Early Bactericidal Activity of Different Isoniazid Doses for Drug-Resistant Tuberculosis (INHindsight): A Randomized, Open-Label Clinical Trial.
rct · Level II
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- Record sourced from PubMed, PMID 31945300.
- Also identified by DOI 10.1164/rccm.201910-1960OC and PMC identifier 7258626.
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Abstract
<b>Rationale:</b> 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 <i>inhA</i> or <i>katG</i> mutations are unknown.<b>Objectives:</b> To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by <i>inhA</i> mutations.<b>Methods:</b> 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 <i>inhA</i> 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<sub>10</sub> cfu on solid media (EBA<sub>cfu0-7</sub>) or as time to positivity (TTP) in liquid media in hours (EBA<sub>TTP0-7</sub>) using nonlinear mixed-effects models.<b>Measurements and Main Results:</b> 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<sub>cfu0-7</sub> at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log<sub>10</sub> cfu/ml/d, respectively, and 0.16 log<sub>10</sub> cfu/ml/d in control subjects. EBA<sub>TTP0-7</sub> patterns were similar. There were no drug-related grade ≥3 adverse events.<b>Conclusions:</b> Isoniazid 10-15 mg/kg daily had activity against TB strains with <i>inhA</i> mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with <i>katG</i> mutations will be explored next.Clinical trial registered with www.clinicaltrials.gov (NCT01936831).