Assessment for Antibodies to Rifapentine and Isoniazid in Persons Developing Flu-like Reactions During Treatment of Latent Tuberculosis Infection.

BACKGROUND: Flu-like reactions can occur after exposure to rifampin, rifapentine, or isoniazid. Prior studies have reported the presence of antibodies to rifampin, but associations with underlying pathogenesis are unclear. METHODS: We evaluated PREVENT TB study participants who received weekly isoniazid + rifapentine for 3 months (3HP) or daily isoniazid for 9 months (9H) as treatment for M. tuberculosis infection. Flu-like reaction was defined as a grade ≥2 of any of flu-like symptoms. Controls (3HP or 9H) did not report flu-like reactions. We developed a competitive enzyme-linked immunosorbent assays (ELISA) to detect antibodies against rifapentine, isoniazid, rifampin, and rifapentine metabolite. RESULTS: Among 128 participants, 69 received 3HP (22 with flu-like reactions; 47 controls) and 59 received 9H (12 with flu-like reactions; 47 controls). In participants receiving 3HP, anti-rifapentine IgG was identified in 2/22 (9%) participants with flu-like reactions and 6/47 (13%) controls (P = 0.7), anti-isoniazid IgG in 2/22 (9%) participants with flu-like reactions and 4/47 (9%) controls (P = 0.9), and anti-rifapentine metabolite IgG in 2/47 (4%) controls (P = 0.9). Among participants receiving 9H, IgG and IgM anti-isoniazid antibodies were each present in 4/47 (9%) controls, respectively, but none among participants with flu-like reactions; anti-rifapentine IgG antibodies were not present in any participants with flu-like reactions or controls. CONCLUSIONS: We detected anti-rifapentine, anti-isoniazid, and anti-rifapentine metabolite antibodies, but the proportions of participants with antibodies were low, and did not differ between participants with flu-like reactions and those without such reactions. This suggests that flu-like reactions associated with 3HP and 9H were not antibody-mediated.

Symptoms and Systemic Drug Reactions in Persons Receiving Weekly Rifapentine Plus Isoniazid (3HP) Treatment for Latent Tuberculosis Infection.

BACKGROUND: Three months of weekly rifapentine plus isoniazid (3HP) therapy for latent tuberculosis infection (LTBI) is recommended worldwide. The development of symptoms and systemic drug reactions (SDRs) on 3HP have not been fully characterized. We aimed to determine the patterns of symptom development and identify SDRs and associated factors in patients taking 3HP. METHODS: We analyzed symptoms data in participants receiving 3HP in the Tuberculosis Trials Consortium's iAdhere study (Study 33). We examined the patterns of symptom reporting across participants from baseline and 4 monthly visits. Bivariate analyses and multivariable regression models were used to identify factors associated with SDRs. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Among 1002 participants receiving 3HP, 768 (77%) reported at least 1 symptom; 97% of these symptoms were grade 1 (79%) or grade 2 (18%). Most symptoms developed in the first month and resolved. A total of 111 (11%) participants had symptoms that met criteria for SDRs; however, 53 (48%) of these participants completed therapy. Factors associated with SDRs and discontinuation included female sex (RR: 2.05; 95% CI: 1.19-3.54), age ≥45 years (RR: 1.99; 95% CI: 1.19-3.31), and use of concomitant medications (RR: 2.26; 95% CI: 1.15-4.42). CONCLUSIONS: Although most patients receiving 3HP reported symptoms, most were mild, occurred early, and resolved without stopping treatment. Among patients experiencing SDRs, nearly half were able to complete therapy. Patient and provider education should focus on differentiating severe reactions where 3HP should be stopped from minor symptoms that will resolve. Clinical Trials Registration. NCT01582711.

Identification of Mycobacterium tuberculosis Peptides in Serum Extracellular Vesicles from Persons with Latent Tuberculosis Infection.

