Updates in TB: From Basic Science to Global Health Policy

[00:00] Lecceme Santos today filling in for our chair Dr. Bob Wachter who is away and it is my distinguished pleasure to introduce today's grand rounds which include some of my no-bias-here favorite specialists from Pulmonary and Critical Care Medicine. Today's grand rounds is an actually fascinating multidisciplinary interdisciplinary panel on

[00:20] updates in tuberculosis from basic science to global health policy and everything in between. And we have truly three global TB experts here who've been meeting for months to figure out how to communicate year's worth of policy and basic science updates distilled into a user-friendly hour. So you're in for a treat. We're going to talk about

[00:40] innovations in pulmonary critical care and tuberculosis from again the bench to the bedside to the global health policy arena with these three speakers in order it is my delight to introduce. First off Dr. Babik Javed he is an associate professor of medicine in the division of experimental medicine at ZSFG and he's also the associate director of the

[01:00] UCSF Center for Tuberculosis. He's a physician scientist, he's been awarded numerous awards, he's a welcome trust investigator, and he really focuses fundamentally on the mycobacterial pathophysiology, everything from how do the proteins interact, what are the molecular mechanisms behind tolerance, behind resistance, behind

[01:20] immunity to tuberculosis, and we've been delighted to welcome him to the UCSF faculty starting in 2020. Thank you so much for being here, Dr. Javett. Next up, we have Dr. Payam Nahid, who's a professor of medicine in pulmonary critical care medicine at ZSFG. He is also the director of clinical trials operations in the UCF

[01:40] Office of Research. He's also the director of the UCSF CTSA Trials Innovation Network Hub and the director of the UCSF Center for Tuberculosis. He really focuses on everything from clinical trials, epidemiology, translational TB research, global health implementation science research, and he led to the creation of the

[02:00] he sees treatment of tuberculosis guidelines, he's also served on the WHO guideline development committee, and more. Last but certainly not least, my wonderful colleague Dr. Priya Shatay. She is an associate professor of medicine in the division of pulmonary critical care medicine, also at ZSFG, and she really takes a global.

[02:20] policy perspective to this question with her research, again, award-winning, focusing on improving access to quality and access to TB care as well as COVID-19 care for our vulnerable populations here and worldwide. She worked with the global TB program at the WHO, has spent time in Geneva, and she's

[02:40] served as the public health advisor to USAID as well as the team lead for the California Department of Public Health to look at modeling and analytics not just for TB but also for the COVID-19 response. So it is my distinct pleasure to introduce these three wonderful guests. We're in for a lot of learning. Thank you so much.

[03:00] Lechmue, thanks so much for that very kind and generous introduction. I should say we met for weeks and months to decide a date where my esteemed colleagues were actually free because they're so busy and involved in a global TV policy.

[03:20] Okay, so I've been given the dubious pleasure of kicking off. Just to go over briefly our learning objectives, we're going to go over some of the, briefly, the epidemiology and burden of TB both in San Francisco itself and globally, more broadly.

[03:40] Get some familiarity with TB diagnosis, prevention and care, and especially about innovations and bottlenecks around those areas. Become aware of some recent guidelines. And also will be along the way as a thread throughout all three presentations touching on what you see.

[04:00] UCSF is doing to address the TB epidemic. Okay, so I have to say that as an infectious disease physician, but also as a TB researcher, it had been very frustrating for most of my professional career seeing, salivating, but also being somewhat

[04:20] envious of the limelight that other infections get compared to us in the TB community.

[04:40] Honestly, I can say has never happened before in my memory. So that's really incredible, including this sort of amazing leader with the New York Times, the Sun, which is a tabloid paper in the UK but read by millions of people, and even our beloved SFK.

[05:00] gates for a local outbreak in a casino in the Bay Area. So there you go, TB hits heart home if you're a gambler. But the other thing that's been really missing for the TB community compared to many other infectious diseases, especially ones that...

[05:20] affect disadvantaged populations globally is that we haven't really had a superstar spokesperson or advocate. But again, that's also changed from an unlikely source. So John Green is a bestselling young adult novel author who I really wasn't much aware of.

[05:40] until I realized that despite the fact that I filled my teenage daughter with propaganda about TV for her entire life, the only time she started to share stuff with her friends on WhatsApp or whatever were these videos that were made by John Green about tuberculosis. And he's been an incredibly

[06:00] credible activist for TB. He's made numerous videos about TB. But this is one where he talks about his barely contagious rage around TB.

[06:20] for millions? Like this year, of the 10 million people who will get sick with TB, about 4 million people will go undiagnosed, often dying before they can get an accurate test. And among those who do get diagnosed, most are still diagnosed via a person looking through a microscope at a sputum sample, which is precisely how we diagnose

[06:40] tuberculosis 130 years ago. There are two big downsides to the microscope method. First, it misses more than 50% of cases, especially in young children and immunocompromised people. And second, even if it finds TB, microscopy can't tell you whether a case is resistant to antibiotics, which means that many people end up on the wrong treatment

[07:00] regimen and commonly die before they can get on the right one. Now I know what you're thinking, gosh, I wish we had a miraculously fast and accurate test that could tell people not only whether they have TB, but which drugs their TB will respond to so we could immediately begin curative treatment. Well, good news, we do.

[07:20] machine and it is incredible. It's made by a company called Cefiad that's owned by a larger company, Dannacher, that also owns lots of other companies. And this gene expert machine can test not just for TV, but also for HIV, COVID, and many, many other diseases. Everywhere I've traveled in high TB burden countries, people sing the praises of this.

