Although uncommon in the United States, hepatitis D, or hepatitis delta virus (HDV), is the most aggressive form of viral hepatitis—in a great many cases, resulting in cirrhosis or even liver disease or cancer.
HDV is unique in that it infects only people who are already infected with hepatitis B virus (HBV); globally, it affects 5% of people who have HBV. HDV also shares some similarities with HIV—like HIV, HDV may be transmitted through contact with blood of an infected person; for example, through shared needles, or through sex with a person who is living with the virus. HDV and HBV coinfection also appears to be more common in people living with HIV (PLWH).
Compounding matters further for people who have HDV is that there are very few effective therapies, with current treatments consisting of high doses of pegylated interferon alpha, a drug also used to treat hepatitis B and C. For some patients and due to the rapid progression of HDV, liver transplantation remains the only option, says Charles Béguelin, P.D., Dr.Med., a senior physician in a regional hospital in Biel, Switzerland, specializing in internal medicine and infectious diseases. He also serves on the viral hepatitis co-infection panel of the European AIDS Clinical Society.
At the 28th Conference on Retroviruses and Opportunistic Infections (CROI 2021) held in early March, Béguelin presented the results from a recent study he and his colleagues at Bern University Hospital conducted on the prevalence of HDV in PLWH in Europe. Analyzing data from two large HIV cohorts, the Swiss HIV Cohort Study and EuroSIDA, the researchers found that HDV prevalence among PLWH in Europe varies strongly across regions and is particularly high in people who inject drugs. In conversation with Terri Wilder, Béguelin spoke about the study’s findings and goals, and the broader implications for people living with HIV.
The Most Severe Form of Hepatitis Virus
Terri Wilder: Thanks so much for speaking with me today. At the beginning of your CROI presentation, you stated that hepatitis D is the most severe form of hepatitis. People are probably more familiar with hepatitis C or B. Could you start off by talking a bit about hepatitis D? What is it? How do people get it? How do you test or screen for it? And why is it the most severe form of hepatitis?
Charles Béguelin: We hear much more about hepatitis C and B. Hepatitis delta is some kind of a defective virus. It needs the hepatitis B virus to survive in our body and to replicate. And we don’t know it for such a long time.
Furthermore, you really have to look for it, which means that usually when you look for hepatitis and you find one, sometimes you don’t go further. One point among the aims of our study was to show the prevalence of coinfection with hepatitis D and hepatitis B in certain groups. It’s really important to, first of all, look for it and search it.
And then, it is the most severe form. This was shown in hep B and D coinfected patients. It seems to be even worse in patients coinfected with HIV, as we showed in our study, which means that while usually people get infected pretty much like they get infected with hepatitis B—as you have to have both viruses. But finally, it also has a lot in common with HIV, which is spread through contact with blood, which probably is the most efficient, but also through unprotected sexual relationships.
You asked me about vertical transmission, which is really not happening so often. It can happen when delivery happens and there is blood. We see it in a person who injected drugs—and through unprotected sex, like for hep B and HIV, and more common in homosexual sex.
So then, it really depends. We think that either you can have hepatitis B and then get super-infected with hepatitis delta, or you could basically also get coinfected with the two at the same time.
We know from the natural histories that if you get super-infected—you got hepatitis B and then hepatitis D—in 90% of the cases you will have chronic hepatitis. Whereas, if you get coinfected with both at the same time, only a minority, like 5% to 10%, will have chronic hepatitis.
And the thing is, when you have this coinfection with those two viruses, usually the hepatitis delta virus predominates, because we found more of it in the blood than hepatitis B.
We see that the way to hepatitis, to chronic hepatitis, to finally cirrhosis, and then to hepatic decompensation or liver cancer is much more rapid in a person that has coinfection with hepatitis delta than in those that only have hepatitis B. We think that it’s three to five times more likely to develop hepatocellular carcinoma. And 70% to 80% of people will develop cirrhosis in five to 10 years, which is pretty rapid. A few of them even can develop cirrhosis really fast, in one or two years. So this is why we say it’s the worst among hepatitis. It seems to be even worse in patients that are infected with HIV, regarding those different outcomes.
Wilder: Hepatitis D occurs in people who are already infected with hepatitis B. Why does that happen?
Béguelin: It’s a defective virus. So, it needs the HBs antigen to make, kind of, its envelope. The hepatitis delta virus is really small, with two—one large and one small—particles. It needs this to go out of the cell. So, you can only get hepatitis delta if you have hepatitis B. Either you can get coinfected, if you get infected from somebody who already has both, or you can get hepatitis B and then at a later point get super-infected with hepatitis delta.
