Very helpful, thank you again for all of your help!
Integration is an important component on the path to hcc. It is a hit and miss event, however, many integrations will not be relevant to hcc development, depending on integration site, different in each cell and for each integration event.
Chronic liver inflammation and damage from any source adds further mutational events in the multistage process towards hcc.
In the inactive stage with low dna and alt, new integration events should be rare.
The immune clearance phase is where we expect most integrations to happen.
but the existing burden of integration in your case is unknown, hbsag levels might however give a good hint.
The chances to achieve a functional cure will likely depend on integration levels. Drugs designed to reduce cccDNA will not be able to reduce the hbsag from the integrated gene, making a seroconversion very difficult.
I would think that further dna reduction by antivirals will not have a substantial impact on the current level of further integrations.
This is likely the reason that a discrepancy often exists between the dna and hbsag levels.
In the presence of antivirals thus is easily explained, but here we are talking about non treatment patients.
An alternative explanation would be that the t cell induced cytokine action on the liver cells acts much stronger on hbv replication mechanisms than on the mere transcription and translation of the hbsag gene from the cccDNA.
The place us called the integration site. In most cases it is not in a place where such integration and hence disruption of genome function is critical.But sometimes it will take place in a cancer preventing control gene, leading to a first or further step in the cancerous development of thus cell.
The hbsag is just a protein, made directly into the endoplasmatic reticulum membrane to form later small spheres that are secreted to the outside.
It cannot participate in the integration formation process, but it is frequently produced directly from the cells genome after the integration of its genetic dna and not of the cccDNA that is initially the source of all hbsag.
If a cell has noncytolytically cleared all cccDNA through the action of interferon induced gene products, such integrated gene segments will remain and keep producing hbsag particles without being otherwise infected.
High amounts of hbv dna inside the dividing cell will favor the frequency of integration. This is particular the case once an e antigen positive starts the immune clearance phase where a high degree of cell division is required to compensate for the loss of hepatocytes. Length and intensity of this transition process will vary widely between patients, hence also the degree of resulting hbv dna integration and genoically produced hbsag.
Antivirals will reduce the amount of hbv dna present in the cells.They should reduce the speed of integration.