Bridging dolutegravir clinical viral response across doses and formulations using model-based exposure-response analysis in pediatrics.

OBJECTIVE: Dolutegravir (DTG) is a once-daily HIV-1 integrase inhibitor approved for the treatment of HIV-1 infection in adults and children from 4 weeks of age. The posology of DTG in children has been driven by exposure-matching relative to the adult dose for efficacy and safety. However, higher variability in pediatric exposures raises concern that efficacy may not be reliably extrapolated from adult trials. Therefore, we evaluated the relationship between DTG exposure and virologic response in children. DESIGN/METHODS: A population exposure-response analysis using logistic regression for virologic response was undertaken based on DTG exposure and covariate data from 146 pediatric participants with HIV-1 from age ≥4 weeks to <18 years treated for up to 48 weeks with DTG in IMPAACT P1093 study. RESULTS: None of the DTG exposure metrics were predictive of virologic response over the range of exposures in this analysis. Of the covariates tested, VL ≥100,000 copies/mL at enrolment was a significant predictor of virologic response showing a lower probability of achieving a virologic response of HIV-1 RNA <50 copies/mL compared to participants with VL <100,000 copies/mL at enrolment. Baseline VL was also a significant predictor at Week 48 whereby the probability of achieving a virologic response at Week 48 decreased with increasing baseline VL. CONCLUSIONS: This exposure-response analysis suggests that DTG exposures in children are all above the plateau of the exposure-response relationship. These results suggest that matching pediatric pharmacokinetic exposure parameters to those in adults is a reasonable approach for dose determination of DTG-containing formulations in pediatrics.

Impact of Genetic Variants in ABCG2 , NR1I2 , and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children.

BACKGROUND: Dolutegravir plasma concentrations and pharmacokinetic (PK) parameters in children display considerable variability. Here, the impact of genetic variants in ABCG2 421C>A (rs2231142), NR1I2 63396 C>T (rs2472677), and UGT1A1 (rs5839491) on dolutegravir PK was examined. METHODS: Children defined by age and administered dolutegravir formulation had AUC 24 at steady state, C max and C 24h determined. Associations between genetic variants and PK parameters were assessed using the dominant inheritance model. RESULTS: The 59 children studied had a median age of 4.6 years, log 10 plasma HIV RNA of 4.79 (copies/mm 3 ), and CD4 + lymphocyte count of 1041 cells/mm 3 ; 51% were female. For ABCG2 , participants with ≥1 minor allele had lower adjusted mean AUC difference (hr*mg/L) controlling for weight at entry, cohort and sex (-15.7, 95% CI: [-32.0 to 0.6], P = 0.06), and log 10 C max adjusted mean difference (-0.15, 95% CI: [-0.25 to -0.05], P = 0.003). Participants with ≥1 minor allele had higher adjusted mean AUC difference (11.9, 95% CI: [-1.1 to 25.0], P = 0.07). For UGT1A1 , poor metabolizers had nonsignificant higher concentrations (adjusted log 10 C max mean difference 11.8; 95% CI: [-12.3 to 36.0], P = 0.34) and lower mean log 10 adjusted oral clearance -0.13 L/h (95% CI: [-0.3 to 0.06], P = 0.16). No association was identified between time-averaged AUC differences by genotype for adverse events, plasma HIV RNA, or CD4 + cell counts. CONCLUSIONS: Dolutegravir AUC 24 for genetic variants in ABCG2 , NR1l2 , and UGT1A1 varied from -25% to +33%. These findings help to explain some of the variable pharmacokinetics identified with dolutegravir in children.

Prevalence and Correlates of Intimate Partner Violence Victimization Among Urban Adolescents and Young Adults Living With Perinatally-Acquired HIV Infection or Perinatal HIV Exposure.

