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Entry inhibitors show promise as drugs

Entry inhibitors like REP9 AC and Myrcludex-B are promising as they are the only drugs that offer a complete CURE for Hepatitis B compared to immune modulators like Pegasys and Anti-virals like Entecavir... I think more research and concentration should be diverted to release inhibitor drugs as they seem to be promising and appropriate....
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Avatar universal
Hey brother are these allowed/availble
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1 Comments
No they are still imaginations
Avatar universal
It is drug candidate from Arrowhead Research.  It works by RNA interference.  They are planning on filing IND by 2nd quarter next year.  Below is an excellent discussion on how it works and it's possible shortcomings.  

http://www.medhelp.org/posts/Hepatitis-B/Arrowhead-Presents-Data-Showing-99-Target-Knockdown-in-/show/1834213#post_8472641
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Avatar universal
What is Arc-520?
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Here is update for Arc-520. It looks like proceeding on schedule, for clinical trials next year.  

http://www.dailyfinance.com/2012/10/16/arrowhead-research-receives-notice-of-patent-allow/

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Avatar universal
phase 2 where everybody will start getting myrcludex B will be in spring of 2013.

Phase 2 is planned all over Eastern Europe.  O hope Gilead people that follow us on this forum very closely are aware of it and act accordingly with doing better clinical trials of their Imiquimod pills.
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Avatar universal
really good to hear myrcludex is on schedule.
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Avatar universal

the doctors making the trials, you just email them if you are interested in that trial
they require to stay in russia for 6 months and be available for tests weekly if not more often.75% will get myrcludex+stadard of care and 25% will have standard of care+placebo

i d go in russia for 6 months but only if i know i am getting myrcludex 100%, at this time better wait for trials with 100% myrcludex
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Avatar universal
Hi Stef,
"myrcludex is used added to standard care antivirals or peginterferon, also trials that started now in sept use combo"
Where's the source of this info pls?
Cheers mate.
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Avatar universal
Any update on rep 9ac?
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Avatar universal
myrcludex is used added to standard care antivirals or peginterferon, also trials that started now in sept use combo

i dont think myrcludex alone can clear hbv
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Avatar universal
If I start on tenofovir now, and in future would like to switch to myracludex B, is it safe? I don't want to cause unecessary flares due to switching of meds.
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Avatar universal

they are using russia instead of germany because they dont have all the stupid laws that drug makers use to benefit and wait for patents to expire in western countries,

moving to russia it will probably be available next year possibly still on trial so free of charge, as to safety it is safer and less toxic than approved drugs we use now
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Avatar universal
My dr said that myracludex B is still in phase 1 study: meaning still many more years before actual approval. Phase 1 study generally means trying out and see if people can tolerate the drug. Many drugs starts and actually ends with phase 1 study. Phase 2 study usually is dose-finding; meaning trying out different doses and see what is appropriate in terms of benefit and risk. Phase 3 is the proper clinical trial in real patient. each phase can take months to years.

Anyone has latest news abt myracludex B?
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Avatar universal

Hi,,

What is the latest happy news of Myrcludex trial?


Thanks a lot...
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Avatar universal
Is Myrcludex effective for high viral load individuals,antigen positive or Immunotolerant pt? Earlier you mentioned that they are now testing the antigenn negative pt? Is this drug intended for both groups?

thank you for your response
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Avatar universal
"So is it confirmed that they will try other combinations (such as myrcludex + interferon), not just myrcludex alone?"


Unfortunately, there is no exact information for now. I asked this question to director of Hepatera company by mail. She recommended to ask her this info in August. So, we will wait for August ..
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Avatar universal
Sorry again, my arrogant point 1 to 4 was gone for some sentence. This is due to the symbol i use for "t approaches infinity", the website thought it was HTML tag and hid it after posted. Hopefully this time is ok.
-----------
1. The direction of the exp function (up or down). This is determined by the relative strength of infected cell and non-infected cell: k1+k2-k3.

If k1+k2-k3 > 0, meaning generating relatively more infected cell, then percentage will go up; if k1+k2-k3< 0, meaning generating relatively more non-infected cell, then percentage will go down.

2. The life-long treatment percentage goal (the limit, when t approaches +infinity): K2 / (k3-k1-k2). Important when the percentage is going down (k1+k2-k3<0), not important when percentage goes up, because we care only t approaches +infinity.

The minimal is 0 when reinfection is totally blocked (k2=0); when reinfection is not blocked, the life-long treatment will be higher than 0 ,i.e, dynamic equilibrium between virus and immune system.

3. Initial percentage (when t=0): r0 + k2/(k1+k2-k3). This is not a determining factor. No matter how high it is, it could be mitigated by exp fall.

4. Speed of the percentage change: k1+k2-k3 (same as the direction factor). If k1+k2-k3<<0, meaning infected cell growth plus reinfection is much smaller than non-infected cell growth, the percentage should drop pretty quickly.
-------------
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Avatar universal
May I ask one question about myrcludex trial?

