Immunologic, virologic, and neuropsychologic responses in human immunodeficiency virus-infected children receiving their first highly active antiretroviral therapy regimen.

Our objective was to measure the early dynamics, evolution, and durability over 96 wk of immunologic responses in children receiving their first highly active antiretroviral therapy (HAART) regimen. The study was designed as a prospective, single-arm study. Twelve human immunodeficiency virus (HIV)-infected children (median age, 11.8 yr) were enrolled. All subjects received stavudine, nevirapine, and ritonavir. Serial measurements included HIV viral load, lymphocyte subsets, thymic volume by computed tomography (CT), neurocognitive testing, and brain CT. Baseline median CD4(+) T cell count was 589 cells/mm(3) , viral load was 3.9 log(10) HIV RNA copies/mL, and thymic volume was 16.3 cm(3) . Ten children had an undetectable viral load at week 48. Eight maintained an undetectable viral load at 96 wk. The median increase in absolute CD4(+) T cell count was 225 cells/mm(3) by week 48, and 307 cells/mm(3) by week 96. The median increase in naive (CD45RA(+) CD62L(+) ) CD4(+) T cells was 133 cells/mm(3) by week 48, and 147 cells/mm(3) by week 96. The median number of naive CD8(+) T cells increased from 205 to 284 cells/mm(3) by week 24; this increase was sustained to week 96. The number of B cells increased and was associated with a decrease in immunoglobulin levels. The number of natural killer cells was stable. There were no significant changes in thymic volume. Most children exhibited stable cognitive function over the course of the study. We conclude that, in this cohort of relatively immunocompetent HIV-infected children, an initial HAART regimen was associated with rapid and sustained increases in total CD4(+) T cells, in naive CD4(+) and CD8(+) T cells, and in B cells through 96 wk.

Cognitive functioning in school-aged children with vertically acquired HIV infection being treated with highly active antiretroviral therapy (HAART).

In today's era of highly active antiretroviral therapy (HAART), few children with HIV-1 infection experience severe central nervous system (CNS) manifestations indicative of encephalopathy. However, little is known about the neurocognitive strengths and weaknesses of HIV-infected children treated with HAART. This cross-sectional study is the first to systematically investigate the relation between cognitive functioning and medical markers in HIV-infected children and adolescents treated with HAART with varying levels of computed tomography (CT) brain scan abnormalities. The Wechsler Intelligence Scale for Children-Third Edition was administered to 41 vertically infected children (mean age = 11.2 years) treated with HAART for at least 1 year. Other procedures at the time of testing included CT brain scans and collection of CD4 cell counts and plasma HIV1 RNA PCR. Although global cognitive functioning among participants was in the Average range, children with minimal to moderate CT brain scan abnormalities scored significantly lower than children with normal scans on composite measures of cognitive functioning and five specific subtests, especially tasks involving executive functions. Furthermore, children with worse immune status (CD4+ counts < or = 500) scored lower on subtests measuring processing speed. Viral load was unrelated to cognitive test scores. Thus, children with HIV being treated with HAART remain at risk for developing CNS disease. Findings emphasize the importance of conducting neuropsychological assessments in this population, particularly for children with cortical atrophy and absolute CD4+ cell counts < or = 500.

Antiretroviral exposure during pregnancy and adverse outcomes in HIV-exposed uninfected infants and children using a trigger-based design.

