Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial.

Abstract:

RATIONALE:High-dose isoniazid is recommended in short-course regimens for multidrug-resistant TB (MDR-TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown. OBJECTIVE: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 controls with drug-sensitive TB received standard dose (5 mg/kg/day). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity of isoniazid was estimated as the average daily change in log10 colony forming units on solid media (EBACFU0-7) or as time to positivity 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 isoniazid-sensitive and 41 with isoniazid mono-resistant or MDR TB, were enrolled at one site in South Africa. Mean EBACFU0-7 at doses of 5, 10 and 15 mg/kg in the inhA group was 0.07, 0.17 and 0.22 log10CFU/mL/day, respectively, and 0.16 log10CFU/mL/day in controls. EBATTP0-7 patterns were similar. There were no drug-related Grade >3 adverse events. CONCLUSIONS:Isoniazid 10-15 mg/kg daily had similar activity against TB strains with inhA mutations as 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.

authors

Dooley KE,Miyahara S,von Groote-Bidlingmaier F,Sun X,Hafner R,Rosenkranz SL,Ignatius EH,Nuermberger EL,Moran L,Donahue K,Swindells S,Vanker N,Diacon AH,A5312 Study Team.

doi

10.1164/rccm.201910-1960OC

subject

Has Abstract

pub_date

2020-01-16 00:00:00

eissn

1073-449X

issn

1535-4970

pub_type

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