Kathleen Malee

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.

Understanding the mental health of youth living with perinatal HIV infection: lessons learned and current challenges

Across the globe, children born with perinatal HIV infection (PHIV) are reaching adolescence and young adulthood in large numbers. The majority of research has focused on biomedical outcomes yet there is increasing awareness that long‐term survivors with PHIV are at high risk for mental health problems, given genetic, biomedical, familial and environmental risk. This article presents a review of the literature on the mental health functioning of perinatally HIV‐infected (PHIV+) adolescents, corresponding risk and protective factors, treatment modalities and critical needs for future interventions and research.

Severe acidosis and subsequent neurologic status

To examine the relationship between severe acidosis at birth and evidence of subsequent neurologic dysfunction, a 4-year review was performed encompassing 15,528 neonates. One hundred forty-two (0.91%) of these neonates had an umbilical cord arterial pH less than or equal to 7.05 with a base deficit greater than or equal to mEq/L. Neurologic assessments found 101 of 110 term neonates (91.8%) and 17 of 32 preterm neonates (53.1%) with severe acidosis to be free of neurologic deficits at the time of hospital discharge. Follow-up developmental evaluation data were available for 7 of 9 term neonates and 8 of 15 preterm neonates with abnormal examinations. Although 5 term and 6 preterm infants demonstrated mild developmental delays or mild tone abnormalities in the first year of life, none exhibited a major motor or cognitive abnormality at 12 to 24 months of age. Consequently, acidosis in umbilical cord blood, even when severe, is a poor predictor of subsequent neurologic dysfunction.

Adherence to antiretroviral treatment among pregnant and postpartum HIV-infected women

Abstract Among women with HIV infection, pregnancy is a time when maintenance of maternal health and reduction of vertical HIV transmission are primary concerns. Few studies have examined adherence to Antiretroviral Treatment (ART) during pregnancy and in the postpartum period when the demands of childcare may significantly interfere with womens self-care behaviors. This study examined ART use and adherence in HIV-infected pregnant and postpartum women participating in the Women and Infants Transmission Study (WITS-IV) in the US. Adherence was assessed through a self-report interview during the third trimester of pregnancy and six-month postpartum. Data were also collected on demographics, biomedical markers and health related symptoms. During the third trimester visit, 77% (309/399) of women completed the self-report adherence measure; 61% (188/309) reported complete adherence. Factors associated with non-adherence included advanced HIV disease status, higher HIV-RNA viral load, more health-related symptoms and alcohol and tobacco use. At six-month postpartum, 55% (220/399) completed the measure; 44% (97/220) of these women reported complete adherence. Factors associated with non-adherence during the postpartum period were ethnicity, more health-related symptoms and WITS clinical site. Results of multivariate analyses using Generalized Estimated Equation analyses across the two visits revealed that more health-related symptoms, higher HIV-RNA viral load, increased alcohol use and clinical site were independently associated with ART non-adherence. These analyses indicate that medication adherence is more likely during pregnancy than postpartum in HIV-infected women, perhaps provoked by motivation to reduce vertical transmission and/or intensive antepartum surveillance. Further investigation is warranted to clarify factors implicated in womens decision-making process regarding ART medication adherence.

Effects of perinatal HIV infection and associated risk factors on cognitive development among young children

OBJECTIVE. We examined the effect of HIV, in combination with other important health and social factors, on the development of cognitive abilities of children perinatally exposed to HIV. METHODS. Serial cognitive assessments were performed for 117 children who were infected vertically and 422 children who were exposed to but not infected with HIV, in a multicenter, natural history, longitudinal study. Repeated-measures analyses were used to evaluate the neurocognitive development of children between the ages of 3 and 7 years, as measured by the McCarthy Scales of Children’s Abilities (MSCA). RESULTS. Children with HIV infection and class C status scored significantly lower in all domains of cognitive development, across all time points, than did those who were HIV infected without an AIDS-defining illness and those who were HIV exposed but not infected. There were no significant differences between the 2 latter groups in General Cognitive Index or specific domain scores. Rates of change in cognitive development were comparable (parallel) among all 3 groups over a period of 4 years. Factors that were associated consistently and significantly with lower mean scores were HIV status, number of times an examination had been completed previously, primary language, maternal education, and gender. No factors were related to rate of change of any mean domain score. CONCLUSIONS. An early AIDS-defining illness increased the risk of chronic static encephalopathy during the preschool and early school age years. Children with HIV infection but no class C event performed as well as noninfected children in measures of general cognitive ability. No significantly different profiles of strengths and weaknesses for verbal, perceptual-performance, quantitative, or memory functioning were observed among children with or without HIV infection. A number of factors were found to have significant effects on the mean scores of children in all 3 groups; however, they were not related to the rate at which learning occurred.

