Evaluation of the Patient Medication Adherence Questionnaire As a Tool for Self-Reported Adherence Assessment in HIV-Infected Patients on Antiretroviral Regimens

Michel Duong, MD,1 Lionel Piroth, MD,1 Michle Grappin, MD,1 Fabien Forte, MD,1 Gilles Peytavin, PhD,2 Marielle Buisson, MD,1 Pascal Chavanet, MD,1 and Henri Portier, MD1
1

Division of Infectious Diseases, University Hospital, Dijon, France; 2Department of Clinical Pharmacokinetic, Bichat Hospital, Paris, France

Purpose: Adherence to antiretroviral medications is critically important for the success of therapy in patients treated for HIV infection. Patient self-report is a simple method to measure and explore adherence. Even though a variety of surveys have been developed to monitor self-reported adherence, there is no standardized instrument that may be used in routine clinical practice. The usefulness of the Patient Medication Adherence Questionnaire (PMAQ) was evaluated in HIV-infected patients on protease inhibitor (PI)-containing regimens. Method: Data from 149 patients were collected. Study participants completed the PMAQ and provided blood samples to measure plasma HIV-1 RNA concentrations and trough plasma levels of PI. Patients were considered adherent if they had a virologic response and/ or had an adequate trough plasma level of PI. Results: A close relationship was found between patient reports of adherence during the previous 4 days and objective measures such as HIV RNA level and plasma levels of PI. Motivation with regard to antiretroviral treatment, confidence in personal skills, and an optimistic attitude to life were identified as important determinants of adherence. On the other hand, sociodemographic background, social support, alcohol and illicit drug use, bothersome symptoms, and depression were not associated with a lower medication adherence. Conclusion: Patients psychological and behavioral factors are central in the acceptance and adherence to antiretroviral therapy. To improve the feasibility and the reproducibility of the PMAQ, we propose a revised form of the PMAQ, focusing on the variables identified as strong predictors of adherence. Key words: self-reported adherence, antiretroviral therapy, Patient Medication Adherence Questionnaire

ntiretroviral (ARV) therapy with potent combinations of drugs has remarkably improved the prognosis of HIV infection. ARV regimens that include HIV-1 protease inhibitors (PIs) have been shown to reduce plasma HIV-1 RNA and to increase concomitantly CD4 cell count. The extensive use of such treatments has resulted in a substantial decrease in AIDS-related morbidity and mortality. However, the efficacy of ARV therapies may be limited by poor adherence resulting in a lack of clinical or viral response, the selection of drug-resistant variants, and secondary drug failure.13 Additionally, suboptimal adherence can lead to a misinterpretation of clinical efficacy and to inappropriate changes in treatment. Because adherence to ARV medications is critically

important for the success of therapy in patients treated for HIV infection, it is particularly warranted for clinicians to have a convenient tool to monitor it. Several methods such as clinician reports, returned pill counts, surrogate laboratory markers, drug levels, and computer-assisted electronic monitoring devices have been proposed to evaluate adherence.4,5 However, all of these

For correspondence or reprints contact: Pr Pascal Chavanet, Service des Maladies Infectieuses, Hpital du Bocage, 2 Boulevard Marchal Delattre de Tassigny, Dijon, 21034 France. Email: P.Chavanet@planetb.fr.
HIV Clinical Trials 2001;2(2):128135 2001 Thomas Land Publishers, Inc.