Identification of biomarkers for latent Mycobacterium tuberculosis infection and risk of progression to tuberculosis (TB) disease are needed to better identify individuals to target for preventive therapy, predict disease risk, and potentially predict preventive therapy efficacy. Our group developed multiple reaction monitoring mass spectrometry (MRM-MS) assays that detected M. tuberculosis peptides in serum extracellular vesicles from TB patients. We subsequently optimized this MRM-MS assay to selectively identify 40 M. tuberculosis peptides from 19 proteins that most commonly copurify with serum vesicles of patients with TB. Here, we used this technology to evaluate if M. tuberculosis peptides can also be detected in individuals with latent TB infection (LTBI). Serum extracellular vesicles from 74 individuals presumed to have latent M. tuberculosis infection (LTBI) based on close contact with a household member with TB or a recent tuberculin skin test (TST) conversion were included in this study. Twenty-nine samples from individuals with no evidence of TB infection by TST and no known exposure to TB were used as controls to establish a threshold to account for nonspecific/background signal. We identified at least one of the 40 M. tuberculosis peptides in 70 (95%) individuals with LTBI. A single peptide from the glutamine synthetase (GlnA1) enzyme was identified in 61/74 (82%) individuals with LTBI, suggesting peptides from M. tuberculosis proteins involved in nitrogen metabolism might be candidates for pathogen-specific biomarkers for detection of LTBI. The detection of M. tuberculosis peptides in serum extracellular vesicles from persons with LTBI represents a potential advance in the diagnosis of LTBI.

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. We evaluated candidates for a disease prevention trial to determine reasons for nonparticipation and to identify factors that can be addressed to improve recruitment efficiency. METHODS: During 2001-2009, the Tuberculosis Trials Consortium conducted Study 26 (PREVENT TB), a randomized clinical trial at 26 sites in four countries, among persons with latent tuberculosis infection at high risk for tuberculosis disease progression, comparing 3 months of directly observed once-weekly rifapentine plus isoniazid with 9 months of self-administered daily isoniazid. During March 2005-February 2008, non-identifying demographic information, risk factors for experiencing active tuberculosis disease, and reasons for not enrolling were collected from screened patients to facilitate interpretation of trial data, to meet Consolidated Standards of Reporting Trials standards, and to evaluate reasons for nonparticipation. RESULTS: Of the 7452 candidates screened in Brazil, Canada, Spain, and the United States, 3584 (48%) were not enrolled, because of ineligibility (41%), site decision (10%), or patient choice (49%). Among those who did not enroll by own choice, and for whom responses were recorded on whether they would accept treatment outside of the study (n = 1430), 68% reported that they planned to accept non-study latent tuberculosis infection treatment. Among 1305 patients with one or more reported reasons for nonparticipation, study staff recorded a total of 1886 individual reasons (reason count: median = 1/patient; range = 1-9) for why patients chose not to enroll, including grouped concerns about research (24% of 1886), work or school conflicts (20%), medication or health beliefs (16%), latent tuberculosis infection beliefs (11%), and patient lifestyle and family concerns (10%). CONCLUSION: Educational efforts addressing clinical research concerns and beliefs about medication and health, as well as study protocols that accommodate patient-related concerns (e.g. work, school, and lifestyle) might increase willingness to enter clinical trials. Findings from this evaluation can support development of communication and education materials for clinical trial sites at the beginning of a trial to allow study staff to address potential participant concerns during study screening.

Passive Underwater Target Tracking: Conditionally Minimax Nonlinear Filtering with Bearing-Doppler Observations.

The paper presents an application of the Conditionally-Minimax Nonlinear Filtering (CMNF) algorithm to the online estimation of underwater vehicle movement given a combination of sonar and Doppler discrete-time noisy sensor observations. The proposed filter postulates recurrent "prediction-correction" form with some predefined basic prediction and correction terms, and then they are optimally fused. The CMNF estimates have the following advantageous features. First, the obtained estimates are unbiased. Second, the theoretical covariance matrix of CMNF errors meets the real values. Third, the CMNF algorithm gives a possibility to choose the preliminary observation transform, basic prediction, and correction functions in any specific case of the observation system to improve the estimate accuracy significantly. All the features of conditionally-minimax estimates are demonstrated by the regression example of random position estimate given the noisy bearing observations. The contribution of the paper is the numerical study of the CMNF algorithm applied to the underwater target tracking given bearing-only and bearing-Doppler observations.

Dynamics of electron-emission currents in plasmonic gaps induced by strong fields.

The dynamics of ultrafast electron currents triggered by femtosecond laser pulse irradiation of narrow gaps in a plasmonic dimer is studied using quantum mechanical Time-Dependent Density Functional Theory (TDDFT). The electrons are injected into the gap due to the optical field emission from the surfaces of the metal nanoparticles across the junction. Further evolution of the electron currents in the gap is governed by the locally enhanced electric fields. The combination of TDDFT and classical modelling of the electron trajectories allows us to study the quiver motion of the electrons in the gap region as a function of the Carrier Envelope Phase (CEP) of the incident pulse. In particular, we demonstrate the role of the quiver motion in establishing the CEP-sensitive net electric transport between nanoparticles.

