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Replicor presents amazing interim results on AASLD 2017
Replicor recently presented interim results on their on-going rep401 study that is assessing efficacy of rep2139 and rep2169 in achieving functional cures. Amazingly, 8/10 patients in the rep2139 subgroup achieved hbsag loss on treatment which has persisted after end of treatment for over a year and continues to persist. It seems like these patients are indeed functionally cured and given that this drug has a success rate of 80%, it's a breakthrough! You can access the AASLD poster showcasing these results from the following link.
http://replicor.com/science/conference-presentations/
How excited does it make you guys?
http://replicor.com/science/conference-presentations/
How excited does it make you guys?
http://replicor.com/replicor-inrs-institut-armand-frappier-collaborate-identify-mechanisms-subviral-particle-assembly/
That makes me very excited Bravesoul. Thank you for posting it.
A few things I noticed:
• This was tested on people with a viral load of at least "HBV DNA > 10000 copies / ml at screening"
(https://clinicaltrials.gov/ct2/show/NCT02565719)
• This was tested on people who had fibrosis, but not cirrhosis (from the same page)
• Just taking a cursory glance at the pdf, it seems that the people with high hbsag developed much higher anti-HBs at FW4 (you can worry less about your mildly high hbsag now ;)
• It seems to need months upon months of interferon treatment and to be pre-treated with antivirals etc and then it takes quite awhile to get a response after starting with REP 2139. Not that I wouldn't jump at this at a heartbeat if I could get it, but due to the fact that some of these drugs have to be given intravenously etc it could be awhile before treatment starts becoming available. I imagine they'll do everything they can to get it into a pill.
Aside from that, due to the fact that they tested this on people with advanced disease (high hbv dna, with fibrosis, etc) it will be extremely interesting to see what the results look like of typical hbv carriers like most of us. Obviously I'm hoping it'll be faster for us.
A few things I noticed:
• This was tested on people with a viral load of at least "HBV DNA > 10000 copies / ml at screening"
(https://clinicaltrials.gov/ct2/show/NCT02565719)
• This was tested on people who had fibrosis, but not cirrhosis (from the same page)
• Just taking a cursory glance at the pdf, it seems that the people with high hbsag developed much higher anti-HBs at FW4 (you can worry less about your mildly high hbsag now ;)
• It seems to need months upon months of interferon treatment and to be pre-treated with antivirals etc and then it takes quite awhile to get a response after starting with REP 2139. Not that I wouldn't jump at this at a heartbeat if I could get it, but due to the fact that some of these drugs have to be given intravenously etc it could be awhile before treatment starts becoming available. I imagine they'll do everything they can to get it into a pill.
Aside from that, due to the fact that they tested this on people with advanced disease (high hbv dna, with fibrosis, etc) it will be extremely interesting to see what the results look like of typical hbv carriers like most of us. Obviously I'm hoping it'll be faster for us.
Thanks for posting yet another encouraging news from Replicor in the race towards the development of a hbv cure. From my little knowledge, the presence of hbsag is the biggest hindrance for chronic hepB patients that prevents proper functioning of their immune system. Let's say these patients achieve sustained clearance of hbsag as indicated in these trials; I'm curious what would happen if they are given a hbv vaccination. Would their immune system be able to mount a response, so that they develop anti-hbs?
8 Comments
They all have anti HBs at the end of treatment, we few exceptions. The problem is to hold that antibody level in the positive range, it goes downhill with time and can recovert to hbsag positiv. Then the protection against viral respreading in the liver is lost. I recommend to go to the actual poster presentation and look at the data.it is two clicks away at the replicor website.
I don't agree with what you've been saying all along studyforhope. The reason is that even if the integrated hbsag producers (cccdna) do act as a viral reservoir, if you have anti HBs then it will (almost) never overtake the anti HBs so it will remain resolved.
The reason for this is because the only reason the disease can become chronic in the first place in due to pd-1 signal produced by hepatic macrophages anyway, and that signal will not be produced or relevant if there is sufficient anti HBs present for an immune response.
The reason for this is because the only reason the disease can become chronic in the first place in due to pd-1 signal produced by hepatic macrophages anyway, and that signal will not be produced or relevant if there is sufficient anti HBs present for an immune response.
landloper pls be specific with what it is that you do not agree with.
