EASL Highlights from the Hannover Liver Team

Now you can see the webbinar - EASL Highlights from the Hannover Liver Team

According to Heiner Wedemeyer from Hannover Medical School, the 2025 EASL Congress in Amsterdam highlighted significant advancements in liver diseases. Lisa Sandmann presented new findings in viral hepatitis, including long-term data for Hepatitis C virus (HCV) infection and new European guidelines for Hepatitis B virus (HBV). Katharina Hupa-Breier discussed metabolic dysfunction-associated fatty liver disease (MASLD) and new treatment options like semaglutide and firmin for various fibrosis stages. Benjamin Maasoumy focused on complications of liver cirrhosis, particularly acute kidney injury and portal hypertension, and new data on albumin treatment and TIPS procedures. The congress also showcased promising progress in cholestatic liver diseases and liver tumors, with positive Phase 3 studies for primary sclerosing cholangitis (PSC) and new immunotherapies for hepatocellular carcinoma (HCC). Common to the presented areas is the importance of individualized treatment and addressing metabolic risk factors in addition to viral causes.

(this summary is AI generated and not proofread, scroll down for a full transcript of the webinar)

Chair: Heiner Wedemeyer

Speakers from the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at Hannover Medical School (MHH), Germany:

• Heiner Wedemeyer
• Katharina Hupa-Breier
• Benjamin Maasoumy
• Lisa Sandmann

Thanks to our sponsor

Full transcript:

Heiner Wedemeyer: [00:00:00] Welcome everyone. I'm really happy to, uh, yeah, be here for the easel highlights from the Hanover Liver Team. Um, uh, my name is Heay. I have the privilege to chair here, the department in Hanover, and I'm really thankful for media who's to, to organize, uh, this very special event, uh, that is supported by Gilead Scientists.

But I really have to highlight, we are thankful to Gilead, but they had no insights at all in our selection of, um, our highlights, uh, from the Easel Congress, uh, 2025, uh, which has been held in Amsterdam. Uh, I have the privilege to, uh, hold this meeting together, uh, with Katina Rupa, AMI Masumi, and, uh, Lisa Sandman.

I will, uh, introduce them in a minute, but be before, uh, going into [00:01:00] more details. Um, I want to briefly introduce you, our team here in Hanover. Uh, you know, maybe that Hanover Medical School, um, has a long history. Michael Munz was, uh, chairing this department, uh, for more than 25 years. And, uh, we are, um, really dedicated to liver diseases and therefore we are very thankful that we have been asked to present our selection, um, of highlights from this Congress.

Um, our department is taking care about liver diseases, but I have to highlight that we are also taking care about infectious diseases, endocrinology, but also GI oncology, liver transplantation, nutrition, medicine, intensive care, and also, um, endocrinology, uh, including diabetes, uh, and lipid, um, mechanisms of, of lipid diseases.

So, so I think, uh, that is important because when we talk about the liver, the liver is really in the center of [00:02:00] pathophysiology of a variety of diseases and therefore this broad knowledge, um, uh, I think is extremely helpful to understand liver diseases in more detail. These are my potential conflicts of interest and obviously there's a selection, um, uh, uh, of, of papers which we are think are of interest.

And for those of you are listening and checking whether your own presentation is, uh. Uh, also selected during this, um, meeting. Uh, you may think about publishing your work in the Journal of Hepatology, which is the leading liver journal, uh, worldwide. And, uh, we have, uh, VLA Zi being the editor in chief since October, 2020, uh, four.

And he's supported by the deputy editors, um, and, uh, a team of co-editors and, uh, think about the Journal of Hepatology. As being your prime journal to publish your exciting work. Uh, right now I'm sitting here. This is Hanover Medical School. [00:03:00] Um, uh, we are, uh, located in a very green city. You can see the Park of Hanover Medical School, uh, transplant centers, but we are surrounded also by very nice translational research facilities.

Um, uh, together with the EG uh, Helel Center for Infection Research, we have a clinical trial unit here. Uh, I think a quite exciting environment. Um, we have been asked to cover highlights from the either Congress, uh, that has been held in Amsterdam, uh, from May 7th to May 10. And I can tell you this was really exciting.

There were, uh, more than 7,000, uh, interested or people interested in liver diseases attending these meetings. A lot of educational activities, but most importantly, really super exciting original work that has been presented for the first time in Amsterdam, uh, uh, across all liver diseases. And this is what we would like to show you what we think is really important.[00:04:00]

Uh, highlighting already at this stage is that, uh, we do not have the time to cover the entire meeting. Uh, some of you may be disappointed that your, uh, presentation is not mentioned specifically. Uh, and therefore I really invite you all to check the websites for additional presentations. Uh, there's also very nice material online available, uh, regarding, uh, best of easel contents, which has been selected by the Easel Scientific Committee.

Uh, have a look at this one. I think it's very useful also for educational purposes. I, uh, I'm happy now to introduce the team here. Uh, Lisa Sandman and Katerina are already, uh, on the screen. Uh, uh, both of them have been working in our department for quite some years. Uh, Lisa dedicated to Port Hyper Hypertension and viral Hepatitis Catarina to nutrition medicine, um, and metabolic liver diseases.

Both of them [00:05:00] have been working really very nice translational work. Um, uh, and, uh, also clinical work. Uh, Lisa has been involved also in the national guidelines for Hepatitis B, and she will probably mention also in the European guidelines, which Marcus Beck presented during the meeting. So at this stage, thank you Lisa and Katarina, um, for joining me, AMI Masumi.

I will introduce him later. He's slightly delayed, uh, for Trevor reasons, but he will, uh, be joining us in a couple of minutes here. So welcome, Lisa.

Lisa Sandmann: Yes. Thank you Haina for hosting the session and for the introduction. So I will start sharing the screen. I.

Heiner Wedemeyer: Okay. And we, we start with Lisa and then followed by Katarina and Lisa, uh, will start with viral hepatitis.

Uh, Katarina then will follow with, um, metabolic liver diseases, uh, ve masumi, all the issues around, uh, liver cirrhosis, [00:06:00] complications of liver cirrhosis. And then I will take in the end the task to cover, uh, the topics on choatic liver diseases, uh, liver tumors, and other, uh, highlights presented during the meeting.

But at this stage, uh, I would like to remind you all that you can also ask questions during this meetings. Just post them. Uh, we can, uh, all, uh, uh, address these questions here among this team. Uh, and therefore, feel free to have this as an interactive session. You're all invited to post your questions, but, uh, without further ado know, I would like to hand over these are very hepatitis easel 2025.

Uh, viral hepatitis was dominating the Congress for quite some years. Um, but, uh, to me the question is now, is there really still new things ongoing in viral hepatitis, um, C mission computed, uh, completed B, yes, back new therapies, Delta [00:07:00] is still the devil. Um, so I'm, were there new things or only the old, uh, topics, uh, let's say shown from a different perspective?

What is your, what are your thoughts?

Lisa Sandmann: Yeah, sure. Haina, there were many new things and it was really difficult for me to select, uh, to select among the huge variety of lectures and also excellent presentations and interesting poster presentations. So I will try to cover a little bit of everything in the next 20 minutes.

Um, but of course it's impossible to include everything because there were so many things presented at the easel. So I want to start with, um, two studies that indeed focused on hepatitis C virus infection, though. So there is still something going on for Hep C. So first of all, there is, was a study presented that included long-term follow-up data from patients that were treated in Egypt.

And this is a study that was conducted in the rural area of Egypt [00:08:00] and, um, in the beginning of treatments. So over the time they included almost 15,000 patients that received DA treatment. And the aim of the study was to follow up on these patients and to assess the incidence of hepatic decompensation, HCC mortality and importantly also fibrosis changes in these patients.

In this study that was presented at EA little bit more than 3000 patients were included for these follow up analysis and they had a follow up time of, uh, eight to nine years. Overall there were, in fact, despite the removal of the, of the virus, there were decompensation events. There were HCC development and there was quite some high mortality was 20% of the cohort.

What was also done was that the fibrosis, uh, stage was assessed by noninvasive techniques. So every patient receives FibroScan measurements. And um, additionally also laboratory, um, parameters were me [00:09:00] measured. And what you can see here that for the vast majority of patients, there was indeed either a stationary fibrosis stage or also a fibro improvement of fibrosis stage.

But you also see that in almost 20% of the patients, there was a progression of fibrosis stage and the progression of liver disease. So they concluded that overall, of course, there was beneficial outcome after HCV eradication. However, there was certain risk factors identified for decompensating events or for worse, um, health outcome that were older age elevated liver enzymes through albumin and advanced fibrosis at baseline.

But importantly, also other risk factors for fibrosis progression were identified. And these were basically metabolic risk factors. So this underlines that. Despite the viral eradication, we have to be aware for other diseases contributing to liver disease. The second study I want to highlight is a study focusing [00:10:00] on, um, acute hepatitis, acute HCV infection or recently acquired HCV infection.

And in this study a single r multicenter prospective phase three study patients with recently acquired HCV infection were included and were treated with GZA vir, so GP treatment for eight weeks. Importantly, um, patients were included that had either a reinfection or the first HCV infection. Overall treatment was, um, treatment performed well and you can see here the high SVR rates for patients that were included in this study irrespective, um, of the, um, status of prior HCV infection.

So in fact, it didn't really matter if this was a reinfection or a newly acquired HCV infection. So the authors concluded that also in recently acquired HCV infection, eight weeks treatment of GP is effective and safe. And those individuals that are [00:11:00] reinfected can successfully be treated with GP regardless of their prior history or prior HCV medication that was used.

So coming now to the next virus, the hepatitis B virus. And like Haina already mentioned, one of the highlights, of course, was the presentation of the new hepatitis B guideline, where I also had the pleasure to be part of the, of the group working on this, um, guideline for, yeah, a little bit more than two years.

So the final version of the guideline was presented at the Congress, and in fact, in this guideline, 10 chapters are covered. And of course I cannot, I cannot tell you everything that is included in the guideline. Um, but I want to highlight two aspects. And the one, the first one is about the treatment indication.

And one of the aims of this guideline was to like, in a way, simplify treatment indication for patients. Of course, all the [00:12:00] definitions or the definition of the phases and the consequences for treatment are still included in the guideline, but we generally, we designed a figure, um, like a flow chart that is yeah, hopefully helpful for deciding about treatment indication for the individual patient.

So the first step is always the HBS antigen positivity. And the second step is the question if there is advanced fibrosis or cirrhosis. And if there, if this is the fact, then it's pretty easy. As long as you can detect H-P-V-D-N-A treatment is possible depending on the cirrhosis or advanced fibrosis.

It's either a strong recommendation or weak recommendation to start antiviral treatment. On the other hand, we also included a statement focusing on the patients with really low H-P-V-D-N-A and um, no sign of actually liver disease. And this is a statement here that underlines that in this group of patients, there is actually a very, very low [00:13:00] risk of disease progression and that these patients do not require immediate antiviral treatment.

Secondly, there are patients that have, despite the low H-P-V-H-P-V Viremia still have elevated liver enzymes and basically it's possible to treat those patients. But we also wanted to emphasize that it's important to, to consider potentially other liver related liver diseases that, uh, contribute to these, um, elevated a LT.

So one example here is the ME D or the mesh. And of course there's another strong recommendation for patients with H-P-V-D-N-A levels higher than 2000 that have elevated liver enzymes or show, show other signs of liver disease or, for example, have risk factors for HCC development. The second thing I want to highlight is the second figure, and it's a figure on the stopping of nuke treatment.

And this is something that is new that hasn't been included before. [00:14:00] So there has been a recommendation that is possible in principle for certain situations to stop nuke treatment despite, um, not achieving H-B-H-B-S antigen loss. And in this, this up, in this new HPV guideline, this chapter is, um, we, we elaborated more on this topic.

So one important thing is, first of all, if you want to stop new treatment in a HPV patient, uh, expert should be consulted because, um, yeah, because, um, certain things has to be checked before stopping antiviral treatment. Of course, there's also a strong recommendation to stop new treatment in the case of confirmed HBS antigen laws.

So this is also a strong recommendation not to continue with new treatment. Um, yeah, just, yeah, just to rethink how long you should use the, the, the, the treatment in the case. If [00:15:00] HBS antigen is still present, there are little bit more detailed information and recommendation in which scenarios antiviral treatment can be stopped in patients, there are, there is a focus on the, on the, um, on the HBS antigen level.

So this could, should be determined and guide you in decision making. And last but not least, one important recommendation is also a statement on the reintroduction of nucleoside analog treatment, which is linked to the severe, to the HPV Viremia. So, and this has the, you all know about cases where HPV relapses occurred and these can be potentially, uh, harmful to the patient.

So it's always really important to monitor those patients closely and to start re-treatment at the right time point. Coming now to treatment and stopping treatment. Of course, there were some presentations or at ease also focusing on this topic. And in the next slides, I want to [00:16:00] guide you through the results of a long-term follow-up data of the retract, be the study cohort.

This is a cohort, uh, a global cohort, including patients fulfilling the, um, recommended stopping criteria for HPE antigen negative HPV infection, um, in patients that received nuke treatment, but are still HPS antigen positive. So in this, in this study, the former hb uh, the former Retract B cohort, um, was followed up for up to 10 years, and additionally, patients were included.

