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Trials Apr 2024The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly...
A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT.
INTRODUCTION
The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China.
METHODS
This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18-65 years) in China. The trial design mainly mirrors that of the "Evaluation of a Standardized Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB" (STREAM) stage 2 study, while also incorporating programmatic data from South Africa and the 2019 consensus recommendations of Chinese MDR/RR-TB treatment experts. Experimental arm participants will receive a modified STREAM regimen C that replaces three group C drugs, ethambutol (EMB), pyrazinamide (PZA), and prothionamide (PTO), with two group B drugs, linezolid (LZD) and cycloserine (CS), while omitting high-dose isoniazid (INH) for confirmed INH-resistant cases. BDQ duration will be extended from 6 to 9 months for participants with Mycobacterium tuberculosis-positive sputum cultures at week 16. The control arm will receive a modified STREAM regimen B without high-dose INH and injectable kanamycin (KM) that incorporates experimental arm LZD and CS dosages, treatment durations, and administration methods. LZD (600 mg) will be given daily for ≥ 24 weeks as guided by observed benefits and harm. The primary outcome measures the proportion of participants with favorable treatment outcomes at treatment completion (week 40), while the same measurement taken at 48 weeks post-treatment completion is the secondary outcome. Assuming an α = 0.025 significance level (one-sided test), 80% power, 15% non-inferiority margin, and 10% lost to follow-up rate, each arm requires 106 participants (212 total) to demonstrate non-inferiority.
DISCUSSION
PROSPECT aims to assess the safety and efficacy of a BDQ-containing SCR MDR-TB treatment at seventeen sites across China, while also providing high-quality data to guide SCRs administration under the direction of the China National Tuberculosis Program for MDR-TB. Additionally, PROSPECT will explore the potential benefits of extending the administration of the 9-month BDQ-containing SCR for participants without sputum conversion by week 16.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05306223. Prospectively registered on 16 March 2022 at https://clinicaltrials.gov/ct2/show/NCT05306223?term=NCT05306223&draw=1&rank=1 {2}.
Topics: Adult; Humans; Antitubercular Agents; Clinical Trials, Phase IV as Topic; Diarylquinolines; Randomized Controlled Trials as Topic; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 38561815
DOI: 10.1186/s13063-024-07946-9 -
Journal of Clinical Medicine Feb 2020Accurate and timely detection of drug resistance can minimize the risk of further resistance development and lead to effective treatment. The aim of this study was to...
Accurate and timely detection of drug resistance can minimize the risk of further resistance development and lead to effective treatment. The aim of this study was to determine the resistance to first/second-line anti-tuberculosis drugs in rifampicin/multidrug-resistant (RR/MDR-MTB) isolates. Molecular epidemiology of strains was determined using whole genome sequencing (WGS)-based genotyping. A total of 35 RR/MDR-MTB isolates were subjected to drug susceptibility testing against first/second-line drugs using 7H9 Middlebrook in broth microdilution method. Illumina technology was used for paired-end WGS applying a Maxwell 16 Cell DNA Purification kit and the NextSeq platform. Data analysis and single nucleotide polymorphism calling were performed using MTBseq pipeline. The genome-based resistance to each drug among the resistant phenotypes was as follows: rifampicin (97.1%), isoniazid (96.6%), ethambutol (100%), levofloxacin (83.3%), moxifloxacin (83.3%), amikacin (100%), kanamycin (100%), capreomycin (100%), prothionamide (100%), D-cycloserine (11.1%), clofazimine (20%), bedaquiline (0.0%), and delamanid (44.4%). There was no linezolid-resistant phenotype, and a bedaquiline-resistant strain was wild type for related genes. The Beijing, Euro-American, and Delhi-CAS were the most populated lineage/sublineages. Drug resistance-associated mutations were mostly linked to minimum inhibitory concentration results. However, the role of well-known drug-resistant genes for D-cycloserine, clofazimine, bedaquiline, and delamanid was found to be more controversial.
PubMed: 32046149
DOI: 10.3390/jcm9020465 -
Antibiotics (Basel, Switzerland) Oct 2020Perchlozone ([PCZ] 4-thioureido-iminomethylpyridinium perchlorate) is a new thiosemicarbazone approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in...
