Reply to Decroo et al.: High-Dose First-Line Treatment Regimen for Recurrent Rifampicin-Susceptible Tuberculosis

From the Authors:

We read with interest the letter from Decroo and colleagues referencing our INHindsight clinical trial, in which we show that 7 days of high-dose isoniazid (HD-INH) is active against pulmonary tuberculosis, with INH resistance mediated by inhA mutations (1). We agree that in addition to its utility as an agent against multidrug-resistant tuberculosis (MDR TB), HD-INH, as part of a regimen using optimally dosed first-line drugs, could play a role in the treatment of INH-resistant, rifampicin-susceptible (INH-R) TB. We acknowledge that INH has some advantages over levofloxacin, the currently recommended drug for INH-R TB, in general—it is more readily available and narrow-spectrum—and drug susceptibility testing may be more commonplace for INH than for levofloxacin (now or in the future). Certainly, higher doses of rifampicin are also needed for drug-susceptible and INH-R TB, as current doses result in suboptimal efficacy—especially in patients who are underweight or have advanced disease, meningitis, or HIV—and allow no forgiveness for missed doses (2).

Although we share Decroo and colleagues’s enthusiasm, in our opinion, more needs to be done before HD-INH can be generally recommended. A one-dose-fits-all dosing approach must be carefully weighed against the risk of toxicity in patients with slow NAT2 (N-acetyltransferase 2) metabolizer status, whose INH concentrations can be up to threefold higher than those in fast acetylators, and the consequences of potential differences in efficacy related to mutation type. Accumulating indirect evidence that HD-INH has activity against strains with katG mutations (which tend to produce higher minimum inhibitory concentrations in vitro) needs confirmation (3–5). In the next phase of INHindsight, we will measure the early bactericidal activity of HD-INH (15–20 mg/kg) in patients with pulmonary TB caused by Mycobacterium tuberculosis strains with katG mutations. Eventually, simple and low-cost tests to determine host and bacterial genetic characteristics (NAT2 status and INH resistance mutation type) may be of great help for selecting patients who would benefit from HD-INH, and the dose that would provide the strongest microbiologic activity for a given patient with INH-R or MDR TB. It is important to appreciate that safety data for HD-INH (especially doses of ≥15 mg/kg) given for prolonged periods of time are still limited. However, with a broader roll-out of the “short-course” MDR TB regimen, information about the safety and tolerability of the 10-mg/kg dose across multiple geographic populations should soon be available.