Hepatitis B Community
efficacy of two-step peginterferon and etv combo, hbsag clear 30% vs 0%
About This Community:

This forum is an un-mediated, patient-to-patient forum for questions and support regarding Hepatitis B. Topics in this forum include but are not limited to, Causes, Diagnosis, Family and Relationships, Living With Hepatitis B, Research Updates, Treatment, Success Stories, Support, Symptoms.

Font Size:
A
A
A
Background:
Blank
Blank
Blank
Blank Blank

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

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)
Related Discussions
28 Comments Post a Comment
Blank
Avatar_m_tn

looks like etv can restore some immune system response for interferon to kick in
Blank
Avatar_m_tn
Interesting paper. Wish I know what the results mean.
Blank
1738923_tn?1327330269
what does "2-step" peg-interferon mean?
Blank
Avatar_m_tn
Step 1 - use Entecavir
Step 2 - Add Peg Interferon (then stop Entecavir)
Blank
Avatar_m_tn

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 (chronic) 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
Blank
Avatar_m_tn

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
Blank
Avatar_m_tn

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
Blank
Avatar_f_tn
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?
Blank
Avatar_m_tn
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.
Blank
Avatar_m_tn
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
Blank
Avatar_m_tn
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001227

this study shows one of the ways imune system can keep hbvdna low with normal alt.this is by nk cells secreting interferon gamma
Blank
Avatar_m_tn

i had cd counts at about 6 weeks full dose gcmaf, all cd counts were different than those observed on serum hbv cronic (chronic) carriers.
if i can get a measure of interferon gamma and cytokines we can get an iades if all those counts are high for hbv or for other pathogens.

the ebest test would be cd isotopes towwards hbv in the liver but this test cant be obtained due to highly research type of test and biopsy requirement, but hbsag count, cd counts serum and cytokines should help get an idea of what gcmaf is boosting and of course nagalase return to normal levels
Blank
Avatar_m_tn

very interesting part of the study:

IL-10 is induced in CHB and recapitulates the NK cell defect in IFN-γ production

Effector function of NK cells is tightly regulated by the cytokine milieu and their production of IFN-γ can be inhibited by immunosuppressive cytokines such as IL-10[12], [16] and IL-17[13]. The levels of IL-17A were not elevated in sera from patients with CHB compared to controls (Fig3a). In contrast, circulating concentrations of IL-10 were significantly increased in patients with active HBV disease (Fig3b,c by CBA, confirmed by ELISA, data not shown), correlating with viral load (r = 0.48, p = 0.002) and ALT (r = 0.37, p = 0.03). IL-10 levels showed a trend to decrease on antiviral treatment but remained significantly higher than in controls (Fig3c), consistent with the limited restoration of NK cell IFN-γ production in these patients.
To test whether IL-10 could induce the defect in NK cell IFN-γ production seen in CHB, we re-assessed NK cell effector function with or without the addition of exogenous IL-10. IL-10 significantly suppressed NK-cell derived IFN-γ (Fig3d), particularly in those patients in whom it was not already substantially reduced (Fig3e, and in healthy controls, data not shown). By contrast, IL-10 had no effect on cytolytic ability or TRAIL phenotype (Fig3f) and did not affect the percent of NK cells (FigS3a). The ability of IFN-α to further induce NK cell TRAIL expression in vitro[4] was also not abrogated by IL-10 (data not shown). The effect of IL-10 was consistent but more modest on purified NK cells (FigS3b), suggesting that some of its suppressive activity on NK cells is mediated indirectly via other constituents such as APCs. The contrasting effects of IL-10 on TRAIL and IFN-γ expression represented differential regulation of these effector functions in the same NK cells rather than the emergence of two distinct subsets. The small population of TRAIL-expressing NK cells present in healthy donors were at least as able to produce IFN-γ as the rest of the NK cell population (FigS3c). The addition of exogenous IL-10 suppressed IFN-γ in NK cells regardless of their TRAIL expression (FigS3c). In line with this, gating on the expanded population of TRAIL-expressing NK cells found in CHB demonstrated that their IFN-γ-producing capacity was no more reduced than that of the non-TRAIL-expressing fraction (FigS3d).
Blank
Avatar_m_tn
Our findings raise the possibility of immunotherapeutic targeting of IL-10 and TGF-β in CHB, with the caveat that these cytokines govern a critical balance between impeding pathogen clearance and restraining immunopathology.

