Therapeutic drug monitoring (TDM) is a tool used for dose optimization to achieve therapeutic concentrations associated with improved outcomes. However, evidence supporting its benefits for tuberculosis (TB) treatment remains limited. This scoping review evaluated clinical studies on TDM and its impact on TB treatment outcomes. A scoping review was performed using a systematic search in PubMed, Embase, Web of Science, ClinicalTrials.gov, and the World Health Organization (WHO) Clinical Trials Registry for interventional and observational studies published until 3 May 2025. We included studies evaluating TDM in adults or children treated for drug-susceptible or drug-resistant TB at any setting worldwide, which reported treatment outcomes, adverse events, or clinical/microbiological surrogate markers. The PRISMA guidelines for scoping reviews were followed to report the findings. Of the 5820 studies screened by title and abstract, 31 studies from 10 countries were eligible for inclusion in this review. No published clinical trials on the implementation of TDM were identified, although two are currently ongoing. Overall, compared with the non-TDM group, TDM was associated with faster culture conversion (mean 34 versus 49 days), shorter treatment duration (mean 32 versus 36 weeks) and fewer adverse events. Although all included studies reported high treatment success rates (ranging from 67

BACKGROUND:Isoniazid is a cornerstone of management therapy for tuberculosis (TB). Our aim was to determine the association between isoniazid exposure and clinical outcomes, to develop a pharmacokinetic model, and to optimise the dosing regimen in children treated for drug-susceptible (DS)-TB. METHODS:For this individual participant data meta-analysis, PubMed was searched for observational studies, involving children (aged 0-18 years), being treated for DS-TB. The relationship between isoniazid exposure and clinical outcomes was analysed using a mixed effects logistic regression model. Pharmacokinetic parameters were described using non-linear mixed effects modelling. The pharmacokinetic target was the median adult area under the concentration-time curve at steady-state (AUCss) of 23.4 mg·h·L-1. RESULTS:Six studies provided clinical outcomes, including 405 patients, of which 21% had unfavourable outcomes. 16 studies (1255 patients) were included in the pharmacokinetic model. Unfavourable outcomes were only related to lower body mass index (BMI) for age z-score (BAZ) (OR 0.96, 95% CI 0.93-0.99; p<0.05). Isoniazid exposure was impacted by N-acetyltransferase 2 (NAT2) genotype, weight, age and nutritional status (using BAZ). With currently recommended World Health Organization (WHO) doses, isoniazid exposure was similar to that of adults. Pharmacokinetic target attainment was 71.7% and 29.5% for slow and fast metabolisers, respectively (p<0.05); 50.5% for patients with BAZ >0 and 42.6% for malnourished patients (BAZ < -2) (p<0.05). The model-informed dosing regimen showed that fast metabolisers could benefit from higher isoniazid dosing, especially in malnourished children. CONCLUSION:Our findings showed that the only predictor of unfavourable clinical outcomes was a lower BAZ. We support the current WHO-recommended dosing regimen for isoniazid. To equalise and attain our pharmacological target for all children, dosing regimens could be adjusted on NAT2 genotype and nutritional status.

BACKGROUND:High-dose rifampicin could potentially shorten tuberculosis preventive therapy (TPT) and improve outcomes. We aimed to characterize population pharmacokinetics of standard- and high-dose rifampicin for TPT among individuals with tuberculosis infection. METHODS:Intensive and sparse pharmacokinetic substudies were conducted in Indonesia, Canada, and Vietnam within the 2R2 randomized trial, which compared 2 months of high-dose rifampicin at 20 mg/kg/day (2R20) or 30 mg/kg/day (2R30) with 4 months of standard-dose rifampicin at 10 mg/kg/day (4R10) in adults and adolescents aged ≥ 10 years. Venous blood samples were collected after 4 weeks of treatment. Rifampicin pharmacokinetics were analyzed using nonlinear mixed-effects modeling in NONMEM. RESULTS:Among 1368 trial participants, 440 were included in model development (51 intensive and 389 sparse sampling), with 191 (43%) assigned to 4R10, 159 (36%) to 2R20, and 90 (20%) to 2R30. A 1-compartment model with saturable hepatic extraction and transit-compartment absorption best described rifampicin pharmacokinetics. All disposition parameters were allometrically scaled using fat-free mass. Country-specific differences, particularly variation in drug formulation, were associated with lower bioavailability in Canada {-21.8% (95% confidence interval [CI] -27.9 to -18.0%)} and Vietnam (-12.3% [95% CI -17.7 to -7.9%]) compared with Indonesia. The 24-hour area under the concentration-time curve increased more than proportionally with dose and was higher across treatment arms in Indonesia, followed by Vietnam and Canada. CONCLUSIONS:High-dose rifampicin for TPT resulted in greater-than-proportional increases in exposure due to nonlinear clearance at higher doses. Substantial between-country variability in exposure was observed, which may have been due to multiple factors, including differences in country-specific formulations, fat-free mass, and unmeasured confounders.