INTRODUCTION: Because of privacy and ethical concerns, the data cannot be made available because of the sensitivity of the HIV data and the relatively small sample and ease of identifying people if a few demographics are known.Few studies have examined intimate partner violence (IPV) victimization among adolescents and young adults (AYAs) with perinatally acquired HIV-infection (PHIV) or perinatal HIV exposure without infection (PHEU) in the United States. The purpose of this study was to (1) estimate lifetime and past-year prevalence of IPV victimization and (2) examine correlates of IPV victimization by subtype (physical, psychological, and sexual) and severity (low, moderate, and severe). METHODS: Data came from the sixth interview of an ongoing New York City-based longitudinal study of primarily Black and Latinx AYAPHIV and AYAPHEU. We examined 232 participants (142 PHIV; 90 PHEU) who had reported having been in at least 1 romantic relationship. We used logistic regression models to explore the association between IPV victimization outcomes and select sociodemographic, psychiatric, and environmental factors. Models were adjusted for age, gender, race, ethnicity, and HIV status. RESULTS: IPV victimization prevalence was 84% for lifetime and 65% for the past year. There were no differences in IPV victimization prevalence by PHIV status. Having a recent substance use disorder, reporting higher levels of neighborhood stress, and being male were all positively associated with at least 1 IPV outcome; stronger familial relationships exhibited a protective effect. CONCLUSIONS: The present study suggests that the prevalence of IPV victimization among AYAPHIV and AYAPHEU is exceedingly high that warrants targeted IPV screening and programming for this population.

Identifying the Mental Health Effects of Cumulative Traumatic Exposure in HIV-Affected Youth: A Longitudinal Assessment.

INTRODUCTION: Traumatic events (TEs) in early life can precede adult psychopathology. Limited research exists on this relationship in young adults with perinatally acquired HIV-infection (PHIV) or perinatal HIV-exposure without infection (PHEU), who often experience social and health disparities. This study examined TEs experienced in childhood/adolescence and their association with psychiatric and substance use disorders in young adults with PHIV and PHEU. METHODS: Participants in a New York City-based longitudinal cohort study were assessed for TE exposure at enrollment (mean age = 12 years) and the first 2 follow-up interviews. Past-year psychiatric and substance use disorders were evaluated via psychiatric interview (DISC-IV) at the fifth follow-up interview (mean age = 22 years). Unadjusted and adjusted logistic regression models assessed associations between cumulative childhood/adolescence TEs and young adult psychiatric and substance use outcomes. Group differences were tested for PHIV and PHEU subgroups. RESULTS: Among 236 participants (60% Black, 51% Latinx), mean cumulative traumatic event count was 3.09 (SD = 1.77); 26% had a past-year psychiatric diagnosis, and 28% had a past-year substance use diagnosis. Increased TEs were associated with past-year psychiatric diagnoses in young adulthood [average marginal effects (AME) 4.21, 95% confidence interval (CI): 0.83 to 7.58]; for PHEU participants, increased TEs were associated with a past-year substance use disorder (AME 15.67, 95% CI: 8.08 to 23.25). CONCLUSIONS: High levels of TEs in childhood/adolescence may contribute to psychiatric and substance use disorders in young adults with PHIV or PHEU. Research exploring relationships between TE exposure and later psychiatric problems is needed to inform interventions for HIV-affected youth.

Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents.

BACKGROUND AND OBJECTIVE: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. METHODS: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. RESULTS: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. CONCLUSIONS: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization.

Risk Factors for Perinatal Transmission of Hepatitis C Virus.

