Drs Alan Bonder and Robert Gish Discuss Screening and Treatment for Hepatitis D

In this podcast, Drs Alan Bonder and Robert Gish discuss the need for universal screening for hepatitis D, the types of screening tests that should be used, and treatment options.

Robert Gish, MD, is Principal, Robert G. Gish Consultants LLC and clinical professor of medicine at Loma Linda University Liver Transplant Institute, Las Vegas, Nevada. He is also the Medical Director of the Hepatitis B Foundation, Doylestown, Pennsylvania. Alan Bonder, MD, is medical director of liver transplantation at Beth Israel Deaconess Medical Center and assistant professor of medicine at Harvard University Medical School in Boston, Massachusetts.

TRANSCRIPT:

Welcome everyone. This is another podcast of the Gastroenterology Learning Network.

I'm your host, Alan Bonder. I'm the medical director liver transplant here at Beth Israel in Boston, and I have the pleasure to have with me today Dr. Robert Gish, who is a well known expert in hepatitis B and hepatitis D. So we'd like to thank Dr. Gish for his presence and for his knowledge.

So welcome Dr. Gish.

Dr Gish:  Thanks, Alan. Great to be here and where would you like to start?

Dr Bonder: So let's start with, there's a lot of difference of opinions in the different societies about who should we scream for hepatitis D. So as an expert clinician in this topic, can you go over about the details about, what would you do and who should we suspect of having hepatitis D in today's practice?

Dr Gish: All right, Alan, we've made this quite simple recently, including the WHO guidelines that came out 2 weeks ago while we were at APASL in Japan. So when I say 2 weeks ago, I'm talking about early April 2024. And that was to test everybody. Everyone who has been involved with risk-based testing has failed. HIV failed—we test everybody. Hepatitis C failed—we test everybody. Risk-based testing for Hepatitis B has failed—CDC said test everybody. Now WHO said test everybody for Delta. This aligns with the EASL, hepatitis B and Delta guidelines. EASL is updating their guidelines now and AASLD also. So in 2024 we're going to have new guidelines, I think even from APASL possibly.

Definitely AASLD and EASL guidelines should be out this year. And just for reference, what we're going to talk about today, Alan, are covered in the EASL Delta guidelines that were released about a year ago. They are fantastic, detailed, well-written, and on target.

Dr Bonder: So this is very important because I know AASLD basically still does not recommend screening for hepatitis D in everyone unless you have high-, I think, risk behaviors. That's what actually the statement in the AASLD guidance, but I think this is very important, as you mentioned that everyone should be screening for hepatitis D.

And again, as far as screening, Bob, is like, what type of test you do screening? I think most of us, I mean, I would say I start with an antibody, but can you just go in detail about what is the screening test that we should do in a patient that we suspect hepatitis D?

Dr Gish: So great question and life is simple. The screening test is a total antibody test. Do not order IgM Delta, it has almost no value. So most labs have actually given up the IgM. So that's also good news. You can't order it even if you're thinking about it. And the good news is just a short time ago in early 2024, LabCorp came out with their antibody test and they also have a PCR quant. So now all the major labs in the United States have antibody testing. And the next wave in this, Alan will be reflex testing.

So hopefully sometime this year, most of the labs will order or offer surface antigen, positive will go to Delta antibody. If Delta antibody is positive, it will go to reflex or PCR quant. And we want to think, but we don't have to think about all that level of detail ee're all busy and the lab will take care of us by having this reflex testing.

Dr Bonder: This is really so important because I think right now is kind of the thought process of doing kind of like step-wise testing actually makes a huge difference for clinicians.

So let's just start with, you know, we have a patient with hepatitis B. You do diagnose them with hepatitis D. So, can you comment on the differences between hepatitis D, coinfection, and hepatitis D superinfection?

Dr Gish: Sure. So, of course, when you have delta antibody, the only way you can diagnose active delta infection is PCR. The antibody just means exposure, similar to hepatitis C. So, coinfection infection is when you get the 2 diseases, B and Delta, at the same time. This has a very high rate of acute liver disease, occasionally fulminant liver failure, but the great majority of people clear Delta when that happens. And of course in adults, we're lucky, most people clear B. So those patients end up looking like B exposure, Delta exposure, but again, RNA -PCR will define the chronicity state for them.

The superinfection is when you have B in the background, which many people have globally, and then Delta superimposes, superinfects comes on top of the B. That setting, the chronicity rate is 70% approximately of being delta RNA PCR long -term.

Right. So and then I think, you know, one of very kind of the important things now that you, know, you mentioned it, 2 different kind of, say, clinical phenotypes. Is there a specific kind of therapeutic option for either one or we actually basically treat those both as the same and trying to get the hepatitis D cleared?

Dr Gish: So the chronicity is defined as Delta RNA PCR long-term after exposure, after acute coinfection or superinfection. But once somebody is Delta RNA positive and you've documented that over time, it doesn't require multiple tests. So if somebody said, "Oh, I had high-risk behavior," in 1995, and they're Delta positive now, you can believe that that Delta RNA is a chronic state for them.

And then management is interesting because we've had interferon therapy for Delta infection for probably 30-some years. The first treatment with interferon probably dates back to late 1980s, early 1990s, but interferon has a problem that the chance of it clearing Delta RNA long-term is about 20%. Some people say as low as 15%. And that's 1 year of interferon treatment that was published in multiple studies in New England Journal.

