Transcription:
Tailoring Liver Transplant Immunosuppression

Dr Pam Peeke: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Dr. Pam Peeke. And joining me today is Dr. Josh Levitsky, Professor of Medicine in the Division of Gastroenterology and Hepatology, Medical Education and Organ Transplantation at Northwestern Medicine.

Dr. Levitsky has been awarded a $16.4 million grant over seven years for his clinical trial on the utility of biomarkers of rejection and kidney injury in tailoring liver transplant immunosuppression. This award has been funded by the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health, Department of Health and Human Services under grant number U01AI163081. So here we are. Dr. Levitsky, welcome to the podcast.

Dr Josh Levitsky: Thank you, Dr. Peeke. It's really great to be here.

Dr Pam Peeke: Well, first of all, congratulations on the award. That is wonderful. I'm sure that was a happy day in your life.

Dr Josh Levitsky: Yeah, it's been almost a decade of work leading up to being able to put together a strong grant submission with really an amazing team at Northwestern and some collaborators and centers outside of Northwestern. So, thank you. I'm really excited to be here to talk about it.

Dr Pam Peeke: All right. Well, let's talk about it then. Tell us all about your clinical trial.

Dr Josh Levitsky: Sure. I think by way of background, I'm a transplant hepatologist and I take care of patients after liver transplant. And one of the big issues is that, right now, we practice very similarly to how we did 20, 30 years ago, which is lower the immunosuppression therapy after a liver transplant, kind of in, blinded fashion. And it's not really guided by anything other than we think they should be on less medicine as they get further out from the transplant. And it's a caveat here. It's a real balance between over- and underimmunosuppression. So if there's too much immunosuppression, they can develop complications like kidney problems from there are medications and risk of cancer and heart disease, infection, et cetera. But if we are to underimmunosuppress, they can develop rejection very easily. And so we really don't have a guide right now other than liver tests and blood levels of the drugs, which really only become abnormal when there's a problem.

And so we've been working the last decade on developing some biomarkers in the blood that can first sense the onset of rejection or immune activation as we are modifying the immunosuppression therapies such that by detecting that, we could maybe hold on lowering the therapy or go further if we don't detect that.

In addition, we've also developed blood tests that hopefully can predict whether somebody has a risk of developing kidney problems from their immunosuppression medicine, because not everybody does. And if we can predict that, then that might be a perfect candidate for someone to be on a real lowering protocol and lowering their immunosuppression with the use of the rejection biomarker.

Important thing is these are all in the blood and they're all being done serially rather than every six months or so. These things can be done at any time. And so the clinical trial we put together is basically doing just that. We're going to have 450 patients enrolled over five years of the study itself in seven centers around the country. And that patients will be looked at a month after the transplant and determine if they have a risk of kidney problems from the immunosuppression medicine or not. Those who are deemed lower risk are put into a control kind of a monitoring group as a comparison. And those who are at higher risk will be put on a strategy to really minimize their main immunosuppression medicine, which can affect the kidney and also increase risk of cancer, et cetera. These are called calcineurin inhibitors.

And what we're going to do is take them through a protocol to take them off of the calcineurin inhibitor much earlier than we do now and use the rejection biomarker to guide that lowering and withdrawal of the calcineurin inhibitor. And we replace it with something else called an mTOR inhibitor, which is everolimus. And this has no real effect or problem with the kidney. And it can be more favorable immunosuppression if patients are able to be lowered and taken off there calcineurin inhibitor and kept on the everolimus long-term. And we're hoping that the biomarkers really can reach that goal and the people who do not do well with lowering the calcineurin inhibitor or show signs of early rejection by the blood marker, we just maintain them on that drug. And therefore, the hope is ultimately this strategy will balance out the immune system problems, but lead to better outcomes in the subset who we predict can be off of the medication.

So really what it is, it's tailoring and personalizing a large patient cohort medication in a proactive way, rather than reacting to complications. And ultimately, at the end of this study, we hope that these biomarkers can be put into clinical practice to manage our patients in a more precision way than ever before.

