Okay, good morning again, I'm Ami Patrawala, nice to see you all. So our first presentation today, and I think we have a bunch of really interesting topics, our first presentation is Rapid Diagnostics for Tuberculosis and their Impact. Patricio Escalante from the Mayo Clinic will be presenting on this topic. And I think we'll probably have some time at the end for questions, so please save those up. Thank you, Ami. And thank you for the organizers to invite me to the presentation, it's really a pleasure to be here, especially in sunny Honolulu. So let me see if this thing works, no, all right, perfect, all right, thank you. So just a few disclosures, I have some patent technologies for immunodiagnostic LTBI, which I'm not going to be talking about today, and it has no financial relationships relevant for this talk, and this is the acute code. The main objective of this talk is to talk a little bit about the global state of tuberculosis control, just briefly about that and put a stage of this session discussion, and also to gain some knowledge about the advances in the new diagnostics and rapid molecular testing for TB, as well as how these can implicate in the rapid assessment and determination drug susceptibility testing to facilitate effective treatment arrangements, hopefully quickly in these patients. First I want to present two cases, real cases, to illustrate the importance of these diagnostic approaches and new testing. This is a man who was seen a few years ago from Laos, 45 years old, and was able to, after immigration, asymptomatic, had a tuberculosis skin test of 70 millimeters of induration that was not confirmed back then. He had normal examination and had fairly unrevealing pathological history. This is x-rays back then, was read as negative, which I concurred, and that was in 2003. Fast forward 11 years later, the same man, now 56. He actually was offered treatment for late TB infection and took isoniazid for two months and didn't like it and lost the follow-up. Now he presented with dry cough for one month, and now is treated by his primary care physician with a course of azithromycin. He didn't have any fevers, chills, night sweats, or weight loss, and noticed to have some wheezing when he was lying down, and was recently diagnosed with asthma. And his pathological history remained about the same. Now he works in a school cafeteria and comes to present to a primary care physician and seek advice from the TB clinic group. So this is x-ray, and this is an evaluation. His x-ray was unchanged, and there was no obvious infiltrates or other abnormalities as per the earlier report. Now his pontiferon test was positive. So first question, let's see if this works, still working. So there will be two audience response, the first one. In this case, what is the next most appropriate management step? Prescribe albuterol for thinking this is a upper respiratory viral infection that will go away, send him home, follow up in six weeks, and to consider treatment with rifampin for suspected latent infection, patient with negative x-ray and posiquantifer. Collect three sputums for SV smear and mycobacteria cultures. Collect also these three sputums, but add a nucleic acid amplification test or a gene expert MTB test in addition to that. Or check his base in lab testing and start four drugs for suspected TB and follow up in a month with an x-ray. We'll wait a few more minutes, and all right. So we got, yeah, perfect. I think this is a great audience, and I think this is the most likely answer for this question. And we'll get back to this case. The second case, another real one, a 20-year-old young man, a student from Taiwan who recently arrived to a college campus in Minnesota, and we were called because he had a screen testing. We showed a skin test in duration of 18 millimeters and had subsequent quantifer test was positive. He was HIV negative and has these x-rays on this screen assessment in this college. No prior TB history, no prior exposure, asymptomatic, playing volleyball, happy camper. A favorable examination was unrevealing, no past medical history, a very young, healthy man. So this is a chest CT when he arrived, and some significant abnormalities, as you see, a small cavity area with thick walls, as well as some trim buds and some other non-specific molar and macronodular opacities, especially in the right parietal area. No significant mesthian lymphadenopathy, although that was without contrast, had three screen testing. He was isolated, placed in the hospital for isolation. Negative testing, including two MTB PCR equivalent to the gene expert, this is a Mayo rapid real-time PCR, and had even a BAL, which was negative. So question is, what is the next most appropriate management step? Take him to his missing home, to his college dorm, and wait for a micro-bacterial culture from the sputum and BAL. Check his baseline lab testing, start for drugs, or consult the CDC to get molecular testing for MDR concern, or refer for surgical lung biopsy. By the way, the BAL had negative testing for fungal infections. or a couple more seconds. Great. Well, thank you for your votes, let's see. Yeah, I think most people would aim to start treatment and then follow. I think that's a very appropriate step and we'll discuss the other options after we follow up in this case. All right, so TB, where we are in TB. This is the most recent WHO report and there's still a quarter of mankind suspected to be infected. Unfortunately, we continue having the sequela from the COVID-19, which divert a lot of resources from TB to COVID. And there's more cases of TB and a little 40% of those undiagnosed, which fuel the transmission and ongoing epidemic. There's about 30 to 80%, depending what country and survey, that's considered subclinical active TB. So about 50% of cases with active TB in the world are actually subclinical. Either no symptoms or symptoms are not specific and mild patient is not suspected. And these patients, unfortunately, do not produce much sputum and they're being seen by their family, friends and in healthcare facilities. And we know now for recent data that transmission can occur with tired out breathing, not necessarily with just cough. And the early diagnosis of TB can decrease TB progression and decrease transmission by 50%. So there's a really strong emphasis to try to diagnose TB earlier and act early. Unfortunately, there's still ongoing drug-resistant TB in many areas of the world. Empirical treatment can be challenging in those areas. And there's still significant