Evaluation of the Patient Medication Adherence Questionnaire As a Tool for Self-Reported Adherence Assessment in HIV-Infected Patientson Antiretroviral Regimens Michel Duong, MD,1 Lionel Piroth, MD,1 Michèle 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: Patient’s 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 A 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.1–3 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, Hôpital du Bocage, 2 Boulevard Maréchal Delattre de Tassigny, Dijon, 21034 France. Email:
[email protected]. HIV Clinical Trials 2001;2(2):128–135 © 2001 Thomas Land Publishers, Inc. 128 RTV. Study participants were asked to complete the PMAQ version 1. The interday percent coefficient of variation for these assays was lower than 10%. Self-Report Adherence The PMAQ was filled in by the patient. CD4 cell count. RTV. HIV RNA level. 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. cross-sectional study of HIV-infected patients who were followed at the Dijon Hospital AIDS day-care unit. a patient’s clinical. 129 methods have limitations. The assays were found to be linear over the concentration range and the lower limits of quantification were 5 ng/mL. NFV. 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. saquinavir (SQV). 0. Brachburg. there is no standardized instrument that may be used in routine clinical practice. NFV. or (ii) trough plasma PI levels were above reference values. and 9 ng/mL for IDV. and easy to implement in the patient’s follow-up. routine bio- chemistry analysis. either indinavir (IDV). to date.1.03 mg/L. respectively. METHOD Study Design and Patients This study was approved by our Human Subjects Protect Care Committee. at the moment. It was a prospective.1 mg/L. 0. 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. and SQV. RTV = 2. whether symptomatic or not. Plasma HIV RNA levels were assessed using the HIV-1 Amplicor Monitor assay (Roche Diagnostic Systems. Conversely. 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. social. and SQV = 0. USA) with a limit of detection of 20 copies/mL and were transformed to log10 values.07 mg/L. Measure of Adherence to ARV Therapy Adherence was assessed by the means of two biological markers: plasma PI levels and plasma HIV concentrations. and nonconsistent results were found when it was compared to more objective measures. This questionnaire contained 61 items that were designed to evaluate a patient’s treatment adherence behavior and its determinants by providing a quantitative measure of adherence .6 However this method has been shown to overestimate adherence. which is simple. In the present study. or ritonavir (RTV). and the level of protein binding.8–10 Even though a variety of surveys have been developed to monitor self-reported adherence. both in the HIV setting and non-HIV setting.7 Nevertheless. 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. which is why. Another approach may be patient self-report.4. adherence was considered inadequate when conditions (i) and (ii) were not met. psychological. the pharmacokinetic properties of the drug. relatively inexpensive.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. A trained research assistant was present to give explanations to patients who had difficulty understanding some items of the PMAQ. Patients with documented HIV infection.1 mg/L.11.PREDICTORS OF ADHERENCE TO ANTIRETROVIRAL THERAPY • DUONG ET AL. and behavioral variables are among the most important factors that influence adherence. The eligible patients were asked by the nurse if they wanted to participate in the study. and trough plasma PI level were performed the same day. Self-reported nonadherence has been demonstrated to be associated with worse virologic outcomes. These reference values were the following: IDV = 0. no reference method can be recommended. Full blood count. The determinations of masked plasma PI levels were performed using chromatographic methods coupled with an ultraviolet detection for IDV. NFV = 1 mg/L. NJ. In fact. few studies have assessed the impact of such factors.0. 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. nelfinavir (NFV).03 mg/L. and SQV. At the time of study. and “I have never missed any doses of my medications over the last three months. 