#88 Tuberculosis: The Forgotten Pandemic

Dr. Jun Liu, Full Professor in the Department of Molecular Genetics at University of Toronto working to develop novel strategies and vaccines in the fight against tuberculosis

January 13, 2020

Tuberculosis (TB) is a bacterial infectious disease that affects millions of people globally every year. Despite being one of the oldest infectious diseases in humans, control of the epidemic through treatment and vaccination has remained out of reach. In today’s episode, we learned about what makes TB so difficult to control, from immunology to stigma. First, Dr. Jun Liu, a Professor in the Department of Molecular Genetics at University of Toronto, guides us through current knowledge on TB and discusses the difficulties and advances in developing TB vaccines. Next, Dr. Amrita Daftary, a Professor in the Department of Global Health at York University, explains the process of diagnosing and treating TB, and later highlights challenges that patients with TB may face while accessing care. Finally, Dr. Sarah Fortune, the Director of TB Research Program at Harvard T. H. Chan School of Public Health, helps us understand how TB drug resistance can arise, and why TB-HIV co-infection poses such a challenge. The fight against TB continues every day, by millions of patients, healthcare providers, and researchers alike. Join us as we learn about this forgotten pandemic.

Written by: Tsukiko Miyata

Dr. Jun Liu - profile
Dr. Amrita Daftary - profile
Dr. Sarah Fortune - profile
What is DOTS? - report
Paul Farmer on Partners in Health, Harvard-Haiti, and making the lives of the poor the fight of his life
TB Personal Stories
Vaccine Preventable Diseases

Dr. Amrita Daftary [0:00] TB is the world's oldest infection. It's preventable. It's curable. 1000s of years since it was first identified. it continues to devastate people, communities, families, countries. Until this year, TB was the leading infectious cause of death.

Jason Lo Hog Tian [0:17] Tuberculosis is an infectious disease caused by mycobacterium tuberculosis or MTB. It usually starts from a small infection in the lung, which can lead to coughs, chest pain, chills, and fever. As we just heard from Dr. Daftary, TB is one of the leading infectious diseases in the world, affecting many lives every year.

Claire Mazzia [0:37] Some of the difficulties with preventing and treating TB come from the complex mechanism of how the bacteria invade our immune system, as well as from some socio-economic factors that impact the epidemiology and stigmatization of the disease. In today's episode, we will review prevention, diagnosis, and treatment of this preventable disease and then explore specific challenges we face with regards to tuberculosis, including drug resistance, co-infection, and stigma.

Zeynep Kahramanoglu [1:06] Before we begin, we would like to acknowledge that here in Toronto, we are on the traditional territory of many indigenous nations, including the Mississauga of the Credit River, the Anishinaabe, the Chippewa, the Haudenosaunee, and the (Huron-)Wendat. This meeting place is still home to many First Nations, Inuit and metis peoples. And we are grateful for the opportunity to live and work on this land. As we explore stories of medical science, we also ask our listeners to learn about and reflect on the long history of science and medicine as tools of oppression against indigenous people, and the complex perceptions of and barriers to healthcare that are still experienced by indigenous peoples in Canada today.

Claire Mazzia [1:49] I'm Claire.

Jason Lo Hog Tian [1:50] I'm Jason.

Zeynep Kahramanoglu [1:51] And I'm Zeynep. And this is Raw Talk Podcast.

Jason Lo Hog Tian [2:04] First, we spoke with Dr. Liu, a professor at the University of Toronto, in the Department of Molecular Genetics, who is currently developing novel strategies for the control of tuberculosis.

