During this 20-25 minute pre-recorded lecture, Dr. Douglas T. Dieterich discusses the topic of hepatitis B. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards.
Hello, this is Doug Dietrich discussing Hepatitis B complicated virus, which is easy to treat, but it's really hard to understand. Mhm the prevalence is pictured here inside too. Um globally This is 2015. The official number is 257 million. But realistically it's probably closer to Um 500 million and probably a billion people with A. B. Have been exposed to Hepatitis B. Mm. Many of them are migrating to the US and large numbers or at least they were for a while there and you can see the places with the highest prevalence uh china India southeast asia Australia and sub Saharan africa. Yeah, it's still a huge global health problem. It's preventable by vaccine by vaccines. It affects 3.5% of the global population that is at least have a core antibody At about 900,000 deaths per year are attributed to Hepatitis B. And those are mostly from a paddle cellular carcinoma. All right. Yeah. So since the discovery of the Australia, Aunty, so how old is hepatitis B? That's a good question paleo. Virologists have been asking for a while. They thought they would have an answer from this money that was found um and uh just south of Naples and in Italy originally they thought the child had died of smallpox because of these lesions on the skin as you can see. But uh tests for variola DNA were negative and then they they realized it could be Hepatitis B because sometimes overwhelming Hepatitis B does produce a skin rash and indeed it was hepatitis B. So they thought, well we could sequence this, here's the money here, it's just south of Naples saying to medical imaging jury this is near pompeii and Herculaneum. And um and actually then date the virus back to when it entered entered mankind. So they did that they compared it also to a korean mummy also from about the same time period The 1500s so about 600 years ago. And they were extremely disappointed um to learn that actually the jena types uh did not actually change almost almost at all. They were both filed genetically closely related to present a genotype D. So they could not date the virus back as to when it entered mankind. Um Then also in 2018 some skeletal remains were discovered in Germany About 7000 years old. And um researchers recovered d. n. a. This was the best preserved skull from a farmer they believe. Um Here they here are the skeletons and the viruses that they isolated. We're all strains of hepatitis B. Two separate teams of researchers independently discovered the DNA and 15 different skeletons. The oldest About 7000 years ago. And what they found was that it's it's almost it's extremely close to the present day um Hepatitis B. Gene type D. But it actually had some sequence Hamal aji with gorilla. Hepatitis B. So hepatitis B is nearly universal in the animal kingdom. Um And you know an orangutan, chimpanzees um in in the uh in the ducks and the bird kingdom here parrots, herons, ross, goose um ducks and other kinds of goose swans actually and even storks Um frogs and fish even have strands of have had the virus in it. And if you if you date these back um they can go back as far as 300 million years. And then of course the famous horseshoe bat which is also the home of coronavirus. Um So it seems like this virus has been with mankind ever since we came out of africa the genotype sar geographic and uh and man genotype C. From southeast asia genotype japan genotype D. Is worldwide. This is probably the first genotype and then these others split off from genotype D. U. S. Public service task force recommends um screening and high risk individuals that's household and sexual contacts. It's extremely contagious. Um I've seen family a family of four who all got hepatitis B from their Haitian nanny about two months after she moved in with him. Um Anyone with HIV injection drug users, men who have sex with men uh and certain immuno suppressed individuals hemodialysis patients etcetera. I mean frankly uh and these are the same as the C. D. C. And the A. S. L. D. I mean anybody who comes into your office um though I think should be screened for hepatitis B. And this is really important screening for, hepatitis B. Is not just surface and again and it's not just surface antibody. It's also core antibody. So you have to do all three tests to have an accurate picture of hepatitis B. Surface antigens, surface antibody and core antibiotic. So U. S. P. S. T. F. Also recommends screening all pregnant women um at their first prenatal visit. Um and then those who are at high risk for Hepatitis B infection. We'll talk about this in a little bit. But um yeah there's some pretty established data that treating pregnant women with HBV DNA levels over 200,000 will uh significantly reduce the risk of maternal fetal transmission of hepatitis B. Now this is acute hepatitis B. As you can see here vaccines have had a great effect In terms of starting here since we started vaccinating in the in the 90s. The acute Hepatitis uh Hepatitis B. Here except for in one group um here this is the 40-49 year old group. This is the the group that didn't get vaccinated as kids and the ones who were getting divorced and actually um are back on the dating market again um And acquiring hepatitis B. Um That way now this is the bible of hepatitis B. This is the main way to think about it. Really wonderful study done in Taiwan called reveal looking at all cause and liver related mortality. So total mortality here on the left according to s. Anderson status um S antigen positive versus negative. As you can see there's a huge difference with a big p value. 