Predictors of resolution and persistence of renal laboratory abnormalities in pediatric HIV infection.

BACKGROUND: Among human immunodeficiency virus (HIV)-infected youth, the role of renal disease (RD) and its management has become increasingly important as these children/adolescents mature into young adults. The identification of predictors of abnormal renal laboratory events (RLE) may be helpful in the management of their HIV infection and its associated renal complications. METHODS: Data collected from HIV-infected youth followed for ≥ 48 months were analyzed to identify predictors of resolution versus persistence of RLE and determine the utility of RLE to predict the onset of RD. Analysis included descriptive and inferential methods using a multivariable extended Cox proportional hazards model. RESULTS: Of the 1,874 at-risk children enrolled in the study, 428 (23 %) developed RLE, which persisted in 229 of these (54 %). CD4 percentages of <25 % [hazard ratio (HR) 0.63, p < 0.002) and an HIV viral load of >100,000 copies/ml (HR 0.31, p < 0.01) were associated with reduced rates of resolution, while in most cases exposure to highly active antiretroviral therapy (HAART)/nephrotoxic HAART prior to or subsequent to RLE were not. Persistence of RLE was 88 % sensitive for identifying new RD. Negative predictive values for RD were >95 % for both the at-risk cohort and those with RLE. CONCLUSIONS: Advanced HIV disease predicted persistence of RLE in HIV-infected youth. Persistent RLE were useful for identifying RD.

The mental health sequelae of traumatic head injury in South Vietnamese ex-political detainees who survived torture.

Little is known about the relationship between traumatic head injury (THI) and psychiatric morbidity in torture survivors. We examine the relationship between THI and depression, PTSD, post-concussive syndrome (PCS), disability and poor health status in Vietnamese ex-political detainees who survived incarceration in Vietnamese re-education camps. A community sample of ex-political detainees (n=337) and a non-THI, non-ex-detainee comparison group (n=82) were surveyed. Seventy-eight percent of the ex-political detainees had experienced THI; 90.6% of the ex-political detainees and 3.6% of the comparison group had experienced 7 or more trauma events. Depression and PTSD were greater in ex-detainees than in the comparison group (40.9% vs 23.2% and 13.4% vs 0%). Dose-effect relationships for THI and trauma/torture in the ex-political detainee group were significant. Logistic regression in the pooled sample of ex-detainees and the comparison group confirmed the independent impact of THI from trauma/torture on psychiatric morbidity (OR for PTSD=22.4; 95% CI: 3.0-165.8). These results demonstrate important effects of THI on depression and PTSD in Vietnamese ex-detainees who have survived torture.

Chronic kidney disease associated with perinatal HIV infection in children and adolescents.

BACKGROUND: This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. METHODS: Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. RESULTS: Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load ≥100,000 copies/mL (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD. CONCLUSIONS: A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.

Possible mitochondrial dysfunction and its association with antiretroviral therapy use in children perinatally infected with HIV.

BACKGROUND: Mitochondrial dysfunction has been associated with both human immunodeficiency virus (HIV) infection and exposure to antiretroviral therapy. Mitochondrial dysfunction has not been widely studied in HIV-infected children. We estimated the incidence of clinically defined mitochondrial dysfunction among children with perinatal HIV infection. METHODS: Children with perinatal HIV infection enrolled in a prospective cohort study (Pediatric AIDS Clinical Trials Group protocols 219 and 219C) from 1993 through 2004 were included. Two clinical case definitions of mitochondrial dysfunction, the Enquête Périnatale Française criteria and the Mitochondrial Disease Classification criteria, were used to classify signs and symptoms that were consistent with possible mitochondrial dysfunction. Adjusted odds ratios of the associations between single and dual nucleoside reverse-transcriptase inhibitor use and possible mitochondrial dysfunction were estimated using logistic regression. RESULTS: Overall, 982 (33.5%) of 2931 children met 1 or both case definitions of possible mitochondrial dysfunction. Mortality was highest among the 96 children who met both case definitions (20%). After adjusting for confounders, there was a higher risk of possible mitochondrial dysfunction among children who received stavudine regardless of exposure to other medications (odds ratio, 3.44 [95% confidence interval, 1.91-6.20]) or who received stavudine-didanosine combination therapy (odds ratio, 2.23 [95% confidence interval, 1.19-4.21]). Exposure to lamivudine and to lamivudine-stavudine were also associated with an increased risk of mitochondrial dysfunction. CONCLUSIONS: Receipt of nucleoside reverse-transcriptase inhibitors, especially stavudine and lamivudine, was associated with possible mitochondrial dysfunction in children with perinatal HIV infection. Further studies are warranted to elucidate potential mechanisms of nucleoside reverse-transcriptase inhibitor toxicities.

