Pharmacokinetics and Safety of Remdesivir in Pregnant and Non-Pregnant Women with COVID-19: Results from IMPAACT 2032.

BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.

Breastfeeding in the United States Among Women With HIV: Con Viewpoint.

To breast feed or not has long been a difficult question for women with human immunodeficiency virus (HIV) in high-income countries, as undetectable HIV in maternal plasma does not translate to zero risk of transmission while breastfeeding, and clean water and formula are readily available. Recent, and more permissive, changes in US and other high-income-country guidelines regarding breastfeeding underscore this issue and acknowledge the information gaps that are essential for informed maternal choice and provider management. These include lack of guidance as to routine monitoring of mothers during lactation, type and length of prophylaxis for infants, and lack of data on factors associated with increased breast-milk viral load and risk of transmission. Ancillary to data are the education and staffing needs for providers participating in the management of breastfeeding individuals. Future studies of breast-milk transmission will need to evaluate these gaps so that we can move transmission to zero.

Are Family Factors Differentially Associated with Externalizing Symptoms Among Youth with Perinatally Acquired HIV?

Youth with perinatally-acquired HIV (PHIV) face unique psychosocial stressors. They are at risk for externalizing problems, including symptoms of oppositional defiant disorder, conduct disorder (CD), and attention-deficit/hyperactivity disorder (ADHD), as well as risk-taking behaviors, such as substance use (SU). Although family factors have been differentially associated with externalizing and SU behaviors based on youth sex in prior research, there is a dearth of literature considering these processes among youth with PHIV. Participants included 314 youth with PHIV (M = 12.88 years, SD = 3.08 years; 50.80% male; 85.30% Black or Latinx). Boys exhibited higher levels of ADHD symptoms than girls. Among boys, lower levels of consistency in discipline were associated with higher CD symptoms. Lower levels of family cohesion were associated with higher levels of SU among girls, and higher levels of CD symptoms across youth sex. Findings support the need for family-focused behavioral interventions among youth with PHIV.

Antibiotic use among admitted pediatric patients in the United States with status asthmaticus before and during the COVID-19 pandemic.

OBJECTIVE: Hospital admission trends of children with status asthmaticus diminished during the Coronavirus-19 (COVID-19) pandemic of 2020, possibly secondary to several factors such as school closures and use of face masks. What effect this had on antibiotic prescribing practices has yet to be described. The objective of our study was to evaluate the use of antibiotics in hospitalized children with a diagnosis of status asthmaticus before and during the COVID pandemic.Methods: A retrospective cross-sectional analysis was conducted using the TriNetX® cloud-based program with a national and institutional database. Each database was queried for all inpatient pediatric encounters from 3 to 18 years old, admitted with a diagnosis of status asthmaticus in the spring seasons of 2017-2019. Admission data and antibiotic usage were queried during the COVID-19 pandemic year of 2020 from both databases and compared amongst all study years.Results: In 2020, there was an overall decrease in the number of admissions as compared to the average number from 2017-2019, by 76.9% in the national database (p < 0.05) and 91.2% in the institutional database. The rates of antibiotic prescriptions significantly dropped among the national database (p < 0.001, z = 3.39) and remained non-significantly changed among the institutional database (p = 0.944 and z = 0.073).Conclusions: Our study demonstrates that the COVID-19 pandemic year of 2020 coincided with a significant decrease in hospital admissions and antibiotic prescribing prevalence among children with status asthmaticus on a national level. Nonetheless, our reported trends in antibiotic prescribing are still grossly similar to that of pre-pandemic times and may demonstrate a continued need for antimicrobial stewardship.

Exploring the value of Mycobacterium tuberculosis modified lipoprotein as a potential biomarker for TB detection in children.

BACKGROUND: Current TB diagnostic methods available have been developed for adults and development efforts have neglected the differences in disease and sampling that occur between adults and children. Diagnostic challenges are even greater in HIV co-infected children and infants. METHODS AND RESULTS: We established a sandwich ELISA assay to detect Mycobacterium tuberculosis modified lipoprotein (TLP) ex vivo in plasma. The study population contains plasma samples from 21 patients with active TB and 24 control samples with no TB, collected in the International Maternal Pediatric Adolescent AIDS Clinical Trails (IMPAACT) P1041 study. Retrospective analysis was performed and the results demonstrate that the median plasma levels of TLP in control subjects are 2.7 fold higher than the median plasma values in active TB subjects (p < 0.001). CONCLUSIONS: Plasma levels of TLP are elevated with active TB disease in HIV positive subjects and deserves further exploration as an indicator for TB detection in children.

Warp Speed for Coronavirus Disease 2019 (COVID-19) Vaccines: Why Are Children Stuck in Neutral?

While adult clinical trials of coronavirus disease 2019 (COVID-19) vaccines have moved quickly into phase 3 clinical trials, clinical trials have not started in children in the United States. The direct COVID-19 impact upon children is greater than that observed for a number of other pathogens for which we now have effective pediatric vaccines. Additionally, the role of children in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has clearly been underappreciated. Carefully conducted phase 2 clinical trials can adequately address potential COVID-19 vaccine safety concerns. Delaying phase 2 vaccine clinical trials in children will delay our recovery from COVID-19 and unnecessarily prolong its impact upon children's education, health, and emotional well-being, and equitable access to opportunities for development and social success. Given the potential direct and indirect benefits of pediatric vaccination, implementation of phase 2 clinical trials for COVID-19 vaccines should begin now.

Coronavirus Disease 2019 (COVID-19) Pharmacologic Treatments for Children: Research Priorities and Approach to Pediatric Studies.

Clinical trials of pharmacologic treatments of coronavirus disease 2019 (COVID-19) are being rapidly designed and implemented in adults. Children are often not considered during development of novel treatments for infectious diseases until very late. Although children appear to have a lower risk compared with adults of severe COVID-19 disease, a substantial number of children globally will benefit from pharmacologic treatments. It will be reasonable to extrapolate efficacy of most treatments from adult trials to children. Pediatric trials should focus on characterizing a treatment's pharmacokinetics, optimal dose, and safety across the age spectrum. These trials should use an adaptive design to efficiently add or remove arms in what will be a rapidly evolving treatment landscape, and should involve a large number of sites across the globe in a collaborative effort to facilitate efficient implementation. All stakeholders must commit to equitable access to any effective, safe treatment for children everywhere.

Evaluation of a serum-based antigen test for tuberculosis in HIV-exposed infants: a diagnostic accuracy study.

BACKGROUND: Non-sputum methods are urgently needed to improve tuberculosis diagnosis and treatment monitoring in children. This study evaluated the ability of a serum assay quantifying a species-specific peptide of the Mycobacterium tuberculosis CFP-10 virulence factor via nanotechnology and matrix-assisted laser desorption ionization time-of-flight mass spectrometry to diagnose tuberculosis in HIV-infected and HIV-uninfected infants. METHODS: Serum CFP-10 peptide signal was blinded evaluated in cryopreserved sera of 519 BCG-immunized, HIV-exposed infants (284 HIV-infected, 235 HIV-uninfected) from a multi-center randomized placebo-controlled isoniazid prophylaxis trial conducted in southern Africa between 2004 and 2008, who were followed up to 192 weeks for Mtb infection and TB. Children were classified as confirmed, unconfirmed, or unlikely tuberculosis cases using 2015 NIH diagnostic criteria for pediatric TB. RESULTS: In HIV-infected infants, CFP-10 signal had 100% sensitivity for confirmed TB (5/5, 95% CI, 47.8-100) and 83.7% sensitivity for unconfirmed TB (36/43, 95% CI 69.3-93.2), with 93.1% specificity (203/218, 95% CI 88.9-96.1). In HIV-uninfected infants, CFP-10 signal detected the single confirmed TB case and 75.0% of unconfirmed TB cases (15/20; 95% CI 50.9-91.3), with 96.2% specificity (177/184, 95% CI, 92.3-98.5). Serum CFP-10 achieved 77% diagnostic sensitivity for confirmed and unconfirmed TB (13/17, 95% CI, 50-93%) at ≤ 24 weeks pre-diagnosis, and both CFP-10-positivity and concentration declined following anti-TB therapy initiation. CONCLUSIONS: Serum CFP-10 signal exhibited high diagnostic sensitivity and specificity for tuberculosis in HIV-infected and HIV-uninfected infants and potential utility for early TB detection and monitoring of anti-TB treatment responses.