[07:40] incredible gene expert machine. I mean, within an hour, you can tell someone whether they have TB and also what course of treatment will cure their TB. Incredible. Amazing. Wondrous. Thank you, Cefiad, for building this machine. Thank you, Danaher, for making it all happen. There's just one problem. As a lab tech in Sierra Leone,

[08:00] very succinctly explained to me, the machine is amazing. If only we could afford the tests. Which brings us to the end. Okay, so I think that gives a nice flavor. This was in response to the fact that Danaher had said that they were not going to reduce the cost of the cartridges for the gene expert. And John Green

[08:20] rallied his troops, he called them, whoops, nerdfighters. And they basically jammed up the Danaher corporate phone line for two weeks nonstop, inundated them with emails and letters and so on and actually caused them to back down. And they will be providing

[08:40] the test at cost in low-income countries in response to this pressure. Before that, six months earlier, John Green had taken on Johnson & Johnson for Bedaquiline, which was this incredible drug that Payam will talk about, where they were going to renege on allowing the

[09:00] an off-paid patent drug to be made generically. And again, the Nerdfighters forced these big pharma companies to back down. And honestly, again, this is again unprecedented in the TV space. And I think it represents, I think, a turning point where we're seeing innovation.

[09:20] occur in the space that hasn't seen a lot of innovation and therefore excitement around it too. Okay, so in terms of the epidemiology, I think we're all aware that TB is a disease of low and especially middle income countries. There's about 10 million cases

[09:40] of active TB a year, resulting in about 1.5 million deaths. And as the graph in the bottom right shows, things are going in the wrong direction, which is, you know, in contrast with, for example, HIV, where things have been really been improving for the last 20 years. And this was exacerbated, especially by the COVID-19 pandemic.

[10:00] COVID-19 pandemic. Our own beloved city of San Francisco has actually one of the highest incidences of TB in the US. And as you can see, by zip code, it's no surprise that the tenderloin has one of the highest incidences of TB in the city.

[10:20] community, and within our own community in San Francisco, TB is a disease of immigration or poverty or both. Okay, so there is good news and we'll go onto that, but also have to be honest that there are bottlenecks in TB, as John Green mentioned.

[10:40] And around 40% of cases of TB, active TB, we get undiagnosed, especially in children, which is a really underserved population. We still take months to treat TB, at least typically 6 to 12 months for even drug-sensitive TB. And we still don't have a vaccine that prevents transmission.

[11:00] of the disease. And you know, this represents lack of innovation in all three of these key areas. As mentioned, most cases globally are still diagnosed by the sputum smear, which is a hundred-year-old technology. The drug-sensitive TB regimen is the

[11:20] same one that was developed by the British Medical Research Council in the 1970s. And we're still using BCG, US-accepted, which is the oldest vaccine currently in use. It was developed over 100 years ago. And why are we still basically using

[11:40] 50 to 120 year old technology for this devastating disease. Well it's partly because of scientific bottlenecks. I've listed some what I call known unknowns that we, you know bottlenecks that we identified. In fact there's a bunch of unknown unknowns as well, but we're not gonna have time to get into those. But in terms of diagnosis,

[12:00] Despite the wonderful gene expert, gene expert still has limitations and we'll touch on those briefly. But we really lack biomarkers with the required sensitivity and specificity, especially for near-patient testing, that's really required for this disease which is going to be, you know,

[12:20] is mostly in underserved populations. The long treatment time of TB is partly because we don't know how to shorten it. We can't rationally design a regimen to shorten TB treatment because we don't know why it takes so long to kill TB. And in terms of a vaccine that prevents trans-

[12:40] transmission, unlike many viral infections, in fact some bacterial infections such as pneumococcal pneumonia, there are absolutely no known correlates of immunity for prevention of TB. We don't have a single correlate and that has really stymied progress in this regard.

[13:00] So with regards to diagnostics and innovation that's occurred in this space, I'm going to touch on some of the work that's been led by UCSF, but in partnership with many partners around the world. And, you know, UCSF has really been remarkable in attracting a lot of both funding from diverse sources.

[13:20] sources, but partnerships with both industry and basic and translational scientists. This is just some of the funding that's supported this work. What's really extraordinary about this, for example, R2D2 network for novel diagnostics is that it incorporates diagnostics that take on phage-based

[13:40] PCR, AI interpretation of cough sounds or chest X-rays through to rapid near-patient tests of patient's urine without needing recourse for sputum or blood sampling, for example. And although many of

[14:00] these tests ultimately are not going to pass the grade, we're confident that some of them will. And beyond the UCSF space, you can see that there's this incredible richness in the diagnostics pipeline, which again is unprecedented in recent or any

[14:20] time, honestly, and incorporates molecular diagnostics, antigen tests, drug susceptibility baked into diagnosis, incorporation of digital tools, and so on. So I think there's a lot to be optimistic about, and I'm sure that some of these tests will become validated for clinical use.

[14:40] use in the very near future. Okay. Why does it take so long to cure TB? Well, this is something that my own lab is interested in. And part of the reason is that even drug-sensitive TB is not killed effectively by antibiotics. Unlike other bacterial pneumonias, which can be cured within five days of a single.

