Factors associated with screening failure and study withdrawal in multidrug-resistant TB.

SETTING: Multidrug-resistant TB (MDR-TB) clinical trial in Lima, Peru and Cape Town, South Africa.OBJECTIVE: To identify baseline factors associated with screening failure and study withdrawal in an MDR-TB clinical trial.DESIGN: We screened patients for a randomized, blinded, Phase II trial which assessed culture conversion over the first 6 months of treatment with varying doses of levofloxacin plus an optimized background regimen (ClinicalTrials.gov: NCT01918397). We identified factors for screening failure and study withdrawal using Poisson regression to calculate prevalence ratios and Cox proportional hazard regression to calculate hazard ratios. We adjusted for factors with P < 0.2.RESULTS: Of the 255 patients screened, 144 (56.5%) failed screening. The most common reason for screening failure was an unsuitable resistance profile on sputum-based molecular susceptibility testing (n = 105, 72.9%). No significant baseline predictors of screening failure were identified in the multivariable model. Of the 111 who were enrolled, 33 (30%) failed to complete treatment, mostly for non-adherence and consent withdrawal. No baseline factors predicted study withdrawal in the multivariable model.CONCLUSION: No baseline factors were independently associated with either screening failure or study withdrawal in this secondary analysis of a MDR-TB clinical trial.

The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis.

BACKGROUND: Previous evidence synthesis has suggested diabetes mellitus (DM) worsens tuberculosis (TB) treatment outcomes. However, these reviews are limited by the number, robustness and conflicting results among the studies included. We conducted a systematic review to update earlier analyses and explore heterogeneity among studies.METHODS: MEDLINE, EMBASE, AIM, LILACS, IMEMR, IMSEAR and WPRIM were searched between 1 January 1980 and 23 July 2018 unrestricted by language or region. All cohort and case-control studies investigating the difference in TB treatment outcomes amongst TB-DM patients compared to those with TB alone were included. Two reviewers independently assessed titles, abstracts, and extracted data. Culture conversion at two/three months, all-cause mortality, treatment failure, relapse and multidrug-resistant TB (MDR-TB) were evaluated using random effects meta-analysis with generic inverse variance. Heterogeneity was explored using subgroup analyses and meta-regression.RESULTS: One hundred and four publications were identified. Sixty-four studies including 56 122 individuals with TB-DM and 243 035 with TB, reported on death. Some outcomes showed substantial heterogeneity between studies, which we could not fully explain, though confounding adjustment and country income level accounted for some of the differences. TB-DM patients had higher odds of death (OR 1.88, 95%CI 1.59-2.21) and relapse (OR 1.64, 95%CI 1.29-2.08) compared to TB patients. More limited evidence suggested TB-DM patients had double the risk of developing MDR-TB (OR 1.98, 95%CI 1.51-2.60).CONCLUSION: DM is associated with increased risks of poor TB treatment outcomes, particularly mortality, and may increase risk of developing primary MDR-TB. Cost-effectiveness of interventions to enhance TB-DM treatment should be assessed.

Point of care HbA1c level for diabetes mellitus management and its accuracy among tuberculosis patients: a study in four countries.

BACKGROUND: Diabetes mellitus (DM) is common among tuberculosis (TB) patients and often undiagnosed or poorly controlled. We compared point of care (POC) with laboratory glycated haemoglobin (HbA1c) testing among newly diagnosed TB patients to assess POC test accuracy, safety and acceptability in settings in which immediate access to DM services may be difficult. METHODS: We measured POC and accredited laboratory HbA1c (using high-performance liquid chromatography) in 1942 TB patients aged 18 years recruited from Peru, Romania, Indonesia and South Africa. We calculated overall agreement and individual variation (mean ± 2 standard deviations) stratified by country, age, sex, body mass index (BMI), HbA1c level and comorbidities (anaemia, human immunodeficiency virus [HIV]). We used an error grid approach to identify disagreement that could raise significant concerns. RESULTS: Overall mean POC HbA1c values were modestly higher than laboratory HbA1c levels by 0.1% units (95%CI 0.1-0.2); however, there was a substantial discrepancy for those with severe anaemia (1.1% HbA1c, 95%CI 0.7-1.5). For 89.6% of 1942 patients, both values indicated the same DM status (no DM, HbA1c <6.5%) or had acceptable deviation (relative difference <6%). Individual agreement was variable, with POC values up to 1.8% units higher or 1.6% lower. For a minority, use of POC HbA1c alone could result in error leading to potential overtreatment (n = 40, 2.1%) or undertreatment (n = 1, 0.1%). The remainder had moderate disagreement, which was less likely to influence clinical decisions. CONCLUSION: POC HbA1c is pragmatic and sufficiently accurate to screen for hyperglycaemia and DM risk among TB patients.

Diabetes and poor tuberculosis treatment outcomes: issues and implications in data interpretation and analysis.

Tuberculosis (TB) remains one of the 10 leading causes of death worldwide, especially in low- and middle-income countries. We conducted a systematic review and meta-analysis including 88 studies examining the association between diabetes mellitus (DM) and TB treatment outcomes. However, we found several common methodological problems among them, including inappropriate adjustments for confounding factors, not using optimal statistical methods for 'time to event' data, misclassification in exposure (DM) and outcomes (TB treatment outcomes) due to study design and non-standardisation of definitions, misunderstanding of basic study design concept, standardisation of TB treatment outcomes and quality control of publications. Many of these problems would apply more broadly to other 'risk factors' for poor TB treatment outcomes. These issues need to be addressed and resolved to improve the quality of the studies and provide more accurate results for policy makers in the future to tackle the burden of TB.

Matrix metalloproteinases in tuberculosis.

Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB.