Drug-resistant tuberculosis: the next sequence of events
Authors: None The Lancet Microbe
Journal: The Lancet Microbe (2023)

2024 marks 30 years of the WHO Global Project on Anti-TB Drug Resistance Surveillance, the oldest AMR monitoring initiative in the world. In 1994, the year the project was launched, The Lancet published an Editorial on the global challenge of tuberculosis. The Editorial lamented on the substandard BCG vaccine, the reliance on rifampicin, the threat of drug resistance, and “national public health systems that have failed to translate their own rhetoric into successful campaigns to control the disease”. Much of this could have been written today. The 2023 Global Tuberculosis Report highlighted the successes in preventing 74 million deaths since the year 2000, but estimated global cases remain high with 10·6 million people falling ill and 1·3 deaths in 2022. These figures have started to recover after disruption caused by the COVID-19 pandemic but key targets set by the 2018 UN High-Level Meeting were ultimately missed. A target that is off track is the number of people being tested with WHO-recommended tests that detect drug resistance, particularly rifampicin-resistant (RR) tuberculosis. RR tuberculosis testing was endorsed by WHO in 2010 and resulted in a 129% increase in people being enrolled on second-line drugs between 2012 and 2019. The Xpert MTB/RIF test (which simultaneously detects M tuberculosis and rifampicin resistance) has been widely used in reference laboratories, but scaling up coverage of the test has been limited by the high price of the cartridges that contain the PCR reagents. In September, 2023, an MSF campaign prompted the manufacturer of Xpert MTB/RIF, Cepheid, to reduce the price of their cartridges from US$9·98 to $7·97. This decrease is a step in the right direction but more can be done. The price of the Xpert MTB/XDR test (which detects resistance to first-line and second-line drugs) has not been reduced and remains at $14·90, triple the cost of production. The decision to maintain these high costs of tests for extensively drug-resistant tuberculosis means that those in most need of intensive treatment will not be able to access it. Despite targets in resistance testing being missed, there have been substantial advancements in understanding the mechanisms of resistance using whole-genome sequencing (WGS). In response to the wealth of genomic data that has been generated over the past two decades, WHO published the first Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance in 2021, with the second edition being published in November, 2023. In this issue of The Lancet Microbe, Ana María García-Marín and colleagues report a retrospective genomic analysis of M tuberculosis isolates from 25 hospitals that uses the catalogue as a reference guide to predict drug resistance profiles. Such studies demonstrate how the catalogue can be used to identify mutations in the M tuberculosis genome and interpret what they might mean for treatment. The isolates in the catalogue underwent comprehensive drug susceptibility screening and only those with high-quality WGS data generated from Illumina machines were included. It is therefore unsurprising that the countries underrepresented in the catalogue are some of the world's poorest. Despite gaps remaining in Africa and Asia, the 2023 version includes isolates from 67 countries, an improvement on the 40 in the original iteration. Including WGS and phenotypic susceptibility data from LMICs is an achievement that shows how much access to sequencing technology has increased since the COVID-19 pandemic. The cost of reagents and training remain barriers to WGS access but the recent scale up of sequencing has provided hope. Illumina have launched the Global Health Access Initiative that will provide discounted pathogen sequencing technology to LMICs, including resistance profiling tools for tuberculosis. This commitment is an encouraging sign that the next iteration of the catalogue will continue to increase the number of isolates and lineages. The past 30 years have shown that molecular tools are invaluable in the fight against drug-resistant tuberculosis. They have also shown that these tools are often not disseminated to countries needing them most. We encourage countries not represented in the WHO catalogue to contribute to the next edition. We encourage manufacturers of sequencing infrastructure to engage in partnerships with NGOs and tuberculosis control programmes and provide equitable access to their products. As the 1994 Lancet Editorial mused of the first advances in molecular testing, the following plea was made: “These new technologies should be made available without delay”—we reiterate this plea today.