Zambia College of Physicians Internal Medicine Podcast
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Zambia College of Physicians Internal Medicine Podcast
Putting it all Together, The Treatment of Tuberculosis
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This final episode in this TB series discusses the management. Learn what's new and other clinical nuggets to build your clinical acumen. Enjoy!!!
Host: Dr CHikoloma Co - Host: Dr Chiwele
Expert: Dr Patrick Lungu
Script Writer: Dr Kabaso Mwewa
Welcome back, everyone, to yet another exciting episode of the Zambia College of Physicians podcast series. We've uh been on a journey to discuss TB with our famous Dr. Patrick Longo, our TB specialist, an immunologist, and also an infectious disease specialist. And to host this uh episode, I'm Dr. Abigail Koloma, and my colleague here is uh Dr. Chipo Chiwele. Uh, and we welcome you back again to this exciting episode. So we have been on a TB series with uh Dr. Longo discussing a number of things. We started from the symptomatology of TB, went through the diagnosis of TB, the patient presentation, and here today we are here to conclude uh the TB series by discussing the treatment of TB. So, Dr. Longo, welcome to today's episode.
SPEAKER_00Thank you so much, uh colleagues, and uh some more knowledge on TB.
SPEAKER_02Thank you very much, Dr. Longo. So, in our settings, Zambia, in particular, we see a lot of TB cases in association with uh HIV. So, let's say we have this speech and two present with the symptomatology and align with TB as we've been discussing, they have a productive core, uh constitutional symptoms, they have chest pain, they are losing weight, and we have investigated, we've done the SPUTAM, we've done the urine LAM, we've done TCT, and everything is pointing towards TB. How do we go about uh treating this patient? What is the recommended uh standard therapy?
SPEAKER_00Yeah, thank you thank you so much. So uh first of all, the mode of diagnosis points to you what type of TB that one has. So the beginning point one has to know are you dealing with pulmonary TB? That's the number one. The second one is what sort of TB are you dealing with? Is this drug-susceptible TB? Is it drug-resistant TB? These aspects need to be considered. Is this individual co-infected with HIV? Are they new on ART or are they treatment experienced? Then the other aspects of nutritional status. Going back to the site of TB infection, it is very important to determine the site of infection. For pulmonary TB and drug-susceptible TB, the duration of treatment is at least six months. So the site of disease determines the duration of treatment for all forms of TB. For extra-pulmonary T B that involves the meninges or TB meningitis or extraarticular which is TB spine or the joints, this sort of TB will be treated for at least 12 months. So site of disease is very important. The second issue is are they new on ART or are they co-infected with HIV? These parameters need to be determined, and it informs how you're going to manage the patient. Of course, it does not determine what sort of anti-TB you are going to put them on. But again, let me go back to the resistance type. So we have determined this is drug susceptible TB, then the choice of drugs becomes your first-line drugs, which is a combination of four drugs, uh Rifampicine, isoniazo, defambito, and PZ. And if it is drug resistant, then now you move to the second line drugs.
SPEAKER_02And uh just on that one, I know we'll come back to discussing the drug resistance uh in uh detail, but um let's say this particular one, we have established that they have pulmonary TB and it's drug susceptible. How do we then go about treating and why do we choose a certain duration for the regimen?
SPEAKER_00Yeah, so if it's pulmonary TB, from studies that have been done, it's been shown that a six-month regimen does work. Now, actually, there's even a four-month regimen which has been recommended. Yeah, which has been recommended in both children as well as adults. So the short the four months is shorter, and of course, the combination of drugs is different. In our setting, we're still using the six-month regimen for the simple reason being that it's there's less pube burden to the patient. When you use a four-month regimen because of the mox foxicine, the there's no fixed dose combination at present in the country. So until then um we're still using the six-month regimen. In terms of efficacy, they are comparable.
SPEAKER_03Okay, and toxicity profile between the four-month regimen and the six-month regimen?
SPEAKER_00In terms of toxicity, also they are comparable. Okay. Yeah.
SPEAKER_02Um, and how does the duration differ when we're treating maybe like TBM, TB pericarditis, um, maybe TB spine? How why is the duration different for these particular ones?
