Activity Transcript

Heiner Wedemeyer, MD: Hello. I'm Heiner Wedemeyer. I'm a professor and chairman of the Department of Gastroenterology, Hepatology, and Endocrinology at Hannover Medical School in Germany. It's a great pleasure for me to welcome you to this program, which is entitled Hepatitis Delta Treatment: Evaluating Endpoints and Goals of Therapy.

What I want to do during the next 30 minutes is discuss with you the pathophysiology and disease burden of hepatitis D virus (HDV) infection, which leads to a need for effective therapies. In this context, I would like to discuss with you the markers of response to treatment, how to use these endpoints and markers in clinical practice, and finally to discuss with you the currently available treatment options and treatment strategies in development.

I would like to start by discussing some basic concepts of HDV infection. Delta is a defective virus that needs hepatitis B surface antigen (HBsAg) for dissemination, so it cannot survive on its own. We think that roughly 10 to 20 million individuals worldwide are actually infected with this virus, and there's a lot of data that has been published during the last 10-20 years clearly demonstrating that HDV causes the most severe form of viral hepatitis, causes more rapid progression to liver cirrhosis, and also a higher incidence of liver cancer. What we have to be aware of is that there are different HDV genotypes worldwide. Here in Central Europe, most of my patients are infected with HDV genotype 1, but in Eastern Asia, there may be patients infected with HDV genotypes two and four, which may take a slightly better clinical long-term course. In South America, in the Amazonian area, we have the HDV genotype 3, which is a distinct virus causing more severe forms of viral hepatitis D virus infection, and in sub-Saharan Africa, we have different genotypes, genotype 5, 6, 7, and 8. Papers were published 2 years ago suggesting that HDV genotype 5 may take a slightly better course than HDV genotype 1, but we certainly need more data to confirm this. For us in Western Europe and also North America, it's important to know that most of our patients are infected with HDV genotype 1.

I would like to discuss with you a patient journey, and this is a virtual case I call Victor. Victor was born in Uzbekistan. He is 38 years of age, and this is already a first feature of hepatitis D virus infected patients because Victor was not born here, in my country, in Germany. About 80 to 90% of our hepatitis D patients are actually immigrants that have been born in endemic regions, which are either countries in Central Asia, the Eastern Mediterranean region, or Sub-Saharan Africa.

Victor was known to be infected with the hepatitis B virus (HBV) for more than 12 years, but even though he has been treated with tenofovir (TDF) for 5 years, he still has biochemical hepatitis. He has an ALT level of 120, he had a platelet count just below the cutoff, indicating maybe some level of portal hypertension. Bilirubin was normal, and the GPs taking care of Victor told him, "Well, Victor, you have a drug against hepatitis B. You still have hepatitis, please stop drinking alcohol."

It took a long time until somebody had the idea to test for hepatitis delta antibodies. He was then finally diagnosed as being anti-HDV positive. What does it mean for Victor now that we know that he's infected with HDV? What additional diagnostic steps now are required? What should we do? It's very simple. On the first view, we need to determine that Victor is really infected with HDV, that he has active replication and therefore we need to determine HDV RNA.

Just a brief remark here, if you are not sure which assay your lab is using, please contact your lab because the assay matters. There have been some reports suggesting that there are different outcomes or different results between different labs. If Victor, for example, tested HDV RNA negative, contact your lab and ask whether they're using a validated commercially available test or whether they use an in-house assay, which sometimes misses HDV RNA. So contact your lab.

The next step is that you do your HBV homework. Make sure that HBV DNA has been tested and also quantitate your HBsAg because this may become important in the context of treatment. If you want to treat your patient with interferon (IFN), you should determine quantitative HBsAg because this is one of our endpoints of treatment of HDV infection. Then we have to do our homework, being hepatologists, so we have to stage the liver disease. We have to make sure if the patient has already portal hypertension, has compensated liver disease, and this is very important because selection of drugs depends on our staging of liver disease.

