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BackgroundHuman immunodeficiency virus (HIV)-exposed, uninfected (HEU) infants experience high rates of infectious morbidity. We hypothesized that early cytomegalovirus (CMV) infection was associated with increased hospitalization rates and decreased vaccine responses in HEU compared with HIV-unexposed (HUU) infants.MethodsAmong infants enrolled in the Tshipidi study in Botswana, we determined CMV infection status by 6 months of age and compared hospitalization rates and responses to tetanus and Bacille Calmette-Guérin vaccines among HEU and HUU vaccinees.ResultsFifteen of 226 (6.6%) HEU infants and 17 (19.3%) of 88 HUU infants were CMV-infected by 6 months. The HEU infants were approximately 3 times as likely to be hospitalized compared with HUU infants (P = .02). The HEU peripheral blood cells produced less interleukin (IL)-2 (P = .004), but similar amounts of interferon-γ, after stimulation with tetanus toxoid. Antitetanus immunoglobulin G titers were similar between groups. Cellular responses to purified protein derivative stimulation did not differ between groups. Maternal receipt of 3-drug antiretroviral therapy compared with zidovudine was associated with increased IL-2 expression after tetanus toxoid stimulation. The infants’ CMV infection status was not associated with clinical or vaccine response outcomes.ConclusionsWe observed that increased rates of hospitalization and decreased memory T-cell responses to tetanus vaccine were associated with HIV exposure and incomplete treatment of maternal HIV infection, but not early CMV infection.

BACKGROUND We evaluated the association between maternal cytomegalovirus (CMV) viremia during pregnancy and adverse birth and infant health outcomes in HIV-infected mothers and their HIV-exposed uninfected infants. METHODS HIV-positive women and their infants were followed prospectively from pregnancy through 2 years postpartum in the "Tshipidi" study in Botswana. We analyzed the association between detectable CMV DNA in maternal blood at delivery and adverse birth outcomes (stillbirth, preterm delivery, small for gestational age, or birth defect), as well as infant hospitalization and mortality through 24 months. RESULTS We measured CMV DNA in blood samples from 350 (77.1%) of 454 HIV-positive women from the Tshipidi study. The median maternal CD4 count was 422 cells/mL, and median HIV-1 RNA at entry was 3.2 log10 copies/mL. Fifty-one (14.6%) women had detectable CMV DNA. In unadjusted analyses, detectable CMV DNA was associated with higher maternal HIV-1 RNA [odds ratio (OR) 1.4, 95% confidence interval (CI): 1.1 to 1.9], presence of a birth defect (OR 9.8, 95% CI: 1.6 to 60.3), and occurrence of any adverse birth outcome (OR 2.0, 95% CI: 1.04 to 3.95). In multivariable analysis, we observed a trend toward association between detectable maternal CMV DNA and occurrence of any adverse birth outcome (adjusted OR 1.9, 95% CI: 0.96 to 3.8). Maternal CMV viremia was not associated with infant hospitalization and/or death by 24 months. CONCLUSIONS Approximately 1 in 6 HIV-positive women in Botswana had detectable CMV DNA in blood at delivery. The presence of maternal CMV viremia had a borderline association with adverse birth outcomes but not with 24-month morbidity or mortality in HIV-exposed uninfected children.

This study is a randomized controlled trial of a 12-week community-based group parenting intervention ("CASITA") in Lima, Peru. CASITA improved neurodevelopment in a pilot study of 60 Peruvian children and subsequently scaled to 3,000 households throughout the district. The objective of this study was to assess intervention effectiveness when implemented at scale. A total of 347 children ages 6-20 months (52.7% male, 100% identified as "mestizo") at risk for developmental difficulties were randomized to immediate or delayed CASITA. At 3 months after enrollment, the immediate arm showed significantly higher overall development, based on the Extended Ages and Stages Questionnaire and Home Observation for Measurement of the Environment scores (Cohen's ds = .36 and .31, respectively). Programs demonstrably effective at scale could help address children's development risks worldwide.