Severe Acute Respiratory Syndrome Coronavirus 2 Convalescent Plasma Versus Standard Plasma in Coronavirus Disease 2019 Infected Hospitalized Patients in New York: A Double-Blind Randomized Trial.

OBJECTIVES: Four peer-reviewed publications have reported results from randomized controlled trials of convalescent plasma for coronavirus disease 2019 infection; none were conducted in the United States nor used standard plasma as a comparator. To determine if administration of convalescent plasma to patients with coronavirus disease 2019 increases antibodies to severe acute respiratory syndrome coronavirus 2 and improves outcome. DESIGN: Double-blind randomized controlled trial. SETTING: Hospital in New York. PATIENTS: Patients with polymerase chain reaction documented coronavirus disease 2019 infection. INTERVENTIONS: Patients were randomized (4:1) to receive 2 U of convalescent plasma versus standard plasma. Antibodies to severe acute respiratory syndrome coronavirus 2 were measured in plasma units and in trial recipients. MEASUREMENTS AND MAIN RESULTS: Enrollment was terminated after emergency use authorization was granted for convalescent plasma. Seventy-four patients were randomized. At baseline, mean (sd) Acute Physiology and Chronic Health Evaluation II score (23.4 [5.6] and 22.5 [6.6]), percent of patients intubated (19% and 20%), and median (interquartile range) days from symptom onset to randomization of 9 (6-18) and 9 (6-15), were similar in the convalescent plasma versus standard plasma arms, respectively. Convalescent plasma had high neutralizing activity (median [interquartile range] titer 1:526 [1:359-1:786]) and its administration increased antibodies to severe acute respiratory syndrome coronavirus 2 by 14.4%, whereas standard plasma administration led to an 8.6% decrease (p = 0.005). No difference was observed for ventilator-free days through 28 days (primary study endpoint): median (interquartile range) of 28 (2-28) versus 28 (0-28; p = 0.86) for the convalescent plasma and standard plasma groups, respectively. A greater than or equal to 2 point improvement in the World Health Organization scale was achieved by 20% of subjects in both arms (p = 0.99). All-cause mortality through 90 days was numerically lower in the convalescent plasma versus standard plasma groups (27% vs 33%; p = 0.63) but did not achieve statistical significance. A key prespecified subgroup analysis of time to death in patients who were intubated at baseline was statistically significant; however, sample size numbers were small. CONCLUSIONS: Administration of convalescent plasma to hospitalized patients with coronavirus disease 2019 infection increased antibodies to severe acute respiratory syndrome coronavirus disease 2 but was not associated with improved outcome.

Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth.

OBJECTIVE: To characterize the demographic and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes and identify admission variables predictive of disease severity. STUDY DESIGN: We conducted a multicenter, retrospective, and prospective study of pediatric patients hospitalized with acute SARS-CoV-2 infections and multisystem inflammatory syndrome in children (MIS-C) at 8 sites in New York, New Jersey, and Connecticut. RESULTS: We identified 281 hospitalized patients with SARS-CoV-2 infections and divided them into 3 groups based on clinical features. Overall, 143 (51%) had respiratory disease, 69 (25%) had MIS-C, and 69 (25%) had other manifestations including gastrointestinal illness or fever. Patients with MIS-C were more likely to identify as non-Hispanic black compared with patients with respiratory disease (35% vs 18%, P = .02). Seven patients (2%) died and 114 (41%) were admitted to the intensive care unit. In multivariable analyses, obesity (OR 3.39, 95% CI 1.26-9.10, P = .02) and hypoxia on admission (OR 4.01; 95% CI 1.14-14.15; P = .03) were predictive of severe respiratory disease. Lower absolute lymphocyte count (OR 8.33 per unit decrease in 109 cells/L, 95% CI 2.32-33.33, P = .001) and greater C-reactive protein (OR 1.06 per unit increase in mg/dL, 95% CI 1.01-1.12, P = .017) were predictive of severe MIS-C. Race/ethnicity or socioeconomic status were not predictive of disease severity. CONCLUSIONS: We identified variables at the time of hospitalization that may help predict the development of severe SARS-CoV-2 disease manifestations in children and youth. These variables may have implications for future prognostic tools that inform hospital admission and clinical management.

