Andrew J. Levine

Age-Associated Predictors of Medication Adherence in HIV-Positive Adults: Health Beliefs, Self-Efficacy, and Neurocognitive Status

OBJECTIVE Although most agree that poor adherence to antiretrovirals is a common problem, relatively few factors have been shown to consistently predict treatment failure. In this study, a theoretical framework encompassing demographic characteristics, health beliefs/attitudes, treatment self-efficacy, and neurocognitive status was examined in relationship to highly active antiretroviral therapy adherence. DESIGN Prospective, cross-sectional observational design. MAIN OUTCOME MEASURES Neuropsychological test performance, health beliefs and attitudes, and medication adherence tracked over a 1-month period using electronic monitoring technology (Medication Event Monitoring System caps). RESULTS The rate of poor adherence was twice as high among younger participants than with older participants (68% and 33%, respectively). Results of binary logistic regression revealed that low self-efficacy and lack of perceived treatment utility predicted poor adherence among younger individuals, whereas decreased levels of neurocognitive functioning remained the sole predictor of poor adherence among older participants. CONCLUSION These data support components of the health beliefs model in predicting medication adherence among younger HIV-positive individuals. However, risk of adherence failure in those ages 50 years and older appears most related to neurocognitive status.

Drug Use and Medication Adherence among HIV-1 Infected Individuals

This longitudinal study examined the impact of drug use and abuse on medication adherence among 150 HIV-infected individuals, 102 who tested urinalysis positive for recent illicit drug use. Medication adherence was tracked over a 6-month period using an electronic monitoring device (MEMS caps). Over the 6-month study drug-positive participants demonstrated significantly worse medication adherence than did drug-negative participants (63 vs. 79%, respectively). Logistic regression revealed that drug use was associated with over a fourfold greater risk of adherence failure. Stimulant users were at greatest risk for poor adherence. Based upon within-participants analyses comparing 3-day adherence rates when actively using versus not using drugs, this appears to be more a function of state rather than trait. These data suggest that it is the acute effects of intoxication, rather than stable features that may be characteristic of the drug-using populace, which leads to difficulties with medication adherence.

HIV-1 Infection Accelerates Age According to the Epigenetic Clock

Background. Infection with human immunodeficiency virus type 1 (HIV) is associated with clinical symptoms of accelerated aging, as evidenced by the increased incidence and diversity of age-related illnesses at relatively young ages and supporting findings of organ and cellular pathologic analyses. But it has been difficult to detect an accelerated aging effect at a molecular level. Methods. Here, we used an epigenetic biomarker of aging based on host DNA methylation levels to study accelerated aging effects due to HIV infection. DNA from brain and blood tissue was assayed via the Illumina Infinium Methylation 450 K platform. Results. Using 6 novel DNA methylation data sets, we show that HIV infection leads to an increase in epigenetic age both in brain tissue (7.4 years) and blood (5.2 years). While the observed accelerated aging effects in blood may reflect changes in blood cell composition (notably exhausted cytotoxic T cells), it is less clear what explains the observed accelerated aging effects in brain tissue. Conclusions. Overall, our results demonstrate that the epigenetic clock is a useful biomarker for detecting accelerated aging effects due to HIV infection. This tool can be used to accurately determine the extent of age acceleration in individual tissues and cells.

Normative Data for Determining Significance of Test–Retest Differences on Eight Common Neuropsychological Instruments

Clinicians and researchers who use neuropsychological tests to track functioning over time are in need of a method to correct for the effects of practice. Drawing from a large database of healthy, male subjects, we present data that can be used to calculate predicted retest scores for eight widely used neuropsychological instruments either via simple regression or reliable change index (RCI) methods. These methods are useful for individuals assessed across a wide time interval, 4–24 months. Limitations are discussed regarding the applicability of the data. Those with a need to factor out the effects of practice, test–retest reliability and other statistical confounds will find the information within this article useful.

Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study

Objective: To evaluate the frequency of HIV-associated neurocognitive disorder (HAND) in HIV+ individuals and determine whether the frequency of HAND changed over 4 years of follow-up. Methods: The Multicenter AIDS Cohort Study (MACS) is a prospective study of gay/bisexual men. Beginning in 2007, all MACS participants received a full neuropsychological test battery and functional assessments every 2 years to allow for HAND classification. Results: The frequency of HAND for the 364 HIV+ individuals seen in 2007–2008 was 33% and for the 197 HIV+ individuals seen at all time periods during the 2007–2008, 2009–2010, and 2011–2012 periods were 25%, 25%, and 31%, respectively. The overall frequency of HAND increased from 2009–2010 to 2011–2012 (p = 0.048). Over the 4-year study, 77% of the 197 HIV+ individuals remained at their same stage, with 13% showing deterioration and 10% showing improvement in HAND stage. Hypercholesterolemia was associated with HAND progression. A diagnosis of asymptomatic neurocognitive impairment was associated with a 2-fold increased risk of symptomatic HAND compared to a diagnosis of normal cognition. Conclusion: HAND remains common in HIV+ individuals. However, for the majority of HIV+ individuals on combination antiretroviral therapy with systemic virologic suppression, the diagnosis of HAND is not a progressive condition over 4 years of follow-up. Future studies should evaluate longitudinal changes in HAND and specific neurocognitive domains over a longer time period.