But if you prolong treatment to 2, 3, then up to 5 years, the chance of clearing delta RNA can approach 40%. And these are basically small case series. These are not large randomized trials, but I believe the data—a lot of it came out of Turkey and Pakistan, where there's a high rate of Delta infection and active treaters. But interferon, the word makes people a little bit apoplectic, as you can imagine.

And now we have a treatment that's available on compassionate use in the US called bulevirtide. That's a daily injection, chronic daily injection. Nobody knows how long to treat. It's probably going to be at least 3 to 5 years as a monotherapy, but that is available if your patient fulfills the right criteria. So it's very narrow, but we're hoping this medication will be approved in 2024. If someone's listening to this later this year and it's approved. We can go into a little bit more detail about bulevirtide. But that's our next wave, our next hope.

Dr Bonder: Let me touch base, because I think I missed one of those kind of new features. I know hepatitis D has also different type of genotypes around the world. Does that impact your chronicity or severity of the disease once you're diagnosing someone with hepatitis D?

Dr Gish: There is a little bit of a difference in terms of severity. There is a genotype 3 that's in South America, Upper Amazonia, and the Oronoco River Valley, and that had a number of different names to it. I think La Brea fever was one of those that has a higher risk of acute liver failure, fulminant liver failure. But in general, the genotypes have relatively similar presentations. And there is genotype 1 in the US, Mongolia, and most of the world.

The new medications that are coming out are pangenotypic, which is probably the most important message. So a little bit different, and there is a concern about the different genotypes and that, depending what primer you use, you may have different sensitivity for the different genotypes. That was published about 8 years ago. I believe it was in Hepatology and that showed the difference by primers, difference by lab, variation in levels between labs. There's a WHO standard, which I believe is for genotype 1, but the primers are set up in a way that you can detect all genotypes and the viral level is reasonably accurate. All of the tests in the US, antibody and PCR, are LDTs, laboratory -determined tests that were developed, as I mentioned, by LabCorp, Quest before them, ARIP before them, and sometime in the middle of this last decade, Mayo Clinic also had their test profile set up.

Those LDTs have good performance. We're not exactly sure what they are but you have to see if they've compared them against the WHO standard and if they've published that. But I have good confidence that the chance of missing Delta with our LDTs in the US might be 3% or so, quite low. So I think we can use those clinically in our practice and not chase Delta too far.

Dr Bonder: Okay, so do you think the genotype right now, this is no prime time for impacting the kind of treatment, but I think you feel that anything in the future will have any impacts like hepatitis C genotypes, like hepatitis D, or do you feel that we are not there yet?

Dr Gish: I think all new medications for Delta will be pangenotypic or they won't be released. And there are other medications in various levels of the pipeline, but I understand they're all pangenotypic, which is good news for the providers and the patients.

Dr Bonder: This is great.  And then, I think you mentioned a little bit about treatment, you know, which we have PEGinterferon one of the new therapies. But I think we need to focus ourselves about kind of prevention. So can you comment on how to prevent hepatitis D infection?

Dr Gish: Hepatitis B vaccination. Big message. We have the CDC that says test everything. and the ACIP that says if you are triple panel negative then you need to get hepatitis B vaccine—that’s the ultimate prevention. And of course modifying risk behavior, harm reduction. In adults Delta is transmitted by sharps so I'd say in Europe in North America. It's a little bit more having to do with IV drug use and sexual transmission. In Mongolia and Pakistan, 2 of the hotspots, it's a variety of sharps that are involved with tattooing, sharps in household, dental work, also barbers—that's one of the attributions. And then there's a lot of Delta throughout Central Asia. The former Soviet states of the “stans” have a lot of Delta. I've been in both Uzbekistan and Kazakhstan. in the last 12 months. I was in Kazakhstan 6 weeks ago. And there's a lot of Delta in these countries, but I think it's from poor medical practices as well. These countries have emerged to be first world countries with first world sterility, but that wasn't the case 10, 20, 30 years ago. Reusable glass syringes, metal needles were a problem. So knowing geography is helpful. It's interesting. Same thing with genotyping. But in the end, test everybody. And as we get new treatments, I believe we'll end up treating everybody just like we do with HIV, hepatitis C and we're getting there with hepatitis B. As you know, there's another major move by WHO, an even bigger move by the Chinese guidelines, for hepatitis B to treat everybody. So we're going to harmonize across these. these infectious diseases finally.

Dr Bonder:  And one more last thing is about kind of the risk of liver cancer. Can you point out if there is an extra risk or an add-on risk, if you actually develop a coinfection with hepatitis B and hepatitis D?

Dr Gish: So if you're chronically infected with Delta, there's 2 multipliers. One, we think Delta infection itself increases cancer risk. And because Delta has a 70 % risk of cirrhosis, and that cirrhosis usually occurs in less than 20 years, sometimes less than 10 years, there's that cirrhosis that's a multiplier for cancer risk on top of the baseline hepatitis B. Yes, very high risk, and that's why we test everybody, even though if you don't have a treatment, you're going to manage a Delta patient differently than a hepatitis B patient.

For instance, in people who like the old guidelines—that I think are out of date with this 2000 or 20,000 threshold—is a problem, but in Delta, you're going to have any DNA level in a Delta-infected patient with hepatitis B. You're going to treat the B with a nuke and then you're going to wait for your access to new Delta treatment. So put every Delta patient on a nuke is really the bottom line.

Dr Bonder: Well, I think this is very important. We'd like to thank Dr. Gish for his contributions, and hope everyone got some time to learn about news and screening methods about hepatitis D. Thank you very much, and hopefully we'll see you on our next podcast.

Dr Gish: Great. Thank you so much for having me, Alan. This is great.