60 patients were on stage A. All patients completed the PMAQ. USA).130 HIV CLINICAL TRIALS • 2/2 • MAR-APR 2001 Table 1.51 log10 copies/mL). Each item is rated on a Likert scale from 0 to 3 or 0 to 5. The concepts assessed are summarized in Table 1.6 log10 copies/mL (range. A p value < . The chi-square test was used to compare categorical variables. Section 2 contains 55 items pertaining to barriers and motivators to taking medications. 70%) were men. The HIV infection risk factors were the following: heterosexual (40%). 49 on stage B. sex. etc. homosexual/bisexual (33%). education. psychological functioning. 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). Neither the use of alcohol or illicit drugs nor bothersome symptoms was significantly associated with less adherence. intravenous drug use (24%). and “ I have followed the special instructions associated with my ARV medications over the last four days” (80%. employment. The mean age was 40 years (range. 14 patients (9%) were on their first ARV regimen. trust in ARV therapy. p = . 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. Among the six items designed to assess adherence.03). Assessment measures No. stage of HIV infection. CA. and blood products (3%).05 was considered significant. 2–1.0005). and 40 on stage C. One hundred and four patients (104. It is divided into two sections. “I have closely followed the specific schedule associated with my ARV medications over the last four days”. p = . mean CD4 cell count was 485 x 106 cells/L (range. three items were significantly associated with drug adherence: “ I have not missed any doses of my ARV medications over the last four days” (89%. Berkley. 21–79 years). Associations between psychosocial variables and adherence to ARV and information on why a patient is or is not adherent.01). and having children at home did not correlate with adherence (see Table 2). 93 patients (63%) were at least on their second PI-containing regimen. According to the Centers of Disease Control and Prevention (CDC) 1993 criteria. RESULTS Population One hundred and forty-nine (149) HIV-infected patients were enrolled in the study between July .” Determinants of Adherence Age. Conversely. At time of inclusion into the study. Continuous variables (social support. Concerning PI use. Statistical Analysis Patient sociodemographics and measures obtained from the 61 items of the PMAQ were entered into the STATVIEW Statistics program (Abacus Concepts. 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. 0–6. “ I have not missed taking all my pills at least one day over the last four days” (82%. the following three items did not predict adherence: “I did not miss taking my ARV medications last weekend-last Saturday or Sunday”. p = .126 x 106 cells/L) and HIV RNA was mean 4.) were assessed by the Mann-Whitney test. risk behavior. few studies had shown its utility and. positive feelings about personal life and trust in personal skills were significantly associated with better adherence. especially in clinical trials. The firm belief of being able to take all or most of the HIV medications was strongly associated with adherence. In contrast. Neither stress nor depression was significantly associated with poorer ARV adherence. because neither being satisfied with friend and family’s support nor having somebody to remind the patient to take the medications was associated with drug taking. Among the different reasons for missing ARV doses.14 However. “Having problems taking pills at specified times” was more frequently reported by nonadherent patients. there is no clear validation of this self-administered questionnaire. the PMAQ is one of the most frequently used questionnaires.9 07 09 02 05 04 05 06 07 03 00 07 09 07 06 09 07 Adherent (n = 133) 40.45 43 52 33 5 .55 11 23 64 35 . p .76 . to date. insufficient knowledge about the efficacy of HIV medication and the risks of a suboptimal drug adherence was not predictive of nonadherence. DISCUSSION Patient self-report is now commonly collected for assessing adherence in HIV-infected patients. Among psychological variables.60 73 36 .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.7 35 98 . This finding confirms the relevance of an adherence evaluation over short rather than . 