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BACKGROUND Depression and neurocognitive impairment are highly prevalent among persons living with HIV and associated with poorer clinical outcomes; however, longitudinal studies of depression-neurocognition relationships in youth living with HIV (YLWH), and the role of antiretroviral therapy (ART), are lacking. This study tested whether (1) depressive symptomatology, across somatic, cognitive, and affective symptom domains, improved with ART and (2) more severe depressive symptoms at baseline were associated with poorer neurocognitive function and poorer HIV suppression. SETTING Data were collected from 181 YLWH (18-24 years) who were treatment-naive, a subset of whom (n = 116) initiated ART. METHODS Participants were categorized into elevated (DS) or nonelevated (non-DS) depressive symptom groups at entry (Beck Depression Inventory-II ≥14) and followed for 36 months. Neurocognition (5-domain battery) and depressive symptoms were repeatedly assessed. Longitudinal models examined depressive symptomatology, neurocognition, and odds of HIV nonsuppression by group. RESULTS Greater improvements in depressive symptoms were observed in the DS group over 36 months [beta = -0.14, (-0.24 to -0.03)], particularly within cognitive and affective domains. Verbal learning performance increased in the DS group [beta = 0.13, (0.01 to 0.24)], whereas psychomotor function improved somewhat in the non-DS group [beta = -0.10, (-0.22 to 0.00)]. Adjusted for ART adherence, odds of HIV nonsuppression did not significantly differ by group [odds ratio = 0.22, (0.04 to 1.23)]; however, greater somatic symptoms at study entry were associated with an increased risk of nonsuppression over time [odds ratio = 2.33 (1.07 to 5.68)]. CONCLUSION Depressive symptoms were associated with differential neurocognitive trajectories, and somatic depressive symptoms at baseline may predict poorer subsequent HIV suppression. Identifying and treating depressive symptoms at ART initiation may benefit neurocognitive and clinical outcomes in YLWH.

Background We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children. Methods Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA) Results Twenty-nine SNVs in 24 genes reaching P ≤ .002 and OR ≥ 1.5 comparing CSA Conclusions Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children.

This study examined associations of self-regulatory behavior and cognitive functioning with substance use (SU) to inform interventions for youth with perinatal HIV infection (YPHIV) or exposure but uninfected (YPHEU). Youth aged 7-15 years (YPHIV, n = 390; YPHEU, n = 211) were followed longitudinally with cognitive testing and behavioral questionnaires including self-report of alcohol, marijuana, tobacco, and other SU. Cox proportional hazards analyses were used to examine correlates of initiating each substance for those without prior use at baseline and generalized estimating equation analyses were used to address associations of cognitive/behavioral measurements with SU prevalence for the entire sample. Lower self-reported self-regulation skills, but higher cognitive functioning abilities, were associated with initiation and prevalent use of alcohol and marijuana regardless of HIV status. Our findings suggest SU screening tools and self-regulation interventions developed for general adolescent populations should be implemented for those with PHIV, who may be at heightened risk for SU-related health consequences.En este estudio se examina el vínculo del comportamiento autorregulado y la función cognoscitiva con el consumo de sustancias para argumentar intervenciones para los jóvenes con infección perinatal por el VIH (JIPVIH) y los jóvenes con exposición perinatal sin infección por el VIH (JEPSIVIH). Se hizo un seguimiento longitudinal de jóvenes de 7 a 15 años de edad (JIPVIH, n = 390; JEPSIVIH, n = 211) por medio de pruebas cognoscitivas y cuestionarios sobre el comportamiento, incluyendo el autoinforme de consumo de alcohol, marihuana, tabaco y otras sustancias. Se usaron los análisis Cox de riesgos proporcionales para examinar factores correlacionados con el inicio del consumo de cada sustancia por personas no consumidoras en el punto de referencia inicial. Asimismo, se usaron análisis de ecuaciones de estimación generalizadas para examinar la asociación entre la prevalencia del consumo de sustancias y las medidas cognoscitivas y las medidas conductuales para toda la muestra. Habilidades de autorregulación disminuidas, según autoinforme, pero capacidades superiores de función cognoscitiva, fueron vinculadas con el inicio y consumo frecuente de alcohol y marihuana, independientemente de la condición de VIH. Nuestros hallazgos sugieren que herramientas para detectar el consumo de sustancias e intervenciones de autorregulación creadas para la población general de adolescentes se deberían implementar para los JIPVIH que podrían correr mayores riesgos de sufrir consecuencias en la salud relacionadas con el consumo de sustancias.

Using a phased model of intervention development, we developed an intervention to promote resilience in youth living with HIV via improved neurocognitive resources. First, youth completed a naturalistic prospective memory (PM) task and were randomized into a visualization condition or control condition. Next, 47 of these participants completed another naturalistic PM task and were randomized into Calendaring condition, an Alarm condition, a Combined condition, or a Control condition. Youth with low PM demonstrated observable gains from the visualization technique. Youth in the Combined Calendaring and Alarm condition demonstrated significantly better performance than participants in the Control and Calendaring conditions. In a Proof-of-Concept study with 16 youth, the previous findings were translated into a single session in-person intervention followed by tailored text messaging to improve adherence and viral load via improved neurocognitive resources. The resulting intervention showed a signal of effect with viral load reductions in youth with available data. Targeting compensatory strategies to enhance neurocognitive functioning may promote resilience and health outcomes. A randomized pilot study with a control condition is the next step.

Youth with perinatal HIV infection (PHIV) are at increased risk for neurocognitive impairment. Prospective memory (PM) is a complex neurocognitive function that has been shown to be impaired in adults with HIV disease and independently associated with poorer daily living skills, including medication non-adherence. The current study sought to determine the presence and extent of PM deficits in youth with PHIV. Participants included 173 youth with PHIV and 85 youth HIV-exposed but uninfected (PHEU), mean age 14.1 years, 75% black, 18% Hispanic. Among youth with PHIV, 26% had a past AIDS-defining condition (Centers for Disease Control and Prevention [CDC], Class C), 74% did not (non-C). Adjusted generalized estimating equation models were used to compare groups (PHIV/C, PHIV/non-C, and PHEU) on the Naturalistic Event-Based Prospective Memory Test (NEPT) and the Prospective Memory Assessment for Children & Youth (PROMACY). Secondarily, subgroups defined by HIV serostatus and global neurocognitive impairment (NCI) were compared (PHIV/NCI, PHIV/non-NCI, PHEU). PHIV/C had significantly lower NEPT scores than PHEU, with decreases of 40% in mean scores, but did not differ from PHIV/non-C. PHIV/NCI had 11–32% lower PROMACY scores and 33% lower NEPT scores compared to PHIV/non-NCI (all p

