Speaker 1 00:05 Lange, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. Narrator - Dr. Abel 00:11 This podcast is produced by pharmacy faculty to supplement study material and provide relevant drug and professional topics. Speaker 1 00:19 We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. Narrator - Dr. Abel 00:27 This is an educational production copyright Rosalind Franklin University of Medicine and Science. Speaker 1 00:32 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - Dr. Abel 00:47 And now on to the show. Dr. Sean Kane 00:51 Welcome to Episode 18 of HelixTalk. I'm your co host, Dr. Kane. Unknown Speaker 00:55 I'm Dr. Schuman. Unknown Speaker 00:56 I am Dr. couture, and I'm Dr. Patel, Dr. Sean Kane 00:58 and today we actually have Dr. Cottrell is a special guest because we're talking about some of the most popular agents for HIV. So before we dive into the agents, I think it's important to first understand, you know, what are some of the drug targets as it relates to how HIV infects within the body and how it replicates and kind of goes about its business. So Dr. Cottrell, can you kind of give us some concept of some of the popular drug targets as it relates to how HIV works and things like that. Speaker 2 01:26 Sure, overall, there are a few main targets. So HIV is actually a retrovirus, so it comes as RNA needs to be converted to DNA. In order to do that, you need reverse transcriptase. And so reverse transcriptase is one of the big targets. So we have our nucleoside reverse transcriptase inhibitors. These basically act as false nucleosides or nucleotides and insert into the backbone for the RNA to be transferred into DNA. Dr. Sean Kane 01:54 So what you're saying then is that when reverse transcriptase tries to do its job, we give drugs that make it so when it tries to make this DNA molecule that our human cells use the it kind of gets in the way and makes it not be able to replicate its own RNA into human oriented DNA Exactly. Speaker 2 02:10 So there's early strand termination, okay, then there's non nucleoside reverse transcriptase inhibitors that actually inhibit the reverse transcriptase. So they're interfering with that actually at that enzyme level, Dr. Sean Kane 02:24 that kind of makes sense in that we're targeting this thing that is not normal in humans. So as opposed to messing with human DNA or preventing some component of our immune system, we're targeting this thing that isn't normal, reverse transcriptase that HIV happens to come along and bring with it. Speaker 3 02:41 Exactly, okay. And then are there any mechanisms that can come into place once the viral DNA has been produced? Speaker 2 02:47 Yeah, so there are a few others. So there are integrase inhibitors, which is the newest class of antiretrovirals, and they actually block that viral DNA from being integrated into the host DNA. And then further down the line there are protease inhibitors. And so protease is an enzyme that cleaves immature virion particles, and by that cleaving of those, it leads to a mature virion that's able to go out and infect cells. So protease inhibitors block that specific enzyme. So to Dr. Sean Kane 03:18 kind of review, if we were to open up the envelope of an HIV molecule or an HIV virus, what we'd find is RNA, would find integrase, would find reverse transcriptase, and would find protease, and that's kind of all it comes with. Then, right? Speaker 2 03:33 Exactly, yeah. So it comes with all those enzymes and just the host, RNA. Dr. Sean Kane 03:38 And as I remember from pharmacy school, we have a lot of kind of acronyms to describe some of these drug classes, like NNRTIs and NRTIs. Is that still pretty common in how these agents are described? Speaker 2 03:49 Yeah, so we use those interchangeably. It's very rare that somebody says nucleoside reverse transcriptase inhibitor. So we always say NRTI non nucleoside would be NNRTI protease inhibitor will usually say that out, and then integrase inhibitor is also something we'll typically say, but you will also see insti, or insti for an integrase inhibitor. Dr. Sean Kane 04:11 So it seems nice then that we have a lot of different drug targets that we can use, and as we'll talk about, all of the newer, popular agents that we're using clinically take advantage of more than one mechanism. That's kind of the hallmark of our HIV therapy thing, right? Exactly. Speaker 2 04:26 So we find that if we use just one agent that targets one drug, Target, HIV is a virus that replicates very quickly, and resistance also occurs when you're replicating that quickly. And so it's important to target multiple points in viral replication in order to stop the virus from replicating. So we always use at least three drugs from at least two different drug classes. Dr. Sean Kane 04:50 So then, as I remember from pharmacy school, one of the biggest challenges with HIV therapy is the idea of drug interaction. I know that sometimes we actually use drug interaction. To our advantage, calling it something like a booster regimen, where you use an agent to prolong the half life of the other HIV agents. I would assume that that is probably a pretty big role of a pharmacist in a patient who's taking an HIV antiretroviral therapy, the idea