The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment

Background The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. Methods Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform. Results With HIVE the HIV-1 RNA load in brain tissue was three log10 units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. Interpretation Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).

Neurocognition in Individuals Co-Infected with HIV and Hepatitis C

Abstract Due to similar routes of viral transmission, many individuals infected with the human immunodeficiency virus (HIV) are also infected with the hepatitis C virus (HCV). Each virus can cause cognitive compromise among mono-infected individuals; evidence is accumulating that HIV/HCV co-infection may have a particularly deleterious impact on cognition. We present neuropsychological data obtained from 118 HIV+ adults with advanced HIV disease, 35 of whom were co-infected with HCV, who completed a comprehensive neurocognitive evaluation. Rates of global cognitive impairment were higher among co-infected patients than among those with HIV alone (63% vs. 43%). Within the specific domains of learning and memory, co-infected individuals were significantly more likely to be impaired than were the HIV mono-infected participants. Finally, we discuss implications of these findings and potential future directions for research in this area.

Variations in Patterns of Highly Active Antiretroviral Therapy (HAART) Adherence

Strict adherence to highly active antiretroviral therapy (HAART) is necessary for successful suppression of HIV replication. A large number of individuals are not adherent, however, and the reasons for non-adherence are varied and complex. We utilized cluster analyses to identify subgroups of adherers in a sample of 222 HIV positive individuals whose HAART use was electronically monitored. Five distinct subgroups were identified, with characteristic variations across the week and over the course of the 4-week study. Additional comparisons of demographic and behavioral variables found the worst adherers to have higher rates of substance use, and that a group with higher rates of cognitive impairment had a consistent drop in adherence during the weekends. In addition, the group with the best adherence had more individuals over the age of 50 years. The results of the current study indicate that distinct subgroups of adherers may exist, and suggest that interventions designed to improve adherence can be designed to accommodate this variability in behavior.

Adherence to antiretroviral medications in HIV: differences in data collected via self-report and electronic monitoring.

Controversy remains regarding the reliability of methods used to determine adherence to antiretroviral medication in HIV. In this study the authors compared adherence rates of 119 HIV-positive participants during a 6-month study, as estimated via electronic monitoring (EM) and self-report (SR). Adherence for both short (4-day) and long (4-week, or intervisit) periods was examined, as well as factors that underlie discrepancies between EM and SR. Results showed that intervisit EM estimates were consistently lower than those of SR. SR estimates based on shorter periods (4 days) were closer to those of EM. Higher discrepancies between EM and SR estimates were associated with lower cognitive functioning and externalized locus of control. These findings lend support for using both EM and SR methods; however, study design (e.g., length) and other factors (e.g., cognitive status, cost) should be considered.

Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

Objective:The apolipoprotein E (APOE) &egr;4 allele enhances cerebral accumulation of &bgr;-amyloid (A&bgr;) and is a major risk factor for sporadic Alzheimers disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE &egr;4 genotype and cerebral A&bgr; deposition. Design:Clinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium. Methods:We used multivariable logistic regressions to model outcomes [A&bgr; plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE &egr;4 (allelic discrimination assay), older age (≥50 years), A&bgr; plaques, and their two-way interactions] and comorbid factors. Results:Isocortical A&bgr; deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE &egr;4 and older age were independently associated with the presence of A&bgr; plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 − 35.76 and 1.91−17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of A&bgr; plaques among APOE &egr;4 carriers (adjusted OR 30.00, 95% CI 1.41−638.63, P = 0.029, n = 15), but not in non-&egr;4 carriers (n = 57). Conclusion:The APOE &egr;4 and older age increased the likelihood of cerebral A&bgr; plaque deposition in HIV-infected adults. Generally, A&bgr; plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimers disease brains. Nonetheless, A&bgr; plaques were associated with HAND among APOE &egr;4 carriers. The detection of APOE &egr;4 genotype and cerebral A&bgr; deposition biomarkers may be useful in identifying living HAND patients who could benefit from A&bgr;-targeted therapies.