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.).

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.

Drug concentration at the site of disease in children with pulmonary tuberculosis.

BACKGROUND: Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. OBJECTIVES: To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. METHODS: We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. RESULTS: Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. CONCLUSIONS: Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.

Accuracy of Xpert Ultra in Diagnosis of Pulmonary Tuberculosis among Children in Uganda: a Substudy from the SHINE Trial.

Childhood tuberculosis (TB) presents significant diagnostic challenges associated with paucibacillary disease and requires a more sensitive test. We evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Ultra) compared to other microbiological tests using respiratory samples from Ugandan children in the SHINE trial. SHINE is a randomized trial evaluating shorter treatment in 1,204 children with minimal TB disease in Africa and India. Among 352 samples and one cervical lymph node fine needle aspirate, one sample was randomly selected per patient and tested with the Xpert MTB/RIF assay (Xpert) and with Lowenstein-Jensen medium (LJ) and liquid mycobacterial growth indicator tube (MGIT) cultures. We selected only uncontaminated stored sample pellets for Ultra testing. We estimated the sensitivity of Xpert and Ultra against culture and a composite microbiological reference standard (any positive result). Of 398 children, 353 (89%) had culture, Xpert, and Ultra results. The median age was 2.8 years (interquartile range [IQR], 1.3 to 5.3); 8.5% (30/353) were HIV infected, and 54.4% (192/353) were male. Of the 353, 31 (9%) were positive by LJ and/or MGIT culture, 36 (10%) by Ultra, and 16 (5%) by Xpert. Sensitivities (95% confidence intervals [CI]) were 58% (39 to 65% [18/31]) for Ultra and 45% (27 to 64% [14/31]) for Xpert against any culture-positive result, with false positives of <1% and 5.5% for Xpert and Ultra. Against a composite microbiological reference, sensitivities were 72% (58 to 84% [36/50]) for Ultra and 32% (20 to 47% [16/50]) for Xpert. However, there were 17 samples that were positive only with Ultra (majority trace). Among children screened for minimal TB in Uganda, Ultra has higher sensitivity than Xpert. This represents an important advance for a condition which has posed a diagnostic challenge for decades.

Molecular Detection of Mycobacterium tuberculosis from Stools in Young Children by Use of a Novel Centrifugation-Free Processing Method.

The microbiological diagnosis of tuberculosis (TB) in children is challenging, as it relies on the collection of relatively invasive specimens by trained health care workers, which is not feasible in many settings. Mycobacterium tuberculosis is detectable from the stools of children using molecular methods, but processing stool specimens is resource intensive. We evaluated a novel, simple, centrifugation-free processing method for stool specimens for use on the Xpert MTB/RIF assay (Xpert), using two different stool masses: 0.6 g and a swab sample. Two hundred eighty children (median age, 15.5 months; 35 [12.5%] HIV infected) with suspected intrathoracic TB were enrolled from two sites in South Africa. Compared to a single Xpert test on respiratory specimens, the sensitivity of Xpert on stools using the 0.6-g and swab samples was 44.4% (95% confidence interval [CI], 13.7 to 78.8%) for both methods, with a specificity of >99%. The combined sensitivities of two stool tests versus the first respiratory Xpert were 70.0% (95% CI, 34.8 to 93.3) and 50.0% (95% CI, 18.7 to 81.3) for the 0.6-g and swab sample, respectively. Retesting stool specimens with nondeterminate Xpert results improved nondeterminate rates from 9.3% to 3.9% and from 8.6% to 4.3% for 0.6-g and swab samples, respectively. Overall, stool Xpert detected 14/94 (14.9%) children who initiated antituberculosis treatment, while respiratory specimens detected 23/94 (24.5%). This stool processing method is well suited for settings with low capacity for respiratory specimen collection. However, the overall sensitivity to detect confirmed and clinical TB was lower than that of respiratory specimens. More sensitive rapid molecular assays are needed to improve the utility of stools for the diagnosis of intrathoracic TB in children from resource-limited settings.

Stool Culture for Diagnosis of Pulmonary Tuberculosis in Children.