131 Table 2.89 73 59 .15 therapy are summarized in Table 3.PREDICTORS OF ADHERENCE TO ANTIRETROVIRAL THERAPY • DUONG ET AL. Satisfaction with social support was not a significant predictor of adherence. Sociodemographic variables and adherence of HIVinfected patients to antiretroviral therapy Nonadherent (n = 16) 39. Among the different instruments that measure self-reported adherence. being away from home was the only variable significantly associated with nonadherence (see Table 4).13.45 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. A patient’s education and any information about specific ARV therapy are undoubtedly necessary to make decisions about beginning or changing an ARV regimen.2) 1.8 (±1.2 (±1. I felt problems were piling up so high that I could not overcome them.1 (±1.9) 1. suggesting that this recommendation is less crucial than had previously been expected. Although it is obvious and has been demonstrated that side-effects are associated with decreased adherence to ARV therapy.132 HIV CLINICAL TRIALS • 2/2 • MAR-APR 2001 Table 3.5 . Contradictory data concerning these factors have been reported and.16 .2 (±1. I felt unable to control the important things in my life.8 (±.4 (±.16 .01 .22 . I felt that I was on top of things. HIV medications will become resistant if I don’t take my treatment exactly as instructed.7 (±1.7 (±1.1) 0. From named patient self-report.8 (±1.21 .7) 2. these conditions do .3) 2. My friends or family help me remember to take my medication. I felt that things were going my way. in fact. however.76 . I felt nervous and “stressed.3 (±1) 2.” I felt confident in my ability to handle my personal problems. social support. Taking drug “holidays” by skipping doses at the weekend is a well-known pattern of nonadherence.7) 2.3 (±1. I was able to control irritations in my life.2) Variable Social support I feel satisfied with the overall support I get from my friends and my family.05 . Finally. in our study.1) 1. HIV medications have a positive effect. to date.5 (±. p .21 . In fact.1 (±.1 (±1) . Trust in antiretroviral therapy I believe I will take all or most of my medication.1) 1.8 2 (±1.7) 1 (±1.1 (±1) 1.4) 2. we did not observe any effect of sociodemographic background. Several categories of items of the PMAQ were not significantly associated with medication adherence.8 (±1.1 (±1.9 (±1. perfect respect of the specific schedule associated with ARVs did not correlate with adherence.1 (±1) 2.2) 3 (±1) 2. long periods of time.16 However.1) 2.4) 2. many patients cannot accurately remember what doses were missed several weeks or days prior to a survey. and alcohol or illicit drug use on adherence.7) 2.73 . Hecht et al. Emotional limitations and psychological functioning In the past month: I was upset because of something that happened unexpectedly.3 (±1.1) Adherent (n = 133) 2. the differences in predictors of adherence seen between our work and other studies may reflect the differences in populations being studied. Psychosocial variables and adherence to antiretroviral therapy Nonadherent (n = 16) 2 (±1.3 (±.2) 2.4 showed that patients who had missed a dose of medication within the 2 days before their visit were likely to have detectable viremia.3 (±1. I was angered because of things that happened that were outside of my control.6 However.2) 1.53 .8) .3) . we did not find a significant association between this item and nonadherence because this behavior probably concerns a minority of our patients.1) 1.2) 1.2 (±1.0015 .9) .9 (±1.3 (±1) 2. we did not find any correlation between bothersome symptoms and adherence.3) 2.15 1. This finding suggests that patients do not systematically attribute to HIV medications the clinical symptoms they suffer from.1. I found that I could not cope with all the things that I had to do. their exact role as barriers to or motivators of adherence remains uncertain.4 Note: The answer to each item was rated on a Likert scale from 0 to 3 or 0 to 5.6 (±. Thus.17 also found that trust in safety and efficacy of ARV therapy was not associated with a statistically significant increase in drug taking.76 . Previous studies had demonstrated that stress and depression were more frequent in nonadherent patients.09 .9 (±1. I felt depressed/overwhelmed. we have identified some psychosocial behavior factors that are critical determinants of ARV consumption.9) Variable I was away from home.8 (±1.2) 0 . acceptance of ARV therapy) is also associated with the patient’s acknowledgment of the seriousness of the disease and the understanding of its potential complications.9) . I felt sleepy/slept through dose time.1) 1 (±1.9 We also found that faith in the future was a strong predictor of medication adherence.4 (±. Active behavioral coping positively influences the desire and the ability to organize the complicated drug regimens that HIV therapy may require.6 (±1.4 (±1) .3) . Other authors have reported that the most common reasons for missing medications included “simply forgot.7) . 