Hi,
This scientific article states that new liver cells from cell division=mitosis= cell replication contains no cccDNA, so is not infected with hepb virus particles, is clean.
Mitosis of hepatitis B virus-infected cells in vitro results in uninfected daughter cells
Hi @hepb1,
Yes, I wrote this article with my colleagues. If you or anyone else has any questions about this, I’m happy to answer them.
Cheers,
Thomas
Dear @ThomasTu
I see the articles , it is very intersting , so lets assume functional cure achieved , but small amount of cccdna which is also inactive or dormant found, so there is no increase of cccdna , can we say this will gradually eliminated due to mitosis naturally or is there any research conducting on this to speed up this process ?
BR
Dear @lemlem,
It’s hard to know as we need to access liver tissue to understand these dynamics. It is difficult to get the tissue from people who have functional cure, so it’s hard to know what causes it.
Thomas
Dear @lemlem,
We have examples of persons with functional cure or who had no previous documented history of HBV infection who decades later experienced reactivation of HBV infection when undergoing immunosuppressive therapy. This is because latent cccDNA still present in these patients was able to reactivate in this immunosuppressive environment.
There is also a study where patients were followed under NUC therapy with serial liver biopsies for > 6 years after starting NUC therapy to the point where no detectable cccDNA was present in their livers (but who still produced significant HBsAg from integrated HBV DNA). In these patients, rebound of viral infection occurred following removal of NUC therapy which required retreatment in all but one patient. See here.
Very clear @availlant , so this mean still we need more.reserch on latent cccdna part , hopefully soon start more new ideas at least for scientific purpose .
Thank you @ThomasTu and @availlant
Dear @lemlem,
This is the primary challenge with the concept of sterilizing cure (latent cccDNA). This issue with persisting latent cccDNA is made more difficult by the fact that any persisting HBsAg production from integrated HBV DNA will readily allow reactivation of latent cccDNA (as occurred in the paper I cited above). This is because one of the functions of HBsAg is to suppress host control of cccDNA reactivation by inhibiting innate immunity in the liver. Therefore, cccDNA targeting approaches will have to be 100% effective. Even if complete cccDNA removal could be achieved, the persisting HBV DNA integration and HBsAg production would still leave patients at risk for HCC, even in the absence of any viral replication.
Targeting latent cccDNA will present very difficult challenges:
The patient community should remember that ~80% of patients which have been infected by HBV (about 1.7 billion) win the battle with HBsAg and establish functional cure. These people will never know disease and never be infectious and never develop HCC.
Well Noted @availlant ,
I understand functional cure is big and offer almost similar health status like those who never infected but with fear of reactivation , instead of focus on eliminating latent cccdna, which is very difficult , why not science focus on control it without dependent on immune system after functional cure or i mean functional cure would not depend solely on the immune system, which can be unreliable or weakened over time.
Best regards
What percentage of chronic patients develop integrated HBV DNA ? 50%,20% ?
does this mean acute resolved functinal cure == functional cured achieved by DAA or other combine drug treatments in case of HCC risk.
Dear @fsixper ,
Yes in priciple this is very likely correct since HBsAg loss persisting in the absence of therapy can only occur with efficient removal of integrated HBV DNA. Additionally patients no longer have a HBsAg load in their liver (there is data impliacting the large isoform of HBsAg in the formation of HCC). And finally, liver inflammation disappears and fibrosis reverses. All known positive indicators for a lowered risk of HCC.
Experientally this not possible to formally prove yet since there are such a small amount of individuals who have achieved functional cure with therapy for more than a decade (most of these are from pegIFN). This is the minimun length of follow-up to start to have an idea of HCC rates.
@all today i see this , i think they are only one try to eliminate cccdna
Added on top of @availlant’s comments, it has been difficult to quantify the amount of integration (whether it is after functional cure or acute infection). This is one of the major themes of research in our lab, and we have just developed a way to do this from small samples of liver tissue (e.g. from fine needle aspirations).
We have used this assay to confirm previous studies showing that people who have cleared HBV infection (HBsAg loss) still have integrations, but at lower numbers than people with a chronic infection.
TT
Yes, this is an interesting technology, but it is difficult to cut up all the cccDNA (and integrated DNA) in the liver because of delivery and efficiency of the agent. Even at 99.9% effectiveness, there still may be millions of cccDNA and integrated DNA molecules in the liver. I’m really interested in seeing how this works out…
Thomas
The other problem with this approach is that it again is sequence dependent mechanism (like antisense and siRNA) and, like cccDNA, the population of integrated HBV DNA will contain many genetic variants. There will be integrants which will escape recognition of the this gene targeting approach.
Hi @lemlem,
These developments sound really interesting and encouraging if they prove to be safe and lead to a cure. My issue with this type of gene editing is the fear that the targeted section is not cut rather a different section is and what could the effect of that be on the person? If I understand, they program this editing technology like scissors to cut the affected part targeted. But what happens if the treatment ends up cutting a different section that was not targeted? This is my concern with some of these gene editing tools/technologies. One can control a lot in the lab but not 100% in real life situations.
Other than this concern, I think it is a wonderful tool to have. Best, Bansah1
@ThomasTu Good to know this i never imagin with this efficiency still left millions of cccdna, so in that sens after functional cure also do we have this amount of cccdna left ??? If not why not this method should focuse on eliminating inactive ccdna at least will reduce and make it less capable for reactivation . Since i am hopeful functional cure will be optimized with Rep2139 at.lewst for.most population like 70 or 80%. Then other should focuse on complete clearance which is very important part for many similar virus like as @availlant said zostar varcillas and even hiv will have inactive virus (if functional cure achived )integrated to our body.
I do no why with all this information available still try less effective methods like as you mentioned sequence dependent.
@Bansah1 i think this is the biggest risk but we hope these method will have better version gradually or something breakthrough idea, at least good to know with 100% accuracy , can still do or remove all cccdna probably many billions of cccdna.