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Is there any hope for complete instant cure of hepatitis B by medicine.
Is there any hope for complete instant cure of hepatitis B by medicine.
thanks in advance....
thanks in advance....
great news that knocks down even that high amount of hbsag quant. if their drug will finally have the result we hope, maybe we can use it in the imunotolerance phase to. their final updates are revealed at AASLD in november ?
Besides medicine you taking. What good vitamins or suplements u take. Coz my doctor told me no more cure just balance diet and libe normaly take vitamins normal too. Its only in my blood but my liver is well.
Hope theres a miracle to cure us.
Hope theres a miracle to cure us.
I have sincesought clarification from REPLICor regarding its definition of SVR, it does include HBsAg < 1iu/ml. It was also pointed out that some of their patients had very high initial qHBsAg, some as high as 150,000 IU/ml.
I thank REPLICor for the clarification and looking forward to the results of their new HBV/HDV clinical trial.
I thank REPLICor for the clarification and looking forward to the results of their new HBV/HDV clinical trial.
"It is my understanding, which can be wrong of course, that HBsAg-ve would imply zero serum hbvdna, because the coat of the Dane particles released from infected cells is made up of HBsAg and should be able to be detected"
You have to realize, that the quantity of hbsag contained in the virions is extremely small compared with the true hbsag in the subviral particles. I have once made the calculation, how many hbsag particles are still around when you approach the lower limit of hbsag detection.Still a very high number dont remember of hand. You can safely assume that hbsag contained in low viral loads contributes literally nothing to the hbsag quantity.
"patients with very low level of qHBsAg (and of course still tested HBsAg+ve), invariably their hbvdna is usually also undetectable. Yet these patients have not s-seroconverted, indicating to me that profound and prolonged low level of qHBsAg does not quickly lead to re-establishment of T cell functions that can clear the virus"
Yes the profound suppression of hbsag levels alone does not quickly lead to completely effective controlling T cell functions. The first Replicor trial has taught us that in a painfully clear manner. It is powerful, but even the full suppression is usually not enough to kick in the magic epitope Tcell clone combo. I made hints lately what might truly go on behind the scenes if this indeed happens.
More is apparently needed to give this a realistic chance. That additional driver of Tcell clone development and reserve epitope presentation can come from Thymosin alpha or pg ifn long term treatment in a setting of substantially improved immunity due to the non suppression by the hbsag.
That this can actually work to activate this quite unlikely event is the real wonderful surprise of the second replicor trial. But even there the stimulation needs to be profound and long enough to kick in that perpetual mechanism that i am repeatedly referring to here.
You have to realize, that the quantity of hbsag contained in the virions is extremely small compared with the true hbsag in the subviral particles. I have once made the calculation, how many hbsag particles are still around when you approach the lower limit of hbsag detection.Still a very high number dont remember of hand. You can safely assume that hbsag contained in low viral loads contributes literally nothing to the hbsag quantity.
"patients with very low level of qHBsAg (and of course still tested HBsAg+ve), invariably their hbvdna is usually also undetectable. Yet these patients have not s-seroconverted, indicating to me that profound and prolonged low level of qHBsAg does not quickly lead to re-establishment of T cell functions that can clear the virus"
Yes the profound suppression of hbsag levels alone does not quickly lead to completely effective controlling T cell functions. The first Replicor trial has taught us that in a painfully clear manner. It is powerful, but even the full suppression is usually not enough to kick in the magic epitope Tcell clone combo. I made hints lately what might truly go on behind the scenes if this indeed happens.
More is apparently needed to give this a realistic chance. That additional driver of Tcell clone development and reserve epitope presentation can come from Thymosin alpha or pg ifn long term treatment in a setting of substantially improved immunity due to the non suppression by the hbsag.
That this can actually work to activate this quite unlikely event is the real wonderful surprise of the second replicor trial. But even there the stimulation needs to be profound and long enough to kick in that perpetual mechanism that i am repeatedly referring to here.
