- Top of page
OBJECTIVE: Adherence to complex antiretroviral therapy (ART) is critical for HIV treatment but difficult to achieve. The development of interventions to improve adherence requires detailed information regarding barriers to adherence. However, short follow-up and inadequate adherence measures have hampered such determinations. We sought to assess predictors of long-term (up to 1 year) adherence to newly initiated combination ART using an accurate, objective adherence measure.
DESIGN: A prospective cohort study of 140 HIV-infected patients at a county hospital HIV clinic during the year following initiation of a new highly active ART regimen.
MEASURES AND MAIN RESULTS: We measured adherence every 4 weeks, computing a composite score from electronic medication bottle caps, pill count and self-report. We evaluated patient demographic, biomedical, and psychosocial characteristics, features of the regimen, and relationship with one's HIV provider as predictors of adherence over 48 weeks. On average, subjects took 71% of prescribed doses with over 95% of patients achieving suboptimal (<95%) adherence. In multivariate analyses, African-American ethnicity, lower income and education, alcohol use, higher dose frequency, and fewer adherence aids (e.g., pillboxes, timers) were independently associated with worse adherence. After adjusting for demographic and clinical factors, those actively using drugs took 59% of doses versus 72% for nonusers, and those drinking alcohol took 66% of doses versus 74% for nondrinkers. Patients with more antiretroviral doses per day adhered less well. Participants using no adherence aids took 68% of doses versus 76% for those in the upper quartile of number of adherence aids used.
CONCLUSIONS: Nearly all patients' adherence levels were suboptimal, demonstrating the critical need for programs to assist patients with medication taking. Interventions that assess and treat substance abuse and incorporate adherence aids may be particularly helpful and warrant further study.
Available treatment for HIV can dramatically suppress viral load, enhance CD4 counts and decrease morbidity and mortality related to HIV infection.1–6 If antiretroviral medications are not taken as prescribed, treatment failure may ensue.7–21 Nonadherence is widely viewed as a risk factor for drug-resistant virus, which can be transmitted through unsafe sexual and drug use practices.8 It appears that patients must ingest at least 90% to 95% of their prescribed doses consistently to maintain virologic success.7,9 Although patients taking antiretrovirals generally achieve higher levels of adherence than do patients on other chronic medical therapies,7,21 the regimens are complex and lifelong; not surprisingly, a large proportion of patients are unable to achieve the targeted levels of adherence.13,21–25 Therefore, interventions to facilitate patients' adherence to antiretroviral medications are critical to optimal HIV care.
Development of successful interventions to improve adherence requires a detailed understanding of the numerous factors that influence patients' medication taking. Identified correlates of adherence are often grouped into several broad categories: characteristics of the patient,26 features of the regimen,27 aspects of the clinical interaction,28 features of the illness, and socioenvironmental factors.29 Studies that have assessed adherence to antiretroviral therapy (ART) have identified salient factors in each of these categories.22,23,30–56 Unfortunately, many reports have been limited by a cross-sectional design, the use of self-report measures or both.7,13,30–48 Several studies assessed only patients' self-reported reasons for nonadherence, rather than testing for associations between these factors and actual adherence.36,37,45,47,48
We designed a longitudinal, cohort study to address some of the unresolved questions related to the influence of various factors on adherence to ART. We prospectively measured hypothesized predictors of ART adherence and followed patients for a prolonged period of time (up to 48 weeks). Then we used a carefully constructed measure of adherence that has been shown to be significantly predictive of virologic outcomes.21 We derived the following hypotheses from the existing literature and tested them in this study:
We hypothesize that patients who have more-positive attitudes toward ART,22,31,37,38,45
greater self-efficacy toward adherence,44,38
and higher literacy levels42
will be more adherent with ART. We expect patients who are active substance abusers22,31,33,38,46,49
or who report lower emotional well-being7,33
to be less adherent.
