Faculty Bibliography

An established echocardiographic (echo) standard for assessing the newborn right ventricle (RV) for hypertrophy has not been thoroughly developed. This is partially due to the RV's complex architecture, which makes quantification of RV mass by echo difficult. Here, we retrospectively evaluate the thickness of the inferior RV wall (iRVWT) by echo in neonates and infants with normal cardiopulmonary physiology. Inferior RVWT was defined at the medial portion of the inferior wall of the RV at the mid-ventricular level, collected from a subxiphoid, short axis view. iRVWT was indexed to body surface area (BSA) to the 0.5 power and normalized to iLVWT to explore the best normalization method. Ninety-eight neonates and 32 infants were included in the final analysis. Mean age for neonates and infants was 2 days and 59 days, respectively. Mean ± SD for neonate and infant end-diastole iRVWT was 2.17 ± 0.35 mm and 1.79 ± 0.28 mm, respectively. There was no residual relationship between the index iRVWT and BSA (r = 0.03, p = NS). In the infant cohort, the iRVWT was significantly lower and iLVWT was significantly higher compared to neonate, consistent with known physiologic changes of RV and LV mass. Thus, iRVWT may serve as a reliable and accurate proxy for RV mass and the parameter warrants further evaluation.

BACKGROUND:Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. METHODS:In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir- lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (≥37 weeks gestational age) of no more than 3 days of age with birthweights of 2000-4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir-lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir-lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10-14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir-lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10-14 days later (pharmacokinetics 2). Safety visits were done 1-2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). FINDINGS/RESULTS:) were higher at 6-14 days (51·7 mg × h/L for abacavir and 17·2 mg × h/L for lamivudine) than at 19-24 days of age (25·0 mg × h/L and 11·3 mg × h/L), whereas they were similar for lopinavir over this period (AUC 0-12 58·5 mg × h/L vs 46·4 mg × h/L). Abacavir geometric mean AUC0-24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0-tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. INTERPRETATION/CONCLUSIONS:Abacavir-lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. FUNDING/BACKGROUND:Unitaid.

BACKGROUND:Paediatric pharmacokinetic and safety data for clofazimine are limited. We described the pharmacokinetics and safety of clofazimine in South African children treated for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB). METHODS:Children <18 years being routinely treated for MDR/RR-TB were eligible for study participation. Soft gel capsules (Novartis Pharma AG) were administered using WHO-recommended weight-based dosing. Sparse and semi-intensive pharmacokinetic sampling was completed at baseline, Week 2 and 16. Clofazimine weekly area-under-the-concentration-time-curve (wAUC) was compared to target wAUC (60.87 mg*h/L and 111.79 mg*h/L) in adults receiving clofazimine 100mg daily for MDR/RR-TB and leprosy, respectively. Safety monitoring included measurement of QT-interval prolongation and laboratory assessment. RESULTS:Twenty children, six (30%) male, median age 6.0 years (range, 1.6-14.4), were included. Median clofazimine wAUC was 162.94 (IQR 130.06-263.95), >25% higher than the target adult wAUC in adults with MDR/RR-TB (111.79; IQR 81.9-151.9). No serious or grade ≥3 cardiac events occurred. There was a linear relationship between clofazimine concentration and QT-interval prolongation with an increase of 0.02 ms for every µg/L. There were 59 adverse events at least possibly related to clofazimine; one severe adverse event (elevated ALT) led to temporary withdrawal of clofazimine. CONCLUSIONS:Clofazimine doses used achieved substantially higher exposures in children than adults receiving standard clofazimine doses. The association of higher clofazimine exposures and QT-interval prolongation may pose unnecessary risk to children, particularly in combination with other QT-prolonging drugs. Lower clofazimine doses to achieve appropriate clofazimine exposures should be investigated in children using different drug formulations and harmonised weight bands.

