Risk-stratified treatment for drug-susceptible pulmonary tuberculosis
Vincent Chang, Marjorie Z. Imperial, Patrick 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 Sizemore, William C. Whitworth, Wendy Carr, Kia Bryant, Deron C. Burton, Kelly E. Dooley, Melissa Engle, Pheona Nsubuga, Andreas H. Diacon, Nguyen Viet Nhung, Rodney Dawson, Radojka M. Savić, Harriet Mayanja Kizza, Elias Ssaku, Isaac Sekitoleko, Joseph P. Akol, Andreas H. Diacon, Carmen Kleinhans, Julia Sims, Erika Mitchell, Bronwyn Hendricks, Yvetot Joseph, Marie Jude Jean Louis, Cadette Mercy, Alexandra Apollon, Gertrude Royal, Pamela Mukwekwerere, Yeukai Musodza, Wilfred Gurupira, Michèle Tameris, Angelique Kany Kany Luabeya, Mark Hatherill, Mario Camblart, Circée Phara Jean, Mohammed Rassool, Noluthando Mwelase, Jaclyn Bennet, Lerato Mohapi, Ntebo D Mogashoa, Debra L. Peters, Sanjay Gaikwad, Neetal Neverkar, Rahul Lokhande, Cornelius Munyanga, Mina C. Hosseinipour, Charity Potani, Elisha Okeyo, Samuel Gurrion Ouma, Prisca Rabuogi, Rodrigo Escada, Lidiane Tuler, Johnstone Kumwenda, Kelvin Mponda, Lynne Cornelissen, Andriëtte Hiemstra, Umesh Lalloo, Sandy Pillay, Abraham Siika, Alberto Bujardón Mendoza, Pedro Gonzáles, Mey León, Javier R. Lama, Alvaro Schwalb, Eduardo Gotuzzo, Fredrick Sawe, Isaac Tsikhutsu, Sivaporn Gatechompol, Anchalee Avihingsanon, Natthapol Kosashunhanan, Patcharaphan Sugandhavesa, Marineide Gonçalves de Melo, Rita de Cássia Alves Lira, Anne F. Luetkemeyer, Carina Marquez, Kristine Coughlin, Kelly E. Dooley, J Grosset, Eric Nuermberger, Lara Hosey, Anthony T. Podany, Andrey V. Borisov, Nicole Brown, Scott Burns, Crystal Carter, Lauren S. Cowan, Melinda Dunn
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.