Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

Pharmacokinetics and Optimal Dosing of Levofloxacin in Children for Drug-Resistant Tuberculosis: An Individual Patient Data Meta-Analysis.

BACKGROUND: Each year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children. METHODS: Levofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses. RESULTS: Data from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing <24 kg and under <10 years, resulting in approximately half of the exposure in adults. Model-informed doses of 16-33 mg/kg for dispersible tablets or 16-50 mg/kg for nondispersible tablets were required to meet the AUC target without significantly exceeding the median adult Cmax. CONCLUSIONS: Revised weight-band dosing guidelines with doses of >20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

Clinical outcomes in children living with HIV treated for non-severe tuberculosis in the SHINE Trial.

BACKGROUND: Children living with HIV(CLWH) are at high risk of tuberculosis(TB) and face poor outcomes, despite antiretroviral treatment(ART). We evaluated outcomes in CLWH and HIV-uninfected children treated for non-severe TB in the SHINE trial. METHODS: SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, non-severe TB who were randomized to receive 4 vs 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CLWH. RESULTS: Of 1204 enrolled, 127(11%) were CLWH, of similar age (median(IQR) 3.6(1.2, 10.3) vs. 3.5(1.5, 6.9)years, p= 0.07), but more underweight (WAZ; -2.3(-3.3, -0.8) vs -1.0(-1.8, -0.2), p<0.01) and anemic (hemoglobin 9.5(8.7, 10.9) vs 11.5(10.4, 12.3)g/dl, p<0.01) compared to HIV-uninfected children. 68(54%) CLWH were ART-naïve; baseline median CD4 count 719(241-1134) cells/mm3, CD4% 16(10-26)%). CLWH were more likely to be hospitalized (aOR=2.4(1.3-4.6)) and die (aHR(95%CI) 2.6(1.2,5.8)). HIV status, age <3 years (aHR 6.3(1.5,27.3)), malnutrition (aHR 6.2(2.4,15.9)) and hemoglobin <7g/dl(aHR 3.8(1.3,11.5) independently predicted mortality. Among children with available VL, 45% and 61% CLWH had VL<1000copies/ml at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 vs 6 months) on TB treatment outcomes by HIV status (p for interaction=0.42). CONCLUSIONS: We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CLWH treated for non-severe TB. Irrespective of TB treatment duration, CLWH had higher rates of mortality and hospitalization than HIV-uninfected counterparts.

We compared outcomes between children with and without HIV treated for non-severe TB. Regardless of treatment duration (4 or 6 months), children with HIV had similar TB outcomes but had higher mortality and hospitalization rates than their HIV-uninfected counterparts.

Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis.

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.

1-Year Incidence of Tuberculosis Infection and Disease Among Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis.

BACKGROUND: Tuberculosis infection (TBI) and TB disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant TB exposure. We sought to characterize TBI and TBD incidence at 1 year in HHCs and to evaluate TB preventive treatment (TPT) use in high-risk groups. METHODS: We previously conducted a cross-sectional study of HHCs with rifampin-/multidrug-resistant TB in 8 high-burden countries and reassessed TBI (interferon-gamma release assay, HHCs aged ≥5 years) and TBD (HHCs all ages) at 1 year. Incidence was estimated across age and risk groups (<5 years; ≥5 years, diagnosed with human immunodeficiency virus [HIV]; ≥5 years, not diagnosed with HIV/unknown, baseline TBI-positive) by logistic or log-binomial regression fitted using generalized estimating equations. RESULTS: Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median, 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a 1-year 21.6% (95% confidence interval [CI], 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n = 5), probable (n = 3), or possible (n = 8) TBD, yielding a 2.3% (95% CI, 1.4-3.8) 1-year cumulative incidence (1.1%; 95% CI, .5-2.2 for confirmed/probable TBD). TBD relative risk was 11.5-fold (95% CI, 1.7-78.7), 10.4-fold (95% CI, 2.4-45.6), and 2.9-fold (95% CI, .5-17.8) higher in age <5 years, diagnosed with HIV, and baseline TBI high-risk groups, respectively, vs the not high-risk group (P = .0015). By 1 year, 4% (21 of 553) of high-risk HHCs had received TPT. CONCLUSIONS: TBI and TBD incidence continued through 1 year in rifampin-/multidrug-resistant TB HHCs. Low TPT coverage emphasizes the need for evidence-based prevention and scale-up, particularly among high-risk groups.

Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. TRIAL REGISTRATION: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis.

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.