Bacteriological confirmation of Mycobacterium tuberculosis is achieved in the minority of young children with tuberculosis (TB), since specimen collection is resource intensive and respiratory secretions are mostly paucibacillary, leading to limited sensitivity of available diagnostic tests. Although molecular tests are increasingly available globally, mycobacterial culture remains the gold standard for diagnosis and determination of drug susceptibility and is more sensitive than molecular methods for paucibacillary TB. We evaluated stool culture as an alternative to respiratory specimens for the diagnosis of suspected intrathoracic TB in a subgroup of 188 children (median age, 14.4 months; 15.4% HIV infected) enrolled in a TB diagnostic study at two local hospitals in Cape Town, South Africa. One stool culture was compared to overall bacteriological confirmation by stool Xpert and by Xpert and culture of multiple respiratory specimens. After decontamination/digestion with NALC (N-acetyl-l-cysteine)-NaOH (1.25%), concentrated fluorescent smear microscopy, Xpert MTB/RIF, and liquid culture were completed for all specimens. Culture contamination of stool specimens was high at 41.5%. Seven of 90 (7.8%) children initiating TB treatment were stool culture positive for M. tuberculosis Excluding contaminated cultures, the sensitivity of stool culture versus confirmed TB was 6/25 (24.0%; 95% confidence interval [CI] = 9.4 to 45.1%). In addition, stool culture detected TB in 1/93 (1.1%) children with "unconfirmed TB." Testing the same stool by Xpert increased sensitivity to 33.3% (95% CI = 18.0 to 51.8%). In conclusion, stool culture had low sensitivity for M. tuberculosis detection in children with intrathoracic TB. Reducing culture contamination through improved laboratory protocols may enable more reliable estimates of its diagnostic utility.

Direct Susceptibility Testing of Mycobacterium tuberculosis for Pyrazinamide by Use of the Bactec MGIT 960 System.

Pyrazinamide (PZA) is a key antituberculosis drug, yet no rapid susceptibility test is commercially available. PZA drug susceptibility testing (DST) was performed directly on sputum samples from 327 patients and compared with the indirect method by using the Bactec MGIT 960 system in the context of patient screening for participation in a drug trial. Compared to standard indirect PZA DST, direct DST was successful in only 59% of cases, but results obtained were highly accurate and available faster. Agreement between the direct and indirect methods varied from 90 to 100% in each laboratory. The median times for obtaining PZA results from the time when the specimen was collected ranged from 11 to 16 days for the direct test and 18 to 95 days for the indirect test across laboratories. The direct method is accurate and reproducible across laboratories. It can be expected to accelerate results in >50% of cases, but it cannot replace indirect DST for PZA. Phenotypic methods remain the gold standard for DST in drug trials. If future studies can optimize the method to decrease the number of uninterpretable results, direct MGIT DST could be the new phenotypic DST standard for clinical trials, providing more rapid detection of resistance to new drugs in experimental regimens.

Epidemiology and clinical management of tuberculosis in children in Canada.

Although often regarded as a foreign disease, latent tuberculosis or tuberculosis disease will be encountered in many clinical situations by the Canadian child health practitioner. There are key differences between tuberculosis in children and adults. In the present article, the changing epidemiology of tuberculosis in children in Canada and around the world, the pathogenesis of infection, diagnostic tests, and clinical management of childhood latent tuberculosis and tuberculosis disease are reviewed.

Même si la tuberculose latente et la tuberculose sont souvent considérées comme des maladies étrangères, le dispensateur canadien de soins des enfants les observera souvent dans bien des situations cliniques. Il y a des différences clés entre la tuberculose chez l'enfant et chez l'adulte. Dans le présent article, les auteurs analysent l'évolution de l'épidémiologie de la tuberculose chez les enfants du Canada et de l'étranger, la pathogenèse de l'infection, les tests diagnostiques et la prise en charge de la tuberculose latente et de la tuberculose pendant l'enfance.

Quantitation of Circulating Mycobacterium tuberculosis Antigens by Nanopore Biosensing in Children Evaluated for Pulmonary Tuberculosis in South Africa.

Nanopore sensing of proteomic biomarkers lacks accuracy due to the ultralow abundance of targets, a wide variety of interferents in clinical samples, and the mismatch between pore and analyte sizes. By converting antigens to DNA probes via click chemistry and quantifying their characteristic signals, we show a nanopore assay with several amplification mechanisms to achieve an attomolar level limit of detection that enables quantitation of the circulating Mycobacterium tuberculosis (Mtb) antigen ESAT-6/CFP-10 complex in human serum. The assay's nonsputum-based feature and low-volume sample requirements make it particularly well-suited for detecting pediatric tuberculosis (TB) disease, where establishing an accurate diagnosis is greatly complicated by the paucibacillary nature of respiratory secretions, nonspecific symptoms, and challenges with sample collection. In the clinical assessment, the assay was applied to analyze ESAT-6/CFP-10 levels in serum samples collected during baseline investigation for TB in 75 children, aged 0-12 years, enrolled in a diagnostic study conducted in Cape Town, South Africa. This nanopore assay showed superior sensitivity in children with confirmed TB (94.4%) compared to clinical "gold standard" diagnostic technologies (Xpert MTB/RIF 44.4% and Mtb culture 72.2%) and filled the diagnostic gap for children with unconfirmed TB, where these traditional technologies fell short. We envision that, in combination with automated sample processing and portable nanopore devices, this methodology will offer a powerful tool to support the diagnosis of pulmonary TB in children.

