  Molecular testing is rapidly becoming integral to the global tuberculosis
(TB) control effort. Uncommon mechanisms of resistance can escape detection by
these platforms and lead to the development of Multi-Drug Resistant (MDR)
strains. This article is a systematic review of published articles that
reported isoniazid (INH) resistance-conferring mutations between September-2013
and December-2019. The aims were to catalogue mutations associated with INH
resistance, estimate their global prevalence and co-occurrence, and their
utility in molecular diagnostics. The genes commonly associated with INH
resistance, katG, inhA, fabG1, and the intergenic region oxyR-ahpC were
considered in this review. In total, 52 articles were included describing 5,632
INHR clinical isolates from 31 countries. The three most frequently mutated
loci continue to be katG315 (4,100), inhA-15 (786), and inhA-8 (105). However,
the diagnostic value of inhA-8 is far lower than previously thought, only
appearing in 25 (0.4%) INHR isolates that lacked a mutation at the first two
loci. Importantly, of the four katG loci recommended by the previous systematic
review for diagnostics, only katG315 was observed in our INHR isolates. This
indicates continued evolution and regional differences in INH resistance. We
have identified 58 loci (common to both systematic reviews) in three genomic
regions as a reliable basis for molecular diagnostics. We also report 49 new
loci associated with INH resistance. Including all observed mutations provides
a cumulative sensitivity of 85.1%. The most disconcerting is the remaining
14.9% of isolates that harbor an unknown mechanism of resistance, will escape
molecular detection, and likely convert to MDR-TB, further complicating
treatment. Integrating the information cataloged in this and other similar
studies into current diagnostic tools is essential for combating the emergence
of MDR-TB.