mortality with TB, especially with HIV infection or comorbidities in the world. And these are the reference. So our clinical assessment, going back to what we do in our clinics and hospitals is radiological clinical assessment. We do three sputum testing, at least one morning sputum. And that has 40 to 70% sensitivity, depending how good or not the sputum is. And then if the patient is not coughing, we do a sputum induction with no light sailing, which has similar yield. If the patient is still suspected and is not having any revealing testing results, then we usually, if we have those resources, we do a bronchoscopy or gastroasper, especially in infants. Now we have problems with the HIV smear, which as we say is low sensitivity, but also doesn't tell us about drug resistance. The nucleic acid amplification testing can be helpful, especially if the smear is positive, because if the smear is positive and you have positive gene expert or other specific nucleic acid amplification test, this is TB on the problem otherwise. But if the smear is negative and you have negative testing, you're a little bit in the limbo. And if it's positive FBS smear and negative nucleic acid amplification testing will be likely to be NTM, especially in this area of the world. Now we commonly use mycobacterium cultures in solid and liquid media. The solid media takes six to eight weeks to mature those testing have been gradually replaced by liquid media takes three weeks average to get results. And, but those require significant technical expertise and lab equipment. And for us waiting two, three weeks, even that is difficult, especially in hospital settings. There's also maintaining cost issues and the time results as alluded can be difficult to the clinics. So there's really strong need for rapid, affordable, accurate, and easy to use drug susceptibility and testing for MDR and XDR TB, especially resource limited settings where TB is more prevalent. So this is just one example of trying to attempt to optimize the phenotypic testing cultures. And this is a microcosmic observation drug susceptibility testing that takes two, three weeks to mature in comparison to the liquid media could take six weeks or so. So the emphasis now has been going to more rapid molecular diagnostic leveraging on genotypic methods to detect mutations in the DNA of TB to determine drug susceptibility or drug resistance. So the main market refamping, which is the surrogate market for MDR-TB, which has a very strong sensitivity and specificity within a very small part of the genome of the MTB, the RPOB gene. And there's accurate testing as such for refamping and also isoniazid, which also has a specific mutation in different parts of the gene that can be also detected. And that can give us quickly within a day or two, depending how soon we can get DNA, these results and infer whether or not the patient has drug resistance to refamping or isoniazid. So if this is a fast time results time around, and you could also combine these testing with current liquid media and have quickly answering the question about drug susceptibility. Now, some of these new technologies have been evolved and have been actually applied to point of care testing and even direct specimen testing. This is a list that was elaborated a few years ago. There are more, especially GeneXpert has been very successful. It was supported by the Gates Foundation that's been deployed in many parts of the world and replacing some of them. They, as you thought, was just mere testing. There's a new version, the GeneXpert Ultra, which is more sensitive. There's a Indian company made a very similar platform that is applied there, which also very similar diagnostic accuracy is called the Mobio. And there's also line probes have been developed to utilize PCR hybridization, as well as other technologies, like a loop-mediated isothermal amplification. And subsequently, DNA biosequencing. And some of these were used by CDC in the MDDR testing for drug resistance related testing that was used until recently by CDC and now with new testing technologies. The whole genome sequencing have been leveraged also to detect these mutations in a more broad way. But the more, I think, evolving technology is a target next-generation sequencing, which is evolution of this testing to really cover most of the mutation very quickly ways. This is a GeneXpert platform. Within an hour, 45 minutes can detect with good accuracy, not only TB, but drug resistance. This is the 100% specific sensitivity in this corner. As you see, the sensitivity 98%, specifically 100% for SME positive, for SME negative, a little lower sensitivity, but excellent specificity. And in many places, as I said, it's replacing FB smear testing. For an HIV, it's a little bit lower sensitivity, but still very excellent specificity. Refund sensitivity also exactly in a diagnostic accuracy. But most importantly, these tests give answers right away in comparison to more established lab testing results with media. Is this technology has been applied to non-sputum testing. And there are a number of studies out there, including the meta-analysis that show that blurred fluid, you can, this GeneXpert can have good specificity. It's not that great. For CSF testing for suspected meningial TB, this is actually a great advance because sensitivity has improved, especially with the GeneXpert Ultra, which has 90%. These are very, very difficult to treat, especially in children. So this is really make a difference. For FNA of lymphadenopathy, so especially for TB lymphadenitis, excellent sensitivity specificity. For gastric aspirin in children, adequate sensitivity and great specificity. And for urine, also robust diagnostic accuracy. And for refinery system in all these non-sputum samples is pretty, pretty good. And in general, this is one way to apply. However, the current label of the GeneXpert in the U.S. is indicated for sputum, not for any of these. So you have to check with your laboratory testing lab team if they are able to do this. In other parts of the world, this has been done more routinely. So in terms of GeneXpert, the latest version of this technology is increase the sensitivity, at expense of a little bit of specificity in general for all cultures. And the smear negative increase also the sensitivity, which is significant. And in HIV as well. So this is a good test for HIV endemic areas. And the refinery system remains very strong. This is a test that CDC has been offering until February of this year, and that has changed. Still, these