So in the end, the total cohort was a little bit higher than 2000 patients. And what was shown in the oral presentation is that during long-term follow up, 17% of the patients that stopped new treatment showed off treatment HBS antigen loss. When [00:17:00] stratifying, according to HBS antigen level, it was demonstrated that in fact, patients with very low HBS antigen levels were the patients showing the highest HBS antigen loss rates.

And patients with HBS antigen levels higher than, than thousand international units per ML had only HBS antigen loss rates of 6.3%. Similar results were achieved for the, uh, re-treatment after nuke withdrawal. So lowest, lowest rates for re-initiation of NA treatment was present in patients with the lowest HBS antigen levels.

So it was concluded that the highest rates of off treatment HBS antigen loss and lowest rates of re-treatment was present in patients with low HB s antigen at end of treatment. What about. Um, what about complications after stopping, uh, an age treatment? This was also collected during the study period, [00:18:00] and there are decompensating events in the patients.

So 55 patients developed decompensation events and 42 patients showed HCC development, which is 4% in incidence of 4% of the, uh, in the whole cohort. When going a little bit more into detail into those patients that developed HT C, it was shown that in fact, patients that had cirrhosis presence at the, at the end of nuke treatment, these were the patients that developed HTC during follow-up up.

So it was concluded that NA discontinuation should be discouraged in patients with HBS antigen levels higher than 1000. There are adverse events, they are overall rare, but they can still occur. So one have to be aware of this, and there's further research warranted into the D effects of NA withdrawal and HCC development.

A second study, and that was also presented at an oral presentation, investigated the effect of [00:19:00] additional, uh, pegylated interferon treatment after stopping nuke treatment. This was a fa again, a multicenter, randomized phase two study. Where patients, um, were randomized at the time point of stocking, stopping nuke treatment.

They were randomized according to the HBS antigen level, and either one group of patients just stopped the nuke treatment. But the second group and the second group of patients, they received sequential peated interferon treatment for 16 weeks. And the aim of the study was to investigate if the sequential interferon treatment would increase HBS antigen loss rates in those patients.

What you can see here is that in the green, the, the patients that received interferon showed a stronger HBS antigen decline during follow-up, and rates of HBS antigen loss were also higher in patients receiving sequential peated interferon [00:20:00] treatment. Again, the author stratified, according to, um, HBS antigen levels and highest rates of HB s antigen levels were again, achieved in patients with the lowest HB HBS antigen levels.

And with regard to post-treatment flares, they were also lower in patients receiving interferon treatment. So the con the conclusion was that sequential or adjuvant peg interferon increased the rate of HBS antigen loss and reduced the number of post-treatment flares. So coming now to the new components that are investigated for the treatment of HPV.

And I want to, um, highlight one study that was presented in the general session by professor Gain. And this study included the combina or investigates the combination of an HBS antigen antibody tova in combination with NIRA, Elon for the treatment of HPV infected [00:21:00] patients that are unstable, no treatment without significant fibrosis or fibrosis and patients.

In this study, three treatments arms are included. Tova monotherapy, so antibody monotherapy, the dual therapy antibody plus as irna or triple therapy, um, antibody as irna and pegylated interferon alpha. Treatment duration is 44 to 48 weeks, and the primary endpoints of this study are hbs, were HB HBS antigen laws at the end of treatment and after 24 weeks of follow up, the study is still ongoing and uh, the final analysis will be performed after follow up of 48 weeks.

What you can see here regarding the primary endpoint, so HBS antigen loss at end of treatment, and follow up, 24 highest rates for these endpoints were achieved in the triple combination or quadruple combination If you want to include the NA treatment. [00:22:00] But what you can also see is that HBS antigen loss rates declined from end of treatment to follow up 24 when stratifying, according to the, to the levels of HBS antigen, um, higher, higher HBS antigen levels are in lighter colors either for the dual combination or triple combination.

And what you can see in this figure is that overall during the study, HBS antigen levels declined and lower levels are maintained compared to baseline until follow up. 24, the conclusion was that tor and elone with or without interferon achieved HBS antigen loss at 24 weeks post end of treatment. And overall, higher rates of HBS anti loss were present in patients with low baseline HBS antigen.

Now coming to the last viral infection, [00:23:00] HDV virus, in fact, first of all, I want to highlight one study that focuses on bide. You all know bide is the entry inhibitor that blocks NTCP, which is approved in the European Union for some years now, as a late breaking oral presentation, the final results of the MU 3 0 1 study were presented by Meyer in the late breaking session.

So as a quick reminder, the phase three study includes three treatment arms that investigate different doses of olivatti monotherapy for a treatment duration of either two years for the delayed treatment arm, or three years total treatment duration for two milligram, which is the approved dose and bide 10 milligram.

So treatment duration two or three years, which is followed by a follow-up period of 96 weeks. And [00:24:00] at this, um, at the IS of Congress, the final analysis of the fight of the follow up period. So after 96 weeks of stopping olivatti treatment were presented. What you can see here, this is the distribution over the different treatment arms.

These are the end of treatment results. And for the biological response that is defined as H-D-V-R-N-A undetectable, so target not detected. What you can see here is that indeed the highest, um, the highest, um, H-D-V-R-N-A undetectable rates were achieved in the treatment arms in the patients that received bide 10 milligram

after at follow up 48. So 48 weeks after stopping bide treatment. Um. 42 50% of the patients that showed [00:25:00] H-D-V-R-N-A undetectable at end of treatment remained H-D-V-R-N-A undetectable after one year of follow up and higher rates of, um, of biological relapse were detected in the treatment arm in the delayed deferred treatment arm with patients only receiving two year bide treatment.

And now the final results of this study, so after two years of follow-up, all the patients that showed H-D-V-R-N-A undetectable at 48 remained H-D-V-R-A undetectable at follow up 96 weeks, which is 36% of all the patients that had H-D-V-R-N-A undetectable at end of treatment. And importantly, all relapses occurred between end of treatment and 48 in the presentation by solaman also focusing on the mere [00:26:00] 3 0 1 data.

Predictors of biological response defined as HDV RNA undetectable were further investigated, and it was shown that most of the relapses indeed occurred early after end of treatment. So after end of treatment and, uh, follow up. 24. So during the first six months after stopping treatment and importantly, predictors for sustained HDV RNA undetectable were identified, which are lower H-D-V-R-N-A and lower HB s antigen at baseline.

And importantly, earlier and longer on treatment H-D-V-R-A undetectable, which is also visualized in these graphs. So you can see here the duration of htv RA undetectable until end of, until end of treatment and color coded in blue, the non relapses and in red the relapses. So patients with longer duration of continuous HTV, RNHD, VNA undetectable at end of treatment, were less likely to relapse.[00:27:00]

Last but not least, one HDV study investigating again, the combination of tova and ELAP around you. Remember the two components I previously showed, um, in the HBV section of my talk? So the antibody and the S-I-R-N-A. So these two compounds are also investigated in chronic hepatitis delta patients. Again, non-cirrhotic patients receiving NI backbone treatment.

And the patients are randomized in this phase two study to either receive a combination of the two compounds, all the antibody monotherapy, and on this, um, at this easel, the interim analysis after 24 weeks of treatment were presented. And when you look at the results for biological response after 24 weeks of treatment, there were higher response rates in the combination therapy compared to the antibody monotherapy.

And also reduction in HBS antigen levels were more pronounced in the [00:28:00] combination therapy compared to the, um, Tobi monotherapy Clinical studies are ongoing. There's currently a phase three study conducted and also another phase three study and a phase two study investigating the compounds either versus olivatti or in bide naive patients.

So with this, I'm at the end of my talk. There were 20 sessions including viral hepatitis topics at the easel, more than 80 presentations, seven poster sessions, and more than 220 posters. Of course, this is not covered by a talk, but I want to invite you to go to the easel campus and check on, check the demand, um, presentations that are all available, uh, currently at the moment, but also in the upcoming month.

So thank you for your attention and I'm looking forward to the discussion.

Heiner Wedemeyer: Super, Lisa, thank you very much. Very, uh, interesting data and really a lot of things are still ongoing in, in viral hepatitis. We also have some [00:29:00] questions from the chat, but, uh, let me just ask from the beginning. You started with hepatitis C and, uh, basically two main presentations.

The one that was really impressive from Egypt, uh, that presentation, and again, to all of you are listening from Egypt, I think the, the colleagues there have to be congratulated for their spectacular program, um, summarized for those of you who don't know this in detail in the New England Journal of Medicine paper published in March, 2020 with and colleagues, uh, this is impressive and they really saved a lot of lives.

My message from, from your summary is that still, even though, uh, HCV has been cured, some things may still happen thereafter. And then can you, can you still elaborate? Uh, obviously we just listened to presentations, but one questions that was posted here also, um, if you highlight again, how many of them who died, died really from liver [00:30:00] disease versus, uh, maybe non-live related complications, uh mm-hmm.

If you have this information in detail, can, can you comment on that?

Lisa Sandmann: I think, um, in the presentation they, uh, they only demonstrated the liver related death, so this number should be liver related death. But to be sure, I would need to have to and would need to double check. But, um, I think the important finding is that there are still other things going on in the patient and also in the univa and multivariate analysis.

Diabetes malitus popped up as a risk factor. There was higher BMI associated with the development of liver related endpoints and also, um, hypertensive disease. So these are things that remain despite viral eradication and, uh, play contri our major contributor at least to, to also to to liver related outcomes.

And it's important to also treat those conditions.

Heiner Wedemeyer: Heina do you may [00:31:00] comment, I don't know whether you will have this in your summary, but you analyze the German Hepatitis C registry together with Dr. How also after HCV Cure. Highlighting the, the importance of metabolic, uh, diseases. Right?

Katharina Hupa-Breier: Yeah. Um, uh, so I'm happy that you're discussing this point because I think that will be, that will be the challenge in the next year.

That, now that we cured, um, hepatitis C and that we have very promising, uh, therapy treatments for HBV and HDV, I think we, it will be interesting in the future to see what impact will will have, uh, in particular diabetes and obesity on, on the cause of these diseases. And maybe in the end the patients will have a fibrosis development, but not maybe based to HDV or other viral hepatitis, but due to, uh, metabolic disease.

And I think it will be, we need more research on that topic, um, about the, um, influence or impact on metabolic diseases on the long-term follow up [00:32:00] after, uh, on these patients.

Heiner Wedemeyer: But, but what the outcome of your finding from the German Hepatitis C registry? We found

Katharina Hupa-Breier: in our study, we also found that, um, obesity, um, impacts, uh, the long-term progression of liver diseases and that patients, although they were cured from, um, hepatitis C, that they have a higher risk to develop fibrosis if they are obese.

Hmm. And I think the role of alcohol is also, uh, inter discussion. I mean, uh, we've. We did not see a positive, um, or we did not see that, uh, alcohol increased the liver of, uh, the risk of liver fibrosis, which is interesting because there are other studies which, um, demonstrated that alcohol increases the risk of liver fibrosis also in patients, um, after hepatitis C virus infection.

So I think it will be very interesting in the future to to really look at these different, um, categories of just metabolic disease, metabolic with alcohol. Um, that will be our future, [00:33:00] uh, goal or aim to make further investigation from that.

Heiner Wedemeyer: I think that that's important, but to highlight the role of alcohol, we're talking here in that analysis about a very tiny little amount of alcohol in the far majority of patients.

Yeah. So, uh, we don't want to underestimate the risk, but at least on the other hand was a large cohort of German Hepatitis C registry, a couple of thousand patients that a tiny little amount, at least in this analysis, did not worsen the outcome. And it, it's, uh, while on the other hand, the metabolic dysfunction, right?

That was the driver, um, of, of complications. Uh, and there's data from Taiwan also in the context of hepatitis B, that the, the number of, uh, cardiometabolic risk factors really matters. It's a different whether you have one risk factor or three risk factors for, for outcome. I think these are, uh, a brief second question on hepatitis C.

Uh, the, the, the, you mentioned this sub-analysis of the phase three study on recently acquired hepatitis C. Um, uh, if you [00:34:00] could briefly comment, what are your, after having listened to that presentation, what are your thoughts? Are there, is there any reason, let's say not to treat, uh, recently acquired, um, hepatitis C virus infection?

I.

Lisa Sandmann: I don't see any reason not to treat because, um, I mean one factor might be okay, maybe the, the, no, it's not a, I was talking about money, but I, in fact, I don't think that is, uh, any, um, opponent to treatment. So, I mean, there are two things we want to pre prevent, uh, HCV becoming chronic and we want to prevent spreading of HCV.

And when you have a look at the more detailed analysis of the cohort, you see that the, the patients that were act, all of the patients have any risk factor of acquiring HCV, otherwise they would've never acquired HCV. And a lot of these patients are still exposed to risk factors or risks or behavior that is linked.

CAN is, is a potential risk factor of, um, newly acquire or reacquiring, [00:35:00] HCV. And we are, um, reducing the overall burden of HCV in these groups of, of persons or individuals. And I think this is, this is really important and otherwise we will never achieve our WHO goals of eliminating HCV.

Heiner Wedemeyer: So, so, so what are your thoughts?

So I received, I think two or three weeks ago I received a call from a colleague who saw a patient with acute Hepatitis C. He said he would like to treat this. But the patient still had liver enzymes of a LT, I don't know, 1100, and he, he, he asked me, well, should I treat now? Should I wait until the a LT is declining?

Is there any risk in this acute severe hepatitis to start this, uh, direct anti, uh, direct acting antivirus? What would you, you have answered if the colleague would've called you?

Lisa Sandmann: I think so regarding to risk and safety, the data we have, it shows that it's safe to treat those patients. We should, we, there's no need to be, be afraid [00:36:00] of causing harm or causing more liver damage and the time point of treatment.

I think it's also connected to the type of, of patient or individual we have. If it's a patient who wants to wait, who is who will come again to the next appointment, then I can, we can also discuss to wait and see if it clear spontaneously. But if it's a person who I think, okay, maybe it's one or two time contact, seeing a physician, I don't know if he or she will ever come back.

Then maybe it's the better option to just give it the treatment and give it a try.

Heiner Wedemeyer: Yeah. I think that I, I, I completely support this, uh, this, uh, yeah. Strategy of, of addressing hepatitis C. Uh, both regimens have been shown to be safe, uh, also in the acute setting. And, uh, uh, there, there's, I think the data is so overwhelming if you really want to stop this, uh, uh, disease worldwide, the [00:37:00] epidemic of Hepatitis C virus infection, we, we have to treat them early.

Uh, we have a current, in the current issue of the Journal of Hepatology one analysis that, uh, uh, until now about 13 million people worldwide have been treated with hepatitis C virus, infection with interferon free regimens. Um. But only 13 million. Right. And, uh, Nicholas Luman for the WHO wrote on editorial has, uh, that that mission is by far not completed.

And, uh, uh, if we want to complete our mission, I think we have to include acute hepatitis C and also to address what Katarina mentioned, the metabolic risk factors. These are few, few questions on, on HBV. Mm-hmm.

Benjamin Maasoumy: Uh,

Heiner Wedemeyer: the guidelines, uh, quite some discussions. Uh, can you highlight again? So, so you mentioned that you have, I think what is really nice that you differentiate the two wordings you have, uh, where I think there's no discussion when you really have to treat, uh, and, but you also offered now the option, let's say there are [00:38:00] always discussions, gray zone in between, yes or no.

And that you are think, and my understanding were very wise with Marcus Komberg saying you allow treatment in distinct uh, conditions, but it's not an absolutely must. So, um, it's this, this, uh, and, and does this hold true for all gray zones? So the high viremic versus the low vir Viremic. Mm-hmm. Uh, can you, can you summarize also the discussion that you had among the team?

Lisa Sandmann: Mm-hmm. So we are not. Using the term Gray Zone anymore, we wanted to get rid of it because it's causing so much confusion and, um, uh, you co you are completely right. So the aim was to really emphasize the, the, uh, the strength of the recommendation and the strength of treatment indication. And there are scenarios where there is really a strong indication where we should treat or must treat.

We can also say, and there are scenarios and situation where it's still possible to treat since as long as the patient is HBS [00:39:00] antigen positive and wants to be treated, then we can treat, or there's at least it's covered by the guideline that there we can treat these pa these persons. Of course there's a different, there's a different, uh, need behind the treatment or the different, or the, yeah.

Yeah. So. Basically, that's it.

Heiner Wedemeyer: I, I think it, it, it, it is very wise. Uh, then there of, we could talk, uh, for one hour on the HPV guidelines, but, uh, just one topic on the, the stopping nukes, uh, strategy. So you showed this in a very nice figure, which I really like in the guidelines, but on the other hand, uh, you also showed the presentation from retract B, uh, that in distinct patients there were even hepatic decompensations in the off treatment phase.

Uh, so can, can you highlight again the factors that, uh, the, the group identified where we have to be a little more careful, maybe not to [00:40:00] stop, I think, because that's really critical. And then how would you manage one of the most frequently asked questions, uh, patient monitoring after stopping nukes? Uh mm-hmm.

And I think in one of the sessions, uh, Marcus has been asked, what does close monitoring mean? If you wanna talk about

Lisa Sandmann: Yeah, yeah, yeah. So relevant question, all of them. So in the retract B study, so now the 10 year follow-up data was presented, so the study was started 10 years ago, and they also included patients with advanced, uh, fibrosis and also patients with cirrhosis.

And, um, those were the patients that developed complications and, um. For those patients, we do not recommend to stop or we, we say we should not stop treatment in those patients as, as long as they are still HBS antigen positive. Um, second close monitoring. We are afraid [00:41:00] of severe flares leading to hepatic decompensation and patients with, uh, advanced liver disease.

They are in particular at risk of developing those complications. So, uh, even though if we don't stop treatment those patients. Also, for the patients without advanced liver disease, we recommend close monitoring. That means at least every four weeks, uh, we have to control the liver enzymes and also H-P-V-D-N-A and we have to restart treatment.

When patients show these strong elevations of H-P-V-D-N-A and a IT elevations, they are delayed after H-P-V-D-N-A increase. So we do not wait for this, these severe a IT elevations. We also know that these elevations, they are not linked to HBS antigen loss.

Heiner Wedemeyer: You must be by the study

Lisa Sandmann: from, from the Stop nuke trial that has been published.

Heiner Wedemeyer: Yeah. And, and I think also you mentioned the importance of HPVD in a monitoring, yet that may be costly in distinct settings. Uh, but also in the paper published in the Journal of Hepatology from Trac B, [00:42:00] uh, I think in March, uh, they also showed that the level of H-P-V-D-N is really defect of, of, of severe.

So be aware, uh, we could talk again for, for longer time. Last questions, um, on, uh, on Delta, obviously I have to, and you mentioned, uh, the nice presentations and, and I think that the 3 0 1 study, uh, clearly showed you that if you're negative after one year of treatment, that there are no late relapse, which I think I like it.

But can you, can you briefly touch again on the, the bide, let's say real world experience, that, that either mm-hmm. These are better also presented from Milan. Um, uh, any surprises from the real world experience as compared to the trials 3 0 1, uh, 2 0 4?

Lisa Sandmann: I think it's surprisingly interesting that the numbers match so nicely.

So the real world, uh, or the clinical studies nicely reflect the, the response [00:43:00] rates in the real world. So, um, at least for all the patients we are seeing, we are see, we see comparable results. There are some patients that don't show. A biological decline or that, uh, that level to us that, that, yeah, that, that stay at a certain level.

We saw, we see, uh, a LT improvements in most of the patients. And also for the stopping experiment experience, there's data available from Vienna and um, that also show basically comparable results and importantly also the safety of the reinitiation of olivatti treatment. So we are not, uh, like gambling with the response rates.

So the patients that were re-treated with olivatti, they decline. Again,

Heiner Wedemeyer: I think very important. Also very nice that the Delta community is working together, that we combine data, uh, which I think is, uh, reassuring that, uh, the, the treatment is safe. And importantly we have hint from Elizabeth's work that this is reducing the number of [00:44:00] events, uh mm-hmm.

That we are really improving clinical outcome. And that's the last word I'm talking to, to long with you. So I, taking the time, I have a look at the time, but you have to mention, uh, your work also on, again, on this portal, hypertension gradient during bide. So you have 30 seconds claiming your exciting work.

Lisa Sandmann: Yeah. So overall the question is, okay, what does biological response really mean? Does it translate into clinical benefit? And the strongest surrogate marker we have for a clinical deterioration, or on the other hand, clinical improvement, is improvement of portal hypertension, because portal hypertension drives the, the severity of liver disease and the risk for development of liver related complications and death.

And what we did in our study together with, um, AMI Masumi and our colleagues from Vienna, we showed that in fact, what patients that achieved these, um, suggested treatment endpoints from the clinical trials, they show regression of port hyper hypertension measured [00:45:00] by the gold standard of HVPG measurement.

Heiner Wedemeyer: Yeah. So I think that that's remarkable that you manage together with the Vienna team to, to really measure at two time points gradient, uh, which I think is, is really super cool and, uh, uh, and important. Um, Lisa, thank you very much. We will talk, maybe come back to some of the mm-hmm. Hepatitis discussions later on.

Uh, but now Katarina mentioned that it's nice to clear the virus s uh, control the viruses, but it doesn't completely help if you don't address that. People may still suffer from something else. And that is, uh, taken care about the inflammation caused by fat in the liver. Uh, Katarina, uh, I was partially overwhelmed by all the, the data and presentations on metabolic dysfunction associated thetic liver disease.

Uh, we still have to practice to pronounce this long, uh, word correct [00:46:00] way. And again, CATA AYA is taking care in our department about, uh, of nutrition medicine where she's really an expert, uh, and taking care about, um, patients also with fatty liver disease. She also has worked experimentally translational work on mouse models, and she's really an expert in this field.

So thank you Katarina, for, uh, presenting as your selection. I'm really interested now what you will show from this, uh, from these many, many abstracts, what your highlights are. Thank you, Katarina.

Katharina Hupa-Breier: So thank you very much for this nice introduction and, uh, yeah, it was really challenging and I try to focus on the, um, most, uh, clinically important, um, studies.

So these are my disclosures. And let's start with palm prevalence data, which I think are very interesting for us. As we just discussed, um, about the impact of metabolic syndrome on liver disease. And this was a very large, uh, study, uh, from the liver screen cohort. That's a, uh, European [00:47:00] study, which was, um, applicated in nine different European countries.

From May, 2018 until December, 2028. And the aim of the study was just to investigate the overall prevalence of undiagnosed liver fibrosis. First of all, um, just any cause of, uh, liver fibrosis and the use the by CTE. So the, um, FibroScan to detect the liver, um, fibrosis risk. And they set up, uh, that, uh, a liver stiffness, uh, greater or uh, equal than eight kilo plus cals.

Um, that this is a risk for liver di fibrosis. And these patients were included in a further evaluation for liver disease. And the primary outcome was just to know how about how is the prevalence of livers dys nerve more than greater than eight kilo pascal. And, um, these are the overall, uh, demographic results.

And I think it's already interesting that nearly 90% of the included patients where [00:48:00] Caucasian and um, about 60% of the patients were female. And as you already see here in the metabolic risk factors and the alcohol use, obesity and overweight is a problem in the overall cohort. And in this patient. We have to mention there are, uh, patients included, um, age, uh, with a, um, older than 40 years.

So it's, um, it's already covering a large, uh, cohort of patients. Um, the, also we have to mention the alcohol use. So already 18% of these patients had a difficult alcohol use or risk alcohol use, um, for risk of liver disease. And already 3.5 of these patients had a high risk alcohol consumptions. And when you then look at the, um, prevalence of liver stiffness measuring greater than eight already, 4.6% of all patients have a liver stiffness greater than eight point already.

2.5 [00:49:00] patients have greater than 10, and um, 0.8% of all these patients have already liver stiffness greater than 15 kilo pascal. Uh, they also measured the cap value with it, uh, which is a non-invasive marker for the liver steatosis. Already 30% of these patients had a higher risk, uh, or had a, um, elevated calf measurement.

And from all these patients who had, um, uh, liver stiffness measuring greater than eight, there were then, um, followed up to hepatologist, um, um, examinations. And in 32% of all these patient a chronic liver disease was confirmed. And then, as we already discussed, um, we really have to look on the risk factors and, um, it's, yeah, it's not very, uh, unexpected that, um.

Um, on the one hand, the strongest predictors for, um, uh, a an [00:50:00] elevated liver distance measurement were obesity, type two diabetes and alcohol use. And then I think they did an interesting analysis because then they looked on how, um, does the onset on metabolic liver, uh, on metabolic risk factor factors in conclusion with alcohol use?

How does this, um, impact the, um, prevalence of, um, chronic liver disease? And what they could show is the more, um, metabolic risk factors you have and the higher use of alcohol you have, then of course you have a higher prevalence of liver stiffness greater than eight and therefore a higher risk for liver fibrosis.

So I think, um, this study really highlight that obesity type two diabetes and alcohol are the strongest predictor for, um, advanced liver stiffness and that we really have to take care on these patient, even if they have maybe a hepatitis C before then there. I mean, especially for a [00:51:00] metabolic disease. We are now very, um, we have some treatments, uh, in the pipeline and we have already in established, um, or in treatment, uh, which is, um, applicated in the us but now we really have to figure out.

Who pay or who should we treat? And um, normally the liver biopsy is the gold standard to diagnose, um, the M-I-S-L-D, but we really have the need to also find non-invasive markers, which could, uh, accurate, uh, diagnose fibrosis and stare hepatitis. And here there was an interesting study from the litmus, um, study cohort, I think, you know, the litmus study.

It's a, it's a huge, uh, study, which is, uh, taking place in the Europe and, and the us And in this study they prospectively evaluated the diagnostic accuracy of biomarkers in a large multicenter cohort study. [00:52:00] And I mean, there was just recently also, um, published, uh, an interesting study from the German MILD study group, which already highlights, um, that the, uh, YCTE might be difficult to especially detect patients with F two F three fibrosis.

And I think this even highlight that we really need, um, uh, accurate, um, accurate diagnostic markers, um, for both for fibrosis, but as well for STA two hepatitis. So in this cohort, they um, evaluated different markers for both for STA two hepatitis and for for fibrosis. And I think what this study really shows nicely is that it's very hard to identify patients who are at risk.

So patient with a severe STA to hepatitis. Um, that's really challenging. We have some good non-invasive marker to really, um, [00:53:00] um, to, to, um, di um, accurate diagnosis fibrosis. And here again, the elastography based markers such as by CTE and as well MIT based markers. They were really significant and they could show a significant diagnostic accuracy to detect patients with severe fibrosis stage three or four.

