Hi @chigoziekingsley5454, functional cure is defined as the persistent loss of HBsAg in the blood, so they should not test positive for HBsAg.
Thomas
Hi,
I think liver damage happens as a result of immune response to virus. If these new medicines such as bepirovirsen activate immune response, will it impact liver function or cause liver scarring?
Thanks
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Hi @Aman ,
Yes a very good question!
Liver inflammation is indeed caused by immune responses to viral replication in the liver. In chronic HBV infection, liver inflammation is often suppressed (by HBsAg) so that infection can persist for many years with out evidence of liver inflammation. This is one of the reasons why only a small fraction of people with HBV infection get diagnosed.
Persistent liver inflammation causes scarring (fibrosis) which if left unchecked can lead to more severe liver disease (cirrhosis). While this is caused by the infected cells in the liver, this chronic inflammation can effect the healthy cells of the liver as well. The purpose of existing drugs for HBV is to stop viral replication so that liver inflammation disappears. Unfortunately, these drugs to not target the production of HBsAg, which is why they are life-long therapies.
Although immune function drives liver inflammation, in order to restore effective immune control of HBV infection in the liver (we call this functional cure), we have to correct two important problems caused by HBV infection:
- Remove the ability of the liver to produce HBsAg (which prevents immune control of HBV).
- Re-awaken the immune responses to HBV infection which have been “put to sleep” by long term exposure to HBsAg.
For this reason, any approach successful in achieving functional cure will have to achieve both of these actions (and thus require an immunotherapy).
In the case of bepirovirsen, its immunotherapeutic effects appear to be able to achieve #2 above and perhaps even #1 but these immunostimulatory effects are quenched by HBsAg so this drug only shows significant activity in patients with low levels of HBsAg present. There are no data in the current clinical trials ongoing to suggest that these immunostimulatory properties are accompanied by changes in liver function or that they introduce liver scarring.
It is important to note that functional cure will always require the establishment of immune control. This actually occurs in the 75-80% of patients who self resolve their acute HBV infection, most who never show signs of this immunological “battle”. Even in those people who rarely achieve functional cure with current therapies (including more often with the approved immunotherapy pegylated interferon) the clear signs of reestablishing immune control are not accompanied by changes in liver function. The reason for this is that only infected cells in the liver are likely targeted by these immune functions, leaving healthy liver cells intact.
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Hi @availlant,
You mention that high HBsAg levels in the blood prevents the immune system of CHB patients from recovering from immune exhaustion to Hep. B virus. Can you elaborate on how much HBsAg in the blood measured from a HBsAg Quantitative test is considered too high, and would render any immune-stimulating treatment ineffective to “restart” natural immune control of the virus? Does the level of HBsAg in the blood fluctacte greatly within the day or does it stay somewhat consistent for an individual?
Thank you.
Dear @A7xImpulse ,
A very good question.
Using clinical data from the most widely used immunotherapy to date, pegylated interferon, we see that there are large differences between functional cure rates in patients with more than or less than 1000 IU/mL HBsAg at the start of treatment. Generally speaking pegIFN functional cure rates at < 1000 IU/mL of HBsAg can be up to 30% while functional cure rates above 1000 IU/mL HBsAg are < 6%. This also appears to be case for other immunotherapies in development like bepirovirsen. It could be that the “sensitivity” to HBsAg inhibition is different for different drugs which employ different immunosrtimulatory mechanisms but overall the rule still appears to be holding.
HBsAg in the blood is almost entirely derived from non-infectious subviral particles which are not targeted by currently approved oral antiviral therapies for HBV. For every virus there are approximately 10,000-100,000 subviral particles. HBsAg is continually produced from liver cells and is recycled by the liver over a period of a few days. The levels of HBsAg in the blood are fairly constant and reflect a balance between the persistently abundant production of these subviral particles and their rapid clearance from the blood.
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Thank you @availlant for your response.
CHB is a very challenging problem to solve by the looks of it, I am hoping that more funding could be made available to tackle this problem. CHB is an additional source of stress that compounds other challenges in modern life.
There are very few open source scientific studies published on HBsAg, most are behind a paywall. What is the mechanism behind the rapid clearance of HBsAg from the blood when not enough anti-bodies for the subviral partials are produced? Isn’t our Liver the organ responsible to eliminate virus particals from our blood (the irony)?
Thank you.
Dear @A7xImpulse ,
Subviral particles are produced as a high density lipoprotein (HDL) which has the same composition as normally produced HDL in your blood except that it also contains HBsAg. It is likely that the HBV has evolved to hijack this lipoprotein secretion mechanism present in a class of liver cells whcih are responsible for lipoprotein recycling called hepatocytes to produce such large amounts of HBsAg. As such, the antibody independent recycling of HBsAg also likely occurs by the same mechanisms hepatocytes use to recycle HDL. These are the cells in the liver which are (ironically but not accidentally) also infected by HBV.