Medication adherence is a critical but challenging developmental task for children and adolescents with perinatally acquired HIV (PHIV). Understanding how medication responsibility, executive functions (EFs) and adaptive functioning (AF) influence adherence may help prepare adolescents for transition to adulthood.Participants included PHIV children and adolescents 7-16 years of age enrolled in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, who were prescribed antiretroviral medications. Measures included caregiver report and child self-report measures of adherence, medication responsibility and EF, caregiver report of child AF, examiner-administered tests of EF and processing speed and demographic and health characteristics.Two hundred fifty-six participants with PHIV (mean age: 12 years old) were 51% female, 80% black and 79% non-Hispanic. Per 7-day recall, 72% were adherent (no missed doses). Children/adolescents self-reported that 22% had sole and 55% had shared medication responsibility. Adjusted logistic models revealed significantly higher odds of adherence with sole caregiver responsibility for medication [odds ratio (OR): 4.10, confidence interval (CI): 1.43-11.8, P = 0.009], child nadir CD4%15% (OR: 2.26, CI: 1.15-4.43, P = 0.018), better self-reported behavioral regulation (OR: 0.65, CI: 0.44-0.96, P = 0.029) and slower processing speed (OR: 0.54, CI: 0.38-0.77, P0.001), adjusting for demographic variables (age, race and caregiver education).Among children and adolescents with PHIV, continued caregiver medication management, especially during adolescence, is essential. Although global EF and AF were not significantly associated with adherence, behavioral regulation was. Given that EF and AF develop throughout adolescence, their relationships to adherence should be evaluated longitudinally, especially as youth transition to adulthood and caregiver responsibility diminishes.

HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH).Observational cross-sectional study.YWH, ages 20-28 years, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation, and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically adjusted z-scores were combined to form indices of attention, motor, executive function, verbal, and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4 T-cell count, HIV viral load, and ART status.Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (z = -1.59 and -1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, whereas sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels.Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.

Highlights • We performed vertex-wise analyses comparing grey matter in youth with and without perinatally-acquired HIV (PHIV). • PHIV youth had reduced cortical thickness, surface area, and gyrification compared to control youth. • PHIV youth did not exhibit the same pattern of inverse grey matter-age relationships that were observed in control youth., Youth with perinatally-acquired HIV (PHIV) experience specific and global cognitive deficits at increased rates compared to typically-developing HIV-uninfected youth. In youth with PHIV, HIV infects the brain early in development. Neuroimaging studies have demonstrated altered grey matter morphometry in youth with PHIV compared to typically-developing youth. This study examined cortical thickness, surface area, and gyrification of grey matter in youth (age 11–20 years old) with PHIV (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) compared to typically-developing presumed HIV uninfected and unexposed youth (n = 80) from the Pediatric Imaging, Neurocognition and Genetics Study (PING) using structural magnetic resonance imaging. This study also examined the relationship between grey matter morphometry and age. Youth with PHIV had reduced cortical thickness, surface area, and gyrification compared to typically-developing youth. In addition, an inverse relationship between age and grey matter volume was found in typically-developing youth, but was not observed in youth with PHIV. Longitudinal studies are necessary to understand the neurodevelopmental trajectory of youth with PHIV.

Objectives To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. Study design The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5 years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. Results Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200 cells/μL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. Conclusions Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

The purpose of this study was to better understand the prevalence and correlates of substance use behaviors among HIV-infected adolescents in HIV care settings.A cross-sectional sample of 2216 youth living with HIV (YLWH; ages 12-26) were recruited through the Adolescent Trials Network for HIV Interventions. Participants completed a one-time survey on sociodemographic factors, substance use and health behaviors. We used logistic regression models to understand the correlates of substance use outcomes.Overall, weekly or more frequent tobacco use was reported by 32.9% of participants, 27.5% marijuana use, and 21.3% alcohol use; and 22.5% reported any other illicit drug use. In multivariable models, young MSM had higher odds of reporting each substance use behavior, and transgender women had increased odds of marijuana and other illicit drug use. Criminal justice involvement, unstable housing, condomless sex, and suboptimal antiretroviral therapy was associated with increased risk of substance use behaviors.Study findings highlight the need for regular screening for substance use in HIV care settings in order to improve access to and delivery of culturally competent substance use prevention and treatment services.

BACKGROUND Perinatally acquired HIV (PHIV) confers risk for neurocognitive impairment, which potentially affects school performance and functional independence of infected children. In this study, we examined the associations of 2 key neurocognitive domains, memory and executive function (EF), with academic and adaptive skills among youth with PHIV and perinatally HIV-exposed but uninfected (PHEU) youth. METHODS Participants ages 9 to

BACKGROUND Executive functions (EFs) are critical for management of life activities, but few studies have evaluated EFs in children and adolescents with perinatally acquired HIV (PHIV), who are at risk for problems in academics, behavior, and medication adherence. We compared EFs in youth with PHIV and in perinatally HIV-exposed but uninfected (PHEU) youth. METHODS Four Delis-Kaplan Executive Function System (D-KEFS) subtests were administered to 173 youth with PHIV and 85 PHEU youth, aged 9 to

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.

BackgroundPersons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth.MethodsThis is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts.ResultsSeroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively.ConclusionAntibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

BACKGROUND: In utero exposure to nucleoside reverse transcriptase inhibitor (NRTI)-containing antiretroviral treatment (ART) regimens may be associated with poor neurodevelopmental functioning in children of HIV-infected mothers. We investigated neurodevelopmental outcomes of HIV-exposed uninfected (HEU) children of HIV-infected women enrolled in a randomized trial of abacavir/zidovudine/lamivudine (Triple-NRTI regimen) vs. lopinavir/ritonavir/zidovudine/lamivudine (Dual NRTI+PI regimen). SETTING: The Mma Bana randomized trial was conducted in urban and rural sites in Botswana. METHODS: The Mma Bana study randomized HIV-infected pregnant women with CD4 ≥ 200 cells/mm(3) to a triple-NRTI vs. dual-NRTI+PI regimen from 26–34 weeks gestation through planned weaning at 6 months postpartum. Partway through the study, neurodevelopmental assessments were added at 24 months of age, including the Developmental Milestones Checklist, the Bayley Scales of Infant and Toddler Development 3(rd) edition, Ten Questions Questionnaire, and Profile of Social Emotional Development. We evaluated differences in mean scores between the two arms using unadjusted and adjusted linear regression. RESULTS: A total of 197 HEU infants (48% male) completed a neurodevelopmental assessment (101 in triple-NRTI arm; 96 in dual-NRTI+PI-exposed arm). Means for all neurodevelopmental outcomes were similar for children of mothers randomized to either ART regimen, with no significant differences in either unadjusted or adjusted models (estimated effect sizes ranging from −0.12 to 0.14). CONCLUSION: Neurodevelopmental outcomes in 24-month-old HEU children of HIV-infected mothers with baseline CD4≥200 were similar in those randomized to a dual-NRTI+PI-based versus a triple-NRTI-based ART regimen, suggestive of lack of short term toxicity. Monitoring of long term toxicity and newer regimens is warranted.