both IL-10 and TGF-β are available at redlabs
http://www.redlabs.be/documents/Request%20Form%2008-10IMMUen.pdf

of course tests like these have a meaning only on experimental immune therapies like gcmaf, on normal interferon hbsag quant and hbvdna will guide therapy response, while on nucs all immune tests are almost useless since they sometimes suppress immune response or sometimes restore it only partially
Blank
Avatar_f_tn
Very interesting discussion. I will discuss with my doctor on treatment options. To be honest, I am scared to start tx.
Blank
Avatar_m_tn

remember there is a combo which lowers hbsag very fast, 1log in 24 weeks, interferon+telbivudine

the problem is interferon increases peripheral neurophaty which is a telbivudine side effect, so very close monitoring and way to prevent peripheral neuropathy should be applied.
a staggered thereapy interferon+telbivudine is a good option but a researcher/expert on PN is needed to understnd why it develops and how to prevent it
Blank
Avatar_m_tn

the bad thing is not only PN itself but the fact the the drug industry is not interested in lowering hbsag, and everytime they find something no big trials or studies are supported, i think the excuse of PN will definitely stop any study on this
Blank
Avatar_m_tn
Thanks, Stef2011. You are right - lowering hbvdna must be due to either our immune system and/or the virus itself (mutation).  I read:

NK (Natural Killer) cells recognise changes on the surface of infected cells and kill these cells.
CTL (Cytotoxic T cells) recognise antigens on the surface of the infected cells and kill these cells.

Now,  CTL cells recognise peptides displayed by MHC Type I molecules on the surface of a cell. I understand all cells with nucleus constantly display fragments of proteins (peptides) inside the cells using MHC Type I molecules.

I have no idea how NK cells recognise an infected cell.

So basically, I am trying to understand what regulate the amount of CTL? Does lower hbvdna make a cell less recognisable by NK cells and CTL?

Of course, there is also the question: can immune system stops viral protein expression by various cytokines, such as Interferon alpha and gamma? No killing no rise in ALT.

Now, I will go and read your article about NK cells and Interferon gamma.

Cheers.
Blank
Avatar_m_tn

there are only ipotesis on the dentric cells and macrophages non response, we know hbv infects bone marrows before infecting the liver for some weeks and we also know hbv uses macrophages to get to the liver

we know that hbv, like all viruses and bacteria, uses nagalase to inactivate macrophages, onc macrophages are inactivated there is no way to let the immune system know hbv is there because also dentric cells are inactivated
nagalase is used by viruses to enter the cells and to inactivate immune system.i guess that once we see results of gcmaf on me we may confirm this ipotesis.

what we really dont know is how dentric cells are inactivated, if it is because the excess of antigens orother ways

interferon gamma and tgf beta are one of the cytokines stopping hbv replication without liver damage.interferon gamma is low on all cronic (chronic) carriers
Blank
1738923_tn?1327330269
U mean hbv invades the bone marrow 1st before the liver? If that's the case how early does it invade the marrow? I am confused.
Blank
Avatar_m_tn

found new articles about immune effectors of hbsag clearance.i havent read them yet, i will later tonight, just had a look on first link and it is very interesting, i think that we need the effects of gcmaf on cd4 and nk cells and maybe after this boost try a combo interferon+nucs and etc f there is some boost on cd4,cd8, nk cells and of course normal nagalase

http://www.pnas.org/content/107/2/798.full

it is also good to know that steam cells therapies are being dicussed in kiev by most international experts for direct therapy, not just qua qua

i remember a post about it, do you remember the good effects of steam cells?was it about the fact steam cells cant be infected by hbv?
Blank
Avatar_m_tn
http://hub.hku.hk/bitstream/10722/56989/1/FullText.pdf?accept=1