Finally, you should keep in mind that HDV infection has a special feature. HDV infection may be associated with some level of autoimmunity, maybe even autoimmune hepatitis. This is again important when you select your drugs for treatment because IFN, which is one of your treatment options, may worsen an underlying autoimmune hepatitis. This is the reason why I still biopsy most of my patients who are anti-HDV positive.

What was the result of this workup for Victor? Viremia was detected, medium to high viral load. HPV DNA was low, as to be expected as Victor received TDF. HBsAg was rather high, and that is important to note that delta patients have similarly high HBsAg levels to patients infected with hepatitis B alone.

Then Victor has an IgG level of 19, which is medium-high and could indicate some level of autoimmune hepatitis. We did a liver elastography revealing 19 kPa, which may indicate some level of advanced fibrosis, even early cirrhosis, and he had some cholestatic liver enzyme features, which you also frequently see in HDV infected patients.

I biopsied Victor, I confirmed liver cirrhosis but, very importantly, this biopsy did not show clear features of autoimmune hepatitis, which for me allowed me to consider IFN as a backbone of my treatment choices for Victor. Victor then asked me, "Well, okay. I have no liver cirrhosis. What is my risk to develop clinical complications of the cirrhosis?" because otherwise Victor has been feeling quite well. There have been many studies recently showing that delta can be a really severe disease, an aggressive disease, even a malignant disease showing a high incidence of hepatic decompensation.

You can see on this slide the study from Sweden, and I want to highlight 2 points here. First of all, if cirrhosis is already present as has been the case for Victor, you have a really severe disease. Half of the patients develop clinical complications even within 5 years. However, there's another group of patients who have not yet developed liver cirrhosis who may have a rather mild course of disease. You can see here that the long-term outcome of patients without liver cirrhosis at presentations was not too bad. Importantly, in the long term, we really have to understand why some patients have a rather severe disease while others do not. There's research ongoing trying to identify biomarkers, host factors, viral factors, clearly explaining to us why this or that is actually taking place in the individual patients.

I also want to highlight that HDV infection does not only cause higher incidence of liver cirrhosis but also has been associated with a higher incidence of hepatocellular carcinoma. It's very important to perform liver cancer screening in patients with HDV infection, in particular in Victor as he has already liver cirrhosis.

Okay, I showed you delta can be severe, I showed you that Victor has liver cirrhosis, I showed you that Victor is at risk for developing clinical complications. What can we do? What are our antiviral treatment options to prevent disease progression for Victor?

In principle, in my country in Germany, which options do I have right now? I could continue antiviral treatment for hepatitis B only, continuing TDF, that's it. I have pegylated IFN in my treatment options. I have bulevirtide, which is an entry inhibitor. I will show you in detail the data around this treatment strategy. I could combine both bulevirtide plus PEG-IFN, and I could ask if I have maybe a new clinical trial available to include Victor in this clinical trial, and to explore a new treatment options for him.

But before discussing these 5 different treatment strategies, let's really highlight if I apply a treatment, how can I really measure the response to treatment for HDV, which is not a trivial question. You all know in hepatitis C where with HCV RNA, the virus is there or the virus is gone, done. This has been associated with clinical long-term outcomes. In hepatitis B, we measure HBV DNA. If this is suppressed, our treatment works.

In delta, we lack really very strong data correlating viral markers to hard clinical endpoints. There are data that have been generated in different studies over the last 20 years, and this point really has been discussed extensively with authorities, with the FDA, with EMA; what are really good surrogate markers predicting long-term endpoints. What do we have to do? The first marker you want to measure when you treat a patient with an antiviral drug is that you met a viral load. HDV RNA should decline. We agreed among experts and with the agencies that a 2-log decline indicates response to treatment, so really highlighting your drug works because viral load is reduced. There have also been some data published by Patrizia Farci almost two decades ago that a two log HDV RNA decline translated in an improved clinical long-term outcome after IFN based treatment.

Obviously, in an ideal setting my HDV RNA should be undetectable. It should be negative, and with the currently available highly sensitive assays, it should be even better. But I will show you also some data that late viral relapses may occur, and overall also in my experience in the trials we have been performing here in Germany, a 2-log decline is a reasonable endpoint. A little more it would be better, but 2-logs I would like to achieve.

