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[00:00:07] Angela: Hello, and welcome back to Communicable, the podcast brought to you by CMI Communications, Eskmit's open access journal covering infectious diseases and clinical microbiology. My name is Angela Hutner. I'm an infectious disease doctor at the Geneva University Hospital in Switzerland and editor in chief of CMI Comps.

[00:00:25] Angela: I'm joined by my co host, Nav Narayanan, infectious disease pharmacist and clinical associate professor at Rutgers University, New Jersey, USA, and fellow editor at CMICOMS.

[00:00:37] Nav: Hey, Angela. It's great to be here with you again, as always.

[00:00:41] Angela: Today we are tackling tuberculosis. We are thrilled to have two expert guests with us. Lorenzo Guglielmetti works for Médecins Sans Frontières, Doctors Without Borders, where he is director of the End TB Project. He is also a clinical infectious disease physician at the Hôpital de la Pitié Salpêtrière in Paris, and a researcher at the Sorbonne University.

[00:01:04] Lorenzo: Hello, Naveh. Hello, Angela. It's really a pleasure to be here today.

[00:01:07] Nav: And our 2nd guest is Olha Konstantynovska She is an associate professor in the Department of infectious diseases and clinical immunology at the V. N. Kharzin Kharkiv National University in Kharkiv, Ukraine, where she practices as an infectious diseases clinician.

[00:01:23] Olha: nice to, be here and, thank you very much for the invitation.

[00:01:26] Angela: Olha. We're grateful that you're finding time to do this interview from Kharkiv, which continues to be under attack. As our listeners know, we start these episodes with a get to know you question for our guests and also our hosts.

[00:01:40] Angela: Today, I'm going to ask, what is an important moment, , from 2024 that comes back to you again and again?

[00:01:48] Angela: my great memory from 2024 is, A trip I took all the way to Wellington, New Zealand. was very honored to be able to go to the Australasian Infectious Disease Society's annual meeting, .

[00:02:01] Angela: And, I have to say I've met people there that I would not have met otherwise. Including, bringing Josh Davis on board as an editor at CMI comms.

Had I not gone to that conference. we wouldn't have Josh, who, by the way, is the person responsible for these icebreaker questions, so anyway, that was a really important moment for me in 2024 Nav

[00:02:23] Nav: .

[00:02:23] Nav: I actually went back to India with my family for the first time in many, many, many years. My wife does classical Indian dancing. And so this was the 1st opportunity she had to go perform in India. We brought our 2 daughters . That was, probably my best memory in 2024 as well as for a long time. And was a pretty amazing way to start off the new year as well. Lorenzo, ?

fondest memories mixes a little bit professional and personal, it's, the end of, these NTB project, with the presentation of, the second trial and the last part of the study, which happened in, the union conference in Indonesia, it was an opportunity also to travel with a big part of my team from France, and to meet many of the investigators from the countries which implemented the study. We rented a big flat. We went, hiking on the volcano, seeing Manta Rays, and it was a bittersweet moment, but also, the best way to, close this adventure.

[00:03:18] Angela: Wonderful. And Ola?

[00:03:20] Olha: Thank you very much for such a wonderful question, but I have nothing to say, except that we are alive.

[00:03:27] Olha: thanks God we, waking up every day with the, thoughts that, our life is continuing. So we have heating, electricity, internet, and our children are healthy. So that is the most important thing . That's it.

Oh my goodness. Okay. That is beautiful.

[00:03:41] Nav: When we open up about tuberculosis, since it's probably, One of the most fascinating things is thinking through the discovery, in terms of ancient biological history. Lorenzo, If we can just go back in time a little bit and think about the history of mycobacterium tuberculosis, when was the first described, as well as where it's thought to have have emerged. .

TB is. a very long standing pandemic. it's more having an unwanted guest for the human species in, history because mycobacteria have evolved together with, mankind.

mycodermal tuberculosis has been described for the first time by Robert Koch, in 1882, but of course the story begin. Much, much earlier. It is thought that micro bacteria originated more than 100 million years ago.

[00:04:26] Lorenzo: And terms of we continue tuberculosis that we know today, the first proofs of infection humans date to the Egyptian. time so there are, findings of mummies, which have signs of, TB infection of, the spinal, bone. So what we call today pot disease around 5000 years ago.

it's, a long story in terms of where this has all originated, it is thought to come from, the region of East Africa, as for many important, parts of human development.

[00:04:56] Nav: Thank you for that.

It's quite fascinating to understand how long we've dealt with this as a human species. And we're still dealing with it as a major global health threat.

[00:05:06] Nav: In today's world, who does MTB actually infect and what are the reservoirs?

[00:05:11] Nav: Is this like other infections where there are environmental reservoirs ? if you think about tuberculosis, the main bacteria, mycobacterium linked to human disease, this can affect animals. So we can think about, bovis and cattle, but, most of the reservoir is mostly humans, transmission, as you know, is intra human, through the exchange of droplets or respiratory, transmission . just to clarify then, there are lots of different mycobacteria. When we talk about the species of Mycobacterium tuberculosis, does that infect only humans? Could it be a relatively easy target for vaccination because there's no animal reservoir?

[00:05:51] Lorenzo: No, so when we talk about usually about mycobacterium tuberculosis include, also these other species.

[00:05:56] Lorenzo: There are a few. it will be possible for the majority of, my bacteria, which are, circulating. there will be still a reservoir, it is just, the pathogenic, , micro bacteria are mostly residing in humans.

we cannot say that the problems that we have in controlling, TB are linked to the fact that there is this reservoir. It's really our incapability of controlling the transmission and stopping the pandemic, terms of inter human transmission.

interesting to think that it's one micro organism, which could actually be eradicated so theoretically, it is possible. , we are very, very far from that, because we know from modeling studies that, Approximately one fourth of, the human population has encountered mycobacteria. and Considered to be infected, by MTB.

