HR : Attempt for Tenofovir UPDATE 2

[stevenNYer]

HR:  With your help, I felt ready...confident, so I moved up my appointment and saw my GI this afternoon.

My GI did consult with his researching partner from Gilead to consult on the need to switch.  The response from the partner was since patient is UND, it would not seem warranted to alter.  Which surprised me for the obvious reason.

I insisted and my GI said he doesn't agreed with the change but since it looked like I understood my own request, he AGREED to do it since his responsibility is "to do no harm".  He also thanked you for offer a new approach on treatment.   A fresh new bottle of tenofovir is in front of me as I type this post.  So THANK YOU !!!  So hopefully I will e-seroconvert in time.

Which prompted these questions:
1) Tenofovir is recommended to be taken with meal.  So, is it okay to take it 2 hours after or before meal with Entecavir?  Will this affect the absorbing rate / efficacy of the meds?
2) You wrote earlier "BCPs work towards seroconverting PROVIDED that the hepatic viral burden and remaining eAg production falls further", what tips the scale and lead to an active e negative with BCP strain?

THANKS again.

[stevenNYer]

Noted.  Thanks again.

[Hepatitis Researcher]

The stability of the e seroconversion, if achieved by antiviral therapy, is not as good as when achieved "naturally" or by IFN induction.
It could simply mean, that the cccDNA has overall been reduced to such a levels that the  - always in the background existing eAB is not neutralizing the remaining amount. But it is, in this case,  not the immne sytem holding down the virus - it is the antivirals together with some varying amount of help from the immune CTLs, too weak by itself. Stoio the antivirals and the EAg will reappear. Or, often also, stop the antivirals, no eAg but still increasing vireamia/hepatitis. The BCPs will increase the likelihood that this scenario will happen, but it is not an absolute.

It is hard to predict in an individual case, what the situation will be, unless we have extensive sequencing information with clonal sequencing, that would allow to gauge the degree of core epitope erosion that has already taken polace.
Thus if you do loose the eAg and develop the eAB , you would continue the antiviral combo for at least 6 month, and then

very very carefully, with weekly PCRs if possible, let go of the antivirals being on your toes, keeping in mind that HBV might come back and if it does immediately go back onto the antiviral combo so as not to come to a high genomic power/mutational base situation for HBV against your antivirals, risking to loose their unreplacable protection later on.
Also, even if at first the VL does not go up, you need to remain vigilant.

[stevenNYer]

Your right, this is a hard concept to grasp.  And it's freightening that I actually understood that ;)  

I just wanted to clarify that situation.  Like I mention in a previous post, I intially thought that having the BCP while being e-antigen positive means that the seroconversion is already meaningless and my hepatitis would be active forever.

Your are truly the best!

[Hepatitis Researcher]

Remember, we talked about the difficult to understand eAg immune response before.

The BCPs reduce production of eAg in the hepatocyte. When circulating tolerizing eAg is sufficiently reduced, its epitopes, shared with the core protein, will become the target of core specific CTLs.
If eAg is still high, that important  CTL response is blunted by the flooding of the periphery with eAg/core epitopes and the tolerizing effect of eAg on the peripheral immune system.

If no BCP then the lowering of the eAg is just a consequence of enough of a successful elimination of cccDNA, BUT THE INDIVIDUAL HEPATOCYTE that is still infected, will become a sucessful CTL target, because the tolerizing effect is gone, but the epitope presentation on the cells surface is still high. That is the bst situation and reflects the "healthy eAg neg carrier state.

The virus tries to escape this situation by tuning down the eAg production once it has turned from an advantage to a thread to its existence. It does so by introducing the BCPmutations, reducing eAg production or even better, by the precore mutation, eliminating eAg alltogether.  This is easier for the virus while the levels are not ultralow  - greater adaptive powwer -thats why this time of seroconversion as Keefe pointed out is also often a time of introducing this type of immune escape mutations.

After eAg seroconversion, even without BCPs, there is yet another way for the virus to adapt and regain strength : mutation of the epitopes itself-  class I ( normally only one present that really works)
and mutation of numerous class II core epitopes. Once that is achieved ( for HBV) it can climb up to high numbers again, in the face of an existing eAntibody, no serum eAg and even if eAg production at the cellular level exists .  This is the state of

eAg negative hepatitis
and its number grows over time, recruited from the pool of "healthy carriers" where the virus has finally worked its way out of this immuncontrolled status.

Thus each "healthy carrier" is potentially at risk to rise back to this type of hepatitis. Whether it eventually happens or not depends on how low the viral load really went, how many intermediate immune adaptive mutations already existed at the time of the e-conversion, how much stress or other immunesupressive situations a patient has incurred etc. and the length of time for the viral evolution to progress towards that state.

Seroconversion is indeed meaningless in that situation

[stevenNYer]

Thanks for the info on when to take the meds.

I read Dr. Emmet Keeffe archived presentation on Hepb.org, he states: (during immuno-clearance stage) that’s the time that the virus can mutate, and rather than going from e-antigen positive to e-antigen negative and becoming quiescent, one of these two mutations (precore and core promoter) form during the time of attempted spontaneous sero-conversion.

So my question is if BCPs work towards seroconverting, what causes a person to have an e-negative active disease (with the BCP strain) with a high viral load again.  For such a person, won't the seroconversion be somewhat meaningless?

[Hepatitis Researcher]

BCPs are typically associated with a stronger immune attack on the liver beause there is still some eAg production and epitope processing in the hepatocyte as opposed to the precore mutant, that turns the eAg synthesis off completely. With the further decreasing viral cccDNA burden, the e Ag production will further decline, to the point that the Ab will first neutralize - the silent phase with both eAg and Ab  neg (and sometimes both pos) then overwhelm the small remaining eAntigen production.

I am glad you got the Tenofovir and the Entecavir both on board. You are safe now and can calmly wait for the e-neg phase. it might take a while, possibly up to a year, the individual course is hard to precisely predict.

Space the Entecavir and the Tenofovir 12 hours apart, if you can, The Entecavir needs to be taken free of food anyway, while tenofovir should be taken with food, but this is not too critical.