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Irbesartan, might be 60 times more powerful to supress HBV entry than e...
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Irbesartan, might be 60 times more powerful to supress HBV entry than ezetimibe

A recent paper studied the effect of most FDA approved drugs on the inhibition of NTCP, the now known entry receptor for HBV. Ezetimibe was found to have a 50%inhibition conc of  25micromolar, while irbesartan, a commonly used angiotensin inhibitor to reduce blood pressure, was found to inhibit at 11.9 micromolar. Both compounds have similar MW, but irbesartan is given at up to 300mg per day, while exetimibe is dosed at 10mg. Thus the combination of 30fold higher approved dose and the double micromolar inhibition potency makes, in theory, irbesartan 60 fold more potent to inhibit Hbv entry. Of course, binding of these drugs to plasma proteins could cause substsntial differences in the available concentration on the hepatocyte membrane receptor, and the pharmacokinetics could further influence the in vivo efficscy. Tests in chimeric mice are urgently needed to determine the in vivo efficacy of this common, mostly beneficial medication on HBV reinfection inhibition.
Tags: Ezetimibe, Irbesartan, Entry inhibition
95 Comments Post a Comment
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Avatar_m_tn
Here is the abstract.

ABSTRACT: The hepatic bile acid uptake transporter sodium
taurocholate cotransporting polypeptide (NTCP) is less well
characterized than its ileal paralog, the apical sodium
dependent bile acid transporter (ASBT), in terms of drug
inhibition requirements. The objectives of this study were (a)
to identify FDA approved drugs that inhibit human NTCP,
(b) to develop pharmacophore and Bayesian computational
models for NTCP inhibition, and (c) to compare NTCP and
ASBT transport inhibition requirements. A series of NTCP
inhibition studies were performed using FDA approved drugs,
in concert with iterative computational model development.
Screening studies identified 27 drugs as novel NTCP
inhibitors, including irbesartan (Ki = 11.9 μM) and ezetimibe
(Ki = 25.0 μM). The common feature pharmacophore indi-
cated that two hydrophobes and one hydrogen bond acceptor
were important for inhibition of NTCP. From 72 drugs
screened in vitro, a total of 31 drugs inhibited NTCP, while
51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug−transporter interaction determinations
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Avatar_m_tn
This paper is also fascinating, since it clarifies the mystery, recently discussed directly in the ezetimibe thread, how ezitimibe works to block Hbv entry, as shown by ulrike prozer in the hepaRG system. It is simply a NTCP blocker, moderatly potent. Of note,  blockage of this receptor, NTCP, is also the mechanism by which Myrcludex works as an entry inhibitor. It is the membrane protein that normally transports bile acids from the portal blood into the hepatocytes for recycling. No wonder upon sufficient Myrcludex dosing, the bile acids start accumulating in the systemic circulation.
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Avatar_m_tn

i see it has no relevant sides and no toxicity, a combo ezetimibe plus irbesartan is for sure very very interesting.

shall i wait for next hbsag quant test before trying this add on?i also have relatives using these drugs and they confirmed no sides at all from this drug
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Avatar_m_tn
There is an interesting way to test the efficacy of the blockage of the HBV receptor, the NTCP, by measuring your bile acids in the blood. You should check them right now for a baseline. Too bad we dont have a pre ezetimibe value, but they could be mildly elevated. Irbesartan should increase them further, witinin days. We already know, that myrcludex increases the bile acids strongly, which is a beautiful confirmation of its blocking effect on the NTCP. Thus the bile acids could be used as a quick surrogate marker of blockage of the HBV entry receptor. I would expect that one week after irbesartan add on the bile acids w

With regard to the question of waiting how the quant hbsag further responds to the 50mg ezetimibe, before trying the irbesartan, there is no simple answer.
In my opinion, if the ezetimibe blocks HBV reinfection mildly to moderatly, we should expect a shift of the surface antigen over time to a lower value, but there is likely a new level, a new equilibrium where it will stabilize. In this case you would see again a lower than previous value, but no further clear downwards trend. It might be important to clarify that before adding the irbesartan.
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Avatar_m_tn
If you think of using the irbesartan,  remember it is a blood pressure medication. It could cause you dizziness, or even synkope if you get up too rapidly in the morning. Also, clear this approach with your doctors in Pisa. I expect that they will be quite fascinated by the chance to block hbv entry with a harmless, often rather beneficial blood pressure medication.
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Avatar_m_tn

the research center has my frozen blood tests and they are available if necessary, i can get oct 2012 frozen blood samples to get tested for bile acids in blood.i should be able to get this value in april

i ll check hbsag quant and bile acid in blood next week then we can add on Irbesartan
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Avatar_m_tn
One thing that we have to keep in mind is that the bile acids in serum will fluctuate during the day according to bile output during meals and  concomitant reabsorption in the ileum which will raise the systemic ba levels.

Thus testing should be strictly under morning fasting conditions to allow meaningful comparisons. Also bile acid serum samples have to be sent to the lab frozen.

And again, be careful when using irbesartan regarding dizziness. It might take a while to adapt to it, since it will lower your blood pressure.
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Avatar_m_tn

gonna get salt back in my diet....i ll be very careful
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Avatar_f_tn
Do we have more info on next move by FDA following this discovery?
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Avatar_m_tn
No, nobody will even take note of this. Researchers like prozer will hopefully test it soon in culture and animal models to establish if there is in vivo efficacy of hbv entry blocking.
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Avatar_m_tn

i guess that if we reach a good level of reinfection block by these drugs we should see big hbsag drop by 6-8 months of use thanks to hepatocytes turn over indipendently from immune clearance

are there any predictions on myrcludex response in case of tdf or etv combo treatment?
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Avatar_f_tn
Thanks for quick response.
I ll try and make contact with the drug maker as this represent a potential business opportunity although its out of patent.
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Avatar_m_tn
If i had to guess the dynamic equilibriums at work here i would say that ezetimibe alone might reach a 20% drop and the combo with irbesartan another 20%. Myrcludex at effective dose will drive it much lower.