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methods have limitations, which is why, at the moment, no reference method can be recommended. Another approach may be patient self-report, which is simple, relatively inexpensive, and easy to implement in the patients follow-up. Self-reported nonadherence has been demonstrated to be associated with worse virologic outcomes.4,6 However this method has been shown to overestimate adherence, both in the HIV setting and non-HIV setting, and nonconsistent results were found when it was compared to more objective measures.1,7 Nevertheless, another potential interest of patient self-report is that it can provide information about the reasons why a patient did or did not take the medication properly. In fact, a patients clinical, social, psychological, and behavioral variables are among the most important factors that influence adherence; to date, few studies have assessed the impact of such factors.810 Even though a variety of surveys have been developed to monitor self-reported adherence, there is no standardized instrument that may be used in routine clinical practice. In the present study, we evaluated the usefulness of the Patient Medication Adherence Questionnaire (PMAQ) as a self-report instrument to measure and explore adherence in patients on ARV regimens. METHOD Study Design and Patients This study was approved by our Human Subjects Protect Care Committee. It was a prospective, cross-sectional study of HIV-infected patients who were followed at the Dijon Hospital AIDS day-care unit. Patients with documented HIV infection, whether symptomatic or not, were eligible for entry into the study if they had followed an ARV regimen represented by two nucleoside analogues and one or a combination of marketed PIs, either indinavir (IDV), saquinavir (SQV), nelfinavir (NFV), or ritonavir (RTV). Patients were not aware of the study before attending their consultation and therefore did not know that they were having blood drawn to measure PI plasma levels. The eligible patients were asked by the nurse if they wanted to participate in the study. Study participants were asked to complete the PMAQ version 1.0. Full blood count, CD4 cell count, routine bio-

chemistry analysis, HIV RNA level, and trough plasma PI level were performed the same day. Measure of Adherence to ARV Therapy Adherence was assessed by the means of two biological markers: plasma PI levels and plasma HIV concentrations.11,12 Adherence was considered adequate when: (i) HIV RNA was undetectable (with a limit of detection of 20 copies/mL) or HIV RNA level was at least 2 log10 below the pretreatment level for patients who had taken PI for the first time and at least 1 log10 below the pretreatment level for patients who had been treated at least once by another PI regimen, or (ii) trough plasma PI levels were above reference values. Conversely, adherence was considered inadequate when conditions (i) and (ii) were not met. Plasma HIV RNA levels were assessed using the HIV-1 Amplicor Monitor assay (Roche Diagnostic Systems, Brachburg, NJ, USA) with a limit of detection of 20 copies/mL and were transformed to log10 values. The determinations of masked plasma PI levels were performed using chromatographic methods coupled with an ultraviolet detection for IDV, RTV, NFV, and SQV. The assays were found to be linear over the concentration range and the lower limits of quantification were 5 ng/mL, 0.03 mg/L, 0.03 mg/L, and 9 ng/mL for IDV, RTV, NFV, and SQV, respectively. The interday percent coefficient of variation for these assays was lower than 10%. A threshold value for trough plasma concentration was determined for each PI by taking into account the value of the in vitro IC90 of the PI for HIV-1, the pharmacokinetic properties of the drug, and the level of protein binding. These reference values were the following: IDV = 0.07 mg/L, NFV = 1 mg/L, RTV = 2.1 mg/L, and SQV = 0.1 mg/L. The interpretation of each plasma PI level was performed in a blind analysis that took into account the time interval between PI ingestion and blood sampling. Self-Report Adherence The PMAQ was filled in by the patient. A trained research assistant was present to give explanations to patients who had difficulty understanding some items of the PMAQ. This questionnaire contained 61 items that were designed to evaluate a patients treatment adherence behavior and its determinants by providing a quantitative measure of adherence

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Table 1.

Assessment measures
No. of items 06 12 02 05 08 02 02 01 02 12 05 04

Concept assessed Medication adherence Bothersome symptoms Social support Psychological status Depression Stress Confidence in personal skills Optimism Knowledge/attitudes/beliefs HIV medication self-efficacy Attitudes and beliefs about HIV treatment Reasons for missing doses Alcohol and illicit drug use Sociodemographic background
xx