QT Interval Prolongation with One or More QT-Prolonging Agents Used as Part of a Multidrug Regimen for Rifampicin-Resistant Tuberculosis Treatment: Findings from Two Pediatric Studies.

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.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Pharmacokinetics and optimized dosing of dispersible and non-dispersible levofloxacin formulations in young children.

BACKGROUND: Levofloxacin is used for treatment and prevention of rifampicin-resistant (RR)-TB in children. Recent data showed higher exposures with 100 mg dispersible compared with non-dispersible tablet formulations with potentially important dosing implications in children. We aimed to verify and better characterize this finding. METHODS: We conducted a crossover pharmacokinetic trial in children aged ≤5 years receiving levofloxacin RR-TB preventive therapy. Pharmacokinetic sampling was done after 15-20 mg/kg doses of levofloxacin with 100 mg dispersible and crushed 250 mg non-dispersible levofloxacin formulations. A population pharmacokinetic model was developed. RESULTS: Twenty-five children were included, median (IQR) weight and age 12.2 (10.7-15.0) kg and 2.56 (1.58-4.03) years, respectively. A two-compartment model with first-order elimination and transit compartment absorption best described levofloxacin pharmacokinetics. Allometric scaling adjusted for body size, and maturation of clearance with age was characterized. Typical clearance in a 12 kg child was estimated at 4.17 L/h. Non-dispersible tablets had 21.5% reduced bioavailability compared with the dispersible formulation, with no significant differences in other absorption parameters.Dosing simulations showed that current recommended dosing for both formulations result in median exposures below adult-equivalent exposures at a 750 mg daily dose, mainly in children >6 months. Higher levofloxacin doses of 16-30 mg/kg for dispersible and 20-38 mg/kg for crushed non-dispersible tablets may be required in children >6 months. CONCLUSIONS: The dispersible paediatric levofloxacin formulation has improved bioavailability compared with the crushed non-dispersible adult formulation, but exposures remain below those in adults. We propose optimized age- and weight-based dosing for levofloxacin, which require further evaluation.

Relative bioavailability of delamanid 50 mg tablets dispersed in water in healthy adult volunteers.

AIM: Delamanid is a novel drug for the treatment of drug-resistant tuberculosis, manufactured as 50-mg solid and 25-mg dispersible tablets. We evaluated the effects of dispersing the 50-mg tablet, focusing on the relative bioavailability. METHODS: Delamanid, 50-mg tablets administered dispersed vs swallowed whole, was investigated in a phase I, four-period, crossover study. Two of three dose strengths of delamanid (25, 50 or 100 mg) were given to healthy adult participants, in both whole and dispersed forms, with a 7-day washout period. Blood samples were collected over 168 h after each dose. Delamanid and its metabolite DM-6705 were analysed with a validated liquid chromatography tandem mass spectrometry assay. The pharmacokinetics of both analytes were analysed using nonlinear mixed-effect modelling. Palatability and acceptability were determined using a standardized questionnaire. RESULTS: Twenty-four participants completed the study. The bioavailability of dispersed tablets was estimated to be 107% of whole tablets, with a 90% confidence interval of 99.7-114%, fulfilling bioequivalence criteria. The two formulations were not significantly different regarding either bioavailability or its variability. Bioavailability increased at lower doses, by 34% (26-42%) at 50 mg and by 74% (64-86%) at 25 mg, relative to 100 mg. The majority of participants (93%) found the dispersed formulation acceptable in palatability across all delamanid doses. CONCLUSIONS: Dispersed 50-mg delamanid tablets have similar bioavailability to tablets swallowed whole in adult volunteers. This can be an option for children and other patients who cannot swallow whole tablets, improving access to treatment.

SARS-CoV-2 infection and pulmonary tuberculosis in children and adolescents: a case-control study.

