A Systematic Review of Mutations Associated with Isoniazid Resistance\n Points to Lower Diagnostic Sensitivity for Common Mutations and Increased\n Incidence of Uncommon Mutations in Clinical Strains of Mycobacterium\n tuberculosis

Molecular testing is rapidly becoming integral to the global tuberculosis\n(TB) control effort. Uncommon mechanisms of resistance can escape detection by\nthese platforms and lead to the development of Multi-Drug Resistant (MDR)\nstrains. This article is a systematic review of published articles that\nreported isoniazid (INH) resistance-conferring mutations between September-2013\nand December-2019. The aims were to catalogue mutations associated with INH\nresistance, estimate their global prevalence and co-occurrence, and their\nutility in molecular diagnostics. The genes commonly associated with INH\nresistance, katG, inhA, fabG1, and the intergenic region oxyR-ahpC were\nconsidered in this review. In total, 52 articles were included describing 5,632\nINHR clinical isolates from 31 countries. The three most frequently mutated\nloci continue to be katG315 (4,100), inhA-15 (786), and inhA-8 (105). However,\nthe diagnostic value of inhA-8 is far lower than previously thought, only\nappearing in 25 (0.4%) INHR isolates that lacked a mutation at the first two\nloci. Importantly, of the four katG loci recommended by the previous systematic\nreview for diagnostics, only katG315 was observed in our INHR isolates. This\nindicates continued evolution and regional differences in INH resistance. We\nhave identified 58 loci (common to both systematic reviews) in three genomic\nregions as a reliable basis for molecular diagnostics. We also report 49 new\nloci associated with INH resistance. Including all observed mutations provides\na cumulative sensitivity of 85.1%. The most disconcerting is the remaining\n14.9% of isolates that harbor an unknown mechanism of resistance, will escape\nmolecular detection, and likely convert to MDR-TB, further complicating\ntreatment. Integrating the information cataloged in this and other similar\nstudies into current diagnostic tools is essential for combating the emergence\nof MDR-TB.\n