When I was first asked about the meaning of SVR by another member of the forum, I was equivocal, implying it could include HBsAg-ve. However, I am not so sure based on the followings:
.1. I quote from REPLICor: "Despite the complete removal of HBsAg and HBeAg for several months, only 25% of patients achieved SVR off treatment (HBV DNA < 20 copies / ml).".
2. It is my understanding, which can be wrong of course, that HBsAg-ve would imply zero serum hbvdna, because the coat of the Dane particles released from infected cells is made up of HBsAg and should be able to be detected. In the case occult HBV, HBsAg was not detected but hbvdna was
detected is explained by the fact that the S-gene has mutated and was not detected by the usual antibodies.
3. Time to time, we read patients with very low level of qHBsAg (and of course still tested HBsAg+ve), invariably their hbvdna is usually also undetectable. Yet these patients have not s-seroconverted, indicating to me that profound and prolonged low level of qHBsAg does not quickly lead to re-establishment of T cell functions that can clear the virus.
All of these can be easily cleared with more detailed reporting from REPLICor.
.1. I quote from REPLICor: "Despite the complete removal of HBsAg and HBeAg for several months, only 25% of patients achieved SVR off treatment (HBV DNA < 20 copies / ml).".
2. It is my understanding, which can be wrong of course, that HBsAg-ve would imply zero serum hbvdna, because the coat of the Dane particles released from infected cells is made up of HBsAg and should be able to be detected. In the case occult HBV, HBsAg was not detected but hbvdna was
detected is explained by the fact that the S-gene has mutated and was not detected by the usual antibodies.
3. Time to time, we read patients with very low level of qHBsAg (and of course still tested HBsAg+ve), invariably their hbvdna is usually also undetectable. Yet these patients have not s-seroconverted, indicating to me that profound and prolonged low level of qHBsAg does not quickly lead to re-establishment of T cell functions that can clear the virus.
All of these can be easily cleared with more detailed reporting from REPLICor.
When replicor uses the term "SVR" they mean negativity of hbsag together with very low DNA. The Term svr is commonly used in HCV treatment.
What matters is the stability of this state, which is in the end dependent if the internal maintenance TCell surveillance has kicked in, as I have frequently outlined.
Thus the length of time since end of treatment matters here. Will those svrs hold permanently? 6 month is good, but a year is much better to judge an svr.
Hopefully it will soon be known how stable these post immuno enhancement svrs are.
If the hbsag returns, it means the infection is spreading again.most likely the DNA will also increase.
Sometimes a state of low hbsag and DNA seems to be stably maintained also.In these cases an equilibrium has been reached with a relatively higher HBV remnant presence.
One has to realize that even in the hbsag and DNA neg phase there is a large variety of states in terms of cccDNA remnants, integrated full length HBV genomes in transcriptionally silent or active genome Regions, and Integration of HBV Partial genome fragments, causing eg hbsag production without cccDNA or virion synthesis.
While clearly all existing, it is not possible to determine in an individual patient how all these forms of HBV remnants are present.
And even integration events count massively different, if they for example inactivated a cancer protective gene or are just sitting in a silent irrelevant area.
Also full,length integrations in transcriptionally active genome segments cause the unpleasant consequence that this cell cannot be noncytopathically purged by gamma ifn or tnfalpha from cccDNA, the only way to eliminate it as a source of recurrent infection spreading is to kill it by CTL or NK action, a much much less effective process.
In summary, true svr is generally a good thing, it allows a life without further treatment . HCC risk will remain, but reduced due to a vastly reduced number of hbv carrying cells. How much reduction will depend on numerous invisible factors as explained above. That's why 6 month ultrasound and afp screening must continue after svr.
What matters is the stability of this state, which is in the end dependent if the internal maintenance TCell surveillance has kicked in, as I have frequently outlined.