[00:06:45] Nav: it's a good point to understand that, when you're identifying in a clinical lab, you're looking at MTB complex and the vast majority is mycobacterium tuberculosis, but, you know, M. bovis does exist. And, for clinicians, the history, the exposures, as well as the susceptibility pattern give you clues to those things. The fact that specifically, Is primarily a human disease that specific species does not have, animal hosts and it's not an environmental organism.

[00:07:20] Nav: are really important variables when you think about disease eradication, some of the challenges of polio, which we're seeing now is that there's environmental reservoirs. And so those differences contribute a lot.

there's no vaccine that we have for T. B. that's highly effective across the age spectrum. But knowing that about microbial ecology, is really helpful to think about gives a lot of optimism, these, hopefully, TB vaccines come to light future.

So, hola, can you give

[00:07:50] Angela: us an overview of the pathophysiology? How does M. tuberculosis get in to its host? Why can't we get rid of it? What happens over time and to whom? Can you sort of do a refresher for us?

[00:08:03] Olha: Thank you for the wonderful question.

Just to follow Lorenzo, I want to say that Mycobacteria , Is, , the pathogen that can get the host organism through the elementary way of transmission. the majority of cases. But, as we know, well, 95 percent of all cases of tuberculosis are airborne way of transmission.

[00:08:24] Olha: So through the droplets of sputum. And then a person inhaled air that contained. droplet nuclei with mycobacteria tuberculosis, most of the larger droplets become, blocked in the upper respiratory tract, the nose and throat, and, it's very difficult to develop tuberculosis in, upper respiratory tract, infection may begin, then droplets nuclei reach the alveoli.

[00:08:50] Olha: So lower respiratory tract. In the alveoli, some of the tubercular bacilli are killed, but a few multiply in the alveoli, and then they can spread through the lymph vessels to lymph nodes and bloodstream and spread throughout the body. that's why tuberculosis may develops in any piece of body.

[00:09:12] Olha: but for sure, target place, it's, lungs. Pulmonary tuberculosis is the most common, cases of disease, but we can find tuberculosis also in kidneys and brain and bone, except hair and nails. mycobacteria is a specific, microorganism. Within two, to eight weeks, the body immune system usually, tried to, deal with, infection and, prevent the, further spread of infection. And, immune system, protect the body from, developing the active disease. But TB infection means that mycobacteria are in the body, but body's immune system is keeping the bacillus suppressed and under control.

[00:09:56] Olha: our immune system does, producing special [00:10:00] immune cells. That's around the tubercle bacillus and, cells form, a shell, that acts like a barrier and keep the bacillus contained. So that's why it's very difficult to fight with mycobacteria because it's protected by our own immune system.

[00:10:18] Olha: that's why we get infected for very long period of time. And some patients can develop active disease.

. here actually seems like a really good moment to stop and, discuss terminology a little bit, because, we are, no longer latent tuberculosis, right? We are now supposed to say that a human without symptoms does have an infection, but it's simply a tuberculosis infection whereas someone with symptoms has tuberculosis disease. Am I correct?

[00:10:50] Olha: That is true. we have changed terminology. Right now we say that people who have tuberculosis infection, but not TB disease, they are not contagious.

[00:11:01] Olha: They do not feel sick. And couldn't spread the infection to another people. And most of these people have a normal x ray. And, it is important to remember that tuberculosis infection is not a case of active TB disease. But people with, Tuberculosis infection can develop tuberculosis disease later, TB disease develops when immune system cannot keep the mycobacteria under control, and the bacilli begin to multiply rapidly with the high risk TB disease, in some groups of people. Patients, for instance, patients who has immunosuppressed immune system, HIV infected persons or people who get corticosteroids treatment. So, we have, 23 risk group of development of active disease right

[00:11:56] Nav: TB is not something that we deal with in a clinical space, but, it seems like that's getting more attention because of how much it contributes at a population level to transmission. any comments thoughts on. where that fits in, in this spectrum of TB infection and TB disease.

it goes a little bit out of my expertise, I can say that, detecting subclinical disease seems to be, where we are, really bad at. And that's where we need to improve, probably to have a real breakthrough in our capacity to control, pandemic, is more and more evidence that we are not able to, diagnose, TB before, any symptom occur.

[00:12:37] Lorenzo: this is something that has been seen with, the available test. If we go and do, , active case finding, or mass screening campaigns, but, This is not something that we can do, with this mass approach. We need to be able to better, identify and understand which, groups we should be targeted and, have better tests.

[00:12:54] Lorenzo: But this is definitely one of the big, focus of research, in these last years.

[00:12:58] Nav: when we think about the prevalence or, you know, the epidemiology of tuberculosis, where are we seeing hotspots globally of T. B. and where are we also seeing drug resistant TB?

so today, we have every year around 10 to 11, a million new cases of tuberculosis in the world. this is a figure which is It's very high, of course, and it's unfortunately not, really changing, since at least a decade. And basically since the WHO has numbers which are becoming more and more reliable in terms of estimation.

[00:13:30] Lorenzo: what is very striking is the mortality with more than one million people affected by TB who die each year this is really. incredible. If you think that this is such an old disease and is today preventable, like possible to diagnose it also completely curable.

[00:13:47] Lorenzo: TB is concentrated in 30, priority countries, which are defined by WHO. And this is something which easy to, find, checking the WHO global TB report every year. But if you only look at the five highest burden countries, India, China, Indonesia, Pakistan, and the Philippines, we have more than half.

[00:14:07] Lorenzo: Of all the cases. so there are, priority, regions for action the WHO. this is a little bit different if you talk about drug resistant TB talking about AMR which is also a huge concern, for TB since at least, the nineties with the. discovery and description of the first cases of multidrug resistance.

we, have around half a million of, new cases every year, with, people who are infected by strains that are resistant to rifampicin, with or without the additional resistance to azonylizidase. that will, fulfill the definition of MDR TB. These cases, are also localized in specific hotspots, . The highest rates are Eastern Europe, Central Asia,

[00:14:48] Lorenzo: However, if you look at the number of cases and the burden of disease, , the most affected part of the world is still in Southeast Asia just because of the total number of cases which, are higher there.

