Exposing the hepatitis B virus

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Professor Peter Revill from the Peter Doherty Institute for Infection and Immunity in Melbourne, and Dr Thomas Tu from the University of Sydney’s Storr Liver Centre, met and bonded over Hepatitis B. In 2016 Peter and his colleagues formed the International Coalition to Eliminate Hepatitis B, and both he and Thomas have been on the hunt ever since for Hepatitis B’s master virus blueprint, which they believe could lead to a finite cure.

Peter Revill and Thomas Tu recently attended the 2019 International HBV Meeting in Melbourne – the first time the event has been held in Australia. Although both men have medical research backgrounds and a vested interest in disease elimination, for Thomas Tu, who was diagnosed with the disease as a teenager, finding a cure for Hep B is personal.

They took some time out to chat with our reporter Dr Andi Horvath.

ANDI HORVATH
We're in an era where international collaboration in research is critical to eliminate diseases like hepatitis B virus. Let's start with the basics. What is hepatitis B, because there's A, B, C, D, E, if I recall?.

PETER REVILL
Yep. Hepatitis B is one of the hepatitis alphabet. As you say, there is A, B, C, D and E. Hepatitis B is a small DNA virus; it's one of the smallest viruses that infects humans, of only 3200 nucleotides. That's tiny when you think of the human genome of billions of nucleotides. But this virus does a lot of damage and causes liver cancer and chronic liver disease. So, yeah, so it's a very, very tiny, tiny virus.

ANDI HORVATH
Currently, how do we manage hepatitis B, Thomas?

THOMAS TU
The current management includes taking a daily pill that knocks down the replication of the virus so you don't produce new virus particles. But the minute you take a patient off of treatment, the virus comes back. So, a patient needs constant access to take these medications.

ANDI HORVATH
So, there's no cure for hepatitis B at the moment. Can we take a preventative measure?

PETER REVILL
Yeah. We have a very, very effective preventative vaccine which is now given to all children at birth in Australia, for example. It's called the birth dose vaccine. Highly, highly effective. Preventative vaccine, though. It's not a therapy; it's not a cure. There's 257 million people in the world living with chronic hepatitis B; 240,000 Australians. The preventative vaccine is of no benefit to them at all. Look, it's amazing, but it's a very - it's a highly effective vaccine in preventing infection.

ANDI HORVATH
Give us the global context.

PETER REVILL
So, 257 million people chronically infected with this virus, and in fact 1.3 billion people alive today have actually been infected with hepatitis B. Many of them have developed what's called an acute infection and they clear the virus, so the immune system, their healthy immune system controls the viral infection. But in 257 million people, their immune system wasn't strong enough to do that and they developed this chronic or lifelong infection - so 257 million people globally; it's just a number that boggles the mind, 110 million people in our region, the Asia Pacific region, and 240,000 Australians. To put that into some sort of context, we've just had the Grand Final in Melbourne, 100,000 people sitting in the stands. Well almost two-and-a-half times that number live with chronic hepatitis B here in Australia.

ANDI HORVATH
And the burden of that disease is of course liver cancer and liver cirrhosis.

PETER REVILL
Yes. That's - if people are untreated, they're quite likely to develop liver cirrhosis and lead to liver cancer, but - and Thomas mentioned the treatments and the very, very effective antiviral treatments still don't eliminate the risk of liver cancer. There's still a 50 per cent risk of progressing unfortunately to liver cancer, even in the advent of these continual treatments.

ANDI HORVATH
Tell me about diagnosis.

THOMAS TU
Many people are diagnosed just by routine blood test. For example, if you to go donate blood or just a workplace health check, that's because a lot of patients simply don't display any symptoms. They can be chronically infected for much of their life, up to 50 years and still have no symptoms. It's not until they feel sick enough to go to the doctor and get told their liver is failing or they've got liver cancer do they actually know they have hepatitis B.

ANDI HORVATH
Tell me about how this global initiative started where you got together and said hey everybody working on hepatitis B virus, let's all work together and get a cure because we haven't nailed this particular virus. Tell me what led up to those events.

PETER REVILL
In 2015 a number of us conducted a review of cure initiatives for hepatitis B and we realised there wasn't a global approach to curing the virus, unlike HIV, for example. The International AIDS Society has had a global cure initiative since 2010. We don't have the equivalent of an International AIDS Society in the hepatitis B field. So, through the International Hepatitis B Meeting, which I will talk about I'm sure in a moment, that's here in Melbourne in 2019. We got together and said a group of us need to get together and form an organisation to coordinate efforts to cure hepatitis B.