The antivirals, as previously mentioned, act synergistically with any entry inhibitor simply because the number of virions requesting entry will be much smaller. The reduction rates will a actually multiply, true synergism.

The only problem remaining is that reinfection will work for the virus even at a very very low efficiency. If an infected cell manages to place just one lousy virion per week into an uninfected hepatocyte, then the total liver infection will double every week!

Thus entry inhibition has to be extremely efficient and tight to work towards eradication and it has to be coupled with an ongoing elimination of infected cells. That elimination process tends to become very slow in a liver that has a very low number of infected cells remaining.

Anti hbsag antibodies will also work synergistically as entry inhibitors, but the fail at close range unless they are present in very high titers, since the complexing reaction takes time. Thus neighbors can still get infected.

On the other hand once a virion is coated with sntibodies it is out for entry for good. It is unclear if myrcludex rejected virions will get degraded in an endolysosome or if they are able to try entry sgain.
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Avatar_f_tn
What is the chance of intf combo with Irbesartan considering that Otan cleared on intf and simvastatin?
I guess Irbesartan is more potent in theory if the receptor are similar.
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Avatar_m_tn
the ideal scenario remains tdf +pegintf+entry blockers then......when we see a stable hbsag with no furthur decrease the intf might finish the job
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Avatar_m_tn
Simvastatin was also tested in the above paper and it gave about 60 micromolar inhibition of NTCP. But other factors like the strength of the binding to albumin are also important.

These entry inhibitors are likely helpful to lower reinfection in a setting of intensified clearance like on ifn, speeding up the process.
Entry inhibition alone can only work if extremely efficient.
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Avatar_f_tn
I'm on intf mono but think i need to add on  irbesartan or simvastatin or ezitimibe if it acts as HBV inhibitor.
In three of these potential inhibitors, irbesartan has less controversial safety profile although simvastatin has been proven to work... used bu Otan..
I need opinion please.
History: e-antigen negative.
Been on intf for 5 months.
Alt had been high and over 230 before and during treatment.
HBDNA profile:
Baseline = 300,000 iu
6 weeks = 30,000iu
12 weeks= 150,000 iu



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Avatar_m_tn
Yes, if the hbsag stabilizes on a lower level, you have only achieved a first step. Only if the hbsag gets low enough to stop interfering with the immune response will the elimination process move any further.
Ifn will help to kick start the t cell response that will do the further clearing.

But for the hbsag t cell epitopes to participate in this, the surface antigen has to go much lower than what  you commonly assume, probably below one ng per ml. Before that you achieve some removal of macrophage and dendritic cell deactivation, also a function of the hbsag, but not the liberation of the anti hbsag tcell epitope response.
Patients that still have unmutated core epitopes available can continue elimination all the way down to seroconversion of the hbsag and then also by stabilizing activation of the untouched hbsag epitope reservoir.

The lowering of the surface antigen that is often observed in the later full responders is rather a diagnostic indicator of a shrinking cccDNA pool than the causality of the reduction.

Only in the last stages of this reduction the liberation of the hbsag t cell response will start providing mighty t cell responses that will stabilize the elimination.

In summary, when the core tcell response is mutated away too much, then the ifn therapy has a much lesser chance to clear. Replicors   drug will artifically supress the surface antigen and therefore activate all these responses, together with ifn permanent stable clearance is very likely.

Entry inhibitors will help in all scenarios, it weakens the virus capacity to defend itself by reinfection.
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Avatar_f_tn
Ohh sorry dear.. one more thing about my history.
Genetype : B
HBsAg before treatment: 4000iu
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Avatar_m_tn

you forgot the hbsag level which is the most important to predict and precore/bcp

to me you should use irbesartan plus ezetimibe or try sim first and then see if it doesn t work in few weeks you can go for the other combo


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Avatar_m_tn
Obviously no clinical efficacy data are available on irbesartans Hbv Entry effect. What we have here are intelligent extrapolations from the study of its effects on NTCP the recently found HBV receptor and only in the sense that this receptor is blocked best by irbesartan in its primary function, which is transporting bile acids, in a competitive manner. The assumption that this transport blockage will also inhibit HBV binding MIGHT BE WRONG, although it is quite likely. The only compound that will block this receptor in a noncompetitive manner and acts definitely without doubt as an HBV entry blocker in humans is Myrcludex, at a dose that is about 10 times higher than the one currently used in the russian trials.

How is your surface antigen reduction thus far on ifn?
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Avatar_f_tn
surface antigen test quantitation isn't available in the UK so I ll travel to perform this test asap.
It ll definitely provide a lot of info about treatment response.
I ll update you asap.
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Avatar_m_tn
Stefanos data on further hbsag reduction under added irbesartan will give an excellent guidance on its power.
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Avatar_m_tn
Furthermore the bile acid data will give a strong hint if it indeed works as NTCP blocker, even re the relative power of ezetimibe vs irbesartan, and even very soon.

Irbesartan will be in steady state after 3 days, bile acid accumulation might take another week or so.

