Aa
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....
"But if the percentage of infected cells do not vary much with antiviral treatment, I find it hard to understand why the antivirals are effective to prevent the further progress of the disease.
Essentially, i try to understand the relationship of percentage of infected cell vs the progress of the disease. ."
The percentage of infected cells does reduce during antiviral reatment but only by about 50 to 90% as numerous cccDNA studies on biopsies have shown.
The key question, in light of the above, is therefore why do antivirals prevent, in most cases, a further progression of liver disease, reduce ALT, inflammation and fibrosis?
While this is now an undisputed fact, most hepatologist will not be able give you an answer to this question because their training in immunology is limited and the detailed mechanisms are only partially clarified.
However, the most likely reason for this very critical and beneficial phenomenon is, that it is the amount/number of virions, secreted and often captured in the liver by macrophages and dendritic cells,
MOSTLY BY THE PRESENCE OF INTACT CORES WITHIN THOSE VIRIONS,
that ACTIVATE immune responses, often of a type with low effectiveness, but a higher grade inflammation cytokine profile, that cause the intensity of inflammation in the liver,
Remember that a virus has to be seen by its products, by immune cells. The core protein, mostly intact or partly assembled cores as well that are displayed to the macrophages upon hepatocyte death is highly immunogenic and has several classII T cell epitopes that will stimulate CD4 helper T cells upon contact with macrophages or dendritic cells . These stimulated cd4 Tcells then produce inflammatory cytokine cocktails and also stimulate Bcells, cd8Tcells and NKcells by direct contact (cd40 ligand mediated).
All this increases the severity of ongoing hepatitis B, is only moderately effective in inhibiting cccDNA expression and HBV replication and leads therefore to the battle with no end that we call chronic hepatitis B.
Antivirals strongly reduce the primary stimulus (the secreted virions) to this vicious cycle, thats how they exert their fundamental benefit.
Essentially, i try to understand the relationship of percentage of infected cell vs the progress of the disease. ."
The percentage of infected cells does reduce during antiviral reatment but only by about 50 to 90% as numerous cccDNA studies on biopsies have shown.
The key question, in light of the above, is therefore why do antivirals prevent, in most cases, a further progression of liver disease, reduce ALT, inflammation and fibrosis?
While this is now an undisputed fact, most hepatologist will not be able give you an answer to this question because their training in immunology is limited and the detailed mechanisms are only partially clarified.
However, the most likely reason for this very critical and beneficial phenomenon is, that it is the amount/number of virions, secreted and often captured in the liver by macrophages and dendritic cells,
MOSTLY BY THE PRESENCE OF INTACT CORES WITHIN THOSE VIRIONS,
that ACTIVATE immune responses, often of a type with low effectiveness, but a higher grade inflammation cytokine profile, that cause the intensity of inflammation in the liver,
Remember that a virus has to be seen by its products, by immune cells. The core protein, mostly intact or partly assembled cores as well that are displayed to the macrophages upon hepatocyte death is highly immunogenic and has several classII T cell epitopes that will stimulate CD4 helper T cells upon contact with macrophages or dendritic cells . These stimulated cd4 Tcells then produce inflammatory cytokine cocktails and also stimulate Bcells, cd8Tcells and NKcells by direct contact (cd40 ligand mediated).
All this increases the severity of ongoing hepatitis B, is only moderately effective in inhibiting cccDNA expression and HBV replication and leads therefore to the battle with no end that we call chronic hepatitis B.
Antivirals strongly reduce the primary stimulus (the secreted virions) to this vicious cycle, thats how they exert their fundamental benefit.
my doctor made a study on infection dynamics and complex formulas, dr colombatto, i think you can find it by googling doctor colombatto or doctor brunetto pisa
but i dont think it is possible to cover this by formulas, everything can change in the balance immune system/host plus there are immune escape mutations created during the phases of inefction, i think this is mostly wasted time
2. I've formulated a very simple dynamics about the percentage of infected cells under myrcludex treatment, not sure it's correct or not or useful for the folks, I just throw it out here for the review:
x(t) is the number of infected cell; y(t) is the number of non-infected cells. t is time variable.
I formulated the two equations:
(1) dx(t) = k1 x(t) + k2
(2) dy(t) = k3 y(t) - k2
(1) says two scenario for the "replenishment" of infected cell. The division is proportional to existing number of cells infected; second part is the re-infection, assuming it's constant.
(2) says the non-infected cell only have 1 scenario for replenishment, which is division from non-infected cell, and a negative scenario, when a cell got reinfected.
Solved the equation:
(3) x(t) = (1/2) k1 x(t)^2 + k2 x(t)
(4) y(t) = (1/2) k3 y(t)^2 - k2 y(t)
This seems to be a non-controllable setup, so not much sense to calculate the absolute number.
I calculate the ratio.
