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: Introduction: The number of children exposed to HIV and possibly to antiretroviral therapy (ART) in utero and during breastfeeding and are uninfected (HEU) globally will continue to increase from the estimated 15.9 million in 2021. Discussion: There are still significant gaps in our understanding of the impact of HIV and/or ART exposure in children who are HEU, in terms of prevalence/incidence and severity on health and wellbeing, and long after exposure has ended. While there have been substantial programmatic efforts to support the elimination of vertical transmission of HIV, additional rigorous research is needed to better understand the biological, (psycho)social and structural factors contributing to optimal health for populations who are HEU. Furthermore, the best approaches to address and study the gaps in understanding also need to be explored. Given the scope of the problem including the large numbers of affected people as well as the often limited and competing in‐country resources for populations affected by HIV, novel methodologies, including multi‐level approaches and advanced analytics, need to be considered. Conclusions: A growing population of children who are HEU are maturing into adolescence and young adulthood. Research to advance understanding of the possible negative long‐term effects of HIV and/or ART exposure in these youth is supported by the US National Institutes of Health. Both large epidemiological studies and smaller more comprehensive cohort studies may be required to address the complexity of the issue. Integrating both types of studies could allow the establishment of more reliable and validated predictions of which youth who are HEU are at the highest risk for specific negative health outcomes, such as mental health and neurocognitive disorders, and which interventional approaches may be most successful to address specific deficits both in terms of prevention and treatment. Finally, these goals can be more rapidly achieved with data science efforts, data harmonisation between studies and with sustainable data‐sharing practices. It is important to expand the commitment to research to identify biological, social and structural drivers, to develop screening tools, and impactful and contextually appropriate interventions to address the health and wellbeing of children who are HEU from birth through adulthood., INTRODUCTION The number of children exposed to HIV and possibly to antiretroviral therapy (ART) in utero and during breastfeeding who are uninfected (HEU) will continue to increase from the estimated [...]

Objective: Due to potential disease and drug interactions, the appropriate sertraline starting dose and titration range may require adjustment in pediatric patients living with HIV. This is the first report of sertraline pharmacokinetics in HIV-infected youth. Methods: IMPAACT P1080 was a multicenter pilot study describing psychiatric medication pharmacokinetics in HIV-infected and uninfected youth. Participants were stable on sertraline, >6 to -0.5). Conclusions: HIV(-) cohort had the highest sertraline exposure. Sertraline exposure was ~40% lower in the PI/r cohort than in HIV(-); the need to alter sertraline dose ranges for PI/r participants is not clear. The impact of efavirenz on sertraline needs further investigation due to limited numbers of EFV participants.

Remarkable advances in HIV prevention, care and treatment, made through the discovery of antiretroviral drugs, have enabled people living with HIV (PLHIV) to live longer lives [1]. Yet, as they [...], Keywords: HIV; NCD; integrated care; LMICs; epidemiological and clinical data; computational modelling; capacity building

BackgroundThis study assesses the relationships between lymphocyte and monocyte subsets and intelligence quotient (IQ) scores in antiretroviral therapy (ART)-naive, HIV-infected Thai children without advanced HIV disease.FindingsSixty-seven ART-naive Thai children with CD4 between 15-24% underwent cognitive testing by Weschler intelligence scale and had 13 cell subsets performed by flow cytometry including naive, memory and activated subsets of CD4+ and CD8+ T cells, activated and perivascular monocytes and B cells. Regression modelling with log10 cell count and cell percentage transformation was performed.Median age (IQR) was 9 (7-10) years, 33% were male, CDC stages N:A:B were 1:67:31%, median CD4% and count (IQR) were 21 (18-24)%, 597 (424-801) cells/mm3 and HIV RNA (IQR) was 4.6 (4.1-4.9) log10 copies/ml. Most (82%) lived at home, 45% had a biological parent as their primary caregiver, and 26 (49%) had low family income. The mean (SD) scores were 75 (13) for full scale IQ (FIQ), 73 (12) for verbal IQ (VIQ) and 80 (14) for performance IQ (PIQ). Adjusted multivariate regression analysis showed significant negative associations between B cell counts and FIQ, VIQ and PIQ (p

BackgroundWe previously reported similar AIDS-free survival at 3 years in children who were >1 year old initiating antiretroviral therapy (ART) and randomized to early versus deferred ART in the Pediatric Randomized to Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) study. We now report neurodevelopmental outcomes.MethodsTwo hundred eighty-four HIV-infected Thai and Cambodian children aged 1-12 years with CD4 counts between 15% and 24% and no AIDS-defining illness were randomized to initiate ART at enrollment ("early," n = 139) or when CD4 count became

