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 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 log₁₀ 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 log₁₀ cfu/ml/d, respectively, and 0.16 log₁₀ cfu/ml/d in control subjects. EBA_TTP0-7 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).

Keywords: early bactericidal activity; inhA mutation; isoniazid resistance; phase 2 clinical trial; tuberculosis.

Figure 1.

CONSORT (Consolidated Standards of Reporting Trials) diagram showing study participant flow. Participants were selected in a two-step procedure. Only participants with a positive sputum smear of at least grade 1+ and with isolate having no katG mutation were screened for participation in the treatment study. INH = isoniazid; TB = tuberculosis.

Figure 2.

Seven-day early bactericidal activity (EBA) of isoniazid (INH). (A) Mean (95% confidence interval) EBA by decrease in colony-forming units (cfu) on solid culture medium, averaged over 7 days, based on log₁₀ cfu count, by arm. (B) Mean (95% confidence interval) EBA based on decrease in time to positivity (TTP) in liquid medium, in hours, averaged over 7 days.

Figure 3.

Distribution of minimum inhibitory concentrations (MICs) of isoniazid against strains with no inhA or katG mutations, with inhA mutations, or with katG mutations. Strains are from participants who provided sputum specimens only or who provided specimens and also participated in the treatment trial.