of the drug interactions and things like that. Speaker 2 05:17 Yeah, absolutely. Our HIV patients are living longer and longer, which means that they're on more and more drugs, just as a regular aging population. So statins are a big area. Psych agents are another major player. So it's important that we keep those in mind going forward, specifically with the protease inhibitors and NRTIs and then some, with the integrase inhibitors. We see a lot of those. Speaker 3 05:40 So then when we talk about all the complexities of multiple medications and interactions, I'm sure then that drug adherence plays a pretty important role in terms of not just with the other medications, especially when it comes down to the antiretrovirals. Speaker 2 05:52 Yeah, absolutely. So as I talked about resistance with HIV, it replicates very quickly. Adherence is one of the only modifiable risk factors that we have to decrease the development of resistance. And so it's found that at least a 95% adherence to An antiretroviral regimen is required for prolonged ability to use that regimen in a patient. And so just to give you an idea, 95% would be missing no more than one dose per month. Sometimes you can miss two doses per month, but it's really important that patients are adherent. And by adherent, it means not just taking it every day, but taking it around the same time every day, and then also with or without food, depending on the agent, if there are any food restrictions before Dr. Sean Kane 06:35 we get to the drug therapy. I just wanted to briefly talk about some of the efficacy monitoring parameters that we're concerned about with our HIV therapy. I know that CD four counts are important and viral load. Can you kind of just expound on that in terms of what is a good number, and when you start getting worried, and what do these numbers actually mean? Right? Speaker 2 06:51 So your CD four count holds out for a long period of time, so you have virus replicating your CD four count, or your CD four positive cells are what the virus is targeting. So it's not until you're getting a lot of replication that your CD four count is going to start to decline, because you have kind of a reserve, and you have your immune system also trying to target and take out the HIV. So you do have quite a reserve, the HIV viral load is ultimately going to be the target of the drug. So we want to stop replication completely. So that's the goal. We want to stop replication with the medications. With that, once you stop that, the HIV is not going to be taking out those CD four positive cells. So you should have a recovery of CD four positive cells. Now this depends on the patient. Not all patients are going to have a recovery. A normal CD four count is between 500 and 1000 generally. And you know, varies widely depending on what's going on, different stressors, etc. And so depending on the patient when they start treatment, if they start treatment and their CD four count is two cells, then their rebound of their CD four count might be 250 it might not be that 500 in that 500 range. So our goal with CD four count is always to get it as high as possible. And the only way you can do that is by suppressing the virus and keeping it suppressed for a long duration of time. Dr. Sean Kane 08:11 Just to be clear, when you say viral load, you want to stop all of it, that would mean that the viral load would be undetectably loaded. Speaker 2 08:18 Correct Exactly? There are a few different sensitivities in the tests. And so it depends on the institution and what their lower limit of detection is. Northwestern uses an ultra sensitive test, and their lower limit of detection and HIV, number of copies per milliliter is 20. There are some other tests that use 58, 200 400 so it really just depends on what institution you're in, what that lower limit of detection is. Dr. Sean Kane 08:43 And then even if someone has an undetectably low viral load, they could still potentially infect someone else. So things like not sharing needles, you know, safe sex practices, all of those things still go hand in hand with the counseling of the medication. Unknown Speaker 08:56 Exactly. Yeah. Speaker 3 08:59 So then it's also something, as we talked about watching the CD four counts. I know we get in kind of the flu season, so I'm assuming that immunizations play a fairly important role in this population. Speaker 2 09:10 Yeah, immunizations are important, just as any other population, the stigma of these patients being immune compromised is kind of starting to go away, especially because we're starting treatment earlier and earlier, we're not seeing as many opportunistic infections. We're able to start giving live vaccines as long as they have an acceptable CD four count. But giving those immunizations and making sure we're reducing their risk is just as important, if not more important, than the healthy population. Speaker 3 09:38 And when you say opportunistic infections, what exactly are you referring to? Speaker 2 09:42 So as a patient's CD four count declines. They're usually less than 200 less than 350 for some the patient is going to be more susceptible to certain types of infection that the general population is not. This would include mycobacterium, Avium