[00:15:00] Nav: So clinically, I think it helps to make that differentiation about high burden and high endemic countries, as well as what slice of that population is at risk for drug resistant TB, in, that country specifically.

[00:15:12] Angela: So we were talking before about, Tuberculosis infection, which on its own is really what we used to call latent TB, and then you have tuberculosis disease. Ola, you said before that those with asymptomatic or subclinical infection are not the ones transmitting.

[00:15:30] Angela: They're not infectious, , because they're not symptomatic. , they're not coughing, they're not really shedding. but we know from what Lorenzo said that that is actually feeding, , the prevalence really, because those people will live longer, they will reactivate, and they will become infectious one day.

[00:15:47] Angela: So, of course, we want to target them, can you just do a quick review for our audience of screening for this group, this very large group of asymptomatic people who are infected? so we, all I think know the Mantoux test, which in the States is known as the PPD, Purified Protein Derivative.

[00:16:05] Angela: The skin test, , is that completely dead in high income countries, , and can you remind us how does the alternative work, the interferon gamma release assay?

[00:16:15] Olha: Screening for,

[00:16:16] Olha: asymptomatic tuberculosis and, tuberculosis infection is quite difficult to organize sometimes because, it depends on the politics of countries and governments. And, I know definitely that, IGRA tests are much, more effective, but they are expensive and some countries can't, implement it, 100 percent for all people who need that.

[00:16:38] Olha: That's why. TST, Tuberculin Skin Test or Mantoux Skin Test is still, recommended for sure, as one of the tests for tuberculosis infection, this test detect immune system, ization type four or delay type hypersensitivity to mycobacterial protein antigens. And, this test is very good.

[00:17:01] Olha: sometimes it's very useful, for patients who were not BCG vaccinated previously. It's, just a small injection intradermally. We inject, 0. tuberculin. In some countries, it contains 2 tuberculin units. In some countries, it's 5 tuberculin units. had to check the test reaction between, 48, 72 hours.

IGRAs are preferred method for testing for people who might be less likely to return for TST reading and interpretation. For example, homeless persons or drug users. People who have received the BCG vaccine or people who are likely to be infected with mycobacteria tuberculosis and are at low to intermediate risk of progression to TB disease and people who are unlikely to be infected with mycobacteria tuberculosis. Interferon

[00:17:55] Olha: But we have limitations. We had to have laboratory. healthcare workers, should be properly trained. on how to conduct IGRA. And healthcare workers should confirm arrangements for testing in a qualified laboratory.

Arrange for the delivery of the blood sample to ensure testing of samples with viable blood cells. it's quite difficult to organize sometimes. For instance, in Ukraine previously it was available just in commercial labs, but now our public health center, recommend us to use it even in war zone settings.

[00:18:34] Olha: So we are trying to organize this test right now and we see it's very good. what is the, action of this test? Patient's blood samples are mixed with antigens. and incubated. the major antigens, are found in mycobacterial tuberculosis strains. If a person has mycobacterial tuberculosis infection, the blood cells in the sample will recognize the antigens and release interferon gamma in response.

[00:19:02] Olha: Blood samples are also mixed with control substances, and these controls are used for comparison purpose to help verify test results and to determine a person's background level of interferon gamma.

We prefer, IGRA test instead of, TST because we can't, distinguish between , post vaccine immune response or infectious immune response. That's why, we, want. To implement IGRA test routinely in our daily practice, I think it's much more effective and, help us to identify the patients with, tuberculosis infection or with active tuberculosis disease.

[00:19:42] Angela: Thank you. Yeah. In Switzerland, we don't do the skin test anymore.

[00:19:45] Angela: I think it's been several years now. The new medical students have really no experience with that. we still teach it. We teach both. they know that it exists, but, it's not being used at all.

[00:19:57] Angela: A question now for Lorenzo.

[00:19:58] Angela: So I am here [00:20:00] in Switzerland, high income country, and we abuse, our diagnostic tests, and it is tempting to order an IGRA to help rule out active tuberculosis disease, because a negative result is great. Let's you sort of knock tuberculosis off of a long list of differential diagnoses, no prior exposure, no current disease possible, right?

[00:20:22] Angela: But, A positive result can be confusing, so when should IGRAs not be used?

[00:20:29] Lorenzo: To, have a simple answer to this question is that should not be used to rule out active TB disease at all. would be easy, answer. These tests are actually just not designed for that, they're not good enough.

I think Olha has explained very well. The advantages of the IGRAS over,  the Mantoux test. but, these are really limited on being able to discriminate infection in vaccinated people. from that, the performance of the test.

[00:20:59] Lorenzo: in terms of negative and positive predictive value didn't really improve and despite a lot of efforts and also new versions of this test. This tests just not good enough. We cannot be reassured by a negative test. Cannot be completely reassured in difficult to diagnose cases, So this happens a lot in clinical care. So we are all tempted to do that and sometimes these tests are done, but I fear they may, just mislead us more than anything else. , if it's positive these values even more limited. and in, the end it basically doesn't say much, at all.

[00:21:30] Lorenzo: So as a conclusion, I think. We should mostly reserve, like we did with  Mantoux for the diagnosis of, TB infection and everything which is related to, case finding, screening of contacts, and not use it in our routines for the diagnosis of disease.

[00:21:47] Angela: Yeah, thanks. I have a bit of a cautionary tale because I was just on service and we had , a young man who geographically came from a region of very high tuberculosis prevalence. and, He was presenting with fevers of unknown origin, he didn't cough a lot, so that threw some people off, but above all, he had a negative IGRA test a year before that was well documented.

