Risk-stratified treatment for drug-susceptible pulmonary tuberculosis
Authors: Chang Vincent K. , Imperial Marjorie Z. , Phillips Patrick P. J. , Velásquez Gustavo E. , Nahid Payam , Vernon Andrew , Kurbatova Ekaterina V. , Swindells Susan , Chaisson Richard E. , Dorman Susan E. , Johnson John L. , Weiner Marc , Sizemore Erin E. , Whitworth William , Carr Wendy , Bryant Kia E. , Burton Deron , Dooley Kelly E. , Engle Melissa , Nsubuga Pheona , Diacon Andreas H. , Nhung Nguyen Viet , Dawson Rodney , Savic Radojka M. ,   AIDS Clinical Trial Group, Kizza Harriet Mayanja , Ssaku Elias , Sekitoleko Isaac , Akol Joseph P. , Diacon Andreas , Kleinhans Carmen , Sims Julia , Mitchell Erika , Hendricks Bronwyn , Joseph Yvetot , Louis Marie Jude Jean , Mercy Cadette , Apollon Alexandra , Royal Gertrude , Mukwekwerere Pamela , Musodza Yeukai , Gurupira Wilfred , Tameris Michele , Luabeya Angelique Kany Kany , Hatherill Mark , Camblart Mario , Jean Circée Phara , Rassool Mohammed , Mwelase Noluthando , Bennet Jaclyn , Mohapi Lerato , Mogashoa Ntebo , Peters Debra , Gaikwad Sanjay , Neverkar Neetal , Lokhande Rahul , Munyanga Cornelius , Hosseinipour Mina , Potani Charity , Okeyo Elisha , Ouma Samuel Gurrion , Rabuogi Prisca , Escada Rodrigo , Tuler Lidiane , Kumwenda Johnstone , Mponda Kelvin , Cornelissen Lynne , Hiemstra Andriette , Lalloo Umesh G. , Pillay Sandy , Siika Abraham , Mendoza Alberto , Gonzales Pedro , Leon Mey , Lama Javier R. , Schwalb Alvaro , Gotuzzo Eduardo , Sawe Fredrick , Tsikhutsu Isaac , Gatechompol Sivaporn , Avihingsanon Anchalee , Kosashunhanan Natthapol , Sugandhavesa Patcharaphan , de Melo Marineide Gonçalves , Alves Lira Rita de Cassia , Luetkemeyer Anne , Marquez Carina , Coughlin Kristine , Dooley Kelly E. , Grosset Jacques H. , Nuermberger Eric L. , Hosey Lara , Podany Anthony T. , Borisov Andrey , Brown Nicole , Burns Scott , Carter Crystal , Cowan Lauren , Dunn Melinda , DeCausey Barbara , Fagley Melissa , Hedges Kimberly , Henderson Constance , Hott Amanda , Jeffries Carla , Klein Katherine , Mangan Joan , Mazurek Gerald , Moro Ruth , Peddareddy Lakshmi , Posey James , Reichler Mary , Ricaldi Jessica , Sadowski Claire , Willby Melisa , Yuan Yan , Pettit April C. ,   Tuberculosis Trials Consortium, Luu Lien T. , Nguyen Hanh T. T. , Nguyen Hung V. , Nguyen Hue T. M. , Merrifield Cyndy , Xaba Matebogo , Jaffer Maya , Majoro Keitumetse , Chang Kwok-Chiu , Leung Chi Chiu , Pavon Polo , Duque Rogelio , Samuel George , Burzynski Joseph , Elskamp Mascha , Campbell Jill , Quintero Marlon , Guy Elizabeth 
Published: October 2024

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.