The second point we are measuring would be normalization of liver enzymes. As a hepatologist, I strongly believe in normal liver enzymes being a good thing for my patient, and therefore the agencies also suggested that in the treatment endpoints you should have normal liver enzymes. In an ideal setting, then obviously you want to have both. You want to have a biological endpoint 2-log decline in combination with normal liver enzymes, and this is the combined endpoint used currently in clinical trials as a primary endpoint on treatment, which was very important. The US FDA recommends this combined endpoint in their draft guidance, which was published in 2019, and all ongoing trials use this combined endpoint as a primary endpoint.

What is key and what is very important is that we follow our patients in clinical trials. That for example, if your HDV RNA is undetectable, we should monitor this regularly during treatment and also after treatment because relapses may occur once you stop an intervention or antiviral treatment intervention, and therefore RNA should be monitored over time. More importantly, we also should measure other surrogate markers associated with fibrosis progression. For example, liver stiffness measurement should be performed during treatment, and then finally, a liver biopsy would be the hardest endpoint to really show that fibrosis, for example, is not worsening or even improving during treatment. And I want to see in the liver whether inflammation is also reduced. These are usually secondary endpoint in all ongoing clinical trials.

Finally, I want to know what is going on clinically with my patients, so obviously we have to perform liver cancer screening. We have to look for markers for liver decompensation, and finally want to determine survival in the long term, so all clinical trials should include long-term clinical follow-up of our patients.

Let's now come back to Victor. I showed you these 5 treatment options, and the first option for Victor would be simply to continue his antiviral treatment backbone for hepatitis B. Victor receives TDF, but other patients may receive entecavir (ETV). What is the outcome if I don't do anything for HDV specifically, but just continue treatment for hepatitis B? The very unfortunate thing is that all the data that have been published over the last 10 years suggest that this is not a very good treatment strategy because these drugs, TDF and ETV, do not work against HDV. They only suppress the backbone HBV infection with no direct effect on HDV. Therefore, the retrospective studies suggest the poor outcome of patients receiving TDF and ETV only. There have been several studies clearly highlighting that if you give nucleoside or nucleotide analogues in hepatitis D virus infection, these lead to worse outcome as compared with patients who would have been treated with interferon. Yes, there may be a selection bias among these studies, but there are definitely no data showing that we are improving clinical long-term outcomes.

The second option would be then to treat our patients with pegylated interferon alpha-2a (PEG-IFNα-2a). There have been trials using type 1 IFN already in the 1980s. We have seen some studies in the 1990s, and there have been large international randomized treatment trials exploring PEG-IFNα-2a either alone or in combination with nucleoside or nucleotide analogs versus patients in control groups either untreated or receiving nucs alone.

This is one example, a study that we published 11 years ago, and you can see here the short message is that roughly 25% of patients being treated with PEG-IFNα-2a show an on-treatment HDV RNA suppression, which is maintained until 6 months after the end of treatment. Well, 25%, and you have to keep in mind that this already has been a selection of patients because many patients have contraindications against IFN treatment and therefore only a subgroup of delta patients could be treated here with IFN, 25%.

I'm showing you this old data because we just recently published a long-term follow up, a 10-year follow up, after this clinical trial, and I want to highlight here patient 207. This patient was HDV-RNA negative at the end of treatment. He was negative during short-term follow up, but 7 years after the end of treatment, the patient relapsed. What is important, is that this data really shows you that there's a fundamental difference between HDV infection and for example, hepatitis C virus (HCV) infection. When hepatitis C has been successfully treated, the patients are HCV RNA negative, and they remain negative. There are very few cases of late relapses. This is different in delta. We have seen late relapses in up to 50% of our patients and really showing that in terms of endpoint discussion, that HDV RNA undetectable with an old assay may not really mean undetectable. We really need highly sensitive assays confirming that the virus has really gone, and we need to monitor our patients yearly after the end of antiviral treatment.