, first thing, that was done when he came in was an IGRA test, negative. so that really lowered the index of suspicion to many doctors who saw this patient before we did, and , tuberculosis was not high on the list.

[00:22:24] Angela: We really insisted on a lavage because we didn't understand what he had and sure enough, PCR positive right away for M tuberculosis on the first isolates. So think, you're absolutely right. The real answer is just don't do it. If you're dealing with active disease.

[00:22:42] Angela: It's a screening test. It's not there for active disease.

[00:22:46] Nav: I agree. And I hear my attendings teach the fellows all the time about, negative IGRAs. Don't help you when you're trying to rule out disease, right? You have to compartmentalize those, types of tests differently. What are the other ways that tuberculosis can present when we're thinking about extrapulmonary disease?

95% of all cases of tuberculosis, it's a airborne way of transmission. It's pulmonary tuberculosis. ,

[00:23:10] Olha: the most common chest symptoms are cough, sputum, breathlessness, dyspnea, chest pain, and pulmonary bleeding. these symptoms typically accompanied with, intoxication symptoms, the most common of them are sub febrile fever, 37. 5 37. 2, night sweats, fatigue, weight loss, absence of appetite.

So this intoxication symptoms may, mask, Many different diseases, for instance, oncological diseases or something, another. So if we combine two groups of symptoms, chest symptoms and intoxication symptoms, we can think about tuberculosis, pulmonary tuberculosis. But as we already we have 5 percent of another localizations of non pulmonary.

[00:23:59] Olha: And the It's tuberculosis of nervous system tuberculosis, meningitis, and then encephalitis. if we see a person with a unknown reason of intoxication symptoms and with the symptoms of meningitis, we have to think about HIV infection and about tuberculosis especially in countries with high incidence rate of tuberculosis.

[00:24:24] Olha: Because we know that 30 percent of. HIV infected persons are infected with mycobacteria and in contrary 30 percent of tuberculosis patients may be Infected with HIV, so it's a very dangerous combination and , tuberculosis meningitis we have also another localizations of tuberculosis, for instance, tuberculosis joints and bones, tuberculosis of kidney and another organs, so symptoms depends on the localization.

as we said, intoxication symptoms Typical, but local symptoms may, differ. For instance, if patient is infected with mycobacteria bovis, and it is elementary way of transmission maybe Abdominal pain, and we have to think about tuberculosis involvement of lymph nodes from abdomen.

So we have to think about that try to diagnose this condition as early as possible to prescribe treatment in time.

[00:25:32] Nav: Thank you Olha, your point that we can see it in all different sites quite important. Even if the portion of extra pulmonary TB is a small portion, there's enough prevalence of the world, you're going to see these.

although it sounds rare, I mean, TB lymphadenitis and other extra pulmonary disease is something that, Will be encountered at some point.

[00:25:53] Lorenzo: was very nice to hear the possible clinical presentations of TB it is important to remind that, you know, The classic presentation of TB is probably very easy to diagnose, but most of the times this is a disease which is very difficult to differentiate from, others.

[00:26:10] Lorenzo: So it's really complicated. And I think the key, it's adding a high level of suspicion and thinking about TB in particular, looking at the epidemiology. in your center from the providence of the patient and , the proportion of patients who have extra TB is very different actually in different parts of the world.

is not completely explained, for example, in, Ukraine or in Europe, there is a very high prevalence of pulmonary TB striking majority. But in other parts of the world, like the Indian subcontinent, is actually a very high proportion of extra pulmonary TB. As you were saying, lymphadenitis, for example, or TB pleuritis are also very common.

[00:26:48] Nav: Yeah, and there's variability across the age spectrum, too, when you think about contacts and pediatric TB versus adults .

It's such a complicated pathogen, and it can cause so many different presentations. The easy part is when you have classical pulmonary TB, but when it deviates from that, it's really important to make sure you're involving not just infectious disease specialists, but also folks that might specialize management of tuberculosis.

Lorenzo, what is the diagnostic workup for these patients with symptomatic TB disease? And, unfortunately there's a lot of waiting involved,

[00:27:21] Nav: what are you doing in the interim as you're waiting for some of this workup to come back?

[00:27:25] Lorenzo: classic workup for diagnosing TB which is still very much in use, would be collecting a sample. Usually will start with a sputum sample. If, the patient can produce sputum, sometimes you have to be more invasive.

[00:27:40] Lorenzo: Do a lavage, a bronchoscopy, and it could go all the way to biopsy.

[00:27:45] Lorenzo: I have these multiple samples collected and you know, the best possible samples.

[00:27:50] Lorenzo: So the sputum has to be collected in the correct way. The patient has been instructed. It's super important to do it for diagnosis because in particular, if then at one moment we will start an empirical treatment We'll regret if you didn't have these good samples examined. We will collect multiple. Samples . So having at least two or three seen as the best practice still today. And then we would send them to the microbiology lab, which has to be specialized, , perform, microscopy looking at the smear for micro bacteria.

[00:28:20] Lorenzo: And then they will put the sample in culture, which we know it takes a long time. of course, if the smear is positive, that gives you a big confirmation towards the diagnosis of TB. But in many cases, you will just have to wait for the culture. And then finally we also have new tests.

[00:28:36] Lorenzo: Being developed in the last decades which is fortunate so rapid molecular testing have become the standard of care in, many, many settings. These are really well spread out across the world in particular rapid molecular tests that allow the detection and genomic diagnosis of tuberculosis.

[00:28:53] Lorenzo: So the infection by a disease by mycobacterium tuberculosis complex and can also give at the same time an answer on the presence of the most common mutations which are associated with resistance to rifampicin for example. there are other tests which are Equally easy to do rapid that can even give you the answer on resistance to isoniazid, which is the other key drug and fluoroquinolones, which are the key drugs among the second line compounds.

