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.

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.

Nonparticipation reasons in a randomized international trial of a new latent tuberculosis infection regimen.

Background/aims: Efficient recruitment of eligible participants, optimizing time and sample size, is a crucial component in conducting a successful clinical trial. Inefficient participant recruitment can impede study progress, consume staff time and resources, and limit quality and generalizability or the power to assess outcomes. Recruitment for disease prevention trials poses additional challenges because patients are asymptomatic.

Update of Recommendations for Use of Once-Weekly Isoniazid-Rifapentine Regimen to Treat Latent Mycobacterium tuberculosis Infection.

Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI, with limitations for use in children aged <12 years and persons with human immunodeficiency virus (HIV) infection (1). CDC identified the use of 3HP in those populations, as well as self-administration of the 3HP regimen, as areas to address in updated recommendations.

Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis.

Background: Isoniazid-resistant, rifampicin-susceptible (INH-R) tuberculosis is the most common form of drug resistance, and is associated with failure, relapse, and acquired rifampicin resistance if treated with first-line anti-tuberculosis drugs. The aim of the study was to compare success, mortality, and acquired rifampicin resistance in patients with INH-R pulmonary tuberculosis given different durations of rifampicin, ethambutol, and pyrazinamide (REZ); a fluoroquinolone plus 6 months or more of REZ; and streptomycin plus a core regimen of REZ.

Methods: Studies with regimens and outcomes known for individual patients with INH-R tuberculosis were eligible, irrespective of the number of patients if randomised trials, or with at least 20 participants if a cohort study.

Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials.

Rationale: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy.

Objectives: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H).

Methods: Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed.

Factors Associated With Noncompletion of Latent Tuberculosis Infection Treatment: Experience From the PREVENT TB Trial in the United States and Canada.

Background: Overall rates of noncompletion of treatment (NCT) for latent tuberculosis infection (LTBI) in the PREVENT TB trial were 18% for 3 months of directly observed once-weekly rifapentine (maximum dose, 900 mg) plus isoniazid (maximum dose, 900 mg) (3HP-DOT) and 31% for 9 months of daily self-administered isoniazid (maximum dose, 300 mg; 9H-SAT). NCT for LTBI reduces its effectiveness. The study objective was to assess factors associated with NCT for LTBI among adult participants enrolled at US and Canadian sites of the PREVENT TB trial.

Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid.

Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.

Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.

Evaluation of the Informed Consent Process of a Multicenter Tuberculosis Treatment Trial.

Background: Ethical principles obligate researchers to maximize study participants' comprehension during the informed consent process for clinical trials. A pilot evaluation of the consent process was conducted during an international clinical trial of treatment for pulmonary tuberculosis to assess the feasibility of conducting an evaluation in a larger population and to guide these future efforts.

Methods: Study staff administered an informed consent assessment tool (ICAT) to a convenience sample of trial participants, measuring comprehension of consent components as derived from the Common Rule and FDA Title 21 Part 50, and satisfaction with the process.

Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial.

Rationale: Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.

Objectives: We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.

Methods: Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol.

What is the most reliable solid culture medium for tuberculosis treatment trials?

We conducted a prospective study to determine which solid medium is the most reliable overall and after two months of therapy to detect Mycobacterium tuberculosis complex (MTB). MTB isolation and contamination rates on LJ and Middlebrook 7H10 and 7H11 agar with and without selective antibiotics were examined in a single laboratory and compared against a constructed reference standard and MGIT 960 results. Of 50 smear positive adults with pulmonary TB enrolled, 45 successfully completed standard treatment.

How we determined the most reliable solid medium for studying treatment of tuberculosis.

