Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age.

In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6-23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) Cmax and AUC0-24h values were 4.8 (3.7-6.7) mg/L and 23.5 (13.4-36.7) h*mg/L and the adult targets (>3 mg/L and 11.6-26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on Cmax values, but a larger INH AUC0-24h (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.

Multisystem Inflammatory Syndrome of Children: Subphenotypes, Risk Factors, Biomarkers, Cytokine Profiles, and Viral Sequencing.

OBJECTIVE: To assess demographic, clinical, and biomarker features distinguishing patients with multisystem inflammatory syndrome in children (MIS-C); compare MIS-C sub-phenotypes; identify cytokine biosignatures; and characterize viral genome sequences. STUDY DESIGN: We performed a prospective observational cohort study of 124 children hospitalized and treated under the institutional MIS-C Task Force protocol from March to September 2020 at Children's National, a quaternary freestanding children's hospital in Washington, DC. Of this cohort, 63 of the patients had the diagnosis of MIS-C (39 confirmed, 24 probable) and 61 were from the same cohort of admitted patients who subsequently had an alternative diagnosis (controls). RESULTS: Median age and sex were similar between MIS-C and controls. Black (46%) and Latino (35%) children were over-represented in the MIS-C cohort, with Black children at greatest risk (OR 4.62, 95% CI 1.151-14.10; P = .007). Cardiac complications were more frequent in critically ill patients with MIS-C (55% vs 28%; P = .04) including systolic myocardial dysfunction (39% vs 3%; P = .001) and valvular regurgitation (33% vs 7%; P = .01). Median cycle threshold was 31.8 (27.95-35.1 IQR) in MIS-C cases, significantly greater (indicating lower viral load) than in primary severe acute respiratory syndrome coronavirus 2 infection. Cytokines soluble interleukin 2 receptor, interleukin [IL]-10, and IL-6 were greater in patients with MIS-C compared with controls. Cytokine analysis revealed subphenotype differences between critically ill vs noncritically ill (IL-2, soluble interleukin 2 receptor, IL-10, IL-6); polymerase chain reaction positive vs negative (tumor necrosis factor-α, IL-10, IL-6); and presence vs absence of cardiac abnormalities (IL-17). Phylogenetic analysis of viral genome sequences revealed predominance of GH clade originating in Europe, with no differences comparing patients with MIS-C with patients with primary coronavirus disease 19. Treatment was well tolerated, and no children died. CONCLUSIONS: This study establishes a well-characterized large cohort of MIS-C evaluated and treated following a standardized protocol and identifies key clinical, biomarker, cytokine, viral load, and sequencing features. Long-term follow-up will provide opportunity for future insights into MIS-C and its sequelae.

Influence of new antiretrovirals on hematological toxicity in HIV-exposed uninfected infants.

UNLABELLED: Maternal combined antiretroviral therapy (cART) successfully prevents HIV mother-to-child transmission but also causes hematological toxicity in the HIV-exposed uninfected (HEU) infant. We performed a single-center prospective observational study. Hematological toxicity during the first year of life (at 3 and 6 weeks, and 3, 6, and 12 months) was compared between HEU infants born in two different time periods: P1 (2000-2001) and P2 (2007-2013). Mother-infant pairs in P1 (n = 55) and P2 (n = 48) mainly differed in maternal ethnic origin, HIV route of transmission, and cART regimens. Anemia and neutropenia were both less common in P2 than P1, albeit not significantly. Earlier normalization of red blood cell mean corpuscular volume levels in P2 infants suggests that current cART maternal regimens and shorter neonatal prophylaxis are less toxic. Leukocyte, lymphocyte, and platelet counts remained within normal values during follow-up, without differences between groups. CONCLUSION: New cART regimens have had very little impact on the hematological toxicity in HEU infants. WHAT IS KNOWN: • Antiretroviral drugs during pregnancy and the neonatal period very effectively prevent mother-to-child transmission of HIV infection. • Hematological toxicity has been widely reported among HIV-exposed uninfected children. What is New: • In HIV-exposed uninfected children, hematological toxicity is still mainly caused by exposure to zidovudine. • New antiretroviral drugs have very little impact on hematological toxicity among HIV-exposed uninfected children.

Metabolic disorders in vertically HIV-infected children: future adults at risk for cardiovascular disease.

BACKGROUND: Despite metabolic disorders in HIV-infected children being widely described, there is still a lack of agreed criteria for diagnoses and management. Numerous studies are coming from other settings and results are heterogeneous when assessing several analytical and clinical parameters. OBJECTIVES: To describe the prevalence of metabolic disorders and associated risk factors in the Spanish National cohort of HIV-infected pediatric patients (CoRISpe). METHODS: This was a cross-sectional study following all vertically HIV-infected children and adolescents in three referral centers included in the CoRISpe. Metabolic data (fasting lipids, glucose and insulin levels and thyroid hormone levels) were collected. Fat distribution was clinically assessed by expert clinicians. RESULTS: We included 157 patients [median age 13 years, interquartile range (IQR) 10-16]. Median duration of antiretroviral therapy was 10.2 years (IQR 5.0-13.0). Almost 20% of patients had insulin resistance and this was associated with hepatitis C co-infection, current use of stavudine (d4T) and hypertriglyceridemia. Hypercholesterolemia and hypertriglyceridemia were found in 23.9% and 24.8% of patients and were associated with current use of protease inhibitors (p = 0.042 and p = 0.022, respectively). Abnormal fat distribution was observed in 63 patients (40.5%): lipoatrophy in 32 (20.4%), lipohypertrophy in eight (5.1%) and a mixed pattern in 23 patients (14.6%), and it was significantly associated with previous exposure to stavudine (p < 0.001). CONCLUSIONS: Metabolic disorders are a significant problem in our HIV-infected pediatric population. We need to encourage the development of global strategies and the creation of consensus guidelines that can decrease the cardiovascular risk in this population.

Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen.

Recent updates of the guidelines on the prevention of human immunodeficiency virus mother-to-child transmission have shortened the neonatal zidovudine prophylactic regimens from 6 to 4 weeks. We present a prospective observational study in a large cohort of mother-infant pairs and report that the 4-week regimen allows an earlier recovery of the anemia in these otherwise healthy infants.