Bile acids dont feel good when accumulating, thus this might be another limit to entry inhibition by NTCP. Blockage.
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Avatar_m_tn
Any research papers  on Amlodipine  tablets which is  antihypertensive  normally prescribed by Indian Doctors. I read that Amlodipine  will cause Liver Damage in Wiki. Could you please share some thoughts on this.
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Avatar_m_tn
take Irbesartan at this point, not other types of antihypertensive.it has no sides and blocks hbv receptor
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Avatar_m_tn
If I get it right to have an effect on entry inhibition 30 fold aproved dose is required.  Why do you think that 30 fold approved dose will not have sides effects?
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Avatar_m_tn
Stef,
I understand the safe dosage is 300 mg/day.. is this correct?  Also can we have two 150 mg dosage, 2 tabs, one in the morning and another in the evening
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Avatar_m_tn
generics and the price for irbesartan in india: (price in rupees - 1$ = 54.4 rupees)

Irbest - Biochem [Irbesartan ]  

---------------------------------------------------------------

-----------------

Strength Volume Presentation Price*    
Irbest 150mg 10 Irbest TAB 69.30    
Irbest 300mg 10 Irbest TAB 135.00  



Irovel - Sun [Irbesartan ]  

---------------------------------------------------------------

-----------------

Strength Volume Presentation Price*    
Irovel 150mg 10 Irovel TAB 77.00    
Irovel 300mg 10 Irovel TAB 127.00  


Xarb - Piramal HC [Irbesartan ]  

---------------------------------------------------------------

-----------------

Strength Volume Presentation Price*    
Xarb 150mg 10 Xarb TAB 113.48    
Xarb 300mg 10 Xarb TAB 163.01  
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Avatar_m_tn

i d start low dose and then go for the 300mg if no issues, you need hbvdna to be und to have results or even better on pgintf plus tdf plus irbesartan

as discussed with studyforhope it is best to start with tdf plus irbesartan to make hbvdna und and start an hbsag decline, once the decline has stopped add on pegintf.good doctor needed to monitor this
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Avatar_m_tn
i dont know where you took this 30fold, anyway:

ezetimibe, probaly too weak to work at 10-20mg which is the dose to lower cholesterol
i am using 50mg the highest dose used in human trials which was disregarded  because no improvment over 10mg for cholesterol

irbesartan max dose is 300mg to lower blood pressure, and we will use it at this dose because may be sufficent as an entry blocker

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Avatar_m_tn
You have to read the introduction to this thread, where the 30 fold and 60 fold is explained. It is 10mg vs 300, twice micromolar efficacy... Now we have the number 60, since the molecular weight is very similar.
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Avatar_m_tn
Sorry I misunderstood 30 fold in the introduction.  I thought it was related to the dose. Now I checked max approved dose is indeed 300 mg.
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Avatar_m_tn
http://211.144.68.84:9998/91keshi/Public/File/25/21-3/pdf/1-s2.0-S0966327409000215-main.pdf

interesting article which used even 100mg ezetimibe in the trial.

i posted this article because since i started ezetimibe i am feeling a weaker immune system which may confirm this article about the cd4, nk, monocyte cells count decrease.
since gcmaf therapy and high vit d levels i never had any infection of any type (just herpes during imiquimod but that is not relevant).

in these two months of ezetimibe i experienced two infections: one after a tooth extraction and had to use 2 antibiotics (one not responding maybe for resistance)
and the recent cold which was very very mild thanks to the use of liposomal vitamin c at 40-50g daily, but now after about 2 weeks i still have little cold/cough if i dont use high dose lipo c

so nothing to worry about just wanting to confirm this effect from ezetimibe on immune system and still want to combo ezetimibe and Irbesartan, but if one was to choose among the 2 drugs (if both confirmed as hbv entry blockers), Irbesartan maight be the best choice

is my alt lowering during ezetimibe an effect of entry block or the immune suppressive effect from cd4/nk decline?i understand we dont have data to answer this

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Avatar_m_tn

maybe the article is not so relevant since the cells are from transplanted patients but the weaker immune system effect was also noted by my family members since early feb
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Avatar_m_tn
The article describes the slower capacity of immune cells to proliferate in the presence of ezetimibe or atorvastatin. The differences were however not very impressive, around 10 to 15% in cell counts after culture in the presence of these cholesterol blocking drugs. It might not be a big surprise, since the de novo formation of cells requires of course cholesterol, as such a slowing down of cell proliferation is not unexpected.

All cholesterol lowering influences will have, in addition to somewhat slowing proliferation,   the effect of slowing the formation of lipid rafts, which are cholesterol rich plasma microdomains in which immune relevant plasma proteins like T cell receptors are accumulating and sticking together for concerted action.

In summary, a slight reduction in immune reactivity by ezetimibe is not surprising. I doubt however that it can explain the infections that you have recently experienced, it might be simply coincidence.
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Avatar_m_tn
Here is an extended abstract about a clinical study using irbesartan against hepatic fibrosis:

http://www.12340000.com/medicine-health/digestive-system-disease/39413.html

Based on it irbesartan could be an option for Hep B patients with twofold aim: a) to suppress HBV entry, and b) to recover liver function and inhibit hepatic fibrosis progress.
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Avatar_m_tn
Can irbesartan be used as an fibrotic inhibitor agent? I mean besides its entry inhibition function which still has to be proved can it be used safely as an anti-fibrotic agent? Thank you in advance.
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Avatar_m_tn
Yes, if you look at the above paper,  it has an antifibrotic effect as well. This seems to be very fortunate. But we do not know how strong that effect really is. Nor do we know how well it blocks entry of HBV, this has to be tested in vivo, in human patients.
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Avatar_f_tn
I am on 37 week of TDF+Peg+NTZ and also taking Amlodipine 5mg for my blood pressure. Do you think I can change to irbesartan? When I change to irbesartan, should I start with 150mg or 300mg right away??
I am Hbeag negative and with this tx my Hbsag is going down very very slowly; before tx,around 3000iu and after 6 months 2600iu. Before tx, my fibroscan result was about 4.5 kpa and after 7 months of tx it was 6 kpa. I don't want this number goes any higher.  Thanks.
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Avatar_m_tn
Switching to irbesartan for your bp should not cause any problem, so why not using this chance, despite the fact, that we are not sure yet of the magnitude of its effect on hbv entry. I would start with 150mg and then increase if there is no side effect.
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Avatar_m_tn
A layman/patient's question, if I may..

