Risk-stratified treatment for drug-susceptible pulmonary tuberculosis
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, whil...
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Nature Portfolio
2024-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53273-7 |
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| author | Vincent K. Chang Marjorie Z. Imperial Patrick P. J. Phillips Gustavo E. Velásquez Payam Nahid Andrew Vernon Ekaterina V. Kurbatova Susan Swindells Richard E. Chaisson Susan E. Dorman John L. Johnson Marc Weiner Amina Jindani Thomas Harrison Erin E. Sizemore William Whitworth Wendy Carr Kia E. Bryant Deron Burton Kelly E. Dooley Melissa Engle Pheona Nsubuga Andreas H. Diacon Nguyen Viet Nhung Rodney Dawson Radojka M. Savic AIDS Clinical Trial Group Tuberculosis Trials Consortium |
| author_facet | Vincent K. Chang Marjorie Z. Imperial Patrick P. J. Phillips Gustavo E. Velásquez Payam Nahid Andrew Vernon Ekaterina V. Kurbatova Susan Swindells Richard E. Chaisson Susan E. Dorman John L. Johnson Marc Weiner Amina Jindani Thomas Harrison Erin E. Sizemore William Whitworth Wendy Carr Kia E. Bryant Deron Burton Kelly E. Dooley Melissa Engle Pheona Nsubuga Andreas H. Diacon Nguyen Viet Nhung Rodney Dawson Radojka M. Savic AIDS Clinical Trial Group Tuberculosis Trials Consortium |
| author_sort | Vincent K. Chang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-de940f5d4bbc4e00aaa1dfc2d65e721a |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-de940f5d4bbc4e00aaa1dfc2d65e721a2025-08-20T02:25:12ZengNature PortfolioNature Communications2041-17232024-10-0115111210.1038/s41467-024-53273-7Risk-stratified treatment for drug-susceptible pulmonary tuberculosisVincent K. Chang0Marjorie Z. Imperial1Patrick P. J. Phillips2Gustavo E. Velásquez3Payam Nahid4Andrew Vernon5Ekaterina V. Kurbatova6Susan Swindells7Richard E. Chaisson8Susan E. Dorman9John L. Johnson10Marc Weiner11Amina Jindani12Thomas Harrison13Erin E. Sizemore14William Whitworth15Wendy Carr16Kia E. Bryant17Deron Burton18Kelly E. Dooley19Melissa Engle20Pheona Nsubuga21Andreas H. Diacon22Nguyen Viet Nhung23Rodney Dawson24Radojka M. Savic25AIDS Clinical Trial GroupTuberculosis Trials ConsortiumDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoUCSF Center for Tuberculosis, University of California San FranciscoUCSF Center for Tuberculosis, University of California San FranciscoUCSF Center for Tuberculosis, University of California San FranciscoCenters for Disease Control and PreventionCenters for Disease Control and PreventionUniversity of Nebraska Medical CenterCenter for Tuberculosis Research, Johns Hopkins University School of MedicineMedical University of South CarolinaCase Western Reserve University, University Hospitals Cleveland Medical CenterUniversity of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care SystemSt. George’s, University of LondonSt. George’s, University of LondonCenters for Disease Control and PreventionCenters for Disease Control and PreventionCenters for Disease Control and PreventionCenters for Disease Control and PreventionCenters for Disease Control and PreventionDivision of Infectious Diseases, Vanderbilt UniversityUniversity of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care SystemUganda–Case Western Reserve University Research CollaborationTASK, Cape Town, Western CapeVietnam National Tuberculosis Program–University of California, San Francisco Research Collaboration UnitLung Institute and Division of Pulmonology, Department of Medicine, University of Cape TownDepartment of Bioengineering and Therapeutic Sciences, University of California San FranciscoAbstract 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.https://doi.org/10.1038/s41467-024-53273-7 |
| spellingShingle | Vincent K. Chang Marjorie Z. Imperial Patrick P. J. Phillips Gustavo E. Velásquez Payam Nahid Andrew Vernon Ekaterina V. Kurbatova Susan Swindells Richard E. Chaisson Susan E. Dorman John L. Johnson Marc Weiner Amina Jindani Thomas Harrison Erin E. Sizemore William Whitworth Wendy Carr Kia E. Bryant Deron Burton Kelly E. Dooley Melissa Engle Pheona Nsubuga Andreas H. Diacon Nguyen Viet Nhung Rodney Dawson Radojka M. Savic AIDS Clinical Trial Group Tuberculosis Trials Consortium Risk-stratified treatment for drug-susceptible pulmonary tuberculosis Nature Communications |
| title | Risk-stratified treatment for drug-susceptible pulmonary tuberculosis |
| title_full | Risk-stratified treatment for drug-susceptible pulmonary tuberculosis |
| title_fullStr | Risk-stratified treatment for drug-susceptible pulmonary tuberculosis |
| title_full_unstemmed | Risk-stratified treatment for drug-susceptible pulmonary tuberculosis |
| title_short | Risk-stratified treatment for drug-susceptible pulmonary tuberculosis |
| title_sort | risk stratified treatment for drug susceptible pulmonary tuberculosis |
| url | https://doi.org/10.1038/s41467-024-53273-7 |
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