Background We sought to identify predictors of child cytomegalovirus (CMV) infection overall and by maternal HIV status and to assess associations of child CMV status with growth and neurodevelopmental outcomes at 24 months of age in Botswana. Methods Data and samples were used from the Botswana-based observational Tshipidi study (2010–2014), enrolling pregnant women living with and without HIV and following their infants through 2 years of age. Child plasma samples were tested at 18 months of age for anti-CMV immunoglobulin G (IgG). Associations were assessed between detectable anti-CMV IgG and growth (using the World Health Organization Child Growth Standards) and neurodevelopment (using the Bayley Scales of Infant and Toddler Development III and the Developmental Milestones Checklist) at 24 months of age. Results Of 317 children, 215 (68%) had detectable anti-CMV IgG at 18 months of age. Comparatively, 83% (n = 178) of HIV-unexposed uninfected (HUU) children had positive CMV serology vs 47% (n = 139) of HIV-exposed uninfected (HEU) children (P Conclusions We observed high CMV seropositivity in 18-month-old children in Botswana, with higher seropositivity among breastfed (HUU) children. Positive CMV serostatus was not associated with 24-month child growth or neurodevelopmental outcomes, with the exception of smaller head circumference among HUU CMV-positive children.

Prospective memory (PM), “remembering to remember,” has been linked to important functional outcomes in adults. Studies of PM in children and adolescents would benefit from the development and validation of developmentally appropriate clinical measures with known psychometric properties. The Prospective Memory Assessment for Children & Youth (PROMACY), a performance-based measure of PM, was developed for the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol, Memory and Executive Functioning Substudy, and includes Summary, Time-, and Event-based scores derived from eight trials with an ongoing word search task. Fifty-four healthy perinatally HIV-exposed, uninfected children and youth, mean age 13 years, 54% female, 76% Black/non-Hispanic, and 61% impoverished were included in this psychometric analysis. PROMACY Summary Scores demonstrated low, but broadly acceptable internal consistency as measured by Cronbach’s alpha and Spearman-Brown. Better PROMACY performance was associated with older age, but no other demographic factors. Generally medium-sized correlations were observed between the PROMACY Summary Score and standard clinical measures of retrospective memory, working memory, executive functions, and IQ. Findings from this preliminary psychometric study of non-clinical children and youth provide cautious support for the internal consistency and construct validity of PROMACY’s Summary Score that awaits replication and extension in larger samples of healthy children, youth and clinical populations.

OBJECTIVE Conflicting data exist regarding the impact of in-utero exposure to maternal combination antiretrovirals. We compared neurodevelopmental outcomes between HIV-exposed-uninfected (HEU) children exposed in utero to three-drug combination antiretroviral therapy (ART) vs. zidovudine (ZDV) monotherapy. DESIGN Prospective study of child neurodevelopment, nested within two cohorts of HIV-infected mothers and their children in Botswana (one observational, one interventional). METHODS The Tshipidi and Mma Bana studies enrolled HIV-infected women during pregnancy and followed their HEU children for 24 months. Mothers took three-drug ART or ZDV during pregnancy. ART-exposed babies were mostly breastfed, and ZDV-exposed were formula-fed. Neurodevelopmental outcomes, measured at 24 months using Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) and Development Milestones Checklist (DMC), were compared in adjusted linear regression according to antiretroviral exposure. RESULTS Of 598 HEU children with valid neurodevelopment assessments, 382 were ART-exposed and 210 were ZDV-exposed. Adjusted mean Bayley-III scores were similar among ART-exposed vs. ZDV-exposed, with adjusted mean differences (95% confidence interval): Bayley-III Cognitive: -0.3 (-1.4, 0.9); Gross Motor: 0.8 (-0.1, 1.7); Fine Motor: 0.5 (-0.2, 1.3); Expressive Language: 0.7 (-0.3, 1.7); Receptive Language: 0.1 (-0.7, 0.8); and DMC Locomotor: 0.0 (-0.5, 0.6); Fine Motor: 0.3 (-0.3, 0.8); Language: -0.1 (-0.5, 0.4); Personal-Social: 0.2 (-0.7, 1.1). Similarly, when restricted to formula-fed children in one cohort (Tshipidi), there were no differences in adjusted mean scores. CONCLUSION Neurodevelopmental outcomes at 24 months of age were similar in ART-exposed vs. ZDV-exposed HEU children. Maternal ART with breastfeeding does not appear to have an adverse effect on neurodevelopment.