Dr. Jun Liu [2:19] Yeah, so tuberculosis, in short we call TB, is a respiratory infectious disease. So it's caused by a bacteria called mycobacterium tuberculosis, just like the virus Sars-Cov-2 causes the COVID-19. So, it's caused by a single bacteria. It primarily infects lungs, so again, transmitted through airway. So you, we basically can inhale this through aerisol infections; that's the natural infection route, just like Sars-Cov-2. Actually, the transmission rate or infection rate is actually higher than that of Sars-Cov-2. So we call the effect rate of the MTB is higher than Sars-Cov-2. So, it's a highly contagious, very easy to transmit between individuals. And, once it enters the lungs, it's taken up by the lung macrophage. And as you know, that's our primary immune cells, the first line of defense against any invading bacteria or virus. horrible MTB, most of the virus and bacteria try to avoid macrophage; they have a different strategy to do so. But, MTB actually prefers the macrophage. So, macrophage is a primary host for their target. So, in fact, the macrophage, once they enter the macrophage, they can stay inside of the phagosome without getting out of the phagosome. So, they can prevent the so called the phagosome normal maturation. Normally, the phagosome would undergo a series of steps and eventually fuse with lysosomes. And, because of the many enzymes in the lysosomes, also acidic pH, that would kill the invading bacteria or viruses. However, MTB somehow manages to stop this process. And, they are able to prevent the normal phagosome maturation. Not only that, they can actually replicate inside of phagosome into a large number, eventually kill the macrophage by necrosis. And after that, they can invade in neighboring macrophage, and this process just continue; eventually develops in lung pathology. And, the clinical symptoms, including, for instance, fever, and laboring breath, and the body weight lost. Eventually, the patient dies. It is a chronic disease; the patient dies gradually. The old term for tuberculosis is actually "consumption", so that basically the disease consumes the individual. So, that precisely describes the clinical symptoms. And, so our normal, for instance, the antibodies-based immunity does not play a critical role. So, we need to have the T cell immunity in order to control it. And unfortunately, when it comes to T cell immunity, it's, as you know, it's very complicated. And, we actually don't know what is the immunological correlates that predicted protection. In other words, we don't know what the exact immune response to that allows us to control the bacterial infection. Most of the people who are infected, you can get easily infected. In fact, I forgot to mention that, in addition to 1.5 million deaths, there's a 10 million new cases every year. And in the world, it's estimated about more than 2 billion people have been infected, we call it the latent infection. So the spectrum of the disease is huge. So there's a huge reservoir of the individual. When I mentioned this 2 billion people latent infection, it means that you have been infected, the bacteria, as I mentioned, once it gets into macrophage, in fact, the macrophage and then basically can kill the macrophage, and then your immune system starts to realize you have the invading bacteria, then call the immune system, try to control it, and eventually forms what we call it granuloma. It's basically just like a wall of your immune cell fibroblasts surrounding the infected tissue, which have the bacteria. However, in most of the cases, in 90%, of the individual who are infected like this, the bacteria still is, it's not dead. We cannot eradicate it just by our new system. We can control it, but is there still there. so, we call it dormancy, or latency, without active replication but still alive. And ,when your immune system is compromised by, for instance, secondary infection or other medical condition that compromises your immune system, then the bacteria can restart to grow, and it can break out this granuloma and become active disease again. So, so it's very different to other bacteria, and they have a much longer in terms of the infection stage. I will say that, and also because of that, the treatment is also very difficult. So, for normally for infectious disease, most of the bacterial infection, you know, you go to a doctor, they prescribe two weeks of antibiotics, and they ask you to finish that. That's it. For TB, the minimum time to complete the treatment in six months. It requires four to six different drugs and needs to six months. And after that, the doctor will look at the situation and decide whether you have to continue the therapy. So typically, nine to 12 months are the time that you are required to complete this therapy.

Jason Lo Hog Tian [8:04] With such a long course of treatment, and even then, a lot of uncertainty in the treatment outcomes, is a vaccine the best way to stop the rising TB infection rates? Can you explain the BCG vaccine, which is the one most commonly used for TB?

Dr. Jun Liu [8:18] So BCG is a live attenuated vaccine for TB. It's been around for almost 100 years. It was initially developed by two French microbiologist Calmette and Guerin. What they did was that they isolated the M Bovis, a strain of, mutant strain of, mycobacteria from infected cow and then the passaged them in vitro. So at that time, they innoculate it on the, on the plate, actually the potato, the carved the potato, and then use this surface to innoculate the colony at that time. And so, when they did the cell culturing, they kept observing the colony, they found, they noticed that when they did the cell culture, they saw the colony morphology changed. So the reason that, okay, if we kept doing this, perhaps we can reduce the virulence of the bacteria. And that was the idea. So even though, it's, it's amazing because, at that time, there was no molecular biology, right? They didn't know anything about molecular biology. But, they basically, based on this simple observation, they decided they could potentially be able to reduce virulence by simple passaging. And so they thought, okay, we could use this as a vaccine.

Jason Lo Hog Tian [9:37] And how does the BCG vaccine work?

Dr. Jun Liu [9:39] Very good question. So the short answer is that we know some of it, we don't know the full story. The BCG works by induced T cell response, primarily CD-4 T cell response, the TH-1 cytokine and produced by CD-4 T cell, and that's been shown. So, this is, come back to the efficacy of the BCG. I should say that even though this is the the most widely used vaccine in human history, and it's still being used today, it's not a perfect vaccine, right? As you would predict, otherwise we would not have the TB problem today, right? we would not have a 1.5 million people died every year. We would not have the problem with 10 million new cases every year. The clinical efficacy of BCG, the best estimate, is about 40 to 50% on average. And so, the question why the works is because it can induce CD-4 T cell response. Why it doesn't provide the full protection, we don't know. And it's likely to do with that you require other components of the T cells, including CD-8 T cell, including some other NK cells, etc. Antibody unfortunately plays a minor role, although there is some more interests in now trying to develop an antibody-based vaccine, but that, in my view, is, it has to be combined with the T cells to be optimal, effective.