You may now argue, "Okay, these patients have been treated only for 48 weeks, some of them had a late relapse. Why not prolong treatment with IFN to 2 years and then by doing this you reduce the risk for viral relapse?" We've been performing with centers in Romania and in Greece in Turkey and Germany a large, randomized trial where we extended the treatment from 48 weeks to 96 weeks, and here the short message is that extending treatment did not increase response rates. We were not happy with these results because we were hoping to prevent relapses, but during the second year of treatment, there were no further dramatic increases in response rates, and we importantly did not prevent late relapses. At this stage, if you use IFN alpha for your delta patient's, plan initially for 48 weeks.

The question then is if only 25% to 30% benefit, which factors are actually predicting response to interferon treatment? Can I select some patients who may have a higher benefit from treatment, and can I maybe not even start treatment if I have a very low likelihood of response? Different factors have been evaluated in retrospective studies. The short message here is we do not have very good response factors.

For example, in hepatitis C, we have been using IL-28B polymorphisms predicting response to IFN-based treatment. These IL-28B polymorphisms do not really work well in HDV infection, so we do not have good viral factors associated with response. We also do not have reliable host factors predicting virological response. I want to highlight here that even liver cirrhosis is not a negative response factor to IFN-alpha. If you have compensated cirrhosis per se, these patients may still be candidates for IFN-based treatment, but on treatment kinetics, for example HDV RNA or even HBsAg may help you to decide whether you extend treatment beyond week 24 to week 48.

There's some discussion to further use this factors as a response-guided treatment, but we do not have really clear recommendations that let's say that we have a certain cutoff of viral load at week 12 or 24 allowing us to extend treatment or not. This is ongoing research.

If you have treated your patient with IFN, Victor may then ask, "Well, do I really benefit from treatment? What are my long-term consequences of treatment?" Here, the good news is that successful IFN treatment has been clearly associated with an improved clinical long-term outcome. That is very important for Victor, and this will hopefully also hold true for the new treatments in development.

The next option if IFN is not working for Victor, which I have in Germany, is to prescribe bulevirtide. Bulevirtide was approved by the European Medical Agency in summer 2020 for the treatment of compensated HDV infection. The drug has not yet been approved in the US by the FDA, but in Germany I can use this drug. What is bulevirtide? Bulevirtide is a peptide and is an entry inhibitor. Hepatitis B and hepatitis D, enter the hepatocyte via binding of HBS antigen to NTCP. NTCP is a bile salt transporter, and bulevirtide has been derived from the large HBsAg, so basically it's mimicking the large HBsAg entry site and it has been modified. It's a 47 amino acid long peptide, and if you inject bulevirtide subcutaneously, it blocks NTCP, meaning that variants can no longer enter the hepatocytes. As NTCP is exclusively expressed on hepatocytes, the drug is also very safe. It only targets liver cells, and there is no off-treatment effect, which is very good because you really have a unique mode of action in the liver.

There have been phase 2 pilot trials, and they confirm that if you inject bulevirtide subcutaneously on a daily basis, this translates into a linear decline of HDV RNA in infected patients, and roughly half of the patients achieve a 2-log decline after 24 weeks of treatment. When you then stop treatment, most patients relapse, which was to be expected based on the mode of action, and therefore ongoing trials explore longer treatment durations. Very importantly, this HDV RNA decline was associated also with a biochemical improvement, a decline in ALT as you can see on this slide.

Interestingly, and for some people, surprisingly, we did not observe a change in quantitative HBsAg surface levels, and you can see that this was completely flat, this response, suggesting that this HBsAg that we are measuring in patients infected with hepatitis D may not only be produced by actively infected cells, but maybe also by integrates of HBV DNA to the human genome. There is an ongoing phase 3 trial, the 301 trial, and this trial basically confirmed the data from the phase 2 trials. It showed that this combined clinical endpoint, which I explained to you, the 2-log HDV RNA decline with normalization of liver enzymes was achieved in almost half of the patients. The approved dose in Europe 2 two milligrams subcutaneously. This trial also explores a higher dose of bulevirtide of 10 milligram, and you can see here however, that this higher dose did not show higher response rates. The 2 milligram approved dose is the dose we are currently using in Europe.