are based on pyrosequency and Sanger methods, and with good diagnostic accuracy, especially for rifampin, isoniazid, Dambutol, piercinamide, fluoroquinolones, and some of the aminoglycosides. But I think has evolved. And now they are utilizing the new target in the next generation sequencing, which cover all these, but also lenisolid, betaquiline, and clofazamine. But diagnostic accuracy for those testing is not 100%. For genetic testing, still is a field of active research. It's about 60 to 70% sensitivity. Excellent specificity, but not perfect for those new drugs that are going to be very important for certain treatment regimens that our colleagues will be discussing shortly. So, emerging technologies for rapid TB testing include this gene expert for MDR-XDR-TB, which was designed with the WHO show, still was located in using aminoglycoside, but that's a change. So, this has excellent diagnostic accuracy for these drugs, but it's missing the new drugs that we use for repel. And here in the U.S., the main way to diagnose this drug sensitivity or not for betaquiline and lenisolid is still liquid media culture. As I said, CDC has genetic testing, but it's not perfect sensitivity. And there is no available pretunamate drug sensitivity testing as far as our lab chair mentioned to me. So, the target sequencing is just new technology is being applied now. There's new platforms that are going to be probably evolving and be available more readily. That's the one CDC is using. It covers a lot of genes better than our technologies. It's less expensive, simpler informatics, and it requires a knowledge target of the genes. And in comparison to the whole gene sequencing, which is a full genome sequencing, it's more expensive, more comprehensive, can detect cases with mixed infections, which can be trouble in some areas in the MDR-TB, but has significant limitation in the sense that it's much more complex to do and slower the processing and complicated informatics. But you can have also access to genetic molecular testing to determine clusters and really do contact investigation in a very refined way. So, this is something that can be utilized mostly by public health officials. So, there's other emergent TB biomarkers and diagnostics depending on the stage of TB. We know now in recent studies that there's this in-seeping and transitional state of TB that occurs before TB became symptomatic or apparent X-rays. And in this stage, the X-ray is completely normal. You could do a PET scan. You could catch some granulomas still start getting positive activity in that stage, but the patient is completely symptomatic. And if you do some genetic expression testing, gene expression testing, or other technologies that are all investigational, you can detect TB months or even a year before TB occurs. So, there's active research to get new biomarkers for early diagnosis, but it's also a lot of development in terms of triaging testing for TB. So, we know we have a staining culture, but there's also antigen testing, especially LAM in urine, which is very accurate for HIV, especially in immunosuppressed patients. There's WHO supporting the use of tools for the gene expert in children with good accuracy. There's also development of tone sampling with this technology with a gene expert. There's also host biomarkers. Cytokine biomarkers is typically the agri-testing, but there's also a different array of different host biomarkers in development. And there's new triage technologies based on computerized assisted digital X-rays that can detect TB with good sensitivity, especially it's not perfect, but it would be a good triage testing tools for us. And there's also new technologies to see cough analyzers or sound analyzers, as well as breath analyzers. And all this is in development. And this is just one example of what FIND, which track down and support all these developments in the world, has these three platform for X-ray digital testing with good sensitivity and pretty robust specificity. So going back to this case, a Laotian young man, a 58-year-old Laotian man with positive skin test had these three but small signs of infection. So he had negative X-ray, but still significant CT findings. He had one of the three sputum positive for ASB on the MTB-PCR, which then grew pan-sensitive TB. So critical to have this rapid diagnostic in this man who was going back to the school campus as one of the work in the kitchen, cafeteria. So this patient was important to have three sputums including NAIT or Expert Tissue Healthy Level. The old man, a young student from Taiwan who had significant abnormality, highly suspected TB. We decided to get treatment and rightfully so. These tests are not perfect. In 12 days, all the sputums and BL were positive TB. I think if you have high clinical suspicion, you should consider starting treatment after rolling up all the alternatives diagnosis. So, all right, this man was treated and did very well. And also importantly, it was important to go back to his college after rolling out infectious state after a response and treatment. So take home points. TB remains global threat. Asymptomatic TB is common among all active TB cases. Standard laboratory testing for ductility testing have limitations, but there's available rapid molecular testing to allow for active TB. Consider start RIP for drug therapy early for suspected asymptomatic TB. Not only think about TB, but also MDR-TB, XDR-TB, especially people coming from those areas in the world or TB contact for MDR or people being treated for TB in the past. Suspected drug-resistant TB also requires reliable rapid testing. And don't hesitate to consult a local renal TB expert for advice for diagnosis and treatment in these cases. That's all for me. Thank you. Thank you so much, Patricio. That was amazing and such a thorough walk through the diagnostics we have and we can look forward to. We're just loading up our next presentation. If there's one quick question for Patricio, maybe we can take it now. Yes, Sebastian. Sebastian Kurt from Tubing in Germany. Patricio, thanks for the great talk. I want to share a case with you. A lady with extensive carotid, bilateral carotid disease. No question, she was AFB and PCR positive. And I was approached with a question, when can we isolate? She was on treatment, three weeks into the treatment, her AFB smears were still positive. And the way I decided it, they should get drug levels, it was a pan-sensitive strain. If the drug level was negative, the clinic responding is probably okay to be out of