Youth living with HIV (YLH) face significant problems with regularly attending their medical appointments. Poor attendance, consequently, predicts viral non-suppression and other negative HIV-related outcomes. To identity targets of intervention, this cross-sectional study examined correlates of past-year missed clinic visits among a diverse sample of YLH (ages 12 to 24; N = 2125) from HIV clinics in the United States and Puerto Rico. Our results revealed that 36% of YLH reported missing two or more visits in the past year. Several factors were associated with missed clinic visits in our multivariate logistic regression model based on adjusted odds ratios (AORs). Among sociodemographic characteristics and HIV disclosure status, females (AOR = 1.63, compared to males), Black YLH or YLH of mixed racial heritage (AORs = 1.76, 1.71, respectively, compared to White YLH), YLH with an unknown route of infection (AOR = 1.86, compared to YLH with perinatal infection), and YLH endorsing HIV disclosure (AOR = 1.37, compared to YLH not endorsing disclosure) were at greater risk for missed visits. In addition, number of times YLH moved residences was associated with missed visits (AOR = 1.07). Among behavioral health risks, YLH who endorsed marijuana use (AOR = 1.42), frequent other drug use (AOR = 1.60), or a history of incarceration (AOR = 1.27) had greater odds of missed visits than youth not endorsing these health risks. Finally, two social-cognitive factors emerged as protective against missed visits: adherence self-efficacy (AOR = .28) and adherence social support (AOR = .88). We conclude by discussing the ways in which providers and clinics working with YLH can improve this population’s retention outcomes by recognizing youth-specific individual, social, and structural barriers to treatment engagement.

Objective To define inflammatory pathways in youth living with HIV infection (YLWH), assessments of biomarkers associated with lymphocyte and macrophage activation, vascular injury, or bone metabolism were performed in YLWH in comparison with healthy controls (HC). Design Longitudinal multicenter study comparing biomarkers in YLWH suppressed on antiretroviral therapy (ART), those with ongoing viral replication, and HC were compared using single blood samples obtained at end of study. Methods Twenty-three plasma proteins were measured by ELISA or multiplex assays. Principal component analysis (PCA) was used to define contributions of individual biomarkers to define outcome groups. Results The study cohort included 129 predominantly African American, male participants, 21–25 years old at entry. Nine biomarkers of lymphocyte and macrophage activation and cardiovascular injury differed between HC and YLWH. Significant positive correlations were identified between lymphocyte and macrophage activation biomarkers among HC and YLWH. Correlations distinct to YLWH were predominantly between biomarkers of macrophage and vascular inflammation. PCA of outcome groups showed HC and suppressed YLWH clustering together for lymphocyte activation biomarkers, whereas macrophage activation markers showed all YLWH clustering distinct from HC. Cardiovascular biomarkers were indistinguishable across groups. Averaged variable importance projection to assess single biomarkers that maximally contribute to discriminate among outcome groups identified soluble CD27, CD14, and CD163 as the 3 most important with TNFα and LPS also highly relevant in providing separation. Conclusions Soluble inflammatory and lymphocyte biomarkers sufficiently distinguish YLWH from HC. Persistent macrophage activation biomarkers may provide a means to monitor consequences of HIV infection in fully suppressed YLWH.

Although youth living with behaviorally acquired HIV (YLWH) are at risk for cognitive impairments, the relationship of impairments to HIV and potential to improve with antiretroviral therapy (ART) are unclear. This prospective observational study was designed to examine the impact of initiation and timing of ART on neurocognitive functioning in YLWH in the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Treatment naïve YLWH age 18–24 completed baseline and four additional assessments of attention/working memory, complex executive, and motor functioning over 3 years. Group 1 co-enrolled in an early ART initiation study and initiated ART at enrollment CD4 >350 (n = 56); group 2 had CD4 >350 and were not initiating ART (n = 66); group 3 initiated ART with CD4

This study determined the prevalence and patterns of psychological symptoms in adolescents and young adults living with HIV (YLWH) in medical care and relationships between psychological symptoms, route and duration of infection, and antiretroviral treatment (ART). A clinic-based sample of 2032 YLWH (mean age 20.3 years), recruited from 20 adolescent medicine HIV clinics, completed a cross-sectional survey of health behaviors and psychological symptoms using the Brief Symptom Inventory (BSI). Overall, 17.5% of youth reported psychological symptoms greater than the normative threshold on the Global Severity Index. A wide variety of symptoms were reported. The prevalence of clinical symptoms was significantly greater in youth with behaviorally acquired HIV compared to those with perinatally acquired infection (20.6% vs. 10.8%, OR=2.06 in Multiple Logistic Regression (MLR)), and in those not taking ART that had been prescribed (29. 2% vs. 18.8%, OR=1.68 in MLR). Knowing one's HIV status for more than one year and disclosure of HIV status were not associated with fewer symptoms. A large proportion of YLWH have psychological symptoms and the prevalence is greatest among those with behaviorally acquired infection. The high rate of psychological symptoms for youth not taking ART that is prescribed is a cause for concern. Symptoms do not appear to be a transient reaction to diagnosis of HIV.

BACKGROUND:We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana.METHODS:HIV-infected and uninfected mothers enrolled in a prospective observational study (“Tshipidi”) in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics.RESULTS:We evaluated 670 children (313 HEU, 357 HUU) with ≥1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small.CONCLUSIONS:HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring.

Substance use is highly prevalent among youth living with HIV (YLWH) and negatively impacts HIV care. This study sought to determine whether the CRAFFT (Car, Relax, Alone, Forget, Friends, and Trouble), designed to screen for problematic substance use, is reliably associated with substance use behaviors among YLWH. A cross-sectional sample of 2216 youth (ages 12-26) were recruited through the adolescent medicine trials network for HIV/AIDS Interventions. Participants completed a self-administered survey. Over half screened positive on the CRAFFT (i.e., ≥2). Among frequent substance users, those older in age, behaviorally infected, with history of incarceration or unstably housed were more likely to screen positive on the CRAFFT. Study findings suggest that the CRAFFT reliably identifies youth who use substances. Thus, screening measures such as the CRAFFT should be utilized routinely in HIV clinical settings for youth.

