Robert Gish, MD, on Advances in Managing Hepatitis B and D

Dr Gish discusses the recent approval of bulevirtide for the treatment of hepatitis D, and the importance of screening and monitoring patients with hepatitis B for hepatitis D to enable effective treatment.

Robert Gish, MD, is state Medical Director in California of the Hepatitis B Foundation, Professor of Medicine and Adjunct Professor of Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California San Diego, Adjunct Professor of Medicine at the University of Nevada School of Medicine in Las Vegas, and a Clinical Professor of Medicine at Loma Linda University.

FDA-Approved Bulevirtide Expands Treatment Options for Chronic Hepatitis D

• Chronic hepatitis D (HDV): Bulevirtide is the first FDA-approved targeted therapy for HDV, approved via the accelerated approval pathway after receiving Breakthrough Therapy and Orphan Drug designations. It blocks viral entry through the NTCP receptor, has minimal drug-drug interaction risk, and demonstrated an excellent safety profile, with treatment discontinuation due to adverse events occurring in <1% of patients.

• Chronic HBV/HDV coinfection: Oral HBV therapies (TAF, TDF, or entecavir) should accompany HDV treatment to suppress HBV and slow disease progression, although they do not eliminate HDV. Acute HBV/HDV coinfection is generally monitored for spontaneous viral clearance before initiating bulevirtide.

• HDV screening: Dr Gish, along with EASL and other medical organizations, recommends universal HDV screening for all patients with chronic HBV, citing broad US access to accurate antibody and PCR testing through major reference laboratories and emphasizing that HBV vaccination prevents HDV infection.

Gastroenterology Learning Network:

Any views and opinions expressed are those of the authors and/or participants and do not necessarily reflect the views, policy or position of the Gastroenterology Learning Network or HMP Global, its employees and affiliates.

Welcome to this podcast from the Gastroenterology Learning Network. I'm your moderator, Rebecca Mashaw, and I'm delighted to be here this morning with Dr. Robert Gish, who is the state medical director in California of the Hepatitis B Foundation, as well as a professor at the University of California San Diego and one of the leading experts on hepatitis. And he's going to be discussing with us the recent approval of bulevirtide for the treatment of hepatitis D. This is the first FDA-approved and targeted therapy for this condition. So thank you for joining us this morning, Dr. Gish.

Dr Gish::

Glad to be here. Thank you.

GLN::

Let's start out with some basic facts about hep D. Why is it dependent on hepatitis B? What's the interaction there?

Dr Gish:

So this is an incomplete RNA virus. The RNA message is important because that implies that it's curable, but because it's incomplete, it requires the hepatitis B surface antigen to coat the virus, protect the virus, and allow the virus to enter the next liver cell because the surface antigen is part of the uptake of the hepatitis B virus and now delta virus into the liver cell through what's called the NTCP receptor. So it's a clever virus, but it also needs host proteins. That means the human liver cell proteins to replicate. So incomplete, doesn't have its own shell, and it also doesn't have all the enzyme systems that are needed for replication.

GLN:

Can you explain the difference between the concepts of superinfection and coinfection? Does one type present greater treatment challenges or carry a greater risk of poor outcomes than the other?

Dr Gish:

Coinfection is when you acquire the patient acquires B and delta at the same time. This has a high rate of developing fulminant or acute liver failure. And importantly, most of the people clear delta and many of them can clear hepatitis B with this coinfection.

Superinfection is when somebody has chronic B and then gets the second infection with delta at a different time. Most of those patients, more than half, go on to develop chronic delta infection and then are at high risk of progression to cirrhosis, transplant, cancer, or death less than 20 years, often less than 10 years. It's the most deadly of any chronic viral infection other than something like Ebola or hantavirus. You've heard about those in the news recently, but from a chronic perspective, because those are acute infections, this is a chronic infection in general. I didn't mention the acute disease, but the acute delta with coinfection is quite rare these days.

GLN:

How did clinicians treat hepatitis D before this new drug approval?

Dr Gish:

Interferon was the only option. And in that setting, the cure rate was maybe 15 or 20%. We really are strongly advocating that for every patient with B, their hepatitis B be treated and suppressed fully. The guidelines in the past said, "Well, you don't have to treat everybody because it's not so bad, but we've really learned that's wrong. Every delta patient needs to be on B treatment with one of our oral drugs, TAF [tenofovir alafenamide], TDF [tenofovir disoproxil fumarate], or entecavir.