isolation. Wouldn't it be great to have any monoclonal morphine to help with that? Yeah, absolutely. I mean, there's ongoing research to see treatment response. But I think for a practical perspective, knowing the investigation site, I think it's important also to know whether a patient is immunosuppressed or not, whether there's drug resistance or not, if the patient had at least a gene expert to see whether or not the reflamping resistance, because that can also give us some sense about response. It's also important to assess where the patient is going to go. If he's going to go to a nursing home or to other crowded facility or where there are children or immunosuppressed patients, then those patients, you may want to wait a little longer until you get demonstrations it's no longer contagious. But if the patient is doing well and responding clinically, and he's not having going to a high risk setting, oftentimes after two weeks of therapy, the patient's drug susceptible one should consider being transferred non-infectious. But I know I understand your concern, especially positive smear, but sometimes it's a judgment call. But in general, two weeks of therapy in pan-sensitive TB, someone responding and not going to high risk environment is sufficient to let them go. And actually, I exactly used that. It's so sensitive they can stay positive during a long time in the treatment course. Indeed. In fact, in many places in the world where there's a low endemic TB, the GeneXper Ultra can pick up even after the treatment completion positive testing, which can give false positivity in some cases. Thank you. Appreciate it, Sebastian. Thank you. OK. Thank you. So our second presentation is just slightly delayed. So I will go ahead and talk to you about medication-related adverse effects. My name is Ami Patrawala. I'm from Rutgers New Jersey Medical School. And there are some seats in front. There are signs on them, but nobody's sitting in them. So come on up. OK. So I'm going to focus my talk on the main medications we use for drug-susceptible TB. This is me. This is the QR code, but it will come up again. These are my objectives here. And just to kind of set us off on the right track, we kind of want to define what we mean by adverse drug reactions. And there are a lot of different definitions out there. This is the one that I've seen referenced the most. And what we're really focusing on here are these non-preventable adverse drug events. Not so much the medication errors that really take up the main issues with drug safety. We're really focusing on those adverse drug events or adverse drug reactions that are not preventable, that are just inherent to the host and to the medication. Grading of adverse drug reactions is very important. This is how we decide what the next management step is, as well as in studies and clinical trials how we can gauge what we might expect from the medication in a larger population. So there are several different grading systems. This grade 1 through grade 5 system is from the CTCAE. And you can see that a grade 1 mild reaction may not lead to any intervention or any change in the treatment, versus a grade 3 or medically significant moderate reaction, or sorry, severe reaction that may require the patient to be hospitalized. And then when we specifically talk about TB drugs, one of the main side effects, adverse drug reactions we think about are with clinical hepatitis or drug-induced liver injury. And so this is a grading system looking at our various laboratory parameters. And we'll go into this a little bit more. Oops. Back. OK. So this is our first question. Which of the following is true regarding adverse drug reactions in TB disease? ADRs are uncommon in people being treated for TB disease. Most drug reactions occur in the initial months of treatment. ADRs are not associated with poor outcomes among people with TB. Minor drug reactions are less frequent than severe ones. Or E, none of the above. Okay, and this is how you all answered and I will get to this, but yes, you're correct. Most drug reactions occur in the initial months of treatment. So there is a very wide range in the literature of the frequency of drug reactions, anywhere from .55 to seven major adverse events per 100 person months with the first line regimen. And interestingly, the rates of adverse events seem to be going up. So we see higher rates in the more recent cohort studies as opposed to some older studies. The drug reactions tend to occur in the initial two months of treatment. And as you can see here, when we look at hepatotoxicity and the incidence of that drug reaction and then the timeline down here, this is month one, two, three, and four, you can see the peak of hepatotoxicity is really around the second month. Common symptoms like anorexia and nausea seem to really peak early in treatment and then come down quite drastically during treatment itself. Mild reactions are really, really common, much more common, luckily, than moderate to severe reactions. Treatment, as we know, is lengthy, six months, maybe shorter with some newer regimens, which we'll hear about. And adverse drug reactions are common. And of course, we care about the drug reactions, the symptoms, the impact on our patient, but also it may impact the outcome and whether that TB can be cured. So it does, adverse reactions lead to reduced adherence and treatment completion. And as we know, it's really difficult to identify what the offending drug is when you're on four different drugs. And so this often leads to total treatment interruption. There was a study in Rwanda that found a twofold increase of unsuccessful treatment at six months in people who had significant ADRs. In Portugal, severe drug reactions were associated with both an increase in the treatment time and an inability to complete treatment. And the increase in treatment time was about a month, plus or minus almost three months. And again, this may be changing, but if we have to modify the regimen because of drug reactions, this may lead to increased complexity of the regimen, even poorer efficacy than our first-line regimen, and potentially more side effects. And often, this modified regimen will require more intensive monitoring. This was an interesting study, sort of in the bottom right here from Korea, that looked at different quality of life markers and found that there was a lower quality of life associated with drug reactions over here, and then with older age, age over 65. So this is just the answer to the polling question. Most drug