Thus the length of time since end of treatment matters here. Will those svrs hold permanently? 6 month is good, but a year is much better to judge an svr.
Hopefully it will soon be known how stable these post immuno enhancement svrs are.
If the hbsag returns, it means the infection is spreading again.most likely the DNA will also increase.
Sometimes a state of low hbsag and DNA seems to be stably maintained also.In these cases an equilibrium has been reached with a relatively higher HBV remnant presence.
One has to realize that even in the hbsag and DNA neg phase there is a large variety of states in terms of cccDNA remnants, integrated full length HBV genomes in transcriptionally silent or active genome Regions, and Integration of HBV Partial genome fragments, causing eg hbsag production without cccDNA or virion synthesis.
While clearly all existing, it is not possible to determine in an individual patient how all these forms of HBV remnants are present.
And even integration events count massively different, if they for example inactivated a cancer protective gene or are just sitting in a silent irrelevant area.
Also full,length integrations in transcriptionally active genome segments cause the unpleasant consequence that this cell cannot be noncytopathically purged by gamma ifn or tnfalpha from cccDNA, the only way to eliminate it as a source of recurrent infection spreading is to kill it by CTL or NK action, a much much less effective process.
In summary, true svr is generally a good thing, it allows a life without further treatment . HCC risk will remain, but reduced due to a vastly reduced number of hbv carrying cells. How much reduction will depend on numerous invisible factors as explained above. That's why 6 month ultrasound and afp screening must continue after svr.
SVR, sustained viral response, commonly refers to just suppression of viral load.
"...... lead to 89% of patients achieving SVR off treatment." .
if the pacients manage to achieve hbsag -ve SVR, is this helpful ,knowing that cccdna is still there ? can we use that to fasten our cure ?
if the pacients manage to achieve hbsag -ve SVR, is this helpful ,knowing that cccdna is still there ? can we use that to fasten our cure ?
the problem of these new drugs is that they have the wrong target, they target hbsag but not the producer of hbsag which is cccdna
maybe we can get much more from drugs targeting cccdna
maybe we can get much more from drugs targeting cccdna
i understand that hbs seroconversion is a bit hard to achieve, but replicors short term response and aghbs -ve can be only helpful ,having in mind that nucs need 10 years .am i not right ? and having aghbs negative for a long period ,isnt it more easy to try and clear the virus ?
In some way I am very frustrated by the reporting of results from REPLICor. Maybe it is not their faults but my own poor understanding and high expectation. From their first clinical trial with 8 patients, my impression was that profound reduction of serum HBsAg led to s-serconversion with or without development of s-antibodies. The expectation was that this seroconversion was sustained.However, it seems to be the case that it is not and immune boosting is required. I quote:
"The use of two such optimized NAPs (REP 2055 and REP 2139) in human patients are well tolerated and reliably remove circulating HBsAg (up to 5 log reductions) to undetectable levels in patients, resulting in the appearance of anti-HBsAg antibodies, elimination of HBeAg, the appearance of anti-HBeAg antibodies and 3–9 log reductions in viral titers. Despite the complete removal of HBsAg and HBeAg for several months, only 25% of patients achieved SVR off treatment (HBV DNA < 20 copies / ml). Combination therapy with NAPs and immunotherapy was well tolerated and improved the speed of the antiviral response and lead to 89% of patients achieving SVR off treatment."
Even now, we still do not have data regarding whether patients remained HBsAg-ve, instead, we only have a figure of 89% SVR off-treatment. This is still an excellent result, but SVR is far from a "cure".
When ARC520 came along, the hope was high because it seems to provide a delivery method(by injection) that is better than the infusion method used by REP9AC which I thought was the key factor in holding back the progress of REP9AC.
But it is now clear that profound reduction of serum HBsAg over a period of several months is not sufficient to re-establish immune functions that can lead to clearance of the virus. I felt if this is known earlier, then maybe we will not put all our "hope" eggs in the one basket.