Development and reliability of the Prospective Memory Assessment for Children & Youth (PROMACY): A preliminary study in a nonclinical sample.

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 nonclinical 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.

Prospective memory in youth with perinatally-acquired HIV infection.

Youth with perinatal HIV infection (PHIV) are at increased risk for neurocognitive impairment (NCI). 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 nonadherence. 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 perinatally 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 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 < .05); significantly, lower scores for PHIV/NCI versus PHEU also were observed for PROMACY and NEPT indices. Findings suggest a subset of youth with PHIV (those with a prior AIDS-defining diagnosis) is vulnerable to PM deficits. The extent to which PM deficits interfere with development and maintenance of independent living and health-related behaviors during transition to adulthood requires further study.

Validity of Neuropsychological Testing in Young African Children Affected by HIV.

INTRODUCTION: Western-constructed neuropsychological tests have been used in low and middle income countries to assess the impact of HIV/AIDS and other chronic illnesses. We explore using such instruments cross-culturally in a sub-Saharan Africa setting. METHODS: IMPAACT P1104S was a two-year observational study carried out at six clinical sites (South Africa- 3 sites, Malawi, Uganda and Zimbabwe) to assess and compare neuropsychological outcomes in three cohorts of children 5-11 years of age: HIV-infected (HIV), HIV-exposed but uninfected (HEU) and HIV unexposed and uninfected (HU). Descriptive statistics compared socio-demographic characteristics among children at sites. Instruments included the KABC-II cognitive ability, TOVA attention/impulsivity, BOT-2 motor proficiency tests, and BRIEF executive function problems. Test characteristics were assessed using intraclass and Spearman non-parametric correlations, linear regression and principal factor analyses. RESULTS: Of the 611 participants, 50% were male and mean age ranged from 6.6 to 8 years. In Malawi, Uganda and Zimbabwe, substantial proportions of families lived in rural settings in contrast to the South African sites. Intraclass correlation coefficients between weeks 0 and 48 were highest for the KABC scores, ranging between 0.42 to 0.71.Correlations among similar test domains were low to moderate but significant, with positive correlation between KABC Sequential and TOVA scores and negative correlation between BRIEF and KABC scores. TOVA response time scores correlated negatively with the BOT-2 Total points score. Strong and significant associations between individual measures of growth, disability and development with all test scores were observed. Performance-based measures were markedly lower for HIV compared to HEU and HU participants, even after controlling for age, sex and site. Factor analyses confirmed the underlying theoretical structure of the KABC scaled item scores. CONCLUSION: The KABC, TOVA, BRIEF and BOT-2 were valid and reliable tools for assessing the neuropsychological impact of HIV in four sub-Saharan African countries.

Neuropsychological performance in African children with HIV enrolled in a multisite antiretroviral clinical trial.

OBJECTIVE AND DESIGN: Children with HIV infection (HIV+) are at neuropsychological risk, but few studies have evaluated this at multiple sites in low-income and middle-income countries. We compared neuropsychological outcomes at enrollment (>5 years age) among HIV+, HIV perinatally exposed uninfected (HEU), and HIV unexposed uninfected (HUU) children from four sub-Saharan countries. METHODS: IMPAACT P1060 compared nevirapine versus lopinavir/ritonavir-based antiretroviral treatment (ART) in HIV-infected children 6-35 months of age. The present study (P1104s) enrolled P1060 children at 5-11 years of age and evaluated their neuropsychological performance over 2 years using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), Tests of Variables of Attention (TOVA), Bruininks-Oseretsky Test, 2nd edition (BOT-2), and parent-reported Behavior Rating Inventory of Executive Function (BRIEF). Cohorts were compared using generalized estimating equations least-squares means adjusted for site, child age and sex, and personal and social characteristics for child and caregiver. RESULTS: Six hundred and eleven (246 HIV+, 183 HEU, 182 HUU) of the 615 enrolled at six sites [South Africa (three), Zimbabwe, Malawi, Uganda] were available for analysis. Mean age was 7.2 years, 48% male, 69% in school. Unadjusted and adjusted comparisons were consistent. HIV+ children performed significantly worse than HEU and HUU cohorts on all KABC-II cognitive performance domains and on BOT-2 total motor proficiency (P < 0.001), but not on the BRIEF Global Executive Indices. HUU and HEU cohorts were comparable on cognitive outcomes. HIV+ children initiated on ART before 1 year of age had significantly better BRIEF evaluations (lower scores - fewer behavior problems), compared with those started after (P = 0.03). CONCLUSION: Significant cognitive deficits were documented among HIV+ children at school age, even when started on ART at an early age. Earlier HIV treatment, neuropsychological monitoring, and rehabilitative interventions are all needed. Subsequent testing for 2 more years will help further evaluate how HIV infection and exposure affect the developmental trajectory.