[00:29:22] Lorenzo: It's actually not a luxury. I think it's, just the standard of care today. It's really important that each patient gets these rapid molecular tests done. to detect resistance to rifampicin and isoniazid. I think this is really the best care that we can offer that the regimen that we use by evidence and will work well. It's still not done everywhere and there are a lot of constraints in terms of access and cost.

[00:29:45] Lorenzo: Coming to the second part of Nav's question, why we wait for all of these. , if you have a rapid molecular test, this will come in a couple of days. And that is great. It doesn't happen all of the time.

[00:29:56] Lorenzo: Usually the approach would be to assess the risk [00:30:00] of the patient being contagious. this is looking at. the microscopy results also the clinical presentation, the radiological pattern.

[00:30:09] Lorenzo: Of course, we know that the contagious forms are the pulmonary ones, and then based on all these elements decide if the patient has to be isolated, which would be in, most, cases, if there is a high degree of suspicion while waiting for the best, approach.

[00:30:23] Lorenzo: Once you have collected all the good specimens, you have done everything that you can. If the suspicion level is high it is also a good approach to start an empiric regimen, even though it's something we always get discouraged to do, but that is something that happened in some cases, because you cannot wait for the culture results before starting treatment, if you have a high degree of suspicion.

[00:30:44] Nav: that's always a tricky question that I see, our fellows teeter on, , if they should start empiric therapy and it never seems like there's a clear, answer 1 way or the other. But all those factors might push you to watch and wait versus you can't watch and wait. they're too sick, and your index of suspicion is too high that you should be starting them on, , anti TB therapy right away.

[00:31:05] Lorenzo: Is particularly true, actually for special groups of patients where the diagnosis is even more difficult, such as HIV positive patients.

Olha as mentioned, but also children which is really a neglected group of patients with TB. And where it's very difficult to obtain a good sputum sample. Now it's, it's actually the real push by NGOs like MSF and other big stakeholders like the WHO to use clinical algorithms with radiological tests. if there is a high level of suspicion based on a clinic and radiological presentation, even in the absence of, microbiological confirmation, do not wait and treat also because there is a high mortality in small kids affected by TB.

[00:31:49] Nav: And even if you think about extra pulmonary disease, like Olha mentioned, , TB meningitis, the diagnostic yield is quite, Poor and the mortality is extremely high. That's just an example of TB disease that cannot wait. And even with effective therapy, the mortality rates are still high.

if you add on a long lag time to starting effective therapy, then you worry about even more worse outcomes at that point .

[00:32:12] Angela: Yeah, and it's interesting that, now we accept treating people without any microbiologic confirmation it does make sense.

[00:32:19] Angela: I think we all know pretty well now how to deal with these therapies. We understand what the side effects , could be , we can handle it. And ultimately, when you don't have a microbiologic diagnosis, the treatment itself can be kind of a diagnostic maneuver. Right? You see if they're going to respond.

[00:32:36] Angela: If they are, that's a, hint that you're on the right track. so speaking of treatment for active disease. Traditionally the regimen of RIPE has held sway for many years after this combination was tried and tested in .

[00:32:50] Angela: Early randomized trials decades ago, RIPE as a reminder, is made up of. Quadra therapy with Rifampicin, which we call Rifampicin on this side of the Atlantic. I think it's Rifampin as I recall in the States. So we've got Rifampicin and isoniazid that's the R and the I.

[00:33:10] Angela: of ripe. those you get for a full six months. And then the P and the E are parazinamide and ethambutol. the parazinamide and the ethambutol you're giving only in the first two months, hopefully if the organism turns out to be sensitive. So, are things changing now, Lorenzo?

[00:33:27] Angela: Is this regimen still recommended by most expert groups, or are there alternatives that require maybe less time, fewer medicines? Can you give us a little update on what's happening?

[00:33:38] Lorenzo: I really like the RIPE acronym. the field, we, tend to use much less sexy acronyms like H R Z E.

[00:33:46] Lorenzo: So I really appreciate that. Thanks. unfortunately I think it's still ripe time in. most, regions of the world as the standard six month regimen with a few, of course adaptation for specific cases, but a standard building block is still by far the most used the regimen however, there has been a very big breakthrough three years ago, with a phase three.

[00:34:11] Lorenzo: Trial on drug susceptible TB showing for the first time non inferiority of a shorter regimen a four month regimen, which has a very, very similar performance to the six month regimen for all adult patients with rifampicin susceptible tuberculosis. this regimen replaces refampicin with rifapentin, which is a long acting rifamicin, which has overall similar properties apart from the longer half life it's used in the regimen at high dose, is an important point.

[00:34:42] Lorenzo: And the other important change is the use of a fluoroquinolone, moxifloxacin, instead of etambutol, one of the weakest companion drugs, which are there mostly to protect the other drugs.

[00:34:54] Lorenzo: Study 31, a landmark study, because so many trials in the last 20 years actually failed with a similar objective to reducing treatment duration from six to four months. They tried with similar approaches, but in particular with the use of fluoroquinolones, but what is new, as I mentioned, is that also the use of high dose rifamicin. this four month regimen is a little bit different also in that after the initiation phase with the four drugs, the continuation phase is, continue with three drugs. So in addition to

[00:35:25] Lorenzo: Uh,

[00:35:29] Lorenzo: given also for the continuation phase. So this is, really great, but in practice it has not been really rolled out in many countries.

[00:35:38] Lorenzo: And there are actually a lot, of hurdles . I can only say that there is a problem of access in terms of actually Having the drug registered, so Rifapentine is not registered with the EMA, is not available in most countries in Europe, and it's likely not going to be, despite a lot of push, from different organizations, this is not the only access problem the European Union and in Europe.

[00:35:58] Lorenzo: Far from that, but it's maybe one of the most striking in addition to that, there's the cost. We have a problem of pill burden because these new regimen doesn't have fixed dose combination pills that allow to reduce the total number of pills. So the number of this with these new regimen is much bigger than the one with the standard regimen.

