A katG 315 mutation alone should not lead to exclusion of isoniazid in treatment of multidrug-resistant tuberculosis

From the authors:

We thank D. Chesov and co-workers for sharing data on isoniazid-resistant strains in Moldova as a comment on our paper on shorter regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB) [1]. In strains from MDR-TB patients, a high proportion (88%) had a mutation in the katG gene at position 315, results which “…strongly suggest that high-dose isoniazid should not be part of a standardised treatment regimen for patients with MDR-TB…”, based on the “…general consensus that high-level isoniazid resistance due to a mutation in the katG gene at position 315 cannot be overcome by high-dose isoniazid treatment…”. They refer to a recent TBNET/RESIST-TB consensus statement [2] which says that molecular testing for isoniazid resistance should be done since “…it offers the possibility to add INH to a second-line drug regimen in the absence of a katG 315 mutation…”.

We do not agree with this conclusion because there are a number of studies, discussed by amongst others Rieder et al. [3] and Otto-Knapp et al. [4], which compare genotypic and phenotypic drug-susceptibility testing results, and which indicate that strains with this mutation have highly variable minimum inhibitory concentrations and that a majority of strains with low or moderate-level resistance can be effectively treated with isoniazid at normal or high doses. Finding this mutation should not therefore be the sole reason for exclusion of isoniazid from the treatment regimen. Indeed, a previous TBNET consensus statement recommended that dosing of isoniazid should be adjusted according to the minimum inhibitory concentration test results whenever possible [5]. Furthermore, the shortened regimen no longer counts on high-dose isoniazid as a major drug but only as a less toxic companion, since full susceptibility was not expected in the original design [6].