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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....
Thanks for a very informative explanation.
I am a little puzzled by your comment that "the percentage of infected cells does change during the natural history of hbv".I recalled reading that the levels of qHBsAg vary during the various phases of the natural history, the level being lowest during the inactive phase. Obviously the level chnages during the transition from one phase to another. As you have stated the percentage of infected cells "is best reflected by the quant surface antigen", so can we assume the percentages of infected cells also vary during the natural history but relatively stable during the various phases?
It is exciting to see how Mycrludex B will pan out in the trials. Fingers crossed.
I am a little puzzled by your comment that "the percentage of infected cells does change during the natural history of hbv".I recalled reading that the levels of qHBsAg vary during the various phases of the natural history, the level being lowest during the inactive phase. Obviously the level chnages during the transition from one phase to another. As you have stated the percentage of infected cells "is best reflected by the quant surface antigen", so can we assume the percentages of infected cells also vary during the natural history but relatively stable during the various phases?
It is exciting to see how Mycrludex B will pan out in the trials. Fingers crossed.
HDV uses the L protein of HBV for entry and therefore HDV entry should be approximately equally inhibited as HBV.
The "replenishment" of HDV infected cells occurs in two different ways:
1. Reinfection of a cell already infected by HBV, this cell will become a starting point for efficient new HDV virion production.
2. Infection of a cell NOT infected by HDV.
This happens very frequently and a large amount of heppatocytes are infected in this way. These cells CANNOT further spread HDV, but they present the delta antigens epitopes and also activate cd4 helper Tcell responses in the liver upon necrosis, leading to a more severe hepatitis..
Myrcludex will block the spread of hdv and a reduction of HDV viral load can be expected after some time. Hard to say if 3 month are enough to show a clear effect.
The percentage of infected cells does change during the natural history of hbv and during antiviral treatment, it is best reflected by the quant surface antigen, but it is not a fixed factor, since the efficiency of expression figures in this relation.
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. Most of the high VL in untreated patients is not used for reinfection,but is a waste and surplus of the viral system. Once only a few virions are produced under antiviral partial blockage, they all start to count and stick to the liver instead of circulating in the body. Blocking this reinfection becomes critical in this phase to break through this endless simmering and low level propagation/destruction equilibrium.
The spreading by cell division of HBV infected is more important at a high percentage of infected cells than in the setting of a low remnant amount, asssuming equal opportunity to participate in hepatocyte regeneration between uninfected and infected cells. This is quite obvious.
Thus the effect of an entry blocker becomes more pronounced in a low remnant infection level.
You cannot compare the effectiveness of entecavir with that of Myrcludex, since the mchanisms are entirely different They will cooperate however, since the total daily reinfection rate will be the number of virions available to enter times the blocking factor exerted by Myrcludex, eg 001. We do not know this factor yet and it will obviously depend on the dosing.
The "replenishment" of HDV infected cells occurs in two different ways:
1. Reinfection of a cell already infected by HBV, this cell will become a starting point for efficient new HDV virion production.
2. Infection of a cell NOT infected by HDV.
This happens very frequently and a large amount of heppatocytes are infected in this way. These cells CANNOT further spread HDV, but they present the delta antigens epitopes and also activate cd4 helper Tcell responses in the liver upon necrosis, leading to a more severe hepatitis..
Myrcludex will block the spread of hdv and a reduction of HDV viral load can be expected after some time. Hard to say if 3 month are enough to show a clear effect.
The percentage of infected cells does change during the natural history of hbv and during antiviral treatment, it is best reflected by the quant surface antigen, but it is not a fixed factor, since the efficiency of expression figures in this relation.
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. Most of the high VL in untreated patients is not used for reinfection,but is a waste and surplus of the viral system. Once only a few virions are produced under antiviral partial blockage, they all start to count and stick to the liver instead of circulating in the body. Blocking this reinfection becomes critical in this phase to break through this endless simmering and low level propagation/destruction equilibrium.
The spreading by cell division of HBV infected is more important at a high percentage of infected cells than in the setting of a low remnant amount, asssuming equal opportunity to participate in hepatocyte regeneration between uninfected and infected cells. This is quite obvious.
Thus the effect of an entry blocker becomes more pronounced in a low remnant infection level.
You cannot compare the effectiveness of entecavir with that of Myrcludex, since the mchanisms are entirely different They will cooperate however, since the total daily reinfection rate will be the number of virions available to enter times the blocking factor exerted by Myrcludex, eg 001. We do not know this factor yet and it will obviously depend on the dosing.
