TY - JOUR
T1 - Early bactericidal activity of different isoniazid doses for drug-resistant tuberculosis (INHindsight)
T2 - A randomized, open-label clinical trial
AU - Dooley, Kelly E.
AU - Miyahara, Sachiko
AU - Von Groote-Bidlingmaier, Florian
AU - Sun, Xin
AU - Hafner, Richard
AU - Rosenkranz, Susan L.
AU - Ignatius, Elisa H.
AU - Nuermberger, Eric L.
AU - Moran, Laura
AU - Donahue, Kathleen
AU - Swindells, Susan
AU - Vanker, Naadira
AU - Diacon, Andreas H.
N1 - Publisher Copyright:
© 2020 American Thoracic Society. All rights reserved.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Rationale: High-dose isoniazid is recommended in shortcourse 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 log10 cfu on solid media (EBAcfu0-7) or as time to positivity (TTP) in liquid media in hours (EBATTP0-7) using nonlinear mixed-effects models. Measurements and Main Results: Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazidsensitive TB, and 43 with isoniazid-monoresistant or multidrugresistant TB) were enrolled at one site in South Africa. The mean EBAcfu0-7 at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log10 cfu/ml/d, respectively, and 0.16 log10 cfu/ml/d in control subjects. EBATTP0-7 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. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
AB - Rationale: High-dose isoniazid is recommended in shortcourse 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 log10 cfu on solid media (EBAcfu0-7) or as time to positivity (TTP) in liquid media in hours (EBATTP0-7) using nonlinear mixed-effects models. Measurements and Main Results: Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazidsensitive TB, and 43 with isoniazid-monoresistant or multidrugresistant TB) were enrolled at one site in South Africa. The mean EBAcfu0-7 at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log10 cfu/ml/d, respectively, and 0.16 log10 cfu/ml/d in control subjects. EBATTP0-7 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. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
KW - Early Bactericidal Activity
KW - Inha Mutation
KW - Isoniazid Resistance
KW - Phase 2 Clinical Trial
KW - Tuberculosis
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U2 - 10.1164/rccm.201910-1960OC
DO - 10.1164/rccm.201910-1960OC
M3 - Article
C2 - 31945300
AN - SCOPUS:85087187629
SN - 1073-449X
VL - 201
SP - 1416
EP - 1424
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 11
ER -