SPEAKER_00Yeah, a very good question. So the this question will benefit not only clinicians, but also benefit the public who are listening to to this conversation. To begin with, is that TB is a slow-growing bacilli. And then the other issue is that the response to treatment depends on the blood supply. So you find that the joints, the spine, the brain, of course, the brain is well vascularized, but the brain has a barrier, the what we call the blood brain barrier. So you find that the amount of drugs that penetrate the brain is a smaller amount compared to how the lung, to the amount that penetrates the lung. So as a result of that, it's been noted that with you with extended duration of treatment, that's when now you get better outcomes. So with TB meningitis, TB spine, uh TB arthritis, you need to treat for not less than 12 months. And of course, both pulmonary and extrapalmonary TB have a common intensive phase, which is two months. And then while the difference only comes with the continuation phase. So the continuation phase for pulmonary is four months, the continuation phase for extrapalmonary TB, such as TB meningitis, TB spine, is ten months, making the total duration to be 12 months, essentially one year.
SPEAKER_02Um then I'm glad you mentioned uh the aspect of uh the bacilli. So I understand there is a component of it that can be intracellular and extracellular. So looking at the drugs, the the four drugs that we have mentioned so far, um, how do the drugs work? Are they bacteriostatic or are they bacteriocytable? What are the properties of these drugs that help us in treating the TB?
SPEAKER_00Yeah, the four drugs that we commonly use to treat TB have different properties, and hence that combination. Um rifampicine, your PZ are bacteriocyto drugs. So then they kill the bacteria. A thambitus slows down the duplication of the mycobacterium, so it's actually we see we call that bacteriostatic. So that's the difference between these four drugs.
SPEAKER_03Okay. I have a question also in line with treatment. When do we consider the use of steroids in TB management? TBT?
SPEAKER_00Yeah, so steroids we we consider them as adjuvant therapy. And uh there are categories of patients that we we include steroids uh in. For patients with pulmonary TB, there's no need uh for adding steroids as adjuvant therapy. Of course, nowadays there are some consideration of immune modulation, probably the aspects of preventing PTOD. Who knows? Today we may say pulmonary TB does not need steroids, but in the future they may need. So for I think for our clinicians, nurses who are listening to this, for now pulmonary TB should not have steroids as adjuvant therapy. But for TB pericarditis, it's been shown that um uh the addition of steroids does prevent constrictive pericarditis. Of course, there are some studies that are starting to show that uh uh they should we should we should the benefits there the outcomes are not different.
SPEAKER_01True.
SPEAKER_00But I think if we go back to the reasons why we are adding steroids, um it's very obvious that as one responds to anti TB, there's some form of fibrosis. It's an obvious issue. We don't know why that those studies showed similar results, it's a possibility. If we are maybe to dig deeper, we may find that the the the reasons why they did not show any any differences with those that had steroids and those that had. But if we go back to the the way TB heals, it heals with fibrosis. And if you look at the implications of constrictive pericarditis, it's got far-reaching consequences. So for now, I think um uh at least from the patients that have treated and seen constrictive pericarditis occur, I would still utilize constrict, I'll still use uh steroids in in uh TB pericarditis.
SPEAKER_02And were the results comparable both in the HIV positive and HIV negative concerning the steroid use?
SPEAKER_00Yeah, so I think the the studies, I may not, uh it's been a long time since I looked at the study, so uh most than likely they did it in a population that included HIV. HIV. So I think these are things that we need to look at. So we need to probably maybe do these studies in our setting and see how it applies. Uh but I think from the basic science point of view, it makes sense to add quite cost.
SPEAKER_03Yes, it does, and also just anecdotally, like what we get to see on the ground. Um though they did raise a concern about um the people living with HIV being at risk of um having malignancies when they were managed with uh steroids.
SPEAKER_00With the steroids, the beauty is that it's for just a shorter period. True. Up to at least 60 days max, and after that you start to win off. So it's not throughout the entire treatment, but only for a specific period in the treatment period. But then also TB meningitis. Um in the case of TB meningitis, steroids are warranted because without them the calcifications are far-reaching uh implications. So one would have lifelong consequences of or the sequeles of TB meningitis, convulsions, probably mean stroke and and and that aspect. So without without steroids, the neurological deficit that these patients suffer from is quite severe. So hence the steroids.
