Early Bactericidal Activity of Different Isoniazid Doses for Drug-Resistant Tuberculosis (INHindsight): A Randomized, Open-Label Clinical Trial

• Published in: American journal of respiratory and critical care medicine Vol. 201; no. 11; pp. 1416 - 1424
• Main Authors: Dooley, Kelly E., Miyahara, Sachiko, von Groote-Bidlingmaier, Florian, Sun, Xin, Hafner, Richard, Rosenkranz, Susan L., Ignatius, Elisa H., Nuermberger, Eric L., Moran, Laura, Donahue, Kathleen, Swindells, Susan, Vanker, Naadira, Diacon, Andreas H., Issa, Rachel, Lane, Christopher, Lojacono, Mark, Mahachi, Rachel, Murtaugh, William, Purdue, Lynette, Shahkolahi, Akbar, Ssenyonga, Ronald
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.06.2020
• Subjects: Clinical trials; Drug dosages; Drug resistance; Multidrug resistant organisms; Original; Tuberculosis; phase 2 clinical trial; inhA mutation; early bactericidal activity; isoniazid resistance; tuberculosis
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201910-1960OC

High-dose isoniazid is recommended in short-course regimens for multidrug-resistant tuberculosis (TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with or mutations are unknown. To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by mutations. AIDS Clinical Trials Group A5312 is a phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an mutation were randomized to receive isoniazid 5, 10, or 15 mg/kg daily for 7 days (inhA group), and control subjects with drug-sensitive TB received the standard dose (5 mg/kg/d). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity (EBA) of isoniazid was estimated as the average daily change in log cfu on solid media (EBA ) or as time to positivity (TTP) in liquid media in hours (EBA ) using nonlinear mixed-effects models. Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive TB, and 43 with isoniazid-monoresistant or multidrug-resistant TB) were enrolled at one site in South Africa. The mean EBA at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log cfu/ml/d, respectively, and 0.16 log cfu/ml/d in control subjects. EBA patterns were similar. There were no drug-related grade ≥3 adverse events. Isoniazid 10-15 mg/kg daily had activity against TB strains with mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with mutations will be explored next.Clinical trial registered with www.clinicaltrials.gov (NCT01936831).