Megan L. Wilkins

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.

Perinatally acquired HIV infection: Long-term neuropsychological consequences and challenges ahead

Over the past three decades, perinatal HIV infection in the United States has evolved from a fatal disease to a manageable chronic illness. As the majority of youth with perinatal HIV infection age into adolescence and adulthood, management of this stigmatizing, transmittable disease in the backdrop of a cadre of environmental stressors presents challenges beyond those of other chronic illnesses. The neurologic and neuropsychological consequences of this neurotropic virus have important implications for the successful navigation of responsibilities related to increasingly independent living of this aging population. This article will review the neurologic and neuropsychological consequences of perinatal HIV infection and concomitant factors in the era of highly active antiretroviral therapy and will provide an overview of the neuropathology, pathogenesis, neuroimaging findings, and treatment of perinatal HIV infection, as well as recommendations for service provision and future research.

Discordance of cognitive and academic achievement outcomes in youth with perinatal HIV exposure.

Background: To evaluate achievement in youth with perinatally acquired HIV (PHIV) compared with HIV-exposed uninfected peers (HEU) and to examine differential effects of HIV on cognition-achievement concordance. Methods: Cognition and achievement were assessed using standardized measures. Intelligence quotient-derived predicted achievement scores were subtracted from observed achievement scores to calculate discrepancy values. Linear regression models were used to compare achievement discrepancies between PHIV and HEU, adjusting for demographic covariates. Results: Participants: 295 PHIV and 167 HEU youth; 71% black, 48% male, mean age 13.1 and 11.3 years, respectively. PHIV youth were relatively healthy (mean CD4%, 32%; viral load ⩽400 copies/mL, 72%). PHIV and HEU youth had cognitive and achievement scores significantly below population norm means (P < 0.001), but did not differ in cognition (mean full scale IQ = 86.7 vs. 89.4, respectively). In unadjusted models, HEU outperformed PHIV youth on total achievement (mean = 89.2 vs. 86.0, P = 0.04) and numerical operations (mean = 88.8 vs. 82.9, P < 0.001); no differences remained after adjustment. Mean observed-predicted achievement discrepancies reflected “underachievement”. History of encephalopathy predicted poorer achievement (P = 0.039) and greater underachievement, even after adjustment. PHIV showed greater underachievement than HEU for numerical operations (P < 0.001) and total achievement (P = 0.03), but these differences did not persist in adjusted models. Conclusions: Both PHIV and HEU youth demonstrated lower achievement than normative samples and underachieved relative to predicted achievement scores. Observed-predicted achievement discrepancies were associated with prior encephalopathy, older age and other non-HIV factors. PHIV youth with prior encephalopathy had significantly lower achievement and greater underachievement compared with PHIV without encephalopathy and HEU youth, even in adjusted models.

Medication Adherence in Adolescents With Behaviorally-acquired HIV: Evidence for Using a Multimethod Assessment Protocol

PURPOSE The present study investigated medication adherence in an understudied population, adolescents with behaviorally acquired HIV, to improve upon prior methodological limitations using concurrent collection of HIV health status markers (viral load [VL]; percentage CD4 count [CD4%]) and multimethod adherence assessment (pill count, missed doses, off-schedule dosing). METHODS PARTICIPANTS A total of 60 youth with behaviorally acquired HIV receiving routine care in a multidisciplinary specialty clinic in the Mid-Southern United States. Adherence was assessed by routine pharmacy pill count and self-reported 3-day recall of doses missed and doses taken off-schedule, collected concurrently with clinically obtained VL and CD4% indicators. Adherence measures were evaluated as predictors of VL and CD4% using logistic regression analyses. RESULTS Adherence difficulties were detected by all assessment methods, with off-schedule dosing appearing the most problematic (29.4% taken off-schedule). Self-report of doses missed (p = .038) and off-schedule dosing (p = .021) significantly predicted detectable VL. For each percent increase in nonadherence by off-schedule dosing, there was a 2% increased likelihood of detectable VL. No adherence measure significantly correlated with CD4%; pharmacy pill count did not relate to either health status marker. CONCLUSIONS This study is the first to document multimethod medication adherence measurement in a defined sample of adolescents with behaviorally acquired HIV, using imposed concurrent collection of CD4% and VL. Adherence difficulties were detected regardless of assessment strategy, with off-schedule dosing representing the greatest nonadherence behavior. Both 3-day recall methods predicted VL. Further investigation of adherence in larger samples of youth with behaviorally acquired HIV is needed to better understand the relationship to CD4% suppression.