According to ytdthjznyj,
"From autumn will be several groups, perhaps, with different methods of treatment. I will inform when there will be any news."

So is it confirmed that they will try other combinations (such as myrcludex + interferon), not just myrcludex alone?
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Avatar universal
Repost for readability, really sorry to spam the post.

Addition for the importance of blocking reinfection:
From further analysis from eq(5) above:

Firstly, the percentage of infected cell over non-infected cell is an exponential function of time. If infected cell is stronger (+ve: division, reinfection, etc), it will go up to infinity (towards 100% infected cell); if non-infected cell is stronger (+ve: division, etc, -ve: reinfection), it will slope down towards the long-term limit determined by the ability of reinfection over the net effect of force combination (division + reinfection + etc).

There’re four places to look at this percentage: k2/(k3-k1-k2) + (r0 + k2/(k1+k2-k3)) e^((k1+k2-k3)t):

1. The direction of the exp function (up or down). This is determined by the relative strength of infected cell and non-infected cell: k1+k2-k3.

If k1+k2-k3 > 0, meaning generating relatively more infected cell, then percentage will go up; if k1+k2-k3+infinity): K2 / (k3-k1-k2).

Important when the percentage is going down (k1+k2-k3+infinity.

The minimal is 0 when reinfection is totally blocked (k2=0); when reinfection is not blocked, the life-long treatment will be higher than 0 ,i.e, dynamic equilibrium between virus and immune system.

3. Initial percentage (when t=0): r0 + k2/(k1+k2-k3). This is not a determining factor. No matter how high it is, it could be mitigated by exp fall (hopefully).

4. Speed of the percentage change: k1+k2-k3 (same as the direction factor).

If k1+k2-k3 << 0, meaning infected cell growth plus reinfection is much smaller than non-infected cell growth, the percentage should drop pretty quickly.

The above model and its cryptic parameter relates to the treatment option:

k1: reduced by Interferon treatment (or other immunity boost treatment);
k2: reduced by Myrcludex (block the reinfection);
k3: not controllable (non-infected cell division and other mechanisms and complexities studyforhope mentioned).

As we see, reinfection is a very important factor in the virus dynamic equilibrium with immune system, which makes myrcludex an irreplaceable treatment option. Luckily we have this option on the horizon.

This truly tally with studyforhope's statement:
"What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage. Finally the ongoing elimination of infected cells will have a net effect and is not endlessly compensated by the reinfection and spreading that goes on merciless every day."

Sorry for the long post, and thanks for all the patience in you to hear me rambling.
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Avatar universal

Addition for the importance of blocking reinfection:
From further analysis from eq(5) above:
Firstly, the percentage of infected cell over non-infected cell is an exponential function of time. If infected cell is stronger (+ve: division, reinfection, etc), it will go up to infinity (towards 100% infected cell); if non-infected cell is stronger (+ve: division, etc, -ve: reinfection), it will slope down towards the long-term limit determined by the ability of reinfection over the net effect of force combination (division + reinfection + etc).
There’re four places to look at this percentage: k2/(k3-k1-k2) + (r0 + k2/(k1+k2-k3)) e^((k1+k2-k3)t):
1. The direction of the exp function (up or down). This is determined by the relative strength of infected cell and non-infected cell: k1+k2-k3.
If k1+k2-k3 > 0, meaning generating relatively more infected cell, then percentage will go up; if k1+k2-k3+infinity): K2 / (k3-k1-k2). Important when the percentage is going down (k1+k2-k3+infinity. The minimal is 0 when reinfection is totally blocked (k2=0); when reinfection is not blocked, the life-long treatment will be higher than 0 ,i.e, dynamic equilibrium between virus and immune system.
3. Initial percentage (when t=0): r0 + k2/(k1+k2-k3). This is not a determining factor. No matter how high it is, it could be mitigated by exp fall.
4. Speed of the percentage change: k1+k2-k3 (same as the direction factor). If k1+k2-k3<<0, meaning infected cell growth plus reinfection is much smaller than non-infected cell growth, the percentage should drop pretty quickly.
The above model and its cryptic parameter relates to the treatment option:
k1: reduced by Interferon treatment (or other immunity boost treatment);
k2: reduced by Myrcludex (block the reinfection);
k3: not controllable (non-infected cell division and other mechanisms and complexities studyforhope mentioned).
As we see, reinfection is a very important factor in the virus dynamic equilibrium with immune system, which makes myrcludex an irreplaceable treatment option. Luckily we have this option on the horizon.
This truly tally with studyforhope's statement:
"What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage. Finally the ongoing elimination of infected cells will have a net effect and is not endlessly compensated by the reinfection and spreading that goes on merciless every day."

