Relationship Between Neurocognitive Domains and Adherence
After replacing GDS with each of the 7 NP domains, only one, working memory, showed a significant effect on adherence (P = 0.026, Table 3). Worse working memory was associated with poorer adherence. Duration of HIV infection was still associated with adherence in the model that included working memory, but sex was no longer a significant factor and was removed from the final model.
Relationship Between Adherence by Pharmacy Refill Data and Changes in Plasma and CSF HIV RNA
The relationships between adherence and changes in plasma and in CSF HIV RNA were nonlinear. An examination of scatter plots of baseline HIV RNA levels versus change in RNA showed evidence of regression to the mean for viral load in plasma but not in CSF.
Only 12 of 74 subjects with RNA measurements in CSF had detectable baseline levels. Among these participants, better adherence was associated with greater declines in CSF HIV RNA, especially in those with higher baseline viral load (adherence P = 0.058, RNA P = 0.013, interaction P = 0.08, Table 4). For example, mean [standard error (SE)] reduction in CSF HIV RNA (log10 copies/mL) was estimated to be −0.4 (0.7) for baseline RNA of 2 log10 and −1.1 (0.9) in subjects with baseline RNA of 4 log10 and approximately 75% adherence, whereas the mean (SE) changes estimated were −0.2 (0.8) and −2.4 (0.8) log10, respectively, with 100% adherence. Among the 58 subjects for which baseline CSF RNA results were available and undetectable, 52 (90%) had viral loads that remained undetectable at month 6 and had median (IQR) adherence of 96% (85%–100%); the remaining 6, with median (IQR) adherence of 93% (58%–100%), had increases of <1 log10 (N = 4), and between 1 and 2 log10 (N = 2) at month 6.
Evidence of regression to the mean precluded any adjustment for baseline plasma RNA levels.41 For the 46 subjects with detectable baseline plasma HIV RNA, adherence alone, estimated by pharmacy refill data was not associated with plasma viral load change (P = 0.719); 17 (37%) of these subjects had undetectable plasma viral load at the 6-month visit and median (IQR) adherence of 95% (67%–99%); the remaining 29 who had detectable plasma HIV RNA at 6 months had median (IQR) of 92% (78%–100%) adherence. Among the 34 subjects with undetectable plasma RNA at baseline, 29 (85%) had viral loads that remained undetectable at 6 months and had median (IQR) adherence of 95% (85%–99%); the remaining 5 had plasma RNA increases ranging from 0.05 and 3.2 log10 and median (IQR) adherence of 98% (52%–100%).
Antiretroviral Adherence by Self-Report
At baseline, the mean (SD) self-reported 4-day adherence for the 74 subjects for whom these data were available was 98.2% (5.7%), with no site differences. When adherence was defined by this metric as ≥95%, 65% (88%) and 69% (94.5%) of subjects reported being adherent at baseline and the 6-month visits, respectively, with no site differences.
Relationship Between Self-Reported Adherence and Changes in Plasma and CSF HIV RNA
With the lowest self-reported adherence at either the baseline or 6-month visit dichotomized as 100% (n = 39) vs <100% (N = 7) for the 46 subjects with detectable baseline plasma HIV RNA, there was no difference in plasma HIV RNA change between the 2 adherence groups (P = 0.748).
Among the 12 subjects with detectable CSF HIV at baseline, there was a significant effect of self-reported adherence on change in CSF HIV RNA (P = 0.0055) and significant effects of baseline CSF levels and the interaction of these 2 variables (P < 0.0001 and P = 0.0024, respectively). Those with higher baseline CSF HIV RNA and higher adherence had greater decreases estimated in their CSF HIV RNA over 6 months than those with lower baseline CSF viral load regardless of adherence.
The study used a novel metric to assess adherence and evaluated longitudinal plasma and CSF RNA changes. Data from these 2 US sites in the CHARTER study suggest that HIV-infected participants with greater overall NP deficits and specific deficits in working memory have lower ART adherence, as defined by our pharmacy refill record review. This adherence measure was focused on the drug with the maximal CNS ART penetration–effectiveness score.37 Notably, better adherence based on this metric was associated with decreasing levels of CSF HIV RNA over a 6-month time period.