OBJECTIVE: To evaluate the safety of in-utero antiretroviral exposure in children born to mothers with HIV, using a trigger-based design. DESIGN: The Surveillance Monitoring of ART Toxicities Study is a prospective cohort study conducted at 22 US sites to evaluate safety of in-utero antiretroviral drug exposure in HIV-uninfected children born to HIV-infected mothers. Children meeting predefined clinical or laboratory thresholds have more intensive evaluations to determine whether they meet criteria for adverse events. METHODS: Adverse event "cases" were defined for the following domains: growth, hearing, language, neurology, neurodevelopment, metabolic, hematologic/clinical chemistry and blood lactate. We used adjusted log-binomial models to calculate relative risks (RR) of case status overall and within individual domains for various antiretroviral exposures during pregnancy. RESULTS: Among 2680 youth enrolled between 2007 and 2012 (48% female, 66% black, 33% Hispanic), 48% met a trigger and 25% were defined as a case in at least one domain. Language (13.2%) and metabolic (11.4%) cases were most common. After adjustment for birth cohort and other factors, there was no association of any antiretroviral regimen, drug class, or individual drug with meeting overall case criteria (case in any domain). Within individual domains, zidovudine (74% exposed) was associated with increased risk of metabolic case [RR = 1.69, 95%confidence interval (CI) 1.08-2.64] and didanosine plus stavudine (<1% exposed) with increased risk of both neurodevelopmental (RR = 12.40, 95%CI 5.29-29.08) and language (RR = 4.84, 95%CI 1.14-20.51) cases. CONCLUSION: Our findings support current recommendations for combination antiretroviral therapy during pregnancy, although higher risk of metabolic disorder with zidovudine exposure warrants further study.

Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean.

To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6-12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (≥3 drugs from ≥2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than -2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1-11.2), microcephaly in 105 (7.5%; 95% CI: 6.2-9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6-3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p > 0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR] = 1.9; 95% CI: 1.3-2.8), birth weight <2.5 kg (OR = 3.1; 95% CI: 2.1-4.8), 1-min Apgar score <7 (OR = 2.5; 95% CI: 1.4-4.4), and infant infections (OR = 2.5; 95% CI: 1.5-4.1). No ARV investigated was associated with adverse neurologic outcomes. Continued investigation of such associations may be warranted as new ARVs are used during pregnancy and cART exposure during the first trimester becomes increasingly common.

CD40 ligand deficiency: neurologic sequelae with radiographic correlation.

Patients with CD40 ligand deficiency are susceptible to central nervous system infections, but to date the neurologic progression or long-term outcome of central nervous system complications have not been reported in detail. Characterizing the central nervous system complications of immune deficiencies can lead to the identification of new pathogens. For this study, clinical data were reviewed on patients with both CD40 ligand deficiency and neurodegeneration, identified from a larger cohort of 31 patients. Five patients had progressive neurologic and cognitive decline in the absence of clinical signs of acute fulminant encephalitis, with anatomic brain abnormalities and high mortality (60%). Despite multiple evaluations, no pathogens were identified in four patients, all of whom were on standard intravenous immunoglobulin therapy at illness presentation. This clinical phenotype of progressive decline without acute fulminant encephalitis is similar to chronic enteroviral encephalitis in X-linked agammaglobulinemia, another condition with severe humoral immune defects. Whether infection secondary to subtherapeutic levels of central nervous system immunoglobulin G (IgG), inadequately protective levels of serum IgG, or impaired CD40 ligand-dependent IgG-independent antiviral responses contributed remains undetermined. Emerging gene-chip techniques applied in patients with primary immune deficiencies may identify heretofore unknown viruses. Prospective neurocognitive and evaluation of patients with CD40 ligand deficiency may identify affected patients before overt clinical signs appear.

Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue.

Human immunodeficiency virus type 1 (HIV-1) central nervous system (CNS) infection in children is associated with impaired brain growth and neurodevelopmental delays. Neural progenitors are critical for neurogenesis. Human multipotential neural progenitors grown in culture are permissive for HIV-1 infection, but it is not known if infection of these cells occurs in vivo. Brain tissue from pre-highly active antiretroviral therapy (HAART) era pediatric acquired immunodeficiency syndrome (AIDS) patients was examined for evidence of HIV-1 infection of nestin-positive neural progenitors by in situ hybridization; or after laser microdissection harvest, DNA extraction, and polymerase chain reaction (PCR). HIV-1 or viral DNA was identified in nestin-positive cells in four of seven HIV-1-infected children, suggesting in vivo infection of neural progenitors.

Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome.