[15:00] antibiotic course, drug-sensitive TB takes multidrugs over multiple months. And classically, this is thought to be due to non-replicating persisters, which occur in all bacterial infections. But more recent work has shown that there are many mechanisms of antibiotic failure. There's little evidence that actually persisters are the ones that are

[15:20] most physiologically relevant in TB. This was a really beautiful study that was actually published in Science earlier this year by colleagues at Harvard where they described a completely novel form of antibiotic failure called, which they termed antibiotic resilience, where there's reduced lack time following antibiotic

[15:40] exposure in terms of the post-antibiotic effect. And this was incorporating genome-wide studies. They interrogated 50,000 genomes of clinical TB isolates, along with cutting-edge imaging tools and other technologies. It was really beautiful work. I'm a little bit biased because my former graduate

[16:00] student was one of the co-first authors, but it was a beautiful piece of work. Actually, that graduate student had started the way along, you know, looking at another form of antibiotic tolerance from my lab, where we're looking at non-replicating persistence, but actually growing tolerant bacteria. And you can see, for example,

[16:20] that these bacteria grow in the presence of bactericidal concentrations of rifampin and the population that exhibits this phenotype increases with the onset of treatment in patients. And that there's this remarkable three orders of magnitude variation.

[16:40] in the amount of subpopulation of bacteria that are not killed effectively by TB drugs, which shows that studying just lab strains isn't going to be enough to be able to tackle this problem. Why don't we have an effective TB vaccine? Well, the field is really excited.

[17:00] about 15 years ago when the first late-stage clinical trial of a novel TB vaccine candidate since BCG was performed, and unfortunately it had 0% efficacy. This was a prime boost of BCG followed by a modified vaccinia anchorovirus expressing

[17:20] immunodominant antigen. And it did what it was meant to do. It elicited potent CD4-positive antigen-specific T cell responses secreting interferon gamma, but it just didn't work. But honestly, this was also a rallying cry that we need to increase our scientific innovation, to ask the questions that people at a

[17:40] we already knew the answer to in terms of what does constitute protective immunity to TB. And in fact, that's what prompted me. The failure of that trial was prompted me to enter the fray in this regard. One of the lessons we learned from the failure of the MVA-85 trial

[18:00] is that you've got to embed discovery science within clinical trials because then even a failed trial will allow you to make discoveries that will help move the field forward. And I think that that's been an incredible learning opportunity for the field because...

[18:20] Because given the lack of correlates of immunity, every time you want to test a vaccine candidate for efficacy, you need to stamp up hundreds of millions of dollars to do an efficacy trial, and obviously that's not sustainable for 20 or 30 or 40 candidates. Okay. So there's work that, for example, at UCSB.

[18:40] We're doing with the Sulayman and the Recy labs and my lab. We're interested in using agnostic approaches. We're trying to learn from natural immunity, but then improve on it because obviously people are susceptible to TB despite showing evidence of immunity. And, for example,

[19:00] The Ernst's lab is interested in disease-tolerizing vaccines that can not necessarily prevent infection, but prevent disease. And then of course, by learning from this natural immunity, we can also find novel adjunct therapies with regards to host-directed therapy, and colleagues such as John Butzick and some of the other experts.

[19:20] sorry, Salaman, as well as my lab are working in that area. And I want to just end on a hopeful note. So some of you will be aware of the seminal trial that, honestly, after years of failure, caught the field a little bit by surprise, it was a GSK-initiated vaccine

[19:40] called M72, which unlike the former trial, you can see the curves clearly diverging here, showed 50% efficacy. 50% is not where we want to be, but it was really exciting. This was a phase 2B trial. And again, in the news, front-page news in the Financial Times elsewhere, you might have heard that.

[20:00] the Gates Foundation and the Wellcome Trust have stumped up just over half a billion dollars to perform the first phase III trial of a novel vaccine candidate for this vaccine. And one of the reasons this is so expensive is that again, this time they've hard baked in the discovery science in it. But M72, we're hopeful about it, but it's not the

[20:20] only candidate in the pipeline. In fact, we've got this incredibly rich, especially late stage pipeline of novel vaccine candidates, which 10 years ago, if you'd, you know, there was only one candidate in the late stage pipeline. So again, this has been incredibly enriching and rewarding. So I think that there's a lot to be optimistic about.

[20:40] But we're not just putting all our eggs in one basket, and I think that's one of the lessons we've learned. And on that note, I'm going to hand over to Payam. Thanks, Robert. Okay, well, we're going to move from vaccines to the TB treatment space.

[21:00] drug development story so far. So this slide just shows you some of the history up until most recently of drug development. Streptomycin was the first British Medical Research Council trial, randomized trial, frankly conducted. And you can see the journey of additional agents which many of you are aware of and use in your clinics.

[21:20] More recently, there's been the development of bedaculin, the laminin, and protonin with appropriate regulatory approvals for those drugs and optimization of a drug, rifapentine, which is a sister compound of rifampin. And based on, frankly, just those seven.

[21:40] drugs that I've listed here for you, there have been significant advances in TB therapeutics. We have what you already would hopefully know about our once-weekly three-month isoniazid rifapentin preventative therapy that was developed by the CDC. But now we have a one-month daily

[22:00] the rifapentanizet treatment for latent TB infection, a four-month regimen for active drug-steppable TB in adolescents and adults, and a six-month all-oral regimen for drug-resistant TB. And so these really have shown that even with

[22:20] modest resources, a small pipeline of drugs. We've been able to make great ground from the history of 24 months of treatment for drug resistance and six to nine months treatment for drug susceptible TB infection and active disease. So this is good ground. We're delighted that

[22:40] These have resulted in endorsements within guidelines, international global guidelines. The WHO has endorsed the four-month HPZM regimen, which is a trial that UCSF played a leading role in conducted by the CDC, TB trials consortium, and the NIH.