[00:36:17] Lorenzo: there are a few questions on, How much we want to promote using fluoroquinolones for all cases everywhere with all the concerns that we have about amr at the same time. not to reduce our the importance of, these new breakthrough reducing from six to four months could be really, really important in particular in some populations.

[00:36:36] Lorenzo: So I think it's still, something that we would really like to be able to use, in Europe.

We have this regimen. I think we are very much satisfied with that, but we have some limitations because we have pattern of resistance for instance, patient has mycobacterial tuberculosis susceptible to.

rifampicin, but resistant to fluoroquinolone. That's why this regime is not useful. And before the prescription, we have to check the resistance. luckily, we have GeneXpert cartridges, special cartridges, which identified resistance to second line drugs cartridges XDR. They are available, and this is mandatory for us to have this test done before the prescription of this new regime, because it's very important to be sure that mycobacteria is not resistant to fluoroquinolones.

[00:37:27] Olha: So this regime is useful for not severe cases of pulmonary tuberculosis. And we have very good results. But another limitation is that the dosage of rifapentine is very high 1, 200 milligrams. It's eight pills. And sometimes patient they don't want to swallow all these pills. So, with that, we need to explain patient how to, deal with that.

The worry about , the fluoroquinolones, I mean, it's interesting, , we don't like to use fluoroquinolones in the hospital because Patients exchange plasmids and it really can change the entire microbiota of the hospital, right?

[00:38:05] Angela: But when patients are at home, and not in close quarters in theory, right? with other people whose natural flora might be. quite perturbed also getting antibiotics, et cetera, then I think it's really less of a risk less of an ecologic hit, let's say for AMR, AMR development.

[00:38:23] Lorenzo: It's a great point. I think in the TB world specifically, we have a lot of problems with acquired growing drug resistance to every new drug, which is developed, which it's true for every bacteria, of course, but has been really striking. And I think that's a little bit of fear that if we use fluoroquinolones a lot then they may become more and more prevalent among even new cases.

[00:38:44] Lorenzo: of tuberculosis,

[00:38:46] Angela: Yeah, It's that topoisomerase, it's a point mutation, right? At least for regular gram negative bacteria, let's say like Klebsiella, E. coli, it's not very hard for them to become resistant to quinolones.

So let's talk about happier things though, Lorenzo. please tell us about your program with Doctors Without Borders. Tell us about the End TB project.

[00:39:07] Lorenzo: NTB project. is a large program that has started more than 10 years ago funded by Unitaid and promoted by three NGOs, which is quite unusual for research project like these these NGOs being Médecins Sans Frontières , MSF, based based in France. And then we had. Partners in Health in Boston in the U. S. and Interactive Research and Development, or IRD, based between Pakistan and Dubai. And these three NGOs got together with the goal of really improving the management of drug resistant TB

[00:39:40] Lorenzo: uh,

[00:39:40] Lorenzo: with availability these new drugs, which were developed, the first new drugs to be developed for the treatment of drug resistant TB specifically after more than 50 years, which are bedaquiline and laminate, together with other drugs, which were repurposed for the treatment of TB and extremely [00:40:00] resistant forms of TB, such as linazolid and an antileprosy drug like clofazimine.

[00:40:05] Lorenzo: So having this window of opportunity of having multiple drugs. which were developed in part by private companies with a lot of public funding where the development actually stopped at phase two because the company said that phase two was actually enough to get into the market because of the desperate situation of ERTB treatment.

[00:40:25] Lorenzo: So phase three was not really needed. but of course you need phase three trial to have good evidence. to find the combinations of these drugs and to finally get to shorter regimens. Standard of care for drug resistant TB for many years has been a very long regimen of almost two years with a lot of drugs between four and six drugs with a lot of side effects, the use of injectable agents every day for months. So we needed to find a good combination to shorten the treatment and find better tolerated options.

[00:40:57] Lorenzo: And that was the goal of the project. and I, would say the main parts of the projects were two phase three clinical trials called NTB and NTBQ looking at shorter regimens for fluoroquinolone, susceptible and rifampicin resistant tb, and that was NTB. And NTBQ looked at fluoroquinolone resistant, or what we call now pre XDR tb.

[00:41:18] Lorenzo: and testing different regimens of six to nine months which had different combination of these new and repurposed drugs, and also fluoroquinolones and parazinamide for MTB. To make long story short after many years of study, we could identify four new regimens that were non inferior or even in some cases superior to the control. Three for fluoroquinolone susceptible tuberculosis and one for fluoroquinolone resistant TB, which are.

[00:41:48] Lorenzo: Now being recommended by the WHO. So they are among the options or the standard of care for rifampicin resistant TB for the NTB trial for the NTB Q trial in the very evidence free space of breaks. The RTB and TBQ is just being released in terms of. public presentation, and it's the first and only phase three trial in this population.

[00:42:09] Lorenzo: So we hope that this evidence will be reviewed soon by the WHO and will, will lead to recommendations that can be implemented. Worldwide.

[00:42:17] Angela: that's sounds like such a success story that you were able to define and safely test these regimens and come out with good news ultimately.

[00:42:26] Lorenzo: Yes. It's also a story of. NGOs and in particular MSF which was the sponsor of the two trials having to go a little bit beyond what their comfort zone.

So we had a lot of academic partners. And I think it can be a model for other kind of research but on the other side. It's also a failure of the standard system development which basically didn't go all the way.

Also, because the companies were not really encouraged to go all the way in the development. once again, I would like to highlight that. There is a lot of public funding and a lot of help and shortcuts that are provided to companies that work in, this kind of orphan diseases, such as drug resistant TB but there is not much in terms of commitment that the companies have to undertake.

I think there is some space for an improvement also in the overall regulatory framework to make sure that the next coming new drugs, there are lots are actually. More quickly included in new regimens. And so they can have an impact, a fast impact on the life of TB patients.