Background: Hepatitis B virus (HBV) infection during pregnancy is associated with an increased risk of premature birth, cesarean sections, low birth weight, and an increased number of hospitalizations in infants. There are no reported data on the impact of maternal HBV status on pregnancy and infant health outcomes in Botswana. Objectives: We aimed to evaluate the association of maternal HBsAg+/occult HBV infection at delivery with pregnancy and infant health outcomes in Botswana. Methods: HBsAg positivity was tested using a murex HBsAg ELISA kit while occult HBV (OBI) was tested using COBAS® AmpliPrep COBAS® Taqman®. Results: The total number of maternal HBsAg+ and OBI infections was 57 out of 752 and termed as maternal HBV. Binary logistic regression was used to explore the possible impact of maternal HBV status on each outcome, adjusted for maternal HIV status, ART use during pregnancy, and maternal age. Conclusions: In conclusion, there was no association between maternal HBsAg+/occult HBV infection and preterm birth (< 37 weeks), stillbirth, low birth weight (< 2.5 kg), and infant hospitalization (by 24 months).

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.

The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women in Botswana. Samples from 752 pregnant women were tested for hepatitis B surface antigen (HBsAg), and HBsAg-positive samples were tested for hepatitis B e antigen (HBeAg) and HBV DNA load. Samples that were HBsAg negative were screened for occult HBV infection by determining the HBV DNA load. HBV genotypes were determined based on a 415-base-pair fragment of the surface gene. Among the 752 women tested during pregnancy or early postpartum, 16 (2.1%) (95% confidence interval (CI): 2.0–2.2) were HBsAg-positive. The prevalence of chronic HBV infection was higher (3.1%) among HIV-infected (95% CI: 3.0–3.2) compared with HIV-uninfected women (1.1%) (95% CI: 1.07–1.1, p = 0.057). Among the 622 HBsAg-negative women, the prevalence of occult HBV infection was 6.6% (95% CI: 6.5–6.7). Three of thirteen HBsAg-positive participants were HBeAg-positive, and all were HIV-negative. Of the 11 maternal samples successfully genotyped, five (45.5%) were genotype D3, five (45.5%) were genotype A1, and one was genotype E (9%). Low and similar proportions of HIV-infected and -uninfected pregnant women in Botswana had occult or chronic HBV infection. We identified a subset of HIV-negative pregnant women who had high HBV DNA levels and were HBeAg-positive, and thus likely to transmit HBV to their infants.

OBJECTIVES: To prospectively assess rates and detailed predictors of morbidity and mortality among HIV-exposed uninfected children and HIV-unexposed children in Botswana in a more recent era. STUDY DESIGN: We enrolled HIV-infected and HIV-uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010-July 2012. Live-born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling. RESULTS: 893 live-born HIV-uninfected children (436 HEU, 457 HIV-unexposed) were followed. HIV-infected mothers had a median CD4 count of 410 cells/mm(3), 32% took 3-drug antiretroviral treatment (ART) during pregnancy, 67% took only zidovudine, and 1% took

Objective To determine whether the 3-month, community-based early stimulation coaching and social support intervention ‘CASITA’, delivered by community health workers, could improve early child development and caregiver-child interaction in a resource-limited district in Lima, Peru. Design A controlled two-arm proof-of-concept study. Setting Six neighbourhood health posts in Carabayllo, a mixed rural/urban district in Lima. Sessions were held in homes and community centres. Participant s Children aged 6–24 months who screened positive for risk of neurodevelopmental delay (using validated developmental delay tool) and poverty (using progress out of poverty tool) were enrolled with their caregivers. Dyads with children born >21 days early were excluded. Intervention 12-week parenting/support intervention plus nutritional support (n=41) or nutrition alone (n=19). Outcome measures Development and home environment differences and mean changes from baseline to 3 months postintervention were evaluated using age-adjusted z-scores on the Extended Ages and Stages Questionnaire (EASQ) and the Home Observation Measurement of the Environment (HOME) scores, respectively. Results Development in CASITA improved significantly in all EASQ domains, whereas the control group’s z-scores did not improve significantly in any domain. The mean adjusted difference (MAD) in change in EASQ age-adjusted z-scores between the two study arms was 1.39 (95% CI 0.55 to 2.22); Cohen’s d effect size of 0.87 (95% CI 0.23 to 1.50). Likewise, intervention significantly improved global HOME scores versus control group (MAD change of 6.33 (95% CI 2.12 to 10.55); Cohen’s d of 0.85 (95% CI 0.28 to 1.41)). Conclusions An evidence-based early intervention delivered weekly during 3 months by a community health worker significantly improved children’s communication, motor and personal/social development in this proof-of-concept study.

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.

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.