We expect that patients receiving more complex antiretroviral regimens22,27,31,49,52
and regimens that fit less well with the other daily activities35,38,40,41,44,48,52,53
will be less adherent. We also expect that use of adherence aids (such as pillboxes, medication timers, etc.)31
will be associated with better adherence.
Features of the Clinical Interaction:
We expect patients with greater continuity of care, satisfaction with medical care, and trust in their provider to be more adherent,57–65
: We expect patients with more social support to be more adherent.40,45,46,54,55
- Top of page
We conducted a prospective cohort study among patients initiating a new highly active ART regimen to assess their objectively measured antiretroviral adherence during the 48 weeks following initiation of therapy. This study goes beyond prior work by evaluating adherence prospectively over a long time period among patients at the time of initiation of a new combination antiretroviral regimen. On average, patients attending this public hospital–affiliated clinic took about 71% of their prescribed doses. This is consistent with other studies showing that patients on combination ART miss fewer pills than do most patients on other chronic medical therapies.7 However, this adherence level is lower than that required to prevent treatment failure.7 In fact, 96% of patients in this sample took less than the 95% of prescribed doses probably necessary for long-term success.7,21 These data underscore the extraordinary need that exists for interventions to facilitate patient adherence to antiretrovirals.
To help inform such interventions, we tested an a priori conceptual model of hypothesized determinants of adherence to identify factors affecting ART adherence. In multivariate analyses, African-American ethnicity, lower income and education, alcohol use, active drug use, greater dose frequency, and the use of no adherence aids were independently associated with worse adherence.
The relationship between substance abuse and adherence appears to be complex. Patients who drank alcohol were significantly less adherent. Current active drug use was also associated with suboptimal adherence. At the same time, there was no association between adherence and a history of prior drug use. Some studies have shown that any history of intravenous drug use is associated with worse adherence,31,46 while others have found that recovered intravenous drug users demonstrate increased adherence to ART.33,49 Our results are consistent with studies showing that active substance abuse is the important predictor of ART adherence.22,31,33,38,46,49 These findings underscore the need for ongoing assessment of substance abuse and concurrent alcohol and drug counseling for patients on antiretroviral therapy. Use of alcohol and drugs needs to be talked about as a part of in-depth discussions about antiretroviral medication taking.
Patients who used more adherence aids were more adherent. This finding is interesting, and to our knowledge, this relationship has been noted in only 1 prior study.31 We cannot assume a causal relationship between aids such as pillboxes and calendars and adherence, yet such reminder systems may represent important intervention options. Preliminary reports of the impact of reminders on adherence have had mixed results. In a pilot study of 55 patients, only those who received monetary reinforcement in addition to reminders and MEMS feedback were more adherent than controls.79 In contrast, in preliminary data from another randomized trial of an on-line paging system, patients receiving paged medication reminders improved their adherence significantly more than controls over 4 weeks.80 In qualitative studies, HIV-positive patients reported the usefulness of technological adherence aids, but many patients were unaware that such aids existed.56 The incorporation of these aids into clinical practice may be warranted, given their association with adherence in this prospective study. Including standardized patient education about adherence aids during ART initiation is a practical way to introduce patients to these potentially valuable interventions. Further studies are needed to assess the long-term effects of medication reminder systems and to compare the efficacy of different types of reminders to improve ART adherence. Of note, because the use of MEMS precludes pillbox use, the relationship between pillbox use and adherence could be confounded by the measurement technique used. To determine whether this is the case requires more intensive study with a trial focused on types of adherence adjuncts. If such studies show that pillboxes are associated with better adherence than MEMS, then for both ethical and clinical reasons, clinical trials should not preclude pillbox use in favor of MEMS.