complex. You'll hear it called Mac, commonly, that's. More common in patients with CD four counts less than 50 PCP, or pneumocystis jiroveci pneumonia. I know it doesn't match up, PJP. Some people will call it that's a very common form of pneumonia that we'll see as an opportunistic infection in patients when their CD four count drops less than 200 great. Dr. Sean Kane 10:18 So to kind of jump into the drug therapy, almost all of them have the same backbone agent. The brand name is Truvada, which is made up of tenofovir and emtricitabine. Why is that such a popular backbone agent, and what are kind of some of the clinical pearls that a practicing clinician should know when they see this backbone agent on any patient that they're treating for whatever condition. Speaker 2 10:38 So both tenofovir and emtricitabine, which make up Truvada, are NRT eyes, so nucleoside reverse transcriptase inhibitors, and they actually mimic different backbones. So you always want to use two NRTIs together as part of your backbone of HIV therapy, and you're going to combine that with a different agent. The reason tenofovir and emtricitabine are used together so often, and why that's the most common, is because going head to head against another agent, efavirenz, lamivudine and abacavir, it was found to be superior, especially in patients with higher viral loads of greater than 100,000, so there is some benefit to it in that way. And they're also paired together because they're really well tolerated overall compared to some of the other agents, they're only given once a day, and so that's also helps with the convenience and adherence aspect. So usually those are kind of like the package of the factors of why we use Truvada, Dr. Sean Kane 11:30 when you say better tolerated. What are some of the adverse effects that a patient would typically see with Truvada therapy? Speaker 2 11:37 So overall, it's well tolerated. Like I said with the NRTI class, there are some class side effects, like pancreatitis, hepatic hepatic steatosis. These are fairly rare with Truvada, so that's one of the benefits. By adverse effects that we see. You can still see them, but they are more rare. Some of the concerns with Truvada is renal function, specifically with the tenofovir component, it can cause acute renal failure, typically in early treatment. But prolonged use has also been associated with other types of renal dysfunction, and so that's something that we often will stop this component in patients that are developing decline in their renal function over time. Dr. Sean Kane 12:17 So I know you mentioned hepatic steatosis. Can you give the listeners, kind of an idea of what is the risk of that? What exactly is that? And you know, is that something that a patient would know that they have, or is it a lab test that needs to be evaluated? Speaker 2 12:32 The hepatic steatosis is just, it's fatty liver, basically. And so you would see an increase overall in the patient's transaminases. And then they would, they would do other tests, either ultrasound, sometimes they'll do biopsy, but it's fairly rare. The risk is very low, especially with tenofovir and enterocyte Bean. It's more common with some of the older agents, Diana, scene, zidovudine, stabu Dean, those, those are much more common to cause this and this hepatic steatosis, the mechanism behind it. And a lot of the other class effects, like pancreatitis, is actually a mitochondrial toxicity in the host cell, so it hurts and attacks or host mitochondria. And so typically, this is something that develops over time. It's not something that happens really quick, but it's a chronic issue with the class, Speaker 4 13:18 and I believe the other chronic issue with the class of medication and HIV medication in general is issues with lipid levels. Correct, so I'm assuming when you see patients with HIV regimen on board, you have some sort of lipid regimen, or controlling for control of their cholesterol as well. Speaker 2 13:36 Correct, yeah, typically with these agents, we don't see a lot of changes with lipids, specifically with the NRTIs. When you start to look at it closer, it is more of a protease inhibitor issue. Overall, it seems that patients with HIV are more likely to develop lipid issues, so making sure that we're controlling those is very important, just in the population as a whole. A lot of what's looked at with the NRTIs and has come out with the lipid issues is more to be due to other factors than actually the NRTIs themselves, Dr. Sean Kane 14:09 other factors, meaning chronic HIV infection, or other factors, like being older. Speaker 2 14:15 So chronic HIV infection plays a big role. We still don't exactly know what that role is, but we do know that our HIV patients tend to develop heart disease and other chronic disease states, either to a higher extent or much earlier than we would expect to see in the non HIV infected population. So there is a role of HIV itself in some of these lipid and cardiovascular issues, but then also, as the patients live longer and are on therapy longer, they're more likely to develop and then also depends what other concomitant antiretrovirals they're on. Speaker 4 14:50 So I believe the next combination agent the most