Jason Lo Hog Tian [11:13] Given the limited efficacy of the BCG vaccine, what are some ways that researchers have tried to improve it or find other approaches altogether?

Dr. Jun Liu [11:22] Around the 1990s Peter Anderson from Denmark, he was a pioneer, came up with the idea to use a so-called subunit vaccine. So basically, subunit vaccine is sort of referred in contrast to the whole cell bacteria. So, you, you either use a single protein or a few proteins, either purify the protein as the antigen or express using added viral vector or some other DNA form. And, the goal was to use a few T cell antigens as a vaccine instead of the BCG, which is whole bacteria cells. So, they were the one that got this idea. And, so a lot of work around that time was trying to develop a new generation, which would be vaccine primarily using this subunit vaccine. However, this approach, turns out, didn't work very well. So in 2013, they did a clinical trial in South Africa, basically using this subunit vaccine, as opposed to have the BCG, the did a clinical trial. Unfortunately, the premature result was disappointing. Basically, there was absolutely no benefit for this subunit vaccine using as a second post. So, I, on the other hand, I have a different opinion about this. I really think for TB vaccine, I think it has to be whole cell based because, the you know, the bacteria have about 4000 genes. There are many different antigens. There's no single dominant antigen. So, it's very difficult to, you know, pinpoint which one you should use. And, I think the whole cell based vaccine is still the way to go. So, we focused more on trying to improve the BCG itself. So, the so-called recombinant BCG. So, over the years, we we have tried different approach. And, one of the approach we focused on was trying to understand the differences among different BCG strains and trying to figure out the genetic differences among the strains. I should go back a little bit. When I mentioned, you know, I told you about the history of BCG starting from 1924, countries from around the world received the BCG. And I mentioned the BCG is a live attenuated vaccine; it has to be alive to be effective. Around that time, unfortunately, they did not have the -80 freezer, the technology we have today. So, they could not preserve the seed lot. So, the only way they could do is passage in the region. Basically, it kept rolling them every four weeks. Once they have the culture group, they have to take a portion of their cell culturing fresh medium. And, you also have the vaccine. So, they did this all the way until 1960s. So, different countries, they were doing their own in their manufacturing site. As a molecular biologist, you would understand now that, obviously, there are many mutations accumulated through those years from 1920 to 1960s. And because they were all doing differently, all this mutation likely to be adapted to the whatever the condition they used to cell culture. So, you end up with a large number of the sub-strains. And, also the strain we have today is not the strain that the initial isolate in 1921, right? because of all these mutations. So in around the 1966 that the WHO realized this is a problem and then that's when they asked everyone to freeze dry and to preserve the BCG stocks. And that's what we have the seed lots we have for today. Now, because of the history, the complication, and it's, we know there's many different sub-strains, but we don't know which one is the best. And we still don't know, actually.

Jason Lo Hog Tian [15:17] So I understand that your lab is currently working on a TB vaccine as well. What was the approach that you took?