So, through the International Hepatitis B Meeting, through the Doherty Institute and through the ANRS Institute in France, a number of us got together and formed an organisation called the International Coalition to Eliminate Hepatitis B. The acronym is ICEHBV, formed in 2016. That has brought together scientists, clinicians, the HBV-affected community stakeholders such as the WHO to work together to try and fast-track a cure. We released a scientific strategy which was published in 2019, earlier this year, and we launched that in Vienna at one of the big liver meetings in April. So, it's really bringing people together from all over the world to try and fast-track a cure.

ANDI HORVATH
Is there a goal you have in mind for a particular year? If we were doing this interview in 2025?

PETER REVILL
I've got to be very careful not to give false hope here because hepatitis B, gee, it's a tricky little beast of a thing, but we want to fast-track a cure and bring it along much faster than it would happen if we didn't exist.

ANDI HORVATH
Let's talk about the trickiness of the virus, because scientists analyse the virus through detection, you analyse it through the progression of the disease, and obviously you're looking at elimination. So, why is this such a tricky little bugger of a virus?

THOMAS TU
Let's start at the start. Every virus when it infects a cell needs to form a master blueprint of itself, and it's from this blueprint that you produce copies of virus.

ANDI HORVATH
So it replicates itself?

THOMAS TU
It replicates itself.

ANDI HORVATH
Got it.

THOMAS TU
And photocopies this initial blueprint to send off into the ether to infect other cells. With hepatitis B, this master blueprint is really stable. It's as stable as the cell itself. This means that we can't simply knock down the replication of the virus, we need to really target that master blueprint, and that's been one of the major difficulties in hepatitis B research to find that cure.

ANDI HORVATH
What's changed in your field of research that you have seen so far as a scientist?

THOMAS TU
Well, I think the major breakthrough recently has been to find the receptor for the virus. This had not been found before and it had been really hard to culture the virus in the lab without knowing how can we infect a cell.

ANDI HORVATH
Is this the receptor that attaches to our cells? Is that the receptor you're talking about? Where is the receptor?

THOMAS TU
I'm talking about the cellular receptor. That is the protein that the cell produces that the virus latches onto to enter the cell.

ANDI HORVATH
Oh. So, our cells make a protein?

THOMAS TU
Correct.

ANDI HORVATH
And the virus says there you are, now I'm muscling my way in.

THOMAS TU
Right, right.

ANDI HORVATH
So, it's our protein that allows it in?

THOMAS TU
Yes, of course. Yes. This is the way many viruses enter cells is by hijacking our own body to enter and produce more copies of itself. That's the whole goal of a virus is to produce more copies of itself.

ANDI HORVATH
Yeah, they're hellbent on global domination, aren't they, these viruses? They really are.

PETER REVILL
This receptor was only discovered in 2012, so this was a real hamstrung on the science, if you like. It's interesting, it was discovered by Chinese scientists, particularly Wenhui Li. Wenhui Li is co-convening the International Hepatitis B Meeting here in Melbourne in 2019 with me, so this has been a real paradigm shift for the field. As Thomas said, it opened up cell culture studies, it's opened up other studies enabling us to study. The key thing is you can't study that reservoir that Thomas talked about unless you can study infection, because the very first step after infection the virus makes this reservoir. It's called covalently closed circular DNA, or CCC DNA and it's in the nucleus of the cell and it's untargeted by any current therapy.

ANDI HORVATH
So in other words, if I translate that, the virus creates its own reservoir of replicating itself and that's where things go downhill?

PETER REVILL
Yes, and they're not targeted by current drugs, so we need drugs that target that reservoir. Unlike hepatitis C virus, which doesn't have a reservoir, we now have drugs that can completely eliminate hepatitis C virus in as little as eight to 12 weeks of treatment, which is amazing. That's absolutely incredible. We can't do that for hepatitis B yet.

ANDI HORVATH
Right. So, this is the nasty one amongst the alphabet, isn't it?

PETER REVILL
Well, they're all nasty. They all cause terrible liver damage. Hepatitis C is nasty but we've got a cure for it. Hepatitis B we don't have a cure but we've got a preventative vaccine. I would hate to say one is more nasty than the other in terms of the outcome, but it's certainly a terrible virus causing a terrible disease.

ANDI HORVATH
Dr Thomas, tell us about your story. What inspired you to enter this area of research?

