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.

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.

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.).

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.

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.

Live Respiratory Syncytial Virus Attenuated by M2-2 Deletion and Stabilized Temperature Sensitivity Mutation 1030s Is a Promising Vaccine Candidate in Children.

BACKGROUND: The safety and immunogenicity of live respiratory syncytial virus (RSV) candidate vaccine, LID/ΔM2-2/1030s, with deletion of RSV ribonucleic acid synthesis regulatory protein M2-2 and genetically stabilized temperature-sensitivity mutation 1030s in the RSV polymerase protein was evaluated in RSV-seronegative children. METHODS: Respiratory syncytial virus-seronegative children ages 6-24 months received 1 intranasal dose of 105 plaque-forming units (PFU) of LID/ΔM2-2/1030s (n = 21) or placebo (n = 11). The RSV serum antibodies, vaccine shedding, and reactogenicity were assessed. During the following RSV season, medically attended acute respiratory illness (MAARI) and pre- and postsurveillance serum antibody titers were monitored. RESULTS: Eighty-five percent of vaccinees shed LID/ΔM2-2/1030s vaccine (median peak nasal wash titers: 3.1 log10 PFU/mL by immunoplaque assay; 5.1 log10 copies/mL by reverse-transcription quantitative polymerase chain reaction) and had ≥4-fold rise in serum-neutralizing antibodies. Respiratory symptoms and fever were common (60% vaccinees and 27% placebo recipients). One vaccinee had grade 2 wheezing with rhinovirus but without concurrent LID/ΔM2-2/1030s shedding. Five of 19 vaccinees had ≥4-fold increases in antibody titers postsurveillance without RSV-MAARI, indicating anamnestic responses without significant illness after infection with community-acquired RSV. CONCLUSIONS: LID/ΔM2-2/1030s had excellent infectivity without evidence of genetic instability, induced durable immunity, and primed for anamnestic antibody responses, making it an attractive candidate for further evaluation.

Safety, Tolerability, and Pharmacokinetics of the Broadly Neutralizing Human Immunodeficiency Virus (HIV)-1 Monoclonal Antibody VRC01 in HIV-Exposed Newborn Infants.

BACKGROUND: Although mother-to-child human immunodeficiency virus (HIV) transmission has dramatically decreased with maternal antiretroviral therapy, breast milk transmission accounts for most of the 180 000 new infant HIV infections annually. Broadly neutralizing antibodies (bNAb) may further reduce transmission. METHODS: A Phase 1 safety and pharmacokinetic study was conducted: a single subcutaneous (SC) dose of 20 or 40 mg/kg (Dose Groups 1 and 2, respectively) of the bNAb VRC01 was administered to HIV-exposed infants soon after birth. Breastfeeding infants (Dose Group 3) received 40 mg/kg SC VRC01 after birth and then 20 mg/kg/dose SC monthly. All infants received appropriate antiretroviral prophylaxis. RESULTS: Forty infants were enrolled (21 in the United States, 19 in Africa). Subcutaneous VRC01 was safe and well tolerated with only mild-to-moderate local reactions, primarily erythema, which rapidly resolved. For multiple-dose infants, local reactions decreased with subsequent injections. VRC01 was rapidly absorbed after administration, with peak concentrations 1-6 days postdose. The 40 mg/kg dose resulted in 13 of 14 infants achieving the serum 50 micrograms (mcg)/mL target at day 28. Dose Group 3 infants maintained concentrations greater than 50 mcg/mL throughout breastfeeding. CONCLUSIONS: Subcutaneous VRC01 as single or multiple doses is safe and well tolerated in very young infants and is suitable for further study to prevent HIV transmission in infants.

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.

Patterns and Correlates of Serostatus Disclosure to Sexual Partners by Perinatally-Infected Adolescents and Young Adults.

Similar to same-age peers, perinatally HIV-infected (PHIV+) youth in the US are engaging in sex, including condomless sex. Understanding decisions about serostatus disclosure to sexual partners is important to domestic and global HIV prevention efforts, since large numbers of PHIV+ children are entering adolescence and becoming sexually active. Using Social Action Theory (SAT) to inform variable selection, we examined correlates of disclosure among 98 PHIV+ adolescents/young adults in New York City. Over half of these youth reported not disclosing to any casual partners (59 %) or to any partners when using condoms (55 %). In bivariate analyses, increased disclosure was associated with older age; being female; earlier age of learning one's serostatus; and increased STD knowledge, disclosure intentions, and parent-child communication. Multiple regression analyses revealed a strong fit with the SAT model. As with adults, disclosure to sexual partners is difficult for PHIV+ youth and challenges prevention efforts. Effective interventions that help youth with disclosure decisions are needed to curb the epidemic.

