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TBnet newsletter November 2021

Dear TBnet members,

In this issue of the TBnet Newsletter you will find:

1. Today’s TBnet webinar reminder and link

2. New! Question-Answers Session on how to start & implement a TBnet research project

3. Union World Conference on Lung Health 2021 – what I found of interest

A blog by Prof Graham Bothamley, TBnet Past Chair


1. Reminder: monthly TBnet webinar

Today @ 16:00 CET, November 25, join the discussion on TB meningitis in children based on European multicenter studies by ptbnet. The link to the webinar and more information can be found here:

2. Question-Answers Session on how to start & implement a TBnet research project

After the webinar, November 25, 17:00 CET there will be a separate 15 minute-long Question-Answers Session on how to start and implement a TBnet research project. This will be presented and moderated by Graham Bothamley and Olena Rzhepishevska. You will learn what are the ongoing TBnet projects and how to join them as well as how can you start your own project in the TBnet network.

We will try to have this 15-minute drop-in session for TBnet project questions regularly. The idea is to support those colleagues who plan to start or implement the TBnet study but do not know really where to start and how to proceed. Come and talk to us – we will be waiting there at 17:00 CET – same link as the webinar:

3. Union World Conference on Lung Health 2021 – what I found of interest

A blog by Prof Graham Bothamley, TBnet Past Chair

MDR-TB – Tuesday 19 October

Caryn Upton (TBS-01-03) showed that levels of unbound (active) bedaquiline were comparable in plasma and CSF. After Akkerman’s study in CID suggesting that bedaquiline was undetectable in the CSF of a single patient, this is a valuable finding for all those who have had cases of MDR-TB meningitis who want to include bedaquiline in a regimen that will penetrate the blood-brain barrier. Simon Koele (OA12-673-20) presented data showing how the cytochrome P450 system, notably CYP3AA), might be important in the M2 product of bedaquiline and contribute to bedaquiline-induced QTc prolongation.

A poster from Borstel (Jens Sachsenweger, with our very own Maja Reiman: TBS-EP-04) helped identify reasons for toxicity to linezolid (more cell cycle genes and PLK1 signalling expressed). Sean Wasserman (OA12-678-20) identified mtDNA 2706A>C as associated with linezolid-induced lactic acidosis and noted that trough levels >2.6 mg/L were associated with anaemia. These findings may help reduce the toxicity of linezolid by identifying those at particular risk so that the use of this important drug for MDR-TB can be made more acceptable to those with MDR-TB.

Treatment trials and spin-offs – Wednesday 20 October

The whole area of “sub-clinical tuberculosis” (defined as those with microbiological evidence of tuberculosis in the absence of symptoms) remains confused, with several presenters wondering how such patients should be treated! An increase in screening, even using a test with reasonable sensitivity and specificity, will result in more false-positives; other tests will be needed to confirm whether the results are true or false. I can see a TBnet study of asymptomatic TB discovered by screening of at-risk populations may be needed to gain sufficient numbers to ascertain what clinicians are actually doing for such patients and perhaps a consensus on what further tests should be considered.

Diagnosis and treatment – Thursday 21 October

The late-breaking session (21 October 2021) showed the value of miniproteins (see Science 2020; 370:426-31. doi: 10.1126/science.abd9909). Antonio Torres Ortiz (TBS-LBS-04) identified nodes prior to the development of drug resistance and identified mutations in esxL, esxO and lppP, as well as two intergenic regions (useful perhaps to encourage closer follow-up of DS-TB?). Olivier Marcy’s talk was of interest to indicate the frequency of overdiagnosis of tuberculosis in children and the value of using Xpert-Ultra in diagnosis. Kamela Charmain Ng (TBS-02-03) showed unpublished data with Mtb mutations associated with culture-positive at 2 months – another indicator to help plan personalised treatment?

The session on Study S31/A5349 (high dose rifapentine; SP-29) used therapeutic blood monitoring to show how higher blood levels of rifapentine were associated with fewer relapses and a better treatment response and how bacterial load (as assessed by Ct threshold <14) affected prognosis. The wide-ranging additional studies to a treatment trial would be worth imitating in the UNITE4TB program. An explanation of the effectiveness of rifapentine and moxifloxacin was provided by Jacqueline Ernst in a mouse model showing better entry into caseating granulomas compared to other TB drugs.

Vaccines – Friday 22nd October

Using a vaccine to target stringent response Styliani Karanika (TBS-11-04) employed a combination of MIP-3a (targets immature DCs) with RelMtb led to isoniazid being more effective in reducing CFUs (with an inhibitor of epigenetic modification of DNA vaccine). Intranasal vaccination was as good as high dose IM. The e-poster of Ahmed M et al (TBS-EP-33) showed that IFNg binding to MmpL10 together with isoniazid prevents the development of persisters. Both these presentations suggest ways by which the treatment of tuberculosis could be reduced to two weeks, in addition to the many studies of gene induction with standard TB treatment and how such a response by Mtb could be prevented.

Otherwise, the vaccine field seems to continue the use of antigens shown to be highly conserved in Mtb (suggesting a role in pathogenesis rather than protection – see Comas et al. Nat Genet 2010; 42:498-505. doi: 10.1038/ng.590)

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