Speaker 1 00:00 Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. 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 healthcare provider. And now Narrator - Dr. Abel 00:30 on to the show, Dr. Sean Kane 00:31 hi HelixTalk listeners. This is Dr. Kane. I wanted to let you know that this episode originally aired on March 16, but we actually had a correction for the episode that was sent in by one of our listeners. Around 24 minutes into the episode, you'll hear us talk about the Viekira Pak, which is a combination product for hepatitis C. We incorrectly say that it is two tablets in the morning, one tablet at night. In actuality it's three tablets in the morning, one tablet at night. And the confusion comes because one of the tablets, which has three active ingredients ombitasvir, paritaprevir, and ritonavir. You take two of those tablets every morning. The other active ingredient, dasabuvir, you take once in the morning, once at night, equating to three total tablets in the morning, one tablet at night. And now on to the show. Welcome to HelixTalk, Episode 23 I'm your co host, Dr. Kane. Speaker 2 01:23 I'm Dr. Schuman, Dr. cout, and I'm Dr. Patel, and we Dr. Sean Kane 01:26 love Dr. Cotto so much. We've asked her to come back for a very special episode today. This is actually pretty personal to me. So recently, I was going through a glucometer bag for a patient, and the patient left one of his insulin needles in his bag that was exposed, and he's a hepatitis C patient, so I had an accidental needle stick, and now I have to be worried about hepatitis C, and I know that there's a lot of new drug therapies with hepatitis C, and I wanted to kind of pick your guys' brains, given all of these new drug therapies. Speaker 2 01:59 Well, sorry to hear that, Dr. Kane, but we're here to answer your questions. Dr. Sean Kane 02:03 So first off, I know that hepatitis C has some pretty important complications with it. So you know, I haven't been tested yet to confirm that I have hep C, but if I do kind of what is a typical prognosis for a patient like myself. Speaker 3 02:16 Well, one thing we do know is that about 80% of individuals who do have the acute infection, will then go on to a chronic hep, C, and then furthermore, 20% of those will go on to develop cirrhosis, and then furthermore, from there, about 25% will actually go on and develop liver cancer, identified as hepatocellular carcinoma, and they may even have decompensated liver disease as well. Speaker 4 02:40 Yeah, overall, the time course is pretty chronic if you do develop chronic hepatitis C, so those end stage complications of cirrhosis and hepatocellular carcinoma may not occur until 10 to 20 years down the line. So while you might not have any symptoms now, it might be something that you might become sick with later. Dr. Sean Kane 02:59 That's interesting, although the time course might be different with HIV, it reminds me a lot of HIV in the sense that some of the progression of disease doesn't happen for years down the road, as opposed to kind of an acute event, correct? Speaker 2 03:12 And this progression, the chronic nature of hepatitis C, is also considered when people, you know, clinicians and patients like wise, make decisions whether they need to be treated at that moment or they want to put up the treatment to a later time, because there's some time in between this end stage comorbidities come across. Dr. Sean Kane 03:32 And I would guess then that, as we'll talk about with the treatment of hep C, I would guess that the damage done by the virus is not reversible with the drug therapy, so it's probably more important to be on the front end and kind of prevent it, as opposed to treating the Hep C virus after the fact exactly. Speaker 4 03:49 It's more important to treat patients that do have some of those end stage complications. But per guidelines, it's recommended that any patient infected with hepatitis C be treated. Speaker 3 03:59 Dr. Kane just to go off of something you said before, comparing it to HIV. And one thing that is different, though, is that, unlike HIV, where you have the idea about what we're trying to do is decrease the viral load while still sustaining our CD4 count in here, what we're actually able to do is, and the goal is to completely cure the disease, and then again, as was mentioned with Dr. Cottrell, to prevent further complications by catching it as early as possible. And so here cure is SVR, sustained virologic response. Dr. Sean Kane 04:28 So what you're saying is, with hep C, our goal is to actually cure, to make it so the patient has no Hep C virus in them at all, as opposed to HIV, where we're managing viral loads and managing CD4 counts Speaker 2 04:40 correct, and we're evaluating this as we are basically looking at certain copies of virus in the ceremony of the blood, depending on the treatment that you choose, this test will occur either at 12 to 24 weeks in the course of therapy. Dr. Sean Kane 04:55 So most patients will know within a year. Then if whatever regimen they're on. Was successful in the sense of curing them of hep C or not. This is not a 10 year down