But on the other hand, the study really highlight that we need more non-invasive markers, especially to identify patients at risk and maybe, um, patients in the earlier stage of, uh, fibrosis. And there has been, uh, for example, another study from the Rotterdam cohort and the Hanes cohort, which also shout the, that the F four, which is the, um, non-invasive marker, which is currently, um.

Um, um, or which should be currently used according to the guidelines to detect, um, advanced fibrosis. That this marker [00:54:00] has also some difficulties, especially to detect, uh, this intermediate and advanced fibrosis. So I think, um, there is more, um, study needed and when we now go yeah. To the important point of treatment.

Um, uh, I would first of all go to treat me M-I-S-A-D in the early stage of disease with patients who had only maybe F1 to F five, F three fibrosis. And here there was, um. Secondary analysis of a large study, which was already, um, represented on the last year. Uh, it's a study of the, um, GLP one and glucagon receptor agonist zide.

And here I have highlight once again, um, the outcome of the phase two study. So IDE really showed an impressive improvement of, um, fibrosis with no worsening of mesh in this patient. And as [00:55:00] well an impressive improvement of patients, uh, stare to hepatitis without worsening of fibrosis. And the aim of the secondary investigation was to really differentiate between the effects, which are more or mainly mediated by weight loss and the effects which might be mediated behind weight loss.

So, um, if there might be some more direct effect, especially from the glucagon receptor agonism. And, um, for this analyzer, they pooled all the patient, which were included in this first phase two B trial. And then they did a, a mediator analysis to really detect the media, the effects which were made by weight loss.

And what we could see is that, um. It was quite expected that the mesh resolution, so the improvement of inflammation and as well the improvement of, um, stato. This is mainly driven by the weight loss. So [00:56:00] here we could see that the improvement of M-R-I-P-D-F-F, uh, improvement of mesh by, uh, mesh resolution, um, and the cap, um, that this is really driven by weight loss.

But, but interestingly, the liver related endpoints, which were more, um, associated to the improvement, inflammation and improvement in fibrosis, there were, um, less correlated to the amount of weight loss. So the autism concluded that there might be a, a second direct luon effect in this co agonism. And I think, um, there is further, further studies are needed, um, to really figure out, especially for all of these, um, GLP one agonism, which are effects only made it by weight loss and which effects, uh, maybe might be behind weight loss.

Um, talking about GIP one agonism, of course, there was another analysis from Semaglutide. So at the moment we have the Smit run [00:57:00] as the first, um, approved therapy for patient with mesh and F two F three fibrosis and semaglutide, um, has applicated the improvement, um, for treatment in the European country.

And the results of the EMAL GLUT study has been presented last year on the A SLD. And the patient had shown an improvement of, uh, STA hepatitis and as well in improvement of liver fibrosis after the treatment with, uh, the malu. And this was a secondary analysis of this study. And the orders wanted to assess the concordance of, on the one hand histological, uh, endpoints.

And on the other hand as well, and again, the non-invasive, uh, markers response to MLU treatment. And what the study showed is that, um, in these patient who has been treated with mlu, a higher proportions of patients who received semaglutide improved in both, um, on the [00:58:00] histology level, but also on the level of non-invasive markers.

And that the improvement in non-invasive marker was even greater than the improvement in histology, which might mean that, uh, we have an even better, um, rate of response in this patient. And on the other hand, the concordance in the placebo group was also good. And, um, there, um, the histological improvement or placebo improvement of this patient was nearly conant to all the, uh, slight improvements to, uh, the non-invasive marker.

And a last secondary analysis of another very, um, interesting, um, treatment option for patient with mesh. It's, uh, the analysis of an FGF 21 algon. So this is the FDF 21 LON PHE Fain. This is a long-acting, um, only, uh, algon, which only has to be, um, treated once [00:59:00] monthly. And, um. The results has been also po, um, presented last year on the A SLD and for the first two, uh, for the phase two trial.

And, um, here they could really show that patients after 24 weeks of treatment with this serin has an significant improvement of fibrosis and as well, um, um, also good re improvement of mass resolution. And based on this phase two trial, the orders now did another secondary analysis and they had a, um, deeper look into the improvement of non-invasive markers for fibrosis.

And as well, they wanted to look how fast is the response rate of fibrosis improvement after implementation of the treatment. And, uh, what they could show that, uh, also the improvement of the non, uh, non-invasive marker of fibrosis was [01:00:00] significant higher in these patients who ha have been treated with a feos fermin compared to placebo.

And I think, which is interesting, um, is that the author could show that this improvement, um, really developed very shortly after four weeks of, uh, treatment. Then you can already see that there is a shift in the overall balance on fibrogenesis to fibro lysis. And I think this is then interesting, and this might, um, also explain why the FGF 21 NAR logons are so strong in improvement, uh, in the improvement of fibrosis.

Now, I talked a lot about, uh, treatment, but um, I think we already know, and I think we already noticed in our daily life that now we don't see, um, only that we do not see only patient with mesh, but we see more and more patient with mesh um, cirrhosis. So it's important for us that we also have treatments who, uh, which are safe in patient with [01:01:00] advanced fibrosis and even in the stage of cirrhosis.

And here they have been. I think for me, the most important studies have been presented in this field. And we ended, uh, with an FGF 21 NR logon for the patient with F two F three fibrosis. And I will start also with fermin, which is also an FGF 21 algon. And this was a very important study which, um, tested Xi Forin in patients with, um, histological proven compensated cirrhosis.

And these patients have been treated for 96 weeks and then they have been, um, biopsy, um, eval, uh, or have been evaluated with a biopsy at the end of treatment. And what you can see here, this is a very good, um, collective of patients with A-M-I-S-L-D. So we have a high percentage of type two diabetes and as well, we have a still patient with a high BMI.[01:02:00]

So, and this study have been, uh, recently, um, published in the new journal of, um, new England Journal of Medicine. And the primary endpoint in the study was improvement of, uh, fibrosis after 36 weeks of treatment. And after 36 weeks of treatment, Fermin did not have a significant improvement of fibrosis, but now they re uh, they presented the results after 96 weeks of treatment.

And here the orders could show that we have a significant improvement after 96 weeks of treatment in patient, in the fibrosis stage of these patients, and especially in the higher dose in the, uh, 50 milligram dose. And they, um, did two analyzers. They looked in the, on the ITT, um, population where, um, the significance was a little bit lower, and then they just looked at the 96, uh, [01:03:00] complete, um, um, subgroup.

So they only included patient who really completed the 96 weeks and had a biopsy at the end of treatment. And here they could show a significant improvement in these patients. So the orders concluded that the treatment with 50 milligram Roif Fermin for 96 weeks resulted in a more and a higher, uh, improvement of fibrosis in these patients.

And I already mentioned that um, Smit is the first approved therapy for, um, M-I-S-L-D and it's already approved in the, um, US and already used there. Here in Europe, we still cannot use Smit unfortunately, but we hope that it will be approved, uh, that it will be on the market for us at the end of summer.

So I think this study is also an important study for us when we get ResMed, um, in the treatment possibilities. So this was also a study which tested Resm Mitrione in patient with, uh, [01:04:00] liver, um, csis. Um, we have to mention that this was not a placebo controlled study. And, uh, we do not have histological endpoints in this study.

But again, the orders, uh, looked at the non-invasive, uh, markers improvement, um, in these patient regarding the improvement of liver stiffness and as well the improvement of, uh, clinical significant portal hypertension. And Lisa already mentioned that the portal hypertension is, I mean, for patient with liver cirrhosis with the most important clinical aspect because this is a driver of the complication and the further disease.

So, um, regarding the lev, um, measurement in liver stiffness based on five CTE, uh, measurements, and the orders could show that even after one year, um, patients improved after treatment with RIS terone in the liver stiffen. And this improvement was even more significant [01:05:00] after two years of treatment. And interestingly, and they could also show that, uh, there have been a sub support group of patient which really showed and decreased in their liver stiffness or their fibrosis, um, development so that patients who had a, a, a previously staged at four fibrosis based on by CTE and Bino criteria that they have a significant improvement of their fibrosis.

And regarding the clinical most important endpoint, the clinical significant portal, hypertension. The authors could also show that, um, there have been a significant improvement of portal hypertension in patients even after two, uh, after one year. But that this improvement was even more advanced after two years of treatment.

And they divided these patient in two different subgroups. So they looked at patients who had a baseline only a low risk for [01:06:00] significant portal hypertension, or no, um, hint of portal hypertension. And here, there only, um, a, a very small amount of patient progresses to severe portal hypertension. And I think which is even more important that they would show that patient who had significant portal hypertension at baseline, that these patient really improved in the, um, portal hypertension and that we have, um, um, um, significant decrease in patients after two years of treatments who suffering from significant portal hypertension.

So I think this is really an important benchmark, um, study for us, um, because it shows on the one hand that RiskMeter is safe in patient with fibrosis, and on the other hand that Smit is able to improve, um, clinical marker or the um, of, uh, liver cirrhosis. And last but not least, uh, when it comes to liver fibrosis and mesh, there was another late breaker study, um, with a completely different, um, [01:07:00] treatment, um, idea that was a Galatin three inhibitor.

So GALATIN three is, um, uh, pro, uh, is, is a pro fibrotic, um, um, marker. And the GALATIN three inhibitor reduces the fo uh, pro fibrotic activity of galatin three. And there was a phase two trial, uh, which was, uh, published a couple of years ago and which looked on the impact of, um, Galatin three inhibitor bactine on patient with meh cirrhosis and portal hypertension.

And in this previous study, they could not show a significant overall reduction of, um, um, portal hypertension, uh, in this patient. But when they did a subgroup analyzer, they could show that, um, in the subgroup of patient who did not have, um, Verizons at the beginning of the treatment, that these patient on the one hand improve the, um, portal hypertension.

And on the other hand that [01:08:00] the, that there was a reduction of the incidence of new varis in this patient. And so they conducted, uh, another trial, did another analysis in this subgroup of patient and they tested the bila pectin in patients, um, with mesh cirrhosis, portal, hand hypertension, and no riss at baseline.

And the primary endpoint of the study was development of riss or development of river related events or significant adverse events in, um, the indication for tips or, um, more than 12 months, um, of, um, GLP one therapy on non-selective beta blocker therapy. And, um, the auto, first of all, of course, that the in ITT analyzes and then the ITT population, they could not show a significant difference, uh, for the treatment with bapak time.

Although we have to [01:09:00] mention that there was, um, a higher number of patients who did not, um, completed the study. So then they did a pair protocol, um, analyzing with lower amount of patient. But in this subgroup they could show that bila packin with a two milligram significant reduces, um, the amount of psoriasis, um, and the, uh, in this subgroup or in this per protocol, um, population after 18 months.

So I think we have to see whether Bapak team has really, um, yeah, we have to see the, about the future of Bapak team because we have some other treatment options on the market, uh, which might, uh, treat both the portal hypertension and as well the underlying disease. And I think we need further study and I think the field is ongoing and, um, I'm looking forward to the A LD this year.

Heiner Wedemeyer: Super. Uh, thank you very much. Uh, Kalina. [01:10:00] This is, uh, really exciting. A lot of things are ongoing and I think to me, the most important message that, uh, I learned from your presentation and from the Congress is, uh, that there are, let's say there's hope for patients, uh, that, uh, new treatments on the, uh, on the horizon.

Uh, but, uh, there are still challenges, uh, uh, at this stage for patients being, um, affected with metabolic, uh, uh, problems. But my first question is, so quite frankly, I'm a little confused, um, regarding the, uh, all the scores, uh, that have been used, and also you mentioned the very nice litmus data. Pretty cool.

Uh, then we have seen the, the algorithms, uh, for potentially say treatment indications for ResMed room, uh, with, uh, either eight to 15 or 10 to 20 kilo pascal. And, uh, then flip four. And, uh, many people mentioned, uh, that it's in the end not useful. And you know, that Andrea [01:11:00] banal here from our team also showed that, uh, there's a lot of discordance.

Uh, there have been 20 other scores that each meeting you have, uh, many scores. How, how to deal with this. Uh, what would be your idea? Sh shall we do in Germany, we are talking about 20 million people with fatty liver disease, but like we, it's impossible to do 20 thou, 20 million, uh, fibro scans, uh, in these, uh, individuals.

So, uh, even though F four has limitations, is it for you out or is it still a good screening tool in the, in the, at the very first step? Maybe? I,

Katharina Hupa-Breier: so I think this is, um, the really big challenge at the moment that really have to figure out who is it. So we really have to know who's at risk for develop, uh, the disease progression.

I mean, we already know that obesity and type two diabetes are the most important risk factors for patients with M-I-S-L-D to progress, but I think we, we need to know [01:12:00] more. So we need to know more about the, uh, specific risk factors of this patient and coming to the diagnostic. Um, yes, I think FIB four is not out.

No, I wouldn't say, because I think, as you mentioned, we have a, I mean, MS D is affected about 40%, uh, of the worldwide population. So we, what we need is an easy tool, which really rule out significant advanced disease at the beginning. So, and I mean, although some studies showed that the FIP fall might be not the best tool, um, of course we know from the daily routine that it's not able to.

Make an MRI on every patient. So I think MRI based tools are not clinical useful, um, for our daily clinic. So I think the fifth four, um, together with our clinical look so that we, when we look at the patient, we really have to do an ultrasound to see whether they have, um, fibrosis, um, signs in the ultrasound and maybe just look on the thrombosis, just [01:13:00] see whether we have, uh, um, low platelets or not.

