Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September 2013 and December 2019. The genes katG, inhA, fabG1, and the intergenic region oxyR’-ahpC were considered in this review. Fifty-two articles were included describing 9,306 clinical isolates (5,804 INHR, 3,502 INHS) from 31 countries. The three most frequently mutated loci continue to be katG315 (4,271), inhA-15 (787), and inhA-8 (106). However, the diagnostic value of inhA-8 is far lower than previously thought, only appearing in 25 (0.4%) INHR isolates lacking the first two mutations. We catalogued 45 new loci (29 katG, nine inhA, seven ahpC) associated with INH resistance and identified 59 loci (common to this and previous reviews) as a reliable basis for molecular diagnostics. Including all observed mutations provides a cumulative sensitivity of 85.6%. In 14.4% of resistant isolates no mechanism of resistance was detected, making them likely to escape molecular detection, and in case of mono INH resistance likely to convert to MDR-TB. Integrating the information cataloged in this study into current diagnostic tools is essential for combating the emergence of MDR-TB, and its exclusion can lead to an unintended selection against common mechanisms and to diversifying evolution. Observation of many low-frequency resistance-conferring mutations points to an advantage of WGS for diagnostics. Finally, we provide five recommendations for future diagnostic platforms.

No abstract

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 catalogue mutations at 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. Exclusion of this information will lead to an unnatural selection which will result in eradication of the common but propagation of the uncommon mechanisms of resistance, leading to ineffective global treatment policy and a need for region-specific regiments. Finally, the observance of many low-frequency resistance-conferring mutations point to an advantage of platforms that consider regions rather than specific loci for detection of resistance.

No abstract