and November 1998. The mean age was 40 years (range, 2179 years). One hundred and four patients (104; 70%) were men. The HIV infection risk factors were the following: heterosexual (40%), homosexual/bisexual (33%), intravenous drug use (24%), and blood products (3%). According to the Centers of Disease Control and Prevention (CDC) 1993 criteria, 60 patients were on stage A, 49 on stage B, and 40 on stage C. At the time of study, mean CD4 cell count was 485 x 106 cells/L (range, 21,126 x 106 cells/L) and HIV RNA was mean 4.6 log10 copies/mL (range, 06.51 log10 copies/mL). At time of inclusion into the study, 14 patients (9%) were on their first ARV regimen. Concerning PI use, 93 patients (63%) were at least on their second PI-containing regimen. Adherence Assessment Eleven percent (11%) of the 149 patients (16) were nonadherent according to the criteria outlined in the Method section (virologic response and/or adequate PI blood concentration). All patients completed the PMAQ. Among the six items designed to assess adherence, three items were significantly associated with drug adherence: I have not missed any doses of my ARV medications over the last four days (89%, p = .03); I have not missed taking all my pills at least one day over the last four days (82%, p = .01); and I have followed the special instructions associated with my ARV medications over the last four days (80%, p = .0005). Conversely, the following three items did not predict adherence: I did not miss taking my ARV medications last weekend-last Saturday or Sunday; I have closely followed the specific schedule associated with my ARV medications over the last four days; and I have never missed any doses of my medications over the last three months. Determinants of Adherence Age, sex, education, risk behavior, stage of HIV infection, employment, and having children at home did not correlate with adherence (see Table 2). Neither the use of alcohol or illicit drugs nor bothersome symptoms was significantly associated with less adherence. Associations between psychosocial variables and adherence to ARV

and information on why a patient is or is not adherent. It is divided into two sections. Section 1 contains six items pertaining to medication-taking behaviors and asks patients to rank on an ordinal scale how often they missed individual doses or days of medication. Section 2 contains 55 items pertaining to barriers and motivators to taking medications. Each item is rated on a Likert scale from 0 to 3 or 0 to 5. The concepts assessed are summarized in Table 1. Statistical Analysis Patient sociodemographics and measures obtained from the 61 items of the PMAQ were entered into the STATVIEW Statistics program (Abacus Concepts, Berkley, CA, USA). The chi-square test was used to compare categorical variables. Continuous variables (social support, trust in ARV therapy, psychological functioning, etc.) were assessed by the Mann-Whitney test. A p value < .05 was considered significant. RESULTS Population One hundred and forty-nine (149) HIV-infected patients were enrolled in the study between July

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Table 2. Sociodemographic variables and adherence of HIVinfected patients to antiretroviral therapy

Nonadherent (n = 16) 39.9 07 09 02 05 04 05 06 07 03 00 07 09 07 06 09 07 Adherent (n = 133) 40.7 35 98 .55 11 23 64 35 .45 43 52 33 5 .89 73 59 .60 73 36 .45 53 78

Variable Age Sex Female Male Education Grade school High school Technical school College Risk behavior Men who have sex with men Heterosexual IV drug use Blood products Employed Yes No Working outside the home Yes No Having any children Yes No
Note: IV = intravenous.

p .76 .15

therapy are summarized in Table 3. Satisfaction with social support was not a significant predictor of adherence, because neither being satisfied with friend and familys support nor having somebody to remind the patient to take the medications was associated with drug taking. The firm belief of being able to take all or most of the HIV medications was strongly associated with adherence. In contrast, insufficient knowledge about the efficacy of HIV medication and the risks of a suboptimal drug adherence was not predictive of nonadherence. Among psychological variables, positive feelings about personal life and trust in personal skills were significantly associated with better adherence. Neither stress nor depression was significantly associated with poorer ARV adherence. Among the different reasons for missing ARV doses, being away from home was the only variable significantly associated with nonadherence

(see Table 4). Having problems taking pills at specified times was more frequently reported by nonadherent patients. DISCUSSION Patient self-report is now commonly collected for assessing adherence in HIV-infected patients. Among the different instruments that measure self-reported adherence, the PMAQ is one of the most frequently used questionnaires, especially in clinical trials.13,14 However, few studies had shown its utility and, to date, there is no clear validation of this self-administered questionnaire.15 A close relationship was found between patient reports of adherence during the previous 4 days and objective measures such as HIV RNA level and plasma levels of ARVs. This finding confirms the relevance of an adherence evaluation over short rather than

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Table 3.