Dr. Jun Liu [15:24] We start working on BCG around 2000, right after coming to Toronto. And the major question around that time was that, as I said, because BCG is not perfect, so the whole field was trying to improve upon the BCG. We began to really try to figure out what are the genetic differences at a genome level between different BCG substrains. My goal was trying to correlate this genetic mutation with the clinical efficacy of the vaccine. So, we hoped we would be able to figure out perhaps some of the genetic mutations important for efficacy of the vaccine. That's my goal. So, we did that through the years, use different genome platform initially using, you know, whole genome microarray analysis, because that time, the whole genome sequence was very expensive; we didn't have the money to do so. So, we mostly using the microarray based hybridization to detect large deletion or duplication, and different techniques, different platform all the way until 2013, I believe, with the complete the whole genome sequencing for 13 different BCG substrains, including some of the most widely used BCG, Japan BCG, Russia, two Canadian strains, two American strains, BCG classical, the British strain, and the Brazilian strain, basically around 13 different BCG strains around the world. And once we connect all the data, then the biggest question is, you know, it doesn't matter, this genetic mutation, how do you correlate with, come up with idea, which gene mutation affects the efficacy? That's the most difficult questions. So we went back to the history, historical data, there's a lot of study done in clinical study, looking at both the efficacy and immunogenicity. Unfortunately, as I mentioned, there's a number of different clinical trials done, but nobody has ever compared to different BCG strains in the single clinical trial. So, it is difficult to compare different clinical trials, you know, because so many variables. So, essentially, we don't have any data to suggest whether one BCG substrain is better than the others. However, you know, like I said, in 1970s, after the WHO realized there may be some differences among the basic gestion produced by different country, they asked everyone to freeze dry to preserve it. They also did sort of a study compared to different BCG strains and they looked at an immune response, so basically immunogenecity. So, there was a study they published in 1974. They compare about 11 different BCG strains in children. And they noticed just looking at it the immune response, the PPD reactivity, basically. And they found that this one piece of BCG strain called BCG Prague consistently is an outlier; it has much lower intensity compared to other BCG strains. Now, in 2008 or so, when we look at the PCG Prague genome sequence, and I noticed there was a single nucleotide insertion in one of the gene called p4, you know, the p4 for the two component transcription factor for, for the MTB. And, this single base insertion disrupt the DNA binding domain of the p4. So, I immediately relate it back to the data that people who data that shows the BCG Prague has a very low immunogenecity. And, because p4 act positively activate a number of the antigens, so I thought this could be the reason. So, that was the first clue, we think we found one gene that's important for the immunogenecity and potentially efficacy. So, we decided to test the ideas how we basically complement the BCG Prague with a wilde type p4, and then indeed, we were able to restore this immune response, immunogenecity level to the level of other BCG strains. I should say this mutation is only specific to BCG Prague. Other BCG tend to not have this mutation. So, that was very exciting. So, then I asked a question, can we push this further? Can we, let's say, take BCG Japan as an example, and if we overexpress p4 in BCG Japan, which already has p4, wildtype p4, can we even actually increase immunogenecity even further. So, we did that with clone p4 plasmid and then putting it to BCG Japan, and indeed, we were able to increase the interferon gamma production by CD-4 T cell but three fold higher than the BCG Japan itself. So that was very exciting. So with, okay, can we demonstrate this, actually translate into protection. So, we did use the guinea pig as an animal model. We immunize the animal with the PBS, non vaccinated group, and then the BCG Japan, and then the recombinant BCG Japan and overexpressing for p4, and then after eight weeks vaccination, we challenge them with MTB using aerosol infection. And then, we just basically monitor the survival of the animal for different groups. And, that experiment takes about one year. And so, yeah, so and then, we look at the median survival time. So for the PBS group, the median survival time, basically half of the animal died 18 weeks, and the group that vaccine with BCG Japan, the parent strain, was a 27 weeks. And the group that vaccinate with our recombinant BCG Japan with expressing more p4, was the 39 weeks. So we had Yeah, we had a substantially increase the survival of the animals. We're very excited; we're publishing the paper. Right now, I'm actually trying to hopefully do clinical trials in China. But it's it's very challenging because you need a lot of money to do this kind of work.

Claire Mazzia [21:51] So it sounds like there's good news on vaccine development horizons, but in the absence of a highly effective vaccine, for now, we must rely on diagnostics and treatment programs, which the World Health Organization estimates has saved approximately 60 million lives in the last 19 years. Unfortunately, globally, the disease continues to take a large toll. The following eight countries account for two thirds of global cases: India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa. We spoke with Dr. Amrita Daftary to learn about the treatment and diagnosis of TB.

Dr. Amrita Daftary [22:36] It's lovely to meet you, Claire, and I'm a I'm a social science researcher and an educator based out of The New School of Global Health at York University in Toronto, and I study behavioral and social aspects of illness and particularly focus in TB, tuberculosis. I use qualitative approaches in my research. So I talk to patients, to community members, to families, healthcare workers, and learn from their experiences, and apply them to develop programs or interventions that could address their needs from a holistic, biosocial sort of standpoint. I also use their ideas and truths to critique health policy and social policy for TB. Most of my work is based in South Africa and India. But, I've worked in other countries and also contribute to several global projects. There are so many reasons that I ended up in this space. I have family and friends who've been affected by TB, I grew up in India that has a very high burden of disease, but mostly, I'm in the space because TB is an underdog infection, and I've always rooted for the underdog.

Claire Mazzia [23:38] Wow, that's really inspiring. TB is the underdog. So for my understanding, active TB infected individuals show symptoms and can easily spread it to others. And some people may be infected with TB but have no symptoms, which is called latent TB. And some cases of latent TB can become active disease, while others might remain asymptomatic. So, can you tell us a little bit about some of the challenges of TB diagnosis and what some of the current diagnostic tools are? I know many of us may have had a TB test where a nurse injects a small amount of liquid under the skin of our arm.