Just my vent.
"The use of two such optimized NAPs (REP 2055 and REP 2139) in human patients are well tolerated and reliably remove circulating HBsAg (up to 5 log reductions) to undetectable levels in patients, resulting in the appearance of anti-HBsAg antibodies, elimination of HBeAg, the appearance of anti-HBeAg antibodies and 3–9 log reductions in viral titers. Despite the complete removal of HBsAg and HBeAg for several months, only 25% of patients achieved SVR off treatment (HBV DNA < 20 copies / ml). Combination therapy with NAPs and immunotherapy was well tolerated and improved the speed of the antiviral response and lead to 89% of patients achieving SVR off treatment."
Even now, we still do not have data regarding whether patients remained HBsAg-ve, instead, we only have a figure of 89% SVR off-treatment. This is still an excellent result, but SVR is far from a "cure".
When ARC520 came along, the hope was high because it seems to provide a delivery method(by injection) that is better than the infusion method used by REP9AC which I thought was the key factor in holding back the progress of REP9AC.
But it is now clear that profound reduction of serum HBsAg over a period of several months is not sufficient to re-establish immune functions that can lead to clearance of the virus. I felt if this is known earlier, then maybe we will not put all our "hope" eggs in the one basket.
Just my vent.
The answer to question number 2. 3. And. 4 is well known to experts in this field.
Replicor sent its patient samples to Australia for testing, they were in fact sent by the hospital that conducted the study.
I can furthermore tell you that totally independent testing has clearly confirmed the power of their drug to reduce the hbsag over 5 Logs to undetectable Levels by the usual hbsag quant tests and by most high sensitivity qual tests as well.
That part is out of the question, what remains is to define the best regimen for a combo that will achieve the desired long term treatment free hbsag negativity.
Replicor sent its patient samples to Australia for testing, they were in fact sent by the hospital that conducted the study.
I can furthermore tell you that totally independent testing has clearly confirmed the power of their drug to reduce the hbsag over 5 Logs to undetectable Levels by the usual hbsag quant tests and by most high sensitivity qual tests as well.
That part is out of the question, what remains is to define the best regimen for a combo that will achieve the desired long term treatment free hbsag negativity.
No one knows for sure the answers to your obviously good and very important questions, future studies are needed to get these answers
Arrowheads study was conducted by 3rd party researchers, Replicor facilitated their own study and even acknowledged they need to rerun the earlier results with independent researchers before big pharma will buy in. (They want to sell to big pharma, not take this drug public)
Do you have specific reasons to trust arrowheads data more than replicors?
Are you aware of the magnitude of hbsag reduction that is needed to evoke the liberation of immune activity that is needed to afford the real effect of hbsag reduction?
what is the range of typical hbsags in patients and how wold the level be after one full log reduction?
Is the low hbsag level , say 200 iu that some patients spontaneously have the same as a similar messenger RNA suppressed hbsag level in terms on how the chances for further immune clearance will be ?
Are you aware of the magnitude of hbsag reduction that is needed to evoke the liberation of immune activity that is needed to afford the real effect of hbsag reduction?
what is the range of typical hbsags in patients and how wold the level be after one full log reduction?
Is the low hbsag level , say 200 iu that some patients spontaneously have the same as a similar messenger RNA suppressed hbsag level in terms on how the chances for further immune clearance will be ?
The only RNAI at AASLD is Arrowhead and they were very poor at managing expectations for the first cohorts. On Wednesday Tekmira will release data on their TKM-HBV which is a new entry drug that may deliver knockdown around 2 log
Most outside Replicor are very skeptical of Replicors results
Most outside Replicor are very skeptical of Replicors results
While I don't see the miracle one shot cure anytime soon I think fantasy is a bit too strong. There are some really interesting drug technologies in development that are just scratching the surface of there future effectiveness
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only replicor combined with peg had 80% hbsag clearance