[23:00] AIDS clinical trials group. In the drug resistance space, WHO is endorsed a six-month oral regimen, B-PAL and B-PAL-M. And then so far as preventative therapy, the 1HP regimen, daily 1HP regimen has been endorsed by WHO, as well as the DHHS prevention.

[23:20] of comorbidities guidelines in the US. And I will say that these are obviously WHO guidelines, but the US is also adopting these, and the forthcoming in 2024 will be new CDC society guidelines endorsing these regimens for use.

[23:40] I will join, I think. I think that's the best choice. I'm not sure how to join. Normally as TB doctors and TB

[24:00] academics, we are very good at self-sabotaging ourselves, but this takes it to a whole new level. For those who are online, if there is anyone left online, we are having technical issues. Okay. We're back. Okay, good. Just to say the one-month preventative therapy, four-month,

[24:20] susceptible TB, six-month drug-resistant TB has led to a campaign of 146 by 2024. This is an idea that the treatment action group has developed and it's frankly rooted in some mis-messaging messaging that is historically, you know, Paul Farmer has used in other spaces and the idea is that we want update and

[24:40] and usage of these regimens, of a one-month regimen, four-month and six-month, as short-course regimens for global scale-up. But that's what we were able to do with three new drugs and some repurposing of older drugs. The future looks even brighter. This is the 2023 drug pipeline for TB.

[25:00] richest it's ever been from lead through to early stage and then into phase 1, 2, and 3, and really now having multiple areas of attack against the organism to allow us to build a rational regimen that gets us to shorter regimens that Bob Ack was making.

[25:20] describing and one of the things that we have to then take advantage of by virtue of having this array of new options is innovations in our trial methodologies because we cannot be developing one regimen every 50 years. We've got much more in front of us and so this has led to.

[25:40] Next generation of TB trial designs, for which, frankly, UCSF faculty are leaders in. And I'm going to just feature a couple of them just to show you how the field is adapting and progressing. This is a clinical trial that's being led by the AIDS clinical trials group. It's soon to launch next year.

[26:00] colleagues here at UCSF, Radha Savage, Gustavo Velasquez, and colleagues at Johns Hopkins University, Dr. Dooley. And what's wonderful about this, it's a platform adaptive dose ranging trial. It has kind of a backbone of the bedaquiline and protominid that we know is a

[26:20] effective and then it allows, this design allows us to assess different oxazilodones and add an additional fourth drug and in future iterations optimize the dioquinolone, which is the bedaquiline part, for ones that are even more potent, even more safe. And so this is a mechanism of ranking.

[26:40] regimens and making the best choices to go from phase 2 to phase 3. It's a clever way of de-risking those decisions you make into going into large phase 3 trials, which are expensive and when you fail them, really hurts. So this is one example of how that work is being developed. Another one is a European

[27:00] consortium for which UCSF is also a partner called Unite TV funded by the IMI and this should not be automated or animated so let me just move on here but this is unprecedented too this is a seamless phase 2b to seed study design a design that's actually

[27:20] and led and developed by Patrick Phillips here at UCSF, among other collaborators internationally. In this design, there's 10 experimental regimens that combine various new agents against standard controls. First, to identify

[27:40] the most potent and then transition the most potent from phase 2B to a phase 2C duration ranging study. The duration ranging study allows us to then determine what's the optimal duration for that treatment rather than guessing. A third area of innovation is again, UCSF has played a leading role in is

[28:00] We've come to appreciate much more so than before that TB disease is a spectrum of disease and observed data for contemporary trials have reaffirmed this. And there's frankly a minority of patients with TB active disease that have a hard to treat phenotype. And we're in fact over treating 75% or more

[28:20] of our patients in pursuit of assuring cure in a minority of higher risk, those at high risk of poor outcomes. And this is work that's led by Rada Savage's lab in the School of Pharmacy here at UCSF. And this has led to a new stratified medicine trial design that ACTG is also leading.

[28:40] wherein we will be stratifying based on an algorithm, a pragmatic algorithm, of a disease burden to lower risk and higher risk and then evaluating a range of durations of treatment for our best, most potent regimen we have in hand, the HPZM combination.

[29:00] across 10 weeks to 18 weeks for the lower risk group. And in the higher risk group, what we're trying to do is improve cure, because even the 26-week standard control regimen that we all use in clinic for the higher risk group is failing us. It has a 15% or more failure rate, and that's the gold standard. So we want to

[29:20] to improve on that. So that's some of the innovation that's ahead. I'm going to pass over to Dr. Priyashwati to tell you about implementation. Okay so my role in this talk is to kind of

[29:40] level set again back to the bedside a bit and to programs that many of us are used to trying to implement. And this comes from a perspective as an implementation scientist. So I am in awe of all of the many, many innovations in diagnostics, vaccine development, and in therapeutics that

[30:00] have come in the last, I don't know, five to 10 years. But despite these novel advancements, implementation and uptake is really an essential barrier to achieving the outcomes for the people most affected. And that's in part because there are these continuing myths, and we can raise our hands in the audience.

