Holistic acceptability of an adult levofloxacin formulation in children and adolescents on a tuberculosis preventive treatment trial.

Drug-resistant tuberculosis (TB) is threatening global TB control. Although formulations designed for children are a priority, adult levofloxacin formulations are widely used in TB treatment and prevention. TB-CHAMP was a cluster-randomised, placebo-controlled trial evaluating the efficacy and safety of 24 weeks of daily levofloxacin to prevent TB in child and adolescent household contacts of adults with infectious multidrug-resistant TB. Nested in-depth longitudinal qualitative work was conducted in a subset of children and their caregivers to understand broader experiences of treatment acceptability. We conducted 41 interviews with 8 caregivers of children <6 years, and with 6 older children responding for themselves. Children who could not swallow the adult formulation whole, found the tablet unpalatable, although they learnt to tolerate the taste over time. Most caregivers and children came from families with substantial experience of TB, but felt they knew little about TB preventive therapy. Many families experienced challenging socio-economic circumstances. Poor acceptability was mitigated by sympathetic study personnel, assistance with transport and financial compensation. The adult formulation of levofloxacin was disliked by many younger children but was acceptable to children able to swallow the tablet whole. In addition to using acceptable drug formulations, TB preventive treatment implementation models should include patient education and should accommodate patients' socioeconomic challenges.

Chest X-Ray-Based Telemedicine Platform for Pediatric Tuberculosis Diagnosis in Low-Resource Settings: Development and Validation Study.

BACKGROUND: Tuberculosis (TB) remains a major cause of morbidity and death worldwide, with a significant impact on children, especially those under the age of 5 years. The complex diagnosis of pediatric TB, compounded by limited access to more accurate diagnostic tests, underscores the need for improved tools to enhance diagnosis and care in resource-limited settings. OBJECTIVE: This study aims to present a telemedicine web platform, BITScreen PTB (Biomedical Image Technologies Screen for Pediatric Tuberculosis), aimed at improving the evaluation of pulmonary TB in children based on digital chest x-ray (CXR) imaging and clinical information in resource-limited settings. METHODS: The platform was evaluated by 3 independent expert readers through a retrospective assessment of a data set with 218 imaging examinations of children under 3 years of age, selected from a previous study performed in Mozambique. The key aspects assessed were the usability through a standardized questionnaire, the time needed to complete the assessment through the platform, the performance of the readers to identify TB cases based on the CXR, the association between the TB features identified in the CXRs and the initial diagnostic classification, and the interreader agreement of the global assessment and the radiological findings. RESULTS: The platform's usability and user satisfaction were evaluated using a questionnaire, which received an average rating of 4.4 (SD 0.59) out of 5. The average examination completion time ranged from 35 to 110 seconds. In addition, the study on CXR showed low sensitivity (16.3%-28.2%) but high specificity (91.1%-98.2%) in the assessment of the consensus case definition of pediatric TB using the platform. The CXR finding having a stronger association with the initial diagnostic classification was air space opacification (χ21>20.38, P<.001). The study found varying levels of interreader agreement, with moderate/substantial agreement for air space opacification (κ=0.54-0.67) and pleural effusion (κ=0.43-0.72). CONCLUSIONS: Our findings support the promising role of telemedicine platforms such as BITScreen PTB in enhancing pediatric TB diagnosis access, particularly in resource-limited settings. Additionally, these platforms could facilitate the multireader and systematic assessment of CXR in pediatric TB clinical studies.

Severe BCG immune reconstitution inflammatory syndrome lymphadenitis successfully managed with pre-antiretroviral counseling and a non-surgical approach: a case report.

BACKGROUND: Bacillus Calmette-Guérin (BCG) reactions are the most common cause of immune reconstitution inflammatory syndrome (IRIS) in HIV-positive infants who initiate antiretroviral therapy (ART). There is limited evidence regarding the incidence of BCG-IRIS; however, reports from outpatient cohorts have estimated that 6-9% of infants who initiated ART developed some form of BCG-IRIS within the first 6 months. Various treatment approaches for infants with BCG-IRIS have been reported, but there is currently no widely accepted standard-of-care. CASE PRESENTATION: A 5-month-old male HIV-exposed infant BCG vaccinated at birth was admitted for refractory oral candidiasis, moderate anemia, and moderate acute malnutrition. He had a HIV DNA-PCR collected at one month of age, but the family never received the results. He was diagnosed with HIV during hospitalization with a point-of-care nucleic acid test and had severe immune suppression with a CD4 of 955 cells/µL (15%) with clinical stage III disease. During pre-ART counseling, the mother was educated on the signs and symptoms of BCG-IRIS and the importance of seeking follow-up care and remaining adherent to ART if symptoms arose. Three weeks after ART initiation, he was readmitted with intermittent subjective fevers, right axillary lymphadenopathy, and an ulcerated papule over the right deltoid region. He was subsequently discharged home with a diagnosis of local BCG-IRIS lymphadenitis. At six weeks post-ART initiation, he returned with suppurative lymphadenitis of the right axillary region that had completely eviscerated through the skin without signs of disseminated BCG disease. He was then started on an outpatient regimen of topical isoniazid, silver nitrate, and oral prednisolone. Throughout this time, the mother maintained good ART adherence despite this complication. After 2.5 months of ART and one month of specific treatment for the lymphadenitis, he had marked mass reduction, improved adenopathy, increased CD4 count, correction of anemia, and resolution of his acute malnutrition. He completely recovered and was symptom free two months after initial treatment without surgical intervention. CONCLUSIONS: This case details the successful management of severe suppurative BCG-IRIS with a non-surgical approach and underlines the importance of pre-ART counseling on BCG-IRIS for caregivers, particularly for infants who initiate ART with advanced HIV.