You write "even if the integrated hbsag producers (cccdna) do act as a viral reservoir,..."
The integrated hbsag sequences are NOT cccDNA. They act to produce hbsag, not virions. cccDNA is NOT integrated, but resides as an extrachromosomal "minichromosome" in the nucleus.
If the production of hbsag, regardless the source, increases after end of therapy again it will reduce the amount of free anti hbsag antibody that is capable of complexing newly produced virions. There is no magic way the antibody can stop that. You also need to know how relatively little hbsag is needed to neutralize away even a very high antibody level.
Trials have been done in which extremely high external antibody amounts were injected into patients, even in patients with very low hbsag levels the antibody did not stay more than one day on the pos side, thus nothing was achieved and the full hbsag level jumped back to full pretreatment values in a few days.
You write "even if the integrated hbsag producers (cccdna) do act as a viral reservoir,..."
The integrated hbsag sequences are NOT cccDNA. They act to produce hbsag, not virions. cccDNA is NOT integrated, but resides as an extrachromosomal "minichromosome" in the nucleus.
If the production of hbsag, regardless the source, increases after end of therapy again it will reduce the amount of free anti hbsag antibody that is capable of complexing newly produced virions. There is no magic way the antibody can stop that. You also need to know how relatively little hbsag is needed to neutralize away even a very high antibody level.
Trials have been done in which extremely high external antibody amounts were injected into patients, even in patients with very low hbsag levels the antibody did not stay more than one day on the pos side, thus nothing was achieved and the full hbsag level jumped back to full pretreatment values in a few days.
Right, but if anti HBs was present and then hbsag increased, then anti HBs would increase somewhat exponentially in the absence of the pd-1 signal which is normally the thing that stops the proper immune response from taking place. That's why pd-1 inhibitors such as nivolumab can also cure chronic hbv.
To put the way I see it differently:
I think that the main problem is pd-1/pd-l1 which is upregulated by the hepatic macrophages: https://www.ncbi.nlm.nih.gov/pubmed/27156385
I think that after this course and after being functionally cured of chronic hepatitis b for 6 months that the hepatic macrophages will stop upregulating pd-1.
I think that then even if hbsag does increase that the appropriate immune response will take place due to the fact that it will no longer be inhibited by the pd-1. So the patient will be cured in a similar way to someone who had hepatitis b acutely. Of course there will still be some infected cells in the liver, but I don't think that the person will ever become reinfected by the disease in the vast majority of cases.
I think that the main problem is pd-1/pd-l1 which is upregulated by the hepatic macrophages: https://www.ncbi.nlm.nih.gov/pubmed/27156385
I think that after this course and after being functionally cured of chronic hepatitis b for 6 months that the hepatic macrophages will stop upregulating pd-1.
I think that then even if hbsag does increase that the appropriate immune response will take place due to the fact that it will no longer be inhibited by the pd-1. So the patient will be cured in a similar way to someone who had hepatitis b acutely. Of course there will still be some infected cells in the liver, but I don't think that the person will ever become reinfected by the disease in the vast majority of cases.
I do think that the immunosupression stems from release of pd-1 by macrophages which results in a failure of triggering proper helper and killer T-cell responses. And thus theoretically, removal of pd-1 should generate an effective T-cell responses against viral remnants. However, studyforpoint makes an interesting point. He mentions that during a chronic infection, viral epitopes could undergo mutations so that the now "active" tcells are rendered ineffective against them. Studyforhope believes that most cells harbouring integrated HBV DNA and cccdna are eliminated by peginterferon induced necroptosis, an effect that is amplified by use of NAPs. And that tcells have little potential to take care of the mutated infection even if they escape immunosuppression. If that really is the case, I don't understand why scientists wouldn't be able to figure that out and pursue an approach that is likely to fail i.e reawaken T-cells. Even though studyforhope's hypothesis is reasonable, it may not be really what's happening so we can only wait for research and clinical trials to provide us definite answers to all these mysteries.
It would obviously be quite interesting to see the results of a nivolumab trial in chronic hepatitis b. Due to the intense side effect profile this drug has to my knowledge only been used in the treatment of liver cancer caused also by HCV and hbv.