Very importantly, when we then looked into distinct host factors associated with response in terms of virological decline, you can see that all subgroups benefited equally well from bulevirtide treatment irrespective of age, gender, race, biochemical disease activity, or even the presence of cirrhosis, so all patients benefited. Meanwhile, we have also seen real world data highlighting that the drug also is beneficial, for example, in patients with compensated cirrhosis and significant portal hypertension. Data from Italy really confirmed efficacy and also clinical benefit of bulevirtide in this distinct group of patients. Bulevirtide works, IFN works in some group of patients, why not to combine both drugs? There have been also phase 2 trials indeed suggesting that there's synergistic effects when combining bulevirtide and PEG-IFN in treatment; however, we lack really strong data that if you do not lose the underlying HBsAg, in the long term the synergistic effects are also maintained. We need more data. There have been real world data from France presented at the AASLD meeting in 2022 suggesting that some patients may also benefit in the long term from this combination treatment, but we certainly need more data.

Let's come back to Victor. Let's assume that Victor was initially treated with IFN; however, he was suffering from some side effects and after 4 weeks treatment was stopped and then investigators decided to prescribe bulevirtide. If Victor was asking, "Okay, I want to use this new peptide. Are there any side effects?" By the mode of action, as NTCP is blocked, you may expect an increase of bile salts during treatment, and this is exactly what has been observed. There's a dose-dependent increase in bile salts when you inject bulevirtide; however, this has not been associated with any side effects. There is no itching associated with increase in bile salts in these patients, and there has been also very importantly, no treatment discontinuation due to side effects which the investigator considered to be related to bulevirtide, so a safe drug.

What has been shown is in some real world patients is that you may have some T-cell driven allergic cutaneous reactions, which however can be managed with corticosteroids, and you can continue treatment if you observe this. If you then would assume that Victor showed a virological response to treatment, the next question that arises, how long should Victor be treated with bulevirtide? I cannot give you an answer right now. The ongoing phase 3 trial is exploring 2 versus 3 years of treatment, so we will see an answer, but we don't have the answer right now. There have been single case reports suggesting that a 3 year course of bulevirtide monotherapy may indeed cure HDV infection. A patient treated at the Milan site by Professor Pietro Lampertico where a cure was suggested. While we have also seen data from Austria where late relapse has been reported after bulevirtide treatment. The patient was treated for almost 3 years and then still had a late relapse, so we have to wait for more data. At this stage, if I start a treatment, I continue until I have data. At this stage maintenance treatment.

Finally, you may then ask, well, if Victor has a relapse, are there alternative treatment options? We have a phase 3 trial ongoing with lonafarnib, which is a prenylation inhibitor. Data are expected to be presented in 2023. In this trial, there's lonafarnib, which is boosted ritonavir explored as a monotherapy in compared to a combination treatment of lonafarnib with IFN alpha versus interferon alpha, and there's also an untreated control group.

We have then also data on interferon lambda. A phase 3 trial is currently recruiting. We have different approaches like nucleic acid polymers, or siRNA against hepatitis B or even monoclonals against hepatitis B. Here, we wait  for more trials. Data are to be expected during the next years.

So, what are my final conclusions from this patient journey which I showed you? I think it's very important to remember that the key goals of antiviral treatment against hepatitis D are reduction of HDV RNA levels, which should translate into an improvement of liver disease, for example ALT, and in the long-term, obviously this should lead to an improved clinical long-term outcome with lower incidence of hepatocellular carcinoma, lower incidence of hepatic decompensation, and then finally, obviously to improve the clinical long-term survival of our patients suffering from HDV infections. I think there's hope for HDV patients. A lot of new data have been presented and will be presented, and screen your patients for HDV infection. It's worthwhile.

Thank you for watching. Please, continue on to answer the questions that will follow, complete the evaluation. Thank you very much.

This transcript has not been copyedited.