Wilder: How do clinicians test for it or screen for hepatitis D? Are there certain symptoms that they should be looking for?
Béguelin: When you get it, you can have acute hepatitis, like all the other hepatitis, which can have general symptoms: fever, you feel sick, you get stomachaches, and then different lab abnormalities with high transaminases. So, you should be aware of it. And of course then you will start looking for it if you get acute hepatitis.
If you realize someone’s got chronic hepatitis, you also are going to look for it. The point is, you’re used to looking for hep C, for hep B. If you find the patient with active chronic hepatitis B, which means he has positive HBs antigen, you should screen for hepatitis delta.
This is what we recommend in our guidelines: If a patient is HBs-antigen positive, you go and you make a serological test for hepatitis delta. If the test is positive, then, just like in hep B and hep C, you will do a PCR to check for viral load—and you will see if hepatitis delta is replicating. All of the rest of the workup pretty much is the same as in other hepatitis. You go for liver checks, ultrasound, FibroScan, and so on.
A Few Novel Treatments Show Early Promise
Wilder: Is there a treatment for hepatitis D?
Béguelin: We’re still waiting for a treatment. This is the worst point. We have the worst hepatitis, where we, for the moment, have really bad treatment.
For years, pegylated interferon was the only treatment available—and results were bad. As a few people remember from previous treatment from hepatitis C, there are a lot of side effects from this treatment. There were a few trials that showed that people treated for six months to one year with interferon, which is already really hard, will get to 30% of clearance of the virus. And half of them will have advanced later. So, it’s a bad outcome.
However, we still don’t know what the best outcome is. There is not, like for hepatitis C, sustained virologic response if you were negative after 12 or 24 weeks, because we see those rebounds. And it seems that, despite this, if you treat some people, they come down with viremia. They have less hepatic decompensation, and less progression to cirrhosis.
We’re really happy to see that there is some research going on, and there are a few new treatments in the pipeline. There is one called bulevirtide—the brand name is Myrcludex.
And there are a few studies that show a promising result, also in combination with interferon. In Europe, it has been licensed in a few countries. So it’s not clear how long, and in which combination, we will use it. But as we need a treatment, there have been some fast approvals that use this treatment. The second is called lonafarnib, which is also in different phase 3 trials where there are still studies going on, in combination with a booster, ritonavir, and also in combination with interferon, which show promising data. There are even further treatments like pegylated alpha interferon, which are shown in some studies. And finally there was one that is called REP 2139. This is a NAP (nucleic acid polymers), which also seems to be able to suppress hepatitis delta.
So, we’re really in a phase where we have few novel molecules that show promising results, which have less toxicity and where we really need more long-term data. It’s really important that we go on with this study to have a solution for those patients which don’t have any solution other than liver transplantation at the end.
The best treatment, of course, is prevention. If you get people vaccinated for hepatitis B, you will see that hepatitis delta is going to disappear, because without hepatitis B there is no hepatitis delta. One question that always comes again is, what happens if you treat it? But that’s B, because we have treatments for hepatitis B—tenofovir. We did some study on this, and we showed that even if you can suppress hepatitis B, hepatitis delta continues to replicate. So this is not the solution, sadly.
A High Prevalence of Hepatitis D Among PLWH
Wilder: Let’s talk about the study that you and your colleagues conducted. What were the aims of it, the methods, and some of the more significant outcomes?
Béguelin: Our aim was to, first of all, assess the prevalence of hepatitis delta infection in Europe. So we gathered data from two large HIV cohorts, which are the Swiss HIV Cohort Study and EuroSIDA. We wanted to extract main epidemiological and clinical characteristics of these HIV-, hepatitis B–, and hepatitis delta–coinfected individuals. We also wanted to assess the impact of hepatitis delta on clinical outcomes like overall mortality, liver-related mortality, and hepatocellular carcinoma.
We screened these large cohorts for all patients who were HBs-antigen–positive and had hepatitis B. We performed hepatitis delta serologies in all those where we had samples available to do it. Then, when there were positive serologies, we performed RNA measurement by PCR.
We did descriptive statistics for demographic and clinical characteristics at the initiation of antiretroviral therapies, and we did Cox regressions to evaluate the association between hepatitis delta and those main outcomes.
Wilder: What were the results?