Dr. Amrita Daftary [24:14] Diagnosing TB either form is not straightforward. There's no dipstick test, you know, I'll focus for a moment just on active disease for TB disease because that's the one that's associated with greatest morbidity. The recommended test is the xpert MTB/RIF assay, which was developed some years ago, and this can find tuberculosis, the bacillus in your sputum within a few hours, and it'll also tell you what type of TB you have, whether it's resistant to common drugs or not. But, there are many challenges associated with its use. These issues are being sort of taken up slowly and gradually, but for the most part, people who are living in low income settings are first getting placed on TB treatment based on the clinical signs, their symptoms, such as cough, fever, night sweats. They might have an abnormal chest X ray, they might have a smear microscopy test done. But, there are many problems that underlie these tests. They're not particularly sensitive or specific, or if they have sensitivity, they're not very specific or vice versa. The xpert test or culture would be really the most effective option. And, countries, there are some low and middle income countries that are spearheading those assets. South Africa, China, they really take an xpert assay as a first line test for people not to have TB. Perhaps, that's going to be the way to go. But, access and utilization is still sparse. When it comes to latent infection, or TB infection, that's probably the test that you've heard about them, the two tested the skin test. But, it takes a bit of expertise to figure it out how to diagnose latent infection, how to distinguish that from active disease, how to sort of identify people who have that infection when they're compromised -they have a compromised immune system, for example. So there's problems associated with it. And there's a group of researchers at McGill University who have really done a lot to sort of facilitate ease of reading those test results. But, it's not a one stop shop. The patient has to come back to hear their result, and it needs to be sort of, I guess, diagnosed by an expert ultimately.

Claire Mazzia [26:14] So after diagnosis, what does treatment actually look like?

Dr. Amrita Daftary [26:18] When it comes to TB treatment, I'll again just focus on disease. A patient would need to take about six months of treatment with two to four antibiotics, and they start to become non-infectious very quickly, within a few days of taking treatment. So, that's the good news. But the treatment is long. It's six months, and you taking two to four pills a day. You can have some side effects, but for the most part, they're pretty well tolerated. What's nice is that they're totally free. We've come to the stage where no matter where in the world you are, you're able to access those medicines free of cost. So even in resource poor settings, you can find a pretty good rate of treatment success if the patient receives treatment early in time and receives some support to take that treatment. This year, we're also seeing evidence of a very short regimen up to four months, as opposed to the traditional six months of taking this treatment, which is really, really exciting for for patients and health systems. When it comes to prevention of active disease, so really, treatment of the infection, traditionally, it's been, you know, six to nine months of antibiotic therapy, and even that has come down now to as little as a couple of months or once a week, 12 doses of a single pill. So, we're really, we're really seeing some headway in this direction. But not all TB is easy to tweak. So, drug resistant TB, for example, is very severe, very debilitating, complicated to diagnose, requires one to two years of treatment with at least, you know, eight plus medicines, which translate to, I don't know, anywhere from 15 to 25 pills a day. So, that's really where we need greater investment. And there's new regimens now on the horizon. So, I'm very much looking forward to the rollout.

Claire Mazzia [27:50] Because TB requires daily doses of oral medication to cure that often have side effects, I've heard it's really important that patients take their medications every day to avoid the development of drug resistance. I find it really interesting that TB is a reportable illness, which means that the government gets notified of every positive test result. Every country has a TB control program known as DOTS. So what's DOTS?

Dr. Amrita Daftary [28:15] Yeah, DOTS, DOTS is a strategy that was adopted by the WHO back in the 1990s. It has five key elements: the political commitment and financing, the case detection based on high quality tests, standardized treatment together with patient support and supervision, at least 1000s of drug supply management system, and a monitoring framework and evaluation framework to measure impact. The acronym really came about from this idea of direct observation of treatment, or DOT, which is the practice of directly observing a patient take their medicines or adjusting their pills on a daily basis to ensure that they remain adherent to treatment, yeah, as a means to prevent transmission, right, because if you're taking the medicines, you're killing the bacteria, you're not spreading it to anyone else. So, this DOTS really came about at a time when TB rates had spiraled out of control and primarily because of a rise of HIV, which was a leading sort of driver of the TB epidemic in, in parts of southern Africa and also the because of rising drug resistance to TB in many, many parts of the world. So, WHO needed to find some sort of universal strategy to, to control the epidemic. But, we've already seen a shift away from that approach. We now have something called the end TB strategy. It's the latest blueprint for global sort of TB response. It does look for political commitment. It still has many of the tenants of DOTS, but it sees communities and civil society as a huge player in the, in the fight and it really is trying to address issues on equity, human rights, patient-centered care. So, there's some progress we've made, you know, there's autonomy taken away. Now, because there's really no other disease, no other condition in the entire world where we've decided this is the way that we need to monitor patients, this is literally the only disease where DOT has been the mainstream of treatment monitoring. So, there are, there are settings in which, you know, people have really used DOT in a patient friendly way. The Toronto Public Health Program, for example, uses DOT, and they deliver it as, yes, they're observing the patient take their medicine, but they're also using that opportunity to connect to the patient, to explore, is everything else okay with that? I mean, are there social medical needs being mapped to? they have any side effects? It's not this sort of top-down approach that, that strips the patient of dignity and autonomy.

