Sharon Nichols

Predictors of Adherence to Antiretroviral Medications in Children and Adolescents With HIV Infection

BACKGROUND. Most evaluations of adherence to antiretroviral therapy in children with HIV infection have focused on validation of adherence measures via their association with virological outcomes. However, few studies have fully explored associations with other factors to guide development of adherence interventions. METHODS. In this study, we examined the relationship of self-reported medication adherence to health, demographic, and psychosocial characteristics of children and their caregivers, using data from an ongoing multicenter prospective observational study of long-term outcomes of HIV infection conducted by the Pediatric AIDS Clinical Trials Group. Child and caregiver characteristics were evaluated for association with adherence via univariate and multiple logistic regression models. RESULTS. Of the 2088 children and adolescents, 84% reported complete adherence to antiretroviral therapy medications over the past 3 days. The median viral load was ∼10 times higher among nonadherent than adherent children, and the strength of this association increased with age. Factors associated with at least marginally significant increases in nonadherence in a multiple logistic regression model included increasing age in years, female gender, detectable HIV viral load, occurrence of recent stressful life events, repeating a grade in school, self-assessment of adherence by the subject, and diagnosis of depression or anxiety. Having an adult other than the biological parent as the primary caregiver, using a buddy system to remember to take antiretroviral therapy medications, higher caregiver education level, previous adherence assessments, and taking antipsychotic medications were each associated with improved adherence. After controlling for these characteristics, there was no significant association of adherence with race, knowledge of HIV status, medication burden, CD4 percentage, or current antiretroviral therapy. CONCLUSIONS. Rates of self-reported adherence were relatively high and were influenced by multiple child and family characteristics. These findings identify targets for adherence interventions and highlight the importance of evaluating and supporting the family environment to optimize adherence.

Integrated imaging approach with MEG and DTI to detect mild traumatic brain injury in military and civilian patients.

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild (and some moderate) TBI can be difficult to diagnose due to lack of obvious external injuries and because the injuries are often not visible on conventional acute MRI or CT. Injured brain tissues in TBI patients generate pathological low-frequency neuronal magnetic signal (delta waves 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). We hypothesize that abnormal MEG delta waves originate from gray matter neurons that experience de-afferentation due to axonal injury to the underlying white matter fiber tracts, which is manifested on diffusion tensor imaging (DTI) as reduced fractional anisotropy. The present study used a neuroimaging approach integrating findings of magnetoencephalography (MEG) and diffusion tensor imaging (DTI), evaluating their utility in diagnosing mild TBI in 10 subjects in whom conventional CT and MRI showed no visible lesions in 9. The results show: (1) the integrated approach with MEG and DTI is more sensitive than conventional CT and MRI in detecting subtle neuronal injury in mild TBI; (2) MEG slow waves in mild TBI patients originate from cortical gray matter areas that experience de-afferentation due to axonal injuries in the white matter fibers with reduced fractional anisotropy; (3) findings from the integrated imaging approach are consistent with post-concussive symptoms; (4) in some cases, abnormal MEG delta waves were observed in subjects without obvious DTI abnormality, indicating that MEG may be more sensitive than DTI in diagnosing mild TBI.

Impact of HIV severity on cognitive and adaptive functioning during childhood and adolescence.

Background: The influence of disease severity on cognitive and adaptive functioning in perinatally HIV-infected youth with (PHIV+/C) and without (PHIV+/NoC) a previous AIDS-defining illness (Centers for Disease Control and Prevention Class C event), compared with perinatally HIV-exposed but uninfected youth (PHEU) is not well understood. Methods: This was a cross-sectional analysis of cognitive and adaptive functioning in PHIV+/C (n = 88), PHIV+/NoC (n = 270) and PHEU (n = 200) youth aged 7–16 years, from a multisite prospective cohort study. Youth and caregivers completed the Wechsler Intelligence Scale for Children, Fourth Edition and the Adaptive Behavior Assessment System, Second Edition, respectively. We compared means and rates of impairment between groups, and examined associations with other psychosocial factors. Results: Overall mean scores on measures of cognitive and adaptive functioning were in the low average range for all 3 groups. After adjustment for covariates, mean full-scale intelligence quotient scores were significantly lower for the PHIV+/C group than the PHIV+/NoC and PHEU groups (mean = 77.8 versus 83.4 and 83.3, respectively), whereas no significant differences were observed between the PHEU and PHIV+/NoC groups in any domain. Lower cognitive performance for the PHIV+/C group was primarily attributable to a prior diagnosis of encephalopathy. No significant differences between groups were observed in adaptive functioning. Conclusion: For long-term survivors, youth with HIV infection and a prior Centers for Disease Control and Prevention Class C event have higher risk for cognitive but not adaptive impairment regardless of current health status; this finding appears attributable to a previous diagnosis of encephalopathy. Early preventive therapy may be critical in reducing risk of later neurodevelopmental impairments.