common one that I've always seen, also for the prevention of HIV or prophylaxis of HIV. Is a triple law, which is a combination of Truvada, as we discussed earlier, plus ephemerans. Speaker 3 15:06 And I know this is an agent that always intrigues me, because with something that I learned in school that you want to take it at bedtime on an empty stomach, you know you kind of want to minimize some of the psychiatric ADRs. And we've occasionally seen this one come up as a concern in my in my practice, both in inpatient, outpatient mental health. Could you comment on some of maybe the specific concerns with this medication? Sure. Speaker 2 15:27 So Atripla was kind of a revolution in HIV therapy, and that it was the first one pill once a day regimen for HIV. And in the past, we've had a lot of regimens with really heavy pill burden that have led to poor adherence. So Atripla was the first one that combined the two NRTIs and then the one NNRTI efavirenz. So as Dr. Schuman said, it does need to be taken on an empty stomach. This is really important, because high fat or any type of food has actually causes an increase in concentration, and normally we think that's a good thing, but in this case, we don't need it for efficacy, and it just adds to the overall adverse effect profile. Most common adverse effects tend to be Insomnia, Sleep disturbance, and then also vivid dreams, not necessarily nightmares, but just very vivid dreams. Like one patient that dreamt he ate a whole cake, remembered every single bite, and when he got up the next morning, he went to the sink and looked for the plate. So just really, really vivid dreams, this can also carry over. So obviously it has a lot of impact on psychiatric overall picture. And so patients that have an underlying history or have uncontrolled depression are more likely to see some of these adverse drug reactions, and it can cause suicidal ideation, anxiety, worsening of depression, and those are some of the more common ones that we'll see with our patients. So it's really important to look at your patient very closely and see if they do have a history of anxiety or depression, and make sure that it's under control before this medication is started. And then we do have a lot of our patients with a history prior to starting Atripla, make sure that they're evaluated by a psychiatric health professional and so that they have that professional care that they need. And then if there's any issues, to be very cautious and look for other options for treatment of the HIV in patients that are having current psychiatric breakdown, if they're currently having suicidal ideation or uncontrolled anxiety, we caution people against using this agent, especially now, since we do have other options that we'll be talking about. Dr. Sean Kane 17:34 So Dr. Schuman, are there any non HIV therapies that kind of have this similar adverse effect profile of very vivid dreams that come to mind in Speaker 3 17:41 your practice, I immediately thought of a varenicline or Chantix. Dr. Sean Kane 17:46 So can I guess then that a trip Love Plus Chantix is probably not a very smart combination to try again? Speaker 3 17:52 Is, I would say that this would be one where you're strongly looking at that the risk benefit, and is, if you've, you know, eliminated a lot of other options. And then this is probably something that I assume would be closely followed by both infectious disease and psychiatry only then, would you consider it on the table? Speaker 2 18:07 Yeah, and we're very cautious in starting Chantix and anyone that's on these medications. Speaker 4 18:13 Dr. Cottrell, would you be concerned about any other side effects, such as a skin rash for patients who are taking a triple therapy? Speaker 2 18:20 So rash is fairly common. About 25% of adults that start Atripla, specifically, the efavirenz component can develop rash, and that's a common class effect of the NNRTI. You do need to be cautious with the rash, because there have been cases of Stevens-Johnson syndrome or TEN, but overall, the rash is very benign, so as long as the patients don't have a blistering rash, you're not seeing any separation of the epidermis, they don't have a fever, you can continue efavirenz during that rash period. It usually develops within the first two weeks of starting efavirenz and then goes away within about a month, anywhere from two weeks to a month after starting. You don't have to treat the rash, but you can give antihistamine creams, oral antihistamines, or corticosteroid creams, to make the patient more comfortable. Sometimes that helps the rash go away faster, but not always. Dr. Sean Kane 19:10 I think this is fascinating, because anytime, if I was a retail pharmacist and someone called me and said, I just started a new drug, and now I have a rash by default, I'm going to tell them to stop the new drug that gave them the rash. But in this pretty specific circumstance, it sounds like not only is it kind of expected, one out of four patients will have it, but we tell them to keep going. And, you know, maybe some symptomatic benefit from some of these anti histamine agents. But this is a pretty unique scenario where we're okay with the rash, we continue therapy despite the ration