efficacy of two-step peginterferon and etv combo, hbsag clear 30% vs 0%

[stef2011]

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2893.2011.01469.x/pdf

At week 96, five patients of Group 1 plus Group 2
reporting HBsAg loss reached 21.7% (5/23) by two-step
Pegasys treatment, and three more patients had low titre of
HBsAg (<5 IU/mL) and low HBV DNA levels (<1000 copies/
mL) with ALT normalization.
Efficacy of two-step Pegasys treatment in HBeAg-positive
vs HBeAg-negative CHB
For comparison of the efficacy of two-step Pegasys treatment
between Group 1 (HBeAg positive) and Group 2 (HBeAg
negative), the rates of HBsAg clearance and seroconversion
at week 96 were 15.4% (2/13) and 7.7% (1/13) for HBeAgpositive patients; 30% (3/10) and 20% (2/10) for HBeAgnegative patients. The rates of undetectable HBV DNA were
30.8% (4/13) and 30% (3/10, P = 0.968); SVR were 69.2%
(9/13) and 80% (8/10, P = 0.56) for HBeAg-positive and
HBeAg-negative patients, respectively, at week 96. No significant difference was observed (Fig. S1)

[stef2011]

1. Why low serum HBVDNA usually means low ALT? [CTL cells no longer attacking infected liver cells because less antigens appear on the infected liver cells?, Or just less CTL cells (why)?

i am not sure if any study answered this yet but the reason is impared immune response, we have no active dentric cells and macrophages so the immune system doean t see what is happening in the liver, he probably can see only when full virions are a lot and when it lowers them he doesn t see them anymore.there is also the big problem of hbsg almost complitely unseen and very low antibodies for hbcab, another antigene with impared recognition

2. Why in the inactive phase, HBeAg-ve, HBeAB+ve, hbvdna is low, and therefore ALT is normal?
because we have more immune response than those in active hbeag negative replication.
it is difficult to confirm if quasispieces have a role in this, i guess so but it is not just the precore and bcp mutants, inactive replication is present on about the same amount of patients wild type or core mutants

Note: Antivirals lower hbvdna, but what lower hbvdna during the inactive phase?
immune system, the viruses never sleep unless forced to hide latent by immune system waiting for new quasispieces to emerge

[StephenCastlecrag]

Thanks for your explanations. I downloaded the whole paper and read it. I was trying understand what the data is telling us. It seems to me:

1. All the patients had acute flares, high ALT, therefore they were immune active (lots of CTL cells killing infected liver cells).
2. In theory, starting Interferon should (?) boost the immune system, but the doctors were afraid that they may overdo it, causing the patients  too much liver damage.
3. So they use Entecavir to lower hbydna and to lower ALT.
4. When ALT is lower, they add Interferon, then discontinue Entecavir sometime later.

So this is the strategy to treat patients with very high ALT (> 10 x ULN).
So what does the results tell us? This is where I got lost. It seems Group 2 (?), the patients with HBeAg-ve,did the best.  I don't know, what that means, in terms of my own simple understanding. Very frustrating.

I want to know:
1. Why low serum HBVDNA usually means low ALT? [CTL cells no longer attacking infected liver cells because less antigens appear on the infected liver cells?, Or just less CTL cells (why)?
2. Why in the inactive phase, HBeAg-ve, HBeAB+ve, hbvdna is low, and therefore ALT is normal? Is it because we have less infected liver cells (cleared during the preceding immune clearance phase)? Or somehow, cccDNA just stop being active? Note: Antivirals lower hbvdna, but what lower hbvdna during the inactive phase?

SOS.

[Cjb3695]

thats pretty good news, but I wish they would have a better version to interferon that had less side effects. Peginterferon and interferon are the same thing right?

[stef2011]

sorry for the fast sentences, i should have reported more data from the study, hope you can follow me...in any case the concept is staggered interferon+nucs personalized according to hbsag quant/hbcab quant

[stef2011]

there are several clinical reports about the effect of staggered nucs on interferon and improved hbsag decrease/clearance

this was our strategy with researchers in pisa at first and just choosing if to go on staggered or continuous combo according to the effects on hbsag quant and i guess hbcab quant.
then it came out interferon lambda and gcmaf so we choose to wait for lambda and try gcmaf

[stef2011]

etv first to decrease alt and hbvdna, dont remember how long but it is in the paper
decrease of hbvdna on nucs restore some immune function but not continuous nucs

after some decrease of hbvdna and alt, they set soem values in the paper, they introduced interferon and made interferon+etv 14days then stopped etv

the other group just used etv

the results showed an increased hbsag clearance to 30% on hbeag neg and 15% on hbeag positive

interferon monotherapy has just about 5-10% hbsag clearance at 1 year.i remeber i posted a study on about 4 patients who couldn t tollerate interferon sides so researchers stopped interferon 1-2 months and used etv or tnf, then restarted interferon when sides or bad blood testes recovered.these guys lost hbsag and doctors reported this clinical case

my guess is:
etv or tnf has some immune restoring properties which are lost when hbvdna is totally undetactable, so using these nucs to lower hbvdna to something like 20-50iu/ml and swtching to interferon before toally undetactable can have a potent immune effect

i remember a study that said profund hbvdna suppression leads to decrease of immune response towards hbcag, this study was using etv, manteining cronic infection

even in my own case hbsg decreased to 2200iu/ml when hbvdna was about 20-50iu/ml using etv+alinia but when hbvdna was totally undetactable some months later it relapsed to 7200iu/ml
these are all just gusses, but they make some sense to me