Background: In many resource-poor settings such as Peru, children affected by HIV have a high prevalence of neurodevelopmental delays (NDDs) and remain excluded from adequate treatment. Methods: Community health workers (CHWs) administered NDD screening instruments to assess child development and associated caregiver and household factors in 14 HIV-affected parent–child dyads. Focus group discussion with caregivers was conducted to explore their needs and behaviors around early child stimulation and to assess their perceptions of the screening experience. Results: Over 70% of the children had abnormal classification in at least 1 (out of 5) developmental domains according to Ages and States Questionnaire–provided cutoff scores. Caregiver depression and stress were associated with abnormal development as were some parenting behavior factors. Knowledge about child development was low. Caregivers felt testing and discussing results with a CHW were very insightful. Reported caregiver behavior differed between caregivers with HIV-infected children and those with uninfected children. Conclusion: Taken together, these exploratory quantitative data suggest that parenting behaviors associated with low child development scores may be modifiable and that community-based testing is well received and informative to these HIV-infected caregivers.

Background HIV-exposed but uninfected (HEU) children are at increased risk for poorer growth outcomes compared with HIV-unexposed/uninfected (HUU) children. Mechanisms underlying the poorer growth and delays in development of HEU children compared HUU children are not fully understood. We sought to define the relationship between child CMV status and HIV− exposure status and determine if a correlation existed between CMV status and growth (and neurodevelopmental) outcomes by 24 months of age in Botswana. Methods We used existing data and samples from the observational Botswana Tshipidi study, pregnant women living with HIV (WLHIV) and those without HIV, as well as their infants were enrolled and followed prospectively through 2 years postpartum. We tested 18-month child plasma samples from all available children for anti-HCMV IgG. We evaluated the association between positive (vs. negative) child CMV status at 18 months, and child growth, using the World Health Organization’s Growth Standard adjusted for age and sex and neurodevelopment at 24 months of age, using the Bayley Scales of Child Development (BSID) III. Results Of 317 children tested for CMV IgG at 18 months, 215 (67.8%) tested positive. Significantly higher proportions of HUU children had positive CMV serology (82.6%) compared with HEU children (47.4%, P < 0.01); 96.7% of HUU vs. 10.5% of HEU children breastfed. Child CMV infection was not associated with head circumference, weight-for-age, weight-for-height, nor height-for-age z-scores at 24 months. BSID III scores in receptive and expressive language, fine and gross motor, and cognitive domains at 24 months of age also did not differ by child CMV status. Conclusion We observed high rates of CMV seropositivity in 18-month-old children in Botswana with significantly higher CMV seropositivity among HUU children likely owing to breastfeeding. Positive CMV serostatus was not associated with child growth or neurodevelopmental outcomes at 24 months. Disclosures All authors: No reported disclosures.