it improves on its own. Kind of interesting, Speaker 2 19:43 yeah, it's a really important counseling point so that the patients don't automatically stop on their own, because they might see a rash and decide to stop. And just talking about some of the issues earlier, with resistance, adherence, it's important that patients know not to stop right away on their own and really give them those kind of. Lanes, you know, blistering fever, and discussing the importance of, if you don't have those, it's okay to continue. Just call us and let us know. Dr. Sean Kane 20:08 So move on to the next agent. The brand name is Complera. And again, thinking about the cleverness of these brand names, we had Atripla, which was, you know, three different agents with the word triple in it. Complera, kind of like a complete regimen where this is Truvada, again, that same backbone, but now we have rilpivirine. So what is rilpivirine? Speaker 2 20:27 Rilpivirine is also an NNRTI, similar to efavirenz, so a non-nucleoside reverse transcriptase inhibitor. I call it efavirenz-lite, so similar to efavirenz. It does have a risk of depression, anxiety, but to a much less extent; they did have comparative trials that saw a much reduced risk of suicidal ideation, anxiety, and depression. Speaker 4 20:51 Does it bring any other side effect? Though Speaker 2 20:53 it does have some Qt prolongation that you would be concerned about. Overall, complera has some other contraindications that we watch out for. So you cannot use proton pump inhibitors any dose. You can't separate it. So it's completely contraindicated with proton pump inhibitors. So that's a concern, and it is also contraindicated if a patient does have viral load over 100,000 it's shown to be less effective than other therapies. In that case, because of that, I would say it doesn't get used as commonly as some of the other ones, daily one pill regimens. Dr. Sean Kane 21:27 And I know at least in the packaging, it says that this should be taken with a full meal, or at least with food. Is that kind of your experience Speaker 2 21:35 as well? Yeah, and that is for an efficacy standpoint. So it does help with the absorption. In this case, you do need it, as opposed to efavirenz. Dr. Sean Kane 21:42 So this is really the opposite of efavirenz, empty stomach at night. Compare it like a complete meal. You take it with food. Speaker 3 21:49 Then, right, exactly. So I can imagine again, then the role of counseling, somebody who meal may have been switching between regimens, who may be, you know, thinking, Alright, is this the one that I take with food? Is this the one that I take without food? And you could obviously get two very wide spectrum in terms of their absorption Speaker 2 22:04 rates, right? And so with a fabricens or an Atripla as a combination product, there initially a lot of patients were started on it. But now that we're having better treatments that are better tolerated than a favorend, we're starting to do that transfer from one pill once a day to a different one pill once a day. And so it's really important to make that contrast for the patients and explain to them the differences between the two pills Speaker 4 22:27 Other agents, jumping on just the combination of agents, is the brand name Stribild. Again, there is a backbone of Truvada in it, but then there is also a combination of elvitegravir and cobicistat. Elvitegravir is an integrase inhibitor. Speaker 2 22:44 So again, the integrase inhibitor, so that preventing that now DNA strand from being the viral DNA strand from being incorporated into the host DNA. So overall, the integrase inhibitor class is pretty new, but it's very powerful and was really exciting for a lot of people overall. With the integrase inhibitors, they don't go through cytochrome P450, with the exception of elvitegravir. So elvitegravir is metabolized by cytochrome 3A4, and because of that, we're able to give it with cobicistat. Cobicistat, on its own has no HIV activity, so it's not doing anything against the virus. All it's there to do is boost and make the elvitegravir work better. So it inhibits CYP3A4 and allows for adequate concentrations of the elvitegravir. Dr. Sean Kane 23:35 So in this case, it's again, an intentional drug interaction that even if we're using it for the HIV regimen, it may have implications with other non HIV therapy that the patient is taking because of that drug interaction. Absolutely. So I'd imagine then that, because we don't have that nnrtr on board anymore, maybe our psych profile in terms of adverse effects would at least be different, if not better than Speaker 2 23:56 Yeah, overall, we don't see a lot of psychiatric effects with Stribild. Really, what they saw in clinical trials was those patients that were predisposed or had a history were more likely to have psychiatric signs of depression or anxiety. So it's really loosely correlated with this drug. Most times we don't see that issue in any of our patients that don't have a preexisting history. Dr. Sean Kane 24:24 So should strive build be taken with food, or is this one of those don't take it with food, Speaker 2 24:29 just like Complera, it does need to be taken with a meal, and that is very important for Stribild as