reactions occur in the initial months of treatment. So what about risk factors? Can we pre-identify people who might have a tendency to have drug reactions or drug events? And yes, to some degree, we can, but there is a long list of individuals and risk factors who may have higher risk of drug reactions, some of which I've listed here. Certainly for liver toxicity, we know that age, HIV infection, a pyrazinamide-containing regimen can all increase the likelihood of hepatotoxicity. Similarly, in the past, if we had drug resistance, which I'm not really speaking about today, we knew that those medications usually had a higher risk of adverse drug events. There are a whole host of categories, organ systems, that our drug events, our adverse drug events fall into. I'm going to concentrate on sort of the GI toxicity, cutaneous toxicity, and hepatotoxicity. And like we said, most of these side effects will be minor, so mild GI toxicity, maybe just itching or really focal rash. And usually, treatment does not need to be interrupted, and there's really no major intervention, just symptomatic ones. Contrast this with our more moderate to severe reactions, intractable symptoms, real clinical hepatotoxicity, diffuse cutaneous reactions with systemic symptoms. These would all require stopping treatment and then deciding if the person can be re-challenged to that first-line regimen or if they need to go on alternate medications. This is from an older study from early 2000, but kind of shows you which drugs are responsible for which side effects to the best of our ability. So you can see that pirazinamide in the white bar here, oops, pirazinamide in the white bar tends to cause a lot of cutaneous reactions, as well as what we're more familiar with, the hepatitis and GI toxicity. Certainly any drug can cause a cutaneous reaction, and any drug can cause GI toxicity. And then ethambutol in yellow is the one that's most frequently associated with optic neuritis or visual side effects. So we monitor patients for a very long time, up to six months or longer, depending on their treatment regimen in TB disease. And we have to be able to monitor and then decide, are these new symptoms or lab abnormalities true side effects? Are they adverse reactions to the medications that they're taking? Is it a paradoxical reaction? Is it a new disease? Or is this actually, are the symptoms that they're having treatment failure? And sometimes it's easy to figure out, but a lot of the time it becomes complex. So this is my second question. 25-year-old patient with cavitary TB on standard doses of RIPE or HRZE. He's been on this regimen for 10 days. He has daily nausea, one episode of vomiting after taking his medications. His symptoms of TB have improved, his cough and his fever. His appetite is fair. He's taking all his medications in the morning before breakfast, and his liver function tests are normal. So what would you recommend next? Stop all his medications and re-challenge gradually? Rule out viral hepatitis? Stop the pirazinamide and continue his other medications? Take his medications with a light snack? Or change the treatment entirely to ethambutol and moxifloxacin? So great. So this group is really a TB expert group. So the answer is, I think in this case, there can always be alternatives, but really to try some intervention to allow the patient to continue his treatment regimen. If we stop and interrupt treatment for each and every mild side effect, the patient is really at risk of not being cured of their TB disease, and certainly not in a timely way. So we try suggesting that he take his medications with a light snack. In the interest of time, I might skip a little bit so we can get to our third presentation. But a lot of this we've spoken about already. So when we talk about GI upset or GI toxicity, the symptoms overlap a great deal with liver toxicity. But usually, GI toxicity will happen in the first couple weeks of treatment. And as we mentioned before, parazinamide, isoniazid, and rifampin are really the more common drugs to cause GI toxicity, but again, can be any of them. I mention moxifloxacin because in our next talk, you'll hear about a new short course regimen that includes moxifloxacin. And fluoroquinolones can also cause a real amount of GI toxicity. So GI toxicity is common. 12% have GI symptoms. We have to make sure that this isn't hepatotoxicity. So we would get liver function tests. And then if the symptoms are mild, we would counsel the patient to try and adjust the timing of their medication. Perhaps they can take them at night. Perhaps they can take them with a low-fat, light snack, which won't interfere with drug absorption. We can prescribe antiemetics, although I haven't done a lot of that because it just adds to the pill burden most of the time. And if it's really severe, really refractory, some patients just think about their medications and get nauseous. You can try a low-dose benzodiazepine for that anticipatory nausea. And if it's intractable, which doesn't usually happen, but if it is, you may need to interrupt treatment. And in general, with TB disease, especially early on, we would prefer to stop all medications and reintroduce them one at a time rather than picking and choosing one or two medications to stop. So the answer here that everybody already knows. OK. So we're moving on to cutaneous reactions. So this is a young woman with diarrhea, 40-pound weight loss. She has advanced HIV, pulmonary NGITB. She started on RIPE. Her diarrhea resolves. Her weight has increased. But at four weeks, she appears jaundiced. She has a diffuse rash. Her labs show elevated liver function tests, as well as an eosinophilia. So what is the most likely cause of the rash and the next best step? I'll let you read them. Okay, so I agree with you, this sounds like a really severe drug reaction. There are systemic symptoms, and so in this case we would have to stop all of her medications. So when we talk about cutaneous drug reactions, it's really important to characterize the extent, the severity, and whether there's systemic involvement, especially mucosal involvement. Luckily, most cutaneous drug reactions are local, you may not even see a rash, it may just be some pruritus, and these often resolve on their own even if you continue treatment. In the rare cases where we have more severe reactions, like urticaria or sort of immediate type 1 hypersensitivity reactions, or you have any involvement of mucosa, liver dysfunction, kidney dysfunction, these are times where we're worried about a