GLN:

Is the idea there that if you get the B under control or you have a remission from hepatitis B, that the D goes away with it?

Dr Gish:

D does not go away with any of these oral drugs. It's just that you control the B and slow down the disease progression since delta is a double hit. You've got B killing liver cells, you have delta killing liver cells. So you suppress the B, you're going to slow disease.

GLN:

So now that there's an effective treatment, do you think all chronic HBV-infected patients in the country should be automatically screened for hepatitis D?

Dr Gish:

Well, I believe 10, 20 years ago we should have been screening for delta even though there wasn't an effective treatment because these people were sicker, higher risk of cancer, higher risk of progression. We should have started testing 20 years ago, but there were a couple problems with that. There's the psychology of the provider community that we only test for diseases where we have an immediate treatment. That's wrong, but that's reality. The other is access to tests. So in 2013, we had no test for delta in the US that was commercially available. 2013 ARUP, in Salt Lake City, came out with an antibody and then a PCR test. So they were really the first to the clinic with testing. Quest came out with their antibody and then PCR tests around 2017 or 18, about 10 years ago. Then Mayo Clinic came out around 2020 with their delta testing.

And then in 2025, LabCorp came out with their delta testing that was antibody and PCR. LabCorp had some tests for delta, but it was very difficult to get. Specimens got lost, tests didn't get done. So now we have the 4 major labs reference labs all have highly accurate delta antibody and PCR tests. It's really changed access immensely.

GLN:

What about the cost?

Dr Gish:

The cost of testing? It's minimal. I mean, it's the same as really pretty much any other antibody tests, which could be in the $20 to $80 range and the PCR testing is in the $100 to $200 range. There's nothing really special about delta testing, which has a different cost profile. That's great news.

Every reference lab, the 4 major reference labs all have accurate delta antibody and delta PCR testing. These are high quality tests.

GLN:

How complex is treating a patient for both hepatitis D and B? Are there any concerns about any drug-drug interactions or contraindications for patients who are being treated with tenofovir or one of the other hep B drugs and bulevirtide?

Dr Gish:

No. Entecavir, one of the first-line treatments for B, does have a real but small risk of resistance. TDF, which came on the market a number of years ago, has a bone and renal signal. And that's why Gilead came up with TAF, not just for HIV for hepatitis B as well. Minimal bone and renal and no resistance. So TAF is definitely the best drug on the market today, even though it's more expensive and the insurance companies love to block TAF access, but it's the best. Bulevirtide is a drug. It's a lipopeptide. I mean, it's a mixture of a little bit of a fat and a protein that blocks virus uptake into the liver cell, both B and delta. But by blocking B, you block delta infecting new cells or reinfecting cells that may have cleared delta. But it's got such unique mechanism of action that drug-drug interactions risk is going to be really, really small.

GLN:

Tell us about that mechanism of action.

Dr Gish:

So in our bodies every day, we recirculate bile acids into the gallbladder-intestinal tract that's taken back up in the distal small intestine through bile acid receptors and then taken back to the liver cell. And then the NTCP receptor, which is a very specific transport protein, moves the bile acids from the blood back into the liver cell. So this is all part of the recirculation process. And this special protein is blocked by this lipopeptide, which is a little piece of hepatitis B surface antigen in the pre-S1 region. It's one of the proteins the virus makes. And they modify this, attaches to the special carrier and blocks it. So when you take bulevirtide, the blood levels of bile acids in patients goes up also, but that has not led to any safety signal. So high bile acids is really the only side effects besides a local injection site reaction.

If you look at the research data, they talk about headache and nausea and fatigue and a few other things. But patients in these very, very large studies, patients did not come off bulevirtide due to side effects. It's definitely far less than 1%. So the safety profile looks excellent, even though I tell patients about these somatic symptoms, these body symptoms that they may experience.

GLN:

But those are not serious adverse effects at all.

Dr Gish:

That is correct. The biggest is the black box warning on bulevirtide is that when you stop bulevirtide or you stop bulevirtide plus the hep B drugs, the patients can have a flare and decompensate and even, extremely rarely, need a transplant or die. So stopping drug is actually the risk. Not taking the drug is the risk.

GLN:

So is this then likely to be a lifetime drug for people with this virus?