the road kind of thing, exactly, unless they get reinfected, right? Speaker 4 05:09 And so it's really important to also evaluate any partners of the patient to make sure that they're not also infected, because that's a common point of reinfection. Interesting. Dr. Sean Kane 05:19 So I remember when I was in pharmacy school, there was kind of a two drug go to regimen for hep C, but as I understand that there's a lot of newer therapies that have come to the market in the past couple years. So kind of historically, what was the standard of care and what was kind of wrong with it? Why do we need these newer agents on the market? Speaker 4 05:37 So standard of care was really two drugs, as you mentioned, pegylated interferon and ribavirin. And so this was anywhere from 28 to 48 week duration of treatment. Pegylated interferon was injectable, and the two medications together had a lot of adverse drug effects. Speaker 2 05:53 And not only looking at the adverse drug reaction, even though patient go through this chronic therapy and during all these side effects, the response rate was pretty low. And when we look at the SVR rate, was comparatively very low compared to the new medications that are out in the market now, Speaker 4 06:10 yeah, for genotype one, which is the most common genotype that we treat in the United States, SVR rates were anywhere from 30 to 40% with this combination treatment. Dr. Sean Kane 06:19 That's not very good. Then no. So then what would happen historically to a patient where they went through this, let's say, 48 week regimen and didn't attain cure? SVR, what did they have something else that could be done for them? Speaker 4 06:31 Typically, they would go untreated until they were ready to be retried on the medication, although the likelihood of that being effective is very low. Dr. Sean Kane 06:40 So one of the best brand names on the market is one of the pegylated interferon products. It's Pegasus, and I think that that is an awesome brand name. The other one's peg intron. And as I understand, they're not AB rated, meaning that they're not the same drug. Is there a clinical difference between the two types of pegylated interferon or peg interferon? Speaker 4 07:01 No, the dosing is different between the two, but it's still an injection that's given once a week for both preparations, one's interferon two a and one's Interferon 2b however, they both have similar efficacy rates. Dr. Sean Kane 07:12 I know that you guys mentioned some of the adverse reactions associated with this regimen. Are there any kind of standouts that if I were to take this regimen, I want to know about as a patient. Speaker 3 07:22 I know, for me, again, from the mental health side, I always focus on the sometimes tripling psychiatric effects of these medications. In a lot of medications, we say, you know, may cause depression. But in this case, this is one that can cause some really, really nasty depressive symptoms so far, to actually cause a black box warning on this medication that can may cause or exacerbate life threatening neuropsychiatric disorders such as depression. Speaker 4 07:47 The one that patients tend to notice the most are the flu like side effects of the interferon itself, they tend to be awful and lead to a high rate of discontinuation of the medications. Speaker 2 07:57 So I'm thinking there is some sort of prophylaxis that we give patients before they get these injections, Speaker 4 08:02 sometimes they will try to take an NSAID or like ibuprofen or naproxen. However, that's minimally effective. Dr. Sean Kane 08:10 And just going back, what exactly are we doing? What is the mechanism, if you will, of this interferon product, and what does pegylated mean? I think that that's important to understand. Speaker 2 08:21 So regular interferon has a more frequency of administration because that molecule's action of duration is shorter, but if you attach some peg molecules to it, you increase their duration of action. So instead of patients having to take it every day or three times a week, the peglated kind of version can be given once a week. So again, that reduces those horrible flu like symptoms that patient would get with each administration. And basic mechanism of action is it's an antiviral basically, kind of up regulates the hormonal system. There are a lot of different pathways that occur through it. Basically the end result is suppression of hep C virus. Dr. Sean Kane 09:00 So then what you're saying is that this interferon kind of up regulates the immune system that makes your immune system work better to fight off the Hep C virus. That is correct, any other warnings or issues with the drug in terms of adverse effects? Speaker 3 09:14 Well, there is an additional box warning for this one may cause or exacerbate autoimmune, infectious or cardiovascular ischemic disorder, so a CVA or even an MI, so again, not, not a delightful event that you would like to occur. Speaker 4 09:27 Yeah, we also monitor CBC on the patients, because it can cause bone marrow suppression and neutropenia, along with ribavirin, which you can also do the same, the two together