Sorry for the long post, and thanks for all the patience in you to see me rambling.
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Avatar universal
thanks for the info,
i searched for colombatto and found one of his article in 2008:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653343/
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Avatar universal
sorry folks, the above equations solution is wrong. And assuming reinfection is proportional to non-infected cell is more correct than constant.

correction:
(1): dx(t) = k1 x(t) + k2 y(t)
(2): dy(t) = k3 y(t) - k2 y(t)
with initial condition:
(1a): x(0) / y(0) = r0 - initial percentage of infected and non-infected cells

solution:
http://www.wolframalpha.com/input/?i=DSolve%5B%7Bx%27%5Bt%5D+%3D%3Dk1*x%5Bt%5D+%2B+k2*y%5Bt%5D%2C+y%27%5Bt%5D+%3D%3Dk3*y%5Bt%5D+-+k2*y%5Bt%5D%7D%2C+%7Bx%5Bt%5D%2C+y%5Bt%5D%7D%2C+t%5D
(3), (4) : x(t), y(t) refer to above link, too long to type here and not main concern.

(5): x(t) / y(t) = (k2 / (k1+k2-k3) + r0) e^((k1+k2-k3) t) - k2 / (k1+k2-k3)
1. if reinfection is high, then the percentage is highly correlated to the balance of two force: replenishment of infected cell and non-infected cell. Assuming k1+k2 is overwhelmingly higher than k3, infected cell replenishment is higher than non-infected cell, then the percentage will always go up, until hit by the ceiling, which is not captured in this model

2. if reinfection is highly efficiently blocked by myrcludex, then k2 -> 0. Then equation (5) becomes
(6): r0 e^((k1 - k3) t)
the initial percentage of infected and non-infected cell becomes less relevant, more important is the net increment between infected cell thru division, and non-infected cell thru division. Whichever is stronger, the percentage will go to that direction.

Therefore, the conclusion might be:
1. blocking reinfection is necessary for clearance.
2. it is not sufficient. In order to clear, number of non-infected cell division needs to be larger than number of infected cells.
According to studyforhope:
"It does not seem that the infection by HBV reduces the capacity of a cell to divide."
, assuming infected cells and non-infected cells are equally capable to divide, then it's important that the infected cell percentage drops below 50%.

according to studyforhope:
"Measurements of cccDNA in liver biopsies in particular in eAg neg patients have shown ratios of infected vs noninfected of well below 50% anywhere from less than 1% to 30% all approximately",
the number of infected cell division should be less than number of non-infected cell division, in eAg neg patients. Blocking reinfection will therefore able to make the final clearance of the virus in this simple dynamics.

I guess, this is probably why they targets eAg neg patient in myrcludex trial.
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Avatar universal

chrissto:
"Under this setting, I have two more questions:
1. existing ratio for infected cell and non-infected cells, what would they normally look like dynamically? Will they ever dropped under 1 (half cells infected) in any phase or under any treatment?

2. what is the relative ability to divide between infected cell and non-infected cell? Are they equally capable or one kind is more capable? If so, any treatment can target on the capability cell division? Possibly means, control the percentage of the infected cells to die. "

Measurements of cccDNA in liver biopsies in particular in eAg neg patients have shown ratios of infected vs noninfected of well below 50% anywhere from less than 1% to 30% all approximately.

It does not seem that the infection by HBV reduces the capacity of a cell to divide. But overall this is a difficult question, siince there also liver stem cells involved in this regeneation process that are speculated to be not infectable by HBV, which would favor the replenishment of cells from uninfected sources and thus limit the capacity of the virus to spread by cell division.

To complicate matters even further it is now known, in particular by work of Bill Mason, that in a long standing HBV infection a sustantial number of hepatocyte clones develop in the chronically infected liver  that are resistant to HBV infection - up to 30% or so.

This is a logical consequence of selection of hepatocytes that are non infectable due to mutations in the hepatocyte genome, so they are  spared from direct epitope mediated immune targeting.

Nevertheless, while this seems to be a good thing, those clones are also often precursors of HCC and represent a dangerous development.
And the remaining infectable hepatocytes are still in such high numbers that the inflammatory damage continues.

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Avatar universal
An additional important reason that makes virions so much more immunostimulatory than surface antigen particles ( they actually suppress macrophage activation and dendritic cell activation) is the presence of the single stranded region in the HBV DNA inwside the virons. Single stranded DNA is a very strong immunostimulant, it combines with the presence of the core to activate a whole cascade of immune reactions as described above.
It needs to be emphasized that not all cytokines are equally effective to induce antiviral mechanisms inside the infected hepatocytes. Interferon gamma, Interleukin18 and Il-12 are the most effective without having an excessive collateral unspecific proinflammatory effect. Their preferential secretion by cytotoxic cd8 posiitive Tcells specific for virus specific epitopes is most likely the basis for the sometimes surprising reduction of virimia and cccDNA seen in some patients with very little ALT elevations.

This is the "good" antiviral immunity that is desirable, but we have not yet found the magic switch to turn this on, possibly because it depends both on the presence of high affinity HBV classI epitopes combined with CTLs that are not tolerized and impaired in their response.

We can speculate, that the powerful results that we see currrently emerging from the TLR7agonist trials are due to a selective direction of the cytokine response profile in the direction of this "effective, good" immunity, with less collateral damage.
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