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, and fabG1, and the intergenic region oxyR′-ahpC were considered in this review. Fifty-two articles were included that described 9,306 clinical isolates (5,804 INH resistant [INH^r] and 3,502 INH susceptible [INH^s]) from 31 countries. The three most frequently mutated loci continue to be locus 315 of katG (katG315; n = 4,271), locus −15 of inhA (inhA-15; n = 787), and locus −8 of inhA (inhA-8; 106). However, the diagnostic value of inhA-8 is far lower than previously thought, as it only appears in 25 (0.4%) of the INH^r isolates lacking the first two mutations. I catalogued 45 new loci (29 katG, nine inhA, and 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 the case of INH monoresistance, likely to convert to multidrug-resistant TB (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 whole-genome sequencing (WGS) for diagnostics. Finally, I provide five recommendations for future diagnostic platforms.

中文翻译：

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与异烟肼耐药性相关的突变的系统回顾表明分子检测的持续进化和随后的逃避，以及临床结核分枝杆菌菌株多药耐药性出现的可能性

分子检测正迅速成为全球结核病 (TB) 控制的一个组成部分。不常见的耐药机制逃避了这些平台的检测，并削弱了我们控制疫情的能力。这篇文章发表的文章系统回顾所报告的异烟肼（INH）抗性的基因2013年9月和2019年十二月间突变katG基因，的inhA和的fabG1，以及区域间oxyR ' - AHPC在本次审查进行了审议。包括 52 篇文章，描述了 9,306 种临床分离株（5,804 INH 耐药 [INH ^r ] 和 3,502 INH 敏感 [INH ^s]) 来自 31 个国家。三个最频繁突变的基因座继续的轨迹315 katG基因（katG基因315; ñ = 4271），基因座-15的inhA（的inhA -15; ñ = 787），和轨迹-8的inhA（的inhA -8; 106） . 然而，inhA -8的诊断价值远低于之前认为的，因为它只出现在 25 (0.4%)缺乏前两个突变的 INH ^r分离株中。我编目45个新位点（29 katG基因，九的inhA，七AHPC) 与 INH 耐药性相关，并确定了 59 个基因座（本综述和之前的综述常见）作为分子诊断的可靠基础。包括所有观察到的突变提供了 85.6% 的累积灵敏度。在 14.4% 的耐药菌株中，没有检测到耐药机制，这使得它们可能逃脱分子检测，而在 INH 单耐药的情况下，可能会转化为耐多药结核病 (MDR-TB)。将本研究中分类的信息整合到当前的诊断工具中对于对抗 MDR-TB 的出现至关重要，并且将其排除在外可能导致针对共同机制的意外选择和多样化的进化。对许多低频耐药性突变的观察表明全基因组测序 (WGS) 在诊断方面具有优势。最后，