Whole-genome sequencing for TB source investigations: principles of ethical precision public health.

BACKGROUND: Whole-genome sequencing (WGS) of Mycobacterium tuberculosis allows rapid, accurate inferences about the sources, location and timing of transmission. However, in an era of heightened concern for personal privacy and science distrust, such inferences could result in unintended harm and undermine the public´s trust.METHODS: We held interdisciplinary stakeholder discussions and performed ethical analyses of real-world illustrative cases to identify principles that optimise benefit and mitigate harm of M. tuberculosis WGS-driven TB source investigations.RESULTS: The speed and precision with which real-time WGS can be used to associate M. tuberculosis strains with sensitive information has raised important concerns. While detailed understanding of transmission events could mitigate harm to vulnerable patients and communities when otherwise unfairly blamed for TB outbreaks, the precision of WGS can also identify transmission events resulting in social blame, fear, discrimination, individual or location stigma, and the use of defaming language by the public, politicians and scientists. Public health programmes should balance the need to safeguard privacy with public health goals, transparency and individual rights, including the right to know who infects whom or where.CONCLUSIONS: Ethical challenges raised by real-time WGS-driven TB source investigation requires public health authorities to move beyond their current legal mandate and embrace transparency, privacy and community engagement.

Identifying isoniazid resistance markers to guide inclusion of high-dose isoniazid in tuberculosis treatment regimens.

OBJECTIVES: Effective use of antibiotics is critical to control the global tuberculosis pandemic. High-dose isoniazid (INH) can be effective in the presence of low-level resistance. We performed a systematic literature review to improve our understanding of the differential impact of genomic Mycobacterium tuberculosis (Mtb) variants on the level of INH resistance. The following online databases were searched: PubMed, Web of Science and Embase. Articles reporting on clinical Mtb isolates with linked genotypic and phenotypic data and reporting INH resistance levels were eligible for inclusion. METHODS: All genomic regions reported in the eligible studies were included in the analysis, including: katG, inhA, ahpC, oxyR-ahpC, furA, fabG1, kasA, rv1592c, iniA, iniB, iniC, rv0340, rv2242 and nat. The level of INH resistance was determined by MIC: low-level resistance was defined as 0.1-0.4 µg/mL on liquid and 0.2-1.0 µg/mL on solid media, high-level resistance as >0.4µg/mL on liquid and >1.0 µg/mL on solid media. RESULTS: A total of 1212 records were retrieved of which 46 were included. These 46 studies reported 1697 isolates of which 21% (n = 362) were INH susceptible, 17% (n = 287) had low-level, and 62% (n = 1048) high-level INH resistance. Overall, 24% (n = 402) of isolates were reported as wild type and 76% (n = 1295) had ≥1 relevant genetic variant. Among 1295 isolates with ≥1 variant, 78% (n = 1011) had a mutation in the katG gene. Of the 867 isolates with a katG mutation in codon 315, 93% (n = 810) had high-level INH resistance. In contrast, only 50% (n = 72) of the 144 isolates with a katG variant not in the 315-position had high-level resistance. Of the 284 isolates with ≥1 relevant genetic variant and wild type katG gene, 40% (n = 114) had high-level INH resistance. CONCLUSIONS: Presence of a variant in the katG gene is a good marker of high-level INH resistance only if located in codon 315.