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Comments requested from studyforhope-Curing HBV
Recently the International Workshop on Anti-viral Drug Resistance was held in Berlin, Germany. The section on HBV concentrated on future therapies. These presentations are very technical, I would appreciate comments from studyforhope.
http://www.informedhorizons.com/resistance2014/presentations.html
Personally I have two specific questions:
1. China is conducting a Phase 2 clinical trial on GLS4, a nucleocapsid inihibitor based on Bayer 41-4109 (HAP). According to the presentations, HBcAg plays an important role in the degradation of cccDNA by Interferon-gamma, at the same time, HAP can destabilize cccDNA mini-chromosome by deforming HBcAg. Hence Interferon-gamma and HAP may be antagonistic to each other. Is that correct?
2. One of the presentations seems to suggest lowering of viral antigen may not be sufficient to cure HBV, hence anti-PD-L1 or similar measures may be required. But I think anti PD-1 or PD-L1 can have dangerous side effects. Is that right?
Many thanks in advance.
http://www.informedhorizons.com/resistance2014/presentations.html
Personally I have two specific questions:
1. China is conducting a Phase 2 clinical trial on GLS4, a nucleocapsid inihibitor based on Bayer 41-4109 (HAP). According to the presentations, HBcAg plays an important role in the degradation of cccDNA by Interferon-gamma, at the same time, HAP can destabilize cccDNA mini-chromosome by deforming HBcAg. Hence Interferon-gamma and HAP may be antagonistic to each other. Is that correct?
2. One of the presentations seems to suggest lowering of viral antigen may not be sufficient to cure HBV, hence anti-PD-L1 or similar measures may be required. But I think anti PD-1 or PD-L1 can have dangerous side effects. Is that right?
Many thanks in advance.
The opposite assumption, that the HAP drug might actually interfere with the IFn gamma activity is also supported by the presentation, in that the core attachment to the epigenetic loaded cccDNA molecule is somehow needed to activate the dismantlement of the cccDNA. Thus a net antagonistic effect is also possible.
There is a contradiction in these effects, that is not easily resolved by looking at the details given, unfortunately.
There is a contradiction in these effects, that is not easily resolved by looking at the details given, unfortunately.
It is interesting to see that a HP drug is now actually been tested in China. Bayer had these drugs for a long long time since the middle 1990s. It was said that development was halted due to toxicity problems.
From the more detailed mechanisms by which the core half or totally assembled particle exerts its effect in the nucleus onto interferon sensitive genes and as an enhancer of cccDNA expression, it makes sense to assume that reducing the ISG suppressive effects, combined with a reduction in cccDNA activity will act synergistically with interferon gamma, when the core structure is inhibited and possibly distorted by HAP drugs.
anti PD-1 or any therapy that aims to reduce the fundamentally important inhibitory effects on T cell activity can quickly escalate into global Tcell activation, an extremely dangerous situation. One has to realize how powerful and destructive Tcells can be and keeping them in control is paramount to prevent runaway destructive effects on organ function.
If such therapies can be tailored to just partially lift that Tcell control remains to be seen. If it is not specific for the Tcells that are needed to fight HBV, but for any Tcell then i cannot imagine that this is feasible.
From the more detailed mechanisms by which the core half or totally assembled particle exerts its effect in the nucleus onto interferon sensitive genes and as an enhancer of cccDNA expression, it makes sense to assume that reducing the ISG suppressive effects, combined with a reduction in cccDNA activity will act synergistically with interferon gamma, when the core structure is inhibited and possibly distorted by HAP drugs.
anti PD-1 or any therapy that aims to reduce the fundamentally important inhibitory effects on T cell activity can quickly escalate into global Tcell activation, an extremely dangerous situation. One has to realize how powerful and destructive Tcells can be and keeping them in control is paramount to prevent runaway destructive effects on organ function.
If such therapies can be tailored to just partially lift that Tcell control remains to be seen. If it is not specific for the Tcells that are needed to fight HBV, but for any Tcell then i cannot imagine that this is feasible.
i add to this, anti pd-L1 treatment is available in private clinics in germany and being used for cancers.
do we have any data on its safety on hbv when hbvdna is undetectable and hbsag less than 1000iu/ml, is it still dangerous for excess immune response in this status?
although dangerous if not properly studied on human trial, i see anti pd-L1 as the fastest hbv cure combined with nucs
do we have any data on its safety on hbv when hbvdna is undetectable and hbsag less than 1000iu/ml, is it still dangerous for excess immune response in this status?
although dangerous if not properly studied on human trial, i see anti pd-L1 as the fastest hbv cure combined with nucs
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