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Good every one my name is jay I just did a full blood test and I was diagnosed of hep b chronic I’m so scared right now I don’t know what to do I live in Ireland but I have an appointment to see a specialist on the 5th of march I’m scared right now and my family is back in Nigeria I’m scared of them as well because I feel I have also exposure my wife and son to this I planned a beautiful family but this now as taken away my joy I don’t know what do I am glad I found this platform I need advice because I’m scared of my family losing them and even my self anytime I see my son picture I just want to end my life this my test result below can some one explain this to me I’m so tired
HBsAg(Architect) positive
Anti-HCV(Architect) negative
T.pallidum Total (Architect) negative
HCV Ag(Architect) negative
Anti-HBe(Architect) positive
HBeAg(Architect) negative
Anti-HBc lgM (Architect) negative
Anti-Hbc total positive
Anti-HDV total (liaison)negative
Please can some explain this to me my heart is so heavy I feel my life counting by the day
Dear @Jay ,
We are sorry to hear of your recent diagnosis but please do not be scared for yourself or your family. Please have hope - things will be all right for your and your family. Your HBV infection is not your fault. Most people with chronic HBV infection also do not know they are infected (often for decades). You still have your beautiful family - do not despair!
There are good medications which will safely control your viral infection and will allow you to live a long and happy life. Here are some “next steps” for you:
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Keep your appointment with your specialist in Ireland. You are missing some important tests which include HBV DNA and ALT and perhaps some imaging of your liver. These will help the specialist decide how to approach your antiviral therapy.
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You have to discuss your diagnosis with your wife. HBV infection is most frequently transmitted by sexual intercourse or from mother to child during birth. Your wife should get tested as soon as possible.
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The likelihood of you transmitting your HBV infection to your son is small. Nevertheless, he should also get tested as soon as possible.
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If your wife and son test negative for HBV, they should get vaccinated as soon as possible. When your antiviral therapy is actively suppressing your liver infection and they have been vaccinated, the risk for transmission of infection will be almost zero.
Please let us know how things are going. You are not alone.
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Very interesting article. Fast track? Does it mean that certain people will get the approval?
@availlant Your thoughts?
Thank you! Is 1500iu HBSAG consider low base or mid?
Dear @Nass ,
A baseline HBsAg of 1500 IU/mL is low. The average baseline HBsAg is ~ 10,000 IU/mL and can be < 125,000 IU/mL in HBeAg positive chronic HBV infection or during acute HBV infection.
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As always… Thank you so much!!
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Hi @ThomasTu ,
If we can’t target cell with cccDNA, then why don’t we take minimum low dose medication (and hopefully with no side effects) to stop virus till all the liver cells that are infected with cccDNA are all exhausted (converted into virus or die before conversion) and virus is killed/disabled outside cells before it has chance to infects new liver cells?
I know we have antiviral to achieve this but does cccDNA stays present in cells forever? Do we know how long it takes for an infected liver cell to die naturally and continue medication double that time? Does the B virus only affect a particular type of liver cells?
Thanks
Hey Aman,
I read somewhere on here that cccDNA gets deleted when a liver cell undergoes Mitosis (cell division), and the two new liver cells does not have any cccDNA. However, some liver cells (potentially containing cccDNA of the Hep. B Virus) does not divide. We are not sure how long cccDNA will remain active in a non-dividing liver cell. It could also be that since Hep. B virus are replicated in the liver and also infects liver cells, it may have an easier time staying in the liver.
Liver cells as far as I understand are some of the most actively replaced cells in our body, I could be wrong on this one though. It would be nice to hear from some other community members who have been on anti-virals for a long time and see what their experiences have been.
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Welcome @Jay
I’m glad you have found us and shared your story.
It is very scary and uncertain future. Your head must be whirling with questions and terror.
Please, we are here for you. Your life is important for your family’s happiness. They don’t care if you have an illness. As long as they can hug and love you is all that matters.
You are unlikely to have past on to your son and maybe even your wife.
Get them tested and vaccinated as @availlant has said.
You can still have a long and healthy life. Read some of the subjects and stories. I’m sure you’ll find they are similar to yours.
One day at a time.
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Great question, @Aman. And thanks @A7xImpulse for a great summary of the most recent research (which we have published on Mitosis of hepatitis B virus-infected cells in vitro results in uninfected daughter cells - ScienceDirect and has been highlighted by a PhD student working in my lab - Example entry: Hepatitis B cccDNA viral reservoirs - stubborn nails in the quest for a complete cure). I am really so glad that we’ve been able to get such sophisticated complex concepts taken up by the community.
Some additional comments:
The average lifespan of a liver cell is about 6 months, which is fairly long when you think about it. This is why the reduction of cccDNA even while on therapy is very slow.
At the start of an infection (immune tolerance phase) pretty much the entire liver is infected. But when you are in HBeAg-negative phases, something like 1% of liver cells are infected (even when there’s plenty of virus around to infect the other cells). We still don’t know the underlying reason for this and if the one that are infected really represent a different type of cell.
Indeed, I’ve been on antivirals for many years and my levels of HBeAg and HBsAg have remained quite high through the years.
Thomas
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