definitely increases the risk. Dr. Sean Kane 09:39 And you know, if you look in the packaging for pegylated interferon, you're going to see a lot of fairly non specific adverse effects, but fairly high rates of them. Sometimes, I think it's probably hard to discern out between the hepatitis C virus causing things like fatigue, cirrhosis causing fatigue, and then the drug effect itself. Speaker 2 09:58 Yeah, that is definitely true. And you know, this therapy is a chronic therapy, if you can imagine 48 weeks, you know, that's most half, more than half of the year. But looking at chronically too, there are certain ambulatory type of side effects that come in play too, which is hyper triglyceride levels we're looking at, you know, increased blood glucose levels too, so like impaired fasting glucose. So these patients not only have to complete the therapy because we don't want them to retry it, you know, they're already some wet way through the therapy, then we have to add other agents to control their triglycerides or control their blood sugars and etc. Dr. Sean Kane 10:35 And then you mentioned ribavirin. Is that also an injection? Or how is that given to a patient? Speaker 4 10:42 Ribavirin is given as a weight based oral regimen. So if the patient's 75 kilograms or higher, they'll get 1200 milligrams per day, and if it's less than 75 they'll get one gram per day, and it's split in divided doses. Dr. Sean Kane 10:55 So does ribavirin do something different than what pegylated interferon brings to the table in terms of mechanism of action. Speaker 3 11:03 So ribovirno, there's a nucleoside analog. What this one does is cause chain termination for the for the viral RNA. Dr. Sean Kane 11:10 So again, thinking back to HIV, that sounds like some of the HIV drugs that we had, kind of our NRTIs, in the sense that it caused early chain termination by incorporating itself into the RNA process. Although with HIV, I would assume that this would not be active for HIV, right, correct, right? Speaker 2 11:25 And like Dr. couture mentioned earlier, there is a box warning for hemolytic anemia. So along with checking patients CBC, for pag, interferon, we want to also do the same for the rubber urine as well. Dr. Sean Kane 11:38 So when we say hemolytic anemia, I don't know for sure that all listeners would fully understand what that means. So could you kind of go through not even the mechanism, but kind of what is the clinical consequence of hemolytic anemia? Speaker 2 11:50 So basically, hemolytic anemia, like the name says, There is a lysis of the red blood cells, and if you cut open a lot of red blood cells, there is an influx of intracellular material into the extracellular material. Mainly we're worried about the potassium influx, potassium out flux. So increased potassium is hyperkalemia, which can lead to other conduction related cardiac abnormalities. Dr. Sean Kane 12:15 And I'd imagine too that patients given anemia is in the name in your lice and your red blood cells, patients would probably have symptoms of anemia that help hint to them that something isn't right because they're not checking the CBC every morning when they're at home. Speaker 4 12:28 Yeah, typically, fatigue is the thing that people tend to notice first. So we always caution patients when they start to notice new onset fatigue, to let us know as soon as possible. Dr. Sean Kane 12:38 This sounds severe enough that I would almost want it to be a boxed warning, if it is common enough. Speaker 4 12:43 Oh, it is a boxed warning. Actually, this medication also, just to mention, is category X for pregnancy, and so it's important that even men taking the medication are aware of this, because they can actually cause a teratogenic effect to the unborn fetus. Dr. Sean Kane 12:59 So this sounds like it's a pretty involved drug therapy. We see a lot of adverse effects, a lot of monitoring with it, weekly subcutaneous injections. We have some issues with handling around pregnant women, things like that. Given all the toxicities, I'd hope that we get some good efficacy out of the drug therapy. Speaker 4 13:16 Then, unfortunately, not, as we mentioned with the two medications, the response rate is anywhere from 30 to 40% for genotype one, much higher with some of the genotype two and three infections, however, Dr. Sean Kane 13:30 so I can really see a good area then for new drug therapies to come into the market where they're more efficacious and have a better safety profile. Yes, so what? What can you offer me here? Speaker 4 13:43 So you're in luck. There are a lot of new agents. So we have these new direct acting antiviral class. There were some first generation agents back in 2011 that had minimal response, and those were both sepervir and telepervier. Speaker 3 13:58 So these two agents, I know these are ones that came out right when I was beginning my residency, and I remember them being an NS three for a protease inhibitor. So what it cleaves the viral particles into these functional pieces, and it seemed to be more efficacious than the others. And so we've actually gone from about 30 to 40% all the way up to 