Claire Mazzia [30:44] The DOT strategy has some advantages, although it can exacerbate certain populations, marginalization, and stigma surrounding TB, which we'll talk about more later.

Zeynep Kahramanoglu [30:53] Due to the variability between TB cases, we've learned that treatment can get complicated. Dr. Sarah Sortune is a trained infectious disease doctor and now a basic scientist, and the Chair of the Department of Immunology and Infectious diseases at the Harvard Chan School of Public Health. We asked Dr. Fortune how variability between cases impacts TB treatment.

Dr. Sarah Fortune [31:15] So, there are different ways to think about why. For example, some people are going to do fine treatment. And, just to lay out the the treatment problem, TB treatment is typically six months long for like the easiest case scenario, six months long, four drugs for two months and two drugs for four months. That's a lot of, a lot, right? And, it's actually clear, there have been efforts to shorten treatment, it's clear from the treatment shortening trials, that some people will do fine with three months therapy, but enough people, so already 10% of people with our six months of treatment fail. And then you know, in the other windows as you try to shorten that down when people fail. And the question is why. And the classic teaching in TB 101 is it's all patient compliance, and those people fail because we're gonna blame the patient. And, I think there's compelling, now compelling evidence, both from the biologic side and then from the public health side, you know, work from people or groups like Partners in Health, Paul Farmer, who really debunked that myth. And, so we've been looking at, like, are all bacteria the same? We call it all TB, but is my TB different than your TB? And are there differences, independent of the high level drug resistant mutations that we recognize? Are there different flavors of TB? That means, my bacteria are inherently slower to clear in the face of the same treatment than your bacteria? And if we knew that, could we like figure that out at the outset and then tailor therapy appropriately? And, I think the data from our lab says yes, and there're probably different levels I wish that kind of bacterial diversity arises.

Zeynep Kahramanoglu [33:03] So despite many patients following their treatment regimens, they may already be infected with resistant strains. Can you tell us about the different types of resistance?

Dr. Sarah Fortune [33:14] Okay, well, there are different kinds of ways you can think of TB surviving in the face of drug. The, the path to survival that we understand the best is true drug resistance. When, like, people go to the hospital and are told they had drug resistant bacteria, you know, that has one meaning, and it means the bacterium is able to grow at very high levels of the drug. And, we know, for TB, that's what we know about. We know how to find those genetic markers, we know how to diagnose that increasingly, although it's can take a long time, but we're getting better at it with the genetic tests for drug resistance. But then, it turns out below that, that's like the tip of the iceberg, and below that, there's a giant iceberg of different kinds of changes in TB drug susceptibility. Like, TB has been under basically constant drug pressure for the last, since, you know, 1950s. And so, there's just this giant iceberg of different flavors or different paths by which the organism has learned to survive in the face of throat. And so, they're things like drug tolerance, like I won't die, I won't be able to grow in the face of drug, but I won't die, either. And so, when you release the drug, I haven't grown, I haven't like manifested as more disease, and so maybe you're not as aware of me, but when you release the drug, I'm still there. I'm the bacterium that's still there, and we're going to take off. There lots of different flavors of drug tolerance, actually.

Zeynep Kahramanoglu [34:45] Yeah, I was looking into it, and you know, there's the multi-resistant TB, the MDR TB, the XDR TB, and just so many. It's just, where do you start?

Dr. Sarah Fortune [34:57] Those are all sort of the tip of the iceberg, and what you're sayng MDR and XDR. When you hear those terms, what that means is actually is talking about the individual resistances to the individual antibiotics. So, for first line drugs, you know, isoniazid or rifampin, then pyrazinamide. If you are resistant to the best of those isoniazid and rifampin, we call you MDR. And then, there's like a whole suite of second line drugs, like a menu you can choose from if you have resistances to the first line drugs. And, as you're acquiring resistances to the rest of the first line drugs and then the second line drugs, you eventually get to, you know, XDR, or, you know, very high level TDR, we have totally drug resistant flavors of TB.

Zeynep Kahramanoglu [35:47] Another factor that can complicate TB infection treatment and outcomes is HIV. The WHO says that their risk of developing active TB is about 16 to 27 times greater in people living with HIV as compared to those without HIV infection. Dr. fortune told us about how the co-epidemics of TB and HIV actually motivated her interest in TB research.