more systemic reaction and treatment should really be interrupted in that case. Again, most of the time this happens in the first two months. This is sort of the most more commonly occurring with pirazinamide, but it can be very hard to tell because again, they're on multiple medications at the same time. One thing I'll mention is that rifampin can cause a drug-induced thrombocytopenia, and that can sometimes lead to petechiae. And again, the rifamicin in that case should really not be continued, but that's a different type of rash that we should be looking for. And very rarely we can see cutaneous tuberculosis, and so we have to kind of become familiar with some of the rashes and make sure that this is an adverse drug reaction and not actually cutaneous TB. Again, these are common. If the reaction is mild, usually we can get away with topical or even systemic antihistamines, and we can continue treatment. The goal is always, if it's safe, to continue treatment. More severe, like in the patient that we discussed, we need to stop treatment. And if the patient is early on, they're still symptomatic from TB, they have smear positivity, we will have to put them on an alternate regimen in that situation. This was the answer. In terms of re-challenge, I think most of the time re-challenge if the reaction is mild. You start with one or two medications, usually rifampin, and then every two or three days you're adding another medication while you're monitoring the patient. And this is specifically for cutaneous or hypersensitivity reactions. Usually if the first three drugs you start are tolerated and the reaction was bothersome to the patient, you might leave off the fourth drug, especially if it's ethambutol or pirazetamide. In more moderate to severe reactions, I would say I would lean against re-challenging, especially in those severe reactions with mucosal involvement. Occasionally, I have re-challenged in people who had DRESS, but I've always done this in an inpatient setting and always with our allergy immunology colleagues. And I think this can be a little bit tricky. There is this one study that showed successful re-challenge in about 13 patients who had DRESS after they were desensitized. But this is incredibly involved, and I'm just showing you the top one is the re-challenge, sort of re-challenging people with small doses of each drug over a couple of weeks. And then the second one is a true desensitization. These are very, very time intensive and labor intensive. So often, these patients, instead of going through a re-challenge or a desensitization in the hospital, will end up on a new regimen. So last, I'm going to talk about hepatotoxicity, which I think we're probably all most familiar with. Isoniazid and pirazetamide are really the most common that we see that cause true clinical hepatitis. Remember that up to 20% of people can have just a chemical rise in their AST and ALT, usually from isoniazid. If you didn't check the liver function test, that patient probably had no symptoms. And most of the time, those LFTs will come back down to normal. And that is likely a hepatic adaptation to isoniazid. Rarely about up to around 1% of the time, you can have true clinical hepatitis. Pirazetamide tends to cause more severe drug-induced liver injury than isoniazid. And rifampin is generally much less frequent in terms of causing hepatotoxicity. And the pattern is usually more of a cholestatic picture, with a rise in the bilirubin and the alkaline phosphatase. The fluoroquinolones, which we now sometimes use in our first line regimens, can also cause some hepatotoxicity, although not to the degree that isoniazid and pirazetamide do. And typically, MOXIE is a little bit more hepatotoxic than levofloxacin. Many people experience hepatotoxicity. And really upfront, importantly, we need to rule out other causes, like viral hepatitis, other medications. Many patients are on a long list of other medications that may cause hepatotoxicity and alcohol use. So in terms of management, if you suspect drug-induced liver injury and the ALT is less than five times the upper limit of normal and there are no symptoms, then you continue treatment and monitor the LFTs. On the other hand, if the LFTs, if the ALT is greater than three times the upper limit of normal and the patient has symptoms, or if the ALT is greater than five times the upper limit of normal without symptoms, you stop treatment, evaluate for other causes, including the ones that I mentioned, and then you'll follow their liver function tests, their PTT, PTT-INR. And then once their liver function has returned to normal, about less than two times the upper limit of normal, then we would talk about re-challenge. So some of these patients will need a regimen in between to hold them and continue treating their TB disease. And that really depends on how severe and at what stage of their TB treatment they are in. If they are well-controlled, if they have minimal TB, if they're in the second half of their continuation phase of treatment, you may be able to monitor them for a short period of time off of treatment. And then this is my general re-challenge protocol. I usually start ethambutol and rifampin together. They're unlikely to be causing hepatotoxicity. Then add isoniazid. And if they continue to have normal liver function tests feeling well, then I generally would not start pirazinamide if their initial drug reaction was very severe. I'm going to skip optic neuritis. This is just a nice summary of all the drugs and all the organ systems that they can impact. And you can see that there are a lot of X marks because almost anything can cause everything. And I'll leave you here with my summary. And for sake of time, I'm going to introduce our next speaker. Vanessa Soitanto is a second year pulmonary critical care fellow at NYU. And she's going to talk to us about the short course treatment regimen, the new four-month regimen, which is really exciting for TB disease. Thanks. Thank you. Thank you, no problem. Hi, everyone, good morning. Thank you for coming here for this session. I'll try to go faster here. So with the interest of time, I'm Vanessa Satanto. I'm one of the fellows at NYU in Pulmonary and Critical Care Medicine. I have nothing to disclose. And I'm here actually really on behalf of Dr. Carolee Kaplan-Shaw, who's the medical director of our TB program in Bellevue and NYU. She's unfortunately not able to make it here, so I'm here on her behalf. So our lesson objectives today, by the end of the sessions, I would like us to be