Early bactericidal activity of different isoniazid doses for drug-resistant tuberculosis (INHindsight): A randomized, open-label clinical trial

Kelly E. Dooley, Sachiko Miyahara, Florian Von Groote-Bidlingmaier, Xin Sun, Richard Hafner, Susan L. Rosenkranz, Elisa H. Ignatius, Eric L. Nuermberger, Laura Moran, Kathleen Donahue, Susan Swindells, Naadira Vanker, Andreas H. Diacon

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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).

Original languageEnglish (US)
Pages (from-to)1416-1424
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume201
Issue number11
DOIs
StatePublished - Jun 1 2020

Keywords

  • Early Bactericidal Activity
  • Inha Mutation
  • Isoniazid Resistance
  • Phase 2 Clinical Trial
  • Tuberculosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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