Use of antiretroviral (ARV) medications during pregnancy has led to a dramatic decline in mother-to-child transmission of human immunodeficiency virus (HIV)1 while increasing the number of HIV-exposed, uninfected children worldwide.2,3 ARVs may have a negative effect on infant and child health and development.2,4-6 Currently, most pregnant women with HIV in the U.S. receive combination ARV (cARV) therapy to prevent mother-to-child transmission.2,4,7-9 Investigators conducting human and animal studies of prenatal ARV exposure have noted structural and functional changes in the central nervous system (CNS),10-13 suggesting the CNS may be an important target of these agents. In utero exposure to NRTIs such as zidovudine (Retrovir; GlaxoSmithKline, Brentford, Middlesex, UK) has been associated with mitochondrial toxicities in animal and human studies.14-23 Mitochondrial defects adversely affect high-energy organ systems including the brain and peripheral nervous system.24 Conflicting information exists regarding effects of ARV exposure on neurologic and neurodevelopmental functioning. The French Perinatal Cohort study25 examined approximately 1800 children exposed to ARVs and reported 8 with findings compatible with mitochondrial dysfunction, higher than expected in the general population. The European Collaborative Study26 and the Petra study27 found no increase in the rate of severe adverse events in children with perinatal ARV exposure. Among 1037 HIV-exposed, uninfected children, Brogly and colleagues28 identified 20 (1.9%) with possible mitochondrial dysfunction, including 19 with neurological or developmental abnormalities. No clear-cut association with in utero NRTI exposure emerged, but results suggested that first exposure to lamivudine (Epivir; GlaxoSmithKline, Brentford, Middlesex, UK) or zidovudine/lamivudine (Combivir; GlaxoSmithKline, Brentford, Middlesex, UK) in third trimester might be associated with clinical findings of mitochondrial dysfunction. Children with clinical abnormalities in this study tended to have laboratory evidence of mitochondrial abnormalities compared to ARV-exposed and ARV-unexposed children without clinical findings.29 A risk-benefit analysis of ARV use in pregnancy30 found the three least effective regimens demonstrated low toxicity, while three-drug ARV regimens initiated in first trimester resulted in fewer HIV infections but slightly more cases of suspected mitochondrial toxicity. Risk for lowered cognitive performance or increased behavior problems in ARV- and HIV-exposed children is not firmly established.31-35 The French Perinatal Cohort study25 found evidence of developmental delay in children with prenatal ARV exposure, but other investigators26,27,31,32 reported no such association. Some studies did not control adequately for maternal/caregiver and environmental characteristics associated with developmental delays in infants and children, including prenatal exposure to alcohol, drugs, and infections; environmental factors such as poverty, lead exposure, maternal education, and parental medical and psychiatric illness; and, for infants with HIV exposure, severity of maternal HIV disease and pre- and postnatal ARV exposure.28,30,36-41 The primary objective of this analysis was to evaluate safety of in utero and neonatal ARV exposure with respect to development in HIV-exposed, uninfected infants during the first year of life. Specific aims were: (1) describe infant development across developmental domains, (2) evaluate prenatal and postnatal factors confounding the relationship between in utero ARV exposure and infant development, (3) evaluate effects of type and timing of prenatal ARV exposure on development, and (4) evaluate effects of neonatal ARV exposure on development.

Objective To apply a social ecological model to explore the psychosocial factors prospectively associated with longitudinal adherence to antiretroviral treatment in youth perinatally infected with HIV. Methods Randomly selected youth, age 8 to

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

Background In Botswana, more than 10% of HIV-exposed, uninfected infants (HEU) are hospitalized or die in the first 6 months of life, largely due to infectious causes. Vaccine responses can act as a marker of the immune response to infectious antigens. Previous studies of vaccine responses in HEU have had conflicting results. We compared T-cell responses to tetanus and purified protein derivative (PPD), and antibody titers to tetanus, between HEU and HIV-unexposed infants (HUU). Methods A total of 443 HIV-infected and 451 HIV-uninfected mothers and their 453 HEU/457 HUU live-born infants were followed from pregnancy/delivery through 24 months postpartum in a prospective observational study in Botswana (“Tshipidi”). T-cell expression of interferon (IFN)-γ and interleukin (IL)-2 were measured at 6 months using FluoroSpot after stimulation with tetanus toxoid or PPD. Quantitative tetanus toxoid IgG was measured in plasma at 18 months using ELISA. Mean spot-forming units (sfu) per 105 cells and geometric mean antibody titers were compared between HEU and HUU infants who had received 3 doses of tetanus and 1 dose of Bacille Calmette–Guérin (BCG) vaccines by 6 months, and 3 or 4 doses of tetanus vaccine by 18 months. Results. Peripheral blood mononuclear cells were available at 6 months for 63 HEU and 18 HUU. Plasma was available at 18 months for 39 HEU and 42 HUU. HEU infants had significantly lower IL-2 expression after tetanus stimulation than HUU infants (4.4 vs. 16.1 sfu/105 cells, P = 0.004; figure), but no difference in IFNγ expression. There were no differences in T-cell responses to PPD between HEU and HUU. There were no differences in tetanus geometric mean antibody titers between HEU and HUU. Conclusion. In this cohort of infants from Botswana, we found decreased T-cell responses, but not antibody responses, to tetanus toxoid and no differences in T-cell responses to PPD. Cell-mediated immune defects may play a greater role than humoral immune defects in the increased susceptibility to infection among HEU. BCG vaccine produces robust T-helper 1 responses, which may overcome cell-mediated immune defects in HEU. Disclosures All authors: No reported disclosures.

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.

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.

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.