To assume that pd1 inhibition of tcell activation will vanish once the hbsag is close to zero is optimistic but it is a possibility to keep in mind. Replicors trials thus far give us a mixed picture re the stability of the hbsag seroconversion once a pos antibody is achieved. In the second Bangladesh trial , using e antigen pos patients (which have a lower rate of immunadaptive mutstions) after the use of peginterferon or thymosin alpha in combo with the naps, out of 12 patients with intention to treat after two years only two were still seroconverted. However the treatment periods were much shorter than in the current 401 trial, thus a more profound effect could hopefully take place in this extended regimen. That's why the follow up results of this trial are so nail-biting interesting but we will have to wait up to two years to really know the answer re which percentage will truly stabilize.
the question to follow now is how low will the antibody levels fall at longer times after EOT, the current trend is clearly downwards, but a stabilization at some effective level can still be hoped for.
Re the immunadaptive mutations, I have seen the clonal sequencing results of a long standing hbv infection.
while the surface antigen gene was literally untouched, the core region was peppered with mutations all clustered in the tcell epitopes. This fits well with the theory that viral genomes with effective tcell epitopes are targeted and eliminated by the ongoing tcell attacks, leaving a population with low vulnerability to tcell targeting behind.
The surface gene was untouched because the large amount of circulating hbsag will tolerize Tcells aimed at hbsag tcell epitopes. Thus no attack and no resistance selection.
This might improve dramatically once the surface antigen is removed for a substantial period of time and then new Tcells or detolerized might become active against the fully intact hbsag epitopes. This might be sufficient in many patients to stabilize the hbsag seroconversion.
To assume that pd1 inhibition of tcell activation will vanish once the hbsag is close to zero is optimistic but it is a possibility to keep in mind. Replicors trials thus far give us a mixed picture re the stability of the hbsag seroconversion once a pos antibody is achieved. In the second Bangladesh trial , using e antigen pos patients (which have a lower rate of immunadaptive mutstions) after the use of peginterferon or thymosin alpha in combo with the naps, out of 12 patients with intention to treat after two years only two were still seroconverted. However the treatment periods were much shorter than in the current 401 trial, thus a more profound effect could hopefully take place in this extended regimen. That's why the follow up results of this trial are so nail-biting interesting but we will have to wait up to two years to really know the answer re which percentage will truly stabilize.
the question to follow now is how low will the antibody levels fall at longer times after EOT, the current trend is clearly downwards, but a stabilization at some effective level can still be hoped for.
Re the immunadaptive mutations, I have seen the clonal sequencing results of a long standing hbv infection.
while the surface antigen gene was literally untouched, the core region was peppered with mutations all clustered in the tcell epitopes. This fits well with the theory that viral genomes with effective tcell epitopes are targeted and eliminated by the ongoing tcell attacks, leaving a population with low vulnerability to tcell targeting behind.
The surface gene was untouched because the large amount of circulating hbsag will tolerize Tcells aimed at hbsag tcell epitopes. Thus no attack and no resistance selection.
This might improve dramatically once the surface antigen is removed for a substantial period of time and then new Tcells or detolerized might become active against the fully intact hbsag epitopes. This might be sufficient in many patients to stabilize the hbsag seroconversion.
Indeed it's a wait and see scenario. It might be said that you're more bearish on the outcome while I'm more bullish.
A small dose of nivolumab *has* been tested on chronic hepatitis b patients, and it was helpful (and in one case cured the patient): http://www.medhelp.org/posts/Hepatitis-B/Nivolumab-lowers-hbsag-and-cures-chronic-hepatitis-b/show/2973527
I also saw another case whereby a man in hong kong was treated for nivolumab for skin cancer or something, but he also coincidentally had chronic hepatitis b, and the nivolumab cured his chronic hepatitis b. I can find that report again if it interests you.
A small dose of nivolumab *has* been tested on chronic hepatitis b patients, and it was helpful (and in one case cured the patient): http://www.medhelp.org/posts/Hepatitis-B/Nivolumab-lowers-hbsag-and-cures-chronic-hepatitis-b/show/2973527
I also saw another case whereby a man in hong kong was treated for nivolumab for skin cancer or something, but he also coincidentally had chronic hepatitis b, and the nivolumab cured his chronic hepatitis b. I can find that report again if it interests you.
