https://orcid.org/0000-0003-0099-903X
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ABSTRACT
Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.
Trial registration: ClinicalTrials.gov identifier: NCT05117788..
Disclosure statement
SBG, MdV, KV, REC, TCR, AS and MR are consultants or employees of FIND, the global alliance for diagnostics, a not-for-profit foundation that supports the evaluation of publicly prioritized TB assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for TB and other diseases. These agreements strictly define FIND’s independence and neutrality with regard to these private sector companies. MR, PM and DMC are members of the NDWG StopTB Partnership. TCR is a cofounder, board member, and shareholder of Verus Diagnostics, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results, and TCR has not received any financial support from Verus Diagnostics. University of California, San Diego (UCSD) Conflict of Interest office has reviewed and approved TCR’s role in Verus Diagnostics. TCR is a coinventor of a provisional patent for a TB diagnostic assay (provisional patent 63/048.989). TCR is also a coinventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918), and has agreed to “donate all present and future interest in and rights to royalties from this patent” to UCSD to ensure that he does not receive any financial benefits from this patent.