And then I think altogether this makes a very good first impression. And I, we all, I think we have to mention fifth four was mainly useful to rule out advanced fibrosis. And then I think in the next step, uh, the FibroScan is an easy and handle good, good tool to also, um, to rule out significant fibrosis on the one hand.

And on the other hand, to detect, to detect really severe fibrosis. Mm-hmm. It might be not the best tool to detect the intermediate stage state of fibrosis, but, but I think, um, for the, I mean for the clinicians, um, for the diabetologist, um, it might be still a helpful tool to really, uh, differentiate between these patients who are high risk to have a, a severe liver disease or who not.

Yeah.

Benjamin Maasoumy: I have an annoying follow up question. Am I allowed to ask an annoying follow? Absolutely. I would've [01:14:00] challenged you. Welcome Benjamin Masui. So Carolina FibroScan is perfect, but in Germany I. No. And also in other, many other countries actually, um, most of the doctors don't have FibroScan. Yeah. So, um, the question, I have two questions.

The first question is, in terms of FibroScan, what about the other techniques that are widely available and integrated in the ultrasound machines? So share wave, rfi, share, wave, phy. And, um, the second question would be, how can I diagnose F two or F three to start with ome? Yeah. In the US and hopefully in summer in Germany.

So you have 60 seconds to answer the question.

Heiner Wedemeyer: Not

Katharina Hupa-Breier: that's what I mentioned. I mean, uh, the paper from ban and, um, the MIID study group deals with this problem, and I think that's really important that this will be the big challenge, um, for this will be the big challenge for us to [01:15:00] diagnose these patient without a liver biopsy.

And we need more markers, um, um, for that. And I mean, um, some other good non-invasive marker. They're all all based like the AGL three or four. They're all based, um, on liver stiffness measurement as well. So I think this will be the big challenge

Benjamin Maasoumy: in terms of stiffness measurement to, to make that clear. So stiffness measurement is the, are there other techniques also, or

Katharina Hupa-Breier: of, of course there are also other techniques, but the, um, the cutoffs are not as.

As good as Ev evaluated at the cutoff for the FibroScan. I think that's again the problem. Yeah.

Heiner Wedemeyer: So, so my message is, uh, there are good hints, but even if you use FibroScan and because it may not everything, you cannot biopsy everybody, you have not, not, uh, the patient, uh, with, with, uh, FibroScan available, uh, be critical because it's not the answer to everything.

I think the, the, the most important point, if the five, if F [01:16:00] four is really low, below 1.3 and the likelihood is not very high, even though then you can miss some patients with fibrosis and think, have a look at this with a comorbidity, et cetera, for time with Catalina treatment. Super exciting. So we have Rasm Terone, we have the in Incretin mime, we have FGF 21.

We have the new treatments that you showed in the, uh, in the late breaking session that even in cirrhotic patients, uh, we may, uh, go in. So what are your thoughts, um, if, uh, our treatment of, uh, mesh will be in three, four years? Mm-hmm. Will everybody, uh, get a, uh, um, let's say same matter, um, uh, uh, all the other, uh, dual triple mode of action, uh, or is it, uh, is one after the other, uh, in Hepatitis C?

Lisa mentioned the combination treatments all in, uh, at very [01:17:00] first to really be, be successful. What do you think how we will treat, uh, mesh in 3, 4, 5 years?

Katharina Hupa-Breier: Uh, um, I think as a nutritional, um, doctor as well, I think we should not first. I forgot, we should not forgot our, um, the baseline treatment. We should not forgot to treat patients with imp, um, nutrition that we, uh, need, um, them to increase their daily activity and they really need to, um, improve their nutrition because we know that this is so important and we know that we just cannot treat the huge amount of patients, uh, with obesity and maybe, maybe osis.

Um, so I think this is the baseline in a really. Want to mention this once again because I think it's so important that now we, that we have treatments, we might forgot that weight reduction is the most important treatment in this patient first. And I mean, of course, um, then I [01:18:00] think the results, uh, for the GLP one agonism for edema, glut, and as well for, um, the Riss mirum are very, um, promising.

And I think there will be some promising therapies, uh, therapeutic options in the future. I think it will be, it will be not only one therapy, we have to maybe, um, combine, uh, therapies, which on the one hand treat the underlying metabolic conditions such as GLP one agonism. And on the other hand, maybe the, um, fibrosis such as FGF 21, um, nardo, and I mean, they have been, um, published a small interesting study which analyzes patients on a stable GLP one, um, treatment with MLU and add on fermin, which was, it was only a small study with, um, I think 30, 30 patients.

But it showed a very, um, safe, it was safe and it showed a good improvement in both fibrosis and liver fat. [01:19:00] So I think, uh, that, that the treatment combination will be the future and that we really have to, once again, that we really have to figure out more about the specific individual risk factors of the patients.

But, um. I really want to highlight it. Once again, if we cannot change, um, the lifestyle of this patient, that, I mean that we can put on the best treatment, but as soon as we, um, kind of have to stop the treatment, then the stato will come back if the patient didn't change anything else.

Heiner Wedemeyer: Okay. When we talk about nutrition medicine, uh, last question to you.

How much coffee coffee should they drink? And what type of coffee?

Katharina Hupa-Breier: Uh, as of course, as much as I want at least three cups per day, uh, and the good German, uh, I don't know the English word filter coffee, little

Heiner Wedemeyer: coffee, yes. Mm-hmm. Yeah.

Katharina Hupa-Breier: It's, uh, it's the best one.

Heiner Wedemeyer: Yeah.

Katharina Hupa-Breier: And, uh, yeah, I think [01:20:00] maybe just to to to the end, there was a very nice study for a liver transplant patient, uh, who had a pre and post transplant, uh, follow up on with nutrition and medicine.

And that was really impressive because it showed how, uh, so, uh, efficient nutritional medicine is in, even in these, um, thick patients. Yeah.

Heiner Wedemeyer: Quite interesting. So, so, uh, you, you talked in your last part about treatment option for liver cirrhotics, and I think this is a nice bridge to Ben Masumi. Uh, then you see many, many patients with liver cirrhosis also to, to metabolic dysfunction.

I'm very much interested how to deal now with complications of liver cirrhosis in general. Uh, what were, uh, your highlights from the easel Congress 2025? Anything new?

Benjamin Maasoumy: Yeah, thanks. I, of course, many new things and also for being such a creative person in terms of the, uh, presenting the next talk and the next [01:21:00] topic.

Unbelievable. The bridge was excellent. So I start, these are the conflicts of interest. I'm a little bit, I will go to as fast because we have not so much time. So that's, if we talk about liver cirrhosis, obviously more complicated than just CSPH or compensated or decompensated. We can nowadays differentiate several stages of cirrhosis.

But however, here I will keep it simple and I will just use the old, um, the, uh, I will just keep it old fashioned and just, um, show you first some data from, let's say earlier stages of liver cirrhosis, where we have, um, where they're pretty much focused on the, um, on the improvement of CSPH and also rises and Verizon bleeding.

This is an important study, and it's already now almost six years old, but this PRSI trial showed that a actually beta blockers, so lowering portal pressure, portal pressure by [01:22:00] non-selective beta blockers is also beneficial for the patient if he has no or only small psoriasis. This has not been done before this study, but in this study they were randomized placebo controlled trial, and it was not about Verizon bleeding.

Beta blockers prevented hepatic decompensation, and this was pretty new. And this actually also translated into guidelines or let's say the Bino recommendation that nowadays also recommend nbs apart from, uh, from bleeding prophylaxis, apart from high risk psoriasis, just for the prevention of hepatic decompensation in patients with clinical significant portal hypertension.

So our entire paradigm, our entire strategy in patients with a Rosas shifted. From a world that was mainly driven by endoscopy and the detection of arises, and then prevention of rise bleeding. To a world where we [01:23:00] don't want to detect psoriasis, we want to detect clinical significant port lip hypertension, ideally by non-invasive markers.

And as soon as we have diagnosed clinical significant port lip hypertension, we do not want to prevent variety bleeding only, but we want to prevent any kind of hepatic decompensation, including ascites and also encephalopathy. However, there are now some very interesting new data because the question remained whether beta blockers are equally good as the good old varietal bent ligation via endoscopy for the primary prophylaxis of varietal bleeding in those with high risk psoriasis.

Older studies suggested that they are more or less equal, but however, there are no newer data and there was this very nice prospective multicenter, randomized style from the UK and they only cured patients with medium or large horizons. So high risk psoriasis, and [01:24:00] then there were treaters with either cavity law or randomized to band.

Patients were mostly compensated child A, but also you can see that some patients or significant number of patients had some sitis. And the interesting part was that indeed there was no difference. So in terms of a rise of bleeding, there was no difference between car liver treatment and band ligation.

However, if you have a look on secondary outcomes, you can see that beta blockers seem to be beneficial in terms of other HEP events of hepatic decompensation, although I have to say that this was not statistically significant, you can see that there are some, there seem to see some bi benefits in terms of all cause mortality and also a new onset in terms of aus.

However, the study was not powered to show that, and therefore maybe the results were not significant. However, in terms of costs, [01:25:00] cavity oil was less costly because it just is a cheap drug and it does not cost as much as bent ligation. So you have low intervention costs, you have less endoscopic surveillance, which also produces costs.

And due to the fact that there was a numerically decrease of other hepatic decompensation events, you have also lower costs of managing liver complications. So in terms of primary prophylaxis. I would say that in instead of what is stated in, at least in the German guideline currently, that you can use beta blockers or bent implication equally in primary prophylaxis for rise of bleeding.

I would say according to this data, beta blockers should be first because they seem to have other beneficial events, at least cost wise. However, what is, what is this? Um, what is the, what is it, um, what is the situation in patients with more advanced liver disease? And the question remain whether dual therapy, so using [01:26:00] both cardio as, as well as benli in combination might be better than doing again, uh, alone in terms of ation.

And, um, last year this study was published. Where from India, where they also randomized the patients is a smaller trial. Carlo versus Ben Ligation versus Carlo plus Ben ligation. And while Carlo versus Ben ligation was not different in these patients, there was a benefit in terms of rise bleeding prophylaxis if used dual combination therapy.

So this is good for the endoscopy unit. So you can still do endoscopy. However, you have to be aware that this study has some discrepancies in terms of secondary outcomes. So the, it's questionable, at least in terms of the study design. And also you have to be aware that only those patients with child B or C, so decompensated patients were included.

So for child A patients, I think there is no role in combination therapy because there are no data for [01:27:00] that. But for the patients that have decompensated cirrhosis, um, you may think of bent litigation, at least if you see in the endoscopy that you have high risk psoriasis that may even progress during beta blocker treatment.

Talking about progress under beta blocker treatment, and one explanation for this data could be that we have a reasonable number of non-responders to beta blockers. We know from older studies that about 20 30% of patients do not respond to proper neural treatment, but can then be treated with C load.

However, in terms of the CAV response, they're not really good data and it's still a matter of debate whether there are really non-responders to cav load. This study from India investigated 229 patients with cirrhosis and port lip hypertensive bleeding, whether a beta blocker response can be measured or predicted [01:28:00] over time by non-invasive markers.

And they used, um, HVPG as gold standard as well as liver and spleen stiffness at baseline, but also all the three measurements 42 days after car. Lower treatment initiation response was defined by an HVPG three increase of more than 20%. So the first striking result of this study is that actually 61% of the patients were non-responders to NSBB treatments, so, so c treatment, and only 7% of all patients achieved an HVPG response of less than 12 millimeters of mercury, which is associated then with almost no chance of variety of bleeding further on.

But this was only the case in 7% and only 40% roughly were considered as responders. The good news is that spleen stiffness seemed to be of high value in predicting response. So in terms of accuracy to predict response at six weeks after treatment initiation, a decrease of 10% in the [01:29:00] spleen stiffness measurement was quite good with a negative predictive value of 84%.

And if you have no change in spleen stiffness measurement from baseline at week three or an increase even at bleak uh, at week six, this was highly predictive for re-bleeding during further follow up. So another study does suggest that spleen stiffness measurement could be a valuable tool in patient with cirrhosis in the future.

So I'm coming now to the more advanced stages of liver cirrhosis and talking about complications and one of the major complications that comes first in the natural history. At soon as we have really multi-organ failure, the first organ that often fails and is from prognostic, prognostical wise, very important, is a kidney.

So, acute kidney injury is a big deal. You know that in liver cirrhosis. However, it was really complicated and it was really complicated to dive, diagnose, [01:30:00] HEPA syndrome in the past, which is obviously the syndrome that we are most concerned. When it comes to liver cirrhosis, he syndrome was really compensated.

We were very, very at the end of the naturality of liver cirrhosis. However, still maybe the first organ that really failed in terms of, uh, and when it comes to patients with liver cirrhosis, however, it was, it's complete, very complicated diagnose, hyperreal syndrome. And there was a consensus meeting last year and this interdisciplinary international consensus meeting, they really had the aim to facilitate things and facilitate the diagnosis and offer the opportunity to start with tele present earlier.

So instead of the 30, 48 hours that this was currently, uh, that was actually, uh, required to diagnose HEPA syndrome, you needed 1248 hours with albumin treatment. They shortened this to 24 hours and they even stated that [01:31:00] albumin might not be required, but you can also do the plasma expansion with other, other things, for example, thus crystally or whatever.