Genetic Variation Putatively Associated with Resistance to Perchlozone, a New Thiosemicarbazone: Clues from Whole Genome Sequencing and Implications for Treatment of Multidrug-Resistant Tuberculosis.
Perchlozone ([PCZ] 4-thioureido-iminomethylpyridinium perchlorate) is a new thiosemicarbazone approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in Russia and some other countries. The and mutations may confer PCZ resistance. At the same time, mutations are known to mediate resistance to ethionamide (ETH) and prothionamide (PTH). We aimed to study the genetic variation underlying resistance to PCZ through whole genome sequencing (WGS) of consecutive isolates recovered during long-term treatment. This prospective study included patients admitted in 2018-2019 to the regional tuberculosis dispensary, Kaliningrad, Russia, whose treatment regimen included PCZ. Multiple isolates were recovered during PCZ treatment, and the bacterial DNA was subjected to WGS followed by bioinformatics analysis. We identified mutations in the genes putatively associated with PCZ resistance, , and The most frequent one was a frameshift 106 GA > G (seven of nine patients) and most of the other mutations were also likely present before PCZ treatment. In one patient, a frameshift mutation 702 CT > C emerged after six months of PCZ treatment. A frequent presence of cross-resistance mutations to PCZ and ETH/PTH should be taken into consideration when PCZ is included in the treatment regimen of MDR-TB patients.
PubMed: 33022959
DOI: 10.3390/antibiotics9100669 -
Therapeutic Advances in Respiratory... 2024Ukraine remains a high World Health Organization priority country for drug-resistant tuberculosis (TB). Rifampicin-resistant TB (RR-TB) has a more protracted, more... (Observational Study)
Observational Study
Impact of line probe assay-based molecular testing on individualized treatment in patients with rifampicin-resistant tuberculosis: data from the prospective INNOVA4TB cohort study in Ukraine.
BACKGROUND
Ukraine remains a high World Health Organization priority country for drug-resistant tuberculosis (TB). Rifampicin-resistant TB (RR-TB) has a more protracted, more complicated, and more expensive treatment. In 2021, Ukraine reported 4025 RR-TB cases - 5.4 times more (751) than all 30 European Union/ European Economic Area countries together.
OBJECTIVES
The objective of the study was to determine the diagnostic accuracy of line probe assay (LPA), AID Autoimmun Diagnostika GmbH, for detecting resistance to anti-TB drugs and its clinical application for selecting treatment regimens.
DESIGN
A prospective observational cohort study.
METHODS
From May 2019 to June 2020, we consecutively enrolled patients with active TB hospitalized at the Regional Phthisiopulmonology Center (Vinnytsia, Ukraine), aged between 18 and 82 years. The LPA was performed in the Genetic Research Laboratory at National Pirogov Memorial Medical University, Vinnytsia, Ukraine.
RESULTS
A total of 84 clinical specimens and 97 culture isolates from 126 TB patients were tested during the study. Accuracy (95% confidence interval) of LPA for clinical samples in comparison with phenotypic drug susceptibility test (DST) was 80.1 (68.5-89.0) for isoniazid (H), 74.7 (62.4-84.6) for rifampicin (R), 74.4 (62.5-84.1) for ethambutol, 71.4 (41.9-91.6) for streptomycin, 84.6 (62.4-96.5) for prothionamide/ethionamide, and 84.6 (73.6-92.3) for levofloxacin (Lfx), respectively. We found a significantly higher sensitivity of LPA for H, R, and Lfx for the culture isolates compared to clinical specimens ( < 0.05). LPA detected different mutations in 6 out of 17 (35.5%) patients susceptible to R by Xpert. A shorter treatment regimen with an injectable agent demonstrated a low suitability rate of 5% (8/156) in a cohort of RR-TB patients from Ukraine.
CONCLUSION
Initial LPA testing accurately identifies resistance to anti-TB drugs and facilitates the selection of an appropriate treatment regimen, minimizing exposure to empirical therapy.