[30:20] as well if you kind of partake in these myths because they have been passed down to generation after generation and protocol after protocol. TB diagnosis requires two sputum smears done on consecutive days, preferably mornings, with culture, which requires six weeks. As we've heard from Babak, that is

[30:40] is not true. But we still do it. Treatment for TB requires at least six months of a four drug regimen that is pretty toxic followed during that time. But if there is drug resistance, which you might not know until much later, it might require an additional 18 to 24 months of therapy, including with probably an increase of 10 to 15.

[31:00] injectable super toxic drug. Yeah, people still do this. They still believe this is the gold standard. It's not true. Finally, directly observe therapy where we make people in some ways infantilize them to come to a clinic far away from their home and their lives at their own personal cost.

[31:20] To let someone else watch them take a few pills is a required strategy for providing high-quality tuberculosis care. How many people still believe some version of DOT is required? A lot of people. These are myths that really impede our ability to scale up these novel interventions and

[31:40] diagnostics, vaccines, potentially, and therapeutics. And so my version of this talk is to talk a little bit about why that is. So I'll first start by saying that some of the statistics that Babak started the talk with, 10 million people will have incident tuberculosis every year. Half of them will be missed in terms of diagnosis of those that do.

[32:00] have TB in any given year, somewhere between 1 million to 1.5 million will die of this preventable, curable disease, etc., and that children and other vulnerable populations are under-treated in this space. Those are quality gaps. We have tools, right? And so I would just offer two observations.

[32:20] historically. One is that even with these tools, the tools we've had available, gene experts been available since what, 2006, 2004, or something like that, we haven't made many strides in this cascade of care. And so cascades of care are an implementation science tool used to identify

[32:40] performance gaps and to translate the kind of needed delivery of health care services into what's actually happening and to identify where those gaps exist so that we could kind of come up with strategies to address those. On the, let's see what side is this, left, right, left. You see standard cascade of care. In this case

[33:00] for India done by colleagues of ours and Boston, Ramnath Subraman, the first author trained here with us at UCSF. And what you see is huge attrition in the cascade of care, right? People fall off. They don't even make it to diagnosis. Something more close to home, on the far right, you see a cascade of care presented slightly differently.

[33:20] of latent TB infection-related care. That's what those of us who practice local AC, right? And there again, we see we're not screening the right people and we're not even testing them. And the highest risk individuals are actually in our community those who are born outside of the US. Of course, HIV-related TB prevention is a guideline.

[33:40] Of course, for immunocompromise prior to starting immunosuppressants. But really, the biggest risk factor is if you were born outside of the US. And you can see we're failing miserably in providing quality care. So my first observation is that even in the face of existing innovations that work, or interventions that work, we provide poor care. The second observation is that we provide more care.

[34:00] observation I'd like to make is that even with only streptomycin and sputum smear microscopy, countries that have high income got rid of TB. Right? We don't we don't care as much about TB here or in Western Europe, right, or in Australia because we don't see it. But why don't we see it? We don't have the same

[34:20] tools, we don't have a vaccine, et cetera. And so I'll posit that because we fail to kind of deliver person-centered care in those kind of more challenging service delivery environments, we've neglected to make the same strides as high-income countries. I will say that these cascades have been elaborated in more detail. Andrew Kirchhoff.

[34:40] here in the division of global health, HIV, and infectious diseases, as well as other colleagues, has started synthesizing these care cascades to identify ways in which we can use these performance gaps and link them to outcome gaps, create these modifiable targets, and that we can do all of this using routinely available data, which is essential for monitoring.

[35:00] of our progress. So I'm gonna, oops, let me make sure I'm on the right place, yeah, okay. So now I'm going to talk about some policy level things that have come about and how implementation really could be enhanced. So we'll start with the domestic TV space and this is a study that I lead with Matt Morrill also who is a

[35:20] in the Division of Hospital Medicine. Implementation demonstrates how implementation research can change policy. So as I said, you know, immigrants are the highest risk group for TB in the US and in most low burden, high income settings. Over half of individuals who are diagnosed with TB

[35:40] are hospitalized. So this is a high-burn disease for those who have it, right? And almost 1 in 10 of them will die in the US. At 1 in 5 of those diagnosed with tuberculosis, these so-called survivors end up dying in 5 years. And 75% of those who have TB in the US are immigrants and often these are minoritized

[36:00] and marginalized groups. We have a policy in place. What you see highlighted here is a USPSTF, so the US Preventative Services Task Force, recommendation on asymptomatic screening for adults at increased risk of TB. And that's a grade B, which is actually a pretty solid grade.

[36:20] It means that in the setting of primary care, I empower you and the USPSTF services, they empower us all to screen high risk individuals, including those who are not US born, especially those who are not US born, for TB with preferably a blood test called IGRA.

[36:40] Unfortunately, we do a terrible job. So now we have a policy we are supposed to be implementing, we have these tools, we have the tests. How do we do it? So this is a study we've conducted looking at TB prevention in primary care and look at that drop-off. It is astounding, isn't it, that 68% of eligible people did not have a documented test on risk.

[37:00] record. This is only amongst non-U.S. born. Of those that were tested, 34% had a positive test somewhere on record. 19% of those with positive tests were known to have been ever prescribed treatment only, and 76% of those who started treatment completed it. So if we get them to treatment,

[37:20] These myths around people not being able to do it seem false, but we don't get them there. One of the many barriers to this we have found in our research is policy level barrier, which is that the Center for Medicare Services does not currently include asymptomatic

[37:40] screening and its list of covered preventive services. So here we have a major policy gap. We have recommendations from the CDC and USPSTF. We have a tool to do this. We have a setting in which to do this primary care. And yet the major kind of payer in this situation doesn't cover

[38:00] care. So what did we do? We just like kind of like said, oh bummer, let's move on to, I don't know, a new infectious disease. Babak always wants us to move to a new infectious disease. Right. But instead we've created policy memos and advocacy tools using our research as the backbone and the center has kind of led the way in doing this with.

