Discover the ins and outs of utilizing hepatitis C positive donor organs. Why do we utilize, how do we protect the recipient’s liver from hepatitis related chronic injury, methods for prevention and treatment of hepatitis in organ recipients, and how to get insurance coverage of the medications.Â
The information presented during the podcast reflects solely the opinions of the presenter. The information and materials are not, and are not intended as, a comprehensive source of drug information on this topic. The contents of the podcast have not been reviewed by ASHP, and should neither be interpreted as the official policies of ASHP, nor an endorsement of any product(s), nor should they be considered as a substitute for the professional judgment of the pharmacist or physician.
(upbeat music) - Welcome to the ASHP official podcast. Your guide to issues related to medication use, public health, and the profession of pharmacy. - Thank you for joining us for this episode of clinical conversations from ASHP official. This podcast includes discussions about therapeutics, best practices, emerging therapies, case studies, and other topics that the clinical pharmacist will find important in practice. If you are an ASHP member, you will also have the opportunity to earn continuing education for listening to this episode. Stay tuned to the end of this podcast for more information. In accordance with ACPE standards, we must disclose the relevant financial relationships prior to this episode. For everyone on this episode, there were no conflicts of interests. My name is Janice Chaco, and our guests today are part of the transplant team from Mayo Clinic, Arizona, Cassandra Vitruba, and Madeline Hudson. In this episode, we will be discussing hepatitis C positive donors in solid organ transplant. Welcome, everyone. Okay, question number one. Why do we utilize organs from hepatitis C positive donors? Why would we want to give organ recipients hepatitis C? - If we wanna think about this, we wanna kinda take it to a fundamental level of, there's this supply versus demand in solid organ transplant. So when we think about it, there are currently over 103,000 individuals on the transplant wait list in the United States alone. And on average, 17 of those individuals die every single day waiting for an organ transplant. Transplants, wait lists, are far larger than what we have in terms of an available donor pool. And this results in pain distance, dying on the wait list before an organ becomes available. As we've continued to advance in the transplant world, and in this process, one of the things that we have to think about is finding additional donors. So we oftentimes seek, we have these donor registries happen, we're always looking for living donors, depending on what type of organ it is. But we also have to think about our deceased donors and opening up that pool of donors. And so one way that we can do this is by utilizing the avenue of patients who were originally when we first started doing transplants, they weren't option available donors. And that was because they were hepatitis B or hepatitis C positive. We have since done research and found that we can use hepatitis C positive individuals as organ donors. And so with advancements in antiviral therapies, luckily hepatitis C is something that is treatable. And by utilizing these hepatitis C positive organs, we are able to expand that donor pool and transplant more patients sooner, so they're less sick at time of transplant. And they're, we're decreasing those number of patients that are dying on that wait list. And we're able to just give them a very short course of treatment fundamentally for that hepatitis C. And so remember that for every one donor that we have, they can save up to eight lives if this is a deceased donor, and they can potentially impact up to 75 more lives just through donor tissue, donor bone, donor vessels, that type of a thing. So by utilizing hepatitis C positive donors, we are able to give them a longer life we're able to transplant them earlier. So with the development of direct acting antivirals, we have been able to successfully obtain SVR with these patients. So they're able to start those antivirals. We might have patients who are very virumic, but over time and over that course of therapy, they do see that sustained effect, and they are no longer virumic and they are essentially cured from this. Does it matter if the organ donor is currently virumic with hepatitis C at the time of donation? - That's a really good question. So all potential donors do get infectious serology tested. And one of those tests that is completed is hepatitis C with a reflex for NAT, which stands for nucleic acid testing. So NAT, this is basically just a highly sensitive method for testing the blood to see if there's any detectable virus in the blood to use for things like HIV, West Nile, but in this case, we'd be using it for Hep C. And so if you had a positive NAT, this would indicate that they have active virumia. And if the donor is virumic, then we're definitely gonna need to treat the recipient in some capacity, which I'm sure will go into much more detail further on within this chat. But if the donor is not virumic and does not have hepatitis C antibodies, treatment protocol is gonna potentially be very different depending on the organ, as well as each specific institution's protocol. So that's just something to be aware of. But our Hep C NAT negative aligraphs likely actually have a negligible risk of transmission. And often in those cases, no therapy is provided to the recipient and just simply monitoring is often done in those cases. - When do you start hepatitis C treatment for solid organ transplant recipients? - That is something that is really kind of, it varies a lot between different organizations, different guidelines. So really, if you wanna think about it, there are three strategies. And so the original strategy that was utilized in a lot of the very early publications on this and a lot of the early research was looking at late treatment. And so that is essentially once the recipient of the organ is transplanted, we wait until they become virumic, they have detectable viral loads. And that's when we go ahead and initiate the treatment with the antiviral. So this is all done in the outpatient setting once they have gone through their initial hospital course. The second option is early treatment. So this is typically a process where you start pre-transplant and that's typically when we say pre-transplant, it's not weeks or months in advance. It's more of, it's a dose given prior to an osteomosis. So typically it's done