60 to 70% Speaker 2 14:18 so we did increase the SVR rate, which was great. However, these agents cannot be used by themselves, meaning they have to be used with pegylated interferon and ribavirin. So here we're talking about a mound of side effects. Okay, increased side effects than even just the two drug regimen, which was the standard of care before. Not only that, you know, patients are bound to take more pills in terms of both boceprevir and telaprevir, the way the regimen was designed and studied, you know, the patient had to use one to two tablets at least three times a day. So tremendous increase in burden. And we have to, kind of, we consider it a risk of developing resistance if they're not compliant to the therapy. Dr. Sean Kane 15:04 So what kind of toxicities did these agents bring to the table that we didn't have as much of with pegylated interferon plus ribavirin, Speaker 4 15:12 some of them were additive to the fatigue and nausea, however, itchiness, including perianal itching and then also dyslexia or an altered taste, were some of the additional side effects that we saw with these two agents. Dr. Sean Kane 15:26 So then what you're telling me is that you want me to take the ribovirin pegylated interferon and one of these two newer agents that are protease inhibitors that improve efficacy but also worsen the safety profile in terms of the tolerance the patient tolerance to the medication. Speaker 4 15:42 Well, luckily, you don't have to take them, and neither does anyone else, because they've been taken off the market and they've been replaced with some newer, direct acting antivirals. So a similar agent in this class was simaprovir, so similar mechanism of action, but later generation, Dr. Sean Kane 15:59 when we say similar mechanism of action. Again, I'm thinking in my head HIV therapy, although these aren't active for HIV, I think we can probably correlate that a lot to what we know about HIV. So we do have Proteus inhibitors with HIV. Is that kind of the same concept here? Speaker 4 16:13 It's very similar. Overall, I think we know a lot more about HIV and how it replicates, and we're still learning a lot about hepatitis C, but overall, there are a lot of similar pathways to viral replication with hepatitis C as HIV. Dr. Sean Kane 16:29 So you mentioned some protease inhibitors that are new to the market. Are there any other mechanisms out there that we'll probably see more of in terms of hep Speaker 2 16:37 C treatment? Yeah. So just like those protease inhibitors that are NS three, four, a inhibitors, we do have NS five A inhibitors like just like Dr. couture said, there are a lot of different sites of action to prevent the replication of this virus. And basically this NS five a protein is involved in fibroidity of different replication and assembly steps. So if you prevent that from happening, you would dampen the HCV replication, Speaker 3 17:06 similar fashion, again, to the drawing the analogies between this and HIV. We also have what are called ns 5b RNA polymerase inhibitors. And so these come to two classes, which are the NPIs and the nnpis. And again, if that sounds familiar to the same language of NRTIs and NRTIs with HIV, then you're right. Except here it's a nucleoside polymerase inhibitor, and then a non nucleoside polymerase inhibitor. And then we really only have one agent each of these. So we have sofosbavir, which is our NPI, and then the sabavir, which is going to be our nnpi. Dr. Sean Kane 17:41 And again, thinking back to HIV, the difference between the NPI and the nnpi is that the NPI is incorporated into that RNA chain, whereas the nnpi is binding somewhere else on that RNA polymerase, external to the actual chain itself. Right? Exactly. So it seems like we have a lot of novel, direct targets that we're looking at now. And I would imagine that these kind of came out, you know, if both boceprevir and telaprevir came out in 2011 I would imagine these came out after that then, Speaker 4 18:10 yeah, so many of them have been approved very recently. The Viekira Pak, which is a combination product that we'll talk about, is approved as recently as January. Wow. Dr. Sean Kane 18:21 Okay, so this is kind of a super hot topic in drug therapy, terms of what we'll be doing in the future and which regimens will catch on, and things like that. So I'm hoping you'll have good news for me that these drugs are safer and more efficacious than the agents that you were trying to convince me of using previously Absolutely. Speaker 4 18:40 Well, let's talk about them. So one of the first combinations that we started using with the approval of some of these medications was the combination of sofosbuvir and simeprevir. So simeprevir, again, is an NS3/4A protease inhibitor, and sofosbuvir is an NS5B NPI. So the two of these together were taken once daily. Simeprevir has to be taken with food, so we would recommend taking them at the same time. Dr. Sean Kane 19:06 And just to review, then, that simeprevir was similar to the boceprevir in terms of how it worked, Speaker 4 19:12 correct exactly, it had better efficacy overall. And with the approval