African Multi-Site 2-Year Neuropsychological Study of School-Age Children Perinatally Infected, Exposed, and Unexposed to Human Immunodeficiency Virus.

BACKGROUND: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). METHODS: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables. RESULTS: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. CONCLUSIONS: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.

Association between caregiver depression symptoms and child executive functioning. Results from an observational study carried out in four sub-Saharan countries.

Depressive symptoms among HIV-positive (HIV+) women may negatively impact their health and possibly that of their young children through risk of compromised caregiving. We evaluated how depression symptoms in predominantly (97%) female caregivers relate to neurodevelopmental outcomes in their HIV affected children. Data come from the IMPAACT P1104s Study, an observational cohort across six sites in four countries: Zimbabwe, South Africa, Uganda and Malawi. Participants (n = 611) were 5-11-year-old children with HIV (HIV), HIV exposed uninfected (HEU), or HIV unexposed uninfected (HUU). Primary caregivers were assessed for depression with the Hopkins Symptom Checklist (HSCL) and children with Behavior Rating Inventory for Executive Function (BRIEF) parent-report, Kauffman Assessment Battery for Children II (KABC), Bruininks-Oseretsky Test of Motor Proficiency 2nd Ed. (BOT-2), Test of Variables of Attention (TOVA), Multiple Indicators Cluster Survey, Child Disability and Development scales (MICS-4). Caregivers with higher depression scores (>1.75 mean HSCL score) reported more executive function problems in their children, regardless of HIV status. All executive function scores were significantly (p < 0.001) associated with depressive symptomatology at baseline and across time. Caregiver depressive symptomatology was not associated with other assessed neurocognitive outcomes. These results highlight the potential impact of caregiver depression on child behavioral outcomes.

The Role of Pharmacy Refill Measures in Assessing Adherence and Predicting HIV Disease Markers in Youth with Perinatally-Acquired HIV (PHIV).

Antiretroviral (ARV) adherence is critical in monitoring disease response in youth with perinatally-acquired HIV (PHIV). We used pharmacy refill (PR) information for PHIV youth from the PHACS Memory Sub-study to calculate medication availability over 2, 4, and 6 months. PR, a proxy of adherence, was compared with self-reported 7-day adherence in predicting suppressed viral load (SVL < 400 copies/mL) and higher CD4% (≥ 25%). Among 159 PHIV youth, 79% were adherent by 7-day recall, and 62, 55, and 48% by PR over 2, 4, and 6 months, respectively. Agreement between 7-day recall and PR adherence was weak (Kappa = 0.09-0.25). In adjusted logistic regression models, adherence showed associations with SVL for 7-day recall (OR 2.78, 95% CI 1.08, 7.15) and all PR coverage periods (6-month: OR 3.24, 95% CI 1.22, 8.65). Similar associations were observed with higher CD4%. PR measures were predictive of study retention. Findings suggest a possibly independent role of PR adherence measures.

Assessing Psychiatric Symptoms in Youth Affected by HIV: Comparing a Brief Self-Administered Rating Scale with a Structured Diagnostic Interview.

Brief psychiatric assessment tools are needed for evaluating children affected by HIV for emotional and behavioral problems. We compared a self-administered symptom rating scale (CASI-4R) to a semi-structured diagnostic interview (DICA-P) in 136 U.S. children affected by HIV. Agreement and performance measures for the two instruments were computed for attention deficit hyperactivity disorder, depression, anxiety, and disruptive behavior. Correlations and regression analyses were conducted to compare the two instruments, and to evaluate their associations with social, academic, and global function. Higher CASI-4R symptom severity scores were associated with DICA diagnoses (p < 0.02 for all disorders). Agreement (κ) between DICA diagnoses and CASI-4R Clinical Cutoffs (which incorporated symptoms and impairment) was low to moderate (0.19-0.40 for all disorders). Thirty-two percent of cases with a DICA diagnosis were identified by the CASI-4R Clinical Cutoff (sensitivity), yet over 90% of DICA-negative cases were negative by the CASI-4R (specificity). Sensitivity was higher using CASI-4R Severity Score thresholds based on median scores compared to the DICA diagnoses. The presence and severity of psychiatric symptoms and impairment were associated with poorer academic, social, and global function. The CASI-4R symptom checklist can be used to inexpensively screen youth affected by HIV for emotional and behavioral problems, although it is important that there be appropriate mental health evaluation follow-up.