BACKGROUND Little is known regarding effects of perinatally acquired HIV infection (PHIV) on longitudinal change in memory and executive functioning (EF) during adolescence despite the importance of these skills for independence in adulthood. METHODS PHIV (n = 144) and perinatally HIV-exposed uninfected youth (PHEU, n = 79), ages 12-17, completed standardized tests of memory and EF at baseline and 2 years later. Changes from baseline for each memory and EF outcome were compared between PHEU and PHIV youth with (PHIV/C, n = 39) and without (PHIV/non-C, n = 105) history of CDC class C (AIDS-defining) diagnoses. Among PHIV youth, associations of baseline and past disease severity with memory and EF performance at follow-up were evaluated using adjusted linear regression models. RESULTS Participants were primarily black (79%); 16% were Hispanic; 55% were female. Mean memory and EF scores at follow-up generally fell in the low-average to average range. Pairwise comparison of adjusted mean change from baseline to follow-up revealed significantly greater change for PHIV/non-C compared with PHEU youth in only one verbal recognition task, with a difference in mean changes for PHIV/non-C versus PHEU of -0.99 (95% CI: -1.80 to -0.19; P = 0.02). Among youth with PHIV, better immunologic status at baseline was positively associated with follow-up measures of verbal recall and recognition and cognitive inhibition/flexibility. Past AIDS-defining diagnoses and higher peak viral load were associated with lower performance across multiple EF tasks at follow-up. CONCLUSIONS Youth with PHIV demonstrated stable memory and EF during a 2-year period of adolescence, allowing cautious optimism regarding long-term outcomes.

Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7 years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1 years). PHIV youth had smaller (2.8 – 5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0 – 13.4%; marijuana use: 10.1 – 16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume.

Purpose The HIV Care Continuum highlights the need for HIV-infected youth to be tested, linked, and maintained in lifelong care. Care engagement is important for HIV-infected youth in order for them to stay healthy, maintain a low viral load, and reduce further transmission. One point of potential interruption in the care continuum is during health care transition from adolescent- to adult-centered HIV care. HIV-related health care transition research focuses mainly on youth and on adolescent clinic providers; missing is adult clinic providers' perspectives. Methods We examined health care transition processes through semi-structured interviews with 28 adult clinic staff across Adolescent Trials Network sites. We also collected quantitative data related to clinical characteristics and transition-specific strategies. Results Overall, participants described health care transition as a "warm handoff" and a collaborative effort across adolescent and adult clinics. Emergent transition themes included adult clinical care culture (e.g., patient responsibility), strategies for connecting youth to adult care (e.g., adolescent clinic staff attending youth's first appointment at adult clinic), and approaches to evaluating transition outcomes (e.g., data sharing). Participants provided transition improvement recommendations (e.g., formalized protocols). Conclusions Using evidence-based research and a quality improvement framework to inform comprehensive and streamlined transition protocols can help enhance the capacity of adult clinics to collaborate with adolescent clinics to provide coordinated and uninterrupted HIV-related care and to improve continuum of care outcomes.

Background Substance use by youth living with HIV (YLWH) is a concern, given potential interactions with virus-associated immune suppression and adverse effects on risk behaviors, neurocognition, and adherence. Self-report substance use measures provide efficient cost-effective assessments. Analyses describe self-reported substance use among YLWH and examine agreement with toxicology assays. Methods Seventy-eight youth age 18–24 years (87% male, 71% African–American) with behaviorally acquired HIV-1 infection and 55 uninfected youth completed the Alcohol, Smoking, and Substance Involvement Screening Test to assess drug use frequency, including tobacco, marijuana, cocaine, and alcohol, over the prior three months. Elisa-based toxicology assays were used to detect 27 substances in plasma. Chi-square tests compared substance use between YLWH and uninfected youth; Kappa statistics compared agreement between self-report and toxicology. Results YLWH reported marijuana (49%), tobacco (56%), and alcohol (87%) use, with 20%, 28% and 3% reporting daily use of each substance, respectively; other substance use was uncommon. Uninfected youth reported less tobacco use but otherwise similar substance use. All youth who reported daily use of marijuana or tobacco had positive plasma toxicology results, while concordance decreased with less frequent self-reported use. Among youth reporting no substance use, few tested positive (4% YLWH, 2% uninfected youth for cannabis; 8%YLWH for tobacco). Conclusions Youth report high rates of marijuana, tobacco, and alcohol use. Concordance between self-report and toxicology for marijuana and tobacco use, particularly for daily users, supports self-report as a valid indicator of substance use in research studies of youth with or without HIV-1 infection.

Purpose Youth living with human immunodeficiency virus (HIV) account for over one third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. Human immunodeficiency virus–associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy. Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here, we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use. Methods A total of 220 participants, age 18–24 years, who were naive to treatment (except for prevention of mother-to-child HIV transmission; n = 3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery. Results Sixty-seven percent of youth met criteria for HAND (96.4% were asymptomatic and 3.5% were syndromic); deficits in episodic memory and fine-motor skills emerged as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high-risk alcohol use were uniquely associated with neurocognitive deficits. Conclusions Over two thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., nonadherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy.

Individuals with HIV disease often evidence deficits in prospective memory (PM), which interfere with daily functioning and increase the risk of suboptimal health behaviours. This study examined the benefits of simple encoding and cueing supports on naturalistic time-based PM in 47 HIV-positive young adults. All participants completed a naturalistic time-based PM task in which they were instructed to text the examiner once per day for seven days at a specified time. Participants were randomised into (1) a Calendaring condition in which they created a calendar event in their mobile telephone for the specified texting time; (2) an Alarm condition in which they programmed an alarm into their mobile telephone for the specified texting time; (3) a Combined calendaring and alarm condition; and (4) a Control condition. Participants in the Combined condition demonstrated significantly better naturalistic PM performance than participants in the Control and Calendaring conditions. Findings indicate that HIV-positive young people may benefit from a combined calendaring and alarm supportive strategy for successful execution of future intentions in daily life.