i ll try to answer some of your questions:
1 hdv uses hbsag so both hbv and hdv are tied together, when there is no more hbsag also hdv is cleared, infact only hbv carriers can be infected by hdv
even those with some hbsag mutants cna t be infected by hdv
i guess they use 3 months time just to see the general trends, there is too much difference from person to person due to different balance virus/ immune system so there would be just a general trend.probably combos of antivirals, interferon and myr will make the most difference is resuts
2 the ratio of infected cells is different person to person according to balance immune system/virus.those with lowest hbsag have lowest number of infected cells
3 4 no antiviral can block reinfection this is why they all fail to cure hbv, if you look at the most useful tests by biopsies you will see little difference in intrahepatic hbvdna, pgrna, cccdna, hbsag stained cells on antivirals
ratios are different from person to person i guess
1 hdv uses hbsag so both hbv and hdv are tied together, when there is no more hbsag also hdv is cleared, infact only hbv carriers can be infected by hdv
even those with some hbsag mutants cna t be infected by hdv
i guess they use 3 months time just to see the general trends, there is too much difference from person to person due to different balance virus/ immune system so there would be just a general trend.probably combos of antivirals, interferon and myr will make the most difference is resuts
2 the ratio of infected cells is different person to person according to balance immune system/virus.those with lowest hbsag have lowest number of infected cells
3 4 no antiviral can block reinfection this is why they all fail to cure hbv, if you look at the most useful tests by biopsies you will see little difference in intrahepatic hbvdna, pgrna, cccdna, hbsag stained cells on antivirals
ratios are different from person to person i guess
thank you for the helpful analysis, and please allow me to ask further questions.
1. Is your above cell replenishment scenarios apply to hdv as well? If so, does it mean myrcludex can be expected to be equally effective on hbv and hdv in 3 months time?
2. From the natural history perspective, how the ratio of infected cells changes over time? Is it always 100% meaning all cells are infected all the time? Or at first 100%, then drop to 50%, drop to 30%, then bounce back to 70%? and so on.
3. What is the percentage of two replenishment mechanism take place? E.g., 50% is from re-infection of non-infected cells, the rest 50% from infected cell division? Given the fact that drugs like entecavir can effectively keep the virus load low, it implies the re-infection of non-infected cells is very important to hbv's life, so same fact should result the myrcludex to be at least same effective as entecavir or more likely to be more effective than it. Is this reason ok?
4. question 2 is under the context of no treatment. If under the treatment of drugs like entecavir, what will ratio of infected cell comparing to non-infected cell change over time?
thank you very very much
from ytdthjznyj's posts, it seems this round of trials only recruit hbv carriers. Just feel strange why not arrange the hdv trial in the same time. Maybe ytdthjznyj have some more information about this?
1. Is your above cell replenishment scenarios apply to hdv as well? If so, does it mean myrcludex can be expected to be equally effective on hbv and hdv in 3 months time?
2. From the natural history perspective, how the ratio of infected cells changes over time? Is it always 100% meaning all cells are infected all the time? Or at first 100%, then drop to 50%, drop to 30%, then bounce back to 70%? and so on.
3. What is the percentage of two replenishment mechanism take place? E.g., 50% is from re-infection of non-infected cells, the rest 50% from infected cell division? Given the fact that drugs like entecavir can effectively keep the virus load low, it implies the re-infection of non-infected cells is very important to hbv's life, so same fact should result the myrcludex to be at least same effective as entecavir or more likely to be more effective than it. Is this reason ok?
4. question 2 is under the context of no treatment. If under the treatment of drugs like entecavir, what will ratio of infected cell comparing to non-infected cell change over time?
thank you very very much
from ytdthjznyj's posts, it seems this round of trials only recruit hbv carriers. Just feel strange why not arrange the hdv trial in the same time. Maybe ytdthjznyj have some more information about this?
Infected cells die in the liver every day and are replenished with de novo infected cells from reinfection or division of infected cells. This is normally in equilibirum, hence no change in cccDNA and surface antigen levels. Myrcludex can block the reinfection, thus under the assumption of a high rate of infected cell elimination the infected pool will start to shrink.
The daily rate of hepatocyte destruction ( or noncytolytic clearance, as an alternative mechanism) will vary strongly from patient to patient. So will the effectiveness of Myrcludex on the speed of pool reduction, for that reason.
The relative poolsize during treatment can be estimated by VL measurements and quant HbSAg determinations. In 3 month they might see a development towards clear reduction in some patients that have a more rapid intrahepatic turnover of infected cells and a total percentage of infected cells that is rather low, since only then Myrcludex can work, since it cannot prevent viral spreading by infected cell division.
Treatment should be monitored and continued until negativity if the initial 3 month show a signal of reduction in a patient. The majority of chronic HBV patients are unlikely to clear within 3 month. Nevertheless the results of such a trial might give enough information to design the next trial towards a more lasting endpoint.
The daily rate of hepatocyte destruction ( or noncytolytic clearance, as an alternative mechanism) will vary strongly from patient to patient. So will the effectiveness of Myrcludex on the speed of pool reduction, for that reason.
The relative poolsize during treatment can be estimated by VL measurements and quant HbSAg determinations. In 3 month they might see a development towards clear reduction in some patients that have a more rapid intrahepatic turnover of infected cells and a total percentage of infected cells that is rather low, since only then Myrcludex can work, since it cannot prevent viral spreading by infected cell division.
Treatment should be monitored and continued until negativity if the initial 3 month show a signal of reduction in a patient. The majority of chronic HBV patients are unlikely to clear within 3 month. Nevertheless the results of such a trial might give enough information to design the next trial towards a more lasting endpoint.
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