The Role of Alaska's Tribal Health Workers in Supporting Families.

Alaska's Community Health Aides/Practitioners (CHA/Ps) are often the sole medical workers in their communities in rural Alaska, and are instrumental in providing healthcare services and education to otherwise underserved individuals. This qualitative study explored how CHA/Ps support healthy families. Six CHA/Ps from two rural communities in western Alaska were interviewed about their scope of practice, interactions with mothers, infants, families, and teens, relationship to other medical providers, and perceptions of their work. Using grounded theory, verbatim notes were analyzed in Dedoose software and coded by thematic and structural components. Interviewed CHA/Ps shared how the CHA/P program is a culturally relevant way to deliver healthcare, and talked about the challenges of the work, rewards, and suggestions for improvement. CHA/Ps described their unique role as the on-the-ground health and wellness resource in their communities, and talked about consulting with other medical professionals to provide better care for individuals in rural Alaska. CHA/Ps described that they provided prenatal care, patient education during pregnancy, emergency delivery services when necessary, well-child visits, and outreach to teens to give fluoride rinses, vaccinations, and education about issues such as sexual health and drugs/alcohol. CHA/Ps also talked about patient education as a primary responsibility, which also reduced patient load and prevented burn-out. The CHA/P program is a comprehensive and innovative approach to providing healthcare education and services that promotes healthy communities, including positive parent-infant interactions, child wellness, and teen decision-making. The program is a healthcare delivery model translatable to other tribal and limited-resource contexts.

Changing Trends in Complications and Mortality Rates Among US Youth and Young Adults With HIV Infection in the Era of Combination Antiretroviral Therapy.

BACKGROUND: Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur. METHODS: We estimated the incidence of complications and deaths in IMPAACT P1074, a long-term US-based prospective multicenter cohort study conducted from April 2008 to June 2014. Incidence rates of selected diagnoses and trends over time were compared with those from a previous observational cohort study, P219C (2004-2007). Causes of death and relevant demographic and clinical features were reviewed. RESULTS: Among 1201 HIV-infected youth in P1074 (87% perinatally infected; mean [standard deviation] age at last chart review, 20.9 [5.4] years), psychiatric and neurodevelopmental disorders, asthma, pneumonia, and genital tract infections were among the most common comorbid conditions. Compared with findings in P219C, conditions with significantly increased incidence included substance or alcohol abuse, latent tuberculosis, diabetes mellitus, atypical mycobacterial infections, vitamin D deficiency or metabolic bone disorders, anxiety disorders, and fractures; the incidence of pneumonia decreased significantly. Twenty-eight deaths occurred, yielding a standardized mortality rate 31.5 times that of the US population. Those who died were older, less likely to be receiving cART, and had lower CD4 cell counts and higher viral loads. Most deaths (86%) were due to HIV-related medical conditions. CONCLUSIONS: Opportunistic infections and deaths are less common among HIV-infected youth in the US in the cART era, but the mortality rate remains elevated. Deaths were associated with poor HIV control and older age. Emerging complications, such as psychiatric, inflammatory, metabolic, and genital tract diseases, need to be addressed.

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.

Antiretroviral choice and severe disease predict poorer neuropsychological outcomes in HIV+ children from Africa.

