Antivirals indirectly reduce integrated DNA?

General Discussion
1

Hi all,

Came across this which supports the scientific community view about antivirals indirectly affecting Integrated DNA and hence reduce chance of HCC.

Not sure if this is peer reviewed but love that it supports the view if starting antivirals early

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Dear Ash_Malhortra,

Indeed this is a very good paper from a well established group which has been published under peer review.

What this paper shows is a very slow decline in integrated HBV DNA from 1.1x10^9 to 4.9x10^7 integrations in the liver with 10 years of therapy. This shows two things:

  1. NUCs can effectively suppress the establishment of new HBV DNA integration (this is consistent with what we know about how NUCs work and how HBV DNA integration is established.
  2. Turnover of hepatocytes with integrated HBV DNA is very slow (at least under NUC therapy).
  3. Starting NUCs too late in therapy has no impact on HCC (we already know from clinical studies).

It certainly seems to suggest that current treatment guidelines are not optimized for prevention of HCC…

Best regards,

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@availlant @ThomasTu @john.tavis

I’ve been delving into all discussions on this platform to understand cccDNA and IDNA in the context of HBV management, and I have a couple of inquiries that I hope you could shed light on.

  1. After permanently inactivating or silencing cccDNA and subsequently removing HBsAg produced from cccDNA, considering that the source of HBsAg is IDNA(not the complete virus), is there still a possibility of transmitting the virus to others?
  2. When achieving HBsAg loss with NAP, can we say IDNA is eliminated by the immune system with the support of immune modulators, alongside the permanent silencing of cccDNA? and then keeping the immune system healthy is good enough to reduce reactivation of cccDNA untile cccDNA elimination is possible .

Regards

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Hi @lemlem,

  1. There will be no chance of transmitting the virus if the cccDNA is truly inactivated or eliminated. The problem is determining when this occurs because the virus can reactivate from a tiny reservoir if the immune pressure controlling it is released.

  2. Clearance of HBsAg by NAPs is best addressed by Andrew. However, to my understanding, the initial effect of the NAPs is to suppress HBsAg secretion, causing its degradation within cells. After a while, and usually in combination with other agents such as Interferon alpha, the final clearance is mediated by the person’s immune system. Again to the best of my understanding, it does not matter if the HBsAg is being produced from integrated DNA or the cccDNA for the NAPs to work. You are correct that later in infection, particularly in HBeAg negative people, the major (but not only) source of HBsAg is the integrated DNA.

John

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This sounds really promising to achieving a functional cure. What’s the estimated timeline for the approval of NAPs for patients in Canada? It seems like a Canadian company is among one of the drug researching companies working on a NAP.

Thanks.

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I agree that NAPs are among the most promising new waves of compounds under development. Questions about timelines for studies in Canada are for Andrew as he leads the company developing them.

John.

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@availlant What criteria is “too late in therapy”?

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Hi @mantana ,

No definitive time for “too late” has been established in this context. What we do know is that current treatment guidelines which withhold treatment until the development liver disease have not been effective in reducing death rates from HBV (from HCC). There has been some work done suggesting that NUC introduction in HBV infected individuals > 50 years old has no impact on HCC rates whereas starting NUC therapy in patients < 50 years old has some impact.

HBV DNA integration (which drives HCC) starts right after infection. With this understanding, NUC therapy should be introduced as soon as active HBV replication is diagnosed. This is the reason why the new Chinese guidelines recommend starting NUC therapy in any patient with detectable HBV DNA, even if no liver disease is present.

@availlant

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