Could you please share with us your personal opinion (based on what we have been hearing of late), which of the following five (5) medicines hold most promise for chronic HBe-negative HBV patients in terms of (a) more time into research/trials completed, and (b) most promising results so far:

1. Replicor Rep9C
2. MycludexB
3. Ezetimibe (FDA approved drug for cholesterol control)
4. Irbestaran (FDA approved drug for hypertension control)
5. siRNA by Arrowhead

I realize that as of today, we do not yet have sufficient/conclusive information about efficacy of any of these drugs on hbv; but if possible, could you make it a little easier for us patients to understand what is happening?

Many thanks.
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Avatar_m_tn
In terms of most promising results thus far and, even more importantly, in terms of fundamental mechanisms required for cccDNA clearance, regardless of formal processing towards approval, the order is like this:

Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.

Replicor plus ifn plus myr 85

Replicor plus ifn 80

Replicor alone 25

Myr alone 20

Limited time silencing RNA..arrowhead..10

Irbesartan plus tenofovir. 6

Ezetimibe plus tenofovir 5

This applies to high hbsag quant patients. In cases where the combination of epitopes in the current quasispecies hbv cccDNA population and the vigor of the tcell response has reduced the infected cell and cccDNA load and resulting hbsag production to a very low level, the percentages will be substantially higher.

These cases also have a chance with the sequential tdf then tdf plus ifn treatment, the lower the start hbsag the better the percentage of real stable svr will be,  from 10 all the way to 50%. Unfortunately, most patients with hbsag over 1000 will not svr on this treatment.

Note that the formal progression to authority approval is no measure of potential success. Lambda ifn is most advanced, gs9620 and arrowhead are in the initial stages.Those 3 carry the promise of a noticeable shift of svr in very small percentages only, more patients are likely to achieve a more harmless carrier stage with no hbsag seroconversion.
Replicor is still working on the final more practical formula, once this is found and proven, then it will all depend on a powerful new partner or buyer that can provide the 150 million dollars that it might cost to go through all the trials towards approval in the us and eu.

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Avatar_m_tn
I understand that with current nucs, even though reduced, there is still a significant risk of progressing to HCC. Do you think that Myrcludex along with nucs, even if not successful in clearing cccDNA, will reduce that risk of progressing to HCC?
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Avatar_m_tn
Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.  

What is the therapeutic vaccine you are talking about here ?

Could you elaborate more about lamda interferon ?
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Avatar_m_tn
Depending on activity of ongoing infected cell removal and the efficacy of entry inhibition of the myr dose actually used, the cccDNA pool will become progressively smaller with time as long as the patient will be on myr. Lesser infected cells means a reduced risk of HCC, but the overriding factor in HCC risk is the presence of cirrhosis and thev
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Avatar_m_tn
Intensity of ongoing inflammation and oxidative stress. Unless myr is used all the way to hbsag seroconversion, stopping the treatment will restore the initial level of infected cells, of cccDNA and quant hbsag. Myr will cooperate with nucs in reinfection reduction, a combo with ifn will be even better.In all scenarios the myr dose will have to be very high for success.
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Avatar_m_tn
I was referring to the globe immune. Gileads. Therapeutic HBV vaccine. It might however never reach approval, since its solo effect in phase2 trials will be too small to warrant further development.

Lambda interferon is a type of interferon that focuses on the liver and has substantially lesser systemic  side effects compared with interferon alpha.
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Avatar_m_tn
Correction... Should say to small....
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Avatar_m_tn
Why will  cccDNA return to the initial level if the treatment is stopped?
Is there a kind of equilibrium and what does it depend upon?
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Avatar_m_tn
Yes, there is a dynamic equilibrium. For each level of reinfection exists a lev
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Avatar_m_tn
Level of infected cell clearing that will lead to a zero net change. A decrease in reinfection by entry inhibition will therefore initially lead to a reduction of the total number of infected cells, but the lesser the infected cells remaining the slower the removal rate will be until it restabilizes on a lower level. Of course, if the reinfection rate is extremely low, then the removal will progress to such a substantial reduction in cccDNA, that the hbsag production shrinks to a critical threshold upon which its inhibition on immune clearance by s ag specific tells will be very low and a new force of cccDNA removal will slowly initiate, possibly leading to hbsag seroconversion.

If entry inhibition is stopped to early, the infection will spread again until it is matched by the removal rate.
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Avatar_f_tn
@ Studyforhope, did you data on myrc ?
Not much articles available online.
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Avatar_f_tn
I was gonna add on Irbes on intf... but the earlier post was discouraging so i might aswell keep intf mono.
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Avatar_m_tn
Thanks! And  the removal rate depends on the immune respons, right? The less the number of  infected the less the immûne respons , that is why we need interferon addon?
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Avatar_m_tn
Thank you very much for your very informative and useful reply.

Two questions:

1. "..Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.."
Q. Initial HBsAg conversion = When HBsAg becomes undetectable for the first time with use of R+Inf+M? Or..?

2. The news from Arrowhead (AH) says they claim 90% "Antigens" loss in their trial (with a Chimp). (I could not make out whether that was the surface antigen or e-antigen).
Q. Could we in any way compare/correlate the above with the figure you gave of 10% long term svr with AH? Similarly, the only 6% you gave for Irb despite it being possibly 60 times more powerful to suppress hbv than Eztmb (which itself showed promising results- i read Stef's update about that a few days back).

I am sure that with my limited knowledge, I am missing something very basic here.

Lastly, in general, is all the current research/progress reason enough to believe we are getting closer to subjugate this amazingly tough virus?

Thanks again.
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Avatar_f_tn
Just an answer for your first question.
Through 29 days after initial treatment, maximal knock down of HBV DNA, e-antigen, and s-antigen were approximately 95%, 90%, and 90%, respectively..from Arrowhead website.
The second question can only be answered by Studyforhope as i am not clear on the figures myself
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Avatar_m_tn
Thanks.
Thats what I read myself. And I thought these figures do not seem to agree with what I deciphered from studyforhope's reply to my original question. I am sure he can further enlighten us on the subject.
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Avatar_m_tn
What is the maximum time required time to complete the phase I to drug in market time
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Avatar_m_tn
And  the removal rate depends on the immune respons, right? The less the number of  infected the less the immûne respons , that is why we need interferon add on?