SPEAKER_03Thank you, Dr. Lungo, for their insightful information that you've just shared. So, what is the rationale behind the duration of the treatment and also the combination of the drugs? Why do we use the four combination? Um, and then later on we just continue with just true drugs.
SPEAKER_00Yeah, so I think as earlier said, that among the drugs that we use for TB treatment, we have bacterocyta drugs and bacterostatic. This approach is informed by the properties of the mycobacterium uh that we are targeting um uh in in in as we treat TB. One of the properties of mycobacterium is that it's a slow-growing basli. So any bacteria becomes susceptible to antibiotics as it is replicating. A TB bass line replicates or divides into two within 18 to 24 hours. So it multiplies at a very slow rate once in a day. Other bacteria like staff probably every minute, every hour they are replicating. And with that difference, so the mycobacterium is only susceptible to being destroyed once in a day. So that's one. So the ask the fact the fact that mycobacterium is a slow growing bacteria, that's one reason. Then number two, it's got a high tendency to go into latency. So latency is where a bacteria is not dividing at all. And in the latency phase, it is less susceptible to phago to be phagocytose or to be destroyed by the the immune system. By the immune system as well as by by the antibiotics. The third aspects, the lipid bilayer. Difficult to penetrate. The mycolic acid really protects the mycobacteria. And no any other bacteria has such properties. So to break through all these protective mechanisms that the the mycobacterium has put for itself, you need a combination of different drugs. Number one, you want to slow its growth using your ethambitol. Number two, you want to destroy it using your bacteriocyteal drugs, your rifampicine isoniazate, as well as parasinamide. There's one property that isoniazate has, which is very critical. It kills the fast multiplying baslides. So while we're saying that mycobacterium is a slow-growing basite, some of them replicate much faster, and that's what isoniazate targets. Okay. And that's why you find that uh patients who have isonoidase resistance tend to have resistance to other drugs much quicker. And that's why it's a resistance of concern. I thought to bring out because if they are the first multiplying basili are allowed to multiply, they will attain adaptation. And that adaptation is what brings about resistance. So a person who has a sonized resistance mono quickly converts to MDR and probably resistant to the rest of the first-line drugs, the PZ, as well as um uh a thambit as well.
SPEAKER_03Okay, and for patients who are currently on treatment, how do we monitor the response?
SPEAKER_00Yeah, that's a very important um question. Again, not only for us clinicians as well as uh nurses, but also important to the patients. So TB is not one disease where you just start treatment and you assume everything is going to be okay. Uh, one can attain resistance on the while on treatment, and that is that treatment can fail. And for that reason, it's important to monitor how they are responding to treatment. And the other reason is that TB has public health implications. One can be spreading the disease. So, one we want to avoid mortality in this individual and achieve the best results, but at the same time, we don't want the disease to spread. So, for those reasons, monitoring is very important. Now, coming back to your question, how do you monitor? So, number one, we monitor using clinical parameters. Are the symptoms uh resolving? Is an individual stopping to cough? Are the chest pains going away? Are they stopping to have nights weights? Is the fever going away? Those are the first uh parameters that we monitor for. The other parameters is how well are they, are there any radiological changes? Is there an improvement in the chest x-ray? But to our clinicians listening here, you're not going to use a chest x-ray, do the chest x-ray weekly. There's a period and weekly changes. Chest radiological changes do occur. So the changes will not shift within two weeks, at least six weeks apart. So, x-ray, if you're going to use it, it has to be used at least six weeks apart. There are some changes on X-ray that will not go away. Cavitations will never go away.
SPEAKER_01True.
SPEAKER_00Some of the fibrotic changes, those are permanent. Of course, your interstitial infiltrates, your consolidation, those will resolve. Then we also need to monitor for microbiological aspects. And we use microscopy for monitoring. Even if it's an old test, it's still useful, even today, in the presence of the modern technology. So we use microscopy, the AFB, to see if one is clearing, and well as culture as well. So this has to be done at a space of at least one month.
SPEAKER_01Okay.
SPEAKER_00Of course, you could also use parameters like CRP, SR where resources do permit.