THOMAS TU
I am a carrier of hepatitis B. I found out when I was a teenager through a routine blood test, and when I was diagnosed I was obviously quite upset but I don't know - I didn't realise why. I wasn't given much information, just that you will have this for the rest of your life, and that was it. You may get liver disease down the track. So, after that I was a bit despondent, as you can imagine, but then I thought what is this? And so I went online and started really looking up what hepatitis B was and I accrued all of this knowledge and realised I could do something. There's so many unknowns about hepatitis B still that I could do something to lift myself out of this situation. That self-informing was really empowering and drove me to get up and fix it, and so that has been the major inspiration for me to start this research.

ANDI HORVATH
Tell us about your latest research project.

THOMAS TU
The latest research project that I've got has been to detect this master blueprint, this reservoir, this CCC DNA, with a new, very accurate, very sensitive method. I'll be presenting that data at this meeting in 2019. With this method now we can start to use this to screen drugs, for example, and look at ways of targeting this reservoir and hopefully lead to a cure.

ANDI HORVATH
I'm always moved by people who examine scientifically the very conditions they have. You join a long line of quite famous people who have done that. Peter, what got you into infectious diseases? Tell us about young Peter who was interested in studying infection.

PETER REVILL
It's actually a long and sort of interesting story. I did an honours degree in botany and a PhD on mushroom viruses, then a postdoc on plant viruses which led into hepatitis viruses. Because it's funny, viruses are basically all kind of the same, whether they infect a mushroom, a plant, a cat or a human, but the host is actually different, and the diseases are different. Fifteen years ago I moved into hepatitis B and had to learn very quickly about the human immune response as well as all the things about the virus, but I very quickly realised the terrible problems associated with this virus and particularly, the link with liver cancer was of interest to me.

My research group at the Doherty Institute is very interested in also the CCC DNA that Thomas has talked about, we work on that as well, but also in developing a biomarker for liver cancer. There's no way yet of really predicting who is going to go on and develop liver cancer for chronic hepatitis B. Our group is focusing on what we call splice variance of hepatitis B. Now, I said hepatitis B is small; these are even smaller, but they still pack most of the proteins of the virus and in fact, make some different proteins, some novel or funny proteins. We've shown that they are actually associated with and indeed predictive of liver cancer in the lead-up to diagnosis in the five years previous. That's the focus of my research. In fact, I have an NHMRC grant to work on that, which is fantastic.

That's really what inspires me every day, but I tell you what, I am so inspired by this gentleman over here for telling his story. I think Thomas is the first person in our field who has talked about his experiences of living with hepatitis B. I just think - and plus the work that he is doing. He is being a little bit humble; he is one of our leading lights in the field. Why the work he's doing is so important is that this CCC DNA reservoir, if we can't - it's very, very hard to detect.

We have working groups, this international coalition that I work in, we have a working group on detecting CCC DNA. If we can't detect it, we can't work out that the new drugs are actually effective against it, so we need different ways of actually measuring it, and Thomas's new method - and I haven't seen the presentation yet but I've read his abstract; it looks amazing and it could be what we call a game-changer for the field to be able to detect this, because these days it's very, very hard to analyse the liver directly. We need very, very sensitive ways of measuring this CCC DNA reservoir, either in the liver or potentially other markers that are in the serum in the body. So, Thomas is doing amazing work.

ANDI HORVATH
Good on you, Thomas. Get back into the lab.

THOMAS TU
Yeah, right [laughs].

ANDI HORVATH
What are we doing here in the studio, come on, there isn't a moment to waste.

[Laughter]

ANDI HORVATH
We've got to get going, right. But before you go, tell me something that surprises you about your research. Because scientists go in, they do experiments, but every now and again I find that scientists tell me they're surprised about nature or some activity that they see in front of them.

PETER REVILL
This virus surprises me every day. When I said it's small, 3200 nucleotides is nothing and yet this virus carries the messages to cause chronic liver disease of 257 million people, and we've had the best minds working on it for 34 years. This is the 34th iteration of the International Hepatitis B Meeting here in Melbourne in 2019, and yet we still don't know - there's many things we still don't understand about the virus lifecycle or replication cycle, and we still cannot cure it. The most important thing we need to do is develop a finite cure, so a short-term cure, that people can take some pills for a short duration and not have to take pills for the rest of their life, and that inspires me every day.

ANDI HORVATH
Thomas, what surprised you about your journey of research?

THOMAS TU
I was so surprised about how much everyone cares about this virus, even though they may not have met someone with hepatitis B or know what it does. Everyone is trying so hard to get a cure, to find out more about this virus, and I think our listeners out there should know this, that if you are affected by hepatitis B there are people behind you. You're not alone. Just know that there are lots of people working on your behalf to cure the virus.

ANDI HORVATH
Tell me about some misconceptions people might have about hepatitis B.