well, because it is an efficacy issue, so we need to get that concentration up. Dr. Sean Kane 24:40 So is there any downside to Stribild in terms of the adverse effect profile that would be different than, you know, Atripla or Complera overall. Speaker 2 24:48 Stribild is really well tolerated. We don't see a lot of issues with it. However, we do have, I guess, more GI effects than we'll see with efavirenz or rilpivirine. So not easier. Diarrhea are more common. Those usually last within the first two to four weeks of starting the medication, and then do tend to trail off. So it's very rare that those side effects stick around long term, serious side effects. We have seen some patients that have developed liver transaminase issues and pancreatitis, not exactly sure if it's due to the NRTIs that are in the combination or what the exact correlation is with the alvetegravir component of stribuild, but it is something to be concerned and to watch out for. Speaker 3 25:32 And then I believe we have one more of these three-in-one pills. One is recently released, Triumeq, and you tell us a little bit about that one. Speaker 2 25:40 Triumeq is really exciting, I have to say. So this utilizes lamivudine and abacavir. So those are the two NRTIs in the agent, and then another integrase inhibitor, dolutegravir. Lamivudine and abacavir, as I mentioned earlier, they're probably not as good as Truvada as an NRTI backbone, just because they've been shown to be inferior to Truvada when you combine it with other agents, with the exception of when you give it with dolutegravir. And trials that study this combination versus a Truvada containing regimen, they saw this regimen performing just as well and was non inferior to those to those agents. So it's very exciting. Dolutegravir is one of the newest integrase inhibitors, and it's a very potent agent. It is not really eliminated, so it doesn't require adjustment, although there haven't been a lot of studies in patients with really severe renal dysfunction, so that you do have to use caution, and it's not metabolized through cytochrome p4 50, so it reduces greatly the risk of drug interactions. It is glucuronidated, so you do have to be careful giving it with things like rifampin that can increase glucuronidation, but overall, much fewer side effects, really well tolerated drug. And gives us another option for those patients that might not be able to take Truvada because they had a history of developing renal dysfunction on tenofovir. Dr. Sean Kane 27:03 So this seems like a pretty exciting agent, and again, it was just released a number of months ago. So have you seen this a lot in your clinic then? Speaker 2 27:11 Well, while Triumeq is newly approved as of this fall, dolutegravir and Epzicom, which is the combination of lamivudine and abacavir together, have been around a little bit longer, not much, but a little bit. And so a lot of our patients that were on those two agents together, were now changing over to Triumeq. So I think we're starting to see a lot more Triumeq, and just because of the benefit of having reduced number of drug interactions, I think it's really growing in popularity, and it seems to fit a niche that we really needed in our patients. Speaker 3 27:44 Does this medication have the same restrictions in terms of take it with food or no food at all? You can take Speaker 2 27:51 it with or without food, which, again, is very exciting for some of our patients that will wait and take their medication later just because they are not eating, and it takes away some of that difficulty in staying adherent to your medication regimen, Dr. Sean Kane 28:05 especially, like you said, where you are kind of trying to take it the same time every day, not even just like take it in the morning, but 9am and if you're really trying to work around a food schedule in addition to a very specific timetable, I could imagine this could be a big deal for certain patients, Unknown Speaker 28:21 yeah, exactly, Speaker 3 28:22 with all these wonderful things about this one, is there, is there anything then before we just say, you know all go ahead on it is, is there anything we should kind of think about before just traveling to everyone, right? Speaker 2 28:32 You do need to be cautious using the abacavir component of Triumeq. And this is true just using abacavir with any other regimen. You do have to do initial testing of the HLA-B*5701 allele; this allele is the only thing that I'm aware of that we test for. But if it's positive, you would be at a higher risk of developing a hypersensitivity reaction from abacavir. Hypersensitivity can come with a rash, but also very nonspecific flu-like symptoms, so GI effects that can come with fever, and overall, it's not harmless. It doesn't lead to death if you initially start it. But if somebody does develop this hypersensitivity reaction and you rechallenge them with abacavir there is a risk of death. So you do have to be very cautious. And it's important to understand that too, because abacavir, anything that contains abacavir in the package insert, is going to say this medication has a risk of death. So it's important to understand that and why it is, because patients would be concerned when they read that, and