Sorting Adherence Risk Factors to Shape Better Adherence Care

September 22, 2017

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Abstract: Review of recent studies -- from meta-analyses to cross-sectional cohorts -- indicates more than 30 potential reasons for poor antiretroviral adherence. Many of these risk factors overlap with others, and multivariate analysis cannot always disentwine these overlaps. In addition, some studies disagree on whether certain variables impair or promote adherence. Although people taking antiretrovirals often cite "simply forgetting" as the prime reason for poor adherence, several analyses indicate that forgetting does not explain erratic pill taking for most HIV patients and that memory aids will not improve adherence. Adherence factors amenable to change include alcohol and other substance use, smoking, depression, and antiretroviral side effects. Some well-planned studies indicate that treating depression improves antiretroviral adherence. One study offers persuasive evidence that "nonspecific" side effects and seemingly minor side effects like cough, fatigue, and taste disturbances can imperil adherence. Plentiful research shows that adherence often slips measurably in the early postpartum period.

Potential reasons for poor antiretroviral adherence -- and for good adherence -- seem limited only by the imagination of adherence researchers. A review of metaanalyses, prospective and cross-sectional cohort studies, and randomized controlled trials turned up 32 reasons for good or bad adherence (Table 1). Even grouping these reasons into broad categories still leaves seven: demographic, habitual, behavioral, economic, HIV-related, non-HIV clinical, and psychological. And this breakdown relies on studies published mostly in the past 10 years that typically used statistical analysis beyond descriptive comparisons -- such as multivariate analysis or data pooling.

Table 1. Identified Adherence Promoters (+) and Barriers (-)
Female gender (-)1-4
Postpartum vs pregnancy (-)5-8
Black race (-)9,10
Older age (+/-)9,11,12
Younger age (-)13

Forgetting (-)14,15
Being away from home (-)14,15
Change in daily routine (-)14,15
Being busy (-)15
Alcohol use (-)12,16-18
Other substance use (-)12,14,19-24
Smoking (-)9,12,25
Conduct disorder/disruptive behavior in youth (-)26,27
Caregiver factors* (-)28

Employment (+/-)15,29
Financial constraints (-)21
Food insecurity (-)30,31
Housing instability (-)32,33
Social support (+)21,28
Stress/trauma/violence (-)34-36
Poor understanding of HIV (-)15
More education (+)9,25
Concerns about ART (-)21,24
Negative beliefs about necessity/utility of ART (-)21,24
Antiretroviral side effects (-)4,37,38
CD4 count (+/-)9,25,39,40
Trust/satisfaction with provider (+)21

Non-HIV clinical
Comorbidities (-)2,41
Comedications (+/-)9,13,41
Feeling sick/feeling well (+/-)14

Depressive/psychological symptoms (-)14,17,21,22,26,42-44
Antidepressant therapy (+)10
Self-efficacy (+)4,15,21
HIV stigma (-)14,21

* Caregiver not fully responsible for medications, low caregiver well-being, adolescent perceptions of poor caregiver-youth relations, caregiver perceptions of low social support.28

Certain studies disagree on whether a particular factor promotes or impairs adherence. Most studies, for example, find better adherence with older age and worse adherence with younger age. But secondary analysis of data from 326 participants in a US randomized smoking cessation trial linked older age to worse adherence in these smokers.12 In a 28-study meta-analysis, employment promoted adherence in high-income countries and lowincome countries.29 But an older analysis of US patients at 10 AIDS Clinical Trials Group (ACTG) sites found worse adherence among people employed outside the home.15 Analysis of the international SMART trial9 and the Swiss HIV Cohort Study13 confirmed better adherence in people taking comedications for non-HIV conditions, while a prospective cohort study in Spain linked more comedications to worse adherence.41 People with a higher current CD4 count had worse adherence in a cross-sectional Dutch study,40 but a lower enrollment CD4 count predicted worse adherence in a small study of US patients,25 while an 18-study meta-analysis yielded mixed results on the impact of CD4 tallies.39

Reasons for such contradictions -- and for the vast array of potential adherence variables -- reflect wide differences in study populations, methods, and antiretroviral era. Adherence is easier today than when most regimens hinged on a ritonavir-boosted protease inhibitor or efavirenz . But difficulties in pinpointing discrete adherence promoters and barriers also reflect the confounding overlap of both individual variables and whole categories of variables. As just one example, the demographic variable race may easily overlap behavioral, economic, HIV-related, non-HIV clinical, and psychological barriers (Table 1).