OBJECTIVE: To estimate the rate of perinatal transmission of hepatitis C virus (HCV) infection, to identify risk factors for perinatal transmission of HCV infection, and to determine the viremic threshold for perinatal transmission. METHODS: This was a prospective, multicenter, observational study of pregnant individuals at less than 24 weeks of gestation screened for HCV infection from 2012 to 2018 in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Individuals found to be HCV antibody-positive were followed throughout pregnancy. Children were followed for evidence of perinatal transmission at 2-6 months (HCV RNA testing) and at 18-24 months (HCV RNA and antibody testing) of life. The primary outcome was perinatal transmission, defined as positive test results at either follow-up time point. RESULTS: A total of 109,379 individuals were screened for HCV infection. Of the 1,224 participants who screened positive, 772 (63.1%) enrolled and 432 of those 772 (56.0%) had data available to assess primary outcome. The overall rate of perinatal transmission was 6.0% (26/432, 95% CI 4.0-8.7%). All children with HCV infection were born to individuals with demonstrable viremia. In viremic participants (n=314), the perinatal transmission rate was 8.0% (95% CI 5.2-11.5%). Risk factors for perinatal transmission included HCV RNA greater than 106 international units/mL (adjusted odds ratio [aOR] 8.22, 95% CI 3.16-21.4) and vaginal bleeding reported at any time before delivery (aOR 3.26, 95% CI 1.32-8.03). A viremic threshold for perinatal transmission could not be established. CONCLUSION: Perinatal transmission of HCV infection was limited to viremic individuals. High viral loads and antepartum bleeding were associated with perinatal transmission.

Hope for the future protects against suicidal ideation among adolescents and young adults affected by perinatal HIV.

Hope for the future has been found protective against suicidal ideation (SI) in adolescents and young adults (AYA) yet has not been examined in AYA with perinatal HIV-infection (PHIV) or AYA who were perinatally HIV-exposed but uninfected (PHEU), who are at higher risk for SI than general populations. Using data from a New York City-based longitudinal study of AYAPHIV and AYAPHEU enrolled when 9-16 years old, we examined associations between hope for the future, psychiatric disorders, and SI over time using validated measures. Generalized estimating equations were used to estimate differences in mean hope for the future scores by PHIV-status and to estimate adjusted odds ratios for associations between hope for the future and SI. AYA reported high hope for the future scores and low SI across visits, irrespective of PHIV-status. Higher hope for the future scores were associated with lower odds of SI (AOR = 0.48, 95% CI: 0.23, 0.996). Mood disorder was associated with increased odds of SI (AOR = 13.57, 95% CI: 5.11, 36.05) in a model including age, sex, follow-up, PHIV-status, mood disorder, and hope for the future. Understanding how hope can be cultivated and how it protects against SI can help to inform preventive interventions for HIV-affected AYA.

Condomless Sex Among HIV-affected AYA in an Era of Undetectable = Untransmittable and Pre-exposure Prophylaxis.

Given poor adherence to treatment and prevention techniques, condomless sex jeopardizes adolescents and young adults (AYA) with perinatally-acquired HIV-infection (PHIV) or perinatal HIV-exposure who are uninfected (PHEU). We examined condomless sex and its association with PHIV-status, psychiatric disorder, and sociodemographics. Data come from a US-based study of primarily Black and Latinx AYAPHIV and AYAPHEU (N = 340). Linear regression models examined condomless sex longitudinally by PHIV-status, psychiatric trajectories, and sociodemographics. Rates of viremia (AYAPHIV) and PrEP use (AYAPHEU) were assessed. 56% of participants reported recent condomless sex, with higher prevalence among: AYAPHEU vs. AYAPHIV (24% vs. 19%, p = 0.017); Latinx vs. non-Latinx AYA (25% vs. 17%, p = 0.014); and AYA with increasing psychiatric comorbidity (44%) and consistent anxiety (23%) vs. low-level disorder (17%; p < 0.05). AYAPHIV had high rates of unsuppressed viral load and AYAPHEU limited PrEP use. Preventing condomless sex is challenging within AYAPHIV and AYAPHEU. Developing accessible combination HIV/mental health interventions is much-needed.

HIV and suicide risk across adolescence and young adulthood: an examination of socio-demographic, contextual and psychosocial risk factors for attempted suicide in a longitudinal cohort of ageing adolescents affected by HIV living in the New York City Area.