Learning and memory in youth with perinatally acquired HIV (PHIV) are poorly understood, despite their importance for academic, healthcare and daily functioning.PHIV (n = 173) and perinatally HIV-exposed but uninfected (PHEU, n = 85) participants (aged 9-19 years) in a substudy of the Pediatric HIV/AIDS Cohort Study completed age-standardized tests of verbal and visual learning and delayed memory. Linear regression models implemented via generalized estimating equations were used to compare memory measures in PHEU participants versus PHIV youth with and without Centers for Disease Control and Prevention class C diagnosis (PHIV-C, n = 45 and PHIV-non-C, n = 128, respectively), adjusting for sociodemographic covariates.Participants (mean age = 14.10 years) were 54% female, 75% Black and 18% Hispanic. Although unadjusted analyses showed significantly lower visual recognition memory and verbal delayed recall for PHIV-C compared with PHEU participants and lower verbal learning for PHIV-C and non-C groups compared with PHEU, differences persisted only for visual recognition memory after adjusting for sociodemographic covariates. For PHIV youth, current CD4%25 was associated with poorer verbal learning, and older age at peak viral load was associated with poorer verbal delayed recall and design memory.Youth with PHIV, particularly those with Centers for Disease Control and Prevention class C diagnosis, showed poorer performance on some measures of learning and memory compared with PHEU. Although group differences in verbal memory were largely attributable to sociodemographic characteristics, associations of class C diagnosis with poorer visual recognition memory and of current CD4% with poorer verbal learning suggest subtle effects of HIV on learning and memory in youth with PHIV.

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.

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.

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

To examine the relationship between markers of vascular dysfunction and neurodevelopmental status in pediatric HIV disease.A cross-sectional design within a prospective, 15-site cohort study conducted in the United States.Nine vascular biomarkers were examined in 89 HIV-infected children: soluble P-selectin/sCD62P, fibrinogen, adiponectin, monocyte chemoattractant protein-1/CCL-2, interleukin-6, C-reactive protein, soluble vascular cell adhesion molecule-1/sCD106, sE-selectin/sCD62E, and soluble intercellular adhesion molecule-1/sCD54. The Wechsler Intelligence Scale for Children-Fourth edition (WISC-IV) was administered yielding indices for verbal comprehension, perceptual reasoning, working memory and processing speed, and overall composite Full-Scale IQ score. Linear regression models were used to evaluate neurodevelopmental status (measured by WISC-IV scores) as a function of each biomarker while adjusting for demographics, disease severity, and receipt of HAART. Biomarker levels were evaluated in quartiles to evaluate trends in WISC-IV responses.Among the 89 HIV-infected children (median age = 12 years), 56% were girls, 71% black, 16% Hispanic, and 43% had yearly household income below US $20,000. Log (soluble P-selectin) was significantly correlated with all WISC-IV scores; adjusted slopes showed 6-11-point average decrease in scores for each one log unit increase in soluble P-selectin. Final linear regression models for log (fibrinogen) adjusted for sociodemographic and disease characteristics also indicated a negative correlation with all WISC-IV scores (13-30-point decrease for each one log unit increase in fibrinogen); these decreases were significant in the verbal comprehension, perceptual reasoning, and Full-Scale IQ scores.Proinflammatory microvascular and immunologic mechanisms may be involved in neurodevelopmental impairment in children with perinatally acquired HIV disease.

BACKGROUND: Parent/caregiver or child/youth self-report and pill counts are commonly used methods for assessing adherence to antiretroviral therapy (ART) 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=0.032), 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 one month” (p=0.054 child/youth interview, p=0.004 parent/caregiver interview), and no barrier to adherence identified (p=0.085 child/youth interview, p=0.015 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.

Human immunodeficiency virus (HIV) disease is commonly associated with deficits in prospective memory (PM), which increase the risk of suboptimal health behaviours, like medication non-adherence. This study examined the potential benefits of a brief future visualisation exercise during the encoding stage of a naturalistic PM task in 60 young adults (aged 19-24 years) with HIV disease. Participants were administered a brief clinical neuropsychological assessment, which included a standardised performance-based measure of time- and event-based PM. All participants were also given a naturalistic PM task in which they were asked to complete a mock medication management task when the examiner showed them the Grooved Pegboard Test during their neuropsychological evaluation. Participants were randomised into: (1) a visualisation condition in which they spent 30 sec imagining successfully completing the naturalistic PM task; or (2) a control condition in which they repeated the task instructions. Logistic regression analyses revealed significant interactions between clinical neurocognitive functions and visualisation. HIV positive (HIV+) participants with intact retrospective learning and/or low time-based PM demonstrated observable gains from the visualisation technique, while HIV+ participants with impaired learning and/or intact time-based PM did not evidence gains. Findings indicate that individual differences in neurocognitive ability moderate the response to visualisation in HIV+ young adults. The extent to which such cognitive supports improve health-related PM outcomes (e.g., medication adherence) remains to be determined.

Supplemental Digital Content is available in the text, Youth with perinatally acquired human immunodeficiency virus (PHIV+) survive longer with combination antiretroviral therapy, but remain at risk for poor cognitive outcomes. We evaluated whether markers of HIV disease severity relate to default mode resting-state functional connectivity in PHIV+ youth. We conducted resting-state functional neuroimaging and cognitive testing in a subset of 40 PHIV+ youth recruited from a single study site of the Adolescent Master Protocol study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Current and past HIV disease severity measures (nadir CD4 lymphocyte percentages and peak HIV RNA plasma levels) were obtained from medical charts. We evaluated associations of both HIV disease severity measures and cognitive functioning with between- and within- default mode network (DMN) connectivity using Analysis of Functional NeuroImaging multiple regression analyses, controlling for multiple comparisons. Of the 40 youth, 31 (mean age = 16.5 years) with minimal motion during scans were included. We observed global alterations in DMN within- and between-network connectivity, with significant associations between disease severity and DMN BOLD correlations. Furthermore, patterns of connectivity with the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) that varied as a function of peak HIV RNA were found to predict processing speed ability. Alterations in within- and between-network DMN connectivity in PHIV+ youth may reflect global reorganization of the DMN; this could lead to compensatory alterations in both the within- and between-connectivity of large-scale networks, which may ultimately relate to known cognitive processing difficulties in PHIV+ youth.

