Patricia A. Sirois

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.

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.

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.

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.

Medication Adherence in Children and Adolescents with HIV Infection: Associations with Behavioral Impairment

The impact of behavioral functioning on medication adherence in children with perinatally acquired HIV infection is not well-explored, but has important implications for intervention. This report addresses the relationship between behavioral functioning and child self-report or caregiver report of medication adherence among children and adolescents enrolled in Pediatric AIDS Clinical Trials Group Protocol 219C (conducted 2000-2007). A total of 1134 participants, aged 3-17 years, received a behavioral evaluation and adherence assessment. Complete adherence was defined as taking 100% of prescribed antiretroviral medications during three days preceding the study visit. Multivariable logistic regression models were used to evaluate associations between adherence and behavioral functioning, adjusting for potential confounders, including demographic, psychosocial, and health factors. Children demonstrated higher than expected rates of behavioral impairment (≈7% expected with T > 65) in the areas of conduct problems (14%, z = 7.0, p < 0.001), learning problems (22%, z = 12.2, p < 0.001), somatic complaints (22%, z = 12.6, p < 0.001), impulsivity-hyperactivity (20%, z = 11.1, p < 0.001), and hyperactivity (19%, z = 10.6, p < 0.001). Children with behavioral impairment in one or more areas had significantly increased odds of nonadherence [adjusted odds ratio (aOR) = 1.49, p = 0.04]. The odds of nonadherence were significantly higher for those with conduct problems and general hyperactivity (aOR = 2.03, p = 0.005 and aOR = 1.68, p = 0.02, respectively). Psychosocial and health factors, such as recent stressful life events and higher HIV RNA levels, were also associated with nonadherence. Knowledge of behavioral, health, and social influences affecting the child and family should guide the development of appropriate, evidence-based interventions for medication adherence.

Assessment of adherence to antiretroviral therapy in perinatally HIV-infected children and youth using self-report measures and pill count.

Background: Parent/caregiver or child/youth self-report and pill counts are commonly used methods for assessing adherence to antiretroviral therapy among children and youth with HIV. The purpose of this study was to compare these different methods with one another and with viral load. Methods: Randomly selected parent/caregiver and child/youth dyads were interviewed using several adherence self-report measures and an announced pill count was performed. Adherence assessment methods were compared with one another and their relative validity was assessed by comparison with the child’s viral load close to the time of the interview or pill count, adjusting for primary caregiver, child age, and child disclosure of the diagnosis. Results: There were 151 evaluable participants. Adherence rate by pill count was ≥90% in 52% of participants, was significantly associated with log(RNA) viral load (p = .032), and had significant agreement with viral load <400 copies/mL. However, pill count data were incomplete for 26% of participants. With similar proportions considered adherent, a variety of self-report adherence assessment methods also were associated with log(RNA) viral load including: “no dose missed within the past 1 month” (p = .054 child/youth interview, p = .004 parent/caregiver interview), and no barrier to adherence identified (p = .085 child/youth interview, p = .015 parent/caregiver interview). Within-rater and inter-rater agreement was high among self-report methods. Three day recall of missed doses was not associated with viral load. Conclusion: Findings demonstrate the validity of adherence assessment strategies that allow the parent/caregiver or child/youth to report on adherence over a longer period of time and to identify adherence barriers. Adherence assessed by announced pill count was robustly associated with viral load, but there was incomplete data for many participants.

