Modeling Treatment of Latent Tuberculosis: Shortening the Leap of Faith?
Ontology highlight
ABSTRACT:
SUBMITTER: Vernon A
PROVIDER: S-EPMC7049924 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Modeling Treatment of Latent Tuberculosis: Shortening the Leap of Faith?
Vernon Andrew A Bishai William W
American journal of respiratory and critical care medicine 20200201 4
Similar Datasets
Project description: Not available
| S-EPMC10797496 | biostudies-literature
Project description: Not available
| S-EPMC10797497 | biostudies-literature
Project description:BackgroundGiven the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling.MethodsMycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator.ResultsSix weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively.ConclusionThis study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models.
| S-EPMC9159334 | biostudies-literature
Project description:In the past 2 years, remarkable advances have been made in shortening tuberculosis (TB) treatment. In particular, four clinical trials (Study 31/A5349, Nix-TB, ZeNix and TB-PRACTECAL) have provided evidence of the efficacy of regimens based on new and repurposed drugs: the 4-month regimen for drug-susceptible TB, and the 6-month bedaquiline-pretomanid-linezolid regimen with or without moxifloxacin for multidrug-resistant/rifampicin-resistant TB. Even if the evidence at the basis of these new regimens is compelling, several questions remain open, particularly concerning linezolid dose finding, the upsurging threat of bedaquiline-resistant Mycobacterium tuberculosis and the feasibility of applying these results to the paediatric population. Several ongoing trials may fill the remaining gaps and produce further reliable evidence to address the outstanding questions in TB treatment shortening.
| S-EPMC10567072 | biostudies-literature
Project description:Six months of chemotherapy using current agents is standard of care for pulmonary, drug-sensitive tuberculosis (TB), even though some are believed to be cured more rapidly and others require longer therapy. Understanding what factors determine the length of treatment required for durable cure in individual patients would allow individualization of treatment durations, provide better clinical tools to determine the of appropriate duration of new regimens, as well as reduce the cost of large Phase III studies to determine the optimal combinations to use in TB control programs. We conducted a randomized clinical trial in South Africa and China that recruited 704 participants with newly diagnosed, drug-sensitive pulmonary tuberculosis and stratified them based on radiographic disease characteristics as assessed by FDG PET/CT scan readers. Participants with less extensive disease (N=273) were randomly assigned to complete therapy after four months or continue receiving treatment for six months. Amongst participants who received four months of therapy, 17 of 141 (12.1%) experienced unfavorable outcomes compared to only 2 of 132 (1.5%) who completed six months of treatment (treatment success 98.4% in B, 86.7% in C (difference -11.7%, 95% CI, -18.2%, -5.3%)). In the non-randomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total cavity volume and total lesion glycolysis at week 16 were significantly associated with risk of unfavorable outcome in the randomized participants. Based on PET/CT scans at TB recurrence, bacteriological relapses (confirmed by whole genome sequencing) predominantly occurred in the same active cavities originally present at baseline. Automated segmentation of the serial PET/CT scans was later performed, and machine-learning was used to classify participants according to their likelihood of relapse, allowing the development of predictive models with good performance based on CT, PET, microbiological and clinical characteristics. These results open the possibility for more efficient studies of future TB treatment regimens.
| S-EPMC11722446 | biostudies-literature
Project description:In the past 2 years, remarkable advances have been made in shortening tuberculosis (TB) treatment. In particular, four clinical trials (Study 31/A5349, Nix-TB, ZeNix and TB-PRACTECAL) have provided evidence of the efficacy of regimens based on new and repurposed drugs: the 4-month regimen for drug-susceptible TB, and the 6-month bedaquiline-pretomanid-linezolid regimen with or without moxifloxacin for multidrug-resistant/rifampicin-resistant TB. Even if the evidence at the basis of these new regimens is compelling, several questions remain open, particularly concerning linezolid dose finding, the upsurging threat of bedaquiline-resistant Mycobacterium tuberculosis and the feasibility of applying these results to the paediatric population. Several ongoing trials may fill the remaining gaps and produce further reliable evidence to address the outstanding questions in TB treatment shortening.
| S-EPMC10567072 | biostudies-literature
Project description:RationaleCavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.ObjectivesTo assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.MethodsThis study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.Measurements and main resultsEnrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).ConclusionShortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.
| S-EPMC2742745 | biostudies-literature
Project description:The role of the treatment for latent tuberculosis infection (LTBI) has been underscored in the intermediate tuberculosis (TB) burden countries like South Korea. LTBI treatment is recommended only for patients at risk for progression to active TB-those with frequent exposure to active TB cases, and those with clinical risk factors (e.g., immunocompromised patients). Recently revised National Institute for Health and Care Excellence (NICE) guideline recommended that close contacts of individuals with active pulmonary or laryngeal TB, aged between 18 and 65 years, should undergo LTBI treatment. Various regimens for LTBI treatment were recommended in NICE, World Health Organization (WHO), and Centers for Disease Control and Prevention guidelines, and superiority of one recommended regimen over another was not yet established. Traditional 6 to 9 months of isoniazid (6H or 9H) regimen has an advantage of the most abundant evidence for clinical efficacy-60%-90% of estimated protective effect. However, 6H or 9H regimen is related with hepatotoxicity and low compliance. Four months of rifampin regimen is characterized by less hepatotoxicity and better compliance than 9H, but has few evidence of clinical efficacy. Three months of isoniazid plus rifampin was proved equivalence with 6H or 9H regimen in terms of efficacy and safety, which was recommended in NICE and WHO guidelines. The clinical efficacy of isoniazid plus rifapentine once-weekly regimen for 3 months was demonstrated recently, which is not yet introduced into South Korea.
| S-EPMC5771748 | biostudies-literature
Project description:Nine months of daily isoniazid is efficacious in treating latent M. tuberculosis infection, but completion rates are low, limiting treatment effectiveness. In 2011, three important studies were published involving novel regimens for the treatment of latent M. tuberculosis infection. At least 36 months of isoniazid was more effective than 6 months of isoniazid in one study, but not in another-both of which were conducted among tuberculin skin test positive HIV-infected adults living in high tuberculosis incidence settings. Three months of once-weekly isoniazid plus rifapentine or twice-weekly isoniazid plus rifampin (both given under direct observation) resulted in tuberculosis rates similar to those seen with 6 months of isoniazid among HIV-infected persons in high tuberculosis incidence settings. Three months of once-weekly, directly-observed isoniazid plus rifapentine was at least as effective as 9 months of daily isoniazid among predominantly HIV-uninfected persons living in low and medium tuberculosis incidence countries. The 3-month once-weekly isoniazid plus rifapentine regimen demonstrates promise for treatment of latent M. tuberculosis infection in HIV-infected persons.
| S-EPMC3410968 | biostudies-other
Project description:Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the 'one-size-fits-all' treatment currently used worldwide.
| S-EPMC6685538 | biostudies-literature