SPEAKER_03Okay. So just in line with that, what is your comment on patients who have a persistently high ESR despite being on TB treatment? Say you started TB treatment one month into, and the patient still has a high ESR, but the symptoms tend to fluctuate. Should we be concerned about that patient possibly developing a resistant type of TB?
SPEAKER_00I would be very concerned because by month one, we should start to see the ESR going down. Even by week two, ESR starts to go down. So if someone has is having fluctuating in symptoms, certain symptoms remaining persistent, and ESR being elevated, I would start to look at is the patient taking the therapy? That's number one. Two, is this patient resistant to the medication? Are we underdosing this individual? Is there a drug-to-drug interaction with possibly other drugs that the patient is taking? Of course, ATT is the one that mostly reduces the therapeutical effects of other drugs, but there are other drugs that can compromise the therapeutic effects. So in a nutshell, I'll be deeply concerned.
SPEAKER_02Um then as we are talking about uh treatment in our population, we are also seeing a lot of uh HIV cases. So if someone comes for screening, they are sick. Obviously, we do test them for HIV as well. So we find that they're HIV positive and they also have TB. How do we start the treatment? Do we start everything at once or yeah?
SPEAKER_00This this question actually has been has been a question of of great interest uh because of the core uh occurrence of TB and HIV and the implications on on therapy. So number one, the rule of thumb for palm LT, it's good to studies have shown that um starting ART early gives better outcome. Um I saw someone post a study yesterday on LinkedIn that one study has shown that there are better outcomes starting ATT as well as ARRT on the same time. I'm yet to review that paper. But certainly I think the rule of thumb for pulmonary TB starting ART early, probably closer to the point of starting ATT as better outcome. But there are certain Populations within the HIV group where you may delay therapy. So individuals with CD4 below 50 has been shown from the stride trial and other studies done in Brazil that starting ARTL within two weeks period of starting ATT had better outcome in terms of mortality. And the inverse was what was also observed. If you started ARTL in those who had CD4 above 100, they had poor outcome. And the reason being is that an individual who has CD4 above 100 at a higher risk of TBIS. And you know iris can be highly fatal. So the rule for TB meningitis, it's an exceptional rule that you are delaying ART at least four to eight weeks for those with CD4 above 100 as better outcomes.
SPEAKER_03Okay, thank you for that. So coming to special populations, is our approach the TB treatment the same in pregnant women?
SPEAKER_00Yeah, that's a population of great concern. So primarily the approach to treatment is more or less the same for drug susceptible to be. And remember when you're treating a pregnant um woman, you you are not only concerned with the mother, but you're also concerned with the unborn child. You don't want to cause harm to the unborn child. So there are certain you need to be very um attentive and also ensure a lot of safety assessment when you're treating a pregnant woman, including drug-susceptible TB. Of course, most of the first-line TB drugs have not been associated with telatogenicity. Of course, there are some questions around PZAD being having some telatogenic effect. But there's one issue to be really concerned when you're treating a pregnant woman, the risk of drug-induced hepatitis. So pregnant women are highly susceptible to drug-induced, etyt-induced drug hepatitis. So we need to ensure that we remove the modifiable risk factors, ensure they have a good HP. If they have uh HB within the trans uh transfusion window, we transfuse and ensure they are on nematonics so that they are producing the red blood cells. And if there's any element of undernutrition, quickly or rapidly correct the undernutrition because these are two modifiable risk factors for dealing.
SPEAKER_03Okay, so getting to that about um safety of uh TB treatment, what's our approach to um the patient has been on TB treatment, next thing we notice the patient has become jaundice, they have elevated uh liver enzymes. What is our approach to such a patient?