BACKGROUND: The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic has had an impact on the global tuberculosis (TB) epidemic but evidence on the possible interaction between SARS-CoV-2 and TB, especially in children and adolescents, remains limited. We aimed to evaluate the relationship between previous infection with SARS-CoV-2 and the risk of TB in children and adolescents. METHODS: An unmatched case-control study was conducted using SARS-CoV-2 unvaccinated children and adolescents recruited into two observational TB studies (Teen TB and Umoya), between November 2020 and November 2021, in Cape Town, South Africa. Sixty-four individuals with pulmonary TB (aged < 20 years) and 99 individuals without pulmonary TB (aged < 20 years) were included. Demographics and clinical data were obtained. Serum samples collected at enrolment underwent quantitative SARS-CoV-2 anti-spike immunoglobulin G (IgG) testing using the Abbott SARS-CoV-2 IgG II Quant assay. Odds ratios (ORs) for TB were estimated using unconditional logistic regression. RESULTS: There was no statistically significant difference in the odds of having pulmonary TB between those who were SARS-CoV-2 IgG seropositive and those who were seronegative (adjusted OR 0.51; 95% CI: 0.23-1.11; n = 163; p = 0.09). Of those with positive SARS-CoV-2 serology indicating prior infection, baseline IgG titres were higher in individuals with TB compared to those without TB (p = 0.04) and individuals with IgG titres in the highest tertile were more likely to have pulmonary TB compared to those with IgG levels in the lowest tertile (OR: 4.00; 95%CI: 1.13- 14.21; p = 0.03). CONCLUSIONS: Our study did not find convincing evidence that SARS-CoV-2 seropositivity was associated with subsequent pulmonary TB disease; however, the association between magnitude of SARS-CoV-2 IgG response and pulmonary TB warrants further investigation. Future prospective studies, evaluating the effects of sex, age and puberty on host immune responses to M. tuberculosis and SARS-CoV-2, will also provide more clarity on the interplay between these two infections.

UMOYA: a prospective longitudinal cohort study to evaluate novel diagnostic tools and to assess long-term impact on lung health in South African children with presumptive pulmonary TB-a study protocol.

BACKGROUND: Despite a high paediatric tuberculosis (TB) burden globally, sensitive and specific diagnostic tools are lacking. In addition, no data exist on the impact of pulmonary TB on long-term child lung health in low- and middle-income countries. The prospective observational UMOYA study aims (1) to build a state-of-the-art clinical, radiological, and biological repository of well-characterised children with presumptive pulmonary TB as a platform for future studies to explore new emerging diagnostic tools and biomarkers for early diagnosis and treatment response; and (2) to investigate the short and long-term impact of pulmonary TB on lung health and quality of life in children. METHODS: We will recruit up to 600 children (0-13 years) with presumptive pulmonary TB and 100 healthy controls. Recruitment started in November 2017 and is expected to continue until May 2023. Sputum and non-sputum-based samples are collected at enrolment and during follow-up in TB cases and symptomatic controls. TB treatment is started by routine care services. Intensive follow-up for 6 months will allow for TB cases to retrospectively be classified according to international consensus clinical case definitions for TB. Long-term follow-up, including imaging, comprehensive assessment of lung function and quality of life questionnaires, are done yearly up to 4 years after recruitment. DISCUSSION: The UMOYA study will provide a unique platform to evaluate new emerging diagnostic tools and biomarkers for early diagnosis and treatment response and to investigate long-term outcomes of pulmonary TB and other respiratory events on lung health in children.

The Diagnostic Accuracy of Chest Radiographic Features for Pediatric Intrathoracic Tuberculosis.

INTRODUCTION: The chest radiograph (CR) remains a key tool in the diagnosis of pediatric tuberculosis (TB). In children with presumptive intrathoracic TB, we aimed to identify CR features that had high specificity for, and were strongly associated with, bacteriologically confirmed TB. METHODS: We analyzed CR data from children with presumptive intrathoracic TB prospectively enrolled in a cohort study in a high-TB burden setting and who were classified using standard clinical case definitions as "confirmed," "unconfirmed," or "unlikely" TB. We report the CR features and inter-reader agreement between expert readers who interpreted the CRs. We calculated the sensitivity and specificity of the CR features with at least moderate inter-reader agreement and analyzed the relationship between these CR features and the classification of TB in a multivariable regression model. RESULTS: Of features with at least moderate inter-reader agreement, enlargement of perihilar and/or paratracheal lymph nodes, bronchial deviation/compression, cavities, expansile pneumonia, and pleural effusion had a specificity of > 90% for confirmed TB, compared with unlikely TB. Enlargement of perihilar (adjusted odds ratio [aOR]: 6.6; 95% confidence interval [CI], 3.80-11.72) and/or paratracheal lymph nodes (aOR: 5.14; 95% CI, 2.25-12.58), bronchial deviation/compression (aOR: 6.22; 95% CI, 2.70-15.69), pleural effusion (aOR: 2.27; 95% CI, 1.04-4.78), and cavities (aOR: 7.45; 95% CI, 3.38-17.45) were associated with confirmed TB in the multivariate regression model, whereas alveolar opacification (aOR: 1.16; 95% CI, .76-1.77) and expansile pneumonia (aOR: 4.16; 95% CI, .93-22.34) were not. CONCLUSIONS: In children investigated for intrathoracic TB enlargement of perihilar or paratracheal lymph nodes, bronchial compression/deviation, pleural effusion, or cavities on CR strongly support the diagnosis.

Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children.

BACKGROUND: Moxifloxacin is a 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 and QT interval prolongation and evaluate optimal dosing in children with RR-TB. METHODS: Pharmacokinetic data were pooled from 2 observational studies in South African children 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 aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). 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 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 (interindividual 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 coadministered with other QT-prolonging agents.

Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. METHODS: In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation. CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.

BACKGROUND: In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands. METHODS: Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L). RESULTS: In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs. CONCLUSIONS: Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.

Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations.

BACKGROUND: Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. METHODS: Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. RESULTS: In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, and ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. CONCLUSIONS: Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.

Delamanid Added to an Optimized Background Regimen in Children with Multidrug-Resistant Tuberculosis: Results of a Phase I/II Clinical Trial.

Delamanid has been demonstrated to be safe and effective for treatment of adult multidrug-resistant tuberculosis (MDR-TB) and has been approved by the European Commission for treatment of pediatric MDR-TB patients at least 10 kg in weight, making the drug no longer limited to adults. A 10-day phase I age deescalation study was conducted, followed by a 6-month phase II extension study, to assess the pharmacokinetics, safety, tolerability, and preliminary efficacy of delamanid when combined with optimized background regimen (OBR) in children (birth to 17 years) with MDR-TB. Delamanid administered at 100 mg twice-daily (BID), 50 mg BID, and 25 mg BID resulted in exposures in 12- to 17- (n = 7), 6- to 11- (n = 6), and 3- to 5-year-olds (n = 12), respectively, comparable with those in adults at the approved adult dosage (100 mg BID). Exposures in 0- to 2-year-olds (n = 12) following a weight-based dosing regimen (5 mg once daily [QD] to 10 mg BID) were lower than predicted from pharmacokinetic modeling of the older three age groups and below target exposures in adults. Overall, the safety profile of delamanid in children 0 to 17 years of age was similar to the adult profile. At 24 months after the first delamanid dose, 33/37 children (89.2%) had favorable treatment outcomes, as defined by the World Health Organization (15/37 [40.5%] cured and 18/37 [48.6%] completed treatment). A new pediatric delamanid formulation used in 0- to 2-year-olds and 3- to 5-year-olds was palatable per child/parent and nurse/investigator reports. Data from initial phase I/II studies inform our understanding of delamanid use in children and support its further assessment in the setting of pediatric MDR-TB. (This study has been registered at ClinicalTrials.gov under identifiers NCT01856634 [phase I trial] and NCT01859923 [phase II trial].).

Pharmacokinetics and Dose Optimization Strategies of Para-Aminosalicylic Acid in Children with Rifampicin-Resistant Tuberculosis.

Treatment options for children with Rifampicin-resistant tuberculosis (RR-TB) remain limited, and para-aminosalicylic acid (PAS) is still a relevant component of treatment regimens. Prevention of resistance to companion drugs by PAS is dose related, and at higher concentrations, PAS may exhibit significant bactericidal activity in addition to its bacteriostatic properties. The optimal dosing of PAS in children is uncertain, specifically for delayed-release granule preparations, which are the most used. A population pharmacokinetic model was developed describing PAS pharmacokinetics in children receiving routine RR-TB treatment. Model-based simulations evaluated current World Health Organization (WHO) weight-band doses against the adult pharmacokinetic target of 50 to 100 mg/liter for peak concentrations. Of 27 children included, the median (range) age and weight were 3.87 (0.58 to 13.7) years and 13.3 (7.15 to 30.5) kg, respectively; 4 (14.8%) were HIV positive. PAS followed one-compartment kinetics with first-order elimination and transit compartment absorption. The typical clearance in a 13-kg child was 9.79 liters/h. Increased PAS clearance was observed in both pharmacokinetic profiles from the only patient receiving efavirenz. No effect of renal function, sex, ethnicity, nutritional status, HIV status, antiretrovirals (lamivudine, abacavir, and lopinavir-ritonavir), or RR-TB drugs was detected. In simulations, target concentrations were achieved only using the higher WHO dose range of 300 mg/kg once daily. A transit compartment adequately describes absorption for the slow-release PAS formulation. Children should be dosed at the higher range of current WHO-recommended PAS doses and in a once-daily dose to optimize treatment.