Béguelin: What did we find? We had 2,793 patients with positive HBs antigen in the two cohorts. In 56% of them, we had samples where we could test for hepatitis delta. In those 1,556 patients we tested, 15% had a positive serology for hepatitis D. From those 237, we had 200 where we were able to measure RNA, so that 66% of those we were able to test had replicative HDV infection, which pretty much is what we were waiting for.
We had previous data from EuroSIDA and previous data from the Swiss HIV Cohort Study, and this is high prevalence. But we knew that the prevalence was pretty high among HIV-positive persons, and as I explained, the ways of transmissions are pretty much linked.
We wanted to look at the prevalence in the different parts of Europe. In Europe, we looked at Southern, North, Central, and Eastern Europe. The prevalence was lower in Central and Northern Europe, with 13%, and was higher in the South and East, with 28% in the South and up to 32% in the East.
We also wanted to look at which transmission groups were more likely to have hepatitis delta. So we looked at heterosexual versus who inject drugs and MSM. But for this, you have to understand that it’s kind of biased because, for example, in Eastern Europe you have many more persons who inject drugs that will get tested. And MSM sometimes don’t even come into the cohort.
So, basically, what was the most interesting is that across Europe, wherever you look at, North, Central, South, or Eastern Europe, the prevalence among persons who inject drugs is really high, and it was 50% across all the different regions. I think, epidemiologically, this is the thing, we could say. It makes sense to definitely test those people. It was interesting, again, to see that.
We looked at causes of deaths, and we found that 32% of hepatitis D–infected patients died, and 20% of hepatitis D–uninfected died, after a median time follow-up of 10 years. But what is interesting is that 43% of the deaths were really liver-related in those that are infected with hepatitis delta, compared to only 18% in the HDV-negative patients, really showing that those patients who are infected with hepatitis delta die from liver-related problems, and probably the others from other problems.
Then we did this multivariate analysis, which was digested from multiple competing factors. We showed that the hazard ratio for overall deaths was 1.4. So, people coinfected with hepatitis delta were 1.4 more times tending to die, compared to those not coinfected with hepatitis delta. [They] were 2.9 times more likely to die from liver-related deaths, and were 6.2 times more likely to develop hepatocellular carcinoma.
So, the conclusion was that we have a high prevalence of hepatitis delta among HIV/HBV-coinfected persons, and that the prevalence is around 30% in Northwestern Europe, and twice as high in Southern and Eastern Europe, with the prevalence particularly high among persons who inject drugs, with 50% across all Europe. Hepatitis delta is currently associated with mortalities and liver-related events. For this, we recommend that all patients with positive HBs antigens should be screened for hepatitis D.
A Call for Hepatitis D Screening in People With Hepatitis B
Wilder: Based on what your study found, what do you think that medical providers can start doing differently in practice?
Béguelin: Well, it’s more like a reminder. Most of the guidelines agree with what we showed, and it was not totally new to show this. We know that persons who inject drugs are the major population, or were the major population. We also knew that there were risk factors for getting it. So, for the HIV population, of course, the prevalence tends to be higher.
I think the message we can give is, if you have patients with chronic hepatitis B, please also check for hepatitis delta. It’s really not complicated to add this serology. And really, you can guide those patients differently. You have to monitor them closely. And as new drugs are coming out—for example, if you have bulevirtide, which has been approved in several European countries, it starts to have some solution for those patients.
Wilder: Any final thoughts on your study or what you found?
Béguelin: What we showed in our study is based on what is known on hepatitis delta, but there is still a lot unknown. We actually do not really understand the epidemiology in some countries. It’s really difficult because different tests are done, which differ in sensitivity and specificity. There is no gold standard, so it’s difficult to compare.
A lot of tests are only done in hepatology clinics. For example, in countries like Mongolia, there are prevalences reported of more than 50% of coinfected hepatitis B patients. But it’s really difficult to analyze, because those are hepatology clinics.
But there is a report from Africa, for example, of some countries where you have a gradient of prevalence, going from like 2% to almost 20% in certain parts and villages, which is really hard to understand. So there have been some papers looking at and asking: Is it all what we think we know? And the fact that hepatitis D needs hepatitis B, which we asked. So could there be some other viral vectors which can help hepatitis delta to infect someone? Would there be other viruses, like dengue, which could make hepatitis delta [more likely]? It’s a really fast-moving field, and interesting data coming out all the time. For the rest, I was thankful for all the people that helped with this project. And it was really nice to be able to present it at CROI.