Objectives We investigated whether HIV disease severity was associated with alterations in structural brain connectivity, and whether those alterations in turn were associated with cognitive deficits in youth with perinatally acquired HIV (PHIV). Design PHIV youth (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) (mean age: 16 ± 2 years) were included to evaluate how current and past disease severity measures (recent/nadir CD4%; peak viral load) relate to white matter microstructure within PHIV youth. PHIV youth were compared with 314 controls from the Pediatric Imaging, Neurocognition and Genetics (PING) study. Methods Diffusion tensor imaging and tractography were utilized to assess white matter microstructure. Mediation analyses were conducted to examine whether microstructure alterations contributed to relationships between higher disease severity and specific cognitive domains in PHIV youth. Results Whole brain fractional anisotropy was reduced, but radial and mean diffusivity were increased in PHIV compared with control youth. Within PHIV youth, more severe past HIV disease was associated with reduced fractional anisotropy of the right inferior fronto-occipital (IFO) and left uncinate tracts; elevated mean diffusivity of the F minor; and increased streamlines comprising the left inferior longitudinal fasciculus (ILF). Associations of higher peak viral load with lower working memory performance were partly mediated by reductions in right IFO fractional anisotropy levels. Conclusion Our findings suggest that PHIV youth have a higher risk of alterations in white matter microstructure than typically developing youth, and certain alterations are related to past disease severity. Further, white matter alterations potentially mediate associations between HIV disease and working memory.

Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status.The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics.Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P.001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at3 years (both), 73% and 100% at 3-7 years (P.05), and 77% and 97% at ≥ 7 years (P.01), respectively. Seropositivity among recipients of 2 vaccine doses was94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥ 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P.001 for overall dose effect), and in those vaccinated ≥ 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02).Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥ 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use.

In addition to individual characteristics, there may be a wide range of environmental or neighborhood stressors that contribute to elevated cannabis use in groups of youth living with HIV/AIDS (YLHIV); however, the effects of social disorganization on cannabis use in YLHIV to date have not been studied.We examined the effects of individual-level and neighborhood-level factors by developing hierarchical generalized linear models estimating odds of current cannabis use (any use during the past 3 months) and daily cannabis use among a sample of YLHIV (N = 1921) currently receiving medical care.The final model for daily cannabis use in the past 3 months included significant positive effects associated with hostility (O.R. = 1.08, 95% C.I.: 1.05, 1.11), being older (O.R. = 1.12, 95% C.I.: 1.05, 1.20), being a bisexual male (O.R. = 1.72, 95% C.I.: 1.10, 2.70), and residing in a community with a murder rate in the highest quartile (O.R. = 1.91, 95% C.I.: 1.27, 2.87), second highest quartile (O.R. = 1.62, 95% C.I.: 1.06, 2.46), or third highest quartile (O.R. = 1.52, 95% C.I.: 1.01, 2.30).This paper advances our knowledge of the multilevel factors associated with elevated cannabis use among groups of YLHIV and furthers our understanding of social and structural determinants of health in this population. Future research into cannabis use among YLHIV should consider, not only cannabis use within the context of the adjustment of living with HIV/AIDS, but also the stressors that characterize the environments in which groups of YLHIV live.

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.

Event-based prospective memory (PM) tasks require individuals to remember to perform an action when they encounter a specific cue in the environment, and they have clear relevance for daily functioning for individuals with HIV. In many everyday tasks, not only must the individual maintain the intent to perform the PM task, but the PM task response also competes with the alternative and more habitual task response. The current study examined whether event-based PM can be improved by slowing down the pace of the task environment. Fifty-seven young adults living with HIV performed an ongoing lexical decision task while simultaneously performing a PM task of monitoring for a specific word (which was focal to the ongoing task of making lexical decisions) or syllable contained in a word (which was nonfocal). Participants were instructed to refrain from making task responses until after a tone was presented, which occurred at varying onsets (0-1600 ms) after each stimulus appeared. Improvements in focal and nonfocal PM accuracy were observed with response delays of 600 ms. Furthermore, the difference in PM accuracy between the low-demand focal PM task and the resource-demanding nonfocal PM task was reduced by half across increasingly longer delays, falling from 31% at 0-ms delay to only 14% at 1600-ms delay. The degree of ongoing task response slowing for the PM conditions, relative to a control condition that did not have a PM task and made lexical decisions only, also decreased with increased delay. Overall, the evidence indicates that delaying the task responses of younger HIV-infected adults increased the probability that the PM relevant features of task stimuli were adequately assessed prior to the ongoing task response, and by implication that younger HIV infected adults can more adequately achieve PM goals when the pace of the task environment is slowed down.

Two experiments were conducted to examine the effects of task importance on event-based prospective memory (PM)in separate samples of adults with HIV-associated neurocognitive disorders (HAND) and HIV-infected young adultswith substance use disorders (SUD). All participants completed three conditions of an ongoing lexical decision task:(1) without PM task requirements; (2) with PM task requirements that emphasized the importance of the ongoing task;and (3) with PM task requirements that emphasized the importance of the PM task. In both experiments, all HIV+ groupsshowed the expected increase in response costs to the ongoing task when the PM task’s importance was emphasized. InExperiment 1, individuals with HAND showed significantly lower PM accuracy as compared to HIV+ subjects withoutHAND when the importance of the ongoing task was emphasized, but improved significantly and no longer differedfrom HIV+ subjects without HAND when the PM task was emphasized. A similar pattern of findings emerged inExperiment 2, whereby HIV+ young adults with SUD (especially cannabis) showed significant improvements in PMaccuracy when the PM task was emphasized. Findings suggest that both HAND and SUD may increase the amount ofcognitive attentional resources that need to be allocated to support PM performance in persons living with HIV infection.(JINS, 2014, 20, 652–662)Keywords: Infectious disease, Episodic memory, AIDS dementia complex, Marijuana abuse, Attention, Substance-relateddisorders

To examine the relationship between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected (PHIV+) and perinatally HIV-exposed but uninfected (PHEU) youth.Cross-sectional design within a prospective, 15-site US-based cohort study.Neurodevelopmental outcomes were evaluated in relation to nine selected vascular biomarkers in 342 youth (212 PHIV+, 130 PHEU). Serum levels were assessed for adiponectin, C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), monocyte chemoattractant protein (sMCP-1), intercellular adhesion molecule-1 (sICAM-1), and P-selectin (sP-selectin). The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was administered at entry, yielding a Full-Scale IQ score, and four index scores. Factor analysis was conducted to reduce the biomarkers to fewer factors with related biological roles. Structural equation models (SEMs) were used to measure associations between resulting factors and WISC-IV scores.Mean participant age was 11.4 years, 54% were female, 70% black. The nine biomarkers were clustered into three factor groups: F1 (fibrinogen, CRP, and IL-6); F2 (sICAM-1 and sVCAM-1); and F3 (MCP-1, sP-selectin, and sE-selectin). Adiponectin showed little correlation with any factor. SEMs revealed significant negative association of F1 with WISC-IV processing speed score in the total cohort. This effect remained significant after adjusting for HIV status and other potential confounders. A similar association was observed when restricted to PHIV+ participants in both unadjusted and adjusted SEMs.Aggregate measures of fibrinogen, CRP, and IL-6 may serve as a latent biomarker associated with relatively decreased processing speed in both PHIV+ and PHEU youth.