Background: The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1104s study evaluated neuropsychological outcomes over 96 weeks in children living with HIV (CLHIV) aged 5-11 years at 6 Sub-Saharan African sites to explore associations between HIV-illness related biomarkers and neuropsychological outcomes. Methods: Children living with HIV had participated in IMPAACT P1060, which compared efficacy of nevirapine versus lopinavir/ritonavir in children initiating ART at <3 years of age. At age 5-11, neuropsychological evaluations of KABC cognitive ability, TOVA attention-impulsivity and BOT-2 motor domains were assessed and repeated after 48 and 96 weeks. Clinical, antiretroviral therapy (ART) and laboratory (immunological and virological) parameters were used to predict neuropsychological outcomes using linear mixed-effects multivariable regression models, controlling for child and caregiver characteristics. Results: 246 CLHIV (45% male, mean age at initial neuropsychological evaluation 7.1 yrs [SD 1.2]) began ART at a median age 14.9 months (IQR 8.2, 25.2). Nadir CD4 percentage was 14.7% (IQR 11.0, 19.5); the median peak viral load (VL) was 750 000 copies/ml (IQR 366 000, 750 000) and 63% had ≥WHO stage 3 clinical disease; 164 (67%) were on lopinavir/ritonavir, 71 (29%) were on nevirapine and 7 (3%) were on efavirenz. Other antiretrovirals were similar. Nevirapine at P1104s study start or later was associated with poorer neuropsychological scores across all domains except Global Executive Composite, even when controlling for nadir CD4 percent and time-varying HIV VL. Other predictors of poorer scores in KABC domains included low birth weight, WHO stage 4 disease and serious illness history and elevated VL was associated with worse BOT-2 scores. Conclusion: Children receiving nevirapine had poorer neuropsychological scores than those on lopinavir/ritonavir. Antiretroviral choice might adversely impact neuropsychological performance. In addition, low birth weight and markers of severe HIV disease: advanced WHO clinical HIV disease, history of serious illness and an elevated VL, were associated with lower neuropsychological scores.

Forty-Eight Week Outcomes of a Site-Randomized Trial of Combined Cognitive Behavioral Therapy and Medication Management Algorithm for Treatment of Depression Among Youth With HIV in the United States.

BACKGROUND: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12-24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. METHODS: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. RESULTS: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). CONCLUSIONS: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.

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.

Site-Randomized Controlled Trial of a Combined Cognitive Behavioral Therapy and a Medication Management Algorithm for Treatment of Depression Among Youth Living With HIV in the United States.

BACKGROUND: Depression is frequent among youth living with HIV (YLWH). Studies suggest that manualized treatment guided by symptom measurement is more efficacious than usual care. SETTING: This study evaluated manualized, measurement-guided depression treatment among YLWH, aged 12-24 years at 13 US sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Network. METHODS: Using restricted randomization, sites were assigned to either a 24-week, combination cognitive behavioral therapy and medication management algorithm (COMB-R) tailored for YLWH or to enhanced standard of care, which provided standard psychotherapy and medication management. Eligibility included diagnosis of nonpsychotic depression and current depressive symptoms. Arm comparisons used t tests on site-level means. RESULTS: Thirteen sites enrolled 156 YLWH, with a median of 13 participants per site (range 2-16). At baseline, there were no significant differences between arms on demographic factors, severity of depression, or HIV status. The average site-level participant characteristics were as follows: mean age of 21 years, 45% male, 61% Black, and 53% acquired HIV through perinatal transmission. At week 24, youth at COMB-R sites, compared with enhanced standard of care sites, reported significantly fewer depressive symptoms on the Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR score 6.7 vs. 10.6, P = 0.01) and a greater proportion in remission (QIDS-SR score ≤ 5; 47.9% vs. 17.0%, P = 0.01). The site mean HIV viral load and CD4 T-cell level were not significantly different between arms at week 24. CONCLUSIONS: A manualized, measurement-guided psychotherapy and medication management algorithm tailored for YLWH significantly reduced depressive symptoms compared with standard care at HIV clinics.

Substance use and its association with psychiatric symptoms in perinatally HIV-infected and HIV-affected adolescents.