Dr. Sarah Fortune [36:10] I went to medical school in New York City in the early 1990s. So, I started medical school in 1991 at Columbia. And, that was an era that I think many people have forgotten what it was like. So that was at the height of the AIDS epidemic, prior to the introduction of anti-retrovirals. And in fact, in northern Manhattan at that time, there was a coincident TB epidemic. And the rates of TB in northern Manhattan at that time and drug resistant TB were higher than they were in many parts of, say, Sub Saharan Africa. And in fact, the TB epidemic had local hotspots in the Columbia. Teaching hospital's staff were getting drug resistant TB and dying of drug resistant TB. And, it was very clear at that time that the intellectual energy in the medical and scientific community was focused on HIV. And, you can understand why that would be. But, that, there was this concurrent burden of tuberculosis that both took people by surprise. And, where, there was a very, very little investment. There were very few people working in TB. There was basically none of the tools for addressing TB had changed in decades. And, it just seemed like there was enormous need and really interesting scientific questions. And so, I decided then sort of this is what I wanted to work on. I knew I had a lot of training ahead of me, and it seemed like there was a problem that was going to be there when I finished all my training. And so, that's sort of cemented it for me, and I have been interested in tuberculosis ever since.

Zeynep Kahramanoglu [40:42] So why doesn't TB get the attention it deserves? Part of it has to do with the stigma that it's associated with factors such as poverty, immigrants, or displaced persons and HIV coinfection.

Claire Mazzia [40:53] Assumptions are often made about the type of people that get sick from TB. And because it's transmitted so easily, feelings of fear are amplified within communities. Dr. Daftary talks about the harmful effects of stigmatization of TB and how that impacts the lives of those who live with the disease.

Dr. Amrita Daftary [41:11] Yeah, stigma. It's a really pernicious consequence of TB, I would say, you know. The bacteria doesn't necessarily discriminate, but because TB is transmitted through airborne droplets, it's activated through immune suppression. People who live and work in congested spaces, who have compromised immune systems, who come into contact with TB patients, are at a very high risk for acquiring and developing TB. And depending on the context, this can include prisoners, people with HIV, people who live in poverty, immigrants, or displaced persons who are living in highly crowded situations. And, these are exactly the same social groups who have the least power in society. So, it's very easy to cast blame, shame, and even disdain for such patients. The infectious nature of TB also is quite scary to people. You can see what's happening with COVID. And, you know, the mortality rate from TB is about seven times higher than COVID. So you can just imagine, but what's, yeah, what's, what's terrible, I think about TB stigma, whether it's covert, you know, insidious, or very overt and obvious, it comes from everywhere: within patients homes, from their families, from their partners, in their communities, from neighbors, friends, colleagues, employers, and also from social institutions and structures, such as places of work study, health facilities, doctors, cleaning staff, and even governments. Right? Stigma, I would say, it really does affect, I believe, it impacts our efforts to eliminate TB. It's a social determinant, I would say of TB. It's one of the reasons why people delay getting tested for TB, delay in treatment for TB, stopped taking treatment as soon as they start to feel better. It could be a reason why people don't readily disclose their illness to others. So, it could affect sort of contact tracing investigations and follow up. I think it is also a reason why this is really sort of microorganism level consequences of stigma. But at the bigger level, at the sort of programmatic level, stigma can prevent healthcare programs, and social programs, and policies from acting in the best interests of people with TB. By prioritizing, for example, the well-being of a healthy asymptomatic public over the well-being of an individual who was symptomatic and ill with TB. Right? I think that type of stigma, that driver stigma is the most worrisome because without institutional change, we're not going to be able to improve the life of communities, much less that of individuals, living with the disease.

Claire Mazzia [43:36] Wow, it's clear that stigma can affect if and when patients seek care, the quality of care that they receive, and their experience living with TB. Can you tell us a little bit about the differences and approaches to both HIV and TB care, and why they are often compare and contrast it?

Dr. Amrita Daftary [43:53] I've argued so many times that the culture of care or how health though patient care is conceptualized in, in TB is so problematic because the ways in which, you know, we think about TB prevention, case detection, cure. It's really policies and practices around controlling the spread of disease and a little bit less on enhancing the quality of life and well-being of the people who live with the disease. HIV care, in contrast, I feel, has been rooted in equity in person-centered approaches right from the outset. And, I made this comparison because a lot of my research is with people who have both infections, both TB and HIV. So, their sort of disparate experiences with care offer the perfect comparative case study. In much of the world, these services are offered under different programs, clinics, and health facilities. And so, when a person has both TB and HIV, they're shuttling between these programs, are getting exposed to very different ways of care, of doing care. And so, the patients that I speak to in South Africa, family have shared that they really value the individualized attention and the social support, counseling, treatment literacy, the trust that they receive with the nation, the clinics. And they actually note an absence of exactly those facets of care within TB clinics where it's sort of an all business model, you know, the focus is on infection control, treatment, supervision, and cure. And, and, I don't want to say that those aspects are not important in HIV, they most certainly are. I mean, U equals U is all about that in a way. But wherever there's an opportunity to engage a patient to offer some choice or flexibility to sort of deliver an allied form of support, HIV programs have generally actively sought to fill those gaps and sort of moving with the times, right? They're changing with the times. In studies that we've done with coinfected patients in South Africa, we've actually asked them out, would they prefer to access a one stop shop where they can receive both TB and HIV services under the same roof, at the same time, at the same provider? And, yeah, they want support. I mean, who wouldn't be? But, as long as it's under the umbrella of the HIV program, we have a clear preference in a very sort of unfair comparison that's loaded with loads of assumptions, it would be like me asking you, "hey, would you like to go to the spa today or bootcamp?