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. our nonadherent participants significantly reported that they missed ARV doses because they were away from home. and an optimistic attitude to life. In assessing ARV use among HIV-infected female prisoners.10 found that depression was a significant factor.05 .27 .18.3) .3) Adherent (n = 133) . The conviction of being able to take the treatment has been identified in several studies as a central factor.7) .3 (±.8 This belief refers to a patient’s own decision about being treated.6 (±1. Using the Beck Hopelessness Scale.2 .8) .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.3 (±.2) . Monstashari et al.3 (±.3 (±. I did not want others to notice me taking medication. 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.46 .2 .8) .3) .68 . Singh et al.20 “Fighting spirit” was identified as being a strong determinant.4 (±. moreover. I thought the drug was toxic/harmful. 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.7) . Involvement of the patient in treatment (in particular. motivation with regard to ARV treatment. Therefore.8) . Initiation of ARV therapy at an inappropriate time leads in most cases to poor adherence whatever the accuracy of the treatment plan.6 (±1. I felt sick or ill. p . in this study.73 . I simply forgot. Relation between possible reasons for missing an HIV medication dose and adherence Nonadherent (n = 16) 1. confidence in personal skill.7) .25 (±. I found difficult to take pills at specified times.3) .9) . in particular.6 (±1.1) .2 (±. and justifying the need of a perfect fit between ARV medica- . Through the PMAQ.9 (±1.8 (±1. I had a change in daily routine. I was busy with other things.8) .2) .” being busy and being away from home.5 (±. which consists of 20 true–false statements designed to assess hopelessness. I had too many pills to take. 133 Table 4.24 . I wanted to avoid side effects.19 We are unable to confirm these results.3 (±.8) .1 (±.PREDICTORS OF ADHERENCE TO ANTIRETROVIRAL THERAPY • DUONG ET AL.5 (±. individuals who felt more confident in their personal skills were more likely to remain adherent to therapy. Finally.66 . lack of fighting spirit and loss of motivation have been identified as characteristics of the patients at risk for missing doses. clinicians should always evaluate patient readiness to begin therapy.2 (±. 12:463–470. Portier H.1(1):36–46. Germany. Virological failure and adherence to 16. Gal P. et al. AIDS. From a practical point of view. in HIV infection. AIDS. Our revised form of the PMAQ needs to be validated by studies of different populations with a broader spectrum of barriers to drug adherence. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: The AACTG adherence instruments. Finkelstein R. et al.133:21–30. Measuring adherence to antiretroviral medications in clinical trials. Charlebois E. Little S. Nokes K. HIV-1 viral load.. 2000. Patient-reported nonadherence to HAART is related to protease inhibitor levels. Gifford et al. Adherence to protease inhibitors.13:185–197. Murri R. safety. Nevertheless. Gallicano K. Swanson M. Presented at: Fifth Conference on Retrovirus and Opportunistic Infections. Chicago.8. Childress J. Mohr J. AIDS Care. Holzemer W. and convenience of the medication regimen as assessed by the reasons for missing doses. Sewell M. September 1999.134 HIV CLINICAL TRIALS • 2/2 • MAR-APR 2001 tion schedule and the patient’s daily routine. confidence in medication-taking ability. Acceptance and adherence with antiretroviral therapy among HIV-infected . et al. Even though each category of items is potentially interesting. California Collaborative Treatment Group. 11.1998. Chavanet P. Knowledge. Development and initial evaluation of the Patient Medication Adherence Questionnaire. 12:1112–1113. Selwyn P. Hays R. Jimenez-Nacher I. Berman S. resulting in a relatively low number of poorly adherent patients. Hamburg. 2. Thus. Swindells S. Presented at: Sixth European Conference on Clinical Aspects and Treatment of HIV Infection. San Francisco. Aids Patient Care STDS.24:123–128. 10. 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