in the perioperative setting right before they go to the OR. And then they receive a full treatment course for that typically the 12 week course that's standard with most antivirals used for treatment for hepatitis C. Then the last strategy that we have is more kind of a preventative status. And so with this style of treatment is actually more of a prophylaxis. So you're trying to prevent the virumia from happening. So what that appears as is typically it is given as one dose in that perioperative setting and then it's for seven additional days post-op. So eight days total of treatment. And so for lots of institutions depending upon what your typical hospital stay is, the majority of those doses are going to be given in the inpatient setting with maybe just one or two doses given outpatient. Typically with that more of a preventative based style treatment, it's going to be combination therapy. So if you say you have something like maverick you're going to use zetia with it too. And that's because the zetia helps to inhibit the entry of the virumia into the hepatocyte. And it's basically delaying that establishment of the virus into the hepatocytes. And this allows time for then that antiviral to start working. So we're doing this dual synergistic effect to try to prevent the virumia ever entering into those new liver hepatocytes that are happening before. So when we think of these three different strategies we have to be thinking about a bunch of different things as to determine what is best for each of these different organs. So we need to be thinking about what is the actual organ being transplanted. So if this is a kidney or a heart then we can definitely consider the preventative type of treatment strategy. But if this is a liver where the virumia has already occurred and where most of the hepatitis cells or the virumic cells live, then we need to be doing more of a treatment based strategy rather than a preventative strategy because that organ is already a virumic. We also need to be thinking about what are the insurance requirements. So originally that late based treatment was because we couldn't get authorization for insurance to pay for the medication until the patient was virumic, the genotype was identified, that type of a thing. Now insurance companies are being a little bit more open with it being able to start therapy prior to. But again, it depends on what that patient's insurance is. We also need to be thinking about institutional constraints. So is the institution doing a lot of these hepatitis C positive donors? Do they have these antiviral therapies on formulary and available to utilize in patients? Are they going to be reimbursed properly for it, that type of a thing? So there's a lot of different types of avenues and strategies that go into determining which type of therapy you're going to do and it's going to potentially differ a fair bit between institutions, between practice policies, that type of a thing. What medications are typically used with each strategy? Yeah, just as Cassandra had alluded, there's obviously a lot of factors at play when you're kind of picking strategy, but that also comes into play when picking the medication used or sometimes even just the things that you would potentially consider when a drug is actually chosen. So one thing to consider is genotype. So with hepatitis C, it actually has six different genotypes. They're all labeled either one through six and each of those or there are subtypes within those different genotypes as well. And those are all denoted with letters. So most people are actually going to be infected by a single dominant genotype, but thankfully now we do have some of those direct acting antivirals that are considered to be pan-genotypic. So this means that they can treat multiple genotypes and it not have to be a particular medication for an individual genotype. So examples of the medications that would fall within this category would be like your mavera, your epclusa or your bicepii. And the advent of these pan-genotypic therapies has made getting that sustained virologic response and cure obtainable across all genotypes. And in general with rather minimal side effects. So that's a really good benefit of these medications that we have access to now. Cassandra alluded to insurance being a major determining factor. And that may also be true when choosing the actual medication as well. So she talked about how kind of with the shorter perioperative courses earlier on this drugs and using this strategy may have been supplied more for research purposes and maybe were paid for by those drug companies. But since this is a much more widely accepted approach now that may or may not be the case anymore. And possibly that burden may ultimately fall onto the institution. So oftentimes the cost of these drugs are falling on either third party insurances and sometimes patients. So especially in those patients who get the full eight to 12 weeks of traditional therapy course insurance plays a major factor in agent choice and that's chosen to treat that patient. So some insurance companies, they may actually only have one pan-genotypic medication on their formulary. And that's the one that they require that their patients take. Many also do request that genotype testing is done prior to starting therapy despite the fact that we do have these pan-genotypic agents. It's just kind of an extra step that a lot of insurance companies do ask to be completed prior to authorization. And so there's some restraints from a medication choice from that perspective. Another thing to always think about from a pharmacist perspective is always drug-drug interactions. So there is a significant interaction with medications like Cephaspivir, which is in one of the components that's in apclusa and bosebi and in combination with amiodarone. So the use of amiodarone with these medications has the potential to cause bradycardia, which can be rather problematic, especially given the fact that amiodarone does have a rather long half-life. Another potential drug interaction to consider is with maverut. It's contraindicated with certain HIV medications or other medications like adizanovir or refampin that ultimately can reduce the plasma concentrations of the maverut therapy. And obviously we would want to make sure that we're maintaining adequate concentrations of our therapy for treatment purposes. And then another fairly common interaction to see in our solid organ transplant patients is with statins since it is a fairly common medication to see in our patient population. So statins with maverut can result in reduced statin exposure, or sorry, opposite