Language Impairment in Children Perinatally Infected with HIV Compared to Children Who Were HIV-Exposed and Uninfected

Objective: To investigate the risk for language impairment (LI) in children perinatally infected or exposed to HIV. Methods: We evaluated the prevalence of LI in 7- to 16-year-old children with perinatal HIV infection (HIV+) compared with HIV-exposed and uninfected children, using a comprehensive standardized language test (Clinical Evaluation of Language Functioning-Fourth Edition [CELF-4]). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease, and antiretroviral treatment factors with LI category were evaluated using univariate and multivariable logistic regression models. Results: Of the 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ versus 87.5 (17.9) for HIV-exposed and uninfected children. After adjustment, black children had higher odds of Pri-LI versus no LI (adjusted odds ratio [aOR] = 2.43, p = .03). Children who were black, Hispanic, had a caregiver with low education or low intelligence quotient, or a nonbiological parent as caregiver had higher odds of Con-LI versus no LI. Among HIV+ children, viral load >400 copies/mL (aOR = 3.04, p < .001), Centers for Disease Control and Prevention Class C (aOR = 2.19, p = .02), and antiretroviral treatment initiation <6 months of age (aOR = 2.12, p = .02) were associated with higher odds of Con-LI versus no LI. Conclusions: Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI.

Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants.

Background: This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants. Methods: HIV-exposed, uninfected infants (age 9–15 months) enrolled in Surveillance Monitoring for Antiretroviral Therapy Toxicities, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development—Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class) and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates. Results: As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black and 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (9% of protease inhibitor–containing regimens also included non-nucleoside reverse transcriptase inhibitors), 5% to regimens containing non-nucleoside reverse transcriptase inhibitors (without protease inhibitor) and 14% to regimens containing only nucleoside reverse transcriptase inhibitors. Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (P = 0.01). Conclusions: These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study.

Social Ecological Predictors of Longitudinal HIV Treatment Adherence in Youth With Perinatally Acquired HIV

OBJECTIVE To apply a social ecological model to explore the psychosocial factors prospectively associated with longitudinal adherence to antiretroviral treatment in youth perinatally infected with HIV. METHODS Randomly selected youth, age 8 to <19 years old, completed cognitive testing and psychosocial questionnaires at baseline as part of a multisite protocol (N = 138). A validated caregiver-report measure of adherence was completed at baseline and 24 and 48 weeks after baseline. RESULTS In multivariate analysis, youth awareness of HIV status, caregiver not fully responsible for medications, low caregiver well-being, adolescent perceptions of poor caregiver-youth relations, caregiver perceptions of low social support, and African American ethnicity were associated with nonadherence over 48 weeks. CONCLUSIONS Interventions focusing on caregivers and their interactions with the individual youth and extrafamilial system should be prioritized for prevention and treatment efforts to address nonadherence during the transition into adolescents.

Hearing Loss in Perinatally HIV-infected and HIV-exposed but Uninfected Children and Adolescents

Background: Little is known about hearing loss in children with HIV infection (HIV+). We examined the prevalence of hearing loss in perinatally HIV+ and HIV-exposed but uninfected (HEU) children, compared these with the percentage with hearing loss in the general population and evaluated possible risk factors for hearing loss in HIV+ and HEU children. Methods: Audiometric examinations were completed in children who met any prespecified criteria for possible hearing loss. The hearing examination consisted of a tympanogram in each ear and pure-tone air-conduction threshold testing from 500 through 4000 Hz. Hearing loss was defined as the pure-tone average over these frequencies ≥20 dB hearing level. The associations of demographic variables, parent/caregiver, HIV disease and HIV treatment with hearing loss were evaluated with univariate and multivariable logistic regression models. Results: Hearing testing was completed in 231 children (145 HIV+ and 86 HEU). Hearing loss occurred in 20.0% of HIV+ children and 10.5% of HEU children. After adjusting for caregiver education level, HIV infection was associated with increased odds of hearing loss (adjusted odds ratio = 2.13, 95% confidence interval: 0.95–4.76, P = 0.07). Among HIV+ children, those with a Centers for Disease Control and Prevention class C diagnosis had over twice the odds of hearing loss (adjusted odds ratio = 2.47, 95% confidence interval: 1.04–5.87, P = 0.04). The prevalence of hearing loss was higher in both HIV+ and HEU children compared with National Health and Nutrition Examination Survey III children. Conclusions: Hearing loss was more common in both HIV+ and HEU children than in children from a US population sample. More advanced HIV illness increased the risk of hearing loss in HIV+ children.