[38:20] all of the partners that you see below, including those community-based organizations that represent the most underserved of these populations. And we recommend integration of LTBI screening within preventative services. It helps create checklists for FQHCs where most of these people seek care. It can facilitate reimbursement.

[38:40] and actually support scaling up of this really life-saving and high-burden disease. Similarly, on the global side, a lot of the work that our group has done and certainly others in the Center for TB has done has informed global health policy, including this year's

[39:00] United Nations high level meeting in 2023, which set new kind of aggressive, but rightfully so targets for 90% of people globally with TB to be able to not just be diagnosed, right? But to be provided quality diagnostics similar to the ones that Babak has mentioned and John Green.

[39:20] innovation, that 45 million people obtain quality treatment. And here I think that innovation is not just saying treatment or be treated, but we're talking about quality. And when you see the word quality, I really hope that we all take away this idea of integrating implementation research into all of our kind of more esoteric ways.

[39:40] therapeutic study designs. That 90% of at-risk individuals receive preventive care, and I'm sad to tell you that in the United States we don't come anywhere near doing that among our own high-risk populations. And then I've highlighted the bottom one because it's near and dear to my heart in an area that the center is really leading in globally, which is that 100% of affected individuals receive appropriate

[40:00] appropriate social benefits packages. So that second observation I made that interestingly, even in the face of a dearth of diagnostics and therapeutics and the lack of a reasonable vaccine, countries that are high income got rid of TB. And they did that not because of any biomedical advancements, but because of

[40:20] providing wraparound care, social and economic supports to individuals who are affected because we understand that the social and structural determinants of health are really the drivers of this microbacterium. And this just shows work that our group put together. It's a systematic review of various

[40:40] trials that have been done to demonstrate the effectiveness of social protections or these kinds of social and economic supports that provide more resiliency in times of shock to high-risk individuals and their households, and showing that we can actually improve treatment success for TB twofold. Just by giving people things like additional food,

[41:00] cash transfer, maybe a transportation voucher, etc. This was work done by Molly Hudson and others in our group. Molly is a PhD student here in the School of Nursing. What did that lead to? Because of our emphasis on translation between evidence to policy, we've also supported the development of this forthcoming guidance.

[41:20] guidance on social protection for people affected by tuberculosis, which we released, we hope, early January. And what this means is now we have a policy whereby national TB programs and other stakeholders have a mandate to actually do the things that many of us who provide clinical care do anyway, which is like wrap-around care, right?

[41:40] They're not going to take their meds, but if you feed them and give them their meds, then they might have a better chance of success. Finally, just to demonstrate another area of leadership that the Center has had in terms of global health policy, many of us in the Center have contributed to the Lancet Commission on Tuberculosis, led by Eric Guzby, who was formerly the special

[42:00] envoy on tuberculosis for the United Nations, as well as the global AIDS ambassador for PEPFAR during the Obama administration, as well as Mike Reid, who is now again at PEPFAR as chief science officer. And what we've done is used science in a variety of ways, from diagnostics, from therapeutics, from vaccine development, from addressing social determinants of

[42:20] health and use that evidence base to transfer our knowledge into advocacy and a path forward for actually meeting all of those global targets. And you can see on the right hand side here some of the key recommendations that came out of that collective Landsat Commission work. I'll turn it back to Payam now.

[42:40] to round out the discussion.

[43:00] doing in terms of its programs. I should say that this center is a new center. It was established just four years ago with generous seed funding from Dr. Neil Poe and Bob Lachter. And I think what I will show is that we've been able to grow the center to be responsive to this.

[43:20] global pandemic in a meaningful way. And I'm just going to highlight three programs that are new and maybe of interest to those in the audience and to our colleagues at UCSF. One is a research and mentorship program called TBRAMP. This is an R25 that is led by Elizabeth Fair, and has really led to our ability to fund pilot awards as part of the

[43:40] mechanism. The second is a UCTB research advancement award, a P30. This is sort of like a mini-CFAR was modeled after Centers for AIDS Research, but it's focused on TB. And then the third is a research consortium, research and policy consortium called Smart for TB, which is in partnership

[44:00] and a consortium led by Johns Hopkins University and my colleague, Dick Chason, of which we're a part of. And just, we're super proud of this. These are, this is our cohorts of scholars in the TV RAMP program that come from UC Berkeley and UCSF. We've used the resource allocation.

[44:20] medication program, the RAP system to provide mentored scientist awards, as well as URM mentored scientist awards. And we will be offering RAP awards twice a year in the usual RAP cycle. And I encourage those who are interested in working in this space to come and apply.

[44:40] to also point out that the cohorts you see here are very diverse. I'm proud to say our first awardee is someone from the School of Dentistry. So we have School of Pharmacy, Medicine, Dentistry, and we welcome really all comers to tackle this complex problem. The UC track, this is a new

[45:00] partnership with UC Berkeley with Jeff Cox's Co-PI and it has a number of programs that has effectively cores that are supporting the TV science community at two institutions but it has expanded our opportunity to provide pilot monies, it has accelerated awards.