That reduction of the vigor of immune mediated clearance against a dwindling number of infected cells remaining is indeed a major problem in achieving lasting hbsag seroconversion or stable svr. That's why even after initial seroconversion and DNA  undetectability and with a low but positive antibody level 75% of the primary svrs in the first replicor trial lost their seroconversion later.

Since a few infected cells will always remain, there is an absolute need for a maintenance immune function to control the remnants from spreading again.
It must be understood that even a good anti surface AB level is not able to prevent a slow spreading from remnant infected cells. This is caused by the limited speed of the immune complexing reaction, that will coat exiting virions with neutralizing antibodies. But an exiting virion needs to travel only a few microns to reach a neighboring uninflected hepatocyte, only a very high AB level can catch it in this localized scenario. Thus the infection will spread very slowly in local clusters.

This slowly growing cluster needs to be detected by a patrolling CTL, ready and activated enough to produce a high intensity gamma interferon burst, that will clear the cccDNA from this cluster.

Thus, yes in summary, that's why the add on interferon is needed even with replicor , to keep the immune vigor going once the stimulus has gotten very low.
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Avatar_m_tn
1. "..Replicor with interferon plus myrcludex plus therapeutic vaccine after initial hbsag conversion. 95% true long term svr.."
Q. Initial HBsAg conversion = When HBsAg becomes undetectable for the first time with use of R+Inf+M? Or..?

The disappearance of the surface antigen from the peripheral blood occurs after a few weeks of treatment with the replicor compound, but it is only the primary event that allows immune reconstitution and consequential infected cell clearance to the point, that several month later the true hbsag production even without artificial blockage is so low, hat it remains undetectable with most assays and a positive AB level can be detected at this point. This is the definition of initial hbsag conversion in the above context.

But this status is not truly stable in most patients, since a slow regrowth of the infection still occurs. Externally supported activation of immune surveillance is needed at this point, by ifn, therapeutic vaccines, thymosin alpha or by suppression of entry by effective doses of Myrcludex.
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Avatar_m_tn
Thank you for your explanation!

Just one probably stupid question...

Why don't grow antibody in-vitro or take them from a donor, and then put them into the circulation of an infected person?

Sorry I am not a biologist to know if it is possible at all with current technology.
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Avatar_m_tn
2. The news from Arrowhead (AH) says they claim 90% "Antigens" loss in their trial (with a Chimp). (I could not make out whether that was the surface antigen or e-antigen).
Q. Could we in any way compare/correlate the above with the figure you gave of 10% long term svr with AH?

The available webcast lets you see the graph with the chimp data after two injections of the silencing rna mix. Look carefully at the numbers and consider how much hbsag is left after 90% is removed and what this reduction can possibly achieve. In case of the poor chimp, the remaining hbsag was 100000 units, in case of stefano or most of the people reporting their hbsag quant here it would be about 400 iu remaining. This is totally insufficient to unburden the immune system from the paralyzing effects of the surface antigen. If you dont keep injecting it will jump right back to the pretreatment values. The cccDNA or the infected cell number has not changed, it does not even need reinfection to recover to pretreatment values.

Nebertheless, since the polymerase and the core protein expression is likely also reduced, there is a small chance that, in combo with antivirals, the virion production is dramatically reduced to the extent that the reinfection rate becomes very low, allowing a downward shift in total infected cell and cccDNA numbers. If this progresses to the point that the hbsag output crosses the critical threshold...which is very, very low.. then a similar mechanism like with the replicor drug might occur. Provided that the intracellular shutdown of hbsag expression is not so intense as to prevent the processing of hbsag epitope fragments to the MHC pathway for presentation and tcell recognition on the surface of still infected hepatocytes. The combination of the effect estimation of all these mechanisms gives AH its rating towards helping true SVR, in combo with other approaches.

Arrowhead is BTW well aware of its limitations and thats why they call it a functional cure, meaning, that while you keep injecting the AH compounds like once pet month, the liver pathology will subside, since the immune attack will ease up. This is similar to what is achieved with the antivirals.
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Avatar_m_tn
The use of prepared anti hbsag antibodies ifrom high titer donors is commonly done to help to prevent reinfection after liver transplant and slso for newborns from infected mothers and after acute exposure. It is called HBIG .. Hepatitis b immune globuline.

It is very expensive and cannot be used in chronic hbv patients with any chance for a real effect since the amounts needed to neutralize the circulating hbsag levels are astronomical. For example to neutralize the daily production of a patient with 4000 iu about 100000 dollars worth of hbig per day would be needed, ongoingly. And dangerously high levels of immune complexes would be formed, damaging the kidneys.

HBIG was tried in the netherlands on patients with low hbsag, no real,effect, as expected.

A humanized monoclonal antibody named OSTAVIR against hbsag was tried in germany  in cooperation with boehringer msnnheim. The trial was stopped because of a high rate of acute kidney damage.

A dual human monoclonal AB, invented and created by XTL  in israel , named HEPEX B was advanced to a phase II human trial in chronic HBV patients in the usa. As expected, the suppression effect of super high doses in low hbsag patients was indeed achieved, but lasted just days after the treatment was stopped, with no real benefit to the patients.

HEPEX B was later sold to the us company CUBIST that tried to develop it for transplant reinfection prophylaxis. A phase II trial was sucessfully completed, but the FDA. requested over 400 transplant patients for the phase III trial, an impossible request that forced CUBIST to discontinue its development.