Management of the infant born to a mother with tuberculosis: a systematic review and consensus practice guideline.

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.

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.

Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion.

Background: Little is known about post-tuberculosis lung disease in adolescents. We prospectively assessed lung function in adolescents with microbiologically confirmed pulmonary tuberculosis during treatment and after treatment completion. Methods: In a prospective study, we enrolled adolescents diagnosed with microbiologically confirmed tuberculosis and healthy tuberculosis-exposed household controls, between October 2020 and July 2021 in Cape Town, South Africa. Spirometry, plethysmography, diffusion capacity lung function tests and 6-min walking test (6MWT) were completed according to international guidelines 2 months into treatment and following treatment completion. Abnormal lung function was defined as abnormal spirometry (z-score < -1.64 for forced expiratory volume in 1 s (FEV1) and/or forced vital capacity (FVC) and/or FEV1/FVC), plethysmography (total lung capacity (TLC) < 80% of predicted, residual volume over TLC of >45%) and/or diffusion capacity (DLCO z-score < -1.64). Findings: One-hundred adolescents were enrolled; 50 (50%) with tuberculosis and 50 (50%) healthy tuberculosis-exposed controls. Of the 50 adolescents with tuberculosis, ten had multidrug-resistant tuberculosis. Mean age of the group was 14.9 years (SD 2.7), 6 (6.0%) were living with HIV and 9 (9.0%) were previously treated for tuberculosis. Lung function improved over time; during treatment abnormal lung function was found in 76% of adolescents with tuberculosis, compared to 65% after treatment completion. Spirometry indices were lower in adolescents with tuberculosis compared to controls, both at 2 months and after treatment completion. Plethysmography in adolescents with tuberculosis showed that air-trapping was more common during treatment than in controls (12% vs 0%, respectively, p = 0.017); which improved following treatment completion. Adolescents with tuberculosis both during and after treatment completion walked a shorter distance than controls. Interpretation: Adolescents with tuberculosis have impaired lung function even after treatment completion. It is crucial to include adolescents in trials on the prevention and treatment of tuberculosis-associated respiratory morbidity. Funding: EDCTP, National Institute of Health, Medical Research Council, BMBF.

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.

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.

Current Treatment of Drug-Resistant Tuberculosis in Children.

Optimal diagnosis and management of children aged <15 y with rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB) relies on identification of adults with the disease and pro-active screening of their close contacts. Children may be diagnosed with RR/MDR-TB based on microbiological confirmation from clinical specimens (sputum, gastric washings, stool), but usually the diagnosis is presumptive, with a history of exposure to RR/MDR-TB and clinical/radiological signs and symptoms suggestive of TB disease. RR/MDR-TB should also be considered in children where first-line TB treatment fails despite good adherence to therapy. Composition and duration of all-oral RR/MDR-TB treatment regimens in children are based on site and severity of TB disease, drug resistance profile of the Mycobacterium tuberculosis strain (isolated from the child or from the most likely source patient), inclusion of at least four drugs considered to be effective (with priority given to World Health Organization Group A and B drugs), toxicity and tolerability of medications (and feasibility of adverse effect monitoring in the child's setting), and availability of child-friendly formulations of TB medications. Individualized RR/MDR-TB regimens are preferable to the standardised 9-12-mo regimen for children, and injectable agents must not be used. Optimal adherence to treatment relies on education, training and support for caregivers and others who are responsible for administering medications to children, as well as close clinical monitoring and early management of adverse effects. Children who are initiated on adequate RR/MDR-TB regimens have high treatment success rates, but efforts to find and treat more children with undiagnosed RR/MDR-TB are crucial to reduce childhood TB mortality.

Perinatal tuberculosis-An approach to an under-recognized diagnosis.

Tuberculosis (TB) in young infants (<3 months of age), often referred to as perinatal TB, is underdiagnosed, leading to severe morbidity and high mortality. Perinatal TB includes both congenital and postnatal transmission of Mycobacterium tuberculosis. We aimed to increase an awareness of TB in neonates and young infants and to provide guidance on the assessment and management when in contact with mothers with TB during or soon after pregnancy. Approximately 217,000 pregnant women develop TB annually; if they are not diagnosed and treated during pregnancy, their infants are at high risk of adverse birth outcomes and TB disease. Although safe and effective antituberculosis treatment regimens are available during pregnancy, the diagnosis of TB is challenging. Infants born to mothers newly diagnosed with TB, not receiving any effective treatment or with cultures not yet negative, should be assessed for TB disease or M. tuberculosis infection. TB preventive therapy should be instituted if the infant is clinically well but exposed to TB, while prompt initiation of TB treatment is essential if TB disease is presumed. HIV status of mother and infant should be considered as this will affect the management. Further research is needed for the diagnosis and prevention of TB during pregnancy, an early diagnosis of TB in infants, and antituberculosis drug pharmacokinetics in young infants.

