Search

Background: Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. Methods: Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577–87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. Results: For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16–30, p

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H) resistant (Hr) tuberculosis recommend a four-drug regimen- rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx)- with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance.METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure, disease recurrence).RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 [95% confidence interval 0.60-1.82], p-value 0.87; cluster NHS Trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57 [0.14-2.28]) when Hr genotype was included, but this analysis lacked power (p=0.42).CONCLUSIONS: In a high-income setting, we found a 12 month (H)RfZE regimen with a short Z duration to be similarly effective for Hr TB with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

Background Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. Methods Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577–87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. Results For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16–30, p

Background Trials to identify the minimal effective treatment duration are needed in different therapeutic areas, including bacterial infections, tuberculosis and hepatitis C. However, standard non-inferiority designs have several limitations, including arbitrariness of non-inferiority margins, choice of research arms and very large sample sizes. Methods We recast the problem of finding an appropriate non-inferior treatment duration in terms of modelling the entire duration–response curve within a pre-specified range. We propose a multi-arm randomised trial design, allocating patients to different treatment durations. We use fractional polynomials and spline-based methods to flexibly model the duration–response curve. We call this a ‘Durations design’. We compare different methods in terms of a scaled version of the area between true and estimated prediction curves. We evaluate sensitivity to key design parameters, including sample size, number and position of arms. Results A total sample size of ~ 500 patients divided into a moderate number of equidistant arms (5–7) is sufficient to estimate the duration–response curve within a 5% error margin in 95% of the simulations. Fractional polynomials provide similar or better results than spline-based methods in most scenarios. Conclusion Our proposed practical randomised trial ‘Durations design’ shows promising performance in the estimation of the duration–response curve; subject to a pending careful investigation of its inferential properties, it provides a potential alternative to standard non-inferiority designs, avoiding many of their limitations, and yet being fairly robust to different possible duration–response curves. The trial outcome is the whole duration–response curve, which may be used by clinicians and policymakers to make informed decisions, facilitating a move away from a forced binary hypothesis testing paradigm.

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.).