This is really sad, since HEPEX B exists, and could be used in combo with replicor or other approaches as a powerful entry inhibitor to prevent infection respreading in primary hbsag seroconverters that do not develop a high titer antibody.
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Avatar_f_tn
Are we ever gonna see Replicor on the market  in any form or shape?
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Avatar_m_tn
if no big pharma buys replicor to continue its development in the big us and eu markets, then maybe a smaller approval scale in countries like the phillipines, bangladesch, etc is possible. That is exactly what Sciclone has done with thymosin alpha aka as zadaxin. It has approval in about 10 countries. Availability would unfortunately be limited to patients able to afford it by private payment.And one must never forget that it must be combined with strong immune enhancers like ifn or thymosin alpha to effect a truly stable seroconversion in the majority. But it remains by far the biggest step forward, because, for the large majority of patients,  without very very high efficacy of surface antigen suppression, no permanent control of HBV seem possible, with the possible exception of ultra high entry inhibition combined with intense immune activation.
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Avatar_m_tn
Thank you very much. Your posts reassure us that things are moving mostly in the right direction to combat this truly amazingly tough and resilient virus.
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Avatar_m_tn
Hey, Mrt79, what is your age? When you start intf 5 months ago, what was your ALT level and any side effect from intf so far?

What was you on before intf? Thxs.
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Avatar_m_tn
updates on my results, i have got also previous hbsag tests done in pisa and the hbsag decrease was started from oct 2012 before trying ezetimibe and while on imiquimod suppository.
so the decrease was not an effect of ezetimibe.i d say no effect from ezetimibe both on bile acid and hbsag for now

16 oct 2012 hbsag 3687iu/ml blip of hbvdna detected 31iu/ml alt 42  etv+tdf+imiquimod suppository, imiquimod suppository stopped jan 8th 2013 when starting ezetimibe

jan 01 2013 started 10mg (40mg on some days) of ezetimibe plus etv+tdf

jan 10 2013 hbsag 4207iu/ml

feb 01 2013, started daily ezetimibe 50mg, alt 31

feb 28 2013, hbsag 3644iu/ml, hbvdna undetactable

mar 13 2013, alt 30

mar 25 2013 biliary acid 1.2 micromol/l (normal <6)

mar 27 2013, hbsag 4163iu/ml, started ibersartan 300mg daily+ezetimibe 50mg+tdf+etv

effect from ibersartan:
no sides, beneficial effect on irritability present since started nucs in 2009 almost all gone, so in general feeling better, blood pressure normal.

very bad: frequent urination even hourly if i drink water, normal if i drink little water like 1-1.5liters per day

since my family has very low pressure genetically like 40/90 in the morning and 70-100 during the day without feeling abnormal i guess i can feel no difference on iberstartan or nucs increased my blood pressure during these last years
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Avatar_m_tn

discussing with pisa researchers they say etv+tdf is less potent than tdf mono because there might be competition among these drugs.so keeping the combo is beneficial only for resistance which is never seen on tdf mono but less potency and more sides

they suggest tdf mono and peginterferon add on when hbsag reaches 1000iu/ml.the hbvdna 31 iu/ml blip experienced in oct while trying tdf+etv+imiquimod suppository suggests me it is best keep the combo as long as no sides are experienced and that we really have no sufficent data to say tdf mono is superior to etv+tdf
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Avatar_m_tn
the hbvdna monitoring is every 3 months and the detactable hbvdna at 31iu/ml was only in october (never happened while on the combo tdf+etv), i noted i had fever 38° from imiquimod the day of the test, so it may be just an occasional blip due to the imiquimod effects on immune system
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Avatar_m_tn
Regarding blip of DNA positivity after imiquimod:
If there was a temporary increase in liver inflammation, it could reflect the temporary increased lysis of hepatocytes. The intracellular virions are by far more abundant than the ones released into the circulation and also, very importantly, the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading.
But you could have a temp release of intracellular virions by lysis, causing the blip.

The Pisa researchers are incorrect in saying that ENT plus TDF is less potent to suppress replication than TDF alone.
While it is fundamentally true, that the lack of synergism or even very effective additiveness among antivirals is caused by competing for access to the polymerase binding site like several cooks in a tiny kitchen, there is a slight measurable degree of additivity between TDF and ENT, when you have a clean and clear model situation to address that question.
I know of a research situation, where in a particular patient a successive exchange between TDF, then ENT, then TDF plus ENT was performed.
it was also repeated to confirm the findings. It was measured with a research only ultra high sensitive quant assay. The results were clear: TDF alone was slightly superior to ENT alone, and the combo was clearly superior over both monos, almost one log further reduction compared with the monos.

Technically the antivirals have different efficacy on the three block-able modes of the polymerase; Priming, reverse transcription and extension of the incomplete plus strand. ENT is the only one that effectively works on the priming step, but TDf is better in RT and single strand repair mechanisms inhibition.
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Avatar_m_tn
So it looks like the ezetimibe was not realistically working on entry inhibition,
or more precisely to block the NTCP in a reliable 24 hours fashion. Your biliary acids were very low, which shows that there is no blockage of the HBV receptor. You have to consider the pharmacokinetics of the ezetimibe and possibly also the irbesartan. Blockage is only effective if it is a 24 hour continuous affair. If you leave the door open for the rats just one hour a day, your house will be filled with them.

to see if the irbesartan does a better job in vivo, you can simply measure your bile acids now after you take it. Considering the intense dynamic of the bile acid re-circulation ( 15 grams are recycled about 10 times per day!) any effect of blockage will be rapidly noticeable as an increase of circulating bile acids. That level might also change dynamically in response to various level of blockage of NTCP as the drug levels in blood will vary due to the drugs pharmacodynamic behaviour.
In other words, they might increase an hour after irbesartan, only to decrease to baseline  3 hours later. This needs to be considered in order not to interpret the values naively.

