Aa
About GS 7340 ( new Tenofovir )
Link : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1087627/
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The only positive for us about this new Tenofovir is there will be no potential kidney issues.
Gene therapy this is what these companies have to look at if we want to completely kill HBV.. But I think all of us will settle to Anti-HBS+ and live happy and maintain our liver.
Gene therapy this is what these companies have to look at if we want to completely kill HBV.. But I think all of us will settle to Anti-HBS+ and live happy and maintain our liver.
with regards to HIV infection there is technically a cure for it already. Bone marrow transplant they did so far to few patients worked .. http://abcnews.go.com/blogs/health/2012/07/26/two-more-patients-hiv-free-after-bone-marrow-transplants/
This what ALL HIV infected patients must demand from insurance companies and politicians to make this treatment the standard for them.
This what ALL HIV infected patients must demand from insurance companies and politicians to make this treatment the standard for them.
To Study for Hope,
WOW your depth of knowledge reminds of the late great HR, in fact your writing style even reminds of HR...May God rest his sole. My guess is you may have graduated from the same schooling system.
However here is my question. How long do you think you can hold a chronic HBV infection with 150mg of Viread?
WOW your depth of knowledge reminds of the late great HR, in fact your writing style even reminds of HR...May God rest his sole. My guess is you may have graduated from the same schooling system.
However here is my question. How long do you think you can hold a chronic HBV infection with 150mg of Viread?
The stability of the surface antigen loss after stopping the rep9AC medication period is still under investigation. There is no question of a new and additonal strong immune activity after the removal of the decoy/blocking function of the surface antigen for a length of time. It will hopefully lead to a high quality immune control by CTLs in a substantial percentage of patients after the treatment end to achieve permanent suppression of replicating and spreading activity of HBV remnants. Only time can tell.
Do you think this drug ( GS7340) can reduce the HBVcccdna ? It might allow for some increase in dosing so that the liver will see a higher intracellular Tenofovirdiphosphate concentration. Stronger blocking of replication could theoretically translate into a certain degree of lowering of cccDNA, since it is replenished by replication and has some turnover.
But i do not think the chances for a dramatic effect are high at all after reading the above paper.
Do you think this drug ( GS7340) can reduce the HBVcccdna ? It might allow for some increase in dosing so that the liver will see a higher intracellular Tenofovirdiphosphate concentration. Stronger blocking of replication could theoretically translate into a certain degree of lowering of cccDNA, since it is replenished by replication and has some turnover.
But i do not think the chances for a dramatic effect are high at all after reading the above paper.
Recently I read a paper on TB where researchers say our immune system tries to contain the virus but instead of clearing the virus, the immune system " wall off " the virus hence gives them permanent sanctuary & persistence infection.
The researchers use TNF-α inhibitors called etanercept to awaken the sleeping virus. HBV might be the same too
Link : http://www.eatg.org/eatg/Global-HIV-News/TB-Malaria/TB-treatment-paradox-Mouse-studies-show-body-s-own-response-helps-TB-bacteria-survive
The researchers use TNF-α inhibitors called etanercept to awaken the sleeping virus. HBV might be the same too
Link : http://www.eatg.org/eatg/Global-HIV-News/TB-Malaria/TB-treatment-paradox-Mouse-studies-show-body-s-own-response-helps-TB-bacteria-survive
Someone from Gilead just email me they are testing GS 7340 on HBV patients. Do you think this drug can reduce the HBVcccdna ?
Hi studyforhope,
Am i right to conclude from your response that REP9AC suffer from the regrowth/spreading by slow reinfection of remnant virus?
Can you point me to any data to support that assumption?
Cheers.
Am i right to conclude from your response that REP9AC suffer from the regrowth/spreading by slow reinfection of remnant virus?
Can you point me to any data to support that assumption?
Cheers.
That rekindling of the immune system is indeed been tried by Interferon alpha, gamma, by thymic peptides like thymosin alpha ( Zadaxin), Thymus humoral factor gamma 2, numerous failed therapeutic vaccinations and last not least by blocking/removing a key immune decoy Protein particle, the surface antigen particle, with the REP9AC. The TLR7 agonist GS9620 represents another approach, Poly IC (TLR3) has been used in the past and TLR9 activating CPGs were tried.
All these attempts even when initially effective suffer from the regrowth/spreading by slow reinfection of remnant virus, however small, after the cessation of the therapeutic stimulus.
To hold HBV in check after the therapy without outside help , the adaptive Tcell memory response has to be strong and of high quality. The longstanding adaption (eg by epitope mutations) of the virus towards these natural antiviralimmune mechanisms has eliminated many epitopes and made the virus in many cases resistant to the attempts of permanent immune control. Furthermore the small remaining viral burden , while being basically a plus, also holds the problem that the alert signals to the immune control system will become low.
That is where an effective entry inhibitor can and will fundamentally change the therapeutic landscape.
All these attempts even when initially effective suffer from the regrowth/spreading by slow reinfection of remnant virus, however small, after the cessation of the therapeutic stimulus.
To hold HBV in check after the therapy without outside help , the adaptive Tcell memory response has to be strong and of high quality. The longstanding adaption (eg by epitope mutations) of the virus towards these natural antiviralimmune mechanisms has eliminated many epitopes and made the virus in many cases resistant to the attempts of permanent immune control. Furthermore the small remaining viral burden , while being basically a plus, also holds the problem that the alert signals to the immune control system will become low.
That is where an effective entry inhibitor can and will fundamentally change the therapeutic landscape.
Many thanks for the explanation.