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. In 2017, a CDC Work Group conducted a systematic review and meta-analyses of the 3HP regimen using methods adapted from the Guide to Community Preventive Services. In total, 19 articles representing 15 unique studies were included in the meta-analysis, which determined that 3HP is as safe and effective as other recommended LTBI regimens and achieves substantially higher treatment completion rates. In July 2017, the Work Group presented the meta-analysis findings to a group of TB experts, and in December 2017, CDC solicited input from the Advisory Council for the Elimination of Tuberculosis (ACET) and members of the public for incorporation into the final recommendations. CDC continues to recommend 3HP for treatment of LTBI in adults and now recommends use of 3HP 1) in persons with LTBI aged 2-17 years; 2) in persons with LTBI who have HIV infection, including acquired immunodeficiency syndrome (AIDS), and are taking antiretroviral medications with acceptable drug-drug interactions with rifapentine; and 3) by DOT or self-administered therapy (SAT) in persons aged ≥2 years.

Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial.

Background: Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation. Objective: To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation. Design: An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711). Setting: Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa. Participants: 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection. Intervention: Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring. Measurements: The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events. Results: Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups. Limitation: Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically. Conclusion: These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible. Primary Funding Source: Centers for Disease Control and Prevention.

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. METHODS: This was a post hoc exploratory analysis of the randomized, open-label PREVENT TB trial. Factors were analyzed by univariate and multivariate logistic regression (with enrollment site as a random effect). RESULTS: From 6232 participants analyzed, 1406 (22.6%) did not complete LTBI treatment (317 NCT attributed to an adverse event [NCT-AE] and 1089 NCT attributed to reasons other than an adverse event [NCT-O]). The proportion of NCT-AE was similar with both regimens (3HP-DOT = 6.4% vs 9H-SAT = 5.9%; P = .23); NCT-O was higher among participants enrolled in 9H-SAT (9H-SAT = 24.5% vs 3HP-DOT = 12.7%; P = .02). Among those in the NCT-AE group, being non-Hispanic and receiving 3HP-DOT, having cirrhosis and receiving 9H-SAT, alcohol consumption among men, and use of concomitant medication were associated with NCT-AE. Among those in the NCT-O group, receiving 9H-SAT, missing ≥1 early visit, men receiving 9H-SAT, men with a history of incarceration, alcohol abuse, use ever of intravenous drugs, younger age receiving 9H-SAT, and smoking were associated with NCT-O. CONCLUSIONS: Factors associated with NCT, such as missing a clinic visit early during treatment, might help identify persons for whom tailored interventions could improve completion of LTBI treatment. CLINICAL TRIALS REGISTRATION: NCT00023452.

Flu-like and Other Systemic Drug Reactions Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study.

BACKGROUND: Weekly rifapentine plus isoniazid for 3 months (3HP) is as effective as daily isoniazid for 9 months (9H) for latent tuberculosis infection in high-risk persons, but there have been reports of possible flu-like syndrome. METHODS: We identified clinically significant systemic drug reactions (SDR) and evaluated risk factors in patients who did not complete treatment in the PREVENT Tuberculosis study. RESULTS: Among 7552 persons who received ≥ 1 dose of study drug, 153 had a SDR: 138/3893 (3.5%) with 3HP vs 15/3659 (0.4%) with 9H (P < .001). In the 3HP arm, 87 (63%) had flu-like syndrome and 23 (17%) had cutaneous reactions; 13/3893 (0.3%) had severe reactions (6 were hypotensive) and 6 reported syncope. Symptoms occurred after a median of 3 doses, and 4 hours after the dose; median time to resolution was 24 hours. There were no deaths. In multivariate logistic regression analysis, factors independently associated with SDR included receipt of 3HP (adjusted odds ratio [aOR] 9.4; 95% confidence interval [CI], 5.5, 16.2), white non-Hispanic race/ethnicity (aOR 3.3; 95% CI, 2.3, 4.7), female sex (aOR 2.0; 95% CI, 1.4, 2.9), age ≥ 35 years (aOR 2.0; 95% CI, 1.4, 2.9), and lower body mass index (body mass index [BMI]; P = .009). In a separate multivariate analysis among persons who received 3HP, severe SDR were associated with white non-Hispanic race/ethnicity (aOR 5.4; 95% CI, 1.8, 16.3), and receipt of concomitant non-study medications (aOR 5.9; 95% CI, 1.3, 27.1). CONCLUSIONS: SDR were more common with 3HP, and mostly flu-like. Persons of white race, female sex, older age, and lower BMI were at increased risk. Severe reactions were rare and associated with 3HP, concomitant medication, and white race. The underlying mechanism is unclear. CLINICAL TRIALS REGISTRATION: NCT00023452.