BACKGROUND:The optimal pacemaker programming strategy for infants with isolated congenital complete atrioventricular block (CCAVB) remains unresolved. Dual-chamber pacing maintains atrioventricular synchrony and physiological heart rate variability but increases the burden of ventricular pacing on a myocardium that may be inherently prone to left ventricular (LV) dysfunction. OBJECTIVES/OBJECTIVE:This study sought to compare clinical outcomes of dual (DDD)- vs single (VVI)- chamber pacing in infants with CCAVB (DAVINCHI). METHODS:A multicenter retrospective study (2006-2023) identified infants with CCAVB and pacemaker implant at <1 year, with single-site ventricular pacing and no significant congenital heart disease. Outcome measured were clinically significant LV dysfunction, mortality, and complications. RESULTS:A total of 109 infants (64% autoimmune CCAVB) were identified, 60.6% had VVI pacing. Over a median follow-up of 5 years, 60 complications occurred in 47 subjects (43.1%). Smaller infants had more complications. Clinically significant LV dysfunction developed in 11 (10.1%) and was more frequent in DDD (21% vs 3%; P = 0.006). LV dysfunction resulted in mortality in 1 patient and 10 patients required a change in pacing mode. Independent risk factors for LV dysfunction were DDD pacing and neonatal implant. Right ventricular pacing lead placement had a higher HR (HR: 2.67) for LV dysfunction but was not statistically significant (P = 0.2). CONCLUSION/CONCLUSIONS:DDD pacing increases LV dysfunction risk compared with VVI in infants with CCAVB. Single-chamber LV apical pacing should be considered in infants with isolated CCAVB who require pacing. There is a high risk of pacing-related complications, particularly with an increased risk of ventricular lead complications in low-weight neonates.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th-97.5th centiles) of 3.3 (0.5-15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0-271) mg.h/L compared to an adult target of 60.9 (56.0-66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.

Rifampicin-resistant tuberculosis (RR-TB) involves treatment with many drugs that can prolong the QT interval; this risk may increase when multiple QT-prolonging drugs are used together. We assessed QT interval prolongation in children with RR-TB receiving one or more QT-prolonging drugs. Data were obtained from two prospective observational studies in Cape Town, South Africa. Electrocardiograms were performed before and after drug administration of clofazimine (CFZ), levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), and delamanid. The change in Fridericia-corrected QT (QTcF) was modeled. Drug and other covariate effects were quantified. A total of 88 children with a median (2.5th-to-97.5th range) age of 3.9 (0.5 to 15.7) years were included, of whom 55 (62.5%) were under 5 years of age. A QTcF interval of >450 ms was observed in 7 patient-visits: regimens were CFZ+MFX (n = 3), CFZ+BDQ+LFX (n = 2), CFZ alone (n = 1), and MFX alone (n = 1). There were no events with a QTcF interval of >500 ms. In a multivariate analysis, CFZ+MFX was associated with a 13.0-ms increase in change in QTcF (P < 0.001) and in maximum QTcF (P = 0.0166) compared to those when other MFX- or LFX-based regimens were used. In conclusion, we found a low risk of QTcF interval prolongation in children with RR-TB who received at least one QT-prolonging drug. Greater increases in maximum QTcF and ΔQTcF were observed when MFX and CFZ were used together. Future studies characterizing exposure-QTcF responses in children will be helpful to ensure safety with higher doses if required for effective treatment of RR-TB.

BACKGROUND:Moxifloxacin is a priority recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics, QT-interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS:Pharmacokinetic data were pooled from two observational studies in South African children 0-17 years of age with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing. RESULTS:Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were <2 years of age, and 8 (9%) were HIV-positive. The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16 kg child. Stunting and HIV infection increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥ 500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (inter-individual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children. CONCLUSIONS:Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when co-administered with other QT-prolonging agents.

BACKGROUND:Antiretroviral options for neonates (< 28 days of life) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the '4-in-1' fixed-dose paediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates. METHODS:The PETITE study is an ongoing phase I/II, open-label, single arm, two-stage trial conducted in South Africa. In Stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine +/- zidovudine) received single dose(s) of the 4-in-1 formulation followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn following an observed dose at 1, 2, 4, 8- and 12-hours post-dose. Here, we report the planned interim pharmacokinetic and safety analysis after completion of the single dose administration. RESULTS:Sixteen neonates, median (range) birth weight 3130 (2790-3590) g, completed 24 pharmacokinetic visits. The 4-in-1 imposed relatively high mg/kg doses of abacavir 8.6 (6.6-11.4) and lamivudine 4.3 (3.3-5.7), but lower lopinavir doses of 11.5 (8.8-15.2). Geometric mean (GM, 90% CI) AUC0-12 of abacavir, lamivudine and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83) and 3.49 (2.13-5.72) µg.hr/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.hr/mL) and ritonavir concentrations were only detectable in 4/120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1. CONCLUSION/CONCLUSIONS:The high mg/kg abacavir and lamivudine doses and AUCs were safe, and the formulation well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates. Alternative paediatric solid antiretroviral formulations must be studied in neonates.