[45:20] to allow fundamental scientists to get into BSL-3s because of the complexities of TB work. It has consultation services and has established, importantly, a community advisory board to help guide some of our research areas. And this program is new and, as I said, it's

[45:40] deeply modeled after CFAR. The CFAR has been incredibly successful in developing the next generation of HIV scientists and we're trying to do that with TB through this program. And then lastly, this is a USAID-funded smart for TB consortium led by Johns Hopkins, which UCSF and Hopkins are the kind of academic

[46:00] engines for the research ideas, but it's partnered with the Elizabeth Glazier Pediatric AIDS Foundation, the Treatment Action Group, and an in-country implementer KNCV that has got global footprint with our colleagues in Uganda, actually multiple countries from Vietnam to Uganda. And we have seven

[46:20] areas that the USAID has asked us to focus on. I'm not going to go through all of them, but it shows you the diversity of work involved from technical areas on diagnostics, developing new therapeutics for regimens, as well as the WHO for endorsement. We have space for operational research and interruption of transmission, vaccine preparedness, not exactly conducting vaccine.

[46:40] trials, but the issues that PREA brought up around uptake, adoption, and implementation. Capacity strengthening is led by Bob Bollinger and Phil Hopewell and other colleagues here at UCSF and Johns Hopkins. And importantly, translating research findings into policy is embedded into the program. And so for me, it's important to know that we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position where we're in a position

[47:00] For me, this is an incredibly innovative consortium and funding from the USAID that is encapsulating multiple domains into one program and by virtue of that, hopefully accelerating progress. And these are the country sites where we will be implementing Smart4TB activities. And I just share these to you.

[47:20] to hopefully inspire you and excite those of you who are early stage investigators to come to us and work with us, we need as much help as we can get to tackle this ongoing pandemic. So in conclusion, TB is, as you've heard, preventable and curable, but it still remains the number one infectious killer globally from a simple time.

[47:40] pathogen. We showed you that there have been recent advances in diagnostics and therapeutics, and this does represent a step forward in innovation. However, funding is a significant challenge. There's less than 50% of what is estimated to be needed to address the pandemic, and the investing is there.

[48:00] assessments lag, really those that have been made in other infections, HIV and COVID as examples. There are newer tools that are providing better options for patient-centered care, newer therapeutics, newer diagnostics, but adoption and implementation lags and it's an area of research that we hope to have an

[48:20] And then lastly, as Babak pointed out, a lot really remains unknown about just fundamental TB pathophysiology to host pathogen interactions. And these are the aspects that really impaired our progress in all domains, especially in identifying an effective vaccine, which you can imagine if we find the mRNA equivalent vaccine.

[48:40] seen for TB, all three of us will be out of a job and the center can shut down. So thank you very much for your attention. We've really enjoyed presenting to you a very wide spectrum of activities in TB and we welcome any questions you have. Thank you.

[49:00] Thank you so much. Yes, so let's transition to the Q&A part. We'll rejigger our chairs a little bit. And we have some questions from the over 115 people who have tuned in online and stuck with it. So, a couple of questions already.

[49:20] from the audience, and I'll turn the mic over to you all. We have Dr. Lawrence Wong asking, what do you all think about post-TB lung disease and chronic lung disease? You talked about the novel approaches with drug development, vaccine development, implementation, but how do we deal with the global sequelae of the blood pressure?

[49:40] burden of TB.

[50:00] the true burden of the disease and only now kind of we're at the tip of the iceberg with it. So a couple of things come to mind. One in terms of the kind of respiratory, long-term respiratory consequences and the effect that those have on productivity, development if it's a child or an adolescent who's been affected and those sorts of things and the intersection of that with other.

[50:20] diseases including other non-communicable diseases that are increasing in prevalence around the world related to climate change and air pollution. So I think that we're starting to embed additional studies within many of these ongoing research projects to collect data on that because right now we don't actually know the true burden.

[50:40] think we know the tip of it, but not much. And we're increasingly seeing the intersection and syndemics, not just the TB-HIV syndemic, but syndemics related to non-communicable diseases as well. Yeah, I just wanted to add that from basic science perspective, this was one of my unknown unknowns. It was in the early iteration.

[51:00] the slide, but I didn't even know what the bottleneck was. You know, it's so understudied and underfunded, and I think that absolutely we know some of the contributors, but in terms of how we can even tackle post-TB sequelae, I think it's a real, it's going to become, as we get better,

[51:20] At Curing TV, we will have to really shift focus as to how to deal with people who are survivors essentially. And I will just say from the therapeutic side, this has triggered a lot of interest in host-directed therapies as a mechanism by which you can modulate the inflammatory and fibrotic processes that occur.

[51:40] about post TB to try to minimize those. There's some interesting early phase two studies that show lung function is improved, for example, when you use some of these host-directed therapies. Many of the new clinical trials I showed you do in fact have some post TB completion follow-up with spirometry and other measures.

[52:00] So I think the field has woken up to this important issue. Thank you for that question. Another question that came up is you talked about how there's myths that need to be debunked, and there's also gaps. Are we going the very last mile for some patients who maybe don't necessarily need

[52:20] How do you communicate such a nuanced message? Because we do want to, on the purest side, directly observe therapy, treat every case, but on the subtleties, the nuances are actually quite difficult to convey. And so could that be accounting for some of the gap in actual treatments and you see in that cascade?