of sofosbuvir, sofosbuvir is a very potent antiviral. And so the two together was a novel combination, and we found that we could use them without using ribavirin or pegylated interferon. For the Dr. Sean Kane 19:30 first time. You're telling me, I don't have to inject myself every week, probably not. Speaker 2 19:35 Not only that, you don't have to feel like you were having flu every week. Dr. Sean Kane 19:39 Interesting. Okay, Speaker 3 19:40 and then again, so we're looking at side effects, and this is a nice thing where they're fairly well tolerated, generally, a few ADRs, but again, nothing that's coming out to the degree of those, those delightful warnings with some of those other agents. Dr. Sean Kane 19:53 Sorry, I looked this up on Wikipedia, which is where I get all of my drug information, and I saw that I have to worry about photosensitivity. Is that true? Speaker 4 20:00 It, yes. So photosensitivity and itching with some map reviewer in particular is important, so we would recommend staying out of sun as much as possible, or using things like sunscreen and covering up. Additionally, you can see just random itching. This can be very mild, and it can occur anywhere in the body. We had some patients that had random itching in their throat, others in the eye. Otherwise, it can just be on the skin, and it can happen any time of day. So what we recommend is on if it does occur on the skin, just using a fragrance free lotion, and staying as well hydrated as possible. Converse to that if it's in the eyes, using just a regular eye drop or tear replacement. Speaker 2 20:41 So you don't recommend scratching the eyeball. No, we don't. Dr. Sean Kane 20:44 Yeah, and then, unlike both separate ear and teleprovere, this is not restricted to anal itching or anal pruritus, right, correct? Speaker 4 20:52 It can be, like I said, anywhere I actually haven't had anybody that's complained about anal itching, because I would expect that to come up. But typically, the time people notice it the most is usually when they're laying in bed. So one of our patients just got up out of bed, went and got a drink of water, came back just to get his mind off the itching. And when he came back, he wasn't thinking about it, so he didn't notice it as much. So sometimes just changing what you're doing to get your mind off the itch is just as effective as using lotion or a pill. I mean, Dr. Sean Kane 21:20 it almost sounds like this is more than just run of the mill, like a little bit of itching, is this to the point where it could impact the patient's perception of the drug therapy, where they would want to not take it because they're having itching? Speaker 4 21:31 It could be. It's important that we counsel patients on it, and we always tell them to call us before just stopping the medication, because it is very expensive, as we'll talk about, and so once we can get it, we really want them to commit to therapy. And so well, we've done things like prescribed hydroxyzine so that it can help them sleep, especially if they're noticing at bedtime. That's really the best drug, because it's going to help them sleep, it's going to make them drowsy, but it's also going to help with some of the itching. Dr. Sean Kane 21:56 And I would assume that this isn't itching related to cirrhosis with high bilirubin levels. It's actually a drug effect, right, correct? So as a pharmacist, I can generally pronounce drug names fairly well, but patients may be more familiar with the brand name. So are there brand names associated with these newer agents yet? Yes. Speaker 4 22:13 So cefospivir is Sovaldi and semapprovir is olisio, yeah. Speaker 2 22:18 And a good thing about you know, this new combination is that, unlike boceprevir and telaprevir, which are out of the market, now, these agents are only taken once a day. So we're looking at increased compliance to the therapy. Perhaps that can translate into increased SVR as well. Speaker 3 22:33 And the one thing to clarify, though, is that even though they are once daily, there is no combo product available. So would be once daily of each one as a separate entity. So there would be, would be two separate products, just to clarify. Dr. Sean Kane 22:43 So, Dr. Patel, you got my attention with better SVR, better cure rate, so I'm even okay with better adverse effect profile. But if you're going to tell me that we have a better SVR rate, that would make me extremely happy. Speaker 2 22:56 So we're looking at the SVR rate improvement from 30 to 40% just with pegylated interferon and rib ovarian to 60 to 70% if we use vosprevr and teleprevarian in addition to pegylated interferon and rib ovarian to 90 plus percent using this new agent. So we're talking about tremendous increase in the rate of cure. Dr. Sean Kane 23:19 Just think about that for a second that blows my mind. So within the past couple years, we've come out with new drug therapies that take our cure rate, not just treatment rate, but cure rate of a disease that causes hepatocellular carcinomas and cirrhosis, and we've taken it from low 30s all the way up to greater than 90 sometimes even 95% Yeah, it's very