OR38

Drug resistant Tuberculosis (TB) continues to be a major global concern. INH resistance is commonly first to emerge in treatment of TB. Molecular Diagnostics (mDx) is rapidly becoming an integral component of global TB control. Uncommon mechanisms of resistance escape detection and undermine outbreak containment efforts. In this systematic review, we report all INH-resistance-conferring mutations observed from 2013 through 2019. Overall, 9,306 clinical isolates (5,804 INHᴿ, 3,502 INHˢ) from 31 countries were included. 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. I report 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 mDx. Including all observed mutations provides a sensitivity of 85.6%. In 14.4% of resistant isolates no mechanism of resistance was detected, making them likely to escape mDx, 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. Importantly, this diversifying evolution is most frequently observed in Asia, while in Africa, clonal expansion of canonical mutations seems to be most prevalent.