able to identify patients who can be started on this four-month tuberculosis treatment regimen, and this is for drug-susceptible TB. Describe at least one advantage and one disadvantage of the four-month regimen of treatment for tuberculosis. So let's start by talking about our goals in treatment. What defines success? So we wanna reduce the bacilli load in a patient, which hopefully reduces the severity of the disease quickly and then preventing death. And we would like this to be durable. So we'd like patients to be treated and not have a relapse of their disease, and then therefore would not have any resistance acquisitions. And that's only at the individual level, but really we all know that tuberculosis is not just an individual disease. It's a public health concern. It affects our community. So we want to prevent spread of disease by successfully treating an individual. So what do our current guidelines recommend for drug-susceptible TB? So with our initiation phase, we have our four-drug regimen, isoniazid, rifampin, pirazidamide, ethambutol. It can be given in different kind of ways, depending on the availability of direct observation therapy, the ability of the patient themselves to take the medications, and the severity of the disease. So you can do this for seven days of the week, for eight weeks, which is two months, and then down to about two times a week for six weeks. And this is, again, depending on the situation. So if you have really terrible cavitary disease and is also co-infected with HIV, the preference is for more days of the week for a longer period of time. And then we have the continuation phase with two-drug regimen of isoniazid and rifampin. And also, we have different frequencies that can be given throughout the week, and it'll be continued for about 18 weeks, which comes out to about four months, for a total of six months. And I just want to highlight here the range of total doses, and that this is doses, not number of pills that patients are burdened to take every single day, or at least two times a week at the best. So that can be to as much as 182 doses for a complete treatment of six months, or 62 doses. That's a lot of times that you have to take pills in a week or in many, many months. And we know that right now, our studies show that with the greater amount of time that patients are treated, and with more frequency out of the week, it's more efficacious. And again, this is not just for the patients themselves. We also have a lot of people who are involved in giving the medications and making sure that everything is okay, not having any adverse reactions. The laboratory studies are still within normal ranges. So why do we care? Why should we work towards a shorter regimen? And that seems pretty self-explanatory to a lot of us. Well, if I haven't convinced you enough that it's burdensome to have affected patients themselves take all of these medications for such a period of time, let's look at the rest of the infrastructure that help with TB treatment. That's the diagnosis component. Continuing DOT to eradicate the disease, the length of times that take to sufficiently prevent spread in communities who are more vulnerable and living in congregate settings. And then also the national and global efforts that are already there and have to be sustained to complete a high quality of TB services. And I borrowed this kind of chart from Dr. Lonorth and colleagues in his kind of talk on four dimensions of tuberculosis elimination in low incidence countries, but I would argue that it is still in effect in the global setting. And just to kind of give us context, also in Hawaii here in 2021, the rate of TB is one of the highest in the United States. It's only second to Alaska. And it's actually higher than what we see in New York City. So in Hawaii, it's 7.4 cases per 100,000. In New York City, it's about 6.1 cases per 100,000. So more here, actually. Something that I was just recently learned about. So I'm sure many of you now have learned about this landmark trial that came out in 2021, study 31 with Dr. Gromen and colleagues. It's a multi-center randomized controlled trial, phase three, non-inferior trial. And with a total of 2,343 patients with culture negative TB. This included people who are 12 years old and above and also 40 kilograms and above. It was done in 34 different clinical sites in 13 countries and included 194 people with co-infection of HIV. So the trial had three different arms, a control with six months standard therapy and two treatment arms. One with four months of rifampentin, isoniazid, pirazidamide, and ethambutol. And another arm with four months of moxifloxacin instead of ethambutol, rifampentin, ethambutol, isoniazid, and pirazidamide. So all of these have, the treatment arms are given with higher doses of rifampentin of 1,200 milligrams each. And they looked at a primary endpoint of survival free of tuberculosis at 12 months after randomization and again, a secondary endpoint at 18 months. So this is kind of what it would look like if we take a, compare it to our standard of treatment right now. Initiation phase would have four drugs, seven days a week for eight weeks with moxifloxacin being substituted for ethambutol and in the other arm, just having rifampentin is substituted as rifampin. And then the continuation phase is nine weeks, which is a total of about four months with three drugs, rifampentin, isoniazid, and moxifloxacin compared to just the two drug regimen. And this comes to about total doses of 119. Again, to remind you that the six month regimen of taking drugs every single day is, of the week is 182 doses. So what did they see? At 12 months after randomizations, they assess those with confirmed TB, not resistant to isoniazid or rifampin or fluoroquinolones. And they did show that rifampentin moxifloxacin group was non-inferior to the control group in both microbiologically eligible and accessible populations with only 1% difference and 2% difference in unfavorable outcomes respectively. But non-inferiority was not shown in the rifampentin group. So in all the four month rifampentin moxifloxacin group was non-inferior and showed similar safety profile to current standard of care. I also wanna talk about another study that came out actually in August, 2023 of this year, looking at whether we can leverage rifamycin's bactericidal powers to eradicate TB more quickly. Now we know that rifampin is a really important part of our drug treatment. And so a lot of studies have really looked at whether we can increase the