Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.

Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death. Clinical Trials Registration. NCT00332306.

Background Two-thirds of children with tuberculosis have non-severe disease. Method SHINE was an open-label treatment-shortening non-inferiority trial in children with non-severe, symptomatic, presumed drug-susceptible, smear-negative tuberculosis, in Uganda, Zambia, South Africa and India. Children aged <16 years were randomised to 16- versus 24-week standard first-line anti-tuberculosis treatment using WHO-recommended paediatric fixed-dose-combinations and a non-inferiority margin of 6% was used. The primary efficacy outcome was a composite of treatment failure, anti-tuberculosis treatment changes/restarts, on-treatment loss-to-follow-up, TB recurrence or death by 72 weeks, excluding children not reaching 16 weeks follow-up (modified-intent-to-treat). Primary safety outcome was on-treatment grade ≥3 adverse events. Results 1204 children (602 in each group) were enrolled between July 2016 and July 2018; median age 3.5 years (range 2 months-15 years), 52% male, 11% HIV-infected, 14% bacteriologically-confirmed tuberculosis. Retention by 72 weeks and adherence to allocated anti-tuberculosis treatment were 95% and 94%, respectively. Sixteen (3%) versus 18 (3%) children reached the primary efficacy outcome in 16- versus 24-week arms respectively: unadjusted difference -0.4%, 95% CI (-2.2, 1.5). Non-inferiority of 16-weeks was consistent across intention-to-treat, per-protocol and key secondary analyses including when restricting analysis to the 958 (80%) children independently adjudicated to have tuberculosis at baseline. 95 (8%) children experienced grade ≥3 adverse events, including 17 adverse reactions (11 hepatic, all except three occurred within first 8 weeks, when treatment arms were the same). Conclusions 4-months anti-tuberculosis treatment was non-inferior to 6 months for children treated for drug-susceptible non-severe smear-negative tuberculosis. (Supported by University College London; Trial Registration: ISRCTN 63579542)

The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (C max ) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median C max and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC 0 -8 ]) of INH (C max , 2.5 versus 5.1 g/ml, respectively [P ‫؍‬ 0.016]; AUC 0 -8 , 11.1 versus 22.0 g/ml · h, respectively [P ‫؍‬ 0.047[) and PZA (C max , 34.1 versus 42.3 g/ml, respectively [P ‫؍‬ 0.055]; AUC 0 -8 , 177.9 versus 221.7 g/ml · h, respectively [P ‫؍‬ 0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median C max of RMP (1.0 versus 2.8 g/ml, respectively; P ‫؍‬ 0.002) and PZA (31.9 versus 44.4 g/ml, respectively; P ‫؍‬ 0.045) were significantly lower. Among all factors studied, the PZA C max influenced TB treatment outcome (P ‫؍‬ 0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP C max . The PZA C max significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.

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This work aimed to evaluate the once-daily anti-tuberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4–7 kg) and/or human immunodeficiency virus (HIV) infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable). Model-based simulation of optimized (Punfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase respectively from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in development of future pediatric tuberculosis treatment guidelines.

IntroductionShorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study’s objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB.Methods and analysisWe are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of Mycobacterium tuberculosis in sputum, pharmacokinetics and pharmacogenomics of study drugs, drug–drug interactions, safety and tolerability of the various combinations and measurement of autophagy and immune responses in the study participants.Ethics and disseminationThe ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system.Trial registration numberCTRI/2018/01/011176; Pre-results.

BackgroundTuberculosis (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/designSHINE 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.DiscussionAlthough 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 registrationInternational 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.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2608-5) contains supplementary material, which is available to authorized users.