Behavioral Health Risks in Perinatally HIV-Exposed Youth: Co-Occurrence of Sexual and Drug Use Behavior, Mental Health Problems, and Nonadherence to Antiretroviral Treatment

In a sample of perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, uninfected (PHEU) adolescents, we examined the co-occurrence of behavioral health risks including mental health problems, onset of sexual and drug use behaviors, and (in PHIV+ youth) nonadherence to antiretroviral therapy (ART). Participants, recruited from 2007 to 2010, included 349 youth, ages 10-16 years, enrolled in a cohort study examining the impact of HIV infection and ART. Measures of the above behavioral health risks were administered to participants and primary caregivers. Nearly half the participants met study criteria for at least one behavioral health risk, most frequently, mental health problems (28%), with the onset of sexual activity and substance use each reported by an average of 16%. Among the sexually active, 65% of PHIV+ and 50% of PHEU youth reported unprotected sex. For PHIV +youth, 34% reported recent ART nonadherence, of whom 45% had detectable HIV RNA levels. Between 16% (PHIV+) and 11% (PHEU) of youth reported at least two behavioral health risks. Older age, but not HIV status, was associated with having two or more behavioral health risks versus none. Among PHIV+ youth, living with a birth mother (versus other caregivers) and detectable viral load were associated with co-occurrence of behavioral health risks. In conclusion, this study suggests that for both PHIV+ and PHEU youth, there are multiple behavioral health risks, particularly mental health problems, which should be targeted by service systems that can integrate prevention and treatment efforts.

Neurodevelopmental Functioning in HIV-Infected Infants and Young Children Before and After the Introduction of Protease Inhibitor–Based Highly Active Antiretroviral Therapy

OBJECTIVES. The purpose of this work was to examine the effects of HIV infection and the impact of highly active antiretroviral treatment with protease inhibitors on neurodevelopmental functioning during the first 3 years of life. PATIENTS AND METHODS. Pediatric AIDS Clinical Trials Group 219/219C is a longitudinal cohort study that has enrolled HIV-infected (HIV+) and HIV-exposed but uninfected (HIV−) infants and children since 1993. Longitudinal profiles of neurodevelopmental functioning as measured by the Bayley Scales of Infant Development were compared by HIV-infection status before and after the availability of highly active antiretroviral therapy with a protease inhibitor and within infants with Bayley tests available before and after initiating protease inhibitor therapy. RESULTS. In the pre–protease inhibitor era, mean mental and motor scores in HIV+ (n = 54) infants <1 year of age were significantly lower than those among HIV− infants (n = 221) and remained lower up to 2 years of age. After protease inhibitors became available, mean mental and motor functioning of HIV+ infants (n = 91) <1 year of age were still significantly lower than those of HIV− infants (n = 838). However, against a background of declining scores among the HIV− infants, there was evidence of limited improvement in the HIV+ infants relative to their uninfected peers. Among infants who had Bayley II evaluations before and after starting a protease inhibitor, there was a trend to improved mental and motor scores after initiation of protease inhibitor therapy. CONCLUSIONS. The suppression of systemic viral replication and subsequent substantial improvements in survival and immunologic status brought about by highly active antiretroviral therapy have been followed by limited improvements in neurodevelopmental functioning in young children. Additional longitudinal research is needed to better understand the role of antiretroviral therapy as well as the impact of genetic and environmental factors on neurodevelopmental functioning in children affected by HIV.

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.

Timing of perinatal human immunodeficiency virus type 1 infection and rate of neurodevelopment

BACKGROUND Identifying HIV-1-infected children who are at greatest risk for disease-related morbidities is critical for optimal therapeutic as well as preventive care. Several factors have been implicated in HIV-1 disease onset and severity, including maternal and infant host characteristics, viral phenotype and timing of HIV-1 infection. Early HIV-1 culture positivity, i.e. intrauterine infection, has been associated with poor immunologic, virologic and clinical outcomes in children of HIV-infected women. However, a direct effect of timing of infection on neurodevelopmental outcome in infancy has not yet been identified. METHODS Serial neurodevelopmental assessments were performed with 114 infants vertically infected with HIV-1 in a multicenter natural history, longitudinal study. Median mental and motor scores were compared at three time points. Longitudinal regression analyses were used to evaluate the neurodevelopmental functioning of children with early positive cultures and those with late positive cultures. RESULTS Early infected infants scored significantly lower than late infected infants by 24 months of age and beyond on both mental (P = 0.05) and motor (P = 0.03) measures. Early HIV-1 infection was associated with a decline in estimated motor scores of 1 standard score point per month compared with 0.28 point in the late infected group (P < 0.02). Estimated mental scores of the early infected group declined 0.72 point/ month, whereas the average decline of the late infected group was 0.30 point/month (P < 0.13). CONCLUSION Early HIV-1 infection increases a childs risk for poor neurodevelopmental functioning within the first 30 months of life.