Antiretroviral Drug Resistance Among Children and Youth in the United States With Perinatal HIV.

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

Prevalence and Persistence of Varicella Antibodies in Previously Immunized Children and Youth With Perinatal HIV-1 Infection.

BACKGROUND: Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. METHODS: The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. RESULTS: Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at <3 years (both), 73% and 100% at 3-<7 years (P < .05), and 77% and 97% at ≥ 7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥ 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated ≥ 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02). CONCLUSIONS: Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥ 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use.

Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 years.

BACKGROUND: IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)-infected youth. METHODS: Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥ 3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥ 1 log10 reduction between baseline and week 24. RESULTS: The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%). CONCLUSIONS: Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥ 25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses. CLINICAL TRIALS REGISTRATION: NCT00485264.

T cells target APOBEC3 proteins in human immunodeficiency virus type 1-infected humans and simian immunodeficiency virus-infected Indian rhesus macaques.

APOBEC3 proteins mediate potent antiretroviral activity by hypermutating the retroviral genome during reverse transcription. To counteract APOBEC3 and gain a replicative advantage, lentiviruses such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) have evolved the Vif protein, which targets APOBEC3 proteins for proteasomal degradation. However, the proteasome plays a critical role in the generation of T cell peptide epitopes. Whether Vif-mediated destruction of APOBEC3 proteins leads to the generation and presentation of APOBEC3-derived T cell epitopes on the surfaces of lentivirus-infected cells remains unknown. Here, using peptides derived from multiple Vif-sensitive APOBEC3 proteins, we identified APOBEC3-specific T cell responses in both HIV-1-infected patients and SIV-infected rhesus macaques. These results raise the possibility that these T cell responses may be part of the larger antiretroviral immune response.

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.

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 at least 4 weeks to less than 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, viral load at least 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 less than 50 copies/ml compared with participants with viral load less than 100 000 copies/ml at enrolment. Baseline viral load was also a significant predictor at week 48 whereby the probability of achieving a virologic response at week 48 decreased with increasing baseline viral load. CONCLUSION: 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.

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.

Prevalence of detectable HIV-DNA and -RNA in cerebrospinal fluid of youth with perinatal HIV and impaired cognition on antiretroviral therapy.

OBJECTIVE: Central nervous system (CNS) HIV infection can impact cognition and may be an obstacle to cure in adolescents and young adults with perinatal HIV (AYAPHIV). IMPAACT2015 enrolled AYAPHIV on suppressive antiretroviral therapy (ART) with cognitive impairment to detect and quantify HIV in blood and cerebrospinal fluid (CSF). DESIGN: IMPAACT2015 was a U.S.-based multi-site, exploratory, observational study. METHODS: Cognitive impairment was defined as NIH Toolbox Fluid Cognition Composite score (FCCS) > 1 standard deviation below age-adjusted normative group mean. Cell-free HIV-RNA and cell-associated HIV pol/gag -DNA and 10 biomarkers of inflammation/neuronal injury were measured in paired CSF and blood. ART exposure concentrations were quantified in hair. RESULTS: Among 24 participants, 20 had successful CSF collection and 18 also met viral suppression criteria. 9/18 (50%) were female sex-at-birth, 14/18 (78%) were Black. Median (range) age was 20 years (13-27), time on ART 18.3 years (8.0-25.5), and FCCS 68 (53-80). HIV-DNA was detected in PBMCs from all participants. In CSF, 2/18 (11%, 95% CI: 1.4-34.7%) participants had detectable cell-free HIV-RNA, while HIV gag or pol -DNA was detectable in 13/18 (72%, 95% CI: 47-90%). Detectable HIV-DNA in CSF was associated with male sex-at-birth (p = 0.051), lower CD4 count at enrollment (p = 0.016), and higher PBMC HIV pol -DNA copies (p = 0.058). Hair antiretroviral concentrations and biomarkers were not associated with CSF HIV-DNA detection. CONCLUSIONS: We found a high proportion of AYAPHIV with neurocognitive impairment had CSF cells harboring HIV-DNA during long-term virologic suppression. This evidence of persistent HIV-DNA in CSF suggests that the CNS should be considered in treatment and cure studies.

Discordance between aeroallergen specific serum IgE and skin testing in children younger than 4 years.

BACKGROUND: Atopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze. OBJECTIVE: To assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years. METHODS: Concordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36 [9] months) with recurrent wheezing and family history of asthma and/or eczema. RESULTS: In 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = -0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02). CONCLUSION: Our study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01028560.

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.