Mental health functioning among children and adolescents with perinatal HIV infection and perinatal HIV exposure

Mental health problems (MHPs) among children with perinatal HIV infection have been described prior to and during the highly active antiretroviral therapy (HAART) era. Yet child, caregiver and socio-demographic factors associated with MHPs are not fully understood. We examined the prevalence of MHPs among older children and adolescents with perinatal HIV exposure, including both perinatally HIV-infected (PHIV + ) and perinatally HIV-exposed but uninfected (PHEU) youth. Our aims were to identify the impact of HIV infection by comparing PHIV+ and PHEU youth and to delineate risk factors associated with MHPs, in order to inform development of appropriate prevention and intervention strategies. Youth and their caregivers were interviewed with the Behavior Assessment System for Children, 2nd edition (BASC-2) to estimate rates of at-risk and clinically significant MHPs, including caregiver-reported behavioral problems and youth-reported emotional problems. The prevalence of MHPs at the time of study entry was calculated for the group overall, as well as by HIV status and by demographic, child health, and caregiver characteristics. Logistic regression models were used to identify factors associated with youth MHPs. Among 416 youth enrolled between March 2007 and July 2009 (295 PHIV+, 121 PHEU), the overall prevalence of MHPs at entry was 29% and greater than expected based on recent national surveys of the general population. MHPs were more likely among PHEU than among PHIV+ children (38% versus 25%, p<0.01). Factors associated with higher odds of MHPs at p<0.10 included caregiver characteristics (psychiatric disorder, limit-setting problems, health-related functional limitations) and child characteristics (younger age and lower IQ). These findings suggest that PHEU children are at high risk for MHPs, yet current models of care for these youth may not support early diagnosis and treatment. Family-based prevention and intervention programs for HIV affected youth and their caregivers may minimize long-term consequences of MHPs.

Mechanisms of verbal memory impairment in four neurodevelopmental disorders

Profiles of verbal learning and memory performance were compared for typically developing children and for four developmental disorders characterized by different patterns of language functioning: specific language impairment, early focal brain damage, Williams Syndrome, and Down Syndrome. A list-learning task was used that allowed a detailed examination of the process of verbal learning, recall, and recognition (California Verbal Learning Test--Childrens Version). Distinct patterns of performance characterized the four disorders. These patterns were consistent with the language deficits typically seen in the disorders, with the exception of a dissociation seen in Williams Syndrome.

An automatic MEG low-frequency source imaging approach for detecting injuries in mild and moderate TBI patients with blast and non-blast causes

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. Injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). We developed a new automated MEG low-frequency source imaging method and applied this method in 45 mild TBI (23 from combat-related blasts, and 22 from non-blast causes) and 10 moderate TBI patients (non-blast causes). Seventeen of the patients with mild TBI from blasts had tertiary injuries resulting from the blast. The results show our method detected abnormalities at the rates of 87% for the mild TBI group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities were 96% and 77% for the blast and non-blast TBI groups, respectively. The spatial characteristics of abnormal slow-wave generation measured by Z scores in the mild blast TBI group significantly correlated with those in non-blast mild TBI group. Among 96 cortical regions, the likelihood of abnormal slow-wave generation was less in the mild TBI patients with blast than in the mild non-blast TBI patients, suggesting possible protective effects due to the military helmet and armor. Finally, the number of cortical regions that generated abnormal slow-waves correlated significantly with the total post-concussive symptom scores in TBI patients. This study provides a foundation for using MEG low-frequency source imaging to support the clinical diagnosis of TBI.