INTRODUCTION: As children become adolescents and young adults (AYA), their risk for attempting suicide increases dramatically, with chronic health conditions an important risk factor. This study examined correlates of suicidality across development in AYA living with perinatally acquired HIV (AYALPHIV) and those perinatally HIV-exposed but uninfected (AYAPHEU). METHODS: Data come from an ongoing longitudinal New York City-based study (N = 339) with AYALPHIV and AYAPHEU interviewed every 12-18 months from 2003 to 2019 (mean enrolment age = 12 years; current mean age = 27 years). The Diagnostic Interview Schedule for Children (adolescent or young adult version) assessed psychiatric disorders and first-reported suicide attempt. Generalized estimating equations were used to examine associations between first-reported suicide attempt and socio-demographic, contextual and psychosocial correlates measured concurrently across six timepoints. RESULTS: At enrolment, 51% of participants were female, 72% heterosexual, 60% Black and 50% Latinx. Attempted suicide was significantly higher among AYALPHIV (27%, CI 21-33%) compared to AYAPHEU (16%, CI 10-22%), with an OR of 1.74 (CI 1.04-2.92) in a model adjusting for age. For AYALPHIV, anxiety (OR 2.66, CI 1.46-4.85), mood (OR 3.62, CI 1.49-8.81) and behaviour disorders (OR 5.05, CI 2.15-11.87) and past-year arrest (OR 3.05, CI 1.26-7.4), negative life events (OR 1.27, CI 1.11-1.46), city stress (OR 2.28, CI 1.46-3.57), pregnancy (OR 2.28, CI 1.08-4.81) and HIV stigma (OR 2.46, CI 1.27-4.75) were associated with increased odds of attempted suicide, while identifying as heterosexual (OR 0.27, CI 0.14-0.52), higher personal (OR 0.45, CI 0.26-0.80) and family self-concept (OR 0.36, CI 0.22-0.57) were protective. Interactions by HIV status and age were found: substance use was more strongly associated with attempted suicide among AYAPHEU than AYALPHIV, while negative life events and higher religiosity were more strongly associated with increased odds of attempted suicide among AYA ≥ 19 versus ≤ 18 years. CONCLUSIONS: AYALPHIV compared to AYAPHEU faced unique risks for attempted suicide as they age into adulthood, with the highest risk among AYALPHIV experiencing HIV stigma or pregnancy and the highest risk among AYAPHEU with substance use. Assessing for suicide risk and correlates with attention to ageing can inform preventive interventions tailored to meet AYALPHIV and AYAPHEU needs.

Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial.

BACKGROUND: Safe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing. FINDINGS: We recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir. INTERPRETATION: In this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline.

Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study.

P1093 is a multicenter, open-label, phase I/II study of pharmacokinetics, safety, and tolerability of dolutegravir plus an optimized background regimen in pediatric participants aged 4 weeks to <18 years with HIV-1. Most participants were highly treatment experienced. We report the mechanisms of emergent integrase strand transfer inhibitor (INSTI) resistance among adolescents and children receiving dolutegravir. Plasma was collected at screening and near protocol-defined virologic failure (PDVF) for population-level and, for some samples, clonal-level integrase genotyping, phenotyping, and replication capacity. HIV-1 RNA was assessed in all available plasma samples. Phylogenetic analysis of clonal integrase sequences and homology modeling of HIV-1 intasome complexes containing resistance-associated substitutions were performed. Treatment-emergent INSTI resistance was detected in 8 participants who met PDVF criteria. The rare INSTI resistance-associated substitution G118R or R263K developed in 6 participants. The on-study secondary integrase substitution E157Q or L74I was observed in 2 participants. G118R reduced dolutegravir susceptibility and integrase replication capacity more than R263K and demonstrated greater reduction in susceptibility and integrase replication capacity when present with specific secondary integrase substitutions, including L74M, T66I, and E138E/K. Continuing evolution after R263K acquisition led to reduced dolutegravir susceptibility and integrase replication capacity. Structural examination revealed potential mechanisms for G118R- and R263K-mediated INSTI resistance. G118R and R263K INSTI resistance substitutions, which are distinct to second-generation INSTIs, were detected in adolescents and children with prior virologic failure who received dolutegravir. This study provides additional molecular and structural characterization of integrase to aid in the understanding of INSTI resistance mechanisms in antiretroviral-experienced populations. (This study has been registered at ClinicalTrials.gov under identifier NCT01302847.).

