Vincent K. Chang, University of California San Francisco
Marjorie Z. Imperial, University of California San Francisco
Patrick P. J. Phillips, University of California San Francisco
Gustavo E. Velásquez, University of California San Francisco
Payam Nahid, University of California San Francisco
Andrew Vernon, Centers for Disease Control and Prevention
Ekaterina V. Kurbatova, Centers for Disease Control and Prevention
Susan Swindells, University of Nebraska Medical CenterFollow
Richard E. Chaisson, Johns Hopkins University School of Medicine
Susan E. Dorman, Medical University of South Carolina
John L. Johnson, University Hospitals Cleveland Medical Center
Marc Weiner, University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System
Erin E. Sizemore, Centers for Disease Control and Prevention
William Whitworth, Centers for Disease Control and Prevention
Wendy Carr, Centers for Disease Control and Prevention
Kia E. Bryant, Centers for Disease Control and Prevention
Deron Burton, Centers for Disease Control and Prevention
Kelly E. Dooley, Vanderbilt University
Melissa Engle, University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System
Pheona Nsubuga, Uganda-Case Western Reserve University Research Collaboration
Andreas H. Diacon, TASK
Nguyen Viet Nhung, Vietnam National Tuberculosis Program-University of California, San Francisco Research Collaboration Unit
Rodney Dawson, University of Cape Town
Radojka M. Savic, University of California San Francisco
AIDS Clinical Trial Group
Tuberculosis Trials Consortium

Document Type

Article

Journal Title

Nature Communications

Publication Date

2024

Volume

15

Abstract

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

MeSH Headings

Humans, Rifampin, Tuberculosis, Pulmonary, Male, Female, Adult, Middle Aged, Antitubercular Agents, Moxifloxacin, Risk Factors, Treatment Outcome, Mycobacterium tuberculosis, Drug Therapy, Combination, Young Adult

ISSN

2041-1723

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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