This meta-analysis evaluated the safety and efficacy of linezolid-containing regimens for multidrug/rifampicin-resistant tuberculosis. Seven databases (January 2001-February 2026) were searched for randomized controlled trials comparing linezolid-containing regimens with standard of care (SOC). Pooled risk differences (RDs) and 95% confidence intervals (CIs) were estimated using random-effects models. Across 12 included studies (n = 3019), linezolid-containing regimens did not significantly increase myelosuppression or gastrointestinal, renal, and hepatic disorders. However, peripheral neuropathy (RD 0.043 [95% CI 0.005-0.081]) was higher compared with SOC. Lower doses or shorter linezolid durations were associated with fewer adverse events (AEs) and less AE-related treatment discontinuation. The linezolid group had fewer unfavorable outcomes (RD -0.150 [95% CI -0.211 to -0.089]) and higher sputum culture conversion (RD 0.047 [95% CI 0.003-0.092]). Lower-dose (≤600 mg) or shorter-duration (≤9 months) regimens demonstrated improved efficacy than SOC, with comparable tolerability. These findings support linezolid's key role in WHO-recommended regimens, informing safe and more effective TB care globally.

BACKGROUND:Tuberculosis (TB) remains one of the most globally impactful infectious diseases, with a recorded mortality of 1.6 million in 2022. In Romania and Ukraine, two high burden countries in the context of the WHO European region, treatment is geared towards cure; however, this path is paved with significant challenges, from morbidity to loss to follow-up. METHODS:A retrospective study was performed for drug-susceptible TB patients hospitalised in three TB expertise centres in Romania and Ukraine using routinely collected data. Univariable and multivariable logistic regression analyses were used to assess predictors of three treatment outcomes: unfavourable outcomes, loss to follow-up, and death. RESULTS:A total of 838 patients diagnosed with drug-susceptible TB were included. Median hospitalisation was 39 days (IQR 25-67), and treatment duration was 7 months (IQR 6-8). Predictive variables differed by outcome. For unfavourable outcomes, the multivariable model included age > 65 years, chronic kidney disease, at least one cavity on chest X-ray, underweight status, and persistently abnormal laboratory parameters despite intervention. Independent predictors of loss to follow-up were alcohol use, COPD, TB infection within two years prior to admission, obesity, slow treatment response, and sputum microscopy ≥2 + . Predictors of death included age > 65 years, male sex, cirrhosis, chronic kidney disease, underweight status, persistently abnormal laboratory parameters, and slow treatment response. CONCLUSION:Contextualising factors influencing drug-susceptible TB treatment outcomes in different settings can support the development of tailored interventions that enable early identification of patients at higher risk, thereby avoiding unnecessary treatment effects.

BACKGROUND:Data on childhood and adolescent multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in Indonesia are lacking. We aimed to assess clinical features, adverse events (AEs) and treatment outcomes of childhood and adolescent MDR/RR-TB. METHODS:A retrospective cohort study was performed in children and adolescents <18 years old treated for MDR/RR-TB at Hasan Sadikin General Hospital in Bandung, Indonesia, between June 2016 and March 2024. Multivariable logistic regression analyses were used to calculate adjusted odds ratios (aOR) for predictors of all-cause mortality. RESULTS:Among 84 included patients, 69 (82%) were adolescents 10-17 years of age, 54 (64%) were female, 54 (64%) were malnourished and 55 (65%) had culture-confirmed disease. Among 69 (82%) patients with known outcomes, 48 (70%) were successfully treated, 14 (20%) died (including 5 pretreatment deaths) and 7 (10%) were lost to follow-up (LTFU) (including 5 pretreatment LTFU). Predictors of all-cause mortality included shortness of breath on admission [aOR: 6.4, 95% confidence interval (CI): 1.3-49.1], high bacillary burden on Xpert MTB/RIF assay (aOR: 17.0, 95% CI: 1.6-260.5) and the presence of lung cavities on chest radiograph (aOR: 4.8, 95% CI: 1.1-23.3). Among 74 patients who initiated treatment, 39 (53%) had at least one grade 1-2 AE, and 4 (5%) had one grade 3-4 AE each, including hepatotoxicity, QT prolongation, hearing loss and rash/hyperpigmentation. CONCLUSION:Younger children were underrepresented among those treated for MDR/RR-TB, indicating reduced access to care. Severe AEs were uncommon during MDR/RR-TB treatment. Baseline indicators of extensive disease were associated with all-cause mortality. The high proportion of pre-treatment mortality and LTFU may reflect complex patient pathways limiting access to care.

