The Risk of Falsely Declaring Noninferiority of Novel Latent Tuberculosis Treatment in Large Trials.
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ABSTRACT:
SUBMITTER: Abubakar I
PROVIDER: S-EPMC7047458 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
The Risk of Falsely Declaring Noninferiority of Novel Latent Tuberculosis Treatment in Large Trials.
Abubakar Ibrahim I Cobelens Frank G J FGJ Rangaka Molebogeng X MX
American journal of respiratory and critical care medicine 20200301 5
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Project description:In this Collection Review for the Novel Treatments for Tuberculosis Collection, Piero Olliaro and Michael Vaillant discuss the considerations when choosing a non-inferiority margin that is meaningful from statistical, ethical, clinical, and health standpoint.
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Project description:We report an updated method for inferring the time at which an infectious disease was transmitted between persons from a time-labelled pathogen genome phylogeny. We applied the method to 48 Mycobacterium tuberculosis genomes as part of a real-time public health outbreak investigation, demonstrating that although active tuberculosis (TB) cases were diagnosed through 2013, no transmission events took place beyond mid-2012. Subsequent cases were the result of progression from latent TB infection to active disease, and not recent transmission. This evolutionary genomic approach was used to declare the outbreak over in January 2015.
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Project description: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. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS:Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS:Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).
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Project description:BackgroundTreatment of latent tuberculosis infection (LTBI) is highly effective at preventing active tuberculosis (TB) disease. Understanding LTBI treatment practices in US health system settings is critical to identify opportunities to improve treatment prescription, initiation, and completion, and thus to prevent TB disease.MethodsWe assessed LTBI treatment practices among a cohort of adults after their first positive LTBI test (tuberculin skin test [TST] or interferon gamma release assay [IGRA]) between 2009 and 2018 at 2 large integrated health systems in California. We described the prescription, initiation, and completion of LTBI treatment (isoniazid [INH], rifampin, and rifamycin-INH short-course combinations) by demographic and clinical characteristics. We used multivariable robust Poisson regression to examine factors that were independently associated with treatment prescription and completion.ResultsAmong 79 302 individuals with a positive LTBI test, 33.0% were prescribed LTBI treatment, 28.3% initiated treatment, and 18.5% completed treatment. Most individuals were prescribed INH (82.0%), but treatment completion was higher among those prescribed rifamycin-INH short-course combinations (69.6% for INH + rifapentine and 70.3% for INH + rifampin) compared with those prescribed INH (56.3%) or rifampin (56.6%). In adjusted analyses, treatment prescription and completion were associated with older age, female sex, more comorbidities, immunosuppression, not being born in a high-TB incidence country, and testing positive with IGRA vs TST.ConclusionsLTBI treatment is underutilized, requiring tailored interventions to support treatment prescription and completion for patients with LTBI.
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Project description:Despite recent success in reducing its incidence, tuberculosis remains a considerable challenge in Canada, particularly among foreign-born and Indigenous populations. A key component of the strategy for controlling the disease is the treatment of latent tuberculosis infection. The standard treatment consists of isoniazid (INH) daily for nine months. In recent years, shorter regimens have been developed in the hope of increasing rates of treatment acceptance and completion. Of these, the shortest and most recently developed is a combination of INH and rifapentine taken once weekly for 12 doses (3HP), typically using directly observed therapy (DOT). This regimen has been approved by the Food and Drug Administration in the United States but is not yet authorized in Canada. Based on a rapidly expanding number of observational studies and randomized controlled trials, 12 weeks of 3HP appears to have similar efficacy to nine months of INH, a favourable adverse event profile and potentially improved rates of treatment completion. Although rates of treatment acceptance, the role of self-administered therapy and the regimen's cost-effectiveness within the Canadian context remain uncertain, 3HP is a promising alternative to existing treatments for LTBI.
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Project description:Preventing the development of tuberculosis (TB) in contacts of patients with multidrug-resistant TB (MDR-TB) by the treatment of latent TB infection (LTBI) is highly desirable. However, few safe, well tolerated, and effective drugs are available to treat MDR-LTBI and the published guidance is limited. Fortunately, six new chemical entities from four classes developed to treat TB have entered clinical trials in the past decade. We tested three of these drugs alone and in combination in an experimental paucibacillary LTBI chemotherapy model using BALB/c and C3HeB/FeJ mice immunized with a recombinant strain of Mycobacterium bovis bacillus Calmette-Guérin (rBCG30) and then challenged with a low-dose aerosol of M. tuberculosis H37Rv. The regimens tested contained bedaquiline (TMC), PA-824 (Pa), sutezolid (PNU), and/or one of two fluoroquinolones. Control mice received rifampin (RIF) or isoniazid (INH). In BALB/c mice, TMC-containing regimens and the Pa-PNU combination were the most active test regimens and were at least as effective as RIF. Pa, PNU, and levofloxacin had activity comparable to that of INH. Virtually identical results were observed in C3HeB/FeJ mice. This study confirms the potent activity of TMC observed previously in BALB/c mice and highlights Pa alone or in combination with either PNU or a fluoroquinolone as a regimen worthy of evaluation in future clinical trials of MDR-LTBI. Given their closer pathological representation of human TB lesions, C3HeB/FeJ mice may become a preferred model for the experimental chemotherapy of LTBI. Future studies should evaluate additional clinically relevant LTBI regimens in this strain including relapse as an endpoint.
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