But the most important thing, I think was the abbreviation of the time from 48 hours to 24 hours. They also stated that the presence of underlying other underlying kidney diseases, that this does not exclude, that the patient did have has this, that the patient still has Hyperreal syndrome. So HEPA syndrome can also happen in a patient, whereas, for example.

Um, di type two diabetes and an associated kidney disease. However, I'm coming back to this albumin treatment for only 48 hours, uh, for only 24 hours instead of 48 hours because this was simply stated. But there are no data to support that. So there are no data to support that you need 48 hours. But there's also no data to say that 24 hours is better than four eight hours.

And there was a very nice present. And at the end, if you abbreviate the, [01:32:00] the, um, treatment and start earlier with tele present, I have to emphasize the 30 present actually does lead to renal, uh, improvement of renal function and reverse and can achieve reversal of HEPA renal syndrome in patients with liver cirrhosis, which was here shown in the confirmed study four years ago.

But if you have a look on survival, early present does not improve survival compared to placebo on the long term. Not even on the short term. So in terms of the patients that died, 90 day mortality is exactly the same between 30 present and placebo and is even slightly higher. And you have to be aware that 30 present can also have some severe fight effects.

So, coming to that, there was a very nice study, which is already published also in the Journal of Hepatology. From mines and it was together with colleagues from Yna and they investigated in, in retrospective analyzers of prospective, um, prospective. We collected patients from two [01:33:00] different cohorts, whether there's a difference in terms of the response criteria that are proposed from easel and other studies In terms of the, um, response criteria during this albumin treatment, within the first 48 hours, this was the first thing they investigated and they found out that the currently proposed easel definition, which is a simply a zebra creatinine decrease in at least one a KI stage is the best response criteria when it comes to survivor benefit after the, um, after the response.

So the other criteria that have also been proposed in the past were not that good. So if it comes to clinical relevance, you better stick to the creatinine decreases ease definition, which is created decrease in at least, which results in at least one a KI stage. However, the more interesting part of the study was that they also analyzed whether it is, whether the patients that do not respond after [01:34:00] 24 hours of albumin treatment may respond in the second 24 hours.

So until the, until the second day of albumin treatment is over and strikingly, they could show that it doesn't matter which response criteria you use. Above about 20% of the patients that from the entire cohort will not respond after 24 hours, but after 48 hours. So is actually, if you start 30 treatment here, it is an over treatment.

So 20% of the patients that need 30% or in 20% of the patients, 30% can be saved if you use another day. If you wait for another day and, um, treat another day of, um, the patient with omi. And they could also show that if you have an increase of zero creatinine by more than 16%, this actually has a negative within the first day.

This actually has a very high negative predictive value for non-response afterwards. So they suggest that [01:35:00] you should treat the patients for 48 hours with albumin like we did it two or three years ago. But if you have an increase of creatinine on the first day of more than 60%, so after one day of our main treatment, then stop and start TelePro right away.

So albumin is obviously something that is really intensively discussed, and we have two major studies available from the recent years. The first one is the entire trial. In the entire study, patients that were hospitalized for acute decompensation of liver cirrhosis were treated with high dosages of albumin.

Just within the first days. This was actually not. Associated with any improvement in relevant secondary endpoints. Apart from the slide, maybe, um, better, um, better or lower incidence of kidney dysfunction. But however, overall there was no improvement and there was even a higher rate of pulmonary edema in those with high dose that were treated [01:36:00] with high dosages of albumin.

And then there's another trial, the answer study where the patient did not receive a high dose of albumin, but these were outpatients that received on a long term low doses of albumin, which were 40 grams per uh, every two weeks. Um, on, but on a long term. And they actually documented a survivor benefit and a benefit in several different endpoints.

And now we really were quite excited about the data of the Preza study. And this study from the design was let, let's say, a combination of the other two studies, though the patients were included at 62 sites in the, in Europe and also in the, um, US and patients were included if they had liver cirrhosis and they were hospitalized for acute hepatic decompensation.

However, in contrast with the entire study, they did not receive a high dosage of albumin right ahead, but [01:37:00] received albumin for a long time, every 10 to, uh, every 10 to 12 or 10 days. Um, uh. As more or less one and a half every one and a half week. They received albumin for quite a long time for up to one year.

And this was compared with standard of care and the primary endpoint was liver transplantation or deaths within one year. This was a study population that were just highlight that these patients were similar to the ansa study had only moderate asus and also in terms of the male score, they were quite ill median male score of 16, but it was also not end end stage.

So it was pretty much, I think a little bit sicker than those, um, in the ANS answer study, but at least more or less comparable. However, the study was negative, so there was no significant difference in ltx three survival. There was only a small trend towards a better survival in the albumin group and this seemed to be better in those with grade two or three ASCI SOSA patients.

[01:38:00] However, it was still not clinically significant and also if you have a look on the secondary endpoints, there were more or less no really, um, significant effects. There were some effect in terms of HEPA renal syndrome again, so in terms of kidney dysfunction, our mean seems to help. And also in terms of SVP, there was a signal, however, that is all for all.

There were very, very low number of cases that were responsible for the significant difference, however, importantly and told just to the entire study. Where they used this high dosage on the first day of albumin, there was no higher incidence of pulmonary complications. So it was safe treatment wise.

What about other things that can be used with albumin? There was actually really another prospective study in terms of albumin treatment here. It was used for treat hyponatremia, which can be really challenging in clinical practice. And again, it was used for 10 days, one gram per kilogram on the first day, which is a high dosage, and then 40 grams on day two till [01:39:00] 10.

So really high dosage of albumin here, which might be a difficult problem in terms of costs and also safety. However, in terms of resolution of hypernatremia, they were quite successful for 50% of the patients with amine compared to F. Uh, 15% when with standard of care, um, achieved resolution of hypernatremia in this study.

Okay. Last but not least, what about tips? And I will talk about tips not because of personal interest, but also because there was, um, the publication of the clinical practice guideline of E. So the first clinical practice guideline of easel on TIPS treatment, um, was published and presented. And, um, while this was presented, there was also I think another very interesting study.

Uh. That was also presented as oral presentation, and this was from the Euro Chipps registry with also [01:40:00] easel, um, funded. These are real world data from all over the world. Um, prospectively corrected, collected in the Euro chips registry. And this is now an interim analyzers and it gives you a pretty good overview what is really happening in referral centers in terms of the outcome and also in terms of tips, indications.

So currently there are almost 1,900 patients enrolled and 1,334 cirrhotic patient had already a one year follow up and were included in these analyzers. And I think what is very interesting is obviously the MELT score is a media melt score of 14, but also what is really the most important indication for tips.

And I can say in contrast to Hanover, where we have, I think most tips are, um, used for refractory situ on an international level. Majority is actually used for portal hypertensive bleeding, which you can see here. So almost the half of the patients received the tips [01:41:00] primarily for portal hypertensive bleeding in this cohort.

So what about the outcome? On an international level, we see that the one year survival is quite good. It's 80%, however, you have to say that 10 additional percent required liver transplantation. The best outcome, and this is something that we know from other studies. It in primary, uh, in secondary prophylaxis of port lip potential bleeding.

This is far better than if you use the tips in refractory. However, these patients are also less ill, they have less advanced stage of, they're less, um, advanced in the natural history of liver cirrhosis. However, which was quite disappointing in the study was that neither the fryberg index of, um, post tip survival nor the MEL score nor the cliff, um, uh, cliff score.

What a really good predictive value for mortality or complications after tips. So this was, uh, the authors emphasized that we knew that we obviously need new alternative, um, predictors [01:42:00] for positives outcome. In terms of a cyto solution. 80% almost has achieved the cyto solution. However, what we could also see is that above about half of the patients developed over hepatic phalopathy.

Uh, within the first year. Hepatic phalopathy was quite a debate through the meaning of hepatic phalopathy after tips. There were two studies that were published quite recently, one in the Journal of Hepatology from Italy, where said, it's doesn't matter if you develop HE after tips, your survival is similar.

However, they did a mistake and they make, uh, they made a mistake in terms of the. In terms of the immortal time bias, and this was really discussed in the Journal of Hepatology afterwards with several letters, and we also performed an analyzers from the German, um, within the German cirrhosis network, where we could show that if you exclude the, um, immortal time bias that those patients to develop an early age E, so [01:43:00] within the NA first 30 or a 90 days after tips, if they already develop an empathic phalopathy, then this is indeed a problem in terms of survive.

How can we prevent hepatic phalopathy? And, um, I'm quite happy that we already talked about nutrition and um, I want to share this study with you because this was quite interesting. This was a study where they tried to prevent hepatic phalopathy after tips. However, the rational was, from my perspective, is quite confusing.

So they actually stated that protein excess might be a problem for hepatic phalopathy, which is not in line with our current understanding. So they had three groups. One was liberal, so the patient just do whatever they want. Then they have a dilate protein recovery where the patient refers on a protein restriction, and then they increase the protein intake to what is recommended for cirrhotic patients.

And then an accelerated protein recovery group [01:44:00] where they more or less directly started with the protein. Um, commend per the protein intake for the patient with is recommended for cirrhotic patients. And what you can see here, and what's very important is that you can see the liberal diet groups, so where they do whatever they want.

And the delight protein group, they are the worst. Uh, they are, they do not very well. They develop high, uh, they developed quite, quite early hepatic phalopathy while the accelerated group, they have the lowest incidences of hepatic encephalopathy and the curse really separate at the beginning. So this really means that the study was not well designed, but it really supports that you should use proteins and high protein intake right away.

So the very last point, what about other complications and chips? And we recently published a paper about the relevance of Hepato pulmonary syndrome. This was work by, um, Jim Mals and TAM from our department. And they could [01:45:00] show that actually port hyper pulmonary syndrome and, um, intra pulmonary shunts are very, very frequent in patients with cirrhosis affecting about 30% of the patients.

And if you have that, this is worse. Uh, this is bad for your outcome in particular when it comes to cardiac decompensation, but also for hepatic decompensation. However, what we were not able to show in this study in the first study was whether the tips. Really improves maybe HEPA pulmonary syndrome because HEPA pulmonary syndrome on the other side is driven by portal hypertension.

And Jim MAs did a follow-up study where he investigated all the patients, again, six months after tips. And I think this was really fascinating. So 70% of the patients really decreased and 37 patients. Um, so 70% of the patients really decreased from, um, HPS and had no HPS in the follow [01:46:00] up, which I think is striking.

And, uh, this work is ongoing and I hope that we can follow up you later on when we have all the data also from the biomarkers. So I will stop here time-wise to have some discussion time and also to give ena maybe three or four minutes for his talks. Thank you very much.

Heiner Wedemeyer: Thank you. Super cool. Uh, thank you Ben for this.

Um, APK is amazing, really how we personalize the treatment management. Let's start with nutrition loss and Catarina may also jump in there. So, um, uh, first of all, in this, they had three arms and the liberal arm, uh, or liberal behavior. Did worse, which I think reflects my clinical experience. You really have to tell the patients, uh, to behave otherwise, it's, uh, it's usually not ending in a way we wish to.

And, but, but, uh, Catalina, so early protein as much as possible, uh, from, uh, or what is your recommendation if a patient had undergone [01:47:00] tips right now?

Katharina Hupa-Breier: Um, I mean, there was another study which was presented as a poster from, I think it was a Spanish study, which also, um, evaluated the protein enriched diet, uh, in addition to, um, exercise therapy.

And they could even also show that, um, protein enriched diet meant, uh, in combination with exercise before and after tips implantation, uh, significant decrease the rate of, uh, overt hepatic and ence encephalopathy. So I think, um, it is really important, first of all, to, to really, um, make a diet, um, a good diet and, um, to increase the protein intake in this patient.

Still, there might be some patients which. M might not really, um, um, accept or can tolerate this high amount of proteins. And there is still a discussion in the nutritional world going on. Um, but, [01:48:00] um, I think overall these patients should be treated, especially for their thia and, and for their malnutrition, and this is important.

Heiner Wedemeyer: Okay. Ben Mon, do you wanna comment on, on, I think, thank you, Kaar, on, on diagnostics of, uh, encephalopathy after tips? Um, uh,

Benjamin Maasoumy: very well. Yeah. I mean, just briefly maybe to the study that, uh, that, um, Kaari mentioned, interestingly, the exercise and also the nutrition intake was not effective in improving, uh, the physical capacity of the patients and also did not improve any, um, other outcomes in terms of, uh, muscle and SMI and so on.

It was just phalopathy that was improved, but, uh,

Katharina Hupa-Breier: a little bit of, uh, a little bit ofia.

Benjamin Maasoumy: Uh,

Katharina Hupa-Breier: so no, but I think this study, but

Benjamin Maasoumy: sport is good. My message is sport is good for the brain, so I, I got that, that I think that is the thing. But in terms of, of muscle growth, it might be a, a problem. I think. Uh, there were studies last year with testosterone and testone analogs.

Maybe we need also [01:49:00] medical therapy for that. Yeah. In terms of phalopathy, um, uh, diagnosis prior and also post trips I posts, I think there's no role currently in doing really, um, really diagnostics for minimal encephalopathy. So for covered encephalopathy, although. Um, we are still working on that and, um, there might be some tests that might be feasible, but for this time, just right now, just look at the patient and overt hepatic encephalopathy is what really matters.

But early, and this was a study by Martin and also Zaman, uh, which I briefly showed early encephalopathy, um, is really bad for the patient. And this, there are more and more data and we are currently working on international level, on a meter analyze with all the people that wrote letters in the JH uh, in Journal of Hepatology.