Barriers to Medication Adherence in HIV-Infected Children and Youth Based on Self- and Caregiver Report

OBJECTIVE: Nonadherence to antiretroviral therapy among children/youth with HIV often is associated with disease progression. This study examined the agreement between child and caregiver perceptions of barriers to adherence and factors associated with these barriers. METHODS: Children/youth with perinatally acquired HIV and their parents/caregivers (n = 120 dyads) completed a questionnaire about 19 potential barriers to adherence to the child’s antiretroviral therapy regimen. Agreement between the 2 reports was measured via the kappa statistic. Factors associated with the barriers were assessed by using multiple logistic regression. RESULTS: Of the 120 children, 55% were African American, 54% were boys, and the average age was 12.8 years. The most frequently reported barrier by either the caregiver or youth was “forgot.” There were varying degrees of agreement between child and caregiver on the following barriers: “forgot,” “taste,” “child was away from home,” “child refused,” and “child felt good.” Children who knew their HIV status were more likely to report logistical barriers, such as scheduling issues. Children with a biological parent as their caregiver were more likely to report regimen or fear of disclosure as a barrier. CONCLUSIONS: Lack of agreement was observed for more than half of the studied barriers, indicating discrepancies between children’s and caregivers’ perceptions of factors that influence medication-taking. The findings suggest a need for interventions that involve both child and caregiver in the tasks of remembering when to administer the child’s medications, sustaining adherence, and appropriately transitioning medication responsibility to the youth.

Cortical Atrophy and Cognitive Performance in Infantile Nephropathic Cystinosis

A group of children and adolescents with infantile nephropathic cystinosis underwent cognitive testing and were examined for cortical atrophy using magnetic resonance imaging or computed tomography. Ten of 11 patients demonstrated cortical atrophy. A consistent pattern of lower cognitive performance was found in patients with greater atrophy; however, only the relationship between atrophy and short-term memory approached statistical significance. In addition, evidence for greater impairment of visual memory than of other cognitive functions was observed. This latter observation did not appear to be related to the degree of atrophy.

Allocation of Family Responsibility for Illness Management in Pediatric HIV

OBJECTIVE The purpose of the study is to describe allocation of responsibility for illness management in families of children and adolescents perinatally infected with HIV. METHODS A total of 123 youth (ages 8-18) and caregivers completed family responsibility and medication adherence questionnaires as part of a substudy of Pediatric AIDS Clinical Trials Group protocol 219c. RESULTS Approximately one-fourth of the youth reported being fully responsible for taking medications. A smaller percentage of caregivers reported full youth responsibility. Older youth and caregivers of older youth reported higher degree of youth responsibility for medication-related tasks, though age was unrelated to adherence. Caregiver report of greater responsibility for medications was associated with better adherence. CONCLUSIONS Caregivers are likely to transition responsibility for HIV care to older youth but this transition was not always successful as evidenced by poor medication adherence. Interventions supporting successful transition may improve adherence and subsequently health outcomes in pediatric HIV.

Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mild traumatic brain injury

Traumatic brain injury (TBI) is a leading cause of sustained impairment in military and civilian populations. However, mild TBI (mTBI) can be difficult to detect using conventional MRI or CT. Injured brain tissues in mTBI patients generate abnormal slow-waves (1–4 Hz) that can be measured and localized by resting-state magnetoencephalography (MEG). In this study, we develop a voxel-based whole-brain MEG slow-wave imaging approach for detecting abnormality in patients with mTBI on a single-subject basis. A normative database of resting-state MEG source magnitude images (1–4 Hz) from 79 healthy control subjects was established for all brain voxels. The high-resolution MEG source magnitude images were obtained by our recent Fast-VESTAL method. In 84 mTBI patients with persistent post-concussive symptoms (36 from blasts, and 48 from non-blast causes), our method detected abnormalities at the positive detection rates of 84.5%, 86.1%, and 83.3% for the combined (blast-induced plus with non-blast causes), blast, and non-blast mTBI groups, respectively. We found that prefrontal, posterior parietal, inferior temporal, hippocampus, and cerebella areas were particularly vulnerable to head trauma. The result also showed that MEG slow-wave generation in prefrontal areas positively correlated with personality change, trouble concentrating, affective lability, and depression symptoms. Discussion is provided regarding the neuronal mechanisms of MEG slow-wave generation due to deafferentation caused by axonal injury and/or blockages/limitations of cholinergic transmission in TBI. This study provides an effective way for using MEG slow-wave source imaging to localize affected areas and supports MEG as a tool for assisting the diagnosis of mTBI.