Sexually Transmitted Infections in Youth With Controlled and Uncontrolled Human Immunodeficiency Virus Infection.

BACKGROUND: Sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), disproportionately affect adolescents and young adults (AYAs) ages 13-24 years. Sexually transmitted infections likewise are a risk factor for HIV acquisition and transmission; however, there is a lack of data on STI acquisition in HIV-infected AYAs. METHODS: We determined the incidence of STIs in HIV-infected AYAs 12.5 <25 years of age in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 observational cohort study. Univariate and multivariable logistic regression models were used to evaluate the association of HIV control (mean viral load <500 copies/mL and CD4+ T cells >500 cells/mm3 in the year preceding STI diagnosis) and other risk factors with STI occurrence. RESULTS: Of 1201 enrolled subjects, 1042 participants met age criteria and were included (49% male, 61% black, 88% perinatally infected; mean age 18.3 years). One hundred twenty participants had at least 1 STI on study, of whom 93 had their first lifetime STI (incidence rate = 2.8/100 person-years). For individual STI categories, 155 incident category-specific events were reported; human papillomavirus (HPV) and chlamydial infections were the most common. In the multivariable model, having an STI was associated with older age (adjusted odds ratio [aOR] = 1.13; 95% confidence interval [CI], 1.05-1.22), female sex (aOR = 2.65; 95% CI, 1.67-4.21), nonperinatal HIV acquisition (aOR = 2.33; 95% CI, 1.29-4.22), and uncontrolled HIV infection (aOR = 2.05; 95% CI, 1.29-3.25). CONCLUSIONS: Sexually transmitted infection acquisition in HIV-infected AYAs is associated with older age, female sex, nonperinatal HIV acquisition, and poorly controlled HIV infection. Substantial rates of STIs among HIV-infected AYAs support enhanced preventive interventions, including safe-sex practices and HPV vaccination, and antiretroviral adherence strategies.

Impact of Perinatally Acquired HIV Disease Upon Longitudinal Changes in Memory and Executive Functioning.

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.

Roles of Medication Responsibility, Executive and Adaptive Functioning in Adherence for Children and Adolescents With Perinatally Acquired HIV.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, P < 0.001), adjusting for demographic variables (age, race and caregiver education). CONCLUSIONS: 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.

Incidence of opportunistic and other infections in HIV-infected children in the HAART era.

