Journal Article

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

Nsubuga, Pheona, Jindani, Amina, Engle, Melissa, Dooley, Kelly E., Diacon, Andreas H., Velásquez, Gustavo E., Imperial, Marjorie Z., Nahid, Payam, Burton, Deron, Johnson, John L., Vernon, Andrew, Sizemore, Erin E., Dorman, Susan E., Weiner, Marc, Swindells, Susan, Harrison, Thomas, Chang, Vincent K., Chaisson, Richard E., Whitworth, William, Dawson, Rodney, Carr, Wendy, Nhung, Nguyen Viet, Kurbatova, Ekaterina V., Bryant, Kia E., Phillips, Patrick P. J., Savic, Radojka M.

2024

Overview

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. Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154/436/108 / 631/154/436/1729 / 631/154/436/2388 / 692/308/53 / 692/699/255/1856 / Adult / Adverse events / Antibiotics / Antitubercular Agents - adverse effects / Antitubercular Agents - therapeutic use / Drug Therapy, Combination / Effectiveness / Exposure / Female / Health services / Humanities and Social Sciences / Humans / Lung diseases / Male / Middle Aged / Moxifloxacin / Moxifloxacin - therapeutic use / multidisciplinary / Mycobacterium tuberculosis - drug effects / Pharmacokinetics / Phenotypes / Radiography / Rifampin - adverse effects / Rifampin - analogs & derivatives / Rifampin - therapeutic use / Risk Factors / Science / Science (multidisciplinary) / Subgroups / Treatment Outcome / Tuberculosis / Tuberculosis, Pulmonary - drug therapy / Tuberculosis, Pulmonary - microbiology / Young Adult