Entry inhibitors show promise as drugs

[LilHope2010]

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....

[chrissto]

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.

[chrissto]

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.

[chrissto]

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/

[chrissto]

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.

[studyforhope]

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.

[studyforhope]

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.