Background In Botswana, more than 10% of HIV-exposed, uninfected infants (HEU) are hospitalized or die in the first 6 months of life, largely due to infectious causes. Vaccine responses can act as a marker of the immune response to infectious antigens. Previous studies of antibody responses to vaccines in HEU have had conflicting results. We compared antibody titers to tetanus vaccine between HEU and HIV-unexposed infants (HUU), and explored whether tetanus antibody titers predicted risk of hospitalization in the first 2 years of life among HEU. Methods 443 HIV-infected and 451 HIV-uninfected mothers and their 453 HEU / 457 HUU live-born infants were followed in a prospective observational study in Botswana (“Tshipidi”). Quantitative tetanus toxoid IgG was measured in plasma samples from 18-month-old infants. Geometric mean antibody titers (GMT) were compared between HEU and HUU infants, and between HEU infants who were or were not hospitalized by age 2. Results Plasma was available at 18 months for 39 HEU and 42 HUU infants. Within this subset, there were 15 hospitalizations (12 in HEU) [RR of hospitalization among HEU = 1.34 (P = 0.009)]. 73% of hospitalizations overall, and 83% in HEU, were due to infection (primarily pneumonia/bronchiolitis and gastroenteritis). Among infants who had received 3 or 4 doses of tetanus vaccine by 18 months, there were no significant differences in tetanus GMT between HEU and HUU (Fig A). Among HEU who had received 3 or 4 doses of tetanus vaccine by 18 months, there were no significant differences in tetanus GMT between infants who were hospitalized and infants who were not (Fig B). Conclusion In this small sample of infants from Botswana, we did not identify differences in antibody responses to tetanus vaccine between HEU and HUU. Although HEU demonstrated an increased risk of hospitalization, response to tetanus vaccine did not appear to be a significant predictor of morbidity. It is possible that cell-mediated immune defects play a larger role than humoral immune defects in the increased susceptibility to infection among HEU. Disclosures All authors: No reported disclosures.

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.

Despite major advances in the treatment and prevention of HIV/AIDS, there remains a significant impact on children living with the disease as well as the many more children secondarily affected by the disease in Africa. Clearly, there are many risk factors influencing the overall development of these children including known neurodevelopmental deficits associated with the disease and environmental factors that impact multiple areas of functioning. Given these complex issues, there is undoubtedly a need to effectively disentangle causes and create effective interventions as early as possible. Although assessment methodologies and interventions are relatively well developed in Western countries, these do not necessarily directly translate to appropriate use in other countries/cultures. This chapter reviews the current status of assessment of very young children in Africa focusing on the impact of exposure to HIV. Specific tests that have been either developed in and/or adapted for use in Africa are reviewed as are adaptation guidelines, considerations regarding the adaptation of tests, practical constraints that exist when choosing assessment appropriate assessment instruments, and other assessment considerations.

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.

Objectives: We developed a prediction tool to assist in evaluation of pediatric candidates for cochlear implantation (CI) and to help plan for preoperative and postoperative support. Methods: Between 1995 and 2005, 277 patients underwent CI at Children's Hospital Boston. Of these 277 patients, 250 had at least 2 years of post-CI follow-up and adequate pre-CI information for rating by our prediction tool. Of the 250, 106 were randomly selected for inclusion. The patients were divided into group A (auditory/oral communicator); group B (auditory/oral communicator with visual assistance), group C (visual/manual communicator with auditory/oral skills assistance), and group D (will not derive communicative benefit from implant). Predictions were performed with clinical assessment and two statistical techniques: Regression modeling and classification and regression tree (CART) analysis. Results: Among patients who became auditory/oral communicators (group A), clinical assessment predicted that outcome accurately 65% of the time, CART analysis had intermediate sensitivity (79%), and regression modeling was the most sensitive (95%). Groups B through D were predicted 45% of the time by regression modeling, 90% of the time by clinical assessment, and 100% of the time by CART analysis. Conclusions: A combination of speech-language, medical, and educational constructs can provide a reliable prediction of the communication outcome. Our goal for the prognosis tool is to make it part of the overall candidacy process in supporting decision-making about CI and planning for post-CI therapy.

In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting “NeuroAIDS in Africa.” This meeting was held in Cape Town, South Africa, and was affiliated with the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Presentations began with an overview of the epidemiology of HIV in sub-Saharan Africa, the molecular epidemiology of HIV, HIV-associated neurocognitive disorders (HANDs), and HAND treatment. These introductory talks were followed by presentations on HAND research and clinical care in Botswana, Cameroon, Ethiopia, The Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, and Zambia. Topics discussed included best practices for assessing neurocognitive disorders, patterns of central nervous system (CNS) involvement in the region, subtype-associated risk for HAND, pediatric HIV assessments and neurodevelopment, HIV-associated CNS opportunistic infections and immune reconstitution syndrome, the evolving changes in treatment implementation, and various opportunities and strategies for NeuroAIDS research and capacity building in the region.

