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serum HBsAg level not related to cccDNA?
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serum HBsAg level not related to cccDNA?

Stef2011: What do you make of this.

Journal of Hepatology
Hepatitis B surfaceantigen:Relation to hepatitis B replication parameters in HBeAg-negative chronic hepatitis B

Pages61-68
Emanuel K. Manesis, George V. Papatheodoridis,Dina G. Tiniakos,
Emilia S. Hadziyannis, Olga P. Agelopoulou, ThaliaSyminelaki,
Christos Papaioannou, Theodoros Nastos, PeterKarayiannis
Background & Aims

Translation of HBsAg depends on transcription of the appropriate mRNAs from cccDNA, but its relation to other hepatitis B virus (HBV) replication parameters is not known, inasmuch as integrated sequences of HBV-DNA may also contribute to its serum levels,especially in HBeAg-negative chronic hepatitis B (CHB) patients.


Methods
We investigated HBsAg serum levels, its hepatocellular expression,and
their relationship to HBV replicative- and host-response parameters
before treatment in 54 HBeAg-negative CHB patients and in 15 of them
after 40.1 ± 33.3 months of virological response on oral antiviral
(NUC) therapy also.

Liver cccDNA and HBV-DNA quantitation, HBsAg- and HBcAg-immunostaining were performed in the same needle biopsy material, while serum HBsAg and HBV-DNA levels were measured in samples drawn on the day of liver biopsy.
Results


In untreated patients, serum HBsAg correlated positively with
HBsAg-positive hepatocytes/mm2 (p = 0.003) and weakly with serum
HBV-DNA, but not with cccDNA, liver HBV-DNA,HBcAg-positive
hepatocytes/mm2, or ALT.


cccDNA correlated significantly with liver HBV-DNA (p <0.00001), ALT (p = 0.001), and serum HBV-DNA levels (p =0.012) but not with liver HBsAg or HBcAg.


Antiviral therapy decreased serum HBsAg levels by 79.6% (p = 0.012) and liverHBV-DNA by 84.4% (p= 0.026) in paired comparisons and, as expected,significantly decreased serum HBV-DNA and ALT levels, but not cccDNA.


Conclusions

In untreated HBeAg-negative CHB, serum HBsAg levels reflect liver HBsAg, but not cccDNA or liver HBV-DNA, suggesting that they are not solely dependent on the replicative cycle of HBV.
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Avatar_m_tn
Hepatitis B surface antigen Quantification: Why and How to use it in 2011 - A Core Group Report.


this group of researchers are among the most advanced in hbv research...i do know brunetto, locarnini and marcelin as the most expert on hbv field:
Chan HL, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, Tillmann HL, Kao JH, Jia JD, Wedemeyer H, Locarnini S, Janssen HL, Marcellin P; for the Good Practice in using sAg in Chronic Hepatitis B Study Group (GPs-CHB Study Group).




Source

Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong.




Abstract



Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tend to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000 IU/ml), HBsAg <1000 IU/ml in genotype D HBV infection and HBsAg <100 IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100 IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.



Copyright © 2011. Published by Elsevier B.V.
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23 Comments Post a Comment
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Avatar_m_tn

hbsag reflects immune control over hbv, this is the most important meaning about hbsag quantification

as to correlation with cccdna i just follow brunetto studies because there are countries like US where they are trying to keep hbvdna pcr instead of very cheap hbsag and not all studies and researchers are serious the same so i tend to look at the most relevant researchers and care much less of unknown researchers

we do know from brunetto that in hbeag negative there is little correlation with cccdna except for very low levels where there is even immune control over the infection and in this case correlation is pretty clear.

if they studied hbsag under nucs they wasted their time, nucs increase hbsag and suppress immune response....
what are the levels of hbsag studied by these researchers?
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Avatar_m_tn
Don't know. I have requested the whole paper. It just surprised me that they can measure HBsAg+ve hepatocytes /nm2, liver hbvdna, HBcAg+ve hepatocytes, liver HBsAg and liver HBcAg. And of course, the claims that nuc reduces HBsAg.
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Avatar_m_tn
?
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Avatar_m_tn
the claims that nuc reduces HBsAg......