doses to decrease the time to cure. So in 2023, Dr. Jindani and colleagues conducted a non-inferiority randomized control trial, which included six countries and 672 patients, randomized them to three different arms of the control group with standard therapy, and then two treatment arms of 1,200 milligram rifampicin and the 1,800 milligrams per day of rifampicin. And though it is actually good learning for us that there was no significant dose limiting toxicities or side effects, as many people do have hepatotoxicities just in our standard of care, it did fail to meet non-inferiority criteria. So, so far we have seen some advantages, including shorter treatment time, fewer doses, decreased burden of DOT, possible shorter time to culture conversion, and that's just a signal not yet proven. So let's dive deeper into what are some potential disadvantages for this type of treatment. We're gonna talk about a hypothetical case. So Miss Scruffula is a 40-year-old woman with medical history significant for HIV. Most recently, her CD4 count was 84. She also has hypertension, well-controlled hypothyroidism, and a family history of sudden cardiac death. She presented to the emergency room after three months of intermittent non-productive cough, 14-pound unintentional weight loss, and night sweats. She's from Peru, migrated to the U.S. eight years prior, and was never been treated for TB. You obtain a sputum sample to look at acid-fast bacilli, and three subsequent samples were negative for AFB smear and negative for MTB-PCR on gene expert. Chest radiology reveals upper lobe cavitary lesions, so you decide to treat her for suspected or culture-negative TB disease. Which regimen would you choose to start? I'm not actually sure. Is this coming up? Yeah, I don't think this is coming up, but we can discuss this. So before we figure out what she is eligible for, let's talk about which patients are not eligible to start the four-month ribifantine moxifloxacin regimen. And I'll give you just 10 seconds to peruse these. Okay. So anyone with recent antimicrobacterial treatment, patient with HIV with CD4 count less than 100, patients with cavitation in chest radiography, MDR or XDR TB, culture-negative TB, history of prolonged QTC, patients who are pregnant or lactating, and patients with extra-pulmonary TB. And it turns out that a lot of people are excluded from being able to start this medication with the ribifantine N-moxifloxacin regimen. If you look at the exclusion criteria in their supplement, they really wanted to take a look at people who are susceptible, drug-susceptible, and pulmonary TB only, and with well-controlled HIV. So I think that there's a lot of room for us to grow in terms of figuring out what can be more inclusive here. So when we think about Ms. Skrupula, again, she has a lot of things that exclude her from being able to be started on this medication, being that her HIV is not controlled. She had a family history of sudden cardiac death, meaning that perhaps there is some QTC-prolonging, QTC congenital issues that she might have. She's from Peru, which means that she might have MDR or XDR TB. She's also culture-negative or susceptible, so we don't have data on her microbiological studies yet. So it could be the four months of IRPE if she's culture-negative, or we might still need more information after two months of cultures to figure out what she needs. So, you know, this is something that we encounter all the time. We just don't have all the information, and this study really shows only that only a small population would go into this. So there's yet another article that looked at a shorter regimen. There's a study that was done with Dr. Payton and colleagues looking at another treatment strategy for IFAMP-insusceptible tuberculosis. It's a phase two to three trial, multinational, randomized, open-label, adaptive, non-inferiority trial, and for those who are culture-proven TB with IFAMP-insusceptible. So before we look at the design, let's look at which patients we clinicians are able to enroll or use in this regimen in the future. And wow, look at this exclusion criteria. So this is from the supplement, and I just want to highlight a few things here. This, for patients with sputum smear, that's three plus or above, poorly controlled type two diabetes, which a lot of our patients have. Current alcohol and drug use and HIV co-infection were initially not included in this study, which I see a lot of patients with all of these comorbidities that would not benefit from this regimen. So this study originally had five arms, one control and four treatment arms with five drugs, but two of the arms ended up needing to be unaccessible due to number of patients who were lost to follow-up, et cetera. So this was an adaptable study. They looked at clinical symptoms after two months and then decided whether or not to extend it to all five drugs for three more months if missed doses or smear-positive and symptomatic after two months. If they had a relapse, they would then retreat with standard regimen as well. So at 96 weeks, they saw a 2% difference in unfavorable outcomes between the budaquiline and lenazolid group and standard treatment showing non-inferiority, which was not seen in the rifampin-lenazolid group. And there was no significant difference in grade three or grade four adverse events, which we just learned from Dr. Batrawala what that means. The budaquiline-lenazolid group already used in drug-resistant TB seems promising in shorter regimen for drug-susceptible TB. So let's summarize. We have talked about the advantages that it's possible to decrease the burden of DOT and treatment, but the disadvantages is that we have many patients who are not eligible and we don't have as much data now since these studies were done in 2021 and 2023 about recurrence and relapse rates. And then it really does exclude women, children, and in one of the studies, people about 65 years old. And we really should look at the cost that this would take with the newer drugs, budaquiline and lenazolid, the burden of needing to take frequent lab draws for lenazolid since there's a lot of bone marrow suppression that can happen. And then also just looking again at all of the people and community that's involved in treating these people, even though it's a shorter amount of time, there might be a larger pill burden. So that's really it. I want to cut it short from there so that we have some time to discuss if there's any. Thank you all. Thank you.

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