SPEAKER_00Yeah, so from what you've just described, that's a drug-induced liver injury. So most likely the cause of the jaundice is the anti-TB medicine. But of course, this is that assumption needs to be proven. True. So you have to exclude other possible causes of jaundice. Yes. Is this individual co-infected with hepatitis? Are they are they taking other hepatotoxic drugs, especially in our setting? People are uh have a tendency to take her medication, which which which which really destroy the liver. Um, or every time I have a TB patient, I always caution them about concomitant use of herbal medication. So I think let's assume we've excluded other causes. Um this person does not have um viral hepatitis, no use of coccomitant um herbal medication. So we can narrow down that the cause is the anti-TB medicine. So among the TB medicines, the four drugs, focusing much more on drug-susceptible TB, PZ is the most hepatotoxic drug. But of course, your refampicin isinel are also big culprits. And for John Dis, actually, refampicin is is implicated. Refampicin alone can actually cause uh high bilobinemia in an individual. So one of the things then happens is that you need to assess the patient. Is there an NCNS effect, which we call encephalopathy? Uh do they have a fulminant liver injury? Are they bleeding spontaneously? In the absence of those, one may not be in the rush to hold off the ATT. And then also how you handle Dilli depends on one's experience. Of course, there are standard protocols, and I think for the purpose of this, I'll share the standard protocols. So, number one is you have to determine whether this is apartic, is it a mixed picture? Is it as a result of choliostasis leading to one developing joindice? And the approach is different. So, how you you look at it is that you can actually calculate what we call the error factor. And the error factor is of course calculated by your LT divided by the upper limit of the LT.
SPEAKER_02That figure you get divided by the ALP divided by the upper image of the L C.
SPEAKER_00Exactly. Yeah, so when you have the ratio or the fraction at least one to two, what is it?
SPEAKER_02That's cholesterol when it's less than two.
SPEAKER_00Exactly. Uh-huh. And three to five.
SPEAKER_02That's a mix. That's a mix. Yes. And then above five, you're dealing with.
SPEAKER_00Exactly. So you you you get to know that. So then now this point, what that means is that the assumptions are that when it's a patocellular, there is an effect of the drugs causing a direct damage to the hepartocytes. So in that regard, it's not negotiable. Hold off the ATT. Okay, because any further administration will cause more damage to the hepathocytes. And we don't know the end if you continue, most likely, um pushing the patient into fulminant liver failure. But then if it's choleostatic, there's a possibility that this is an effect of iris. Remember also the liver has lymph nodes. Yeah. So at times what we have done in those cases, this is a bedside judgment. In the absence of encephalopathy, permanent liver injury, one could continue the ATT and continue monitoring the liver enzymes. If there's a continued upward trend, you withdraw. Or another approach is to withdraw the most hypertoxic drug, which is your PZ. See how the patient is faring. If you reach the point that with the ATT, there's additional risk for further injury, withdraw the treatment. But another what you also need to do is as part of your assessment, what is it that has predisposed this individual to drug-induced liver injury? Does this patient have anemia? Does this patient have undernutrition? Most of our TB patients are undernourished. And the linkage to the undernutrition is the hyperobuminemia. So when they have hyperobuminemia, meaning most of the drug is not binding to the albumin. It's free and it goes to bind to other tissues and the liver being prone, being one of those prone or um organs. So it is for that reason, as part of the wake up of this patient, you correct the epo albumemia. You could infuse the albumin. You could, if there is anemia, you correct it. So these two will help the patient recover from the drug-induced liver injury. The rule that we should not violate is the introduction of pyrazenamide. Pyrazenamide, once a patient develops deally, it should never reintroduce. Studies have shown that when you reintroduce a larger proportion of individuals they developed dealy. So it reoccurred in the reintroduction. So in any of the approaches, PZ must be eliminated totally.
SPEAKER_02By the way, when we're talking about the risk for dealing, um, is it a risk if someone had a prior history of dealing? Maybe they were treated for TB in the past and they had dealing with it. Does that also affect exactly? Okay, and uh does that mean also in the future they can't take any parasinamide at all?
SPEAKER_00Yes, so parazanamide is totally out. Okay, it should never be reintroduced.
SPEAKER_03So um with such patients, so the three drug combinations would still be effective?
SPEAKER_00It would still be effective. Okay, but what you could also other people start to think, which is still allowable, is to add level floxacine, another bactericidal drug. Okay, but remember level is also apodotoxic. But not as apodotoxic as the other as PZ. So you could you could uh manage the patient that way. Okay, but more importantly to the clinical team, and we should never forget addressing the nutritional aspect because these are the nutrition as well as undernutrition as well as anemia, they contribute greatly to the to the risk for for Dini. So these must be addressed.
SPEAKER_02Okay. And maybe just a different thought from Dilly. So let's say someone already has underlying um chronic liver disease, they already have this uh hepatic failure going on, and we need to start them on ATT. Is there a way we adjust the drugs? Uh same applies to like people with already rhinophilia, how do we adjust the drugs?