Objective To review the candidacy criteria used to counsel parents of profoundly deaf children, to determine if these criteria have changed over time, and to evaluate eventual communication outcomes for these patients. Design Retrospective review of 483 pediatric cochlear implant candidates from September 1995 to December 2006 seen at a tertiary care pediatric hospital. Results Out of 483 implant candidates, 191 patients were initially felt not to be favorable candidates based on CI team evaluation. Of this group, 3 had insufficient records to review and were excluded. The remaining 188 patients underwent a detailed analysis of specific possible contraindications to implantation. This included audiologic, medical and psychosocial parameters. The data was divided into two time periods: Group 1 included 44 patients from 1995 to 2000, and Group 2 included 144 patients from 2001 to 2006. In Group 1, there was a higher percentage of children with language deprivation and developmental concerns and patients not ready, compared to Group 2 which had a higher percentage of families not ready and inadequate support systems. Group 1 had a higher percentage of patients who ultimately underwent cochlear implant, but otherwise the two groups were largely similar. Conclusion Analysis of our data showed that the degree of concern that the cochlear implant team has in relationship to specific candidacy criteria has changed over time. Recommendations against a cochlear implant were often revisited after initial concerns were addressed. The use of a team approach, in conjunction with a validation tool, is important for establishing criteria for successful cochlear implantation in children to support appropriate counseling of patients and families and to plan post-implant management.

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.

Twenty-three leukemic children were studied prospectively to detect chronic effects of therapy. All patients received CNS prophylaxis, including 2400 R cranial irradiation, and intermittent maintenance therapy with intravenous methotrexate, cyclophosphamide and cytosine arabinoside. Neurologic symptoms were observed in 12 patients, all of whom had intermittent limping and mild incoordination, between the 10th and 18th month of maintenance therapy. Five of the 12 sustained seizures and four of these had subsequent abnormalities in motor, perceptual, behavioral or language development. Three school-aged children have learning disability and perceptual-motor defects. Studies of CSF folate and MTX content are presented but not helpful in delineating the etiology of these neurologic symptoms.

We describe a prospective study of histidinaemia. Probands and siblings (n = 21) with typical histidinaemia in 16 families were ascertained by newborn screening; diagnosis was confirmed by appropriate investigations in each subject; none had been treated by low histidine diet. The median age of subjects with histidinaemia was 9.5 y (mean 10.0, SD 3.5, range 6-18). Age-matched sib-pairs and their mothers were studied. IQ scores (Full Scale, Verbal and Performance Scores), Visual-Motor Integration Performance (Bender Gestalt and Koppitz scores), Wide Range Achievement Test (Reading and Mathematics), school performance, and psychological history were evaluated, as well as the medical history (pregnancy, delivery, neonatal, post-natal development). Findings were correlated with biochemical phenotype. CNS development in histidinaemic subjects (mean and distribution of scores) was normal; outlier values did not correlate with degree of histidinaemia. We can conclude that histidinaemia detected by newborn screening is a non-disadaptive phenotype.

The Stroop Color and Word Test was administered once to 20 deaf adults who responded with American Sign Language (ASL) responses, and twice to 29 hearing adults who were fluent in sign language - once using signed responses, and once using spoken responses. For the hearing subjects, signed responses were significantly slower than spoken responses in both the word and color conditions, but not in the color-word condition. No significant differences were found when comparing the rate of signing of the deaf subjects to that of the hearing subjects. These results demonstrate that Stroop responses cannot be signed as rapidly as they can be spoken; therefore, it would be inappropriate to apply standard adult norms to Stroop scores obtained from signed responses. This paper provides preliminary norms which are appropriate for use with deaf adults giving signed responses to the Stroop Color and Word Test.

Trends in intellectual functioning before and after diet termination were examined in 30 children with PKU treated before 6 weeks of age and on a liberal diet for a mean of three years since the mean age of 59 months. Comparisons of trends in pre- and posttermination IQ scores with the linear spline technique revealed no significant differences. Comparisons of pretermination IQ scores with posttermination scores and scores from the most recent evaluation also yielded no significant differences. These data fail to support a relationship between termination of diet and impairment of intellectual functioning, at least during this period of observation.