Attentional functioning was examined in three groups of 7- to 19-year-old male participants with hemophilia: (1) HIV seronegative controls (HIV−, N = 66), (2) HIV seropositive participants with CD4+ lymphocyte counts greater than or equal to 200 (HIV+ CD4+ ≥200, N = 79), and (3) severely immune suppressed HIV seropositive participants (HIV+ CD4+ N = 28). Two measures sensitive to attention deficits were used: the Continuous Performance Test (CPT) and the Span of Apprehension (Span). On the CPT, there was a decrement in attention in both HIV+ groups, as indexed by an increase in false alarm rate from Block 1 to Block 3, that was not present in the HIV− group. The longer the HIV+ children were required to sustain attention to the CPT, the more they responded to the incorrect stimulus. This effect decreased as age increased. Span percent correct and latency to correct were associated with the presence of a premorbid history of intracerebral hemorrhage, but were not sensitive to HIV status or degree of immune suppression in the HIV+ children, suggesting morbidity related to hemophilia. The remaining CPT and Span variables—hit rate, sensitivity, latency, percent correct, and latency to correct—showed the expected associations with age, but none showed conclusive associations with HIV status or immune suppression in the HIV+ participants. (JINS, 2000, 6, 443–454.)

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.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.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.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.

Medication adherence is critical to the success of antiretroviral therapies for children and youth with perinatally acquired HIV. Factors that influence successful transition of medication responsibility from caregivers to youth are poorly understood. The purpose of this study was to evaluate the relationship of medication adherence with demographic, cognitive, academic, and behavioral characteristics.Randomly selected youth, N = 151, aged 8 to 18 years, completed cognitive and academic measures, and they and their caregivers completed questionnaires assessing behavior and emotional well-being. An announced pill count and questionnaires completed by youth and their caregivers were used to evaluate adherence.Of 151 participants, 100 completed all adherence measures. Adherence rates varied by assessment method. Nonadherence (90%) by pill count was associated with older child age, greater youth responsibility for medications, and other demographic and medication regimen variables. Verbal impairment predicted better self-reported adherence and reading problems predicted better self- and caregiver-reported adherence. Youth-reported locus of control was associated with pill count nonadherence, and poor relationships with parents were associated with youth-reported nonadherence.Consideration of youth cognitive or academic status may be helpful in evaluating medication adherence in patients with perinatally acquired HIV infection, particularly when using self- or caregiver reports to assess adherence. Vigilance for adherence problems is indicated when youth are older, responsible for medications, report poor caregiver relationships, and/or sense a lack of control over their lives.

HIV infection has been reclassified as a chronic medical condition, leading to increased study of the long-term mental health care needs of people with HIV. Children and adolescents with HIV experience significant, multiple risks to mental health and quality of life, including viral infection of the central nervous system, viral and drug exposure in utero, developmental delays, poverty, inadequate support networks, unstable housing, and parental mental illness.1 These factors place children and adolescents with HIV at risk for adverse behavioral outcomes, including symptoms of attention-deficit hyperactivity disorder (ADHD).1 With an estimated prevalence of 5 to 7% among school-aged children, ADHD is one of the most common pediatric neurobehavioral disorders.2 The prevalence is higher in children who have comorbid developmental conditions such as intellectual disability and autism spectrum disorders.3,4 Clinical concerns specific to the presence of comorbid HIV and untreated ADHD are that inattentiveness might impair a child’s or adolescent’s ability to adhere to antiretroviral treatment, whereas impulsivity might impair an adolescent’s ability to practice health-promoting behaviors (e.g., safe sex). Psychopharmacologic treatments for ADHD include stimulants and nonstimulants, both commonly prescribed for children with HIV and ADHD. Stimulant efficacy in children and adolescents is well established.2,5,6 For a variety of reasons, including stimulant failure or intolerance, stigma, and potential for abuse, clinicians often prescribe nonstimulants to treat ADHD. One of the most disputed adverse side effects of stimulant medication is growth attenuation in children.2 Although some evidence suggests that age-related increases in height and weight may be diminished in children treated with stimulants,7,8 the clinical relevance of the growth delay remains controversial.9,10 Clinical trials have not demonstrated significant growth attenuation in children treated with nonstimulants.11,12 Children and adolescents with HIV are at risk for growth failure as a complication of their disease.13,14 For children with comorbid HIV and ADHD, the use of stimulants to treat ADHD may exacerbate the risk of growth failure related to HIV. There has been little empirical investigation into growth rates in children with HIV taking stimulants or nonstimulants for ADHD. The primary objective of this study was to examine the relationship between physical growth, as measured by height and weight, in children and adolescents with HIV and the use of commonly prescribed medications for treatment of ADHD. We hypothesized that children with prescriptions for stimulants would be smaller for age and would gain height and weight more slowly than their peers with HIV who were not prescribed stimulant medications.

Advances in medical treatment, through combination antiretroviral therapy (ART) and highly active ART (HAART) with protease inhibitors (PIs), have resulted in improved health outcomes among children with human immunodeficiency virus (HIV) infection (DeMartino et al., 2000; Gortmaker et al., 2001). Adherence to HAART regimens is difficult, however, due to the demanding nature of antiretroviral treatment and other unique challenges faced by children and adolescents with HIV and their caregivers. Antiretroviral medications, particularly regimens containing PIs, share characteristics that amplify the inherent difficulties of medication adherence in children and adolescents: poor palatability, heavy pill burden, dietary restrictions, acute and long-term side effects, and restrictions on daily schedules (Reddington et al., 2000; Van Dyke et al., 2002). Children and adolescents with HIV often face other life stressors that affect their ability to achieve adherence, including parental HIV disease, poverty, and limited or inconsistent social support (Steele, Nelson, & Cole, 2007). Adherence failure is dangerous in HIV disease as it may result in diminished treatment efficacy, development of genotypically resistant mutations, viral rebound, and subsequent reduction in HIV treatment options. Despite the importance of adherence in HIV disease, our understanding of factors predictive of adherence in children and adolescents remains incomplete. Prior studies of adherence in children with HIV infection, while often atheoretical, have identified multiple contextual factors associated with adherence, including disease characteristics, features of the medication regimen, and characteristics of the caregiver and family, such as caregiver education and problem-solving skills, caregiver relationship to the child, and child and caregiver stress (Hammani et al., 2004; Martin et al., 2007; Mellins, Brackis-Cott, Dolezal, & Abrams, 2004; Naar-King et al., 2006; Pontali, 2005). Child and adolescent developmental issues, including older age, knowledge of HIV diagnosis, and adjustment to chronic illness have also been implicated, although findings remain inconsistent (Simoni et al., 2007; Williams et al., 2006). Neurocognitive impairment, due to the neuropathological effects of HIV infection, is a significant complication of perinatally acquired HIV infection (Van Rie, Harrington, Dow, & Robertson, 2007). It has been associated with nonadherence in adults with HIV (Hinkin et al., 2004) and may provoke similar risk in children and adolescents. Global or mild cognitive deficits, if present, may impede or delay development of those functional skills essential for adherence, such as understanding and following parental and provider directions, remembering schedules and dosage, and communicating needs effectively. The purpose of this study was to examine cognitive functioning in children and adolescents with HIV, and to evaluate its relationship with medication adherence. We hypothesized that adherence to ART and HAART with PIs will be compromised in the presence of neurocognitive deficits in children and adolescents with HIV infection. We also evaluated potential confounding factors, including demographic characteristics, biological markers of health, medication and adherence factors, and child and family psychosocial characteristics that have been associated with medication adherence in previous investigations.