Abacavir dosing in neonates from birth to 3 months of life: a population pharmacokinetic modelling and simulation study.

BACKGROUND: No evidence-based optimal dosing guidance is available for abacavir liquid formulation use from birth. We used abacavir pharmacokinetic data from neonates and infants to determine an exact abacavir dosing strategy (mg/kg) for infants aged 0-3 months and to propose dosing by WHO weight band for neonates. METHODS: Abacavir pharmacokinetic and safety data were pooled from three completed studies (1997-2020): PACTG 321 (USA), the Tygerberg Cohort (South Africa), and IMPAACT P1106 (South Africa). PACTG 321 and the Tygerberg Cohort were performed in neonates exposed to HIV receiving a single dose of abacavir. IMPAACT P1106 included predominantly low birthweight (<2500 g) infants on antiretroviral therapy enrolled when they were younger than 3 months. We developed a population pharmacokinetic model and performed simulations to achieve abacavir exposures (area under the curve for 0-12 h) within the target range of 3·2-25·2 µg·h/mL, previously reported in older children. FINDINGS: 45 infants contributed 308 abacavir concentrations; 21 neonates were younger than 15 days. At first pharmacokinetic assessment, median postnatal age for PACTG 321 was 1 day and median bodyweight was 3·1 kg; for the Tygerberg Cohort it was 10 days and 3·3 kg; and for IMPAACT P1106 it was 73 days and 3·8 kg. Our model predicted a slow abacavir clearance of 2·51 mL/min per kg at birth, which doubled by 4 weeks of age. Therapeutic targets were achieved with exact abacavir doses of 2·0 mg/kg twice daily from 0 weeks to 4 weeks and 4·0 mg/kg twice daily from 4 weeks to 12 weeks. A fixed weight-band dosing strategy of 8 mg (for 2-3 kg), 10 mg (3-4 kg), and 12 mg (4-5 kg) abacavir twice daily achieved target exposures throughout the first 4 weeks of life without the need for dose adjustment due to age or bodyweight changes. No adverse events of grade 3 or higher were related to abacavir. INTERPRETATION: Integration of these dosing strategies into national and international guidelines for the abacavir liquid formulation will expand antiretroviral options from birth and simplify the clinical management of neonates with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, and the Collaborative Initiative for Paediatric HIV Education and Research Programme.

Predictors of Attempted Suicide Among Youth Living With Perinatal HIV Infection and Perinatal HIV-Exposed Uninfected Counterparts.

BACKGROUND: Suicide is a leading cause of death among adolescents and young adults (AYA). AYA living with perinatally acquired HIV infection (AYALPHIV) are at higher risk of attempted suicide when compared with AYA who were perinatally HIV-exposed but uninfected (AYAPHEU). To inform interventions, we identified risk and protective factors of attempted suicide among AYALPHIV and AYAPHEU. SETTING: Data were obtained from a longitudinal New York City-based study of AYALPHIV and AYAPHEU (n = 339; enrollment age 9-16 years) interviewed approximately every 12-18 months. METHOD: Our main outcome was suicide attempt at any follow-up. The DISC was used to assess psychiatric disorder diagnoses and attempted suicide and the Child Depression Inventory to assess depressive symptoms. Psychosocial and sociodemographic risk factors were also measured. Analyses used backward stepwise logistic regression modeling. RESULTS: At enrollment, 51% was female individuals, 49% Black, 40% Latinx, and 11% both Black and Latinx. Attempted suicide prevalence was significantly higher among AYALPHIV compared with AYAPHEU (27% vs 16%, P = 0.019), with AYALPHIV having 2.21 times the odds of making an attempt [95% confidence interval: (1.18 to 4.12), P = 0.013]. Higher Child Depression Inventory scores were associated with an increased risk of attempted suicide in both groups and the total sample. The presence of DISC-defined behavior disorder increased the risk of attempted suicide in the total sample and the AYALPHIV subgroup. Religiosity was protective of attempted suicide in AYALPHIV. CONCLUSIONS: AYALPHIV had increased suicide attempts compared with AYAPHEU. Religiosity was protective in AYALPHIV. Highlighting a need for prevention of early mental health challenges was associated with risk.

Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age. DESIGN: Phase I/II, open-label, multicenter, dose-finding study. METHODS: Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics. RESULTS: Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12  h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12  h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued. CONCLUSION: ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.

A randomized trial of subcutaneous allergy immunotherapy in inner-city children with asthma less than 4 years of age.

BACKGROUND: Allergic sensitization to environmental allergens in the first years of life is a strong predictor of asthma morbidity in children. Allergy immunotherapy can improve asthma and allergy outcomes, but its efficacy in inner-city, atopic children of less than 4 years of age with recurrent wheezing has not yet been established. OBJECTIVE: To determine whether subcutaneous allergy immunotherapy improves asthma in a population of US inner-city children when started at less than 4 years of age. METHODS: In a randomized controlled, open-label phase I-II single-center trial in the Bronx, New York, 58 children with recurrent wheezing or physician-diagnosed asthma were randomized to receive asthma standard of care treatment with or without a 3-year course of multiple allergen subcutaneous immunotherapy. RESULTS: A total of 23 children in the control group and 27 children in the immunotherapy group began the study. A total of 20 of 27 children commencing immunotherapy completed at least 2 years of immunotherapy. There was no difference in asthma medication and symptom scores between the treatment or control groups over time. Similarly, naso-ocular symptoms and allergy medication use were similar in both groups over time. Nevertheless, asthma-related quality of life improved in the immunotherapy group compared with the control group (P = .03). CONCLUSION: With the exception of asthma-related quality of life, allergy immunotherapy was ineffective in improving asthma outcomes in this population of inner-city children of less than 4 years of age. These findings suggest that the effects of allergy immunotherapy depend on population-specific factors and highlight the importance of precise predictors of immunotherapy efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01028560.

Restriction Factor Expression in Vertically Infected Children Living With HIV-1.

INTRODUCTION: Around 1.7 million children are estimated to live with HIV-1 worldwide, and about 160,000 infants are newly infected every year. Since adaptive immunity takes time to mature and develop in infants, and maternal antibodies provide limited antiviral activity, innate and intrinsic immunity against HIV-1 in the young is of critical importance. Intrinsic restriction factors are cellular proteins that effectively inhibit HIV-1 replication in vitro, but there is limited understanding of their role in vivo, and little to no data has been reported on the expression of host restriction factors in children. We hypothesized that restriction factor expression might be particularly important in children living with HIV-1 and correlate with disease progression. METHODS: We analyzed gene expression of APOBEC3A, APOBEC3C, APOBEC3G, APOBEC3H, SAMHD1, ISG15, CDKN1A, MX2, TRIM5, and SLFN11 by qPCR in 121 samples of CD4+ T cells from vertically infected children living with HIV-1. Cell surface expression of BST-2/tetherin and markers of CD4+ T-cell activation were analyzed by flow cytometry. RESULTS: After adjusting for gender and age, BST-2/tetherin expression on CD4+ T cells showed significant positive correlation with viral load (P = 0.0006; ρ = 0.33), CD4+ T-cell activation (P < 0.0001; ρ = 0.53), CD8+ T-cell activation (P < 0.0001; ρ = 0.53), and a negative correlation with CD4+ T-cell counts (P = 0.0008; ρ = -0.33). The expression of SAMHD1 correlated negatively with markers of T-cell activation (P = 0.046; ρ = -0.22). DISCUSSION: These results suggest an important role of some restriction factors in the pathogenesis of HIV-1 in children.

Psychiatric trajectories across adolescence in perinatally HIV-exposed youth: the role of HIV infection and associations with viral load.