BACKGROUND:Pharmacokinetic data of rifampin, when used for tuberculosis preventive treatment (TPT) are not available. We aimed to describe the pharmacokinetics of rifampin used for TPT, at standard and higher doses, and to assess predictors of rifampin exposure. METHODS:A pharmacokinetic sub-study was performed in Bandung, Indonesia among participants in the 2R2 randomized trial, which compared TPT regimens of 2 months of high-dose rifampin at 20 mg/kg/day (2R20) and 30 mg/kg/day (2R30), with 4 months of standard-dose rifampin at 10 mg/kg/day (4R10) in adolescents and adults. Intensive pharmacokinetic sampling was performed after 2-8 weeks of treatment. Pharmacokinetic parameters were assessed non-compartmentally. Total exposure (AUC0-24) and peak concentration (Cmax) between arms were compared using one-way ANOVA and Tukey's post-hoc tests. Multivariable linear regression analyses were used to assess predictors of AUC0-24 and Cmax. RESULTS:We enrolled 51 participants in this study. In the 4R10, 2R20, and 2R30 arms, the geometric mean AUC0-24 was 68.0, 186.8, and 289.9 h⋅mg/L, and Cmax was 18.4, 36.7, and 54.4 mg/L, respectively; high interindividual variabilities were observed. Compared with the 4R10 arm, AUC0-24 and Cmax were significantly higher in the 2R20 and 2R30 arms (P < 0.001). Drug doses, body weight, and female sex were predictors of higher rifampin AUC0-24 and Cmax (P < 0.05). AUC0-24 and Cmax values were much higher than those previously reported in persons with TB disease. CONCLUSIONS:Doubling and tripling the rifampin dose led to three- and four-fold higher exposure compared to standard dose. Pharmacokinetic/pharmacodynamic modelling and simulations are warranted to support trials of shortening the duration of TPT regimens with high-dose rifampin.

Background :Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure-response relationships in RR/MDR-TB patients. Methods: We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18-65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10-15 mg/kg/day) for 9-11 months. Intensive pharmacokinetic sampling was performed after >= 2 weeks of treatment. Total plasma drug exposure (AUC(0-24)) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC(0-24)/MIC ratio of 85 and C-max/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. Results :We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC(0-24 )and Cmax were 35.4 h center dot mg/L and 8.5 mg/L, respectively. Lower AUC0-24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC(0-24)/MIC (n = 6/26) and C-max/MIC (n = 5/26). Lower isoniazid AUC0-24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04-0.89)]. Conclusions :Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

INTRODUCTION: Therapeutic drug monitoring (TDM) could improve TB treatment outcomes by avoiding drug toxicity or underdosing. In this study, we describe the patient burden in three TB centres in Romania and Ukraine with a TDM indication, as per the current guidelines, in order to estimate the feasibility of implementing TDM.METHODS: A retrospective multi-centre study was conducted at the Iasi Lung Hospital (Iasi, Romania), Bucharest Marius Nasta Institute (Bucharest, Romania) and Chernivtsi TB Centre (Chernivtsi, Ukraine) in adult hospitalised TB patients.RESULTS: A total of 927 participants were admitted, of whom 37.8% had at least one indication for TDM, the most frequent being slow response to TB treatment (202/345, 58.6%); 55.5% had at least one cavity present on chest X-ray. Patients with a TDM indication stayed in the hospital for a median of 67 days and took on average 2 months more to reach a successful TB outcome.CONCLUSION: TDM could be a valuable tool to improve management of selected TB patients. The decision on whether to perform TDM is often delayed by 2 months due to waiting for culture results after treatment initiation. A randomised control trial should be performed in order to define TDM's precise role in TB therapy.

BackgroundSuboptimal 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.MethodsWe 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 (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were 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 AUC0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis 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.