Global NP impairment has been independently associated with ART nonadherence in studies incorporating multivariable analyses to account for other confounding factors. After controlling for age, current psychiatric disorders, neurologic conditions, and regimen complexity, global NP impairment correlated with ART nonadherence measured by MEMS caps over a 4-week period.22 In a different study, decreased NP function in adults older than 50 years was the sole predictor of ART nonadherence.21 Many studies relating cognition and adherence have been cross-sectional and unable to address causal associations. Does NP impairment result in suboptimal adherence, is poor adherence and consequent ongoing HIV replication causing NP impairment, or are both pathways contributing to a vicious cycle?24 Relatively few longitudinal studies have addressed this issue. Older age is often associated with better adherence. However, Hinkin et al41 reported that 83% of subjects older than 50 years with poor adherence were cognitively impaired. Over 4 weeks, nonadherence (by MEMS caps) was associated with poor baseline global NP functioning in a subset of 23 subjects with consistently poor adherence.42 Retrospective analyses of HIV-infected adults in Los Angeles showed that those with decline in global NP function over 6 months had a greater drop in ART adherence than those with stable function.25 Controlling for baseline factors, our findings suggest that global cognitive deficits were associated with poor ART adherence over the subsequent 6 months.
Some prospective studies have reported that specific cognitive domains are associated with ART adherence. Levine et al42 noted working memory and attention deficits in 27 subjects with poor weekend adherence in a 4-week study. A study of New York City men who have sex with men found worse performance on Trail Making Test Part B (which has a working memory component as well as flexibility of thinking and speed of information processing) was associated with worse adherence over 10 months.43 Prospective memory, the ability to “remember to remember” something in the future correlated with adherence in a clinical trial.44 Deficits in time-based prospective memory were independently predictive of poor ART adherence over 1 month.22 Thus, our finding that worse working memory, in combination with other factors, was associated with lower subsequent ART adherence is generally consistent with these reports and suggests that our results may be generalized to other US adults. Successful antiretroviral adherence is a complex task, requiring intention to take medication at specific time(s) per day, retaining this plan during daily activities, remembering dosing time and any associated instructions (eg, take with food or on an empty stomach), and executing the plan by taking the medication.22 Since others have described that working memory deficits can negatively affect higher level cognition, such as decision making45 and everyday functioning,46 it is not surprising that such deficits can negatively impact ART adherence.
In our study, better adherence was seen in men and those with longer estimated duration of HIV infection. Data on the relationship between sex and ART adherence have been inconsistent, although a recent review suggested that women have worse adherence than men, similar to our findings.47 In that report, depression and lack of support systems were associated with poorer adherence in women. Although some reports link depression to nonadherence, this relationship was not found in other studies or in ours.21,47 We did not collect information on support systems, although our subjects may have benefited from contact with CHARTER staff. In our multivariable model of specific NP domains, working memory moderated the significant association between sex and adherence (Table 3). Our observation that longer duration of estimated HIV infection was associated with better adherence may reflect survivorship bias.48 It is also possible that this association is confounded by age (ie, better adherence in older subjects, after correcting for NP function).
We found that worse NP functioning led to poorer adherence in JHU patients but had a negligible effect in UW participants. Although our multivariable analyses contained likely confounding factors, these analyses may not have adequately adjusted for all potential differences between sites. For example, UW subjects were more likely to be male, younger, and less likely to be African American. Although older patients usually have better adherence, age-related cognitive decline (ie, normal cognitive aging) might have exacerbated the impact of disease-related NP deficits on adherence at JHU.21 Higher level of premorbid intellectual function at UW, as indicated by higher WRAT scores, may also have moderated the impact of NP impairment. Finally, possible differences in adherence support services at the sites might also explain the greater impact of NP impairment on adherence at JHU.
We evaluated pharmacy refill records as an alternative monitoring tool because of concerns about the accuracy of self-reported adherence in NP-impaired patients. Like our pharmacy refill-based adherence data, self-reported adherence was significantly correlated with virologic suppression in CSF, even among the participants who had detectable CSF HIV RNA at baseline. Although pharmacy refill records have previously been correlated with plasma viral load suppression, we were not able to confirm such an association in our study. However, the 4-day self-report has recognized limitations, including overestimating adherence.5 We did a priori identify our pharmacy refill metric as the primary adherence metric for this study, and our refill records-based adherence metric was associated with reduction of CSF HIV RNA values in all subjects studied. Because CPE score was the primary criterion for identifying a sentinel drug in our study, the relationship between better adherence and reduction in CSF HIV suggests that the protection afforded by better CNS-penetrating drugs may have preserved cognition and consequently adherence. This possibility is supported by Cysique et al49 who reported that CPE score was an independent predictor of NP improvement in study participants with HAND who started ART.