again got no time now but will read together

my point is, and not only mine, even dr brunetto said we miss immunological markers in hbv infection..., is see what type of markers can we use to see if our immune system gets activated in fighting hbv

i hope the decrease of hbsag can be useful to see if gcmaf has any effect but i am also thinking tht when immune system is activated hbsag gets down in about 2-4 weeks only.so it may be better to have more sensitive markers that allows to see any immunological improvment much earlier than final immuen activation and hbsag clearance
Blank
Avatar_m_tn
"i remember a post about it, do you remember the good effects of steam cells?was it about the fact steam cells cant be infected by hbv? "

studyforhope said he thinks stem cells in the liver cannot be infected by hbv. I believe when a stem cell divides, one daughter cell becomes a liver cell, the other daughter cell remains as a stem cell. The point is, if we can stop hbv infection (by Mycrludex, e.g.), then over time, infected cells should be replaced by uninfected cells.

Hope, I got it right.
Blank
Avatar_m_tn

i will try to follow dr bradstreet research on steam cells and try to meet with him if possible, i know he is moving between italy and kiev from US for this study on steam cells, gcmaf and autism and we can surely get some from this too

anther thing i do know about steam cells is that when cirrhosis/fibrosis regresses there is a migration of steam cells from bone marrow to the liver, so this is very uselful for liver repair and ccdna depletion
Blank
Avatar_m_tn
I have not been able to catch up on gcmaf. I have been reading about basic immunology. The field is very large and too many things to remember, for me.

NK cells are pretty complicated. It has a tricky way of recognizing a cell infected by a virus. I still don't know whether NK cells will recognize a cell infected by hbv.
Blank
Avatar_m_tn

yes they do when activated, i think it is all linked to macrophages activation which in turn activates nk cells

i have read studies on monocites, macrophages activation and then nk cells activation on hiv too
it looks like pathways of immune escape are the same for all cronic (chronic) viral infections...macrophages inactivation leads to no antigen presentation, no nk cells activation and no cd4 help to mount an effective immuen response on cd4-cd8 against viruses

please also keep an eye on this:
http://drbradstreet.org/

and also blog comments
Blank
Avatar_m_tn
http://vir.sgmjournals.org/content/87/6/1423.full
Silencing T cells or T-cell silencing: concepts in virus-induced immunosuppression

another very good read for tonight, i ve just read first part, this one is ver very uselful since it makes a sum of viruses strategies of immune evasion and hbv which acts like retroviruses (hiv, gammaretroviruses) might use similar immune escapes although hbv targets liver to make damage and does not damage immune system
Blank
Avatar_m_tn
http://hub.hku.hk/bitstream/10722/56989/1/FullText.pdf?accept=1

this last study is even more interesting and just focused on hbv, all the studies report the same immune escape strategies, i think they all just miss the nagalase which supresses antigen presenting and iderectly suppresses cd4/cd8/nk cells on cronic (chronic) infections
Blank
Post a Comment
To
Blank
Weight Tracker
Weight Tracker
Start Tracking Now
Hepatitis B Community Resources
RSS Expert Activity
233488_tn?1310696703
Blank
New Cannabis Article from NORTH Mag...
Jul 20 by John C Hagan III, MD, FACS, FAAOBlank
242532_tn?1269553979
Blank
3 Reasons Why You are Still Binge E...
Jul 14 by Roger Gould, M.D.Blank
242532_tn?1269553979
Blank
Emotional Eating: What Your Closet ...
Jul 09 by Roger Gould, M.D.Blank
Top Hepatitis Answerers
Avatar_m_tn
Blank
stef2011
Italy
Avatar_m_tn
Blank
StephenCastlecrag
Australia
Avatar_m_tn
Blank
Rome70
Moscow, Russia
Avatar_m_tn
Blank
andrey19
Russia
Avatar_m_tn
Blank
mer971
Avatar_m_tn
Blank
makeadifferencenow