of that, may result in increased statin exposure and can increase the risk for myopathies and rhabdomyelosis. And then another kind of prominent interaction that you may think of is with apclusa in our anti-acid agents, like your H2 receptor blockers or your PPI's. And these can reduce your exposure to the apclusa medication. So timing and spacing of these agents is gonna be rather important when concomitant use is necessary. So it's really important, especially in our transplant patient population, 'cause oftentimes these patients are maintained on one or the other of these agents while they're on higher doses of steroids. So it's always important to have a transplant pharmacist review these medications and as well as the other concomitant medications that they're taking to make sure that we're developing the optimal treatment strategy for that patient with the preemptive approach or early treatment approach that Cassandra had referred to, you may see the addition of other medications to help aid in the therapy. So you may see the addition of medications like Zeddia, which act as an antagonist and then you can pick C1 like one receptors, which is required for the actual entry of the hepatitis C virus. And theoretically, this can hopefully reduce hepsy-viremia in patients. So that's the reason that you're seeing the concomitant usage of the Zeddia, oftentimes with your direct acting antiviral agent. So you can obviously tell from the conversations with Cassandra as well as this that there's a lot of different strategies out there. And there's many different reasons to pick one strategy or one medication over another. - What are the advantages and disadvantages of each treatment strategy? - Yeah, so if we think about early treatment strategy, so this was when they were getting potentially a dose in the perioperative space and then they'll receive a full 12 weeks of treatment afterwards, this basically is giving us an opportunity for confirming that true-stained biological response with patients. Then we also have that more of kind of a preventative strategy and that is where we're giving them potentially that one dose in perioperative. And then seven additional doses for eight total doses for more of that preventative process. And so with those ones, we're looking at a super short duration. So we're not worrying about a full 12 weeks of therapy. We're not worrying about insurance, making sure that they can cover it for a full 12 weeks because if we have a patient paying out of pocket for any of these medications, they can be incredibly expensive. We are seeing potentially a little bit more of an increased financial burden though on institutions. So if we think about these patients that are on an eight-day course of therapy, that's the institution basically taking on that financial burden because insurance most likely will not approve and provide authorization for that since it's not an FDA-approved indication for this short course. And so you have to have institutions that are willing to take on that added expenses. These are very expensive medications, recognizing that it might not be covered or reimbursed the same way for insurance on the inpatient side versus outpatient side. And I can kind of play devil's advocate with the late treatment so or the traditional therapy. This ultimately requires that the patient becomes by remik. We have to type or get the genotype for the hepatitis in order to get approval for insurance and then ultimately have that genotype and that authorization before we're able to initiate therapy. So this can cause delays in time to the initiation of therapy since recipients ultimately do have to become by remik before we are able to obtain that genotype and send it off for insurance authorization. So that's one potential disadvantage. And then we obviously do have the longer treatment duration with the traditional strategy. And while the therapies in general do tend to be fairly well tolerated, it is still an eight to 12 week course of therapy compared to just taking like a nice little weeks course around the time of transplant. And there's obviously now the opposite thought in terms of increasing financial burden on the patient for co-pays since that burden for paying for more of the traditional course is gonna fall on that third party payer and then ultimately whatever co-pay that patient owes that payer. Is early treatment an appropriate strategy for all types of solid orange transplants? - So not necessarily the strategy for, for example, one group where it may not be the most appropriate are your patients that undergo liver transplant. So our hepatitis C likes to infect our hepatic cells and we know that it can cause both acute and chronic hepatitis and result in liver cirrhosis. So ultimately this kind of early treatment approach is not a strategy that we have been utilizing in liver transplant and are obviously our liver transplant patients, they may still get organs from hepatitis C, not positive donors, but they do traditionally receive the standard longer treatment approach. - What happens if a patient receives prophylaxis short duration, early treatment and becomes viremic? - So while this rarely occurs, there have been a couple of cases of patients becoming viremic after receiving that early short course therapy of the eight days. And in this situation, it was typically the maverick with setamide zedias, excuse me. In the situation, the patients would then need to complete a full 12 week course of antiviral therapy. It can be the same one that they were on previously or sometimes they'll switch it up and give a different medication. Either way it would be a 12 week course of the antiviral within confirmation of the sustained virologic response at the end of SVR. And typically that's done through that hepatitis C, RNA quant or whatever the local lab equivalent is. If they are still not receiving SVR by that point, then they would need to be on a longer duration of therapy. All of the cases that I've seen where they have positive off after that eight days of therapy, it has resolved by the time that full 12 week course of treatment has happened. And it's been only in a very small number of patient cases that I have personally seen and/or read about in literature. - That's all the time we have today. Thank you to our guests for a great topic and discussion. For our ASHP members, you can find additional resources and earn free continuing education by visiting elearning.ashp.org/podcast. Please note that credit for this podcast expires two years after the date this podcast is published. 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