[00:43:26] Angela: I think it's an important model that you're talking about. First of all, you have three NGOs that were able to cooperate with one another. You have a lot of players, like you say, a lot of academic players as well.

[00:43:38] Angela: You have incredible collaboration going on for what. Shouldn't be an orphan disease, but ultimately for the, industry based world. It is an orphan disease. These things need to be highlighted more.

[00:43:52] Nav: Second, that completely, it's pretty remarkable to think about the biggest infectious killer having also a free market failure in terms of the development therapeutics and the alternative pathway that had to Emerge meet the demand, right? which is NGOs and not the typical highly funded pathways that help attack these diseases that.

[00:44:15] Nav: Affect Everybody globally, I it's really remarkable to see this work done and have these extremely positive results. It's not just 1 regiment. There were multiple regimens tested and so those options, I think are also. Quite important when we think about treating patients and what we need.

[00:44:32] Lorenzo: It was the philosophy of the project to have multiple options and not just 1 winner regimen.

It was really the trial design for End TB different experimental arms and of course the internal control. And it was not classic multi arm multi stage design, , which has been used a little bit in, TB research. we really designed it to find two to three. Different regimens that could give alternatives because we know in the end the choice should be there for clinicians and patients because of intolerances, drug resistance, side effects, et cetera.

[00:45:05] Lorenzo: and this brings quite a few options for the RTB treatment because there's been other trials ongoing this is great. It's very good thing that we have to choose now between different regimens. Countries and stakeholders, should get used to that.

[00:45:18] Angela: that's really interesting because on the one hand, you don't get Very much industry support, enthusiasm, but on the other hand, industry, when they're doing these registration trials, they're looking at one specific indication and it's quite narrow, whereas you at least get the freedom of saying, okay, we want to come up with several therapeutic options.

[00:45:39] Angela: We don't want just one, that's going to sell. Well, . It sounds like it was an adaptive trial. Where you could have several winners. Very nice.

[00:45:46] Nav: Olha, clinically, I don't think anyone out of the 4 of us deals with drug resistance, probably more than you might, especially in your setting in Ukraine. What is the typical pattern that you're seeing of, drug resistance? I think your experience can really be quite enlightening for all of us to understand and how are you treating these patients with rifampin resistance or, sorry, rifampicin resistance?

[00:46:09] Nav: I'll come over to your side of the pond, Angela. Rifampicin resistance, INH resistance how are you dealing with these multi drug resistant strains?

[00:46:17] Olha: Well, with the beginning of war, we have a changing situation with the epidemiological patterns of resistance, because we have a lot of internal displaced persons. For instance, our citizens from our region. from Kharkiv went to west regions of Ukraine and western citizens came to us because we are very close to military conflict and we have a lot of people who are in our settings and that's why we have totally different patterns.

[00:46:49] Olha: Before the starting of treatment, we have to check the resistance for sure. And, as I said previously, we are very much lucky to have XDR machine for GeneXpert, XDR cartridges, and we have the results till the end of the working day. Because need to know the molecular genetic aspects of resistance at the beginning.

[00:47:11] Olha: And we see that 30 percent of all cases of resistance are patterns of

[00:47:20] Olha: So we have combination of resistance to azonazide, rifampicin, and fluoroquinolones, at least three drugs. But we have also different patterns, for instance, resistance to azonazide and etiolamide, without resistance to rifampicin.

[00:47:36] Olha: So these, are quite challenging process to prescribe the treatment because we have to choose what combination will be the better for patient. again, we are lucky because we have B PAL regime. B PAL is a new regimen for treatment of multiple drug resistant tuberculosis contained with at least drugs Bedaquiline, Linazolide, and Pretomanid, and with combination of Moxifloxacin. So these two regimes we have medications for that. And we have Prescription. So we have experience to do that, and we see that these regimes are very good. But again, it has limitation because sometimes we have combination of resistance to moxifloxacin.

[00:48:23] Olha: So we have choose which regime is better for patients. And sometimes we have to stop BPAL. And continue with another schemes to include, for instance another antimicrobacterial, drugs from group B and group C classification. another bad is that we have cases of resistance to beta aquiline.

[00:48:46] Olha: And to linezolid. So we have cases of XDR tuberculosis, extensively drug resistant cases. And we have to change the schemes of treatment. Depends on the resistance. And sometimes it's quite difficult because we have to Totally resistant strains. since 2017 we had about 30 cases of such patients.

[00:49:10] Olha: And unfortunately the majority of them already died. And some of them we don't know because of the beginning of war. some of our patients were lost to follow up because of the military conflict. Some went to Russia, some went to European countries or to another piece of Ukraine.

[00:49:29] Olha: So we don't know the destiny at the end.

[00:49:32] Angela: Thank you, Olha. I think we could do a whole other episode on conflict and disease resistance you know, prevalence of disease. it's kind of

[00:49:43] Angela: shocking.

[00:49:44] Olha: And I want to add one comment since the last several months, we have the,

[00:49:51] Olha: and we hope that for now, we have no cases of resistance to pretomanate. So it's a new drug for treatment of [00:50:00] multiple drug resistant tuberculosis, and hopefully The resistance is developing very slow. We don't know.

Ola, indeed, you have been in a war zone for nearly two years now.

[00:50:12] Angela: And you are managing to continue to conduct research, if I understand correctly, what is the war doing to? , tuberculosis, transmission and control, and what is it doing to your activities your ability to do research? Can you share some of what you're experiencing?

[00:50:30] Angela: Can you tell us a little bit about your research?

[00:50:33] Olha: Thank you for the question. I think that the beginning of war changed us a lot. Do you remember the movie from the 90s? men waking up every day at the same conditions.

. Groundhog Day?