PURPOSE: To determine if rituximab, an anti-CD20 monoclonal antibody, reduces cerebrospinal fluid (CSF) B-cell expansion in opsoclonus-myoclonus syndrome (OMS) and results in clinical improvement. METHODS: Sixteen children with OMS and increased % CD20 B-cells in CSF received 4 rituximab infusions (375 mg/m IV) as add-on therapy to corticotropin (ACTH), intravenous immunoglobulins, or both, and were reevaluated 6 months later. Outcome measures were clinical (motor function, behavior, sleep) and immunologic (CSF and blood immunophenotype and Ig levels). Controls were 16 age-matched and sex-matched children, who did not have OMS. RESULTS: After rituximab, 81% of OMS had a lower motor severity score, and 44% improved one severity category. Mean total score decreased by 44% (P = 0.0005). Rituximab reduced rage score, nighttime awakenings, and the number of children with opsoclonus, action myoclonus, drooling, gait ataxia, and rage. Despite a 51% reduction in ACTH dose, 9 of 11 children on ACTH did not relapse. The percentage of CSF CD19 (and CD20) B-cells was lowered in all children (undetectable in 6), with a 90% reduction in the group mean (P = 0.00003). CSF B-cells were no longer expanded compared with controls. In blood, CD19 B-cells decreased (-90%, P = 0.0003), as did the CSF:blood CD19 B-cell ratio (P = 0.00003). Serum IgM fell by 69% (below reference range), with no statistically significant change in IgG or IgA. CONCLUSIONS: Rituximab seems efficacious and safe as adjunctive therapy for OMS. Selective targeting of CSF B lymphocytes represents a novel and valuable paradigm shift in the therapy for centrally mediated paraneoplastic disorders.

Neurologic aspects of HIV infection in infants and children: therapeutic approaches and outcome.

Central nervous system (CNS) HIV-related disorders frequently have devastating consequences. Significant progress has been made in the early diagnosis and treatment of the HIV-infected patient. As a result, the prevalence and natural history of neurologic illnesses have changed. This paper reviews the epidemiology, clinical manifestations, and neuropathogenesis of HIV-related CNS disorders. Advances in antiretroviral therapy, neuroprophylaxis, and neuroprotective strategies are also discussed.

Cognitive decline with immunologic and virologic stability in four children with human immunodeficiency virus disease.

This case series describes 4 children with vertically acquired human immunodeficiency virus (HIV) infection who exhibited immunologic, virologic, and clinical stability while on a protease inhibitor-containing highly active antiretroviral therapy (HAART) regimen, yet demonstrated significant cognitive decline as measured by standardized intelligence tests. A retrospective review of 107 patient records of children with HIV infection on HAART treatment protocols was conducted. Four patients were identified who responded to protease inhibitor-containing HAART therapy with sustained viral load suppression, and stable immunologic and medical parameters, yet demonstrated significant cognitive decline. Such discordance between biological and clinical markers previously has been reported in adults with HIV disease but not in children. This observed decline in neurocognitive functioning despite stable medical parameters suggests that HAART regimens that are effective for systemic disease may not be as effective for the central nervous system (CNS), perhaps because the antiretrovirals do not penetrate adequately into the CNS. Of note, 3 of these 4 patients did not have zidovudine (ZDV) included in their HAART regimen. The only patient who was treated with ZDV containing regimen received 90 mg/m(2) every 6 hours, which is at the lower end of the recommended ZDV pediatric full-dose range (90 mg/m(2) to 120 mg/m(2)). Two of the 4 patients began ZDV at 120 mg/m(2) every 6 hours following the decline in their cognitive test scores and subsequently showed improved or stable functioning as evidenced by the results of follow-up psychometric testing. Long-term prospective studies using both systemic and CNS measures are necessary to further investigate the effects of HAART in children with HIV disease. Longitudinal cognitive assessments of children receiving HAART appear indicated to identify cognitive decline and to provide appropriate therapeutic intervention when manifestations of HIV-related CNS disease progression occur.