Topics: Humans; Prospective Studies; Adult; Ukraine; Rifampin; Male; Middle Aged; Tuberculosis, Multidrug-Resistant; Female; Mycobacterium tuberculosis; Young Adult; Aged; Adolescent; Antitubercular Agents; Microbial Sensitivity Tests; Aged, 80 and over; Antibiotics, Antitubercular; Predictive Value of Tests; Precision Medicine; Reproducibility of Results
PubMed: 38817020
DOI: 10.1177/17534666241249841 -
Microbiology Spectrum Jun 2024The continuous advancement of molecular diagnostic techniques, particularly whole-genome sequencing (WGS), has greatly facilitated the early diagnosis of drug-resistant...
The continuous advancement of molecular diagnostic techniques, particularly whole-genome sequencing (WGS), has greatly facilitated the early diagnosis of drug-resistant tuberculosis patients. Nonetheless, the interpretation of results from various types of mutations in drug-resistant-associated genes has become the primary challenge in the field of molecular drug-resistance diagnostics. In this study, our primary objective is to evaluate the diagnosis accuracy of the World Health Organization (WHO) catalog of mutations and five WGS analysis tools (PhyResSE, Mykrobe, TB Profiler, Gen-TB, and SAM-TB) in drug resistance to 10 anti- (MTB) drugs. We utilized the data of WGS collected between 2014 and 2017 in Zhejiang Province, consisting of 110 MTB isolates as detailed in our previous study. Based on phenotypic drug susceptibility testing (DST) results using the proportion method on Löwenstein-Jensen medium with antibiotics, we evaluated the predictive accuracy of genotypic DST obtained by these tools. The results revealed that the WHO catalog of mutations and five WGS analysis tools exhibit robust predictive capabilities concerning resistance to isoniazid, rifampicin, ethambutol, streptomycin, amikacin, kanamycin, and capreomycin. Notably, Mykrobe, SAM-TB, and TB Profiler demonstrate the most accurate predictions for resistance to pyrazinamide, prothionamide, and para-aminosalicylic acid, respectively. These findings are poised to significantly guide and influence future clinical treatment strategies and resistance monitoring protocols.IMPORTANCEWhole-genome sequencing (WGS) has the potential for the early diagnosis of drug-resistant tuberculosis. However, the interpretation of mutations of drug-resistant-associated genes represents a significant challenge as the amount and complexity of WGS data. We evaluated the accuracy of the World Health Organization catalog of mutations and five WGS analysis tools in predicting drug resistance to first-line and second-line anti-TB drugs. Our results offer clinicians guidance on selecting appropriate WGS analysis tools for predicting resistance to specific anti-TB drugs.
PubMed: 38904370
DOI: 10.1128/spectrum.03341-23 -
Biomedical Reports Mar 2024Proteasome inhibitor bortezomib is an anticancer agent approved for treatment of multiple myeloma and mantle cell lymphoma. However, its application in other types of...
Proteasome inhibitor bortezomib is an anticancer agent approved for treatment of multiple myeloma and mantle cell lymphoma. However, its application in other types of cancer, primarily in solid tumors, is limited due to poor pharmacokinetics, inefficient tissue penetration, low stability and frequent adverse effects. In the present study, a novel micellar nano-scaled delivery system was manufactured, composed of amphiphilic poly(N-vinylpyrrolidone) nanoparticles loaded with bortezomib. Similar nanoparticles loaded with prothionamide, a drug without anticancer effect, were used as control. The size and zeta potential of the obtained polymeric micelles were measured by dynamic light scattering. Bortezomib-loaded micelles exhibited significant cytotoxic activity in monolayer tumor cell cultures (IC ~6.5 µg/ml) and in 3D multicellular tumor spheroids (IC ~8.5 µg/ml) of human glioblastoma cell lines U87 and T98G. Additionally, the toxic effects were studied in zebrafish embryos, with an estimated 50% lethal concentration of 0.1 mg/ml. Considering that bortezomib and other molecules from the class of proteasome inhibitors are potent antitumor agents, nanodelivery approach can help reduce adverse effects and expand the range of its applications for treatment of various oncological diseases.
PubMed: 38343660
DOI: 10.3892/br.2024.1725