mhhh i think the whole paper is bullsh**, the nucs increase hbsag because when they block hbvdna inside hepatocytes the immune system thinks there is no virus so it decreases antibodies and so on while the cells is actually full of virus

i think the paper is just produced for making disinformation we all know that nucs are useless to clear hbv so hbsag must be studies on immune modulators that reduce both hbsag, cccdna, pgrna not on useless nucs

biopsies measure everything, they wanted to make me a biopsy in pisa just to see clearly everything but i said since there are no cures why should we damage my liver just for curiosity........and in any case we have clear indicators that when hbsag gets to less than 100iu/ml seroconversion is almost 100% within 5 years
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Avatar_m_tn
Hepatitis B surface antigen Quantification: Why and How to use it in 2011 - A Core Group Report.


this group of researchers are among the most advanced in hbv research...i do know brunetto, locarnini and marcelin as the most expert on hbv field:
Chan HL, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, Tillmann HL, Kao JH, Jia JD, Wedemeyer H, Locarnini S, Janssen HL, Marcellin P; for the Good Practice in using sAg in Chronic Hepatitis B Study Group (GPs-CHB Study Group).




Source

Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong.




Abstract



Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tend to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000 IU/ml), HBsAg <1000 IU/ml in genotype D HBV infection and HBsAg <100 IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100 IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.



Copyright © 2011. Published by Elsevier B.V.
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Avatar_m_tn
Thanks, I read it. Look like your doctor friends from Pisa are busy, teaming up with doctors from Hong Kong and Australia (Stephen Locarnini). Good paper.
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Avatar_m_tn

if you check dr.brunetto she has been everywhere getting paid for her research by governments/institutions from US to germany to japan....she is so well known that she could make a research conference with all the most advanced world researchers directly in university hospital in pisa and this is very good because there is no drug makers involvment or interference with this

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Avatar_m_tn
From the first abstract (http://www.jhep-elsevier.com/article/S0168-8278(10)01088-3/abstract)

"Antiviral therapy decreased serum HBsAg levels by 79.6% (p = 0.012) and liverHBV-DNA by 84.4% (p= 0.026) in paired comparisons and, as expected,significantly decreased serum HBV-DNA and ALT levels, but not cccDNA."

do you know what anitiviral was used ?
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Avatar_m_tn
http://www.hivandhepatitis.com/2011_conference/easl2011/posters/Heathcote.pdf

this is lookiong for the relation between qHBsAg and HBeAg seroconversion and we can find some interesting results if we watch qHBsAg variation in time.
- we can see a 1.1 log decrease using tenofovir / - we can see that genotype D have the higher qHBsAg values ....
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Avatar_m_tn
http://www.natap.org/2010/APASL/APASL_05.htm - another report regarding HBsAg decrease (the antiviral used was lam - but we can have a look on both presentation and have a idea)
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Avatar_m_tn
http://www.intmedpress.com/serveFile.cfm?sUID=c0f29db5-b3ac-4ddd-b45d-2b5cd41ef3cc

on the same issue like teh previous link. - this is intresting that mentioned a 3 curse INF (is that 3 years INF ? )
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Avatar_m_tn
I have a theory why antivirals also decrease HbsAg levels. I will try it on you.

HBsAg in the blood comes from 3 sources:
1. Non-infectious HbsAg coated particles (by far the greatest amount)
2. As the surface coat of Dane Particles (new virions)
3. HbsAg produced by S-gene embedded in our genome (very small amount and not always the case).

When we take antivirals, the number of Dane particles is reduced, as reflected by lower hbvdna in the blood. So one source, No. 2, is reduced. Therefore we get a decrease in qHBsAg.

But until  we can also reduce the total amount of cccDNA in all the liver cells, we are not cured. So far, only our immune system, stimulated by Interferon, can reduce cccDNA by killing infected liver cells or inhibit the ability of cccDNA to replicate(?).