exciting. Speaker 3 23:41 And then, to further illustrate it, some patients could then take what's essentially 100% oral regimen, take that once a day as a, you know, a two pill combo, two pills once a day, and then achieve a cure rate within three to six months. Dr. Sean Kane 23:54 This seems like a game changer to me in terms of direct therapy for hep C, Speaker 4 23:58 it is a lot of patients that weren't being treated before. Now being treated, which is really exciting, and Speaker 2 24:03 I'm very excited that our healthcare money is, you know, that's put into research is bringing about such novel medication that would not only improve the efficacy, but also improve the safety profile. Dr. Sean Kane 24:14 So I'm sold. I'm ready for my Sovaldi and Olysio. Is there anything else I have to even consider before saying yes, Speaker 4 24:21 yes, there are other options. So one would be the Viekira Pak. This is the most recently approved combination product that's out there for the treatment of hepatitis C. So this is a combination of four different drugs. Wait a minute, Dr. Sean Kane 24:38 that's way too many for me. I was already sold on a two drug regimen, Speaker 4 24:41 but you don't have to take four different pills, so it's actually just three pills a day, instead of four pills twice a day, or whatever you were thinking. So the different medications that are in this are ombitasvir, paritaprevir, ritonavir, and dasabuvir. Ombitasvir, paritaprevir, and ritonavir are actually in a combination pill and then dasabuvir you do have to take separately. Dr. Sean Kane 25:05 So it's two pills that are taken in the morning and then one other pill, dasabuvir, that I take twice a Speaker 4 25:10 day, right? The combination pill with the three different agents in it is just once a day, and then the disapprover is twice a day. Speaker 2 25:17 So wait a second, I just heard ritonavir. Isn't that the agent we use for HIV treatment. Why is it here? Speaker 4 25:23 So we're actually using it for boosting of this regimen. So we know it's a potent CYP3A4 inhibitor. And so it's actually there to boost part of this regimen. Each daily dose is packaged together, and so that comes in a giant box that the patients have. So each giant box is a one week supply. And by giant, I mean it's probably eight inches tall by four by four, Dr. Sean Kane 25:48 so less convenient than, let's say, a vial, a prescription vial or a bottle. But I would imagine that that probably helps with compliance, given that it's kind of complicated. You have one drug that you take in the morning and then another drug that you take twice a day in terms of which one is which, or things like that. Speaker 4 26:03 Yeah, if you think about the methyl dose pack or the Z pack that's out there, so it's packaged very similar to that, where it tells the patients they need to take two in the morning and then one pill in the evening. Speaker 3 26:13 It's early in and of itself, it makes for a nice compliance aid. Speaker 4 26:16 It does you just have to have a lot of cabinet space in terms Dr. Sean Kane 26:19 of adverse effects, is it fairly similar to what we saw with Sovaldi and Alicia overall? Speaker 4 26:25 Yes, it's pretty well tolerated. We haven't used this medication in a lot of patients in my clinic yet, just because it is so new, and also there are a lot of drug interactions with ritonavir being a CYP3A4 inhibitor. So that is something you have to consider in your patient population, but with ritonavir, we know there's a risk of nausea and GI side effects, and so that's something to keep in mind. And then other things that we've seen have been itching, difficulty sleeping, and then fatigue. Okay? Dr. Sean Kane 26:54 I mean, for right now, I think I'm going to stick with option number one. It sounds like I need a lot of cabinet space. The pill burden is a little worse for me. So personally, I think I'm gonna say no to the vicura pack, but thank you for your offer. But don't you Speaker 3 27:07 want to hear what's between on your door number three, though? Oh, I'm interested. And behind door number three, we have a product called Harvoni. This is a combination product of ledipasvir and sofosbuvir. Ledipasvir is an NS5A inhibitor, and sofosbuvir is an NS5B NPI. That's analogy to the NRTI and HIV. And once again, this is, yeah, once daily with or without food. So you got options, yeah. Speaker 2 27:37 I mean, if you look at the package inserts, it says it's fairly well tolerated side effects, such as, you know, mild fatigue, some headaches, some nausea and insomnia. Seen. I mean, what do you say? Dr. cochrael, what have your experience been in the practice, Speaker 4 27:51 overall, since Harvoni came out, it's pretty much dominated what we've been prescribing for patients because of the convenience, and it also has less drug interactions compared to the Viekira Pak or even Olysio combination products, because Olysio, going back to this, simeprevir, is a cytochrome P450 3A4 substrate, whereas ledipasvir and sofosbuvir don't have CYP3A4 interactions to the same extent as the other groups. Yeah, I've Speaker 3 28:18 got a