Phase 2 clinical trials for tuberculosis (TB) treatment require reliable culture methods to determine presence or absence of Mycobacterium tuberculosis (Mtb) over the course of therapy, as these trials are based primarily on bacteriological endpoints. We evaluate which of 5 solid media is most reliable: Lowenstein-Jensen (LJ) egg-base medium and 4 Middlebrook agar media (nonselective 7H10 and 7H11 and selective 7H10 and 7H11). We analyze 393 specimens from 50 HIV-negative Ugandan adults with newly-diagnosed, pulmonary TB and high acid-fast bacillus smear grade.

Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

Rationale: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment.

Objectives: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment.

The association between symptoms and microbiologically defined response to tuberculosis treatment.

Rationale: The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials.

Objectives: To evaluate the association between symptoms and microbiological response to tuberculosis treatment.

Methods: We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures.

Substitution of rifapentine for rifampin during intensive phase treatment of pulmonary tuberculosis: study 29 of the tuberculosis trials consortium.

Background: Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment.

Methods: In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol.

Geographic differences in time to culture conversion in liquid media: Tuberculosis Trials Consortium study 28. Culture conversion is delayed in Africa.

Background: Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding.

Evaluation of time to detection of Mycobacterium tuberculosis in broth culture as a determinant for end points in treatment trials.

Time to detection of Mycobacterium tuberculosis in broth culture was examined for utility as a treatment efficacy end point. Of 146 patients in a phase IIB trial, a decreased mean time to detection was found in 5 with treatment failure. Time to detection in an analysis-of-covariance model was associated with lung cavities, less intensive treatment, and differences in the bactericidal effects of treatment regimens.

Updated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection - United States, 2010.

n 2005, CDC published guidelines for using the QuantiFERON-TB Gold test (QFT-G) (Cellestis Limited, Carnegie, Victoria, Australia) (CDC. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR;54[No.

Latent TB infection treatment acceptance and completion in the United States and Canada.

Background: Treatment of latent TB infection (LTBI) is essential for preventing TB in North America, but acceptance and completion of this treatment have not been systematically assessed.

Methods: We performed a retrospective, randomized two-stage cross-sectional survey of treatment and completion of LTBI at public and private clinics in 19 regions of the United States and Canada in 2002.

Results: At 32 clinics that both performed tuberculin skin testing and offered treatment, 123 (17.

Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis.

Rationale: Moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro and in a mouse model of antituberculosis (TB) chemotherapy, but data regarding its activity in humans are limited.

Objectives: Our objective was to compare the antimicrobial activity and safety of moxifloxacin versus isoniazid during the first 8 weeks of combination therapy for pulmonary TB.

Methods: Adults with sputum smear-positive pulmonary TB were randomly assigned to receive either moxifloxacin 400 mg plus isoniazid placebo, or isoniazid 300 mg plus moxifloxacin placebo, administered 5 days/week for 8 weeks, in addition to rifampin, pyrazinamide, and ethambutol.

Education level, primary language, and comprehension of the informed consent process.

TO OBTAIN INFORMATION ON HOW PERSONS from diverse backgrounds experience the informed consent process, we surveyed adults with a wide variety of educational levels and different primary languages (English, Spanish, or Vietnamese) who had recently enrolled in a study requiring written informed consent. Of the 100 participants, 62 were non-White, 43 had less than a high school education, and 60 had a primary language other than English. The median score for comprehension was 62% (IQR 50-76%); the median satisfaction score was 86% (IQR 71-100%).

Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin.

Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters.

Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis.

Rationale: Moxifloxacin has promising preclinical activity against Mycobacterium tuberculosis, but has not been evaluated in multidrug treatment of tuberculosis in humans.

Objective: To compare the impact of moxifloxacin versus ethambutol, both in combination with isoniazid, rifampin, and pyrazinamide, on sputum culture conversion at 2 mo as a measure of the potential sterilizing activity of alternate induction regimens.

Methods: Adults with smear-positive pulmonary tuberculosis were randomized in a factorial design to receive moxifloxacin (400 mg) versus ethambutol given 5 d/wk versus 3 d/wk (after 2 wk of daily therapy).