Psychosocial variables and adherence to antiretroviral therapy

Nonadherent (n = 16) 2 (1.1) 1.2 (1.1) Adherent (n = 133) 2.3 (.9) 1.3 (1.2)

Variable Social support I feel satisfied with the overall support I get from my friends and my family. My friends or family help me remember to take my medication. Trust in antiretroviral therapy I believe I will take all or most of my medication. HIV medications have a positive effect. HIV medications will become resistant if I dont take my treatment exactly as instructed. Emotional limitations and psychological functioning In the past month: I was upset because of something that happened unexpectedly. I felt unable to control the important things in my life. I felt nervous and stressed. I felt confident in my ability to handle my personal problems. I felt that things were going my way. I found that I could not cope with all the things that I had to do. I was able to control irritations in my life. I felt that I was on top of things. I was angered because of things that happened that were outside of my control. I felt problems were piling up so high that I could not overcome them.

p .16 .8

2 (1.3) 2.3 (1) 2.1 (1)

2.6 (.7) 2.5 (.7) 2.4 (.8)

.0015 .21 .15

1.3 (1.7) 1 (1.4) 2.2 (1.3) 2.3 (1) 2.3 (1.1) 1.2 (1.4) 2.8 (.7) 2.1 (.9) .9 (1.2) 1.1 (1)

1.1 (1) .7 (1.1) 1.8 (1.2) 3 (1) 2.8 (1.2) 1.1 (1.2) 2.9 (1.1) 2.7 (1.2) 1.1 (1.3) .8 (1.1)

0.5 .22 .21 .01 .16 .73 .76 .05 .53 .4

Note: The answer to each item was rated on a Likert scale from 0 to 3 or 0 to 5.

long periods of time; in fact, many patients cannot accurately remember what doses were missed several weeks or days prior to a survey. From named patient self-report, Hecht et al.4 showed that patients who had missed a dose of medication within the 2 days before their visit were likely to have detectable viremia. Taking drug holidays by skipping doses at the weekend is a well-known pattern of nonadherence; however, we did not find a significant association between this item and nonadherence because this behavior probably concerns a minority of our patients. Finally, perfect respect of the specific schedule associated with ARVs did not correlate with adherence, suggesting that this recommendation is less crucial than had previously been expected. Several categories of items of the PMAQ were not significantly associated with medication adherence. In fact, we did not observe any effect of

sociodemographic background, social support, and alcohol or illicit drug use on adherence. Contradictory data concerning these factors have been reported and, to date, their exact role as barriers to or motivators of adherence remains uncertain.1,6 However, the differences in predictors of adherence seen between our work and other studies may reflect the differences in populations being studied. Although it is obvious and has been demonstrated that side-effects are associated with decreased adherence to ARV therapy, we did not find any correlation between bothersome symptoms and adherence. This finding suggests that patients do not systematically attribute to HIV medications the clinical symptoms they suffer from. A patients education and any information about specific ARV therapy are undoubtedly necessary to make decisions about beginning or changing an ARV regimen.16 However, in our study, these conditions do

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Table 4. Relation between possible reasons for missing an HIV medication dose and adherence
Nonadherent (n = 16) 1.6 (1.3) .9 (1.3) .8 (1.2) .3 (.8) .4 (1) .6 (1.1) .8 (1.2) 0 .3 (.8) .3 (.8) .6 (1.1) 1 (1.3) Adherent (n = 133) .9 (1.3) .6 (1.2) .5 (.9) .2 (.7) .3 (.8) .4 (.8) .4 (.9) .1 (.3) .3 (.7) .25 (.7) .2 (.7) .5 (.9)

