomized clinical trial. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S41-S47.
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15. 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. 2001;23:1417-1423.
15a. Fennie KP, Bova CA, Williams AB. Adjusting and censoring electronic monitoring device data implications for study outcomes. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S88-S95.
16. 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. 2006;10:227-245.
17. Liu H, Golin CE, Miller LG, et al. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med. 2001;134:968-977.
17a. Simoni JM, Pearson CR, Pantalone DW, et al. Efficacy of interventions in improving highly active antiretroviral therapy adherence and HIV-1 RNA viral load: a meta-analytic review of randomized controlled trials. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S23-S35.
17b. Gordon CM. Commentary on meta-analysis of randomized controlled trials for HIV treatment adherence interventions: research directions and implications for practice. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S36-S40.
18. Collier AC, Ribaudo H, Feinberg J, et al. A randomized study of serial telephone call support to increase adherence and thereby improve virologic outcome in persons initiating antiretroviral therapy. J Infect Dis. 2005;192:1398-1406.
19. Knobel H, Carmona A, Lopez JL, et al. Adherence to very active antiretroviral treatment: impact of individualized assessment. Enferm Infecc Microbiol Clin. 1999;17:78-81.
19a. Freedberg KA, Hirschhorn LR, Schackman BR, et al. Cost-effectiveness of an intervention to improve adherence to antiretroviral therapy in HIV-infected patients. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S112-S117.
19b. Petersen ML, Wang Y, van der Laan MJ, et al. Assessing the effectiveness of antiretroviral adherence interventions: using marginal structural models to replicate the findings of randomized controlled trials. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S96-S102.
19c. Maneesriwongul WL, Tulathong S, Fennie KP, et al. Adherence to antiretroviral medication among HIV-positive patients in Thailand. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S118-S121.
20. Oyugi JH, Byakika-Tusiime JB, Charlebois ED, et al. Multiple validated measures of adherence indicate high level of adherence to generic HIV antiretroviral therapy in a resource-limited setting. J Acquir Immune Defic Syndr. 2004;36:1100-1102.
21. Nachega JB, Knowlton AR, Deluca A, et al. Treatment supporter to improve adherence to antiretroviral therapy in HIV-infected South African adults: a qualitative study. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S126-S132.
22. Wong IY, Lawrence NV, Struthers H, et al. Development and assessment of an innovative culturally sensitive educational videotape to improve adherence to highly active antiretroviral therapy in Soweto, South Africa. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S141-S147.
23. Pearson CR, Micek M, Simoni JM, et al. Modified directly observed therapy to facilitate highly active antiretroviral therapy adherence in Beira, Mozambique: development and implementation. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S133-S140.
24. Ware NC, Wyatt MA, Bangsberg DR. Examining theoretic models of adherence for validity in resource-limited settings: a heuristic approach. J Acquir Immune Defic Syndr. 2006;43(Suppl 1):S18-S22.
*This author recalls a panel discussion, which she cochaired with Dr. Molly Cooke of the University of California at San Francisco, at a national meeting of the Adult AIDS Clinical Trials Group on nonadherence to HIV that was primarily attended by hotel workmen who delayed their task of clearing the room to query the speakers about nonadherence to antihypertensive medication. Cited Here...
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