Dose frequency was related to adherence, although the total number of pills and the total number of antiretrovirals prescribed was not. This supports prior studies demonstrating the importance of the number of times per day medications must be taken, although not all of these studies also assessed the number of medications taken.22,27 More frequent dosing may lead to missing doses because patients have difficulty with the middle of the day dose.56 The impact of dosing complexity on adherence can guide clinicians in selecting medication regimens and delineates a role for adherence aids to help to remind patients of midday doses. In addition, the fact that dose frequency is the only aspect of regimen complexity that affected adherence may have important implications for the development of combination pills, particularly if these medications are taken more frequently and/or are more expensive.
Lower educational achievement and lower income each were independently associated with having lower adherence. The relationship of lower socioeconomic status with ART adherence has been identified in other studies34,44,50 but not consistently. This strong association does not appear to be mediated by access to care or literacy, neither of which were related to adherence in this study. Literacy, found to be related to adherence in other studies,42 may have been compromised in this evaluation because of the large number of imputed values. The finding that lower education level is associated with worse adherence is consistent with the fact that understanding of treatment recommendations is necessary for adherence.
The finding that after controlling for other sociodemographic features, African-American patients were less adherent than others has also been noted in some studies34,44,50 but not others.22,41,42 Attempts to understand the mediators of the association between African-American ethnicity and nonadherence were unsuccessful in this study. We evaluated patients' beliefs about antiretrovirals, their trust in the provider, and their access to care. Post-hoc analyses indicate that there was no correlation between African-American ethnicity and beliefs about the medication. Further, there was no association between ethnicity and trust in the provider or access to care. It may be that because we measured trust in the physician only and access to medications specifically, we did not assess the exact beliefs that might explain these differences. Further studies to understand the mediators of nonadherence in relation to ethnicity are needed.
Several factors hypothesized to be associated with antiretroviral adherence were not. Patients who reported that their provider performed more adherence counseling and those with more-positive beliefs about the medications and more social support were no more adherent than other patients. However, adherence counseling was measured by patient report and may not accurately reflect provider behavior. At the same time, the trend toward greater adherence among patients with more trust in their provider and who were in a drug study suggests that the contact and rapport with the medical provider may play a role in influencing adherence. The vast majority of patients had positive beliefs about their medication, including high self-efficacy to take the medications. The minimal variation in responses to these questions may explain the lack of association between beliefs and adherence. Alternatively, some of the nonsignificant associations between predictors and the adherence measure could be due to limitations of the measures.
It is interesting that the reasons that patients gave for missing doses differed from those identified in comparative analyses. Although patients reported that factors related to fitting the regimen into their lifestyle (such as being busy, having a change in routine, being asleep) were important reasons for missing doses, perceptions of the medication fit with their routine was not associated with objectively measured adherence. This is in contrast to studies of self-reported adherence.44 Hence, patients' perceptions of how well the regimen fits into their lifestyle may be more related to perceived adherence than to actual adherence.
The findings of this study must be interpreted in light of its limitations. Because it was conducted at a single site, the findings may not be generalizable to dissimilar clinical settings. In addition, this is an observational study, and the associations found cannot be assumed to be causal. However, the prospective design does reduce temporal ambiguity, and our multivariate analyses reduce confounding bias. Although the method we used to measure adherence allowed us to exclude MEMS data that were likely to be invalid (such as with the use of pillboxes), we may have missed some episodes in which patients took more than 1 dose out of their bottle at a time. Missing such episodes would result in a slight underestimate of adherence, but failure to adjust for these errors is extremely unlikely to change the findings of the study. Further, we did not assess predictors of different patterns of adherence, which may also be related to virologic outcomes. Finally, our sample size may have prevented us from detecting some relationships.
In summary, consistent with other studies, the vast majority of patients in this longitudinal study need interventions to improve adherence. Interventions are needed that attend to the needs of low-income, low-education patients. We also confirm other studies that underscore the need for ongoing assessment and treatment of substance abuse in concert with antiretroviral therapy. In addition, data reported here suggest a new finding: interventions that include technological aids and other reminders to help patients take their doses may be particularly useful and warrant further study. Finally, more forgiving, less-frequently dosed medications are needed to help patients on ART adhere and maintain virologic success.