OBJECTIVE: Identify factors associated with trajectories of psychiatric disorder among 340 adolescents and young adults (AYA) living with perinatal HIV infection (PHIV) and perinatal HIV-exposure but not infection (PHEU). DESIGN: Longitudinal cohort study of AYA in New York City, 9-16 years at enrollment. METHODS: We used multivariate longitudinal latent class analysis to identify trajectories of psychiatric disorder, and logistic regression to examine predictors of trajectories (e.g. PHIV status) and associations between trajectories and viremia in young adulthood (AYA with PHIV only). RESULTS: Among all AYA, we identified three psychiatric trajectories: relatively 'low disorder' (63%), 'consistent anxiety' (26%), and 'escalating comorbidity' (11%). Compared with AYA with 'low disorder', AYA with 'escalating comorbidity' were significantly older, reported more neighborhood stress, and lived with a caregiver with alcohol use disorder, whereas AYA with 'consistent anxiety' were more likely female individuals. Although we found no statistically significant HIV status differences, among AYA with PHIV, nearly half (48%) were viremic in young adulthood, with higher odds of viremia among AYA with 'escalating comorbidity' (OR: 3.88, 95% CI: 0.93-16.26) and 'consistent anxiety' (OR: 2.41, 95% CI: 1.011-5.75) compared with 'low disorder'. CONCLUSION: Despite significant adversity, AYA with PHIV and PHEU had relatively low prevalence of psychiatric disorder over time, although one-third had consistent or escalating psychiatric disorders. Among AYA with PHIV, psychiatric trajectories were associated with viremia in young adulthood. Given the growing population of AYA living with PHIV and PHEU worldwide, addressing the substantial and evolving mental health needs of both groups as they reach young adulthood is critical.

Live-Attenuated Respiratory Syncytial Virus Vaccine With M2-2 Deletion and With Small Hydrophobic Noncoding Region Is Highly Immunogenic in Children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1. METHODS: RSV-seronegative children aged 6-24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. RESULTS: All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. CONCLUSIONS: D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. CLINICAL TRIALS REGISTRATION: NCT03102034 and NCT03099291.

Psychiatric disorders and young adult milestones in HIV-exposed, uninfected youth.

The global population of perinatally HIV-exposed but uninfected (HEU) children is growing, with relatively little known about their psychosocial outcomes, particularly across adolescence and young adulthood. Using data from a longitudinal cohort study of HEU youth in New York City (N = 134), we examine rates of substance use disorders (SUD) and non-SUD psychiatric disorders (mood, anxiety, and behavioral) at five time-points during adolescence and young adulthood, as well as associated demographic and environmental factors and the association of ever having a disorder with young adult developmental milestones. HEU participants in this study experienced high rates of psychiatric disorders, particularly SUD in young adulthood. During the entire study period (2003-2018), over one third were diagnosed at least once with a SUD, and 69% were diagnosed with a non-SUD psychiatric disorder. Older age and female gender were associated with higher rates of non-SUD diagnoses. A history of meeting criteria for any disorder at any time point was associated with reduced odds in young adulthood of working or being in school and increased odds of reporting incarceration, homelessness, and recent condomless sex. There is an urgent need to develop systems to follow HEU youth and provide services to intervene and treat psychiatric disorders, including substance use.

Preliminary Validation of an Unannounced Telephone Pill Count Protocol to Measure Medication Adherence Among Young Adults With Perinatal HIV Infection.

Unannounced telephone pill counts are an objective antiretroviral therapy adherence measurement tool, but this method has not been validated in young adults (YA) living with perinatal HIV infection. Perinatally infected YA, recruited from the Child and Adolescent Self-Awareness and Health Study, agreed to unannounced telephone pill counts to measure medication adherence over 4 months and phlebotomy to measure viral load (VL). Differences in pill count adherence scores among YA with a VL of ≤20 versus >20, and demographic differences were assessed. Participants (N = 62) were, on average, 24 years old; 57% were African American, and 40% were Latino. Participants with VL of ≤20 (60%) had significantly higher adherence scores (85% versus 62%; p = .004). Associations were not significant among older YA (range, 25-28 years) or Latinos. Unannounced telephone pill counts are a valid measure of antiretroviral therapy adherence in YA with perinatal HIV infection. Studies with larger samples are needed.