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.

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.

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.

Three months of rifapentine and isoniazid for latent tuberculosis infection.

BACKGROUND: Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. METHODS: We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%. RESULTS: In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). CONCLUSIONS: The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).

Isoniazid-Rifapentine for Latent Tuberculosis Infection: A Systematic Review and Meta-analysis.

CONTEXT: Latent tuberculosis infection diagnosis and treatment is a strategic priority for eliminating tuberculosis in the U.S. The Centers for Disease Control and Prevention has recommended the short-course regimen of 3-month isoniazid-rifapentine administered by directly observed therapy. However, longer-duration regimens remain the most widely prescribed latent tuberculosis infection treatments. Limitation on adoption of 3-month isoniazid-rifapentine in the U.S. might be because of patients' preference for self-administered therapy, providers' lack of familiarity with 3-month isoniazid-rifapentine, or lack of resources to support directly observed therapy. This review examines the most recent evidence regarding 3-month isoniazid-rifapentine's effectiveness, safety, and treatment completion when directly compared with other latent tuberculosis infection regimens primarily comprising 9-month isoniazid treatment. EVIDENCE ACQUISITION: Using Community Guide methodology, reviewers identified, evaluated, and summarized available evidence published during January 2006-June 2017. Analysis of the data was completed in 2017. EVIDENCE SYNTHESIS: The analysis included 15 unique studies. Three-month isoniazid-rifapentine was determined to be equal to other latent tuberculosis infection regimens in effectiveness (OR=0.89, 95% CI=0.46, 1.70), and has higher treatment completion (87.5%, 95% CI=83.2%, 91.3%) compared with other latent tuberculosis infection regimens (65.9%, 95% CI=53.5%, 77.3%). Three-month isoniazid-rifapentine was associated with similar risk to other latent tuberculosis infection regimens for adverse events (relative risk=0.59, 95% CI=0.23, 1.52); discontinuing treatment because of adverse events (relative risk=0.48, 95% CI=0.17, 1.34); and death (relative risk=0.79, 95% CI=0.56, 1.11). CONCLUSIONS: The 3-month isoniazid-rifapentine regimen is as safe and effective as other recommended latent tuberculosis infection regimens and achieves significantly higher treatment completion rates.

Depression during pegylated interferon-alpha plus ribavirin therapy: prevalence and prediction.

BACKGROUND: Interferon-alpha (IFN-alpha) plus ribavirin is used to treat hepatitis C virus (HCV) infection and is associated with a high rate of depression. Newer, pegylated preparations of IFN-alpha have a longer half-life, require once-per-week dosing, and may be associated with reduced neuropsychiatric burden. Limited data exist on depression during pegylated IFN-alpha therapy. METHOD: Depressive symptoms were assessed using the Zung Self-Rating Depression Scale (SDS) in 162 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of treatment with pegylated IFN alpha-2b (PEG IFN) plus weight-based (N = 86) versus standard dose (N = 76) ribavirin. Data were collected from March 2001 to April 2003. RESULTS: Compared with baseline, mean SDS index scores were significantly increased by week 4 and remained elevated throughout the study. Thirty-nine percent of the sample experienced moderate to severe depressive symptoms (SDS index score > or = 60) at some point during PEG IFN/ribavirin therapy. Baseline depression scores significantly predicted severity of depressive symptoms during PEG IFN/ribavirin treatment (simple regression analysis: Y = 0.55X + 32.7, p < .0001). In addition, assignment to weight-based ribavirin treatment and history of depression were associated with increased likelihood of developing moderate to severe depressive symptoms (odds ratio [OR] = 2.7, 95% CI = 1.3 to 5.6, p < .01, and OR = 3.3, 95% CI = 1.3 to 8.1, p < .01, respectively). CONCLUSIONS: Development of moderate to severe depressive symptoms occurred frequently during PEG IFN/ribavirin treatment and was predicted by baseline depression scores and higher doses of ribavirin. History of major depressive disorder was also a significant predictive factor, but only through association with elevated baseline depression status. All of these factors can be evaluated and addressed to limit neuropsychiatric morbidity during HCV treatment.

Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression.

BACKGROUND: Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. METHODS: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. RESULTS: Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05). CONCLUSIONS: These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.

Depressive symptoms and viral clearance in patients receiving interferon-alpha and ribavirin for hepatitis C.

Interferon (IFN)-alpha plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. We examined whether increased symptoms of depression during IFN-alpha/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-alpha-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR). Only 34% of subjects (10 out of 29) with a 20-point or greater increase in SDS Index score were HCV PCR negative at 24 weeks, compared to 59% (24 out of 41) of patients with a 10-19 point increase in SDS Index and 69% (22 out of 32) of patients with a less than 10 point increase (chi2=7.6, df=2, p <0.05). In addition, a 20-point or greater increase in SDS Index score during IFN-alpha/ribavirin therapy significantly predicted failure to clear virus when considered alone [crude odds ratio (OR), 3.2; 95% confidence interval (CI), 1.3-8.0; p <0.01] or when controlling for other factors that affected IFN-alpha treatment response (adjusted OR, 3.6; 95% CI, 1.3-9.5; p=0.01). These preliminary findings suggest that individuals who experience significant increases in depressive symptoms during IFN-alpha/ribavirin therapy may be less likely to clear virus, highlighting the importance of identifying and treating depressive symptoms in this patient population.