22,000 patients in that section. Um This is 3600 patients here, liver related mortality by baseline. HBV. D. N. A. And patients without evidence of hepatitis C. So I mean, the main number here is as you can see in the top two lines of the Kaplan meier graph here in blue and brown, they're overlapping. So there does not appear to be any difference. Any statistical difference Uh and sort of survival or liver-related mortality in patients with less than 10,000 copies. These are copies which translates to Less than 2000 I used. So I think in general, most guidelines and there are many. Now I would suggest that less than 2000 I us um there is no statistical justification for treating hepatitis B. That doesn't mean that there couldn't be other justification. For example, first degree relative with a liver cancer or a patient with basil core promoter mutation, which is the same risk or some other issues. Um that might cause you to want to treat. Now, this is also the reveal study. This is progression to liver cancer and liver related death. In quote inactive hepatitis B carriers. I'm not a believer in this word, it's still in the U. S. Guidelines. A. S. L. D. Guidelines. Uh it's pretty much it's gone from the european guidelines and I think they're pretty much um more modern and way way ahead of us on this. This is the cumulative hazard of progression to liver cancer here and quote inactive carriers um and progression to death here. So, as you can see there are dramatic increases in liver cancer and death and patients who are so called inactive carriers, they're not so inactive after all. So these are carriers and these are carriers carrier pigeons and they're extinct. So, I think you should think about that word as extinct when it comes to hepatitis B patients. This is the easel guidelines. Um and there are patients who have chronic infection or chronic hepatitis and there Yanez and positive or Yanez a negative. Um And I think uh these are s androgen levels, although we just we just recently have been able to get those in the US, but only from quest um not from the other big labs. Um And then here's the here's the 2000 IU level. Um They have chronic hepatitis because they're lT is elevated. That doesn't mean you have to wait for that or not treat If they have over 2000 I use and there's a reason to treat and the same thing here for the patients with who are Yanez in positive and this is the old terminology. So I think there is one overriding rule for treating hepatitis B. There are no rules because it's very complicated patients can have s and again and s antibody at the same time. He and agent indiana body at the same time. Um I'm always getting these texts from the fellows about this. It's really um it's really an art actually more than a science I think in terms of treating hepatitis B, you have to consider all the factors um that are involved. Mhm. So these are the advances in hepatitis B treatment. We kind of talked about this basically there's four drugs that are used nowadays. Uh Tenofovir elephant Might or Taff Tenofovir um in tech of here and speculated interfere on and that's really it. And not many people use Peg elated interfere on and and tech appearance. Tenofovir or generic. So they're cheap. Taf is not although it's much um safer than Tenofovir and no resistance has ever been reported to Tenofovir or Taft but within tech of their their um and you can't use in tech of beer and patients who have been previously treated with lamiVUDine. So our endpoints and Hepatitis B treatment. Once we decide to treat we want to knock the DNA down um bring about e an agent zero conversion if the patient is he and is in positive uh decrease the D. N. A. To undetectable. And then clear the S. And again if possible. And then of course clear C C C. DNA. And then the Holy Grail here would be to clear integrated HPV DNA sequences into the in the host genome. So these are the drugs that we talked about um before Peg elated interfere on Taf Tenofovir and in to cover Now. This is one way to think about it. A nice paper by Raj Ready at the end of 2019. Um He's still talking about immune tolerant um state like I said this is not at all clear but um the energon detectable high DNA Ages 30- 40. Sure, patients with low replica of ST um these actually I I wouldn't treat myself in general unless there are those exceptions. We talked about uh first degree relative with liver cancer, beautiful core promoter mutation etcetera possibly indicated in the middle here over 30. Uh Here's the mutations we talked about. Genotype C is uh seems to be the worst actor. Um any immuno suppression, any extra hepatic manifestations HIV or hep C. Co infection and then the family history stuff that we talked about and then um treatment obviously indicated these are easy. Um Over 2000 I use with A. L. T. Twice the upper limit of normal um or any any anything above the upper limit of normal. Um No one recommends liver biopsy anymore for this cirrhosis Pregnancy with more than 200,000 copies B cell depleting agents. riTUXimab mostly. And that acute happy infection with a significant liver injury. Um I don't think this should be a problem. Um For most people these are the risk factors for HCC Except for actually in Africans the risk factors start at age 20 Not at age 40. So frankly yes all of these things are risk factors? Um I um I think we should just screen everybody with ultrasound and alpha feta protein and then decide uh about M. R. I. If they have cirrhosis or if they have some other complicating factors. Yes. And again, as I mentioned, is now available from Quest, but I don't think from anybody else. Um Ac and actually it does look like it's it's um it's a it's about correlates with HBV DNA which is much easier to get Uh in general, the lower the standards and the more likely people are to zero convert. Um So and declining s androgen is certainly a very good prognostic sign for um serial conversion or at least uh loss of energy. Uh huh. This is a newer data just presented uh 2020 easel, the european liver meeting and it looks like recurrence free survival. Uh and patients Who were treated within tech of beer or 10ofovir um after resection for HTC. Um Turn off of your patients actually uh went a little further without recurrence. Pretty much the same thing in this study. Hear from last year's easel. They did retract this and change the 7% to 6% because of a statistical change in the way they analyzed the data, but it does look like 10ofovir seems to be a better a better drug. Um And there are no associations observed between HPV treatment and negative control outcomes. That is lung cancer. And am I so this is something that's being studied now is stopping