Dr Pam Peeke: This is fantastic. And I know that this is going to impact on the future of liver transplantation if you do achieve these primary and secondary outcomes that you've already outlined. Taking a step back for a moment, Dr. Levitsky, can you just give us a general feeling for the overall morbidity mortality for people who undergo liver transplantation, just so we can understand what is the actual state of the art right now?

Dr Josh Levitsky: Sure. So one thing I want to say that liver transplantation is a very successful procedure in comparison to having liver failure, which, again, we don't have any kind of liver device that can support the liver. And so the benefit if patients are candidates are genuinely always in favor of undergoing a liver transplant than having end-stage liver disease.

That said, we want the outcomes to be better after a liver transplant. So one-year survival after liver transplant is about 90%, but then it continues to decline. So at about five years, it's around 70%. And at 10 years, some data show that it's about 50%. And this is the issue and the reason people have death occur or die after a liver transplant tends to be related to things that associate with overimmunosuppression complications. The top three are cardiovascular disease, cancer, infection, and then kidney dysfunction is right close to that also.

But we don't really have a great way, as I mentioned of reducing those risks right now. And we keep people on probably too much immunosuppression long-term because we're fearing rejection. And so, ultimately, to improve on that long-term survival, we really want to make an impact early on after the transplant. And that's the goal really is to get people enjoying a longer term survival with their transplant, with a lower rate of complications. And of course, quality of life too is very important. Some of these medicines can cause side effects that we also hope to minimize too, to improve their quality of life after a transplant.

Dr Pam Peeke: And this is such an important point, quality of life. Oftentimes when we get stuck in the weeds with metrics and looking at biomarkers and the rest of it, we have to step back as you've done so beautifully and really honor that whole issue of quality of life, because it's a huge change. And it's interesting, if I remember correctly, there were quite a few transplants performed throughout the country in general. What is it? Over 40,000?

Dr Josh Levitsky: That's overall. The number of liver transplants is a little bit over 9,000 per year. But, if you add that up, there's probably a couple of 100,000 liver transplant patients who are alive in the United States currently. And this is also increasing, too. The numbers of liver transplants have steadily increased in the last 10 years. I believe about 10 years ago, it was 6,000. And every year it goes up about 500 or 600. So we'll be crossing 10,000 liver transplants in the near future.

Dr Pam Peeke: I think it's really important for everyone out there just to hear these numbers, because many people who are not in this field are unaware. So there are over 40,000 total transplants, but, well over 8,000 right now, soon to be 10,000 at the rate we're going. So that's something that really needs to be fully appreciated. There's no question about that.

And I have a final question for you as you're doing this study, as you're looking at potential changes that will be taking place potentially, based upon your findings, how long does it take for new standards and new protocols to actually be integrated into the practice of medicine as it relates to liver transplants?

Dr Josh Levitsky: That's a really great question. And I think just by way of understanding that there's companies that are interested in these biomarkers and actually trying to implement them in a general practice, in addition to doing a study like mine, which is more of a definitive study. And so this is an evolving thing. And it does take time, especially with biomarkers where you need to really have very good validation and multicenter validation and prospective studies. It does take time, but I think in organ transplantation in general and the liver, I think is a little bit behind other organs like kidney and even heart transplant, and that there are actually approved biomarkers for managing those non-liver organ recipients. But we're getting close to this in liver. And I think it's really exciting. And I think because this is an expanding field, I think this technology will take off more readily than it was 5, 10 years ago when it was a little more like hype and hope. And so I think we're very close and this is really kind of an exciting direction the field is going,

Dr Pam Peeke: This is fantastic. Everyone, we've been speaking with Dr. Josh Levitsky, Professor of Medicine, the Divisions of Gastroenterology and Hepatology, Medical Education and Organ Transplantation at Northwestern Medicine. Dr. Levitsky, thank you so very much for sharing your knowledge and also the exciting news about your recent grant from the National Institutes of Health.

Everyone out there, if you want to learn more about this, please go to breakthroughsforphysicians.nm, like Northwestern Medicine, dot org slash gastro. This is an episode of Better Edge, a Northwestern Medicine podcast for physicians. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. For updates on the latest medical advancements and breakthroughs, follow us on your social channels.