patient who has been kind of trucking right along with his Warfarin regimen while we've had him on this and it's been no issues there. Dr. Sean Kane 28:24 So just to review, with Harvoni, it's one tablet. It's a combo product that I take once a day, with or without food that has very few drug interactions and a relatively favorable adverse effect profile. With that said, just out of curiosity, if we don't have drug interactions on the liver side, are there any renal issues that we have to worry about with any of these regimens? Speaker 4 28:45 So overall, unfortunately, we don't know. Once a creatinine clearance drops below 30, that has been something that many patients were excluded from the clinical trials for, and so we don't have data as far as how these drugs do in patients with really low creatinine clearance. Mild changes in renal function are unlikely to affect these agents, since most of them are going through metabolism pathways. So a lot of these regimens, either the sofosbuvir/simeprevir or Olysio and Sovaldi, the Viekira Pak, and then also Harvoni, are primarily recommended for treatment of genotype one. For genotypes two and three, which are the other genotypes that we see here in the United States, most commonly we're still actually using a combination of sofosbuvir and ribavirin for the majority of those patients. Dr. Sean Kane 29:36 All right, so I'm sold probably on Harvoni, although this podcast doesn't endorse any specific regimen. It does sound like that. That's a pretty good regimen to take one tablet once a day, very few, if any, drug interactions. How long do I have to take the drug for? Speaker 2 29:49 So it actually really depends on many different factors. So meaning, what type of hep C infection you have? You got four different genotypes, right? 123, and four depends. Yes. Well, in your case, you know we can consider your treatment naive, but in a lot of patients who have failed therapy with pegy, later, interferon, ribovirin, there might be some resistant pattern in the the RNA of the Hep C virus. So we might have to maybe approach it a little differently when we treat these patients and patients who have that end stage complications, such as cirrhosis, they are also treated a little bit differently, but in general, most patients will receive this treatment for 12 to 24 weeks. Dr. Sean Kane 30:29 So just to review, decades ago, we were giving pegylated interferon with rapid virus for how Unknown Speaker 30:34 long? 24 to 48 weeks, Speaker 3 30:37 and now we've gone to 12 to 24 weeks with oral only therapy, no injections, exactly. It's crazy. I'm sold. What, what? What could possibly be any downside to this new oral therapy? I guess the issue is, How deep are your pockets? What do you mean by that? The one thing about these medications are going to be the average wholesale price of these can get a little bit high again, due to, you know, the amount of research and development that's been taken to produce these medications. So we have Harvoni. It's a WAC, about $38,000 per month. Dr. Sean Kane 31:10 38,000 per month. Per month. Really, you got it? I've got health insurance. Does that help? Speaker 4 31:16 It? Can? It depends on the insurance. Usually there's a lengthy prior authorization approval process needed. So it's not something I would expect to start right away. Typically, they have to go back and forth with your physician's office to make sure that they have all the proper labs and that you're being appropriately followed up on. And because they're so expensive, a lot of insurance companies want to make sure the right people are getting treated first. So sometimes they make you form a little bit of a line. Dr. Sean Kane 31:43 So when it is covered, is it, is there still a significant out of pocket cost for a patient, or is the insurance company truly providing, you know, a full coverage of that that drug? Obviously, it depends on the insurer. But speaking in generalities, Speaker 4 31:57 typically, not. Typically, there's a percentage out of pocket cost for most of these medications. However, the manufacturers of these drugs do have very generous patient assistance programs, so they'll typically have co pay assistance coupons that are available. Those are really only for privately insured patients. So if patients have Medicare or Medicaid, they're generally not eligible for these types of programs. Patients that do have Medicaid or Medicare and can't afford the out of pocket costs or don't get the medications approved. There are patient assistance programs also through the companies that will provide the medication free of charge. Again, it's something where you have to fill out a lot of forms, and there's a lot of back and forth, typically with the physician's office. However, we've been very successful in getting these for patients when they really need them. And so how it works is the drug companies will typically ship the medication to the physician's office, and then we'll dispense each month of the medication to the patient directly. They do have to submit income information, and so they usually if they have significant