[00:50:45] Olha: Yeah, and

[00:50:46] Olha: I think that the majority of people we are living in the same feeling I don't know how to explain, Right now, we have about 1 million inhabitants, even in Kharkiv, 25 kilometers from the war zone.

[00:51:00] Olha: And I don't know how, it works, but our tuberculosis is under control. Because we have enthusiastic people who work with us. We have a lack of health care workers

[00:51:12] Olha: but people who are still here, they are totally enthusiastic and we try to do something. How to explain? We are trying to manage with all these things with very new ideas because at the beginning before we even have no food.

[00:51:29] Olha: But now we have everything because we have volunteering people who move from one region to another region. We have a special car with a portable X ray viewer and with a nurse and radiology technician. This car with two health care workers moved from one village to another village to check the citizens of this village in near war zone.

[00:51:53] Olha: And we tried to collect samples of sputum, to collect blood and to do the x rays. I think it's very good because People who are living in these conditions, they have no possibilities for health care at all. And regarding our research, just before war, we had clinical trial approved with FIND.

[00:52:12] Olha: You know, this organization from Switzerland, and just before war 22nd of February, approved the clinical trial, and since the beginning of COVID, we didn't know what to do. Postpone this trial or stop it totally we didn't know, but at the beginning of June 2022, we decided to continue.

[00:52:37] Olha: The management of FIND decide that it's risky, but we have to start because our setting is very high prevalent with tuberculosis. we had a lot of challenges and issues with the logistics, border control, custom service. But we try to find how to deal with that. We have a lot brilliant experience how to transport the equipment, the cartridges test tubes or something, because we have lack of that at the beginning of war. And we find the ways . Volunteers help us to organize all that, and we were able to enroll patients for this study.

So I'm very proud of that. I think this experience help us to understand that doing research is because of enthusiastic people. Because we want to fight tuberculosis, we want to stop a pandemic spread. And you know that tuberculosis and war go hand in hand.

[00:53:35] Olha: So I think it's a best time to do something new.

I'm interested in the epidemiology of strains of mycobacteria tuberculosis. And I did the sampling collection since. the 2016 and we did next generation sequencing and whole genome sequencing and found that we have the majority of strains from the big gene lineage.

[00:53:58] Olha: It was five, six years ago. And I'm sure that for now we have something changed because we have different patterns of. Resistance, so I, strongly believe that we need to do the mapping of strains of mycobacteria in Ukraine because it's interesting and

[00:54:16] Olha: should be studied.

[00:54:18] Nav: Thank you,

[00:54:19] Nav: your insight really incredible. I mean, in the work that you're doing before the war, and even now during the war is, incredibly admirable. think we have a lot that we can learn from the work that you do and the way that you're able to sustain it.

tuberculosis is incredibly complex, , public health epidemiology, and also the social aspects to it and the population level health. so thank you both. As we come to a close there's so many things that we didn't even get to talk about. But what we can do to end Oja Lorenzo is if you can give your key messages,

[00:54:52] Nav: what you want our listeners to be able to take away

[00:54:54] Lorenzo: Even in this very conservative and slowly progressing field of TB, which is a little bit like the mycobacteria, really slow and resistant to change.

[00:55:03] Lorenzo: We are looking at new approaches to the management, in particular the treatment of TB, this opens the door to having A more personalized approach and in approaches that we are not stratified medicine are being more and more advocated. So having different options knowing different straight off risk that can lead to different treatment duration and treatment regimens.

[00:55:27] Lorenzo: I think this is something . Within reach and, more and more accepted in the field. So that, is really exciting for the next years. And then on, the less bright side all this innovation is, is completely useless if there is no access on the field.

[00:55:40] Lorenzo: And this is. That's a big problem just quickly discussed about cost issues, registration issues we are talking about lack of funding for research, lack of political commitment to address TB with ambitious goals.

[00:55:55] Lorenzo: the main message would be that we know this disease treatable. we have the tools now to do much better than what we do. And, there are no excuses not

[00:56:03] Lorenzo: to do it everywhere.

[00:56:05] Angela: Thank you so much, Lorenzo. These are important messages that maybe we don't want to hear, but we do need to hear. Hola,

[00:56:11] Olha: I think that

[00:56:12] Olha: the center of all our things that we are doing should be patient because tuberculosis is very stigmatized disease and patient doesn't want to be diagnosed with tuberculosis and we have to do something to advocate this because As Lorenzo said, and as we all understand, tuberculosis is a preventable and treatable disease, but we have to help our patient and society to be together we see in, our settings, for instance tuberculosis is very stigmatized even in families. we see that families divorced because of disease of husband or wife. it's quite difficult to explain the society that Tuberculosis patients, since the beginning of treatment, after two weeks, patient stopped being dangerous.

[00:57:05] Olha: And that is the most important thing, that we have to more advocate this. And for sure personalized treatment, as Lorenzo said many times, that we have to, Maybe change the dosage, change the schemes of treatment. Special schemes should be prescribed. Depends on the resistance.

[00:57:25] Olha: And for sure, if we have access to drugs, we have to make access to drug susceptibility testing. In all settings there this need.

Thank you so much for these important last messages. And thank you so much to our guests, lorenzo Guglielmetti of Doctors Without Borders and Ola Konstantinovska of Kharkiv National University. And thank you for listening to Communicable, the CMI Comms podcast. This episode was hosted by NAV.

[00:57:55] Angela: Narayanan and Angela Huttner, editors at CMI. com's ESCMID's Open Access Journal. It was edited by Dr. Katie Hostetler and peer reviewed by Dr. Maria Ana Flores of Lisbon, Portugal. Theme music was composed and conducted by Joseph McDade. This episode will be citable with a written summary referenced by A DOI in the next eight weeks.

any literature we've discussed today can be found in the show notes. You can subscribe to Communicable on Spotify, apple, wherever you get your podcasts. Or you can find it on Estimate's website for the CM i COMMS Journal.

[00:58:29] Angela: Thanks for listening and helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along.