That's my theory. :-)
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Avatar_m_tn
yes, this can be the case but in this case we should have a correlation between the reduction of Dane Particles (new virions) and reduction of qHBsAg and I don't remember to notice that correlation.

what do you think ?
I agree that cccDNA is the best indication of cured or not, but is hard to a obtain a value for cccDNA. (also i don't remember to notice a correlation of "something" with cccDNA)
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Avatar_m_tn
http://www.intmedpress.com/serveFile.cfm?sUID=ba638ef5-bdee-40df-b11c-81f4467a73e7

this is a good study with all parameters registered, hbsag, hbvdna and cccdna both blood and liver, this is a very good source to see what happens in real combo where dana particles are stopped by nuc (keeping in mind adv is sooo weak and tnf can do much better) and interferon clearing cccdna

this is an old study published 2007, study probably from 2006 or even earlier.the very bad thing is that this is the last study showing all parameters, they just filter all those tests now and just look at blood hbvdna and alt (very rarely hbsag) which is totally useless.
as you all know drug makers can filter and publish what they like from a study and keep data they dont like for themselves
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Avatar_m_tn

good observation on this study is that those clearing hbsag had higher alt baseline and during treatment, this reflects higher clearance of inceted cells by immune system, while cccdna baseline wasn t different from the others
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Avatar_m_tn

look also graphics, there was a sharp decrease on hbsag on all (Except one) despite high hbvdna because both interferon and adv are weak on hbvdna, i am sure tenofovir and truvada can do so much more in combo with interferon as some single clinical cases showed
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Avatar_m_tn
what is the conversion rate from ug/ml to IU/ml for HBsAg ?
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Avatar_m_tn
http://www.md2010.org/files/presents/s2/c2-1.pdf

there are some conversions here and good explanation of hbsag meaning
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Avatar_m_tn
thanks!
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Avatar_m_tn
"yes, this can be the case but in this case we should have a correlation between the reduction of Dane Particles (new virions) and reduction of qHBsAg and I don't remember to notice that correlation."

The correlation is decline in serum qHbsAg follows decline in serum hbvdna.

"what do you think ?
I agree that cccDNA is the best indication of cured or not, but is hard to a obtain a value for cccDNA. (also i don't remember to notice a correlation of "something" with cccDNA) "

When serum hbvdna is undetectable, serum qHbsAg is a marker for transcriptionally active cccDNA as some scientists believed.
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Avatar_m_tn

there is only correlation with hbsag and cccdna when hbsag gets low to immune control range like less than 1000iu/ml, weak or no correlation when higher with cccdna

no correlation at all with serum hbvdna until hbsag very low/undetactable

immune system doesnt work directly on hbvdna, it cuts antigens/cccdna first, hbvdna undetactable comes with hbsag negative and sometimes very low hbvdna remains for years despite immune control.this is also a clever way because hbvdna und is of no use to gain immune control, the attack must be towards hbsag and cccdna and this is exactly what interferon does on responders
some more non responders can be rescued by long term hbvdna suppression and then interferon add-on

i think focus of therapy must be on hbsag lowering only because the rest have no importance to clear or to achieve immune control
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Avatar_m_tn
I think most of what you say may be correct when one is not taking antivirals.

When you take antivirals, your serum hbvdna can go undetectable, but your serum qHBsAg will still be high. Then serum qHBsAg is correlated to cccDNA.

My comments to 4est are in the context of someone taking antivirals.

When you are not taking antivirals and your hbvdna is low or undetectable, then obviously you are under immune control (this new phrase is what we are going to hear a lot more of from now on). Precisely how this is achieved is unknown(?), most likely it is by cytokines (such as Interferon) that inhibit viral replication and they do not kill the infected liver cells, such as by CTL, otherwise your ALT will be elevated.

These are just my own understanding
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Avatar_m_tn

we have also to keep in mind the nagalase test, until now we have only 2 members who did the test:
nagalase about 1 and hbvdna 900iu
nagalase 0.69 (normal <0.6) decreasing hbvdna with hbsab 30-50miu/ml

my idea is low naglase correlates with immune control

if we get more people to make this test we can easily make a connection.hbsag is not correlated at all with nagalase in these two

pisa was interested to check nagalase of their patients but i dont think they will ever get the funds

nagalase on other diseases, the higher the more advanced disease:
autism 0.9-3
hiv+  2-5
lyme 1-3
CFS 1-3 the most, few with advanced disease 3-6
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