Multivariate analysis can help sort out individual impacts of isolated factors, but no multivariate analysis can control for the dozens of confounders that may cloud results. One resonant example is female gender. HIV-positive women throughout the world endure disadvantages that also imperil adherence (Table 1) including (to name but a few) unemployment, financial constraints, food and housing insecurity, lack of social support, trauma and violence, less education, and HIV stigma. A 29-state 5177-person analysis of adherence in Medicaid recipients 50 to 64 years old found that men were 11% more likely to be adherent than women (adjusted prevalence ratio 1.11, 95% confidence interval [CI] 1.02 to 1.21, P = 0.0127).2 But that analysis adjusted for only age and state, not for the just-listed socioeconomic variables.


Should Adherence Motivators "Forget About Forgetting"?

Some research rates "just forgetting" the primary reason for shaky antiretroviral adherence. A 125-study meta-analysis involving 17,061 adults, 856 adolescents, and 1099 children found forgetting the most frequent patient-reported adherence barrier in adults (41.4%) and adolescents (63.1%), far ahead of the second-place barrier, being away from home (30.4% in adults and 40.7% in adolescents).14 A survey of 75 adult ACTG study participants at 10 trial sites found "simply forgot" the reason for missing doses in 66%, ahead of being away from home (57%) or being busy (53%).15 And multivariate analysis in an 80-person US CHARTER cohort substudy linked worse pharmacy refill adherence to worse working memory on standard tests.45

Despite the frequency of forgetting to take antiretrovirals14,15 and the intuitively compelling tie between faulty memory and poor adherence,45 other research in the United States argues that "just forgetting" does not fundamentally explain erratic pill taking for most people with HIV. This work is important because, if correct, it means clinicians should spend less time promoting adherence memory aids and more time drilling down to underlying causes of poor adherence that need to be addressed. Here are the key findings:

A University of Connecticut group analyzed 556 people with less than 95% antiretroviral adherence according to phone-based unannounced pill count, dividing them into severely nonadherent patients (75% or fewer medications taken) and moderately nonadherent patients (more than 75% to less than 95% taken).46 As in other studies,14,15 forgetting topped the list of reasons for missing doses in severely nonadherent people (54%) and in moderately nonadherent people as well (41%). Reasons related to mental health, structural barriers, and substance use proved much less frequent. High and similar proportions of the severely and moderately nonadherent groups relied on multiple dosing-reminder strategies, such as using bedtime as a cue (67% and 65%), using mealtimes as a cue (61% and 61%), storing medicines where they can be easily seen (58% and 56%), and using pill box organizers (42% and 39%).

Multivariate logistic regression to distinguish severe nonadherence from moderate nonadherence controlled for the four sets of adherence barriers analyzed: cognitive/organizational (which includes forgetting), mental health (such as depression), structural barriers (such as running out of pills or being unable to pay for them), and substance use. Neither cognitive/organizational nor mental health barrier composites distinguished severe from moderate nonadherence. But structural barriers boosted odds of severe nonadherence almost 50% (adjusted odds ratio [aOR] 1.49, 95% CI 1.17 to 1.89, P < 0.05), and substance use raised odds of severe nonadherence by one third (aOR 1.32, 95% CI 1.02 to 1.73, P < 0.01). The researchers suggest that colleagues "forget about forgetting" as a way to improve antiretroviral adherence. Rather, they propose, efforts should "concentrate on substance use treatment and providing case management to resolve structural barriers to adherence."46

In a study of 223 US adults with adherence measured by electronic MEMS pill bottle caps, the more adherence reminders people used, the worse their adherence got.47 The largely male (83%), white (66%) study group completed the Prospective Memory for Medications Questionnaire to assess use of 28 adherence strategies. Participants reported using an average 8.7 strategies at least sometimes. The most frequent memory aids were leaving pill bottles in a prominent place (69% at least sometimes), linking dose times to something done routinely (68%), and thinking about dosing times at the beginning of the day (61%). But statistical analysis linked use of more adherence strategies to worse antiretroviral adherence (-0.15, P = 0.02). The study also found that using more reminder strategies did not reflect patient belief that they would work. Perhaps the researchers discovered a dismal feedback loop in which people use more and more reminders, yet adhere less and less, leading to less belief that strategies work, prompting use of even more reminders (Figure 1, outside arrows). Or maybe the loop runs the other way: people use more and more reminders, yet believe less and less that the strategies work, fulfill their own forecast by taking fewer antiretrovirals, and thus prompt use of even more reminders (Figure 1, inside arrows).