And maybe there will be the definite answer, uh, within the next month.

Heiner Wedemeyer: Okay. Second question from my side, albumin now. So, um, I'm confused. Yeah, that's good. [01:50:00] I'm, I'm really confused, uh, seeing the, the, the papers from the uk the data now. So what shall I do in clinical practice now with albumin? Those, when, how long outpatient, what is your take home for which patients?

Um,

Benjamin Maasoumy: I think from now on, as for, for now, I think we are quite good with sticking to the rules that are there for 10 years or 20 years. So Hepa renal syndrome, do it. Um, in terms of SVP, do it. But in terms of other, all the other indications, this should be, be something that, that is No, there's no role for, let's say, uh, that you use it in your entire patient population.

It can be really on an individual based situation that you have a patient that really has problems with the citus and you can do it and try whether you can improve phalopathy in an individual patient, whether you can improve hyponatremia. But on the [01:51:00] large scale, there's no role apart from the indication that are already in the guideline.

Hmm.

Heiner Wedemeyer: And, and, uh, uh, few points also, you mentioned effects hyponatremia. Can, can you comment a little, uh, how to deal with this? If I, if a patient is coming in, uh, sodium 1 27, uh, maybe you're not really sure whether it is he based with ammonia or whether, uh, let's say these, uh uh, yeah. Uh, hyperemia may contribute to this one and, and how to manage this from the clinical perspective.

Benjamin Maasoumy: I think hypernatremia is really tough because, um, it's multifactorial and, um, also underestimated and the clinical consequence, it is really a very, very important contributing factor for phalopathy. Mm-hmm. Because it targets exactly the same, it from, from the petrol mechanism, exactly the same like, like, um, the [01:52:00] hypo ammonia.

Um, the only thing that you can do is you can stop the diuretics. You can use your brain and think once because you have to figure out whether this really true hyponatremia, which is really rare, or this is like the volume overload, which is in the, is the case in the majority of cases. And if you have a volume overload, obviously the correct thing is that you use fluid restriction and you can use also albumin.

Other medical therapies are not really valid in the cirrhotic population. However, I have to emphasize in terms of the true hypernatremia. This can also happen in patients with cirrhosis. Mm-hmm. Um, Tiga published a very nice paper where we use this continuous drainage of sitis. If you have, for example, if you have a tunnel catheter, um, a peritoneal catheter, and you or you have also patient in a hospital where you use large volume para sizes every day, they really lose sodium via this paracentesis and this drainage.

And then you can really have a true hyponatremia. So [01:53:00] true. Um, lack of sodium. And then you may even. Substitute sodium even intravenously. Or you can also do it bionutrition. So this needs to be, um, considered because it can happen in very, very sick patients.

Heiner Wedemeyer: Thank you, Ben. So again, cirrhosis is, uh, complicated.

Uh, we have concepts and I really like that with, uh, many clinical trials, some. All concepts have been challenged to give some answers, but I think we can really personalize treatment starting from nutrition, sports. Thank you Katerina, uh, to these, uh, um, yeah, uh, intelligent uses of, uh, the treatment options we have.

Let me give, let me take few minutes on, uh, addressing other intelligent, uh. Uh, developments, uh, in choatic liver diseases, which I found very interesting. I don't know what your feelings were guys, but, um, uh, it was the very first ease of Congress where, [01:54:00] uh, PBC was really almost dominating, uh, the, the agenda.

Uh, and, uh, a few messages. Please fasten your seatbelts. I will run through some slides and data. My, my very first message is, uh, from, uh, the general session talk and the paper is, uh, accepted that, uh, if you want to predict outcome, we have, uh, Paris classification Toronto, different response criteria, which factors really determine outcome and the message from that.

Very nice, uh, multicenter large data analysis is that the. Current Elastography. So not the pre-treatment, the current elastography below 10 kilo pascal. That is really the best marker to predict a good outcome. Uh, remember that number? I think that was a clear message. Then we have obviously the treatment, um, the new treatment options.

We have the PPR agonists, uh, which were published, uh, a little more than a year ago in the New England Journal of Medicine, um, Elafibranor and, [01:55:00] uh, del Par. Uh, we have seen the data during recent liver meetings. At this liver meeting, we have, uh, first phase three data on ibet inhibitors, uh, targeting in particular the symptom of itching, uh, Ariba, uh, wa.

The data was presented by Gideon Hirschfeld, a very nice presentation. You can see here the, uh, study design and the sort method was yes, the drug works to reduce itching, uh, scores. Um, there were changes from baseline, uh, improved over time. Um, obviously by the mode of action, the drug also had some side effects, meaning causing diarrhea.

Uh, which also was to be expected if you wanna use an i a inhibitor. So, uh, phase three data published. We also saw phase two data for another i a inhibitor and also this drug works. Um, also in terms of, um, uh, the, the, the effect size, uh, you cannot compare between both drugs, but it looks pretty [01:56:00] similar. Uh, then obviously there were additional data on the two approved compounds.

Sdel par, uh, really in this post-hoc analysis, uh, of, of, uh, uh, trials that have been presented previously really improves. Um, as you can see here, pruritus and sleep disturbance. And for cila, we also saw, uh, data suggesting that the drug may lead to improved clinical long-term outcome as the globe score, um, improved.

Um, um, over time, um, as you can see here, um, uh, uh, that, uh, that this really increase in patients that received citadel par. While this was not the case in patients receiving placebo, um, again, uh, supporting, uh, the fact that the surrogates that are established for. Uh, PBC for all drugs also translate hopefully in long-term clinical improvement, which I like.

And for ELA we also saw data that in patients who had a [01:57:00] baseline, um, uh, increased or moderate to severe fatigue, uh, that really we saw also in, in this is, uh, there are other scores, but this course we also saw an improvement. And for both drugs, there's also additional research ongoing, just showing here one highlight.

That, for example, proteome screening was, uh, presented by Mark Swain, which I think is very interesting. A lot of markers we learn for the mode of action, uh, regarding these drugs, uh, these pprs, uh, more data to become, for those of you interested to have a look at this late breaking poster. The highlight of the meeting was, but certainly the very first positive phase three trial for PSC presented by Michael Traer.

Nor or no Oxic colic acid, um, for the treatment of PSC, uh, uh, which is a landmark study, uh, presented at the late breaking session, um, nor also, um, is a drug, uh, that has been [01:58:00] investigated by the grads and Vienna groups for quite some years, uh, in the end showing anti-proliferative, anti-fibrotic and anti-inflammatory effects.

This was a study design and Myron presented the primary endpoint at week 96, which was a combination of improvement of a LP normalization or below 1.5 a um, upper limit of normal and in parallel no worsening of liver fibrosis. And I think that is very important this. Uh, this combined endpoint was analyzed, um, the patients were PSC patients, uh, with quite some advanced stages.

You can see here the fibro stiffener, uh, fibro scores and F scores. Uh, but the most important point is the study was positive, uh, in different analysis, both per protocol as patients with no missing values. You can see here these, uh, clear signals for patients, um, receiving no also. As compared to placebo.

Um, and also here the [01:59:00] individual biochemical parameters, clear signals that the drugs may lead to. Uh, also long-term improvements in clinical outcomes. Very interesting data, more data to become, but certainly one of the highlights. Um, for ILA Fior, there was also a phase two study presented showing also in PSC also showing, uh, quite some significant improvements, which I think is remarkable when you see here the changes, uh, in a p changes over time, other biochemical changes.

Um, so, uh, more data to be seen in the next years, but certainly showing that PPRS may also work not only for PC, but for PBC. Then for liver, liver tumors, we saw, uh, many, many posters. Uh, also very nice signs, uh, to identify biomarkers of response. I just want to highlight that that's in this issue of the Lancet.

Um, the, uh, checkmate, uh, nine w uh, DW study was, uh, published. Um, and uh, at the [02:00:00] meeting, uh, Bruno Sandro presented, um, uh, as part of this data, uh, for the. Uh, nivo IPI study versus, uh, standard TKIs, uh, for HCC. And, uh, this is just one figure, uh, that was presented, um, in the, uh, generous session. One, uh, that the drugs, a combination of nivo ipi, also in patient with more advanced liver disease, LB grade two and three, uh, was safe and superior to the standard treatment.

Uh, and that I think this data we need, uh, it's easy to treat, uh, let's say completely compensated patient cirrhosis, patients with, uh, HCC. But if you had tried B uh seven, uh, B eight or LB two three, that's may be more complicated. Therefore, I really like this data, and that was basically my very brief highlight of some of the papers.

There have been more papers, uh, that were presented, uh, during the [02:01:00] meeting. We may discuss few points. Um, but, uh, my question to, to you guys would be, um, uh, if we would start with PSC, um, uh, and Lisa Catarina, Ben, you may comment. When you saw the data, is it convincing? Um, is the very first phase three trial being positive, but the absolute amount of improvement with this combined endpoint, uh, was, let's say.

Uh, not too spectacular from, I don't know, five to 20% or so. Um, but still, if you would the, the drug have in your hand tomorrow, uh, Lisa, Catarina and Ben, would you use it? Lisa?

Lisa Sandmann: I would use it because what else should I do? I mean, the, the other, the data we have for the other compounds is worse, so this is the best option we have in our hands and we will see what comes out of it.

Heiner Wedemeyer: Anything to add? KA then? [02:02:00]

Benjamin Maasoumy: So 100% yes. Because I think the important thing is that, um, most of the patients already had ozo. Yeah. But it was an addition. So it is not instead, so we obviously, we still don't know what is the role of Ozo, but we know that this worked in addition, it worked better in patients that had no response to Ozo or no Ozo.

I think there was a sub analyzers, however, it also worked in the others. So definitely I would use it. Yeah. I think I. That you could have a brief thing, who knows the stage prior to the meeting?

Heiner Wedemeyer: No. No. But, but what is, uh, what is important? You mentioned there were this analysis of patients not receiving also, that, that the effect was even better.

And that the same discussion we had with the pprs, uh, both Sila as, uh, that, um, uh, how would it be if the PBC patients would not receive orso? And how would the effect of these, uh, [02:03:00] compounds be? And, uh, shouldn't we perform trials, uh, without orso? These, these are discussions ongoing, but I think, uh, for, for both PDC and PSC, I think it's really very nice to see for the patient that we have new drugs in our hands that, um, give promise to the patient.

And therefore also this, uh, globe score analysis for Sila, I think was, uh, to me quite important and convincing that we are doing a good thing when, uh, prescribing these, uh, drugs, uh, to our patients. And in more and more European patients, uh, both compounds are available and I think is a, is a really good and promising thing.

So guys, last round, um, uh, again, Lisa, you may start What was in the end? Your take home Final highlight of the easel, Congress 2025 in Amsterdam. What is the viral hepatitis highlight?

Lisa Sandmann: Of course, I'm a Hepatitis D [02:04:00] person, so I think it was, I was very happy to see that we can stop lide in patients and that some of these patients actually stay negative.

So 20% of all the patients.

Heiner Wedemeyer: Yeah, I think it's, uh, curable. I, I completely agree, and again, I mentioned this in the discussion that, uh, uh, seven, eight years ago, I would've questioned that with an entry inhibitor alone, that we would be able to maybe cure some Delta patients when s antigens present. Right.

That's, I think, to me, remarkable. And at least in 20% it seems to work. Katarina metabolic liver diseases. What is the highlight of the Congress? You mentioned quite some highlights, but what's the, the most important, uh, take home message?

Katharina Hupa-Breier: I think the most important highlight is that we have some drugs in the pipeline, which might even work in patient with liver fibrosis due to mesh.

I think this is most important because now we have, uh, [02:05:00] options for all stage of the disease.

Heiner Wedemeyer: Yeah, I think that that's, I, I completely agree that beyond, uh, F two, F three, which is important and that we have similar til that will come, uh, but that even for cirrhotics, uh, there are perspectives and both FGF 1 21 as well as the new compounds presented are promising.

And Ben, from your side, the highlights.

Benjamin Maasoumy: The highlight, uh, well, from my side is that, uh, I do not have to, um, to go to all my patients and ask them to come once a week to give them albumin, but can still use it in selected cases. So I think the PREZA study, uh, was a highlight, although in negative study, also in negative study can be, can be a highlight sometimes.

Yeah. That's good.

Heiner Wedemeyer: And, uh, my highlight again, I think is no, also I think that that's spectacular. And to answer one question that just came in a minute ago in, in the chat from my side here, is that, uh, if we believe that the improvement in alcohol and [02:06:00] phosphatase really translate into, uh, improved clinical outcomes in PSC, uh, in PBC, we have strong data in PSC, we don't have that, uh, the, the strong data.

But, uh, I, I'm a hepatologist and I believe in normal values both for A-L-T-A-S-T and also alkaline phosphol. I, I strongly believe. And, uh, uh, remember when, when also was, uh, let's say for PSC no longer suggested by some guidelines, 15 years ago, many patients stopped also, then a LP increased dramatically.

And they also had, uh, more progressive, uh, course of liability, some of them. So even though we don't have that strong evidence, I think there is evidence that a OP improvements matters. I, I believe in that one.

So these were the highlights of the Hanover Limmer team, um, of the, the [02:07:00] easel meeting, uh, this year in Amsterdam. I don't know if, uh, whom of you attended really the meeting? Some questions are right now jumping in now. We'll address them, um, in a minute. Uh, but again, I think this selection really highlights that, uh, quite some things are ongoing in liver diseases in general, which I think is exciting.