In a recent paper by Locarnini published in GUT, it was stated:
"Although the cccDNA pool appears to be very stable in the absence of cell division, accumulating evidence indicates that hepatocyte proliferation can induce drastic reduction of the intrahepatic cccDNA loads in vivo. Since the cccDNA lacks centromere structures ensuring correct migration during mitosis, immune-mediated cell death and compensatory hepatocyte regeneration may facilitate cccDNA loss."
The paper also stated: "In contrast (to NA therapy), immune-based therapies do reduce transcription and viral protein levels through non-cytolytic and cytolytic mechanisms, as part of their broader antiviral activity.". It went on to say:
"CD8 T cells also have a non-cytolytic effect through the production of IFNgamma and tumor necrosis factor alpha (TNFalpha) (also produced by NK and NKT cells), which are known to elicit antiviral effects via multiple mechanisms."
So, it seems to me, short of discovery of potent molecules that can directly attack cccDNA, we must re-kindle the immune system to control and eventually clear the virus.But how?
In a recent paper by Locarnini published in GUT, it was stated:
"Although the cccDNA pool appears to be very stable in the absence of cell division, accumulating evidence indicates that hepatocyte proliferation can induce drastic reduction of the intrahepatic cccDNA loads in vivo. Since the cccDNA lacks centromere structures ensuring correct migration during mitosis, immune-mediated cell death and compensatory hepatocyte regeneration may facilitate cccDNA loss."
The paper also stated: "In contrast (to NA therapy), immune-based therapies do reduce transcription and viral protein levels through non-cytolytic and cytolytic mechanisms, as part of their broader antiviral activity.". It went on to say:
"CD8 T cells also have a non-cytolytic effect through the production of IFNgamma and tumor necrosis factor alpha (TNFalpha) (also produced by NK and NKT cells), which are known to elicit antiviral effects via multiple mechanisms."
So, it seems to me, short of discovery of potent molecules that can directly attack cccDNA, we must re-kindle the immune system to control and eventually clear the virus.But how?
Even with the co-administration of an entry blocker,this will only ensure the pool of cccDNA is not increased. Since cccDNA is lost only when an infected liver cell divides, mathematical modeling predicts the pool will only diminish significantly after decades. However it has been reported that patients sometimes experienced a flare after stopping antivirals after years of undetectable viral load, then cleared the virus. Also, Interferon is supposed to affect the transcription of cccDNA, leading to a reduction in production of HBsAg. With no new potent antiviral being developed, it is hard to see a cure can come from.
A fascinating paper for the scientifically inclined. The problematic aspect of the results from the aspect of use against HBV is that the selective presence/final concentration in liver tissue is only showing a small (1.4) factor over TDF, whereas the lymph tissue and others , like the lung, show about a 15 fold enhanced intracellular presence of the final effective drug.
Thus it seems to be very promising to further and stronger inhibit HIV in lymphatic tissue, but not in the liver where it would be needed to increase the replication suppression of the Hepatitis B virus.
It should be noted in this context that the main reason that the antivirals do not ""cure" HBV is that there is still a remnant replication at low levels ongoing, with a slow but constant spread of resulting virions to uninfected cells. Thus the total level of cccDNA is decreased but not enough and this is reflected by the ongoing transcription/production of surface antigen from this remaining cccDNA. An even more potent antiviral would help to improve this, but from this paper it does not look like GS9340 will be able to achieve this for HBV.
An entry blocker that deals with the blockage of entry and reinfection of secreted virions will however be an ideal partner for a replication inhibitor, with true and full synergism.
Thus it seems to be very promising to further and stronger inhibit HIV in lymphatic tissue, but not in the liver where it would be needed to increase the replication suppression of the Hepatitis B virus.
It should be noted in this context that the main reason that the antivirals do not ""cure" HBV is that there is still a remnant replication at low levels ongoing, with a slow but constant spread of resulting virions to uninfected cells. Thus the total level of cccDNA is decreased but not enough and this is reflected by the ongoing transcription/production of surface antigen from this remaining cccDNA. An even more potent antiviral would help to improve this, but from this paper it does not look like GS9340 will be able to achieve this for HBV.
An entry blocker that deals with the blockage of entry and reinfection of secreted virions will however be an ideal partner for a replication inhibitor, with true and full synergism.
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Loss of cccDNA is not achieved when a liver cell divides, since normally there are more than one copy of cccDNA present in the nucleus which then distribute to the daughter cells. Why do you think division leads to cccDNA loss? One could argue that after several divisons the cccDNA copies are thinning/diluting out, but as you know their numbers are replenished intracellularly directly by a side pathway from maturing cores, somehow maintaining a low but constant number of copies per cell, different between avian and human HBV.
Loss of cccDNA is the result of cell death, ideally selectively by induced apoptosis or lysis by cognate HBV proteins epitope CTLs (cd8 Tcells) patroling the liver, or by cell death for other reasons, like metabolic stress.
cccDNA can also be lost from a hepatocyte under the strong influence of high local cytokine concentrations that activate InterferonResponse Genes, that will in turn selectively und noncytopathically eliminate/lyse the cccDNA.
If you can block de novo infections of hepatocytes by an entry inhibitor completly, then the ongoing slow elimination will tend to reduce the remaining cccDNA cells, by the mechanisms mentioned above, all quite related to the remaining vigilance of the immune system.
If that immune activity is of a low efficiency, then stopping a replication inhibitor can, even after years, lead to a respread of infected cells, causing a new flare. This cannot happen as long as the entry inhibitor is in place, or the antiviral ( if it is potent enough).
Yes, Interferon is also reducing the transcriptional activity of the cccDNA template for all the viral proteins, thus it will lead to an apparent reduction in the surface antigen level that DOES NOT just reflect the cccDNA level, which can be misleading.