SPEAKER_00Yeah, so in patients who already have um liver injury, let's say patients with hepatocellular carcinoma, um, patients with hepatitis B, um of course not all hepatitis B have a dysfunctional liver, but does this give an example of a person with a hepatocellular carcinoma certain is given, they'll have a dysfunctional liver. So you may introduce all the 4FTC, probably at a much lower dose. No, okay. Because remember a good your pharmacine isoniazid will be cleared through excreted through your through the liver. Of course, PZ literature is pointing to that the it's renally excreted, by the way. Double check that literature. Yeah, so you could start at a much lower dose and stuff and and increase depending on how the patient adapts. Okay. Yeah, but any sign that there's a worsening liver functions, you withdraw your pizza. Okay. And and give your bearest minimum dose. It would be nice to do drug levels in a patient like this one. Where where resources allow, it would be nice to do drug levels. And just keep the patient within the therapeutical window and not above and not below.
SPEAKER_02Okay. I may have moved a little quickly from the dealing. So when we are reintroducing the drugs, do we wait for the liver enzymes to normalize completely? Or maybe like they can be slightly above the upper limit of normal before you can reintroduce?
SPEAKER_00So I think number one um enzyme you're looking at paying attention to is your AOT. Yeah. So once your AOT goes below 100, or at least at least two times the upper limit, you could reintroduce it.
SPEAKER_03Okay.
SPEAKER_00Anything five times above the upper limit? No. But at least two to three you could reintroduce it. Then for bililubin as well, it's the hundred threshold. Okay. So you wait until your bililubin levels drop to higher below a hundred before you reintroduce.
SPEAKER_03Okay.
SPEAKER_02So we're about to give a comment on the drug adjustments in uh renophania CKD.
SPEAKER_00Yeah, so in CKD, you have to calculate the creatine clearance all the time. And many times actually, this is what we we we all need to shift. We we mainly adjust for a thumb better. And our adjustments usually we say three times per week. Once a day, once, three times a day. Once a week. So you're giving the drug once in a day, but given on alternate days. I think that's that's uh a good and okay approach, and we've seen it work. But there's another drug we need to adjust. Parasenamite. Parazenamite. Yes. And even at 2TH, we are guilty of that. We are guilty. We hardly pay, we had to adjust parasenamides. So in the similar fashion that we adjust for a thambiter, we should also adjust parasenamide.
SPEAKER_03So now just a practical um question. So we have this patient, end-stage kidney disease, undergoes dialysis. When do we time when to give the thambiton?
SPEAKER_00Very, very critical question. So remember your dialysis is going to wipe out all your drugs, including your repampinisoniaz, and of course your thambiton PZ. So these drugs must be given post-dialysis.
SPEAKER_01Okay.
SPEAKER_00Not before the dialysis. So if a patient is going for dialysis at 10 hours or 10 a.m., you give post-dialysis. Of course, you know we always want to give the ATT before meals, 30 minutes before meals for good absorption. So in this regard, you give after the dialysis. Then you could ask the patient, and you know the complexity.
SPEAKER_01So patients with dialysis want to eat and take their medication and then go for dialysis.
SPEAKER_00Exactly. So the issue is probably maybe they can get take liquid diet. Yeah. Within the period at least at least uh three to two hours, two hours, two to three hours before the time that they are indicated to take the medication. So that they do not have low sugar, at the same time they do not take the ATT with a full stomach. Okay. So those are things to look into. Okay.
SPEAKER_03And then we talked about drug, um, drug-drug interactions for people living with HIV, especially those on TLD.
SPEAKER_00Yeah.
SPEAKER_03Um, what's the approach to the dosing?
SPEAKER_00Yeah, so the approach to dosing, not only with with um with with um TOD, baby let me start this way. The what the effect of ATT on TOD is that it reduces the blood levels of um of the of the gravel because of the P450 cytochrome A3, 3A4 uh inducer. So the drug levels will reduce, and what studies have pointed out too is that these individuals ended up developing drug resistance to the HIV or either treatment failure. So their rationale is to double up the dose of the DTG. So we add another tablet to be taken in the evening. So they will take the TLD in the morning and the T and the DTG separate in the evening.