THOMAS TU
I'll give you my story. Even though I was born in Australia, I'm different to what I see in Australian culture, for example, who's on TV, who's on movies, who's in power, who's representing me in Parliament. My family are from Vietnam. They are the first migration wave after the White Australia Policy was repealed, so we had faced quite a bit of discrimination. I think whether I like it or not and whether it's accurate or not, I represent a community that has been discriminated in the past. So, this complicates how I talk about hepatitis B, how open I am about having hepatitis B. I'll give maybe a story about that.
I went to a party once and met a girl, as you do, and I sort of liked her and we got talking and it turns out she lived close to me and she offered me a ride home. I had just come from the lab so I needed to pick up my stuff and we got talking and she asked oh, what do you do. I said I study hepatitis B virus. Why do you study it? I said well, my family come from Vietnam, it's quite common there, it's known within my family, and she came up and said just bluntly, oh, do you have it? Now, at this point I have to think and make a judgement about how this person is going to react. As my parents are from Vietnam, they told me to keep my head down, to not make waves, work hard, no politics, no personal incriminating facts to strangers.

So, I have to think what are the consequences of my response; is she going to respect the honesty, which would be nice; is she going to refuse me a ride or refuse to go out on a date with me; is she - is this going to reinforce this view of dirty immigrants coming to our country and taking our health care; is it somehow going to be notified to the authorities and my family being chucked out of the country? All of these issues come up from this single, fairly benign question. That is sort of something I have to live with each day, and that can get quite tiring. Just as an ending to that story, I did tell her yes, I do have hepatitis B. She gave me a ride back home anyway, and long story short, we actually celebrated our fourth-year wedding anniversary this year.

[Clapping]

ANDI HORVATH
That's a happy ending I love.

PETER REVILL
Oh my gosh.

ANDI HORVATH
And a lesson for many.

PETER REVILL
Thomas, it's a beautiful story.

ANDI HORVATH
It is a beautiful story. Listeners, I actually saw that he had a wedding ring on so I knew where this story was going.

THOMAS TU
Oh, you would hope it's not the one that didn't put the wedding ring on [laughs].

ANDI HORVATH
Congratulations on your wedding anniversary.

PETER REVILL
Can I touch on something else that Thomas raised there too, about hepatitis B being present in Australia for a very long time. It's a terrible situation that in 2019 rates of chronic infection in Indigenous Australians are between four and 10 times higher than non-Indigenous Australians. Some work at the Doherty Institute and in collaboration with the Menzies Institute in Darwin has shown that hepatitis B has probably been in this country with the longest culture on earth for 60,000 years. It turns out that in the Northern Territory there's a particular strain of the virus called the C4, which is not found anywhere else in Australia - sorry, anywhere else in the world. Another little-known fact is that hepatitis B was discovered in 1965 in the serum of an Indigenous Australian and was first known as the Australia Antigen.

ANDI HORVATH
This virus really gets around.

PETER REVILL
It does. But I think it's terrible that in 2019 we're still seeing these huge rates of chronic disease. That's why a cure is so important.

ANDI HORVATH
Peter, next time we hear a new story about hepatitis B or encounter something to do with infectious diseases like hepatitis B, what would you like us to think about?

PETER REVILL
I want us to think about people like Thomas, people who are living with chronic hepatitis B infection, the people - World Hepatitis Alliance has a campaign called Find the Missing Millions of people living with viral hepatitis, be it hepatitis C or hepatitis B. I want us to think about the missing millions, be they in Australia, be they in Mongolia, be they in Africa. We need to find these people; we need to treat these people and we need to fast-track a cure for these people.

ANDI HORVATH
Bill Gates, I hope you're listening. There's a project for you to fund. Thomas, what would you like us to think about?

THOMAS TU
I would like you to think about the people that have the disease and how they're not people out there but they're us. They are people among us who are suffering and it's not someone to chuck out of the country or to put away in the corner; it is someone to lend a helping hand and help out.

ANDI HORVATH
Hepatitis B is a global problem. Gentlemen, I wish you all the very best of luck and good scientific work. Thank you, Professor Peter Revill.

PETER REVILL
Thank you. You're welcome.

ANDI HORVATH
And thank you, Dr Thomas Tu.

THOMAS TU
Thank you very much for the invitation.

CHRIS HATZIS
Thank you to Professor Peter Revill from the Peter Doherty Institute for Infection and Immunity, and Dr Thomas Tu from the University of Sydney’s Storr Liver Centre. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on September 30, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2019, The University of Melbourne. If you enjoyed this episode, review us on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.