Our results are limited by a relatively small sample size. In addition, these findings are most generalizable to patients obtaining medications at a single pharmacy. Filling prescriptions does not guarantee that medications are taken. Finally, factors such as stockpiling doses or obtaining medications from other pharmacies could have affected our refill metric. In spite of these limitations, we believe that this is the first prospective study with virologic outcomes using pharmacy refill records to quantify adherence to ART in HIV-infected patients who have undergone rigorous NP, psychiatric, and substance-use assessments.
In conclusion, poor adherence to ART in our study population was correlated with working memory and global NP deficits. Careful assessment of working memory and cognition before ART initiation and in patients with suboptimal virologic responses to ART may help identify persons in need of adherence support. Working memory training for stimulant addicts and strategies for rehabilitation of working memory deficits in persons with HIV infection have been described.50,51 Such strategies should be further investigated in persons with HAND to determine whether they can improve adherence and optimize benefits of ART.
The authors thank the study participants for their contribution. The authors would also like to thank Stephen Van Rompaey, PhD, Bradley Kosel, PharmD, and Mari Kitahata, MD, MPH for their assistance with accessing and cross-checking the UW pharmacy records; Deborah Lazzaretto and Chris Ake, formerly at the CHARTER Coordinating Center, who made contributions to the early stages of this project; and Steven P. Woods, PsyD, for helpful comments on the manuscript. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with the Johns Hopkins University, Mount Sinai School of Medicine, University of California, San Diego, University of Texas, Galveston, University of Washington, Seattle, Washington University, St. Louis and is headquartered at the University of California, San Diego (UCSD) and includes Igor Grant, MD (UCSD, Director); Ronald J. Ellis, MD, PhD (UCSD, Codirector); Scott L. Letendre, MD (UCSD, Codirector); Ian Abramson, PhD (UCSD, Coinvestigator); Muhammad Al-Lozi, MD (Washington University, Coinvestigator); J. Hampton Atkinson, MD(UCSD, Coinvestigator); Edmund Capparelli, PharmD (UCSD, Coinvestigator); David Clifford, MD [Washington University, Site Principal Investigator (PI)], Ann C. Collier, MD (University of Washington, Site Co-PI), Christine Fennema-Notestine, PhD (UCSD, Core PI), Anthony C. Gamst, PhD (UCSD, Core PI), Benjamin Gelman, MD, PhD (University of Texas, Site PI), Robert K. Heaton, PhD (UCSD), Thomas D. Marcotte, PhD (UCSD, Core PI), Christina Marra, MD (University of Washington, Site Co-PI), J. Allen McCutchan, MD (UCSD, Site PI), Justin C. McArthur, MD (Johns Hopkins, Site PI), Susan Morgello, MD (Mount Sinai, Site Co-PI), David Simpson, MD (Mount Sinai, Site Co-PI), Davey M. Smith, MD (UCSD, Core PI), Michael J. Taylor, PhD (UCSD, Core Coinvestigator), Rebecca Theilmann, PhD (UCSD, Imaging Physicist), Florin Vaida, PhD (UCSD, Coinvestigator), Steven Paul Woods, PsyD (UCSD, Coinvestigator); Study Coordinators: Terry J. Alexander, RN (UCSD, Neuromedical Coordinator), Clint Cushman (UCSD, Data Manager), Matthew Dawson (UCSD, Neurobehavioral Coordinator), Donald Franklin, Jr. (UCSD, Center Manager), Eleanor Head, RN, BSN (University of Texas, Site Coordinator), Trudy Jones, MN, ARNP (University of Washington, Site Coordinator), Jennifer Marquie-Beck, MPH (UCSD, Recruitment Coordinator), Letty Mintz, NP (Mount Sinai, Site Coordinator), Vincent Rogalski, CCRP (Johns Hopkins, Site Coordinator), Mengesha Teshome, MD (Washington University, Site Coordinator), Will Toperoff, BS, ND (UCSD, Site Coordinator).
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HIV; adherence; cognitive impairment; pharmacy refill records; HAND; CPE
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