Protease inhibitor therapy and aggressive multidrug regimens have increased the likelihood that children perinatally infected with HIV will survive into adolescence and young adulthood. Improved understanding of the pathogenesis of HIV and viral activity has suggested that medication adherence must be nearly perfect to minimize viral load and prevent drug resistance (Paterson et al., 1999). Unfortunately, treatment for HIV presents special challenges for adherence. Antiretroviral (ART) medications often involve demanding dosing schedules and have significant adverse effects. Because pediatric HIV most often affects disadvantaged families through maternal–child transmission, illness management may be affected by family and caregiver issues such as parental illness and stress, substance abuse, lack of adequate support networks, loss and change of caregivers, and poor access to healthcare resources. Additional adherence challenges related to HIV infection include potential cognitive and learning limitations and the stigma of the disease. Studies of youth with other pediatric chronic medical conditions suggest adherence to treatment regimens deteriorates in adolescence (Drotar & Ievers, 1994), and medication adherence in pediatric HIV has been found to decline as children grow older (Mellins, Brackis-Cott, Dolezal, & Abrams, 2004; Williams et al., 2006). Parents tend to decrease their involvement and supervision of their children's daily activities as they move into adolescence (Laird, Pettit, Bates, & Dodge, 2003; Wysocki et al., 1996). While this facilitates the process of adolescent separation and individuation necessary for transition to adulthood, multiple studies have shown that low levels of parental involvement in illness management result in poorer management and health outcomes among youth with chronic illness (Allen, Tennen, McGrade, Affleck, & Ratzan, 1983; Boland, Grey, & Mezger, 1999; Ellis et al., 2007; LaGreca & Schuman, 1995). Transitions in responsibility for illness management from parent to adolescent are ultimately necessary for appropriate self-management to become established when the adolescent becomes a young adult. These transitions, however, also allow possible ambiguity about family members’ responsibilities for completion of illness-management tasks. In a study demonstrating the potential for disagreement during the adolescent developmental period, Dashiff (2003) examined perceptions of responsibility for diabetes management tasks. Mothers and adolescents agreed the adolescent was primarily responsible for diabetes care tasks, but fathers believed mothers to be primarily responsible. Such ambiguity can create problematic adherence behavior and health outcomes. Agreement between maternal and adolescent perceptions of the allocation of responsibility for diabetes management tasks significantly predicted better metabolic control within a sample of middle-class White adolescents (Anderson, Auslander, Jung, Miller, & Santiago, 1990). Walders and colleagues (2000) assessed disagreement between adolescents and their caregivers regarding the allocation of responsibility for illness-management tasks in a sample of inner-city African-American adolescents with chronic asthma. Parental overestimation was defined as tasks for which the parent maintained the adolescent took responsibility, but the adolescent reported he or she did not. Parental overestimation of adolescent responsibility was found to be related to decreased adherence to asthma treatment. One study (Naar-King, Ellis, Idalski, Frey, & Cunningham, 2007) found that an intervention that improved adherence and health outcomes for adolescents with type 1 diabetes also reduced parental overestimation of adolescent responsibility in an urban sample. Wysocki et al. (1996; 2006) found that high child responsibility for management of type I diabetes was related to poorer health outcomes. The research literature on allocation of responsibility for management of pediatric HIV is limited. Only two studies to date have addressed the issue of delineation of responsibility for illness management in this population. Mellins et al. (2004) found a trend for greater child responsibility for medications to be related to poorer adherence, while increased parental involvement was associated with improved adherence. However, the study did not include adolescents older than 13 years, and responsibility was measured with a single likert-type item. Martin et al. (2007) assessed responsibility with a nine-item scale adapted from responsibility scales used in the studies of asthma and diabetes described earlier. They found that children perceived themselves to have more responsibility than caregivers described, and this discrepancy was associated with nonadherence. However, the relatively small sample of 24 families was not representative of the families typically receiving health care in urban HIV clinics. As noted earlier, studies of other pediatric chronic conditions in urban settings show the opposite pattern, that parents rate their children as more responsible than children report themselves to be (Walders et al., 2000). The current study is the first large multisite study of allocation of responsibility in the management of pediatric HIV. This report provides descriptive data on allocation of responsibility in older children and adolescents (heretofore referred to as youth) with perinatally acquired HIV in 36 urban clinics. We hypothesized that parent and youth report of increased child responsibility would be associated with parent and youth report of lower levels of adherence to anti-HIV medications.

To identify virologic correlates associated with central nervous system (CNS) abnormalities in children infected with human immunodeficiency virus type 1 (HIV-1), cerebrospinal fluid (CSF) was examined for virologic markers and correlated with neurodevelopmental status and neuroimaging abnormalities. Of 30 children, 18 (60%) had at least 1 culture-positive CSF sample; in total, 21 (55%) of 38 CSF specimens were culture-positive. CSF white blood cell counts were higher in specimens that were culture-positive (P = .01). HIV-1 RNA was detected in 90% of CSF samples, and RNA levels > or = 10,000 copies/mL were found in 6 (75%) of 8 children with severe neurocognitive impairment (P = .08) and 11 (73%) of 15 children with a cognitive index < or = 85 (P = .04). Higher RNA levels were associated with abnormal brain imaging scans (P = .04) and with neurocognitive deficits (P = .04). Thus, HIV-1 is present within the CNS of most infected children, and neurocognitive impairment appears to be associated with increased HIV-1 replication.