Variable I was away from home. I was busy with other things. I simply forgot. I had too many pills to take. I wanted to avoid side effects. I did not want others to notice me taking medication. I had a change in daily routine. I thought the drug was toxic/harmful. I felt sleepy/slept through dose time. I felt sick or ill. I felt depressed/overwhelmed. I found difficult to take pills at specified times.

p .05 .24 .27 .73 .68 .2 .2 .46 .66 .76 .09 .08

Note: The answer to each item was rated on a Likert scale from 0 to 3 or 0 to 5.

not seem to be sufficient to ensure adherence. In assessing ARV use among HIV-infected female prisoners, Monstashari et al.17 also found that trust in safety and efficacy of ARV therapy was not associated with a statistically significant increase in drug taking. Previous studies had demonstrated that stress and depression were more frequent in nonadherent patients.18,19 We are unable to confirm these results. The discrepancy between our study and the others may be related to the fact that the PMAQ is not an appropriate tool to evaluate depression precisely. Using the Beck Hopelessness Scale, which consists of 20 truefalse statements designed to assess hopelessness, Singh et al.10 found that depression was a significant factor. Through the PMAQ, we have identified some psychosocial behavior factors that are critical determinants of ARV consumption; in particular, motivation with regard to ARV treatment, confidence in personal skill, and an optimistic attitude to life. The conviction of being able to take the treatment has been identified in several studies as a central factor.8 This belief refers to a patients own decision about being treated. Involvement of the patient in treatment (in particular, acceptance of ARV therapy) is also associated with the patients acknowledgment of the seriousness of the disease and the understanding of its potential complications. Thus, patients feelings about illness and their mental capacities to handle a regimen are

important factors that must be taken into consideration when making decisions about beginning HIV therapy. Initiation of ARV therapy at an inappropriate time leads in most cases to poor adherence whatever the accuracy of the treatment plan. Therefore, clinicians should always evaluate patient readiness to begin therapy.20 Fighting spirit was identified as being a strong determinant; in this study, individuals who felt more confident in their personal skills were more likely to remain adherent to therapy. Active behavioral coping positively influences the desire and the ability to organize the complicated drug regimens that HIV therapy may require; moreover, lack of fighting spirit and loss of motivation have been identified as characteristics of the patients at risk for missing doses.9 We also found that faith in the future was a strong predictor of medication adherence. Our finding confirms those of other studies that reported that individuals who had an optimistic attitude toward their life were more likely to take their medications regularly. Finally, our nonadherent participants significantly reported that they missed ARV doses because they were away from home. Other authors have reported that the most common reasons for missing medications included simply forgot, being busy and being away from home, and justifying the need of a perfect fit between ARV medica-

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tion schedule and the patients daily routine.8,13 Interestingly, Gifford et al.8 have shown that integrating medication regimens with daily activities was a central factor to achieve plasma HIV suppression. The main limitation of our study lies in our gold standard of adherence, which leads to a generous definition of adherence (a great majority [89%] of the patients was adherent) and a somewhat harsh definition of nonadherence, resulting in a relatively low number of poorly adherent patients. These criteria detected patients with very low levels of adherence but probably missed people with moderate level of nonadherence (i.e., 25%50%). Thus, our study did not evaluate the factors associated with the more subtle cases of nonadherence. Nevertheless, the present study confirms the central role of a patients psychological and behavioral factors in the acceptance and adherence to ARV therapy and provides some evidence of the usefulness of the PMAQ. Even though each category of items is potentially interesting, our findings suggest that the PMAQ should focus on several key variables. From a practical point of view, limiting the number of items in this questionnaire could improve its feasibility and its reproducibility in routine practice. We propose a revised form of the PMAQ that focuses on the variables that have been significantly correlated with adherence in the present study and have also been found to be strong predictors of adherence in other studies. These variables are the following: self-reported adherence over the 4 days before the visit; confidence in medication-taking ability; psychological status, including an evaluation of depression and coping style; and convenience of the medication regimen as assessed by the reasons for missing doses. Our revised form of the PMAQ needs to be validated by studies of different populations with a broader spectrum of barriers to drug adherence. These studies may ideally be conducted with other validated measures of adherence such as electronic monitoring or pill counts.