SPEAKER_01Okay.
SPEAKER_00And then for other PIs, Lopinova and the like, it's the same issue. Okay. But actually the beauty with that is that we could substitute rifar pecine with with rifabutin.
SPEAKER_03Okay.
SPEAKER_00So if you have patients who have uh who are on a PI-boosted regimen, um you you still prioritize both, but switch remove riformpecine from the regimen and replace it with rifabutin instead of doubling the dose of of of the PIs. Yeah.
SPEAKER_03Another drug interaction, something we commonly encounter, is those who need anticoagulation.
SPEAKER_00Yeah. Very important question, and I think to some extent we have been seeing TB patients with DVT. Yes. TB patients with pulmonary embolism. And that also just creates um uh a dilemma in the treatment. How do you manage? So I think I and I think this is also an area for further exploration. I think we should develop interest in this topic. I would like to invite academicians to research further on approaches to treating uh TB patients with DBT. And here are the reasons, and what we've seen is that the door works are um are reduced greatly by at least 60 to 70 percent by the effects of rifumpacine. Of course, it's also true that rifampicine affects the the therapeutic levels of wafarin. But the beauty, the difference between the doax as well as wafarin is that with wafarin, we have we're able to monitor the anticoagulation exactly. And we have no opportunity and means of monitoring the anticoagulant coagulant effects of doax. So in that regard, so you use wafarin as your anticoagulant.
SPEAKER_02Okay. Uh then earlier you had mentioned in passing that um there's uh what is known as monodrug resistance. I understand there's also polydrug, not drug, and also we have uh uh XDR as well. So um can you just elaborate further on the definitions for these various terms?
SPEAKER_00Yeah, so mono simply means single, right? Or one. And many times when we're talking about mono, we are referring to isoniazid, mono resistance because of isoniazid forms part of the pillar for treating TB. How do you concern about PZ resistance, etherbital resistance, but we are mainly concerned with this with uh isoniacid because of the role it plays in in treatment. Then we have multidrug resistant TB, MDR in short, which is resistance to isoniazed as well as um um refampisine. Then now your pre-HDR is your MDR with resistance to the fluoroquinolone. Okay, then your HDR is resistance to at least two of the first of the second line drugs which are in group A. So it could be your renezolid together with pedacoline or your Foloquinolone together with betaquiline, then that forms XDR. Then you have another form, extremely drug resistant, to be your XXDR, which is now you have additional resistance to the second-line drugs, including those that are in group B, your cyclosarine, chlopazamine, maybe resistant together with the ones that are in group group A. Yeah. So essentially those are the different classes of um of drug-resistant T B.
SPEAKER_02We see a lot of cases for MDR and TB now thinking. How do we go about treating these patients?
SPEAKER_00Yeah, so there are multiple options for treating drug resistant TB. So number one, also of course with um with the drug resistant TB, you have to determine whether this individual which category they fall in. Is this person MDR or are they falling in the pre-XDR? Are they falling in the XDR? So the choice of drugs are informed by those categories. So let's take this patient and then also age matters. And then also other commodities conditions do matter. If they have a cardiovascular disease, for example, you're not going to go for your bedacoline. If they are pregnant, you're not going to go for your B-PAM regimen. So to a very large extent, most of the patients will fall within the B-PAM regimen, which is your bedacoline, plutonamanid, benzoid, as well as mox floxasin, a combination of four drugs. So that's the largest population. But there are newer regimens that have been recommended by the WHO for pregnant women. At least now we have a much shorter regimen for pregnant women. Otherwise, they would go only a longer regimen, which is 18 months. So those are the things to consider. Pregnancy, age, of course, HIV is not considered, but is there a presence of um viral hepatitis? Is there a presence of um uh uh cardiovascular disease? So those with pre-existing cardiovascular disease, um bedacklin is contraindicated because of the effects of the QT prolongation.
SPEAKER_03Just a brief um just a recap and to remind us because we have different audiences here. What are the uh mutations, main mutations? Just going back to because we're talking about resistance. So what are the genes that are responsible for the mutations in the first line TB drugs?