so they know that they've been adequately screened by having this HLA testing done. And it's only if they discontinue the medication and then restart it, that they would have that risk of death. Dr. Sean Kane 29:44 And I know I'm a huge nerd, but when I was in pharmacy school, one of the mnemonics I used was abracadabra, you have a rash with the back of ear. That was one way that I remembered that that was the one that needed the HLA testing because of rash. But also, like you said, other hypersensitivity issues. With it. So the agents that we picked are kind of the newer agents that are more common, that tend to be these triple regimen therapies. And we did talk about protease inhibitors briefly, but we didn't actually talk about a protease inhibitor. Is there a reason why we're not seeing, you know, triple therapy with a protease inhibitor, and instead we're going to the NNRTIs or the integrase inhibitors. Speaker 2 30:20 Well, protease inhibitors have to be boosted. So protease inhibitors like atazanavir and darunavir, those are the most commonly ones that we prescribe currently and need to be boosted by ritonavir. Ritonavir is a protease inhibitor that does have activity against HIV, but not at the doses we're giving it at. So we're giving it a low dose, but just to inhibit cytochrome P450, so that we're getting adequate levels of the other protease inhibitor. Unfortunately, these medications don't come as a combination product, so that's one of the big drawbacks to utilizing these agents. So you have to be giving them also with two NRTI. So if you give Truvada, which is one pill, daruniver, which is another pill, and ritonavir, which is a third pill, they're taking three pills once a day. This is definitely a drawback. Patients don't want to be taking more than one pill, if they can help it. Additionally, we have long term metabolic issues. These are less of an issue with darunavir and atazanavir and by metabolic issues, I mean, you can have the increase in belly fat, that's pretty common, increase in triglycerides, LDL cholesterol, and then also some insulin resistance can be seen. And so overall, again, going back to our patients being at higher risk for this just because of their HIV infection, we don't want to be adding to that either. And so we do know that that's a risk that develops over time. So we're trying to go to better tolerated agents earlier on. Speaker 4 31:46 And that seems to be the case, because when I was in school, you know, there were a lot of agents or regiments that were part of the protease inhibitors were part of. And now it seems like more and more combination therapies are coming out where patients are benefiting from them, because they require once a day administration, and that improves the adherence. Speaker 2 32:05 Yeah, protease inhibitors are still great drugs. It's just a matter of more pills and sometimes increase in side effects. There is a new agent that's atazanavir co-formulated with cobicistat that we just talked about that should be coming out shortly, so that might increase our utilization of those drugs for some patients. Dr. Sean Kane 32:25 So I wasn't kind of in the pharmacy game at the time, but I'd imagine that a triple must have been a game changer when it came out with the idea of one single pill one time a day, that without food, but still fairly convenient when you consider some of the other regimens that were around at the time. Speaker 2 32:41 Yeah, now our patients get upset if they can't go on just one pill once a day, even two pills once a day is difficult for them to come to terms with. So the one pill once a day is definitely preferred, and there is now data coming out that that shows we have a decrease in resistance, probably due to an increase in adherence with these regimens, and so that's kind of an argument we get into with insurance companies sometimes that don't want to pay for one pill once a day, and they want us to try something else because of price. But now we're getting data that says, no, these pills are doing better in our general population. Speaker 4 33:17 It makes sense. It's a win win situation for the clinician who's looking for efficacy outcomes and for patients who are trying to reduce the number of pills they have to take Dr. Sean Kane 33:26 a day. Dr. Cottrell, would you mind just reviewing the agents that we talked about today? Speaker 2 33:31 The first agent was Truvada, tenofovir and emtricitabine. Atripla, that's emtricitabine, tenofovir and efavirenz. Complera is tenofovir, emtricitabine and rilpivirine. Stribild is emtricitabine, tenofovir, elvitegravir and cobicistat. Triumeq is lamivudine, abacavir and dolutegravir. Dr. Sean Kane 33:58 So that concludes today's HelixTalk podcast. If you'd like to join us online, we're at HelixTalk.com we're also in iTunes, under the name of HelixTalk. We'd really appreciate a five star review in iTunes. I wanted to thank our special guest, Dr. CO and with that, I'm Dr. King, Unknown Speaker 34:13 Dr. Cottrell. I'm Dr. Schuman, Unknown Speaker 34:15 and I'm Dr. Patel. And as always, study hard. Thank Narrator - Dr. Abel 34:21 you for listening to this episode of HelixTalk. For more information about the show, please visit us at HelixTalk.com you.