nucleoside analogue or nucleotide analog therapy and energy negative patients before s and vision loss. It looks like in at least this one study here uh from this year at Diesel. Uh the S and vision loss was about eight uh Post at 96 weeks post do cliffside analog or nucleotide analog discontinuation. This is just to reinforce that anybody with a positive core antibody who's receiving significant immuno suppression, particularly with B cell agents like riTUXimab should be prophylaxis Uh with either in tech, a beer or 10ofovir and they should continue on for um For 6 to 12 months after completing therapy. Okay. Uh there's a bunch of new biologics that are out now for uh inflammatory bowel disease and for psoriasis. Um The risks of all of those are unclear. So in general we tend to uh lean towards prophylaxis since using in tech of your .5 mg is such a benign um treatment. Now, these are the general definitions of the cure that we talked about. I'm just going to quickly run through a few of these slides just so you have a general idea. Yeah. Um a lot of people are working on this uh probably as many as we're working on HEp C. Uh The difference here of course is this is an integrated DNA virus uh and we Mhm. Need to clear the C. C. C. D. N. A. And maybe also the integrated HBV DNA into the host genome. One thing though that that's important to understand is that no one understood the the purpose of all the excess surface androgen that the virus produced uh far in an excess of what it needed um to make new viral particles. It turns out that it's probably shock and awe for the immune system. It just overwhelms the both B. And T cell mediated immunity. Uh So they interpret s and again not as as foreign but as um as um as host proteins so they stop um any immunity. So these are some of the places where um drugs can interfere uh they can actually interfere here. Berkel Adex B does that, it blocks the NtC P receptor. Um There's lots of capsized inhibitors uh and the the virus has to be decapitated uh in order to release its D. N. A. Uh into the nucleus where it it makes new C. C. C. D. N. A. It also repairs the old C. C. C. DNA, which degrades. Um And then of course there's transcription translation. Um you know there's lots of S I. R. N. A. S out there which can interfere with translation. And of course PG RNA pre genomic RNA um is um is helpful uh to measure uh in place of C. C. C. D. N. A. So D stabilizers work this way. And of course DNA synthesis nucleoside analogue uh work that way. So this is the this is some of the things that core inhibitors do um trafficking to the nucleus. They block they block packaging into the nuclear capsules. Uh And they also then therefore um block refreshing of the C. D. C. D. N. A. Which looks like actually now that With this one experiment by assembly Biosciences that um C. C. C. DNA um Which was previously thought the last many years looks like it. It only will last 12-16 weeks without getting refreshed. Here's at least one picture of the many uh captain inhibitors that are out there. Um And you can see there's a a synergistic decline in D. N. A. With a nuke and a caps inhibitor and even more synergistic decline in HPV. All right. Uh just to point out that this is just to point out that S. I. R. N. A. S. Um can aim at multiple overlapping reading frames using the hepatitis B complexity against itself here. This one looking at the mostly the hepatitis B. S. And a gin. And over here this one looking at the X. And so are in A I. Therapy. This is the J and J drug presented also at easel in 2020 shows a substantial to log drop um in essonne region which is actually most of what we to look at. Um This is the rep drug, this is a nuclear side um you click acid polymer which also seems to have extremely good at activity against pre genomic RNA and core antigen. So a functional cure following a nap based combination therapy looks really good. Yes Anderson was very low and H. B. B. R. N. A. We're also below the limit of quantification. This is core protein variants, looking at a core protein inhibitor first in man. Uh And then even CRISPR technology which some people consider to be dangerous uh can be used actually to snip out the HPV. D. N. A. Both in the C. C. C. D. N. A. And in the in the viral particles. So overall hepatitis B infection and the you ever sent. Mhm. So in general these are the recommendations for HCC surveillance. I think we just make it easy and screen everybody. But for the boards you should probably follow these guidelines although and I don't see the African guideline here of patients over 20 years of age need HCC um screening. Mhm. Um Don't forget delta hepatitis. It depends on where you are geographically can infect a large number of patients or a tiny percent most of what we see in the U. S. Comes from um uh that the former soviet Union. This is a study which is ongoing of λ Interferon Lana Farnellb and right on up here for 24 weeks does look like there's a significant drop in Delta RNA with this combination uh And then actually the new uh core Alistair Alistair IQ modulators here and the companies um and the expected approval dates Are are shown here. So between now and 2020 for we do expect quite a few new anti virals to be on the market. So fatty liver worsens hepatitis B. Uh It looks like we've got lots of shots on goal here for new drugs. HCC surveillance reduces HTC mortality and of course treating hepatitis B reduces that as well. Um Maybe aspirin does the same thing vaccinate if they're not vaccinated. There's a new one out called helpless A. B. Two shots With about a 95 efficacy rate. Uh So take home points. Hepatitis B is an incurable disease so far. But and um it's very preventable. Um Core antibody equals C. C. C. DNA. Test everybody for delta screen for HCC. Be aware of the risk of HCC reactivation of HBV reactivation um suppress DNA. It reduces inflammation and fibrosis and reduces the risk of liver cancer and liver related events. It's very controllable. Uh But cure is on the horizon With combination therapy with many drugs to three or 4 drugs with different mechanisms of actions and it may also require immuno stimulation. So let's make hepatitis history. Thank you