ObjectiveThe NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox) is a comprehensive battery of brief assessment tools. The purpose of this article is to describe plans to establish normative reference values for the NIH Toolbox measures.MethodsA large sample will be obtained from the US population for the purpose of calculating normative values. The sample will be stratified by age (ages 3-85 years), sex, and language preference (English or Spanish) and have a total sample size of at least 4,205. The sample will include a minimum of 25-100 individuals in each targeted demographic and language subgroup.ResultsNorming methods will include poststratification adjustment calculated using iterative proportional fitting, also known as raking, so that the weighted sample will have the same distribution on key demographic variables as the US population described in the 2010 Census.ConclusionsAs with any set of norms, users should be mindful of the reference population and make conclusions consistent with the limitations of normative sampling, since it is not a probability-based sample. However, the NIH Toolbox norming study has been designed to minimize bias and maximize representativeness and precision of estimates. The availability of a "toolbox" of normed measures will be an important foundation for addressing critical research questions in neurologic and behavioral health.

OBJECTIVE. We examined the effect of HIV, in combination with other important health and social factors, on the development of cognitive abilities of children perinatally exposed to HIV. METHODS. Serial cognitive assessments were performed for 117 children who were infected vertically and 422 children who were exposed to but not infected with HIV, in a multicenter, natural history, longitudinal study. Repeated-measures analyses were used to evaluate the neurocognitive development of children between the ages of 3 and 7 years, as measured by the McCarthy Scales of Children's Abilities (MSCA). RESULTS. Children with HIV infection and class C status scored significantly lower in all domains of cognitive development, across all time points, than did those who were HIV infected without an AIDS-defining illness and those who were HIV exposed but not infected. There were no significant differences between the 2 latter groups in General Cognitive Index or specific domain scores. Rates of change in cognitive development were comparable (parallel) among all 3 groups over a period of 4 years. Factors that were associated consistently and significantly with lower mean scores were HIV status, number of times an examination had been completed previously, primary language, maternal education, and gender. No factors were related to rate of change of any mean domain score. CONCLUSIONS. An early AIDS-defining illness increased the risk of chronic static encephalopathy during the preschool and early school age years. Children with HIV infection but no class C event performed as well as noninfected children in measures of general cognitive ability. No significantly different profiles of strengths and weaknesses for verbal, perceptual-performance, quantitative, or memory functioning were observed among children with or without HIV infection. A number of factors were found to have significant effects on the mean scores of children in all 3 groups; however, they were not related to the rate at which learning occurred. Key Words pediatric HIV, cognition, longitudinal Abbreviations WITS--Women and Infants Transmission Study MSCA--McCarthy Scales of Children's Abilities GCI--General Cognitive Index HAART--highly active antiretroviral therapy, THE EFFECTS OF HIV infection on children's physical growth, psychological health, and neurodevelopment can range from mild to devastating. (1) Delays in the mental and motor development of very young [...]

Objective. Descriptive studies and clinical reports have suggested that human immunodeficiency virus (HIV)-positive children are at risk for behavioral problems. Inadequate control groups and sample sizes have limited the ability of investigators to consider multiple influences that place HIV-positive children at risk for poor behavioral outcomes. We examined the unique and combined influences of HIV, prenatal drug exposure, and environmental factors on behavior in children who were perinatally exposed to HIV. Methods. Participants included 307 children who were born to HIV-positive mothers (96 HIV infected and 211 seroreverters) and enrolled in a natural history, longitudinal study of women to infant HIV transmission. Caregivers completed parent behavioral rating scales, beginning when the children were 3 years old. Data were also collected on prenatal drug exposure; child age, gender, and ethnicity; caregiver relationship to child; and birth complications. Results. Multivariate analyses comparing the HIV-infected children with perinatally exposed but uninfected children from similar backgrounds failed to find an association between either HIV status or prenatal drug exposure and poor behavioral outcomes. The strongest correlates of increased behavioral symptoms were demographic characteristics. Conclusions. This study suggests that although a high prevalence of behavioral problems does exist among HIV-infected children, neither HIV infection nor prenatal drug exposure is the underlying cause. Rather, other biological and environmental factors are likely contributors toward poor behavioral outcomes. Pediatrics 2003;111:384-393; pediatric HIV infection, behavioral outcome, Conners' Parent Rating Scale., ABBREVIATIONS. HIV, human immunodeficiency virus; ADHD, attention-deficit/hyperactivity disorder; WITS, Women and Infants Transmission Study; CPRS, Conners' Parent Rating Scale; CI, confidence interval. The psychological effects of human immunodeficiency virus (HIV) [...]

