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本帖最后由 风雨不动 于 2012-4-14 14:56 编辑
The following is from Studyforhope. As I don't know Studyforhope, please accept this is his/her opinion only. Personally, I wish to thank Studyforhope for the valuable discussions.
To Stephen and Stef
1." Antivirals typically reduce the amount of cccDNA, but nor dramatically, at best about 10 times" - This is good news. Is this a recent discovery or well known fact? No antiviral manufacturers seem to state this fact.
This has been frequently reported at the liver meetings since years now, in poster format.The effect is just not very impressive and reflects the fact that the cccDNA concentration in a single liver cell is dynamically maintained/turned over at a very very slow rate and that a tiny part of the genomically synthesized DNA does not enter into the virions but recycles to the cccDNa pool thus less produced - by reverse transcription of the genomic RNA - genomic DNA reduces mildly the cccDNA concentration The decrease in cccDNa is reflected somewhat in the surface antigen concentration, since it is transcribed off the cccDNA, but the decrease typically stops at a new equilibrium, very rarely - up to 6% - it leads to surface antigen to Ab seroconversion.
2. The liver stem cells, do they get infected too by HBV ?
The common thinking is NO, the satellite cells are not infectable, probably due to their lack of expression of the critical surface protein receptor gene.
Finally, how do you see the future of treatment for chronic HBV? New drugs, new types of interferons, therapeutic vaccines, combination treatments?
Therapeutic vaccines have little chance, unless combined with something like replicor, since the antigen flooding prevents any effective immune response to reach the liver. Core epitope vaccines, even particle vaccines, fail, because the core is free of class I epitopes with only one exception the 18 to 27 AA core protein epitope as was used in the classical Cytel vaccine. it failed, because in most chronic carrier of the HLA A2 type, this epitope gets mutated and inactive, so the T cells stimulated/produced by the vaccine target nothing that exists in the virus anymore. This is BTW the only class I epitope that evolution has left in the core protein, against which the virus is normally protected by the e-Antigen flooding, it is also the epitope that is typically responsible for the clearance in acute HBV. It often mutates from one sequence to another when in the eantigen neg carrier an escape mutatnt against its response arises, causing a rise of a new mutant epitope in the high titer virions, followed by a new surge of new cytotoxic Tcells against this mutated epitope, causing severe flares, mostly without final clearance, since now we are looking at a HBV quasispecies at this critical locus.
The surface protein has about 8 class I epitopes of various vigor and affinity, and many more classII epitopes.
Thus core vaccines will produce some class II response of limited effectiveness, leading to temporary increased liver inflammation with a reduction in virion production (reduced viral load) and viral protein expression. But the effect is too unspecific and will rarely lead to clearance and seroconversion. A similar picture applies to the preS type vaccines.
A combination of replicor, Myrcludex and antivirals, with therapeutic vaccines in the surface antigen negative phase to enhance the anti surface response while the surface antigen is still artificially suppressed by replicor, should drive the SVR rate in the 80 to 90% range. Interferon, possibly more tolerable like lambda Interferon, might also help dramatically at this stage, but it apparently gets complicated and who would compose or pay for such a combination therapy?
to Chantou;
Replicor is an entry inhibitor for HCV but has not been tested in humans yet.It is very promising for HBV patients, but the current response SVR rate is only 50% and its currently complicated mode of application and high price for the substance will still pose substantial hurdles for its future development.We all hope it will become available through further improvements in the practicability of its use
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