Under Myrcludex full blocking dose, the bile acids go up quite dramatically but  its effect needs to be maintained 24 hours also, since obviously partial time  entry inhibition is ineffective. Virions can wait in line until the doors open again, even if only shortly within 24 hours.
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Avatar_m_tn
i have been using about same time daily (just forgot totally ezetimibe one day)

i ll use iber every day exactly same time or if necessary even 30min in advance and recheck bile acids few hours after taking it

imiquimod did make inflammation fibroscan increased from 4.5kpa in october to 4.9kpa instead keeping constant decline as previously

i ll also keep etv+tdf, the local prescribing liver specialist prefers the combo too he wants to stay on the very safe side

thank you so much for your help

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Avatar_m_tn

it is interesting to note that between 10 oct 2012 and 16 oct 2012 i used daily suppository of imiquimod 12.5mg and had tests among these close dates (but just had results on hbsag 16 oct now):

10 oct 2012 hbsag 43696iu/ml alt 44 creatinine 0.7, started imiquimod daily suppository for 9days
16 oct 2012 hbsag 3681iu/ml hbvdna 31iu/ml alt 42 creatinine 1.2
21 oct 2012, stopped using daily suppository and switched to weekly suppository 25mg which showed no results until i stopped definitively on early jan 2013 and started ezetimibe

if imiquimod is to be ever tried by others or me daily suppository maybe the best schedule although inflammation is high from creatinine increase, fever was not high just 37.5°
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Avatar_m_tn
sorry typing error
10 oct 2012 hbsag 4396iu/ml

used architect with automated quant kit for both tests, no sample diluition
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Avatar_m_tn
"..the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading."

So do you agree with AASLD's practice guidelines for treatment criteria of hbe- Hep B? And the difference between chronic hbv and inactive hbv? (Or would you add/emphasize something else (tests like fibroscan, or even invasive ones like biopsy) in addition to the usual ALT, ultrasound and HBVDNA?).

Thanks
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Avatar_m_tn
The practice guidelines draw somewhat arbitrary lines to allow the practitioner to follow a programmed path and reduce responsibility in case there is a later bad development. I think that at Fibroscan or in certain cases even the addition of a biopsy helps to see the true status of the liver. The quant hbsag will help to decide whom to recommend for the ifn add on therapy and even more importantly to assess the response and likelihood early , so that unnecessary harmful ifn treatment can be early terminated.
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Avatar_m_tn
If you can measure the bile acids under irbesartan treatment, it would be useful to measure them before taking the pill and then again two hours after,
If there is no increase after, then it means that the ntcp blockage is simply too  weak in vivo even at max blood concentrations. If the bile acids are not elevated before the drug intake, then it would mean that the effect is not lasting long enough since the blood levels fall too quickly. Ideally they need to be above norm at both time points to hope for realistic HBV entry inhibition.
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«so that unnecessary harmful ifn treatment can be early terminated»
Why is interferon treatment harmfull? How bad is it harmfull? I think many people on interferon mono experience situation when there is no strong decline in hbs but DNA becomes undetectable. Statistics say if no decline in Hbs than stop interferon and switch to Nucs. The nucs goal is to make DNA undetectable. The question is – If hbv dna is already undetectable during the treatment by interferon and If interferon high cost is not an issue, what are the reasons for switching to NUCs rather then keeping interferon for 96 weeks? Are there any advantages of staying undetectable with interferon even no hbs decline (in short term, we all hope for hbs decline in long term post treatment) comparing to staying undetectable on NUCs?
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i also like to menthion that on lampertico study with intf use for about 2 years there was one patient with no response for the first 48weeks who experienced  the best response at 72 or 96weeks with the highest hbsab titer of the all patients in the trials....this is to say that sometimes you can t predict everything

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Avatar_m_tn
If a patient becomes und on ifn mono then he should stay on ifn for at least a year, even if no drop in hbsag.
The reaction to ifn in terms of side effects is quite variable, many suffer from intense fatigue,  feel like having a constant flu or become depressed, aggressive, even loose their jobs or marriages. If the sides are tolerable, then it should be given a chance to at least switch to a state of better immune control, even if hbsag loss cannot be achieved, which is currently the case in the majority of patients.
If there is any sign of autoimmune disorders, then the use of ifn can exercabate these, so there is a need to consider many variables.
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Avatar_m_tn
April 08, 2013 12:05 PM Eastern Daylight Time
Transgene to Present New Data on TG1050 and TG4040 to Treat Chronic Hepatitis B and C at EASL 2013

STRASBOURG, France--(BUSINESS WIRE)--Regulatory News:

“TG4040 has recently completed successful phase 2 trial in patients with CHC”
Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and infectious diseases, today announced that favourable pre-clinical and clinical data on two Transgene products – TG1050 and TG4040 to treat chronic hepatitis B (CHB) and chronic hepatitis C (CHC), respectively – will be presented in oral presentations at this year’s European Association for the Study of the Liver (EASL) Conference (Amsterdam, Netherlands, April 24-28, 2013). The full abstracts are available at http://www.easl.eu.

“We are delighted to have the opportunity to present data at EASL, Europe’s largest liver conference. TG1050 is a novel immunotherapeutic to treat CHB that has shown very promising preclinical results and will soon be moving to early clinical development” stated Philippe Archinard, Chairman and CEO of Transgene. He added: “In addition to the preclinical proof-of-concept data published in September 20121, we have today released supplementary information, obtained in pre-clinical naïve and HBV murine models, on the immunogenicity of TG1050 and its capacity to induce long-term T cell response. This evidence further underlines our belief in the product’s potential to become an important new first in class immunotherapeutic to treat CHB, an area of unmet medical need.”
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Can you please share your opinion regarding stem cell treatment for chronic liver diseases? I have read a lot regarding this type of treatment and a lot emphasize that it will become the mainstream in the near future for liver disease mainly for ESLD which is curable only by liver transplant. Thank you in advance.
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Avatar_m_tn
As long as you have your own liver cells regenerating themselves  there is no need or use for stem cells. Once the majority of these will have died and somehow their capacity to regenerate is exhausted , this type of treatment will make more sense, like in ESLD.
But the problem remains, that in the severely fibrotic and cirrhotic liver, there is also so much collagen, that the establishment of a meaningful liver micro-architecture is exceedingly difficult.
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Avatar_m_tn
people, we should be more focused where do they apply all this to real life cases.