Indinavir seems to be effective in treating children with HIV infection and well tolerated by them. The dry capsule form of the protease inhibitor seems to be more useable by the body. In testing 54 HIV infected children between 3.1 and 18.9 years old, with three different dosage levels, the average CD4 cell count rose by 64 cells/mm after two weeks. Some patients had blood in the urine at the higher doses. The drug was also well tolerated in combination with lamivudine and zidovudine., Background. Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Methods. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/[m.sup.2], 350 mg/[m.sup.2] and 500 mg/[m.sup.2] per dose given orally every 8 h) were evaluated in 2 age groups ([is less than] 12 years and [is greater than or equal to] 12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Results. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median C134 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/[mm.sup.3] and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Conclusions. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine. Pediatrics 1998;102:101-109, protease inhibitor, child, HIV-1, CD4 cells, HIV RNA, pharmacokinetics. ABBREVIATIONS. AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control and Prevention; HIV, human immunodeficiency virus; RNA, ribonucleic acid; NCI, National Cancer Institute; AUC, area under the time-concentration curve; FSIQ, full scale intelligence quotient; VIQ, verbal intelligence quotient; PIQ, performance intelligence quotient; PPD, purified protein derivative., As of December 1997, [is greater than] 7900 children with an acquired immunodeficiency syndrome (AIDS)-defining illness have been reported to the Centers for Disease Control and Prevention (CDC) in the [...]

Ritonavir may be effective and well-tolerated in children infected with HIV. Ritonavir is a protease inhibitor drug used to treat HIV-infected adults. Researchers evaluated the safety and effectiveness of ritonavir in 48 children, aged 6 months to 14.4 years. Ritonavir therapy resulted in an average increase in the CD4 white blood cell count of 79 cells per cubic millimeter, and a decrease in blood levels of the virus. Gastrointestinal complaints were the most common side-effects. Ritonavir may be an appropriate component of combination drug therapy in pediatric HIV disease., Background. Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. Methods. HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/[m.sup.2] given every 12 hours) were evaluated in two age groups ([is less than or equal to] 2 years, [is greater than] 2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. Results. A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/[mm.sup.3] after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 [log.sub.10] copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/[m.sup.2] for the 24-week period. Conclusions. The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine. Pediatrics 1998;101:335-343, protease inhibitor, child, HIV-1, CD4 cells, HIV RNA, pharmacokinetics., As of December 1996, [is greater than] 7600 children have been diagnosed with acquired immunodeficiency syndrome (AIDS) in the United States.[1] Approved treatment options for human immunodeficiency virus (HIV)-infected children [...]

HIV infection in children appears to be associated with language difficulties. The language skills of 36 HIV-positive children between the ages of 1.2 and 10.8 years were evaluated. Additionally, the language skills of 10 of the HIV-positive children were compared with 10 of their HIV-negative siblings. Prior to the study, 21 of the HIV-positive children had been classified as having an abnormal brain condition. Expressive language function, in which there is an inability to form words, was significantly impaired in HIV-positive children. HIV-positive children with an identified brain abnormality scored lower on expressive language function tests than HIV-positive children without an identified brain abnormality. However, the average scores between the two groups were similar. The HIV-negative siblings scored higher on measures of both expressive and receptive language. Receptive skills are those needed to understand language., Objectives. To investigate the effect of HIV disease on the receptive and expressive language of children and the relationship between CT scan brain abnormalities and language functioning. Methods. Thirty-six children (mean age, 5.5 years; range, 1 through 10 years; 75% vertical transmission; 58% classified as encephalopathic) with symptomatic HIV infection and 20 uninfected siblings (mean age, 7.8 years; range, 3 through 15 years) were administered an age-appropriate comprehensive language test assessing both receptive and expressive language (Reynell Developmental Language Scales or Clinical Evaluation of Language Fundamentals--revised). Each HIV-infected child had a CT scan of the brain as part of the baseline evaluation, which was rated independently and blindly by two neurologists, for presence and severity of brain abnormalities using a semiquantitative rating system. Results. Expressive language was significantly more impaired than receptive language in the overall sample of HIV-infected children. The encephalopathic children scored significantly lower than the non-encephalopathic children, however, the degree of discrepancy between mean receptive and expressive language scores was not significantly different between these two groups. The uninfected sibling control group did not have a significant discrepancy between receptive and expressive language, and they scored significantly higher than the infected patient group. Greater severity of CT scan abnormalities was significantly correlated with poorer receptive and expressive language functioning in the overall HIV-infected sample and a higher discrepancy between receptive and expressive language in the encephalopathic group. Conclusion. Pediatric HIV disease is associated with differential receptive and expressive language functioning in which expressive language is significantly more impaired than receptive language. The sibling data and CT scan correlations suggest that the observed language impairments are associated with the direct effects of HIV-related central nervous system disease. Pediatrics 1995;95:112-119; pediatric AIDS, HIV infection, neuropsychology, language, encephalopathy, CT scan.