Possible Reminder-Adherence Feedback Loops

Possible Reminder-Adherence Feedback Loops

Figure 1. Research linking more adherence reminders to worse adherence -- with no link between using more reminders and believing they work47 -- suggests one of two negative feedback loops in which people use more adherence reminders to no avail.

Analysis of 1496 adults in 11 ACTG studies that ended from 2002 through 2012 also found memory-related pitfalls the most common self-reported reasons for poor adherence at treatment week 12.48 But forgetting ranked far behind other barriers (too many pills, side effects, depression) in explaining a detectable viral load at 24 weeks. The most frequently cited adherence barriers were being away from home (21.9%), simply forgetting (19.6%), a change in daily routine (19.5%), and falling asleep (18.9%). Multivariate analysis adjusted for all 14 potential adherence barriers found one independent predictor of failure to have an undetectable viral load at 24 weeks, "felt sick" (aOR 0.53, 95% CI 0.37 to 0.76, P < 0.001). Two variables marginally predicted virologic failure, "too many pills" (aOR 0.61, 95% CI 0.37 to 1.01, P = 0.06) and "felt drug was harmful" (aOR 0.62, 95% CI 0.37 to 1.04, P = 0.07). "Simply forgot" had no impact on virologic response in bivariate analysis (OR 0.99, 95% CI 0.76 to 1.30, P = 0.95).

Dominance analysis to assess the relative importance of each adherence barrier at 12 weeks in promoting virologic detectability at 24 weeks rated "simply forgot" ninth in importance. (Dominance analysis is a regression-based approach calculating effect size.49,50) The top five barriers were (1) felt sick, (2) too many pills, (3) felt drug was harmful, (4) wanted to avoid side effects, and (5) felt depressed/overwhelmed. The 1-through-14 dominance ranking did not even remotely reflect the 1-through-14 self-reporting frequency (Table 2). The ACTG researchers propose that "interventions should focus on barriers that have been associated with poor virologic outcomes rather than focusing on the most commonly reported barriers."48

Table 2. Adherence Barriers in 11 ACTG Trials Ranked for Impact on Virologic Response vs Self-Reported Frequency
Resistance BarrierRanked Impact on Undetectable Viral Load (24 wk)Patient Self-Reported Frequency (12 wk)
Felt sick16
Too many pills213
Felt drug was harmful312
Wanted to avoid side effects48
Felt depressed/overwhelmed59
Ran out of pills614
Busy with other things75
Taking pills at specified time87
Simply forgot92
Need to hide pill taking1011
Felt good1110
Change in daily routine123
Fell asleep134
Away from home141

Source: Saberi et al.48

Another study used dominance analysis49,50 to rank the importance of nine barriers to self-reported nonadherence (a 4-day interruption) in 1217 US adults (95% men, 76% white, 87% with an undetectable viral load).51 The analysis relied on an online survey to rate self-reported frequency of the nine barriers in this order:

  1. Simply forgot
  2. Day-to-day life
  3. Alcohol or illicit drug use
  4. Felt depressed/overwhelmed
  5. Ran out of pills
  6. Fell asleep
  7. Pharmacy/insurance problems
  8. Wanted to avoid side effects
  9. Felt sick

In the dominance analysis "simply forgot" fell to sixth place while "fell asleep" jumped to first:

  1. Fell asleep
  2. Felt depressed/overwhelmed
  3. Day-to-day life
  4. Wanted to avoid side effects
  5. Alcohol or illicit drug use
  6. Simply forgot
  7. Ran out of pills
  8. Felt sick
  9. Pharmacy/insurance problems

The ACTG researchers suggest that forgetting to take pills "may be ... multi-faceted and may include other barriers such as stigma, depression, drug and alcohol use, and lack of social support."48 They propose that basing adherence strategies solely on patient report frequency "may potentially lead investigators in the wrong direction and may result in ineffective interventions."

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