SPEAKER_00Yeah, so your first line TB drugs, um the mutations occurs in the RPOB gene. So the presence of RPOB gene indicates that this individual has refambacine resistance. Then now you have um to isonized, you have your CAT G and INHA. So your and this tells us whether this is high resistance or low level resistance. Remember your the isonazid comes in as a pro drug, so it has to be converted to a an active metabolite. So your INHA is involved in the early phases of of of um the activation then the activation, and then you have your catalyst enzyme which is involved for the conversion of the INHA into an active metabolite. Okay catalyst oxidase. So your cat G, if there's CAT G presence, that means that there's mutation around around your catalyst oxidase enzyme, and meaning that there will be no conversion from the pro drug to the acting metabolite. So your CAT G is therefore responsible for a high-level resistance. So essentially the is knocked out when there's CAT G mutation. With INHA, you could double up the dose and have a breakthrough uh MIC, and the drug can still be effective with the doubling of the dose, but not in the case for CATG. So these are the three mutations of keen interest.
SPEAKER_03So with INHA, if I remember correctly, it's also the mutation for perizenamide. Yeah. So if it's there, it means perizamide is also out.
SPEAKER_00Yeah, yeah. Okay. But the thing about parasitomide mutation is that we the testing modalities are unreliable. Both culture as well as molecular, it's po is impossible to reproduce. So you can get the same specimen. One test tells you it's resistance. On the same specimen, you repeat the test, it tells you uh it's not. So we had we we ignore PZ resistance. But there are times when even when PZ is resistant, we'll still use it, especially in MDR. And here's the reason. So it potentiates the effects of floorquinalence. So that for that reason we'll give it. And recently we had the patient who we use that approach. Patient had, I think, documented resistance to PZAID, some susceptibility to flourquinolence, and we used PZ still in the regimen to potentiate the effects of floquinolence. And that patient within one to two months were able to get a culture negative. Okay. So it's you can use you can still use PZAD in those circumstances, even if there are some indications or pointers to resistance.
SPEAKER_02How do we go about choosing which patients we give the B power and which ones we give the B palm?
SPEAKER_00Yeah, so the the decision is very easy actually. So for once one of the things is that once you determine this patient has refampsin resistance or MDR, you need to bring in the liflex test, which is your XDR uh uh cartridge, and um that would tell us about resistance to two drugs, isoniacate as well as um foloquinolon. So if they have foloquinolone resistance established on the XTR uh method or cartridge, then you knock out the foloquinolons. There's no point in giving a drug that an individual is resistant to. So then now you there will only be on two drugs. That's why that regimen is BPAO BPAM M. Yeah. In terms of therapeutic, of course, they are comparable. It's best to add mocks, but when it's resistant, no need to add it.
SPEAKER_02Um, it's been such an exciting journey going through the TV series with you, and I'm sure if you are starting to listen to us on this very episode, you may be wondering about the terminologies we've been using. So you do want to go back to the previous episodes to listen through everything and understand uh how we're making the diagnosis of um MDR TV, uh XDR TB. Uh, we have uh episodes where we were discussing uh all these issues and talked around uh these things. So maybe just to conclude our TB series with you, uh Dr. Longo, and message the public. I know how much you love the public and how much you helped our nation when you are the T the national TB coordinator in our country. So maybe just a message the public on uh TB.
SPEAKER_00Yeah, thanks. And uh so the message to the public is that TB is a curable disease, and at the same time, TB is preventable. What they should always do whenever they have symptoms suggestive of TB, a cough that is incurable by ordinary antibiotics, they should seek help and seek to be diagnosed for TB. If we have directives closer to us who we think may have symptoms of TB, we speak to them and we encourage them to seek medical care. So early TB diagnosis saves lives. And to the healthcare workers listening to this, the message uh to them is that whenever we have a TB patient, let's take a system approach. So beyond that TB patient, there are multitudes of TB patients. Let's initiate contact tracing and also add a sound nutritional support to that patient for those co-infected with um HIV-ART as early as possible. And we monitor these patients as close as possible. TB is a curable disease. So with that, I thank you for the opportunity to share what I know about TB and wishing everyone the very best.
SPEAKER_02Thank you very much Dr. Lung from Asian boss and Dr. Choloma and uh Dr. Chuedong. Thank you very much for listening until next time. Bye.