Family Contextual Factors are Differentially Associated with Depressive Symptoms among Boys and Girls with Perinatally Acquired HIV.

Youth with perinatally acquired HIV (PHIV) are at risk for depressive symptoms, which are associated with a range of adverse outcomes. Although family contextual factors associated with depressive symptoms differ among boys and girls without PHIV, it is unclear whether this is also the case among youth with PHIV. Participants included 314 youth with PHIV (M = 12.88, SD = 3.08 years old; 51% male; 85% Black/Latinx) and their caregivers. Higher levels of caregivers' own depressive symptoms, caregiver-child detachment, and family conflict were associated with higher levels of caregiver-reported youth depressive symptoms. Less consistent discipline was associated with higher levels of youth-reported depressive symptoms. Higher youth-reported depressive symptoms were associated with greater family cohesion among boys and greater caregiver detachment among girls. Consideration of contextual variables is essential for interventions for depressive symptoms among youth with PHIV, but attention to sex differences with family contextual factors is also important.

Interest in HIV pre-exposure prophylaxis (PrEP) among adolescents and their caregivers in Malawi.

Over a third of new HIV infections occur in adolescents aged 10-19 globally. Pre-exposure prophylaxis (PrEP) could be a powerful tool for prevention. Understanding more about the drivers of PrEP interest could inform implementation strategies among this age group. Moreover, family dynamics may play a uniquely critical role for this younger age group, thus it is important to gauge whether caregivers would support their children's use of PrEP. We surveyed 2,089 adolescents (aged 10-16) and their caregivers in Malawi during 2017-2018. Data were collected on PrEP interest, factors that may facilitate PrEP use, and preferences for PrEP modality. We used multivariate logistic regression to estimate the association between the above characteristics and PrEP interest. We find that young adolescents are engaging in behaviors that would put them at substantial risk of acquiring HIV, would likely benefit from PrEP, are largely (82%) interested in using such, would prefer to get an injection over taking a daily pill, and are considerably discouraged by the prospect of side effects. Endorsement by caregivers was even greater (87%). Our findings demonstrate initial support for adolescent PrEP, and suggest parents may be a surprising advocate.

Symptom Profiles of CD and ODD Among Youth With Perinatally Acquired HIV.

OBJECTIVE: Youth with perinatally acquired human immunodeficiency virus (PHIV) face increased risk for conduct disorder (CD) and oppositional defiant disorder (ODD) symptoms, and heterogeneous findings indicate that there may be subgroups of youth with PHIV differing in the quality and/or frequency of symptoms. The present study examined symptom profiles of CD and ODD among youth with PHIV and whether profiles differed in terms of parent-child and family correlates. METHODS: Participants included 314 youth with PHIV, aged 6-17 years (M = 12.88 years, SD = 3.08; 51% male; 85% Black or Latinx), and their caregivers who were recruited from 29 clinics in the US involved in the International Maternal Pediatrics Adolescent AIDS Clinical Trials (IMPAACT) Group's P1055 study. Caregivers reported on youth CD and ODD symptoms, parent-child interactions, and family environment. RESULTS: Latent class analysis indicated that a four-class model (i.e., moderate CD/high ODD, high ODD, moderate ODD, low CD/ODD) best fit the data. Ancillary analyses to validate these classes revealed differences for family cohesion and conflict; and child-centeredness, detachment, guilt-induced control, and consistency in parent-child interactions. The low CD/ODD class generally differed from other classes with additional differentiation between some higher risk profiles. CONCLUSIONS: Findings suggest that homogeneous classes of CD/ODD symptoms can be identified among youth with PHIV, and these profiles differ in terms of family processes, consistent with previous work among chronically ill youth.

Provider attitudes about childhood tuberculosis prevention in Lesotho: a qualitative study.