The results look really good and fascinating thus far. But the follow up data are available only for 4 patients at the 24 week mark after end of therapy. Not over a year as you write. The long term stability of the hbsag seroconversion is indeed the key question now, but one or even two years have to pass before the final stability can be certain.
6 Comments
Sorry, I miscalculated. 24 weeks would indeed amount to less than a year, 6 months to be precise. Nevertheless, the results are pretty good. I strongly predict this 'functional control' would persist for a year and beyond similar to how all patients in the rep301 study who achieved functional control maintained it for a year and beyond.
@studyforhope The kind of end point treatment with replicor achieves is basically the same as an individual with a resolved acute infection. You'll observe all patients who achieved this 'functional control' have undetectable HbsAg and viral load. Why then could these guys experience a potential viral activation following treatment? Wouldn't it be highly unlikely?
@studyforhope The kind of end point treatment with replicor achieves is basically the same as an individual with a resolved acute infection. You'll observe all patients who achieved this 'functional control' have undetectable HbsAg and viral load. Why then could these guys experience a potential viral activation following treatment? Wouldn't it be highly unlikely?
Unfortunately, the situation after an acute resolved infection and after achieving hbsag neg as a result of this treatment is NOT THE SAME.
"Functional control" is just a catchword, the reality is much more complex.
Most importantly an acute resolved infection is characteristed not just by neg hbsag and very low hbv dna, but also by the presence of a strong and effective t cell response against actually existing, undamaged and nonmutated epitopes present in the viral remnants after the seroconversion. These memory Tcells now control these viral remnants indefinitely , since they are fully susceptible to these Tcells.
The stability of the seroconversion after the therapy induced suppression of hbsag release depends very much on the reawakening of effective tcell control against an immune adapted population of virus remnants, with many of the best epitopes mutated and rendered ineffective.
This understanding of the situation is not very popular, since testing the tcell population and the epitopes in a patient is a tedious research undertaking and the mainstream hepatologists know therefore little to nothing about it.
Thus a "second hand" reserve tcell response would or will have to lend stability to the seroconversion. Each patient will be quite different in that capacity.
Check the antibody levels for each patient after EOT and you will see an ongoing decline. How low will it finally go?
"Functional control" is just a catchword, the reality is much more complex.
Most importantly an acute resolved infection is characteristed not just by neg hbsag and very low hbv dna, but also by the presence of a strong and effective t cell response against actually existing, undamaged and nonmutated epitopes present in the viral remnants after the seroconversion. These memory Tcells now control these viral remnants indefinitely , since they are fully susceptible to these Tcells.
The stability of the seroconversion after the therapy induced suppression of hbsag release depends very much on the reawakening of effective tcell control against an immune adapted population of virus remnants, with many of the best epitopes mutated and rendered ineffective.
This understanding of the situation is not very popular, since testing the tcell population and the epitopes in a patient is a tedious research undertaking and the mainstream hepatologists know therefore little to nothing about it.
Thus a "second hand" reserve tcell response would or will have to lend stability to the seroconversion. Each patient will be quite different in that capacity.
Check the antibody levels for each patient after EOT and you will see an ongoing decline. How low will it finally go?
The rep 301 study is not a good model to predict the further development of the eag neg not coinfected patients after EOT. The simultaneous presence of the hdv virus acted like a strong antiviral against hbv, keeping low viral loads and preventing much mutational adaption in the hbv genome.
What's this thing called 'functional control' (defined as HBSAG less than 1 iu/ml, HBVDNA less than 10 iu/ml)?
I have heard about functional cure. Is it very different?
I have heard about functional cure. Is it very different?
if someone who resolved the chronic hbv infection, either naturally or by anti-viral, would that be the same good condition as someone who resolve acute hbv? during the last visit, my GI dr. told me i can live as normal and healthy as hbv vaccinated person, I am still monitoring every 6 months for almost 3 years now, no longer taking any pill, and my hbsag has been non-reactive, hbv dna undetected, and hbsab is reactive(< 10ui/ml) since hbsag seroconversion.
sorry, typo, my hbsab > 10 ui/ml
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