CONTEXT: Combination anti-retroviral therapy or highly active antiretroviral therapy (HAART) has resulted in a dramatic decline in the incidence of opportunistic and other infections in human immunodeficiency virus (HIV)-infected adults and children. OBJECTIVES: To estimate the incidence of 29 targeted opportunistic and other infections occurring in the era of HAART-between January 1, 2001, and December 31, 2004-in HIV-infected infants, children, and adolescents followed up in Pediatric AIDS Clinical Trials Group (PACTG) 219C; to compare incidence rates in the HAART era to those of the pre-HAART era; and to test for linear trends over time in the HAART era. DESIGN, SETTING, AND PARTICIPANTS: Ongoing, multicenter, prospective cohort study designed to examine long-term outcomes in HIV-infected children. The study population included 2767 children enrolled between September 15, 2000, and December 31, 2004, with information entered in the database up to August 1, 2005, when data analysis was conducted. The pre-HAART era comparison population included 3331 children enrolled in 13 PACTG protocols from October 1988 to August 1998. MAIN OUTCOME MEASURES: First occurrence of each of the 29 targeted infections. RESULTS: Seventy-five percent of the children were enrolled in 2000 and 2001, 90% acquired HIV perinatally, 52% were girls, and 59% were black. The median age was 8.2 years (range, 6-13 years). The median duration of follow-up was 3.4 years. Overall, 553 first episodes of a specific infection occurred among 395 (14%) of the study participants. The number of events for the 4 most common first-time infections and their incidence rates (IRs) per 100 person-years were 123 bacterial pneumonia (IR, 2.15; 95% confidence interval [CI], 1.79-2.56), 77 herpes zoster (IR, 1.11; 95% CI, 0.88-1.39), 57 dermatophyte infections (IR, 0.88; 0.67-1.14), and 52 oral candidiasis (IR, 0.93; 95% CI, 0.70-1.22). Incidence rates of first bacteremia, Pneumocystis jeroveci pneumonia, disseminated Mycobacterium avium complex, lymphoid interstitial pneumonitis, systemic fungal infection, cytomegalovirus retinitis, and tuberculosis were all less than 0.50 per 100 person-years. There were no statistically significant linear trends in incidence for any of the 29 infections over the 4 calendar years. However, infection rates were significantly lower than those reported in the PACTG in the pre-HAART era. The pre-HAART IRs were as follows: for bacterial pneumonia, IR, 11.1; 95% CI, 10.3-12.0; bacteremia, IR, 3.3; 95% CI, 2.9-3.8; herpes zoster, IR, 2.9; 95% CI, 2.6-3.3; disseminated M avium complex, IR, 1.8; 95% CI, 1.5-2.1; P jeroveci, IR, 1.3; 95% CI, 1.1-1.6; oral candidiasis, IR, 1.2; 95% CI, 1.0-1.5; cytomegalovirus retinitis, IR, 0.5; 95% CI, 0.3-0.6; and tuberculosis, IR, 0.2; 95% CI, 0.1-0.4. CONCLUSIONS: Opportunistic infections and other related infections are uncommon in children in the HAART era, and infection rates continue to be lower than those reported in the pre-HAART era. Continued surveillance is important to assess the long-term effect of HAART on the occurrence of opportunistic and other related infections in children.

Executive Functioning in Children and Adolescents With Perinatal HIV Infection and Perinatal HIV Exposure.

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 <19 years, who were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) Memory and Executive Functioning Study. Youth with PHIV, with or without history of a Centers for Disease Control and Prevention Class C (AIDS-defining) condition (PHIV/C [n = 45] and PHIV/non-C [n = 128], respectively), were compared with each other and with PHEU youth. Among youth with PHIV, associations with measures of current and past disease severity were evaluated using adjusted linear regression models. RESULTS: The PHIV/C group (mean age, 15.5 years), compared with the PHIV/non-C and PHEU groups (mean ages, 14.5 and 12.9 years, respectively), were significantly slower on the Inhibition and Color Naming/Reading Combined conditions of the Color-Word Interference subtest and made more errors on Inhibition; differences between the PHIV/C and PHEU groups persisted in adjusted models. No differences in adjusted means for fluency or problem-solving were found. The PHIV/non-C and PHEU groups did not differ on any measure. Associations of specific EF measures with HIV RNA viral load, CD4-positive T-lymphocyte percentage, and age at greatest disease severity were observed. CONCLUSIONS: Youth with PHIV and previous AIDS-defining conditions performed more poorly on some EF measures. Relationships of EF development with the degree and timing of disease severity require further study. Implications for long-term outcomes and interventions are important avenues for follow-up.

Learning and Memory in Children and Adolescents With Perinatal HIV Infection and Perinatal HIV Exposure.

BACKGROUND: Learning and memory in youth with perinatally acquired HIV (PHIV) are poorly understood, despite their importance for academic, healthcare and daily functioning. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Associations of Memory and Executive Functioning With Academic and Adaptive Functioning Among Youth With Perinatal HIV Exposure and/or Infection.