Cardiac Effects of in utero Exposure to Antiretroviral Therapy in HIV-Uninfected Children Born to HIV-Infected Mothers

Objectives:We evaluated the potential cardiac effects of in-utero exposures to antiretroviral drugs in HIV-exposed but uninfected (HEU) children. Design and methods:We compared echocardiographic parameters of left ventricular function (ejection fraction, fractional shortening, and stress–velocity index) and structure (left ventricular dimension, posterior wall/septal thickness, mass, thickness-to-dimension ratio, and wall stress) (expressed as Z-scores to account for age and body surface area) between HEU and HIV-unexposed cohorts from the Pediatric HIV/AIDS Cohort Studys Surveillance Monitoring for ART Toxicities study. Within the HEU group, we investigated the associations between the echocardiographic Z-scores and in-utero exposures to maternal antiretroviral drugs. Results:There were no significant differences in echocardiographic Z-scores between 417 HEU and 98 HIV-unexposed children aged 2–7 years. Restricting the analysis to HEU children, first-trimester exposures to combination antiretroviral therapy (a regimen including at least three antiretroviral drugs) and to certain specific antiretroviral drugs were associated with significantly lower stress–velocity Z-scores (mean decreases of 0.22–0.40 SDs). Exposure to combination antiretroviral therapy was also associated with lower left ventricular dimension Z-scores (mean decrease of 0.44 SD). First-trimester exposure to combination antiretroviral therapy was associated with higher mean left ventricular posterior wall thickness and lower mean left ventricular wall stress Z-scores. Conclusion:There was no evidence of significant cardiac toxicity of perinatal combination antiretroviral therapy exposure in HEU children. Subclinical differences in left ventricular structure and function with specific in-utero antiretroviral exposures indicate the need for a longitudinal cardiac study in HEU children to assess long-term cardiac risk and cardiac monitoring recommendations.

A randomized clinical trial of adolescents with HIV/AIDS: pediatric advance care planning

ABSTRACT The objective of this study is to determine if pediatric advance care planning (pACP) increases adolescent/family congruence in end-of-life (EOL) treatment preferences longitudinally. Adolescents aged 14–21 years with HIV/AIDS and their families were randomized (N = 105 dyads) to three-60-minute sessions scheduled one week apart: either the pACP intervention (survey administered independently, facilitated conversation with adolescent and family present, completion of legal advance directive document with adolescent and family present) or an active control (developmental history, safety tips, nutrition and exercise education). This longitudinal, single-blinded, multi-site, randomized controlled trial was conducted in six pediatric hospital-based HIV-clinics, located in high HIV mortality cities. The Statement of Treatment Preferences measured adolescent/family congruence in EOL treatment preferences at immediately following the facilitated pACP conversation (Session 2), and at 3-month post-intervention. The mean age of adolescent participants was 18 years (range 14–21 years); 54% were male; and 93% were African-American. One-third had an AIDS diagnosis. Immediately post-intervention the Prevalence Adjusted Bias Adjusted Kappa showed substantial treatment preference agreement for pACP dyads compared to controls (High burden/low chance of survival, PABAK = 0.688 vs. 0.335; Functional impairment, PABAK = 0.687 vs. PABAK= 0.34; Mental impairment, PABKA = 0.717 vs. 0.341). Agreement to limit treatments was greater among intervention dyads than controls (High burden: 14.6% vs. 0%; Functional impairment = 22.9% vs. 4.4%; and Mental impairment: 12.5% vs. 4.4%). Overall treatment preference agreement among pACP dyads was high immediately post-intervention, but decreased over time. In contrast, treatment agreement among control dyads was low and remained low over time. As goals of care change over time with real experiences, additional pACP conversations are needed.