Claire Mazzia [46:05] Wow, it's so interesting that patients who have both HIV and TB learn about dramatically different cultures of care and clearly feel more supported when they're at HIV clinics. Do you think that might have to do with advocacy? I understand that some patients become advocates for their disease in part to help raise awareness about it and reduce stigma? Do you know why there have been fewer advocates for TB compared to HIV?

Dr. Amrita Daftary [46:29] I'll say that, historically, I mean, any advocacy around TB has always been sort of a little bit fragmented because the most affect people who reside in resource poor settings, or they're marginalized communities in higher income settings. But by large, they have, you know, relatively little power to rally together and fight for political and public sort of attention. So, there's been very little inclusion of their voice in, in the TB world, in the TB space. I think another reason is that there's been some consensus right from the get go. We know it's from the bacteria, we know that it can cause death if it's not treated, you know it spreads. So, the public has not had a reason to really get involved in the science behind TB, because those questions came about quite quickly, quite conservatively. And, everybody sort of agreed upon that. So as a result, any decisions around policy in TB happen behind closed doors where scientists, medical practitioners, policymakers were allowed in and the community was not necessarily seem to have any need. By contrast, any debate about the origin and treatment about HIV came from its inception in the 1980s. There was constant questioning about the origins of HIV, what it led to the sort of AIDS denialism. And so the patient and the public at large, by necessity, had to get involved. And, ironically, this exact denialism that helped to facilitate people with HIV to actually find a seat at the table at that decision making table very early on. There was no consensus. And so, they sort of had to rally for a seat at the table. HIV has also disproportionately affected the gay community who were vulnerable to the disease but also had an immense social strength in numbers. And already, we're quite familiar with grassroots sort of human rights and equity frameworks around advocacy. So, any policy in HIV that's going to have been autocratic, coercive, or diminish the rights and dignity of people who are affected by HIV was quickly questioned and fought. It was also prevalent in, in, very high income countries among people who have wealth, and they can support those grassroots movements. Yeah, and TB with thankfully, okay, you know, we're moving towards that. Yeah, we're seeing a lot of efforts now. People with lived experience are coming forward, advocating against tokenism, you know, for right to seat at the decision making table. But, it's really been spurred, I would say. in large part by the hesitant rollout of these new drugs that have come about in, you know, over four and five decades. This is the first time we've seen new TB drugs come out. And so, it's the first time our community has had to come out and say, wait a minute, don't hesitate to roll them out, make their access equitable. And, and, now there's a reason to sort of rally the troops, and demand access ,and, and really spearhead advocacy efforts in TB.

Jason Lo Hog Tian [49:15] That's it for today's episode. As always, this episode would not be possible without the time and expertise of our gracious guests, Dr. Jun Liu, Dr. Sarah Fortune, and Dr. Amrita Daftary. Many thanks to all three. To learn more about their work and other information on TB, check out the resources in our show notes.

Claire Mazzia [49:35] Although we had many great speakers that provided valuable information about the current landscape of TB, we wanted to acknowledge that this episode is missing the perspective of someone who has had the disease and navigated the lengthy treatment course.

Zeynep Kahramanoglu [49:48] We'd also like to thank our wonderful production team including first time host Claire Mazzia, veteran hosts like myself Zeynep Kahramanoglu and Jason Lo Hog Tian, content creator Tsukiko Miyata, producer Jesse Knight, and our amazing audio engineer Alex Jacobs. Finally, thank you for listening. See you in two weeks with Episode 89, where we dive deeper into the technology and development of vaccines.

Claire Mazzia [50:18] Raw Talk Podcast is a student presentation of the Institute of Medical Science in the Faculty of Medicine at the University of Toronto. The opinions expressed on the show are not necessarily those of the IMS, the Faculty of Medicine, or the university. To learn more about the show, visit our website rawtalkpodcast.com and stay up to date by following us on Twitter, Instagram and Facebook @rawtalkpodcast. Support the show by using the affiliate link on our website when you shop on Amazon. Also, don't forget to subscribe on iTunes, Spotify, or wherever else you listen to podcasts and rate us five stars. Until next time, keep it raw.