BACKGROUND: The World Health Organization estimated that 1.12 million children developed tuberculosis (TB) in 2018, and at least 200,000 children died from TB. Implementation of effective child contact management is an important strategy to prevent childhood TB but these practices often are not prioritized or implemented, particularly in low- and middle-income countries. This study aimed to explore attitudes of healthcare providers toward TB prevention and perceived facilitators and challenges to child contact management in Lesotho, a high TB burden country. Qualitative data were collected via group and individual in-depth interviews with 12 healthcare providers at five health facilities in one district and analyzed using a thematic framework. RESULTS: Healthcare providers in our study were interested and committed to improve child TB contact management and identified facilitators and challenges to a successful childhood TB prevention program. Facilitators included: provider understanding of the importance of TB prevention and enhanced provider training on child TB contact management, with a particular focus on ruling out TB in children and addressing side effects. Challenges identified by providers were at multiple levels -- structural, clinic, and individual and included: [1] access to care, [2] supply-chain issues, [3] identification and screening of child contacts, and [4] adherence to isoniazid preventive therapy. CONCLUSIONS: Given the significant burden of TB morbidity and mortality in young children and the recent requirement by the WHO to report IPT initiation in child contacts, prioritization of child TB contact management is imperative and should include enhanced provider training on childhood TB and mentorship as well as strategies to eliminate challenges. Strategies that enable more efficient child TB contact management delivery include creating standardized tools that facilitate the implementation, tracking, and monitoring of child TB contact management coupled with guidance and mentorship from the district health management team. To tackle access to care challenges, we propose delivering intensive community health education, conducting community screening more efficiently using standardized tools, and facilitating access to services in the community.

Profiles of caregiving behaviors among children and adolescents with perinatally acquired HIV.

Although parenting behaviors are widely considered an important factor in the adjustment of children and adolescents with chronic physical health needs, few studies have addressed this topic as it pertains to youth with perinatally-acquired human immunodeficiency virus (PHIV). We examined profiles of child-centeredness, control through guilt, consistent discipline, and detachment, and whether these profiles differed in terms of parent- and youth-reported psychiatric disorder symptoms in a cohort of HIV infected youth (N = 314). Latent profile analyses of caregiving behaviors were conducted separately for children (6-12 years) and adolescents (13-18 years). Two profiles were identified among children: (a) moderate caregiving (87%, n = 130) and (b) high detachment caregiving (13%, n = 19), and three profiles were identified among adolescents: (a) moderate caregiving (55%, n = 88), (b) high detachment caregiving (19%, n = 30), and (c) high control through guilt caregiving (26%, n = 42). The high detachment and high control through guilt caregiving profiles displayed higher levels of parent-and youth-reported symptoms than the moderate caregiving profile. These findings suggest that caregiver behaviors of PHIV youth vary as a function of children's developmental period and differ in terms of youth psychological symptoms.

Relative bioavailability of bedaquiline tablets suspended in water: Implications for dosing in children.

AIMS: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets. METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 h was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability. RESULTS: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell. CONCLUSIONS: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

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

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

H1N1 influenza vaccination in HIV-infected women on effective antiretroviral treatment did not induce measurable antigen-driven proliferation of the HIV-1 proviral reservoir.

OBJECTIVES: Antigen-induced activation and proliferation of HIV-1-infected cells is hypothesized to be a mechanism of HIV persistence during antiretroviral therapy. The objective of this study was to determine if proliferation of H1N1-specific HIV-infected cells could be detected following H1N1 vaccination. METHODS: This study utilized cryopreserved PBMC from a previously conducted trial of H1N1 vaccination in HIV-infected pregnant women. HIV-1 DNA concentrations and 437 HIV-1 C2V5 env DNA sequences were analyzed from ten pregnant women on effective antiretroviral therapy, before and 21 days after H1N1 influenza vaccination. RESULTS: HIV-1 DNA concentration did not change after vaccination (median pre- vs. post-vaccination: 95.77 vs. 41.28 copies/million PBMC, p = .37). Analyses of sequences did not detect evidence of HIV replication or proliferation of infected cells. CONCLUSIONS: Antigenic stimulation during effective ART did not have a detectable effect on the genetic makeup of the HIV-1 DNA reservoir. Longitudinal comparison of the amount and integration sites of HIV-1 in antigen-specific cells to chronic infections (such as herpesviruses) may be needed to definitively evaluate whether antigenic stimulation induces proliferation of HIV-1 infected cells.

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.

Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children.

BACKGROUND: The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS: We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS: Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS: Primary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).