Executive Functioning in Children and Adolescents With Perinatal HIV Infection

Background: Perinatal HIV (PHIV) infection may place youth at risk for impairments in executive functioning (EF). We examined associations of EF with HIV infection, disease severity and other factors among youth with PHIV and perinatally HIV-exposed, uninfected youth (PHEU). Methods: Within the US-based Pediatric HIV/AIDS Cohort Study, 354 PHIV and 200 PHEU youth completed a standardized EF measure (Children’s Color Trails Test, CCTT) and youth and/or caregivers completed a questionnaire measuring everyday EF (Behavior Rating Inventory of Executive Function, BRIEF). Covariates included HIV status, current and historical disease severity, demographic and caregiver variables and other cognitive measures. Analyses used linear and logistic regression and proportional odds models. Results: No significant HIV status group differences were found on CCTT scores. Caregiver BRIEF ratings indicated significantly fewer problems for PHIV than PHEU youth. However, PHIV youth with past encephalopathy self-endorsed significantly greater metacognitive (ie, cognitive regulation) problems on the BRIEF and performed more slowly on the CCTT than PHEU youth. CCTT and caregiver BRIEF scores had significant associations with indicators of past and present disease severity. Both PHIV and PHEU had significantly worse scores than population means on CCTT and BRIEF; scores had significant associations with demographic covariates. Conclusions: Youth with PHIV show EF problems likely associated with risk factors other than HIV. However, cognitive slowing and self-reported metacognitive problems were evident in PHIV youth with a history of encephalopathy. Assessment and treatment of EF impairment may be important to identifying PHIV youth at particular risk for poor health and behavioral outcomes.

Longitudinal Pediatric Palliative Care: Quality of Life & Spiritual Struggle (FACE): Design and methods

As life expectancy increases for adolescents ever diagnosed with AIDS due to treatment advances, the optimum timing of advance care planning is unclear. Left unprepared for end-of-life (EOL) decisions, families may encounter miscommunication and disagreements, resulting in families being charged with neglect, court battles and even legislative intervention. Advanced care planning (ACP) is a valuable tool rarely used with adolescents. The Longitudinal Pediatric Palliative Care: Quality of Life & Spiritual Struggle study is a two-arm, randomized controlled trial assessing the effectiveness of a disease specific FAmily CEntered (FACE) advanced care planning intervention model among adolescents diagnosed with AIDS, aimed at relieving psychological, spiritual, and physical suffering, while maximizing quality of life through facilitated conversations about ACP. Participants will include 130 eligible dyads (adolescent and family decision-maker) from four urban cities in the United States, randomized to either the FACE intervention or a Healthy Living Control. Three 60-minute sessions will be conducted at weekly intervals. The dyads will be assessed at baseline as well as 3-, 6-, 12-, and 18-month post-intervention. The primary outcome measures will be in congruence with EOL treatment preferences, decisional conflict, and quality of communication. The mediating and moderating effects of threat appraisal, HAART adherence, and spiritual struggle on the relationships among FACE and quality of life and hospitalization/dialysis use will also be assessed. This study will be the first longitudinal study of an AIDS-specific model of ACP with adolescents. If successful, this intervention could quickly translate into clinical practice.

Antiretroviral Drug Resistance Among Children and Youth in the United States With Perinatal HIV

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

Human Immunodeficiency Virus Type 1 DNA Decay Dynamics With Early, Long-term Virologic Control of Perinatal Infection

Background. Early antiretroviral therapy (ART) limits proviral reservoirs, a goal for human immunodeficiency virus type 1 (HIV-1) remission strategies. Whether this is an immediate or long-term effect of virologic suppression (VS) in perinatal infection is unknown. Methods. We quantified HIV-1 DNA longitudinally for up to 14 years in peripheral blood mononuclear cells (PBMCs) among 61 perinatally HIV-1-infected youths in the Pediatric HIV/AIDS Cohort Study who achieved VS at different ages. Participants in group 1 (n = 13) were <1 year of age and in group 2 (n = 48) from 1 through 5 years of age at VS. Piecewise linear mixed-effects regression models assessed the effect of age at VS on HIV-1 DNA trajectories during VS. Results. In the first 2 years following VS, HIV-1 DNA levels decreased by -0.25 (95% confidence interval [CI], -.36 to -.13) log10 copies/million PBMCs per year and was faster with early VS by age 1 year compared with after age 1 (-0.50 and -0.15 log10 copies/million PBMCs per year, respectively). Between years 2 and 14 from VS, HIV-1 DNA decayed by -0.05 (95% CI, -.06 to -.03) log10 copies/million PBMCs per year and was no longer significantly different between groups. The estimated mean half-life of HIV-1 DNA from VS was 15.9 years and was shorter for group 1 compared to group 2 at 5.9 years and 18.8 years, respectively (P = .09). Adjusting for CD4 cell counts had no effect on decay estimates. Conclusions. Early effective, long-term ART initiated from infancy leads to decay of HIV-1-infected cells to exceedingly low concentrations desired for HIV-1 remission strategies.