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 <19 years enrolled in the Pediatric HIV/AIDS Cohort Study's Memory and Executive Functioning Study completed standardized measures of reading and math. The primary caregivers completed a standardized measure of their child's adaptive behavior. Participants with PHIV, those with (PHIV/C) and without (PHIV/non-C) a Centers for Disease Control and Prevention class C diagnosis, and PHEU participants were compared. Retrospective memory (RM), prospective memory (PM), and EF were evaluated relative to outcomes using general linear regression models adjusted for sociodemographic characteristics. RESULTS: Of the participants (N = 258; mean age, 14.1 years), 46% were male, 75% were black, and 18% were Hispanic. Adjusted mean scores in math and adaptive behavior did not differ among the youth with PHIV/C (n = 45), those with PHIV/non-C (n = 128), and PHEU youth (n = 85). Youth with PHIV/C had lower adjusted mean reading scores than PHIV/non-C and PHEU youth (86.9 vs 93.8 [P = .02] and 93.2 [P = .04], respectively). There were positive associations of RM, PM, EF, and some sociodemographic characteristics with higher reading and math scores. Immediate and delayed verbal memory, delayed visual memory, PM, and some EF measures were positively associated with adaptive behavior. CONCLUSIONS: Higher-order cognitive abilities such as memory and EF seem to play a key role in academic and adaptive capacities, regardless of a child's HIV status, and might serve as intervention targets for improving functional outcomes.

Executive Functioning in Children and Adolescents With Perinatal HIV Infection.

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

Tenofovir treatment duration predicts proteinuria in a multiethnic United States Cohort of children and adolescents with perinatal HIV-1 infection.

BACKGROUND: Tenofovir is associated with renal proximal tubule injury. Such toxicity has not been extensively studied in HIV-1-infected children, in whom tenofovir is increasingly used. METHODS: History, urine and blood were collected at regular intervals from 448 children and adolescents with perinatal HIV-1 infection followed in the Pediatric HIV/AIDS Cohort study. Relationships between tenofovir use and proteinuria and chronic kidney disease (CKD) outcomes were examined using multivariable logistic regression models. Proteinuria was defined as at least one urine protein/creatinine ratio (uPCR) ≥ 0.2, and CKD as ≥ 2 sequential uPCR ≥ 0.2 or estimated glomerular filtration rates <60 mL/min/1.73 m with no subsequent resolution, or a clinical diagnosis not contradicted by a normal uPCR. Subjects with ≥ 2 uPCR <0.2, and no abnormal uPCR and eGFR comprised the comparison group. RESULTS: Subjects were 47% male, 72% black, 24% Hispanic, with entry mean age (± standard deviation) of 11.5 ± 2.5 years. Proteinuria prevalence at entry, and annually during 3 years, ranged from 10.3% to 13.7%. The cumulative prevalence of proteinuria was 22% (94/434, 95% confidence interval: 18%-26%) and CKD 4.5% (20/448, 95% confidence interval: 2.7%-6.8%). Duration of tenofovir use was an independent predictor of proteinuria, with >3 years of exposure having the highest risk compared with no exposure (odds ratio: 2.53, 95% confidence interval: 1.23-5.22, overall P = 0.01). Overall, duration of tenofovir use did not significantly predict the presence of CKD. CONCLUSIONS: Rates of proteinuria and CKD were lower than those seen in the pre-highly active antiretroviral therapy era. However, prolonged exposure to tenofovir increases risk of renal injury.

Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes.

BACKGROUND: Advances in therapy have allowed children with perinatal HIV infection in the United States to survive into adolescence. We sought to describe the disease status of a large cohort of such children and identify predictors of their current CD4 count and HIV viral load (VL). METHODS: The Pediatric HIV/AIDS Cohort Study AMP Protocol is an ongoing prospective study conducted at 15 sites in the United States. Between 2007 and 2009, we enrolled a population-based sample of 451 children with perinatal HIV who were 7-16 years of age at entry. RESULTS: The median age of subjects at entry was 12.2 years, 53% were female, 70% were African-American, and 24% Hispanic. Their median entry CD4% was 33%, and 78% had a CD4% ≥25%; 68% had a suppressed VL. The more recent birth cohorts (1994-2002) had a significantly higher CD4% over time than the earliest birth cohort (1991-1993). The significant independent predictors of a higher CD4% at entry were a suppressed entry VL, a higher nadir CD4%, and starting antiretroviral therapy at a younger age. The mean CD4% at entry for children with a nadir CD4% ≥25% was 9.5% higher than for those with a nadir CD4% <15% (P < 0.001). Independent predictors of a suppressed entry VL were membership in a recent birth cohort, male gender, highly active combination antiretroviral therapy use at entry, and fewer prior antiretroviral therapy regimens. CONCLUSIONS: Most children with perinatal HIV maintain virologic suppression and good CD4 values. Earlier treatment results in better immune outcome.

Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors.

BACKGROUND: Survival of HIV-infected children continues to increase and the use of antiretrovirals (ARVs) is expanding; however there are few data regarding the incidence of renal dysfunction and associated risk factors among HIV-infected children and youth. METHODS: A total of 2102 children enrolled in Pediatric AIDS Clinical Trials Group Study 219/219C, were followed and assessed prospectively for >30 months. Occurrence of clinical events and laboratory abnormalities were recorded using standardized criteria and forms. Therapeutic decisions were made by clinicians at each site. Occurrence of persistent renal laboratory abnormalities was the main outcome measure. RESULTS: Four hundred forty-six (22%) enrollees exhibited at least one persistent renal laboratory abnormality. Elevated serum creatinine (Cr) was more common than persistent proteinuria (15% vs. 8%). The incidence of new renal laboratory abnormalities was 3.7 events per 100 person-years with rates increasing between 1993 and 2005. Older age (>or=6 years vs. <6 years), Hispanic ethnicity, and Black non-Hispanic race were associated with increased risk of renal dysfunction, but CDC clinical class and plasma HIV RNA levels were not. Subjects exposed to ARV regimens containing tenofovir and/or indinavir had approximately twice the risk of developing renal dysfunction compared with persons exposed to other ARVs. The risk of renal dysfunction was also elevated for other antivirals (hazard ratio = 5.4) and amphotericin B (hazard ratio = 28). CONCLUSIONS: Persistent renal function abnormalities occur frequently in HIV-infected children. Improved survival, Black race and Hispanic ethnicity, and exposure to tenofovir, indinavir, and other antimicrobial agents increase the risk for renal dysfunction. All HIV-infected children should be monitored closely for evidence of renal disease.

Brain structural abnormalities and mental health sequelae in South Vietnamese ex-political detainees who survived traumatic head injury and torture.

CONTEXT: A pilot study of South Vietnamese ex-political detainees who had been incarcerated in Vietnamese reeducation camps and resettled in the United States disclosed significant mental health problems associated with torture and traumatic head injury (THI). OBJECTIVES: To identify structural brain alterations associated with THI and to investigate whether these deficits are associated with posttraumatic stress disorder and depression. DESIGN: Cross-sectional neuroimaging study. SETTING: Massachusetts General Hospital and McLean Hospital. PARTICIPANTS: A subsample of Vietnamese ex-political detainees (n = 42) and comparison subjects (n = 16) selected from a community study of 337 ex-political detainees and 82 comparison subjects. MAIN OUTCOME MEASURES: Scores on the Vietnamese versions of the Hopkins Symptom Checklist-25 (HSCL) and Harvard Trauma Questionnaire for depression and posttraumatic stress disorder, respectively; cerebral regional cortical thickness; and manual volumetric morphometry of the amygdala, hippocampus, and thalamus. RESULTS: Ex-political detainees exposed to THI (n = 16) showed a higher rate of depression (odds ratio, 10.2; 95% confidence interval, 1.2-90.0) than those without THI exposure (n = 26). Ex-political detainees with THI had thinner prefrontotemporal cortices than those without THI exposure (P < .001 by the statistical difference brain map) in the left dorsolateral prefrontal and bilateral superior temporal cortices, controlling for age, handedness, and number of trauma/torture events (left superior frontal cortex [SFC], P = .006; left middle frontal cortex, P = .01; left superior temporal cortex [STC], P = .007; right STC, P = .01). Trauma/torture events were associated with bilateral amygdala volume loss (left, P = .045; right, P = .003). Cortical thinning associated with THI in the left SFC and bilateral STC was related to HSCL depression scores in THI-exposed (vs non-THI-exposed) ex-political detainees (left SFC, P for interaction = .007; left STC, P for interaction = .03; right STC, P for interaction = .02). CONCLUSIONS: Structural deficits in prefrontotemporal brain regions are linked to THI exposures. These brain lesions are associated with the symptom severity of depression in Vietnamese ex-political detainees.