Sustained TB infection overproduces reactive oxygen species (ROS) as a host defense mechanism. Research shows ROS is destructive to lung tissue. Glutathione (GSH) neutralizes ROS, although it is consumed. NAC is a precursor of GSH synthesis, and administering an appropriate dose of NAC to patients with respiratory conditions may enhance lung recovery and replenish GSH. The present review searched for articles reporting on the effects of NAC in TB treatment from 1960 to 31 May 2022. The PICO search strategy was used in Google Scholar, PubMed, SciFinder, and Wiley online library databases. The COVIDENCE tool was used to delete inappropriate content. We eventually discovered five clinical trials, one case report, seven reviews, in vitro research, and four experimental animal studies from the twenty-four accepted articles. The use of NAC resulted in increased GSH levels, decreased treatment time, and was safe with minimal adverse events. However, the evidence is currently insufficient to estimate the overall effects of NAC, thus the study warrants more NAC clinical trials to demonstrate its effects in TB treatment.

Half the global tuberculosis health burden is due to post-tuberculosis lung disease. Host-directed therapies have been proposed to reduce this burden. N-acetylcysteine (NAC) provides the conditionally essential amino acid cysteine required for synthesis of glutathione, an antioxidant thiol. We recently reported clinical outcomes of a trial of adjunctive NAC in patients with pulmonary tuberculosis, finding that NAC improved the secondary endpoint of recovery of lung function. Here we report the effects of NAC on biomarkers of oxidation, inflammation, and infection in that trial. 140 adults with moderate or far-advanced pulmonary tuberculosis were randomly assigned to standard tuberculosis treatment with or without NAC 1200 mg twice daily for months 1-4. Sputum and blood samples were obtained at specified intervals to measure total glutathione, MTB-induced cytokines, hemoglobin, whole blood mycobactericidal activity (WBA), and sputum MTB burden. NAC treatment rapidly increased total glutathione (P<.0001), but levels did not reach those of healthy volunteers (P<.001). NAC reduced MTB-induced TNF-α (P =.011) without affecting IL-10, and accelerated the recovery of hemoglobin in participants with low values on entry. NAC did not affect killing in ex vivo whole blood culture but did slow the clearance of MTB from sputum (P=0.003). Adjunctive NAC showed antioxidant and anti-inflammatory effects consistent with the amelioration of immunopathology seen in preclinical models. Two biomarkers of antimicrobial activity showed discordant results; neither demonstrated the enhanced antimicrobial effects seen preclinically. The reduction of oxidative stress and inflammation by NAC may explain its effects on the recovery of lung function post-TB.

Alternative tools are needed to improve the detection of M. tuberculosis (M. tb) in HIV co-infections. We evaluated the utility of Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) compared to lipoarabinomannan (LAM) to detect M. tb in urine. Sputum Xpert MTB/RIF-positive patients were consented to provide urine at baseline, weeks 2, 8, 16, and 24 of treatment for TB-MBLA, culture, and LAM. Results were compared with sputum cultures and microscopy. Initial M. tb. H37Rv spiking experiments were performed to validate the tests. A total of 63 urine samples from 47 patients were analyzed. The median age (IQR) was 38 (30–41) years; 25 (53.2%) were male, 3 (6.5%) had urine for all visits, 45 (95.7%) were HIV positive, of whom 18 (40%) had CD4 cell counts below 200 cells/µL, and 33 (73.3%) were on ART at enrollment. Overall urine LAM positivity was 14.3% compared to 4.8% with TB-MBLA. Culture and microscopy of their sputum counterparts were positive in 20.6% and 12.7% of patients, respectively. Of the three patients with urine and sputum at baseline, one (33.33%) had urine TB-MBLA and LAM positive compared to 100% with sputum MGIT culture positive. Spearman’s rank correction coefficient (r) between TB-MBLA and MGIT was −0.85 and 0.89 with a solid culture, p > 0.05. TB-MBLA has the promising potential to improve M. tb detection in urine of HIV-co-infected patients and complement current TB diagnostics.

Culture‐based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non‐culture‐based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB‐MBLA), could represent a solution. Our objectives were to evaluate TB‐MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modeling could provide insight into underlying biological processes. We generated TB‐MBLA (LifeArc) data from sputum samples from all 78 patients from the PanACEA BTZ‐043 Phase Ib/IIa trial and derived a summary measure of the joint distribution of the three TB‐MBLA, colony forming units (CFU), and time‐to‐positivity (TTP) biomarkers as the first principal component derived from a probabilistic principal component analysis (pPCA). With TB‐MBLA marker and the principal component 1 (PC1) values, we reevaluated the original stage IIa dose–response and stages Ib/IIa pharmacokinetics—pharmacodynamics (PK‐PD) exposure‐response analyses, applying linear and non‐linear mixed models, respectively. For TB‐MBLA, we could not detect an exposure‐response effect in the PK‐PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced E _max exposure–response between days 0–3 compared with CFU and TTP alone. We also successfully applied pPCA as a modeling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. In this study, we present novel EBA data for the first‐in‐class antimycobacterial compound BTZ‐043 and contextualize the value of emerging bacteriological markers within the EBA trial framework. Trial Registration: ClinicalTrials.gov identifier: NCT04044001

Culture-based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non-culture-based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB-MBLA), could represent a solution. Our objectives were to evaluate TB-MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modelling could provide insight into underlying biological processes and reduce data loss. We generated TB-MBLA (LifeArc ^(R) ) data from sputum samples from all 78 patients from the PanACEA BTZ-043 Phase Ib/IIa trial. In addition, we defined a joint biomarker as the first principal component derived from a probabilistic principal component analysis (pPCA) integrating TB-MBLA, colony forming units (CFU), and time-to-positivity (TTP) data. With TB-MBLA alone and the principal component 1 (PC1) marker we reevaluated the original stage IIa dose-response and stages Ib/IIa pharmacokinetics - pharmacodynamics (PK-PD) exposure-response analyses, applying linear and non-linear mixed models, respectively. For TB-MBLA, we could not detect an exposure-response effect in the PK-PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced Emax exposure–response between days 0–3 compared with CFU and TTP alone. We also successfully applied pPCA as a modelling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. STUDY HIGHLIGHTS: What is the current knowledge on the topic?: BTZ-043 is a first-in-class antimycobacterial compound with promising applications in drug-sensitive pulmonary tuberculosis. TB EBA trials are typically conducted using sputum culture assays for dose-exposure-response modelling, but the technical challenges of these assays limit their effectiveness. What question did this study address?: How does the novel RT-qPCR assay TB-MBLA perform as a dose-exposure response marker for novel antitubercular compound BTZ-043 and what are the effects of joint modelling approaches in EBA modelling tasks? What does this study add to our knowledge?: We did not observe a significant exposure response for BTZ-043 in TB-MBLA over the 14-day treatment window. Joint modelling with pPCA can overcome the issues of missing and contaminated data that are canonical of culture data from TB treatment monitoring cohorts. How might this change drug discovery, development, and/or therapeutics?: Designing EBA trials should consider the drug-bacterial subpopulation axis of the specific study drug to maximise efficiency. Latent variable modelling techniques can be an effective and efficient framework for modelling Mycobacterial tuberculosis load in EBA trials.