income, even if their out of pocket costs are very high, they might not be eligible for this patient assistance. Dr. Sean Kane 33:08 So it sounds like there's a lot of different avenues that you can go down in terms of not paying a full cash price for the direct product. Then Exactly. I'm not great with pharmaco economics, but I would imagine that this drug cost came from somewhere. So Dr. Shipman, as you alluded to, part of it was the drug discovery process in terms of coming up with a novel and really, really important way to treat Hep C in terms of less adverse effects and shorter duration of therapy, shorter duration oral only better efficacy. Are there any other reasons why the drug cost might be so high. Speaker 4 33:42 So if you look at the cost of needing a liver transplant, that's another way that you can compare it. So the cost of a liver transplant is $160,000 plus. And so these medications, by contrast, are much less compared to that. So that's something to keep in mind as well. Dr. Sean Kane 34:01 And I'm sure, you know, obviously thinking about the cancer cost as well. If you, instead of just decompensated cirrhosis, if you're treating a carcinoma in the liver, I'm sure that the cost associated with that is pretty substantial as well, exactly. And although we didn't talk about the costs of the other drugs and combinations, I'd imagine that the drug cost is fairly similar to what we mentioned with harbony, right, correct. Speaker 4 34:24 So because of the cost, so with the Viekira Pak, it's about $33,000 per month. With sofosbuvir and simeprevir, each are about $1,000 per pill. So if you have 28 plus 28 you end up getting $56,000 per month. So that's very expensive. One of the things we tell patients is to treat these like gold. Make sure that they don't leave them in their car if they lose them. We're not sure that we can always get them replacements. So it's very important that they know where their medication is at all times. Another important counseling point is if they have to go into the hospital, that they take at least a few pills with them. So. That they don't miss any doses. A lot of hospitals are not keeping these on formulary because of the cost, and so it's something that they might miss a dose if they have to, even if they get into a car accident and have to go in or have, unfortunately, some other incident or accident that occurs, it's very important that they get every dose in order for these regimens to be successful. Dr. Sean Kane 35:21 So just to wrap up, I wanted to focus on a couple things here. So one thing is, in terms of our therapeutic goal for hep C treatment, as opposed to just preventing cirrhosis or preventing hepatocellular carcinoma, our therapeutic goal is SVR, or sustained virologic response, which means cure, meaning that the Hep C virus has gone from the body undetectable. That's pretty rare for some of the antiviral therapies that we think about with other disease states. Specifically, what I'm thinking of would be HIV. There isn't a cure for HIV, whereas with hep C, with our drug therapy, cure is actually a possible thing, and it's, you know, within reach in terms of the drug therapies that we have in the market, Speaker 2 36:02 yeah, so we have come across a great way in achieving this SVR, sustained virologic response, from, you know, 30 to 40% with the couple standard of care that we had about six years ago, to now 90 plus percent of SVR with the new regimens we mentioned, such as the Viekira Pak, or Sovaldi and Olysio, or using Harvoni. Speaker 3 36:27 And furthermore, we're getting these cure rates without, without compromising our quality of life. We've gone from these black box warnings with for things such as the severe psychiatric disturbances and this hemolytic anemia and auto immune disorders. And we're looking at maybe more reasonable burdens on an individual patient or client, such as nausea. There is still a concern with simeprevir about itching, but beyond that, we're looking at more general concerns such as nausea and vomiting, again, a far cry from those those earlier warnings. Speaker 4 36:59 So just as a review, I'm going to go over the pronunciation of the brand names, as well as the generic names of the agents that are more commonly used and newly on the market. So the first one is the sofosbuvir brand name is Sovaldi. Second we have simeprevir brand name is Olysio. And those two are typically used together. The Viekira Pak, which is the brand name for ombitasvir, paritaprevir, ritonavir, and dasabuvir. And then finally, we have Harvoni, which is the brand name for a combination of ledipasvir and sofosbuvir. Dr. Sean Kane 37:37 So with that, I wanted to kind of conclude, for those listeners who haven't done so already, we'd really appreciate a five star review in iTunes. We're available at HelixTalk.com if you have any episode suggestions or topic suggestions, we're taking any comments again at HelixTalk.com with that, I'm Dr. Kane. I'm Dr. Schumann, Speaker 2 37:55 Dr. cout, and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 38:00 Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com you.