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Updates on diagnostics and new treatment guidelines for TB

Dave Moore presents updates on diagnostics and new treatment guidelines for Tuberculosis (TB).
SPEAKER: So I’m going to say a few words about updates to the guidelines both for the diagnosis of drug-resistant TB and for the treatment of drug-resistant TB. In 2021, WHO received these consolidated guidelines on TB and this is module 3, Diagnosis Rapid Diagnostics for TB Detection. And in this 2021 document, items that have not previously featured in earlier iterations included descriptions of moderate complexity automated nucleic acid amplification, tests for detection of TB, and resistance to rifampicin and isoniazid. The detection of isoniazid is something that was not done in an automated fashion very much before this. A description of low complexity automated NAATs for detection of resistance to isoniazid and second-line anti-TB agents and that’s primarily the Xpert platform.
And then an important gap in our diagnostic armamentarium has been assessing susceptibility to pyrazinamide which is very important in many of the regimens used for drug resistant TB treatment as well as for drug susceptible TB. And so there is a recommendation about high complexity hybridization based NAATS for detection of that resistance. What’s missing from this document is anything about whole genome sequencing which many would argue may well be the future of drug resistance testing in many settings, including those that are low and middle income. And not least because the cost of whole genome sequencing has come down dramatically. So maybe that will be part of the next step, the next iteration of these guidelines.
The same guidelines issued in 2020 presented data on Xpert MTB/RIF and Xpert MTB/RIF (Ultra) which is the more sensitive version, as well as on an alternative platform, the Truenat platform for detecting TB at Truenat MTB Plus and Truenat MTB-RIF Dx.
And in addition, there were guidelines about the lateral flow assay for LAM, that’s lipoarabinomann which is a mycobacterial wall constituent that is detectable in the urine of people with advanced HIV. In the most recent guidelines, there’s updated recommendations about which particular patients this assay should be used in. There are still no recommendations about the usage of the Next-Generation LAM assay. So the assay is described in these guidelines as the Alere LAM assay but Fujifilm have also released a LAM assay which shows better performance, also however in patients with HIV. And then in 2016, these same diagnostic guidelines issued some recommendations on the use of the LAMP assay, a diagnostics used for many diseases.
But has here been used for TB, and the use of molecular line probe assays for the detection of resistance to isoniazid and rifampicin as well as the use of these line probe assays for the detection of resistance to second-line anti-tuberculosis drugs. Now what is the first-line and the second-line drug is set to change in the coming years as our use of new regimens starts to expand and I’ll talk about that in the slide after next. So in the update that I’ve just shown you, the 2021 guideline, the products that have been included include the MTB Xpert, MTB/RIF Xpert, MTB/RIF Ultra, both which are made by Cepheid, the Truenat which is made by Mobilo.
And then the moderate complexity automated NAATs, and these are the large platforms that are often used in larger laboratories. There’s one made by Abbott, another by Becton Dickinson, Roche and then Hain Life Science as well. The TB-LAMP lamp is made by Eiken and the lateral flow assay that I’ve mentioned, the LAM assay is the Alere version. For the detection of isoniazid and second-line anti-TB agents, that’s the Xpert MTB/XDR which is essentially a new cartridge on the same platform. And the line probe assays are these genotype MTBDR plus version 1, version 2. And then the MTDR SL which is the second-line drug detection assays. These line probe assays detect detect mutations that are associated with drug resistance.
The other platform is the Genoscholar platform which works both for MDR-TB, non-tuberculous mycobacteria but also for pyrazinamide resistance conferring mutations. So these are all included in the diagnostic guidelines.
One comment really related to COVID is that this platform, the Xpert platform was used for detection of SARS-CoV-2 during the COVID outbreak global pandemic in many parts of the world. So this is a technology that was, if you like, transformed into a near-patients test for COVID. And then finally, really because the diagnostics tell us what is needed, but it’s the treatment that gets the patient better. And there are updated guidelines on treatment of multi-drug resistant tuberculosis in the same suite of WHO consolidated guidelines on tuberculosis. These are from 2020, and it is likely that in 2022 after the meeting of the guideline development group, there will be another iteration of these, not least because this is a fast moving field.
But in the most recent version of this is 2020, there was an update on the treatment of tuberculosis that was susceptible to rifampicin but resistant to isoniazid which accounts for about 10% of all TB. And the recommendation for that was to give six months of rifampicin, ethambutol, pyrazinamide, and levofloxacin. And there was also a move towards all oral regimens for the treatment of multi-drug resistant, which is resistant to isoniazid and rifampicin, or rifampicin resistant which is treated effectively the same as MDR-TB. In that, shorter, that is to say 9 to 12 month regimens as opposed to 18 to 24 months regimens, were recommended provided they contained bedaquiline, one of the novel agents.
And provided the patients have not received more than one month of any of the other second-line medications in the regimen that has been constructed and in whom fluoroquinolone resistance had been excluded. So that actually demanded that a test with fluoroquinolone resistance had been done prior to starting that regimen which in itself was a bit of a barrier. Finally, there was an acknowledgment that this new regimen, the BPaL regimen, bedaquiline, pretomanid, and linezolid may be used under operational research conditions in MDR-TB that was resistant to the quinolones in people who had not had prior exposure to these agents.
And indeed, one of the reasons I think the guidelines are likely to change next year is that recent release of the data from the TB-PRACTECAL randomised controlled trial run by Medecins Sans Frontieres, MSF, in collaboration with the TB Alliance has revealed data that show that a BPaL plus regimen, adding moxifloxacin to BPaL gives extremely good outcomes with a six month all oral regimen. So it’s highly likely that within a year, BPaLM, if you like, regimen for six months will become one of the recommended standards of care.

The WHO held an expert consultation on the definition of extensively drug-resistant tuberculosis on 27-29 October 2020, the outcomes can be summarized as follows:

Cover of WHO expert consultation meeting report

Unchanged definitions

  • Rifampicin-resistant TB: TB caused by M. tuberculosis resistant to rifampicin
  • Multidrug-resistant tuberculosis (MDR-TB): TB caused by Mycobacterium tuberculosis (M. tuberculosis) resistant to at least isoniazid and rifampicin

Updated definitions as of January 2021

  • Pre-XDR-TB: TB caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and that are also resistant to any fluoroquinolonea
  • XDR-TB: TB caused by M. tuberculosis strains that fulfil the definition of MDR/RR-TB and that are also resistant to any fluoroquinolonea and at least one additional Group A drugb
  1. The fluoroquinolones include levofloxacin and moxifloxacin, because these are the fluoroquinolones currently recommended by WHO for inclusion in shorter and longer regimens.
  2. The Group A drugs are currently levofloxacin or moxifloxacin, bedaquiline and linezolid; therefore, XDR-TB is MDR/RR-TB that is resistant to a fluoroquinolone and either bedaquiline or linezolid (or both). The Group A drugs may change in the future; therefore, the terminology “Group A” is appropriate here and will apply to any Group A drugs in the future.

Source: WHO

The WHO has also issued updated diagnostic and treatment guidelines for tuberculosis this year. In this video Professor David Moore from the London School of Hygiene & Tropical Medicine and Director of the TB Centre at the School presents a summary of the updated guidelines and discusses their implications for the detection and management of TB cases, especially for high burden countries.

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