Uh, we need, however, also to select this and we could not discuss all in particular. My last part I could not, uh, address, uh, uh, other pretty cool data, uh, EG. Um, there was an analysis on non-cirrhotic portal hypertension, uh, portal vein thrombosis, uh, management of, uh, anticoagulants, uh, in, in, in these settings, et cetera.

So more things to be discussed. I'm happy to take, um, additional questions, uh, which I can discuss with you now, uh, in the remaining minutes. And again, thanks you for, for your, of your, uh, all of you listening. Also, late evening after [02:08:00] a long working day. So, uh, a question that is, uh, coming in regarding I, I go through this, start with a viral hepatitis questions again, which have been addressed.

Uh, one question obviously relates, uh, to thank you to my presentation on the bide treatment. Uh, really to highlight again, um, not only when to stop, and I think this has been answered, uh, by that trial, that we can safely stop bide monotherapy if patients have been h dv RNA negative for at least 96 weeks.

But the question that is coming in is how shall we manage those guys? Who have not been, let's say, completely undetectable, maybe a tiny little dip, um, uh, at week, uh, 72, then negative again, then maybe a hundred, 200. Uh, what to do is simply continue monotherapy, or, and that is the question whether we should add interferon.

And, um, that is, uh, something that, [02:09:00] uh, Lisa could not address in detail. Um, but there has been a presentation during the Congress from, from Austria where they analyze, I think 70 patients or so. Um, the entire aide cohort, and some of these patients were switched, uh, were where interferon was added in suboptimal responders.

Um, and indeed then they could, uh, uh, induce HTV RNA and Detectability over time, which I think is a reasonable strategy. Um, even though there were also quite some patients where this strategy was not successful. So, to answer this specific question, yes, if a patient had been, uh, not completely undetectable, but very low residual viremia, uh, maybe between week 48 and week 96 of therapy, then I may consider to add interferon eg for 24 weeks and then to stop.

Um, the good news is still, if the patient is relapsing, and I showed that there are flares of a [02:10:00] LT, but they, they become normal, that we have a current, um, investigation ongoing. That re-treatment is IDE as possible. So even if you, if you, uh, let's say lose the response, uh, there may be a risk, maybe different replication space, different number of, uh, cells being infected.

Um, what we have, uh, quite some good evidence, uh, we, uh, that HT VRNA is declining in a similar way. That's basically my message, uh, for this one. Then there was another question, regard HPV, um, again, related to non stop therapy. Liza did not discuss in detail the value of additional markers. H-P-V-R-N-A.

Correlated antigen to guide, nook, stop. Uh, um, there has been also, we discussed this in previous three years after the easel. Yes. If you have access to H-P-V-R-N-A testing or HPV correlated antigen testing, uh, before stopping, you may ask for this information. Still in my practice, [02:11:00] I do not base, uh, the decision to stop nooks yes or no in HPV monotherapy on, on this marker.

If, if you're a little uncertain, let's say HPS antigen levels borderline, um, and, uh, uh, if you need an additional marker, then these markers may help. But there are also have been now negative studies that the additional value in the end is limited. There have been positive studies. So to answer that question, if you can test this, do this, it may give you slightly additional information.

I do not do this in my clinical practice. This is regarding viral hepatitis. Um. Then regarding metabolic liver diseases, there are also questions, um, uh, coming in, uh, now here. Uh, and I think we have to differentiate two parts of metabolic liver diseases. The one is the diagnostic value of all the screening tests and, um, uh, what I learned from easel is, uh, yes, FIP four has limitations and there has been also publications also here from [02:12:00] Ban, uh, and Andrea Gaia from Germany Ban is working here also at Hanover.

That indeed, even in patient with low fit four values, there may be some patients who have, uh, uh, significant, uh, liver disease and you may exclude them even though they may require treatment. But this number is small. Uh, and therefore I think we, uh, we, I still use FIP four as a very first screening, uh, tool in public health.

For example, we have here a big project ongoing, uh, you know, maybe Northern Germany, uh, lower Saxony. We have big factories of the car company, Volkswagen. And, um, they have a very good medical system for their employees. And, uh, we just informed them that they use the F four scores of the very first screening.

And if then have patients at risk, they refer them to us and Hanover, and then we can take care of that one. Yes, F four alone in [02:13:00] distinct setting has limitations. Um, and there are these, these other markers, um, liver risk score, et cetera, which may be, may be helpful, um, but for clinical practice. A low F four score, I think is at this stage, probably the most reasonable way to exclude patients, um, who have a, a major risk of liver disease.

The other way around, uh, the higher level of scores, the other F four score definitely has limitations. So if you are above 1.3, do your homework, do liver elastography, et cetera, uh, and don't rely on the cutoff of 2 6 7, uh, that there may be on the, on the other range. So, P four is for me, important below 1.3.

I call them back, let's say in one or two years. And, uh, I think that's a reasonable strategy in those scientifically at easily. We also saw other, uh, answers. The, the other question that, um, is asked here, which I think is a very good one. I like this question. Um, uh, we have [02:14:00] seen data during this meeting on Resm Miro.

We have, uh, seen data, uh, on, uh, uh, also in the England Journal of Medicine paper, the phase three study on semaglutide. We have, we have the Incretin mimes, uh, and then we have FGR, uh, FGF 21, um, uh, targeting agents. Then obviously the question is, what about combination? Uh, and, uh, is this reasonable? Uh, how many patients in the semaglutide received, um, uh, an OME trials received an addition in Incretin?

Mimetic? Uh, and this is an ongoing discussion. Um, everybody's talking about personalized medicine and in particular for metabolic liver diseases. Uh, we have to, uh, consider a personalized strategy considering also the cardiometabolic risk profile. Um, in general, uh, what's about the [02:15:00] heart? What's about, uh, uh, LDL levels?

What about kidney function? And then we have to personalize things. I think in the future there will be not one size fits all strategy for these diseases, and uh, we definitely need combination. Trials, prospective combination trials. There were no trials presented at easel. But I really like this question.

Uh, in particular also for patients with liver cirrhosis who still have metabolic problems, even though, uh, let's say the, the neither nor semaglutide is indicated in patients with compensated cirrhosis, but if they have metabolic liver dis if they have a metabolic condition, diabetes MEUs that justifies, uh, treatment with CMA or with tilt, of course, I would do this right now, even though the evidence that I improve liver disease is limited, if I then have the option to add on, uh, for example, Esme, uh, or in future and FGF 21, uh, uh, strategy, targeting strategy, [02:16:00] I would not exclude this, but, uh, it's too early to give here.

Uh, I think, uh, a definite answer. And there are also the other drugs which are development, um, that, um, uh, cater mentioned, uh, uh, that has been presented, for example, in the late breaking session, uh, in patients with liver cirrhosis, uh, completely new mod of actions. Um, the, the journey is ongoing. And, uh, at exciting times, um, which I think where we could, um, uh, uh, address these, um, uh, issues anymore.

Then, uh, there have been some questions coming in right now. Also on the topic of liver cirrhosis. I don't have the time to discuss them all in detail. Um, one, uh, question that, uh, is. Has been asked also during recent years, again, is, uh, the diagnosis of hepatic encephalopathy, both in the setting of patients with liver cirrhosis, but also after tips implementation.

Um, [02:17:00] uh, which tests do we use in Hanover here in our real life? I may refer here to some of the papers that have been published also from our unit, professor Weisbaum, the neurologist, uh, Ben Masumi, who presented the data here on, on cirrhosis selection. Um, also, uh, together with, with Professor Weisbaum, has evaluated all the six or six different tests, uh, that are used to diagnose hepatic encephalopathy, starting from, um, stroop tests to the paper, pencil tests, uh, to, uh, the, uh, uh, the animal naming tests, et cetera.

And, and they compared all the different settings, both, um, in patients with, um, um, uh. A cold HEV, uh, to diagnose, uh, the patients in the long term as well as after tips implantation. The short message is that, uh, the good old paper pencil test, uh, and different studies performed, uh, outperformed, uh, many of the other tests.

So you do not need fancy, [02:18:00] new technologies. Um, the, the good old paper pencil test is, uh, I think reasonable. They're also working on a simplified paper pencil test that's, that is faster to be used. Um, the animal naming test is usually reasonable, even though the cutoff or what is normal, what is not normal, you may practice as yourself how many animals you can name in 20 in, in one minute, and whether the cutoff is, uh, 2022 or 18 or 23.

Uh, you may also know that there are different cutoffs even within European countries, um, between Germany and Italy. There's a difference, which I still don't understand. Men and women education plays a role, but it's, I think it's a reasonable screening test. Why I'm spending time on this, because this is important.

This has, um, therapeutic implications. This has prognostic implications and the diagnosis even of minimal, uh, encephalopathy. It's clearly associated with long-term outcome. And, and obviously it sets also [02:19:00] practical implications for the life of these, um, affected individuals with cirrhosis. Uh, I just, I don't touch the, the, the, the whole topic of car driving, uh, whether they can keep their license, uh, yes or no.

And, uh, we are all taking care of patients with liver cirrhosis. Uh, we have to address these issues, um, uh, how fit these patients are, how fit our patients were. Um, and an adequate diagnosis of cardiac encephalopathy I think is, um, uh, something that. Frequently worldwide is not addressed in a an appropriate way.

It's an important diagnostic tool for patients with liver cirrhosis. And we should all follow this one. This was one question. There are other questions coming in and Ben answered them in part already. What do I now do with albumin substitutions in which setting in the long term is, I do mean, um, substitution completely out.

Uh, I don't know. How is the case in, in Australia and, and in, in clinical [02:20:00] practice? Uh, in my view, um, uh, for us it's logistically very problematic in Germany to, to, uh, uh, ensure, let's say once weekly albumin infusion, uh, and the data that we saw in Amsterdam is supporting the strategy that this is not needed for every patient.

Again, also here the usual answer, we're talking about personalized treatment strategies. The book is not closed in my view on this topic. And lastly, obviously cholestatic liver diseases. Um, I presented some of the data. Uh, we have, uh, new PPR targeting agents, uh, that are approved. Uh, uh, I can prescribe both cila as well as Ila Fino on both, uh, drugs.

Uh, I can prescribe in Germany. We are using both compounds. Uh, and, uh, also some questions around this topic came in, uh, to me it's, um, uh, then I've been finishing out. We use, uh, Eila or [02:21:00] Sila, uh, and, uh, in which condition, maybe symptoms, uh, is, uh, EA, the fatigue, uh, drug and cila, the, the itching drug, uh, which what some people state.

I don't think so, that you can generalize this. And for me, I think both compounds, um, have, uh, have, uh, their role. Uh, we have seen phase three data. I'm really happy that I can use both compounds. It's always good to have two compounds and not only one compound. Um, uh, we still have to develop obviously, uh, broader experience to use this.

Compounds. Uh, and data presented at easel are. Uh, to me convincing that it is really useful also real world to, to make prescriptions. And I just want to highlight again what I, I showed you one, one slide on the, uh, improvement of the Globe score, uh, uh, with cellular treatment. Um, it's, you may argue, well, what does it matter?

It's a theoretical score predicting long-term [02:22:00] outcome based on biochemical parameters. Um, but it's important, and I think we have very good evidence from, from the, the huge international cohorts that these scores are reliable and predicting long-term outcome. And when you saw these graphs that really, they, they moved up with cila so that the risk to develop clinical complications is really reduced.

I think it's, um, to me, important data also in the discussion with insurances with payers who have to cover for these drugs. Um, we need to generate more data. We need to exchange this, and I'm interested to see more data also in the future. On the other hand, we need to understand more about both compounds, both Cila and Ella, um, uh, to how we can apply them what may be other biomarker, surrogates.

And therefore, I also mentioned this proteome screening that Max Wain presented at the late breaker poster for, um, uh, which is just the first screening. It's on the [02:23:00] first view. Quite hard to understand, but there's so much information in that poster. Uh, and therefore I'm, I'm really interested to see, um, more investigations here, to understand different pathways also correlations with symptoms.

Uh, to me these are really, um, exciting, uh, times where we can, uh, uh, look for further data in the future. So these were some questions. I could address more questions here, but for time reasons was a long day for you guys. Um. I have to thank, uh, again, you for listening for the, the interactions. I hope that you got some ideas, some insights, um, from the ease of Congress in Amsterdam.

I have to thank, uh, Gilead for supporting this meeting. The logistics, the agencies, um, uh, that we can help this interaction. I think this is, um, not trivial. They had no interaction at all with us, uh, to influence us, which, uh, um, abstract to [02:24:00] be selected. So it was really a completely unrestricted support, which I appreciate.

And obviously I have to thank media who said, and the entire team, uh, in Sweden, uh, for organizing, uh, this event. Uh, again, it worked. Everything worked very well. Thank you for the technical support. Um, and best regards from Hanover Medical School in Germany. I hope to see you in future meetings around the world.

Um, come back to e for those of you attended the meeting next year. We are back in Spain, in Barcelona, a very nice city, um, uh, and a little later, not early May, uh, but a little later during the year. But, um, uh, hopefully you have the chance and to, to visit us here in Europe. Best regards, have a great evening.

Uh, stay involved, stay tuned. Studying, investigating treating liver disease is really exciting. Bye bye. Thank [02:25:00] you.