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REFERENCES
1. Paterson D, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133:2130. 2. Rodriguez-Rosado R, Jimenez-Nacher I, Soriano V, Anton P, Gonzalez-Lahoz J. Virological failure and adherence to

16.

17.

antiretroviral therapy in HIV-infected patients. AIDS.1998; 12:11121113. Bangsberg D, Hecht F, Charlebois E, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS. 2000;14:357366. Hecht F, Colfax G, Swanson M, Chesney M. Adherence and effectiveness of protease inhibitors in clinical practice. Presented at: Fifth Conference on Retrovirus and Opportunistic Infections; February 1998; Chicago. Abstract 151. Miller L, Hays R. Measuring adherence to antiretroviral medications in clinical trials. HIV Clin Trials. 2000;1(1):3646. Haubrich R, Little S, Currier J, et al. The value of patientreported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group. AIDS. 1999;13:10991107. Frick P, Gal P, Lane T, Sewell M. Antiretroviral medication compliance in patients with AIDS. Aids Patient Care STDS.1998;12:463470. Gifford A, Bormann J, Shively M, Wright B, Richman D, Bozzette S. Predictors of self-reported adherence and plasma HIV concentrations in patients on multidrug antiretroviral regimens. J Acquir Immune Defic Syndr. 2000;23:386395. Holzemer W, Corless I, Nokes K, et al. Predictors of selfreported adherence in persons living with HIV disease. Aids Patient Care STDS. 1999;13:185197. Singh N, Berman S, Swindells S, et al. Adherence of human immunodeficiency virus-infected patients to antiretroviral therapy. Clin Infect Dis.1999;29:824830. Duong M, Piroth L, Forte F, Chavanet P, Portier H. Serum protease inhibitor level as a marker of adherence to HAART; correlation with self-reported adherence and HIV RNA. Presented at: 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 1999; San Francisco. Abstract 2069. Murri R, Ammassari A, Gallicano K, et al. Patient-reported nonadherence to HAART is related to protease inhibitor levels. J Acquir Immune Defic Syndr. 2000;24:123128. Chesney M, Ickovics J, Chambers D, et al. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: The AACTG adherence instruments. AIDS Care. 2000;12(3):255266. Eron J, Yetzer E, Ruane P, et al. Efficacy, safety, and adherence with a twice-daily combination lamivudine/ zidovudine tablet formulation, plus a protease inhibitor, in HIV infection. AIDS. 2000;14:671681. Childress J, Jhingran P, Scott-Lennox J, Tolson J. Development and initial evaluation of the Patient Medication Adherence Questionnaire. Presented at: Sixth European Conference on Clinical Aspects and Treatment of HIV Infection; October 1997; Hamburg, Germany. Weiss L, French P, Finkelstein R, Waters M, Kluger M, Agins B. Knowledge, attitudes and adherence to HAART: Results of a multisite adherence evaluation project. Presented at: 13th International AIDS Conference; July 2000; Durban, South Africa. Abstract ThPeB 5018. Mostashari F, Riley E, Selwyn P, Altice F. Acceptance and adherence with antiretroviral therapy among HIV-infected

PREDICTORS OF ADHERENCE TO ANTIRETROVIRAL THERAPY

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women in a correctional facility. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:341348. 18. Valente S, Saunders J, Ulman G. Self-care, psychologycal distress and HIV disease. J Assoc Nurs AIDS Care. 1993; 4:1525. 19. Singh N, Squier C, Sivek C, Wagener M, Nguyen M, Yu V. Determinants of compliance with antiretroviral therapy in

patients with human immunodeficiency virus: Prospective assessment with implications for enhancing compliance. AIDS Care.1996;8:261269. 20. Andrews L, Friedland G, Mannheimer S, et al. A method for assessing patient readiness to begin and adhere to HAART. Presented at: 13th International AIDS Conference; July 2000; Durban, South Africa. Abstract ThPeB 4987.