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

Abstract

Rationale: 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 inhA or katG mutations are unknown. Objectives: To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA mutations. Methods: 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 inhA mutation were randomized to receive isoniazid 5, 10, or 15 mg/kg daily for 7 days (inhA group), and control subjects with drugsensitive 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(10) cfu on solid media (EBA(cfu0-7)) or as time to positivity (TTP) in liquid media in hours (EBA(TTP0-7)) using nonlinear mixed-effects models. Measurements and Main Results: 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(cfu0-7) at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log(10) cfu/ml/d, respectively, and 0.16 log(10) cfu/ml/d in control subjects. EBA(TT)(P0-7) patterns were similar. There were no drug-related grade >= 3 adverse events. Conclusions: Isoniazid 10-15 mg/kg daily had activity against TB strains with inhA mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next.