High yield of culture-based diagnosis in a TB-endemic setting.

BACKGROUND: In most of the world, microbiologic diagnosis of tuberculosis (TB) is limited to microscopy. Recent guidelines recommend culture-based diagnosis where feasible. METHODS: In order to evaluate the relative and absolute incremental diagnostic yield of culture-based diagnosis in a high-incidence community in Cape Town, South Africa, subjects evaluated for suspected TB had their samples processed for microscopy and culture over a 21 month period. RESULTS: For 2537 suspect episodes with 2 smears and 2 cultures done, 20.0% (508) had at least one positive smear and 29.9% (760) had at least one positive culture. One culture yielded 1.8 times more cases as 1 smear (relative yield), or an increase of 12.0% (absolute yield). Based on the latter value, the number of cultures needed to diagnose (NND) one extra case of TB was 8, compared to 19 if second specimens were submitted for microscopy. CONCLUSION: In a high-burden setting, the introduction of culture can markedly increase TB diagnosis over microscopy. The concept of number needed to diagnose can help in comparing incremental yield of diagnosis methods. Although new promising diagnostic molecular methods are being implemented, TB culture is still the gold standard.

High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-resistant Tuberculosis.

BACKGROUND: Household contact (HHC) investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited. METHODS: In preparation for and to inform the feasibility of an interventional trial, HHC of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon-gamma release assay and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (<15 years) HHCs. RESULTS: Of 303 child HHCs, median age (range) 7 years (0-14), 57% [95% confidence interval (CI): 50%-64%] had a positive interferon-gamma release assay result (TB infected). TB infection was associated with the index case smoking (P = 0.034), being the parent or sleeping in the same room (P = 0.002) and the child HHC being age ≥5 years and having attended school (P = 0.013). Four had study-defined confirmed TB and 9 had probable TB, a prevalence of 4.3% (95% CI: 2.6%-7.1%). Using the international consensus definitions, 4 had confirmed TB and 49 had unconfirmed TB, a prevalence of 17.2% (95% CI: 12.9%-22.4%). Twenty (7%) children had received TPT. CONCLUSIONS: The prevalence of TB infection and disease was high in child HHC exposed to rifampin-resistant TB. Few children had routinely received TPT. High-quality evidence is needed to inform strong recommendations for and access to TPT in children exposed to TB resistant to rifampin.

Association between clinical and environmental factors and the gut microbiota profiles in young South African children.

Differences in the microbiota in populations over age and geographical locations complicate cross-study comparisons, and it is therefore essential to describe the baseline or control microbiota in each population. This includes the determination of the influence of demographic, clinical and environmental factors on the microbiota in a setting, and elucidates possible bias introduced by these factors, prior to further investigations. Little is known about the microbiota of children in South Africa after infancy. We provide a detailed description of the gut microbiota profiles of children from urban Cape Town and describe the influences of various clinical and environmental factors in different age groups during the first 5 years of life. Prevotella was the most common genus identified in the participants, and after infancy, the gut bacteria were dominated by Firmicutes and Bacteroidetes. In this setting, children exposed to antibiotics and indoor cooking fires were at the most risk for dysbiosis, showing significant losses in gut bacterial diversity.

Positive Mycobacterium tuberculosis Gastric Lavage Cultures from Asymptomatic Children With Normal Chest Radiography.

Mycobacterium tuberculosis culture from gastric lavage from apparently healthy children following tuberculin skin test conversion, despite normal chest radiography (CR), is well known but is a contentious subject. A consensus statement regarding classification of childhood tuberculosis excluded this condition, stating that more data were needed. To assist in this discussion, we reviewed early publications that reported the occurrence of this phenomenon and early anatomical pathology studies that described changes that occur in children following tuberculosis infection. Pathology studies describe frequent cavitation in primary foci in children from whom positive M. tuberculosis cultures might easily arise. These foci were very small in some children who might have normal CR. Positive cultures might also arise from ulcerated mediastinal lymph nodes that are invisible on CR. Young children with recent infection very likely have active primary pulmonary tuberculosis.

Diagnostic utility of bronchoalveolar lavage in children with complicated intrathoracic tuberculosis.