Oral didanosine treatment appears to improve CD4 cell counts over the long term in some children with HIV infection. Didanosine is also known as DDI. CD4 cells are component of the immune system and are measured to evaluate immune system functioning. A group of 103 children with HIV infection, ranging in age from 6 months to 18 years, underwent didanosine therapy. Children had symptomatic HIV infection or a CD4 count of less than 500. Median length of therapy was 23 months. The CD4 count increased in 32% of patients after six months of therapy. Forty-one percent of these children improved CD4 counts for three years. The probability of survival for the 51 children with CD4 counts greater than 100 at the beginning of the study was 80% versus 39% for children with CD4 counts below that level. Treatment was discontinued in 11 children because of side effects and in 34 because of disease progression despite treatment., Background. Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine. Methods. Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x [10.sup.9] cells/L, received oral didanosine at doses between 20 mg/[m.sup.2] to 180 mg/[m.sup.2] every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients. Results. Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months, range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by [greater than or equal to] .05 x [10.sup.9] cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x [10.sup.9] cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration. Conclusions. Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment. Pediatrics 1994;94:724-731; HIV, didanosine, survival, toxicities, CD4 counts, pharmacokinetics, child.

Combined therapy with zidovudine (AZT) and didanosine (ddI) may benefit children with HIV infections more than either drug alone. Researchers administered varied doses of combined therapy and evaluated the outcome of 49 children who were previously untreated and 12 who had prior AZT-related toxicity. The patients tolerated AZT and ddI well at all dose levels and showed no evidence of new or enhanced toxicity. Fifty-one children gained weight while on the combined therapy program. After 24 weeks, the midpoint CD4 cell count increased from 331 to 556 cells per millimeter cubed for all patients. Among the previously untreated group, cell counts increased from 386 to 726 cells per millimeter cubed. CD4 cells are immune cells that are depleted as HIV infection progresses to advanced immune deficiency disease. Of 36 samples tested for HIV, only eight were positive after combination treatment, compared to 24 at the beginning of the study., Objective. Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy. Design. We conducted a phase I-Il study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/[m.sup.2] every 6 hours and doses of didanosine ranging from 90 to 180 mg/[m.sup.2] every 12 hours. Results. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/[m.sup.2] every 6 hours orally and didanosine ranging from 90 to 180 mg/[m.sup.2] every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/[mm.sup.3] (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/[mm.sup.3] (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to

Dideoxyinosine (ddI), like zidovudine (AZT), was designed to inhibit the replication of retroviruses such as the AIDS virus. Unfortunately, such drugs are not perfect; not only is the inhibition of the virus far from total, but normal physiological processes are also affected, causing potentially serious side effects. However, although dideoxyinosine is very effective against the human immunodeficiency virus (HIV) in tissue culture experiments, its side effects seem to be milder than those of zidovudine. In a study of 43 children with symptomatic HIV infection, ddI was shown to be beneficial and to have relatively low toxicity. Sixteen of the children had been previously treated with zidovudine; ddI was effective in these cases as well. The children showed an increase in the number of CD4 lymphocytes in the blood and a decrease in the amount of the p24 viral antigen. Six patients died during the course of the study and one patient was taken off the drug regimen as his disease progressed. In addition, one patient was removed from the study due to toxicity of the ddI. The major toxicity observed was inflammation of the pancreas, which had been observed previously in trials of ddI among adults. During the course of the study, the levels of ddI in the blood were monitored, and it was found that the patients with higher blood levels tended to do better than patients with lower levels. This suggests that individual differences in the absorption of the drug in the intestine, or individual differences in the elimination of the drug, may be important in determining the response of the patient. It may be that customizing dosage procedures to the individual patient may result in a greater degree of effectiveness when treating HIV infection with dideoxyinosine. (Consumer Summary produced by Reliance Medical Information, Inc.)