To the Editor—We read with interest the article by Thee et al [1], which reported high morbidity and mortality in children routinely treated for tuberculous meningitis (TBM) in 9 European countries, despite the low proportion of patients who presented with the most severe (grade 3) disease and ready availability of advanced supportive care [1]. The casefatality rate in this study (n = 10/104, 9.6%) was lower than global estimates in a recent meta-analysis (19.3%; 95% confidence interval [CI]: 14.0–26.1%), but the risk of neurological sequelae among survivors was high (n = 45/94, 47.9%) and comparable with global estimates (53.9%; 95% CI: 42.6–64.9%) [2]. Optimal treatment for childhood TBM remains unclear, and research should focus on optimizing mycobacterial killing and minimizing deleterious immunological responses to prevent and manage disease complications [3]. We agree with Thee et al [1] that the use of intensified antimicrobial therapy containing high-dose rifampicin and other anti-tuberculosis drugs with good cerebrospinal fluid penetration should be advocated. Based on real-world data from South Africa, a high-dose intensified regimen for 6 months composed of isoniazid, rifampicin, and ethionamide at 20 mg/kg/day and pyrazinamide at 40 mg/kg/day is currently recommended by the World Health Organization as an alternative treatment option for childhood TBM [4]. However, longer-term treatment recommendations will be strongly influenced by 2 ongoing clinical trials to shorten TBM treatment and hopefully improve TBM outcomes in children (TBM-KIDS: NCT02958709; SURE: ISRCTN40829906). A dysregulated host immune response with excessive inflammation and immune-mediated tissue damage contributes to TBM-related morbidity and mortality [3]. As the mainstay of host-directed therapy, corticosteroids have been shown to improve the TBM survival rate [5], but there is no evidence that corticosteroids reduce neurological morbidity and many children develop progressive brain pathology during TBM treatment, despite corticosteroid inclusion [2, 3]. Moreover, corticosteroids are ineffective in reducing cerebrospinal fluid tumor necrosis factor α (TNF-α), the key cytokine involved in the inflammatory response of childhood TBM and a potential major driver of adverse outcomes that occur despite adequate mycobacterial killing [6]. The use of anti–TNF-α agents is a promising approach to limit TNF-α–mediated immunopathology in children with TBM. Recently, 2 case series reported favorable treatment outcomes with infliximab, a monoclonal TNF-α antibody, in childhood and adult patients with TBM in whom the disease course was complicated by paradoxical reactions refractory to steroid treatment [7, 8]. Thalidomide, another anti–TNF-α agent, has also shown encouraging results from observational studies when used at low doses in children with TBM complications [9]; this drug was given in 8.6% of patients in Thee et al study [1]. Prospective clinical trials are warranted to assess the efficacy and safety of these drugs for severe paradoxical reactions, but potentially also for TBM in general given the frequency of severe immunemediated sequelae (mainly, irreversible stroke resulting from cerebral vasculitis) and the poor neurological outcomes achieved with standard treatment [3, 10]. When accompanied with effective antimicrobial therapy, we believe that suppressing TNF-α–mediated inflammation has the potential to reduce long-term neurological sequelae. Additional studies on the value of highdose aspirin for treatment of cerebral vasculitis, and other new or repurposed host-directed therapies based on new knowledge from pathogenesis studies, are also warranted [3]. It is clear that improved childhood TBM treatment outcomes require optimization of both antimicrobial and antiinflammation treatment, with optimal rifampicin and other anti-TB drug dosing and consideration of immunomodulatory treatment beyond corticosteroids.

Objective — to conduct a retrospective analysis of factors that affect the results of treatment of patients with tuberculosis. Materials and methods. A retrospective multi-center study was conducted on adult (> 18 years) patients diagnosed with drug-sensitive susceptible TB of any form and initiated treatment between 1st of January 2019 — 31st of December 2019. The Bucharest Marius Nasta Institute, the Iasi Lung Hospital in Romania, and Chernivtsi TB Centre in Ukraine participated in this study. The study was approved by the ethics committee of each centre (Iassi: 5483/2021, Bucharest: 10592/2019, Chernivtsi: 234/2021,). The need for written informed consent was waived due to the retrospective nature of this study. Results and discussion. It is important to study the factors that influence the course and effectiveness of TB treatment, as they can be useful for the development of new methods of diagnosis and treatment. Our retrospective study identified such factors in an Eastern European population. The risk of adverse consequences increases for the elderly, people without a permanent place of residence, patients with already diagnosed chronic kidney disease, the presence of cavities on a chest X-ray, rapid relapse of TB, under­weight or obesity.These factors may help tailor care to specific populations and may lead to improved TB scoring systems to identify patients at risk of treatment failure. Conclusions. Our study presented common risk factors for unfavourable outcomes with previous research, including age, sex, nutritional status, lifestyle, comorbidities, TB-related parameters, but introduced a new, paraclinical parameter, and highlighted differences for East Europe.

We retrospectively evaluated clinical features and outcomes in children treated for tuberculous meningitis (TBM) at Hasan Sadikin Hospital, Bandung, Indonesia, during 2011-2020. Among 283 patients, 153 (54.1%) were <5 years of age, and 226 (79.9%) had stage II or III TBM. Predictors of in-hospital death (n = 44 [15.5%]) were stage III TBM, hydrocephalus, male sex, low-income parents, seizures at admission, and lack of bacillus Calmette-Guérin vaccination. Predictors of postdischarge death (n = 18 [6.4%]) were hydrocephalus, tuberculoma, and lack of bacillus Calmette-Guérin vaccination. At treatment completion, 91 (32.1%) patients were documented to have survived, of whom 33 (36.3%) had severe neurologic sequelae and 118 (41.7%) had unknown outcomes. Predictors of severe neurologic sequelae were baseline temperature >38°C, stage III TBM, and baseline motor deficit. Despite treatment, childhood TBM in Indonesia causes substantial neurologic sequelae and death, highlighting the importance of improved early diagnosis, better tuberculosis prevention, and optimized TBM management strategies.

Objective To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM). Design Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis. Setting Hasan Sadikin Hospital, Bandung, Indonesia. Patients Individuals aged 0–18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines. Interventions Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment. Main outcome measures Plasma exposures during the daily dosing interval (AUC0–24), peak plasma concentrations (C max) and CSF concentrations. Results Among 20 eligible patients, geometric mean AUC0–24 of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC0–24 and C max of all drugs. All patients had suboptimal rifampicin AUC0–24 for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2–3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC0–24 of isoniazid, rifampicin and pyrazinamide along with C max of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05). Conclusion Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies. Children with TB meningitis do poorly, and this paper examines the pharmacokinetics of a commonly used drug combination to understand if drug factors contribute.

Background Tuberculosis (TB) in children and adolescents is a sentinel event for ongoing transmission. In the Netherlands, epidemiological characteristics of childhood and adolescent TB have not been fully evaluated. Therefore, we aimed to assess TB epidemiology within this population to provide guidance for TB elimination. Methods A retrospective time-series analysis using national surveillance data from 1993–2018 was performed in children (aged <15 years) and adolescents (aged 15–19 years) with TB. Poisson regression models offset with log-population size were used to estimate notification rates and rate ratios. Trends in notification rates were estimated using average annual percentage changes (AAPC) based on the segmented linear regression analysis. Results Among 3899 children and adolescents with TB notified during 1993–2018, 2418 (62%) were foreign-born (725 (41.3%) out of 1755 children and 1693 (78.9%) out of 2144 adolescents). The overall notification rate in children was 2.3 per 100 000 person-years, declining steadily during the study period (AAPC −10.9%, 95% CI −12.6–−9.1). In adolescents, the overall notification rate was 8.4 per 100 000 person-years, strongly increasing during 1993–2001 and 2012–2018. Compared to Dutch-born children and adolescents, substantially higher notification rates were observed among African-born children and adolescents (116.8 and 316.6 per 100 000 person-years, respectively). Additionally, an increasing trend was observed in African-born adolescents (AAPC 18.5%, 95% CI 11.9–25.5). Among the foreign-born population, those from countries in the horn of Africa contributed most to the TB caseload. Conclusion TB notification rate among children was low and constantly declining across different demographic groups. However, heterogeneities were shown in adolescents, with an increasing trend in the foreign-born, particularly those from Africa.

BACKGROUND: Despite considerable efforts to globally eradicate TB, and the availability of effective antibiotics, TB elimination goals are falling behind. While non-adherence to TB drug regimens may compromise effective treatment, its full impact is still unknown. OBJECTIVE: To determine the clinical and economic impact of non-adherence to TB medication on treatment outcomes in drug-susceptible TB patients (DS-TB). METHODS: A systematic review was performed using PubMed and Embase for studies published between 2009 and 2019 reporting associations between adherence and WHO-defined TB treatment outcomes and economic outcomes in DS-TB patients. RESULTS: A total of 14 studies were included. Eight focused on the association between non-adherence and death, 2 on treatment failure, 1 study on successful treatment outcome, 1 study on both successful and unsuccessful treatment outcomes and 2 on cost outcomes. Most studies (71.4%) were retrospective cohort or case-control studies. The results showed that non-adherence to TB drug regimens was associated with death, treatment failure and lower cure rates. CONCLUSION: Non-adherence to TB drugs has a profound impact on both clinical and economic TB outcomes. To reach WHO TB elimination goals, preventing non-adherence and the implementation of cost-effective intervention programmes should receive the highest priority.