Drug use in combination with psychiatric illness may lead to unsafe sexual risk behavior and increased risk for secondary HIV transmission among adolescents with HIV infection. We compared the prevalence of substance use for perinatally HIV-infected youth to uninfected adolescents living in families affected by HIV infection, and evaluated the association of psychiatric symptoms with risk of substance use. Among 299 adolescents (196 HIV+, 103 HIV-) aged 12-18 years enrolled in IMPAACT P1055, a multisite US cohort study, 14% reported substance use at enrollment (HIV+: 13%, HIV-: 16%). In adjusted logistic regression models, adolescents had significantly higher odds of substance use if they met symptom criteria for ADHD [adjusted odds ratio (aOR) = 2.7, Wald χ(2) = 5.18, P = 0.02], major depression or dysthymia (aOR = 4.0, Wald χ(2) = 7.36, P = 0.01), oppositional defiant disorder (aOR = 4.8, Wald χ(2) = 12.7, P = 0.001), or conduct disorder (aOR = 15.4, Wald χ(2) = 28.12, P = 0.001). Among HIV-infected youth, those with lower CD4 lymphocyte percentage (CD4% < 25%) had significantly increased risk of substance use (aOR = 2.7, Wald χ(2) = 4.79, P = 0.03). However, there was no overall association of substance use with HIV infection status, and the association between psychiatric symptoms and substance use did not differ by HIV status. Programs to prevent substance use should target both HIV-infected and uninfected adolescents living in families affected by HIV infection, particularly those with psychiatric symptoms.

Prevalence of pain and association with psychiatric symptom severity in perinatally HIV-infected children as compared to controls living in HIV-affected households.

This cross-sectional study evaluated the prevalence of pain and psychiatric symptoms in perinatally HIV-infected children at entry into P1055, a multicenter investigation of the prevalence and severity of psychiatric symptoms in HIV-infected children. Subjects 6-17 years of age and their primary caregivers were recruited from 29 International Maternal Pediatric Adolescent AIDS Clinical Trials sites in the USA and Puerto Rico. A total of 576 children (320 HIV and 256 HIV- children) were enrolled from June 2005 to September 2006. Subject self-reports of pain were measured by the Wong-Baker visual analog scale and Short-Form McGill Pain Questionnaire. Symptomatology for anxiety, depression, and dysthymia was assessed through Symptom Inventory instruments. Caregiver's assessment of their child's pain and psychiatric symptomatology was similarly measured. Logistic regression models were used to evaluate predictors of pain. We found that a higher proportion of HIV-infected than uninfected subjects reported pain in the last two months (41% vs 32%, p=0.04), last two weeks (28% vs 19%, p=0.02), and lasting more than one week (20% vs 11%, p=0.03). Among HIV-infected youth, females (OR=1.53, p=0.09), White race (OR=2.15, p=0.04), and Centers for Disease Control (CDC) Class C (OR=1.83, p=0.04) were significantly more likely to report pain. For all subjects, only 52% of caregivers recognized their child's pain and just 22% were aware that pain affected their child's daily activities. The odds of reported pain in HIV increased with higher symptom severity for generalized anxiety (OR=1.14, p=0.03), major depression (OR=1.15, p=0.03), and dysthymia (OR=1.18, p=0.01). This study underscores the importance of queries concerning pain and emotional stressors in the care of HIV and uninfected children exposed to HIV individuals. The discordance between patient and caregiver reports of pain and its impact on activities of daily living highlights that pain in children is under-recognized and therefore potentially under-treated.

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.

Building capacity in neurodevelopment assessment of children in sub-Saharan Africa: A quality assurance model to implement standardized neurodevelopment testing.

Compromised neurodevelopment (ND) among infants and children is prevalent in sub-Saharan Africa. Standardized testing of ND is frequently prohibitive in these contexts, as tests require skilled staff for their application. In this paper, we present a quality assurance (QA) model (QualiND) for standardized ND testing, discussing findings and implications from our experience applying the Kaufman Assessment Battery for Children second edition (KABC-II). The QualiND model was implemented within IMPAACT P1104s study, a multisite, prospective study including 615 children affected by HIV. From 2014 to 2016, the QualiND managed 18 testers across 6 sites located in 4 African countries applying the KABC-II in 9 local languages. The QualiND is a multilevel, video-assisted iterative model incorporating remote evaluation, feedback, and supervision roles. Using an ad hoc rubric, videos of test application were evaluated by experienced staff in a centralized QA center. At each study site, testers and supervisors reviewed feedback from videos received via email from the QA center and devised an action plan to address testing errors and deficiencies. There were few instances of invalid tests and few barriers to test completion. Over 97% of KABC-II tests across sites were considered to be valid by the QA center. Overall, the QualiND model was a useful platform for remote supervision to nonspecialist and minimally trained research staff. The QualiND model may be useful to researchers and organizations involved in measuring early child development using standardized tests in low and middle-income countries.

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.