(5) x(t) / (x(t) + y(t)) = ( x(t) / y(t) ) * ( (k1 x(t) + 2 k2) / (k3 y(t) - 2 k2) )
So it shows two forces are in place:
1. The existing ratio: the higher infected ratio, the higher infected ratio will be, vice versa.
2. The second part is where treatment comes in, I call it r(t) for short. Without myrcludex, k2 is very high, r(t) is also very high.
with myrcludex, if it makes k2 very low, then r(t) is approximately (k1 x(t)) / (k3 y(t)), equation (5) becomes approximately (k1/k3) * ( x(t) / y(t) )^2.
This is if reinfection is extremely highly blocked. Under this idealistic scenario, the existing ratio still matters a lot, if existing infection ratio is close to 100%, then myrcludex cannot help much. The relative ability to divide between infected cells and non-infected cells is also a factor, this factor should be independent to myrcludex.
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.
Finally, the above result may illustrate studyforhope's this paragraph "What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage."
x(t) is the number of infected cell; y(t) is the number of non-infected cells. t is time variable.
I formulated the two equations:
(1) dx(t) = k1 x(t) + k2
(2) dy(t) = k3 y(t) - k2
(1) says two scenario for the "replenishment" of infected cell. The division is proportional to existing number of cells infected; second part is the re-infection, assuming it's constant.
(2) says the non-infected cell only have 1 scenario for replenishment, which is division from non-infected cell, and a negative scenario, when a cell got reinfected.
Solved the equation:
(3) x(t) = (1/2) k1 x(t)^2 + k2 x(t)
(4) y(t) = (1/2) k3 y(t)^2 - k2 y(t)
This seems to be a non-controllable setup, so not much sense to calculate the absolute number.
I calculate the ratio.
(5) x(t) / (x(t) + y(t)) = ( x(t) / y(t) ) * ( (k1 x(t) + 2 k2) / (k3 y(t) - 2 k2) )
So it shows two forces are in place:
1. The existing ratio: the higher infected ratio, the higher infected ratio will be, vice versa.
2. The second part is where treatment comes in, I call it r(t) for short. Without myrcludex, k2 is very high, r(t) is also very high.
with myrcludex, if it makes k2 very low, then r(t) is approximately (k1 x(t)) / (k3 y(t)), equation (5) becomes approximately (k1/k3) * ( x(t) / y(t) )^2.
This is if reinfection is extremely highly blocked. Under this idealistic scenario, the existing ratio still matters a lot, if existing infection ratio is close to 100%, then myrcludex cannot help much. The relative ability to divide between infected cells and non-infected cells is also a factor, this factor should be independent to myrcludex.
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.
Finally, the above result may illustrate studyforhope's this paragraph "What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage."
Thanks again for the information.
1. I'm a little confused by this paragraph:
"Antivirals DO NOT reduce the infected percentage or the total cccDNA content in the liver to the extent one would expect or hope, since the relative efficiency of reinfection goes way up upon a low viral load".
Not sure if correct, I assume the severity of the disease is related positively to the percentage of the cells infected. More cell infected, more severe and more damage the liver could get. Because non-infected cell would not get damage by itself or by immune system indirectly.
But if the percentage of infected cells do not vary much with antiviral treatment, I find it hard to understand why the antivirals are effective to prevent the further progress of the disease.
Essentially, i try to understand the relationship of percentage of infected cell vs the progress of the disease.
1. I'm a little confused by this paragraph:
"Antivirals DO NOT reduce the infected percentage or the total cccDNA content in the liver to the extent one would expect or hope, since the relative efficiency of reinfection goes way up upon a low viral load".
Not sure if correct, I assume the severity of the disease is related positively to the percentage of the cells infected. More cell infected, more severe and more damage the liver could get. Because non-infected cell would not get damage by itself or by immune system indirectly.
But if the percentage of infected cells do not vary much with antiviral treatment, I find it hard to understand why the antivirals are effective to prevent the further progress of the disease.
Essentially, i try to understand the relationship of percentage of infected cell vs the progress of the disease.
Please accept my sincere apology for wasting your time. I completely agree with your comment that "the percentage of infected cells does change during the natural history of hbv".
For some stupid reasons (my real puzzle :-( ) I thought you said "the percentage DOES NOT change" Mea maxima culpa!
Very best regards.
For some stupid reasons (my real puzzle :-( ) I thought you said "the percentage DOES NOT change" Mea maxima culpa!
Very best regards.
I was responding to Chrisstos question that I understood to question if the infected percentage of hepatocytes changes as a patient goes through the phases of the natural history. In that sense the infected percentage changes to lower once the inactive phase is reached. The term "natural history' was understood as the progression thorugh the various phases in many patients.
Within each "phase" there will of course also be some variations. 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.
Within each "phase" there will of course also be some variations. 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.
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