Risk-stratified treatment for drug-susceptible pulmonary tuberculosis.

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events.

Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized Controlled Clinical Trial.

Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes.

Synthetic BSA-conjugated disaccharide related to the serotype 3 capsular polysaccharide increases IL-17A Levels, γδ T cells, and B1 cells in mice.

The disaccharide (β-D-glucopyranosyluronic acid)-(1→4)-β-D-glucopyranoside represents a repeating unit of the capsular polysaccharide of serotype 3. A conjugate of the disaccharide with BSA (di-BSA conjugate) adjuvanted with aluminum hydroxide induced - in contrast to the non-adjuvanted conjugate - IgG1 antibody production and protected mice against serotype 3 infection after intraperitoneal prime-boost immunization. Adjuvanted and non-adjuvanted conjugates induced production of Th1 (IFNγ, TNFα); Th2 (IL-5, IL-13); Th17 (IL-17A), Th1/Th17 (IL-22), and Th2/Th17 cytokines (IL-21) after immunization.

Pharmacokinetic-Pharmacodynamic Evidence From a Phase 3 Trial to Support Flat-Dosing of Rifampicin for Tuberculosis.

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes.

Synthesis of methylphosphorylated oligomannosides structurally related to lipopolysaccharide O-antigens of serotype O3 and their application for detection of specific antibodies in rabbit and human sera.

Methylphosphorylated mono-, di- and trimannosides structurally related to the lipopolysaccharide (LPS) O-antigens of of serotype O3 were synthesized and conjugated with a biotin tag. The stereo- and regioselective assembly of target carbohydrate chains was conducted using uniform monosaccharide synthetic blocks. After that, a methylphosphate group was introduced by coupling with a methyl-H-phosphonate reagent followed by oxidation and deprotection to give the target oligosaccharides.

Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).

Background: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH).

Methods: PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART).

Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models.

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.

Interim Guidance: 4-Month Rifapentine-Moxifloxacin Regimen for the Treatment of Drug-Susceptible Pulmonary Tuberculosis - United States, 2022.

On May 5, 2021, CDC's Tuberculosis Trials Consortium and the National Institutes of Health (NIH)-sponsored AIDS Clinical Trials Group (ACTG) published results from a randomized controlled trial indicating that a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment (1). On the basis of these findings, CDC recommends the 4-month regimen as a treatment option for U.S.

Adaptive Digital Hologram Binarization Method Based on Local Thresholding, Block Division and Error Diffusion.

High-speed optical reconstruction of 3D-scenes can be achieved using digital holography with binary digital micromirror devices (DMD) or a ferroelectric spatial light modulator (fSLM). There are many algorithms for binarizing digital holograms. The most common are methods based on global and local thresholding and error diffusion techniques.

Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine.

Background: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB).

Methods: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin.

Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.

Background: Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.

Methods: In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points.

Optimizing drug inventory management with a web-based information system: The TBTC Study 31/ACTG A5349 experience.

Introduction: Efficient management of study drug inventory shipments is critical to keep research sites enrolling into multisite clinical treatment trials. A standard manual drug-management process used by the Tuberculosis Trials Consortium (TBTC), did not accommodate import permit approval timelines, shipment transit-times and time-zone differences. We compared a new web-based solution with the manual process, during an international 34-site clinical trial conducted by the TBTC and the AIDS Clinical Trials Group (ACTG); TBTC Study 31/ACTG A5349.

Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis.

Introduction: With the growing use of online study management systems and rapid availability of data, timely data review and quality assessments are necessary to ensure proper clinical trial implementation. In this report we describe central monitoring used to ensure protocol compliance and accurate data reporting, implemented during a large phase 3 clinical trial.

Material And Methods: The Tuberculosis Trials Consortium (TBTC) Study 31/AIDS Clinical Trials Group (ACTG) study A5349 (S31) is an international, multi-site, randomized, open-label, controlled, non-inferiority phase 3 clinical trial comparing two 4-month regimens to a standard 6 month regimen for treatment of drug-susceptible tuberculosis (TB) among adolescents and adults with a sample size of 2500 participants.

Higher Cytokine and Opsonizing Antibody Production Induced by Bovine Serum Albumin (BSA)-Conjugated Tetrasaccharide Related to Type 3 Capsular Polysaccharide.

A number of studies have demonstrated the limited efficacy of type 3 capsular polysaccharide (CP) in the 13-valent pneumococcal conjugate vaccine against serotype 3 invasive pneumococcal diseases and carriage. Synthetic oligosaccharides (OSs) may provide an alternative to CPs for development of novel conjugated pneumococcal vaccines and diagnostic test systems. A comparative immunological study of di-, tri-, and tetra-bovine serum albumin (BSA) conjugates was performed.

Coronavirus Disease 2019 (COVID-19) in Americans Aboard the Diamond Princess Cruise Ship.

Background: The Diamond Princess cruise ship was the site of a large outbreak of coronavirus disease 2019 (COVID-19). Of 437 Americans and their travel companions on the ship, 114 (26%) tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We interviewed 229 American passengers and crew after disembarkation following a ship-based quarantine to identify risk factors for infection and characterize transmission onboard the ship.

Impact of GeneXpert MTB/RIF® on treatment initiation and outcomes of RIF-resistant and RIF-susceptible TB patients in Vladimir TB dispensary, Russia.

Background: The main advantage of GeneXpert MTB/RIF® (Xpert) molecular diagnostic technology is the rapid detection of M.tuberculosis DNA and mutations associated with rifampicin (RIF) resistance for timely initiation of appropriate treatment and, consequently, preventing further transmission of the disease. We assessed time to treatment initiation and treatment outcomes of RIF-resistant and RIF-susceptible TB patients diagnosed and treated in Vladimir TB Dispensary, Russia in 2012, before and after implementation of GeneXpert MTB/RIF® diagnostic technology.

Isoniazid and Rifampin-Resistance Mutations Associated With Resistance to Second-Line Drugs and With Sputum Culture Conversion.

Background: Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics.

Methods: In a multicountry prospective cohort study of multidrug-resistant TB, we identified inhA, katG, and rpoB mutations in sputum isolates using the Hain MTBDRplus line probe assay.

High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial.

Introduction: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen.

Methods/design: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients.

Quality of reconstruction of compressed off-axis digital holograms by frequency filtering and wavelets.

Compression of digital holograms can significantly help with the storage of objects and data in 2D and 3D form, its transmission, and its reconstruction. Compression of standard images by methods based on wavelets allows high compression ratios (up to 20-50 times) with minimum losses of quality. In the case of digital holograms, application of wavelets directly does not allow high values of compression to be obtained.

Neoglycoconjugate of Tetrasaccharide Representing One Repeating Unit of the Type 14 Capsular Polysaccharide Induces the Production of Opsonizing IgG1 Antibodies and Possesses the Highest Protective Activity As Compared to Hexa- and Octasaccharide Conjugates.

Identifying protective synthetic oligosaccharide (OS) epitopes of capsular polysaccharides (CPs) is an indispensable step in the development of third-generation carbohydrate pneumococcal vaccines. Synthetic tetra-, hexa-, and octasaccharide structurally related to CP of type 14 were coupled to bovine serum albumin (BSA), adjuvanted with aluminum hydroxide, and tested for their immunogenicity in mice upon intraperitoneal prime-boost immunizations. Injections of the conjugates induced production of opsonizing anti-OS IgG1 antibodies (Abs).