INTRODUCTION: Bronchoscopy can be a useful tool in children with pulmonary tuberculosis (PTB) with severe disease potentially requiring intervention or in the face of diagnostic dilemmas. The aim of this study was to determine the value of Xpert MTB/RIF assay (Xpert) on bronchoalveolar lavage (BAL) samples in children with complicated PTB. METHODS: Retrospective analysis of children with clinically diagnosed PTB, who underwent routine bronchoscopy over a 5-year period at a large referral hospital. BAL and other respiratory samples were tested by microscopy, culture, and Xpert. We explored whether clinical, radiographic and bronchoscopy findings, and duration of antituberculosis treatment were associated with bacteriological confirmation. RESULTS: One hundred and twelve out of one hundred and forty-six (76.7%) children (median age 16 months) were on antituberculosis treatment for a median of 10 days at the time of bronchoscopy. Overall, bacteriological confirmation was achieved in 115 (78.7%), with 101 (69.2%) detected on BAL. Of those bacteriologically confirmed on BAL, 61.4% were positive by both Xpert and culture, 34.7% only by Xpert, and 3.9% only by culture. Sensitivity and specificity of Xpert compared with culture on BAL samples for children not on antituberculosis treatment were 94.1% (95% confidence interval [CI]: 71.3, 99.8) and 68.7% (95% CI: 41.3, 89.0), respectively. CONCLUSIONS: In children undergoing bronchoscopy for complicated PTB, Xpert testing of BAL had a high diagnostic yield in children already on antituberculosis treatment. Bronchoscopy should be considered if noninvasive respiratory specimens fail to confirm complicated TB.

Trends in Drug Resistance in Childhood Tuberculosis in Cape Town, South Africa.

BACKGROUND: We determined mycobacterial drug resistance and HIV prevalence among children with bacteriologically confirmed tuberculosis (TB) from March 2013 to February 2017. Results were compared with 5 previous 2-year surveillance studies (2003-2013). METHODS: Prospective surveillance of all bacteriologically confirmed TB in children (0-13 years) completed at Tygerberg Hospital, Cape Town, South Africa. Drug susceptibility testing was done by GenoType MTBDRplus for isoniazid and rifampicin; ofloxacin and amikacin drug susceptibility testing was completed if rifampicin resistance was detected. Xpert MTB/RIF was routinely introduced during this period. RESULTS: Six hundred sixty-two children, median age 34 months (interquartile range 14-79) had bacteriologically confirmed TB; 587 (88.7%) were culture-confirmed and 75 (11.3%) confirmed by Xpert MTB/RIF only. Of culture-confirmed cases, 509 (86.7%) were pan-susceptible, 47 (8.0%) were multidrug-resistant, 13 (2.2%) were RIF-resistant/INH-susceptible and 18 (3.1%) were INH-resistant/RIF-susceptible. Of Xpert-positive cases, 3/75 (4%), 68/75 (92%) and 4/75 (5%) were RIF-resistant, RIF-susceptible and RIF-indeterminate, respectively. Of 573 (97.6%) children tested, 74 (12.9%) were HIV positive. Compared with previous surveillance periods, RIF mono-resistance increased from 0% to 2.2% (trend test: χ = 7.050, P = 0.0079). HIV prevalence decreased from 29% to 10.6% (trend test: χ = 27.975, P < 0.0001). Of multidrug-resistant cases, 15/47 (32%) were ofloxacin resistant. CONCLUSIONS: The increase in RIF-resistant/INH-susceptible cases and ofloxacin resistance among multidrug-resistant TB cases in children, indicative of recent transmission, is concerning. The prevalence of multidrug-resistant TB remains high in children.

Specimen Pooling as a Diagnostic Strategy for Microbiologic Confirmation in Children with Intrathoracic Tuberculosis.

Three-hundred four young children with suspected pulmonary tuberculosis had a gastric aspirate, induced sputum and nasopharyngeal aspirate collected on each of 2 consecutive weekdays. Specimens collected on the second day were pooled in the laboratory for each child individually. The diagnostic yield by Xpert and culture from pooled specimens was not significantly different to a single gastric aspirate.

Levofloxacin versus placebo for the prevention of tuberculosis disease in child contacts of multidrug-resistant tuberculosis: study protocol for a phase III cluster randomised controlled trial (TB-CHAMP).

BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. METHODS: The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15-20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18-24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. DISCUSSION: If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial.

BACKGROUND: Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed. METHODS/DESIGN: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations. DISCUSSION: Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number: ISRCTN63579542 , 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379 , 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017.