Dr Gish:

We try never to use the word lifetime because there's so many new drugs coming. There's a number of other drugs in development for delta today. A company called Mirum bought a company called Bluejay that has a special antibody PReP. Vir has an antibody PReP plus what's called an siRNA. And there's a Chinese company called HHH that has a different type of antibody. There's another company called EIT that has an oral drug for delta called lonafarnib. And then there's a Canadian company called Replicor, which had what are called NAPS, which are these polymers. Although that drug development from my perspective is inactive right now but may be resurrected at some time in the future. Nice news, lots of different pathways, different mechanisms to get to our patients.

GLN:

Does treatment change at all based on whether a patient's diagnosed with acute or chronic hepatitis B and D?

Dr Gish:

If you have acute B and acute delta, you're going to wait to see if the virus clears. You're not going to intervene with bulevirtide in that setting. Maybe you'd intervene with one of the oral drugs for B, depending on liver function. We have to remember we don't use the word LFTs anymore. That's completely out of date, used by the great-grandfathers in our liver world. We use liver enzymes that mark inflammation. We say liver function when we mean bilirubin, albumin, and some other blood tests. So we do monitor enzymes and function in our patients. If liver function is off, that means the liver's not working very well. Then we think about other earlier interventions as opposed to waiting for a virus to clear.

GLN:

Bulevirtide received breakthrough therapy and orphan drug designations from FDA, and it was approved under the accelerated approval pathway. Do you foresee that in creating any impediments to getting insurers to cover the cost of treatment?

Dr Gish:

Never seen accelerated approval used by insurance companies. And we are using surrogate endpoints, which is viral reduction, ALT, liver enzyme normalization. But insurance companies, I think they'd be stupid to try to use that to block drug access. They typically use other tools, just blanket denials that they do for fun. And then they sometimes come up with some type of specifics like, "Well, this drug hasn't been studied in this special population,” but I think this is a rare and highly fatal disease. I think the insurance company's obstruction level will be lower than with other drugs.

GLN:

Well, that's good news. Can a gastroenterologist who's not specifically a hepatologist refer patients with hep B and hep D to hepatology or can they treat the patient in their own practice? In some parts of the country where hepatologists may be pretty distant from where the patient is being treated, what would you do?

Dr Gish:

In the gastroenterology community, there's 2 types of providers that can manage any type of liver disease. We call gastro-heps where gastroenterologists still are doing more than just putting a scope into somebody's body. They're thinking about the liver disease. They follow the information. That's about 20% of gastroenterologists are maintaining high level of liver training and we embrace those to join us in testing and treating for delta. Many gastroenterologists have APPs. These are PAs and nurse practitioners. They tend to be quite sophisticated in the liver world as well and are very intent on applying the newest therapies. So that's really going to help us a lot.

GLN:

Do you have any other points that you'd like to add about screening, testing, or monitoring patients with hep B and hep D?

Dr Gish:

Well, in the US, sometimes we're slow. And the hepatitis B guidelines that came out from AASLD this last year barely even mentioned delta, which in my opinion, it was embarrassing. Delta should have been in those guidelines and said, test everybody, use reflex testing, offer treatment. There's a lot of new drugs coming. The AGA came out with a guidance piece which was lead authored by Tatyana Kushner, which basically said that—test everybody, offer treatment. WHO basically said that if you have delta testing, offer it to everybody. Chinese guidelines said if you have delta antibody PCR available, test everybody. EASL guidelines said that. So I really wish AASLD would become the engine, not the last car on the train, and really lead change by rapid response, rapid uptake. And I think that's one of my complaints about AASLD is they're too conservative, they're too slow. And by being slow and conservative, you don't lead change.

You are to summarize the data, you summarize the literature critically, but that doesn't really affect how the world is managed. That's why the death rate from hepatitis B has gone up every year for 25 years. We have not changed the B death rate in this world. Now younger people aren't getting B because they're vaccinated, because the vaccine is safe, unlike the information you hear from our federal government leaders who have no idea what's going on. The B vaccine is extremely safe, extremely effective. We need to continue implementing birth dose vaccine in every child in this country according to protocol. That will break the B and the delta cycle. Vaccine for B prevents delta. So when you're talking about treating delta, part of treating is prevention and vaccine is prevention. So I want to make that an important plug.

GLN:

Well, we appreciate your time. This is interesting and it sounds like there's going to be a lot happening in the drug development world for hepatitis B and D. And so thank you very much for spending this time with us.

Dr Gish::

Thanks, Rebecca. Thanks for your mission to carry science to our community.