For those of you that are doing research all this is very interesting sit and discuss things.. But we actually live with this nightmare. I am more interested in access to clinics where they apply all this. I will be the mice if it has to be.

The way I see things if things are known to work and not kill right away lets try it. That is what they should be doing.
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Avatar_m_tn
bad news from bile acids test:
25 mar 2013 zetia 50mg bile acids 1.2 micromol/l
11 apr 2013 zetia 50m plus irbersatan 300mg bile acids 1.0 micromol/l

normal range less than 6 micromol/l.drugs taken about 20hrs before test

i havent tested bile acids 2hrs after taking the pills, do you think it worths testing since it seems no ntcp block has happened?does it worth to try these drugs with peginterferon from other members to see if any boosting effect happens under that combo?

irbersatan is starting to be too heavy, extreme tireness especially at wake up has become not tollerable now, i can t get up before 10-11am
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Avatar_m_tn
yes, this is bad news, if the bile acids are not up, then the ntcp is not blocked. It might well be that the blood concentration of irbesartan falls to rapidly, then the blockage will disappear. Unfortunately, unless the blockage is consistent all 24 hours, it will allow reinfection. You could measure the bile acids 2 hours after drug intake, but even if it will increase it does not matter unless the effect lasts. The blockage of ntcp by myrcludex works so efficiently, that the bile acids are between 50 and 100 micromolar all the time, sometimes even higher after meals.

A combo with ifn is not going to increase the entry blocking effect, except of course that the further drop in produced virions will reduce the amount of visions seeking entry, but those will still be plenty enough. IFN will have another effect, however also limited, it will lead to destruction of a good percentage of virions whose core has entered the cytoplasm and prevent establishment of cccDNA in these cells, reducing the overall infection rate. But again, it will not be enough.
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Avatar_m_tn
can i stop both drugs and take them again only the day for the test of bile acids 2 hrs after?

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Avatar_m_tn
if you have a regular meal with some fat or oil or egg in it, then the bile will flow. This will secrete between 5 to 10 grams of bile acids into your jejunum, which will be reabsorbed almost completely in your ileum in one to two hours.
Blood and extracellular space will hold only about 0.5grams at 50micromolar of bile acids. All that means, that if NTCP is blocked efficiently, the bile acids will rise strongly after 2 hours post cenam. If you take the drugs at the same time as the food,  a clear increase in bile acids should occur if the test is done 2 or 3 hours later. It should increase to 20 or even 50 micromolar, if an effective blockage of NTCP is present.

If you stop the drugs now, it might be advisable to take them also one day before the test.

I would like to mention, that there is a second paper on finding substances that can block NTCP, where a database of a million compounds was screened and a few were found that were more efficient than irbesartan. But the efficiency was only moderately higher and those were esoteric chemicals far from any clinical or medical use. Thus the hope, that small moleule drugs can be found that will effectively block HBV entry and that could replace myrcludex seem to have little chance at this time.
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I receive this information from hepatara site that they have clear the 1a study and myrcludex b is in Phase II clinical trials. so is any one has idea about outcome of phase I clinical study results


Product: Myrcludex B, a peptide inhibiting the penetration of virus into the liver cells.

Therapeutic focus: Chronic viral hepatitis B (HBV); chronic hepatitis D (HDV). In the future, indications for use can be expanded: viral encephalitis and other forms of hepatitis, HIV.

Status: Phase II clinical trials.

Partner: MYR, GmbH (Germany)

Description: Myrcludex B is a novel drug candidate, being a linear 47-amino acid chemically synthesized peptide. So far it is the single representative of a novel class of anti-HBV molecules, called entry inhibitors. The postulated mechanism of antiviral action is the highly specific and highly stable binding to HBV receptors on the surface of hepatocytes, which misdirects HBV to an unproductive pathway and thereby prevents an infection of the cell. This unique mechanism of action offers the possibility to address the two most important medical needs, namely long-term HBV eradication as well as antiviral activity against hepatitis D virus (HDV).

Despite the availability of appropriate drugs, there is still a number of unresolved medical problems concerning the treatment of hepatitis B, namely, how to achieve long-term eradication of the virus and how to prevent drug resistance. In view of the above it is essential to develop new therapies aimed at the still untouched stages of viral replication, such as the stage of the virus into hepatocytes.
In addition a similar mechanism of action provides the opportunity to prevent the development of delta hepatitis (hepatitis D).

In a series of preclinical studies Myrcludex B showed good safety and the ability to completely block the development of infection HBV. Phase Ia clinical trial showed the safety and good toleration of Myrcludex B in humans.
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Avatar_m_tn
can this  irbesartan be taken with nucs, can we expect hbsag reduction with high base level, its possibility with interferon, its optimized doseing and possible side effects if any idea? may anybody summarise  this whole disscussion.
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i tried it with etv plus tdf plus ezetimibe plus ibersatan, it simply did not work, there has been no blocking on hepatocytes hbv receptors at least not enough to rise bile acids (which are a clear sign of potent hinibition of hbv receptors)
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Avatar_m_tn
Makes sense irbesartan helps against HBV. It is an ARB, and angiotensin 2 was found increased in hbv patients: http://www.ncbi.nlm.nih.gov/pubmed/1748416 ...too bad that members who already tried did not saw it working, maybe the concentration was not enough for the liver, who knows

But, maybe more important, irbesartan is a VDR agonist, meaning in the right concentration is able to activate the VDR by displacing all that stuff that blocks VDR (25d, bacteria, viruses, etc)...once the VDR is active, the cells can cure themselves
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Avatar_m_tn
we need some members to test it for 1 year at least but that is not easy and test it while on pegintf.same thing ezetimibe and simvastatin

i am worried about another study that finds irbesartan inactivating cd-8 lymphos, so it is very complex
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