A novel home-based method for preparing suspensions of anti-TB drugs.

BACKGROUND: Tablets are the most widely available dosage form for the treatment of TB; however, adult tablets fail to meet the needs of young children who cannot swallow these tablets or require dose titration. We tested a new, simple device (XTEMP-R®) and the methodology for converting tablets of TB drugs into a homogeneous suspension for home use by children and caregivers.METHODS: XTEMP-R is a new device used for converting tablets into liquid preparations. Four TB drugs - pretomanid, delamanid, clofazimine and bedaquiline - were dispersed in the device utilizing water and simple syrup. The reproducibility of accurately delivering aliquots from the suspension upon preparation and upon redispersion after storing for 2 days was studied.RESULTS: Suspensions of each of the drugs tested were easily prepared in about 10 min and were visually uniform in consistency. Dosages in 2 and 5 mL were assessed in suspension, and those in 5 mL tested upon redispersion after 2 days. The observed range for these dosages spanned from 94.6% to 101.1% of the theoretical concentration for the suspensions under examination. The cleaned device had no detectable residual drug.CONCLUSION: XTEMP-R can be used at home by caregivers to prepare doses of suspensions accurately for children and patients who cannot swallow tablets.

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.

Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.

Children´s priorities to improve the acceptability of MDR-TB treatment: qualitative data from South Africa.

BACKGROUND: Multidrug-resistant TB (MDR-TB) treatment for children frequently includes unpalatable drugs with low overall acceptability. This can negatively impact children and their caregivers´ treatment experiences and is an important contributor to poor adherence, and potentially, poor treatment outcomes. Children and their caregivers´ preferences for MDR-TB treatment are not well documented. We describe children and caregivers´ priorities to inform future MDR-TB treatment regimens.METHODS: We conducted a cross-sectional qualitative study at a TB hospital in South Africa using semi-structured interviews and participatory research activities with caregivers and children routinely diagnosed and treated for MDR-TB between June and August 2018.RESULTS: We conducted 15 interviews with children and their caregivers. Children ranged from 2 to 17 years of age (median age: 8.3 years). Children and caregivers had an overall negative experience of MDR-TB treatment. Children and caregivers described how future MDR-TB drugs and regimens should prioritise sweeter flavours, fewer pills, brighter colours, and formulations that are easy to prepare and administer and dispensed in colourful, small and discrete packaging.CONCLUSIONS: MDR-TB treatment acceptability remains low, and negatively impacts children and their caregivers´ treatment experiences. Improving the overall acceptability of MDR-TB treatment requires engaging with children and their caregivers to better understand their priorities for new treatment regimens and child-friendly formulations.

Clinical standards for the management of adverse effects during treatment for TB.

BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.

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.

Recurrent Tuberculosis Treatment Episodes in Children Presenting With Presumptive Pulmonary Tuberculosis in Cape Town, South Africa.

BACKGROUND: Limited data are available on tuberculosis (TB) recurrence in children. The aim of this study was to explore the burden of and risk factors for recurrent TB treatment in children. METHODS: A prospective, observational cohort study of children (0-13 years) presenting with presumptive pulmonary TB in Cape Town, South Africa from March 2012 to March 2017. Recurrent TB was defined as more than 1 episode of TB treatment (microbiologically confirmed and unconfirmed). RESULTS: Of 620 children enrolled with presumptive pulmonary TB, data of 608 children were reviewed for TB recurrence after exclusions. The median age was 16.7 [interquartile range (IQR) 9.5-33.3] months, 324 (53.3%) were male and 72 (11.8%) children living with HIV (CLHIV). TB was diagnosed in 297 of 608 (48.8%), of whom 26 had previously received TB treatment, giving a prevalence of 8.8% recurrence: 22 (84.6%) had 1 and 4 (15.4%) had 2 prior TB treatment episodes. The median age of children with recurrent TB was 47.5 (IQR: 20.8-82.5) months at the current episode: 19 of 26 (73.1%) were CLHIV, of whom 12 of 19 (63.2%) were on antiretroviral therapy for a median 43.1 months and all 12 for longer than 6 months. None of the 9 children on antiretroviral treatment with available viral load (VL) data were virally suppressed (median VL, 22,983 copies/ml). Three of 26 (11.6%) children had documented microbiologically confirmed TB at 2 episodes. Four children (15.4%) received drug-resistant TB treatment at recurrence. CONCLUSIONS: There was a high rate of recurrent treatment for TB in this cohort of young children, with CLHIV at the highest risk.