[52:40] Yes, I think that's a yes. I'll give you two examples of where this comes up in my own work and the work that other colleagues at the Center are undertaking. What is locally, so in our own clinical practices here for those of us who do primary care or even chest clinic or whatever it is.

[53:00] What do we do? And there's a challenge in how, I think, and this is controversial, how TB grew up as an area. Unlike HIV, which fully integrated in primary care service delivery, TB maintained itself within this public health silo. So as a primary care provider.

[53:20] for example, I would never treat someone for TB disease. I would send them to the public health clinic. And that is the same model that is used worldwide. Because it was assumed, and I think it is true, that there are some specialty nuances that are really challenging to wrap your head around. There are toxicities.

[53:40] or drug events, things like that. But I think that that model has created this tension between trying to decide how much nuance to communicate versus how little and who is the end user of that information. So if you're talking to an infectious disease specialist who runs a TB clinic, the nuance is very important. If you're trying to get a primary

[54:00] primary care provider to screen someone for a latent infection somewhere. And then you want to give them all this nuance about what does it mean if the quantifier in gold says 0.35 versus 0.37? What's the difference? Does it mean something bad is happening? Is the world going to end? Those levels of nuance are really challenging.

[54:20] communicate. But I think at the core part of that issue is where we have collectively positioned TB and I do think that is now evolving as we have novel therapeutics and drugs. And on that note another audience question writes, you know, I'm volunteering, this person says that they're volunteering at a

[54:40] free clinic, large population of people have immigrated from other countries. Should I screen asymptomatic patients? And if so, what are the best screening tests available? Yes. You should screen asymptomatic patients who have a risk factor, which includes being non-U.S. born, being immunosuppressed or soon to

[55:00] to be immunosuppressed, having HIV, or being in close contact with someone who's known TB case. There's a lot of noise around these recommendations and it's really challenging to wrap your head around. But you should certainly screen and if you screen, it is challenging because IGRA, so if you're in

[55:20] release assays, which is a blood-based test that can tell if someone with slightly higher sensitivity and specificity than TST, the little skin test, it likely has been exposed and infected. So that would be my recommendation, but I'll ask someone who helped write the guidance.

[55:40] guidelines. I'll just say yes. Wonderful. Questions from the in-person audience. Did you have a question? No. Another question that came up is, I think you highlighted so well about how social determinants of health are

[56:00] key in TB care and really in all infectious diseases. Two questions related to that. From the education piece, you know, there's, there's, I think this is a great use case of how social determinants of health and medical education are really deeply intertwined and should be worldwide because that's an act of controversy online.

[56:20] we speak. And a follow-up question to that is, we're fresh off the fellowship match. Congratulations to all UCSF medicine residents who matched in fellowships yesterday. And while our infectious disease fellowship matched outstandingly well, around the country ID programs will remain unfilled and this has been a persistent problem. So how do

[56:40] How do you think about the infectious disease workforce with the biggest number one ID killer worldwide? And how do you think about education, about social determinants of health, and biomedical sciences being together as in TV?

[57:00] hanging a few questions. Maybe I'll try with the social determinants piece and pass it to colleagues on the other aspects. I think that UCSF does a really great job of integrating social determinants of health, social justice, anti-oppression curriculum, cultural humility, positionality, those sorts of things into our curriculum.

[57:20] And it's something that we do. And as a director of the Implementation science training program, we've all kind of tried to establish some basis for that in our own trainings. But I think that making it kind of part and parcel of not like a separate thing, but like we talk about what are the risk factors for

[57:40] disease, we should kind of include things that are not just like individual-based, but community-based, place-based into that a little bit more holistically. I think now TB is doing that, but it seems like, you know, no one, I always say this in talks in Piamsasai because he gets tired of hearing it. It's not sexy.

[58:00] much cooler to come up with a rad new test and use AI to read a chest X-ray. That's so much cooler than saying, oh, gee, I'm sorry, you're hungry. I guess you could have a sandwich? That's not cool. And so part of it is also, going to the workforce question, is that we have...

[58:20] seem cool to kind of address those things. It is now, increasingly, and in our bubble in the Bay Area certainly has been, but I think like globally it's not yet. I just want to touch very briefly on the lack of ID slots as the only ID physician.

[58:40] And that, well, I don't want to start a firestorm, but it's partly because we're paid less than our pharmacology colleagues because we don't value the specialty knowledge and experience that I.D. has compared to, you know, handling instruments and doing procedures and things. But I also think

[59:00] that that's an opportunity. I think that, you know, traditionally ID has been amazingly fulfilling to do as a physician scientist, not just as a full-time physician, and I think we need to leverage that. I have to say that very few ID fellows want to do basic science, for example.

[59:20] compared to implementation science and I.D.

[59:40] term career pathway and we have to you know we can't properly change the pay gap but maybe we need to open up career pathways better for ID. I'll just say that I mean what are what are our global threats climate change, infectious disease, you know so and they go

[01:00:00] together. We're not done with pandemics. You know, I think these workforce issues ebb and flow and you know I think innovation in science is appealing and attractive to early stage investigators, early career people and that's what we need to do.

[01:00:20] The pull mechanism should be we're doing super cool stuff, whether it's in TB, HIV, COVID, whatever. And that's what I hope will be the pull, but it'll happen. Well, I can't think of a better way to end than a call to action that we need help worldwide from basic science to implementation science and everything in between. Thank you so much to our terrific panel.

[01:00:40] learned a lot.