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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+Show Affiliations

Johns Hopkins University, Medicine, Baltimore, Maryland, United States; kdooley1@jhmi.edu.Harvard University T H Chan School of Public Health, 1857, Boston, Massachusetts, United States.Stellenbosch University Faculty of Medicine and Health Sciences, 121470, TASK Applied Science, Cape Town, South Africa.Harvard University T H Chan School of Public Health, 1857, Boston, Massachusetts, United States.National Institutes of Health, Division of AIDS, Bethesda, Maryland, United States.Harvard University T H Chan School of Public Health, 1857, Boston, Massachusetts, United States. Frontier Science and Technology Research Foundation, 2402, Boston, Massachusetts, United States.Johns Hopkins University, Baltimore, Maryland, United States.Johns Hopkins University, Medicine, Baltimore, Maryland, United States.Social & Scientific Systems Inc, 43740, Silver Spring, Maryland, United States.Frontier Science and Technology Research Foundation, 2402, Boston, Massachusetts, United States.Nebraska Medicine, 21039, Omaha, Nebraska, United States.TASK Applied Science, Cape Town, South Africa.University of Stellenbosch, Internal Medicine, Tygerberg, South Africa.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31945300

Citation

Dooley, Kelly E., et al. "Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): a Randomized Open-label Clinical Trial." American Journal of Respiratory and Critical Care Medicine, 2020.
Dooley KE, Miyahara S, von Groote-Bidlingmaier F, et al. Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial. Am J Respir Crit Care Med. 2020.
Dooley, K. E., Miyahara, S., von Groote-Bidlingmaier, F., Sun, X., Hafner, R., Rosenkranz, S. L., ... Diacon, A. H. (2020). Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial. American Journal of Respiratory and Critical Care Medicine, doi:10.1164/rccm.201910-1960OC.
Dooley KE, et al. Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): a Randomized Open-label Clinical Trial. Am J Respir Crit Care Med. 2020 Jan 16; PubMed PMID: 31945300.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): 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, AU - ,, Y1 - 2020/01/16/ PY - 2020/1/17/entrez PY - 2020/1/17/pubmed PY - 2020/1/17/medline KW - clinical trial KW - drug resistant tuberculosis KW - early bactericidal activity KW - inhA KW - isoniazid JF - American journal of respiratory and critical care medicine JO - Am. J. Respir. Crit. Care Med. N2 - 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. SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/31945300/Early_Bactericidal_Activity_of_Different_Isoniazid_Doses_for_Drug_Resistant_TB_(INHindsight):_A_Randomized_Open-label_Clinical_Trial L2 - http://www.atsjournals.org/doi/full/10.1164/rccm.201910-1960OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -