That’s fascinating on one hand, and frightening on the other.
Even in the unlikely scenario when we figure out a way to get rid of each and every cccDNA - we will continue to express HBsAg.
By pure mathematics it could even be that HBsAg continues to grow with no cccDNA present (i.e. if hepatocytes with integrated HBV DNA undergo mitosis slightly more frequently than healthy hepatocytes)!
Those of us with chronic hepatitis B have an impaired immune system.
When people have a healthy immune system and get infected with HBV (95% of adults infected with HBV can get rid of the virus) - what mechanism clears integrated HBV DNA (what kills hepatocytes with integrated HBV DNA)? NK cells? T cells? Do we even understand a mechanism behind it?
These are great questions and basically you’ve reached the limits of what we know about the virus infection. My lab investigates exactly these aspects and to my knowledge, no-one knows. We do see that people with HBsAg-loss do have a lower amount of integrated HBV DNA than those still with HBsAg, but we don’t understand yet how it comes to be that way.
We also don’t really know how cells with integrated HBV DNA behave compared to uninfected or only cccDNA-containing hepatocytes. This again is another project that we’re carrying out.
What’s the current temperature amongst scientists in reference to Bepirovirsen’s? And feedback on durability for the 30% who had undetectable levels of the HBV? Or any other relevant info
Although bepirovirsen was initially designed to target the destruction of HBV mRNA, we now know that this agent and all other agents with similar mechanistic focus (RNAi) actually achieve HBsAg reduction by stimulating the innate immune response.
In the case of RNAi, this leaves a large proportion of HBsAg (from subviral particles) unaffected in all patients which is why none of these agents can achieve functional cure in the combination regimens achieved to date.
Bepirovirsen acts to stimulate innate immunity but via a different reactivity than RNAi. While HBsAg loss was experienced by some patients, HBsAg rapidly rebounded after removal of treatment and only occurred in the patients with low baseline HBsAg. Additional combination regimens are planned with a therapeutic vaccine but is it unclear how this will alter the outcome.
I read the whole topic, thanks for sharing this knowledge guys!
I think that a good option will be to prepare a page like a google sheet with ongoing / completed programs drugs/treatments and their results. I see in this topic several different links.
We also can use notion.so
What do you think about it?
If you think that there is additional information that would be useful, it might be worth mentioning here and we can get that comment to the Hep B foundation (@chari.cohen)
@ThomasTu I will get acquainted with it.
I have one question at the moment which
categories from this list focus on complete recovery from the virus?
@chari.cohen
I think that we should add timeline from each records (year when notified, first phrases etc - this information will getting us information, which drug developed rapid, which slow and which was suspend).
Hello @Thomas,
I hope you are well. I was looking at the list and I would appreciate if you could share your thoughts regarding the theurapeutic vaccine already in phase II. I undestand that there are a lot of steps but that sounds promising.
Although vaccines work very well to prevent the establishment of chronic HBV infection, to date this approach has failed to have any meaningful antiviral effects in patients who already have chronic HBV infection with any of the vaccines listed in the HBV Drug watch table. There are two reasons for this:
Circulating HBsAg (mostly from non-infectious subviral particles) work to constantly suppress the immune response to HBV.
Because HBV rapidly mutates, there are actually thousands of “quasispecies” of HBV in any one patient who has chronic HBV. At least some of these will always escape the relatively narrow immune response that vaccines can induce.
@availlant thanks for an excellent explanation
for people outside the medicine specialization
I have another question for you:
In the last 20 years, research on the cure for complete recovery hbv made significant progress or do we know a little more about the virus but nothing else on same cure and at the moment there is nothing promising in the near future?
Part of the problem is that the explosion of drug development efforts came soon after the HCV “problem” was essentially resolved in 2012 with the introduction of nucleoside modifications which more effectively targeted NUCs into the liver (sovaldi, harvoni and many others which followed).
In this explosion, drug developers thought that what could be done for HCV by directly and effectively targeting viral replication could also be done for HBV. In this rush to open up new avenues of drug development the field forgot about some important facts which had already been well understood by researchers:
Unlike HCV, HBV has a stable reservoir of genetic material which acts like a minichromosome.
This HBV minichromosome can exist in a condensed, latent and very long lived state (like regular chromosomes) where no antiviral agent can touch them but reactivation can occur to restore viral replication.
Unlike HCV, HBV replication is highly error prone, leading to thousands of “quasispecies” in each person with chronic HBV.
Unlike HCV, infected hepatocytes produce far more non-infectious subviral particles than virus (100,000 to 1) by a pathway distinct from viral replication. In HBV infection, these subviral particles shield infected hepatocytes from host immune control and or clearance. When we talk about circulating HBsAg in the blood and its loss, we are talking about subviral particles. Viral replication is inconsequential here.
HBV DNA can integrate into host chromosomes, providing a permanent reservoir for the production of subviral particles unless these cells are removed from the liver.
So, we have seen since then the failure of every direct acting antiviral agent in development (novel NUCs, capsid assembly modulators, antisense/RNAi and therapeutic vaccines) either because they had no effect on HBV mini chromosomes or the production of subviral particles or an ability to remove hepatocytes with integrated HBV DNA from the liver.
Targeting SVP to restore immune function (by achieving clearance of HBsAg) and re-activating immune function that has been put to sleep by long exposure to HBsAg with immunotherapy are the keys to high rates of functional cure.
These goals are currently being achieved by NAP-based combination therapy in phase II trials.
If these vaccine immune quasispecies are so likely to develop in chronic patients, wouldn’t that mean they can be transmitted to vaccinated people? How can the vaccine claim to be so effective if there are so many variants out there?
It is important to remember the genetically “flexible” nature of HBV infection in my response.
Immune escape quasispecies exist in chronic HBV against a larger backdrop of quasispecies which are still immunoreactive.
Immune escape quasispecies are typically a small fraction of the viral population: This is because their mutations (typically in HBsAg) have the effect of reducing the the secretion of virus.
Even though immunoreactive quasispecies would be recognized in a normal healthy adult, they are also poorly recognized in patients with chronic HBV due to high antigen load (HBsAg) as well as the inactivation / exhaustion and or deletion of species of immunoreactive cells due to chronic HBsAg exposure.
So the viral innoculum which is responsible for the transmission of the virus contains mostly immunoreactive quasispecies and also immune escape (and highly defective) quasispecies.
In a unvaccinated healthy child or adult, most quasispecies initially disappear with the re-emergence of more wildtype-like HBV becuase is has the best replication efficiency and the host immune response has not fully engaged. In patients who develop chronic HBV, a greater diversity of quasispecies will gradually develop again due to immune pressure.
In a vaccinated healthy child or adult, the pre-existing immune response efficiently deals with almost all quasispecies allowing resolution of acute HBV infection.
@availlant thanks for reply!
At the moment all drugs are ineffective, but amount of new testing drugs are bigger or smaller than in previous years?
ps
My doctor told me, that I should forget about drug for HBV beacouse, in west world people have vacine, and small number have HBV, and pharma industry don’t see in this topic money like other topics.
As a researcher in the field for 15 years, I have seen a huge increase in the number of drugs tested compared to when I first started. I think @john.tavis who has been in it for much longer than I have would agree.
To some of the points made above: yes, these drugs have not generated complete cures on their own (or in some cases combinations with other therapies). But they are not failures in that they still work and show suppressive activity against the viral target they are supposed to. They are important to have in our toolbox to give us options in developing combinations in the future (as we have in HCV cure).
In general, I would say that HBV cure is not viewed as important in the Western countries. But, that’s how it is at the moment. I think with all the advocacy work that the Hepatitis B foundation (@chari.cohen), World Hepatitis Alliance (@jessicah), ICE-HBV (@john.tavis) and others have done this is getting more and more prominent. With more voices from the affected community, which we are trying to raise here in Australia as well (@UyenV, @lien.tran, @Nafisa.Yussf), we hope to change this thinking and get pharma, governments, policy makers, etc. to realise the huge issue of Hep B.
I would provide the following counterpoints to Thomas’ comments:
There is a substantial interest in developing drugs for HBV cure as evidenced by multi-billion dollar investments by venture capital in North America and Europe to support small and mid-scale biotech like Arbutus, Enanta, Assembly, Bluejay, Excision Bio, Precision Bio, AiCuris, VBI Vaccines and others and by direct and substantial investment in functional cure by Johnson & Johnson, Glaxo Smith Kline, Roche and Gilead. These investments recognize the value and importance of functional cure not only in Western countries but also in Asian markets, where the need for such medicines in high.
While there have been a lot on new drugs evaluated in the clinic since the explosion of new companies in the space following the successes of direct acting antivirals in the cure of HCV it is important to remember that this does not reflect a diversity of approaches but rather many companies developing the same approaches. The bulk of clinical stage drug development has and continues to be focused on four approaches: capsid assembly modulators, antisense/siRNA, therapeutic vaccines and TLR agonists.
All capsid assembly modulators evaluated to date have been shown to have no better impact on HBV infection than existing NUC therapies and suffer from class-wide drug resistance unlike NUCs such as ETV and TDF. All therapeutic vaccines and TLR-agonists to date have shown no impact on HBV or have been abandoned due toxicity (in some cases severe). Several antisense and RNAi candidates have already been abandoned for lack of activity - those remaining may have a role to play but this is not certain given that the effects of these drugs are not occurring by their intended mechanism.
While it is possible that some of these older approaches may have some role to play, it is clear from the substantial body of phase II data that even in combination these approaches are not likely to have an impact significantly greater than what can be offered by currently available therapies. We look to other novel approaches not yet evaluated in phase II the clinic (FXR agonists, T-cell agonists) to see if they can improve the situation.
Thanks, Andrew. I think there are no real disagreements here in my mind.
Agreed there is substantial interest from industry. I’ve just automatically spoken more from an academic side (given my background) and also from the policy side, where there is less interest (though this is growing).
This I would have thought is due to the point above. My understanding is that academia is where a lot of the novel approaches get discovered and de-risked for industry to take forward. If this is not being funded appropriately, of course we’re going to have a lower number of strategies being translated. Still, having these approaches, appears to be more that I saw being developed than when I started. I admit that I might not have been very perceptive when I was a green scientist though.
and 4. I think this is a valid viewpoint, but it is also one of many in the scientific field. You could also argue that some of these compounds would be helpful in the select patients to tip them towards cure (e.g. with low HBs levels already). I think we can appreciate there are divergent views on the future and potential place for each approach.
I agree that there is a very real serious problem in funding primary research in HBV and this needs to be improved as this is typically where novel antiviral approaches come from (for instance ADV and TDF were discovered in an academic setting by Antonin Holy and Eric DeClerq). Frustration on the academic side is certainly understandable given the lack of political will in understanding the importance of disease burden from chronic HBV. The work of important advocacy groups like the HBV foundation and the European Liver Patient Association, WHA and ICE-HBV will unfortunately become easier as death rates from HBV continue to rise.
However, I would argue however that the real de-risking of technology comes from the extensive pre-clinical and clinical safety evaluations and phase II efficacy studies which can only be supported at the industry level. CAMs and RNAi are good examples of how early academic and preclinical evaluations which appeared promising but turned out to not be the case in human studies.
The case of bepirovirsen (the agent you mentioned with interesting activity in patients with HBsAg < 1000 IU/mL) is another cautionary tale. What was purported to be an antisense is now clearly a TLR 9 agonist (see here Bepirovirsen / GSK3389404: antisense or TLR9 agonists? - PubMed). HBsAg loss following 12 weeks of 300mg bepirovirsen in the first phase II study was followed by universal rebound of HBsAg in these patients. Unlike other oligonucleotides (NAPs and RNAi) which can extend therapy for 48 weeks or longer, a second larger phase II study still limited 300mg bepirovirsen exposure to 12 weeks. Prolonged activation of innate immunity in general has a spotty record with liver toxicity (recall the hepatotoxicity and death associated with the RIG-I agonist SB9200) and TLR9 activity is also a double edged sword in liver disease. We will of course wait to see the follow-up data from the second phase II study but by any standard this is not a satisfactory clinical outcome as the bulk of patients with chronic HBV do not have such low levels of HBsAg. The average baseline HBsAg in chronic HBV is ~10,000 IU/mL. We are now seeing new clinical trials actually excluding patients with typical HBsAg levels. While this may be a useful triage approach for teasing a path forward with some agents, it does not bode well for an overall solution.
What we need from basic research is to target the issues which have been brought into sharp focus from the clinical failures of the past several years:
How to target cccDNA degradation and deal with latent (inactive) cccDNA? Here we hope that the important primary research from labs like yours which are looking at these specific issues can provide new insights regarding this critical target.
How to restore a broadly HBsAg reactive immune response.
i also feel doctors need to understand that just testing DNA is not enough and they should test HBsAg as well. If patient is low level of HBsAg then why not try interferon. Why they just rely on DNA and NUCs.
The challenge with pegINF is that a lot of physicians do not have a lot of experience with this agent (unless they also treat patients with HBV / HDV co-infection). While you will find many physicians in Europe (especially in France) who know pegIFN well and the fact that it is fairly well tolerated in chronic HBV infection, the majority of physicians in other jurisdictions do not have the benefit of this experience and don’t understand that the tolerability issues with pegIFN and ribavirin for HCV (which were significant) don’t translate to HBV. Part of the reason for this is that lamivudine was approved in North America before pegIFN and another part of the reason is alack of understanding of the safety and beneficial nature of liver enzyme flares (which are much more frequent with pegIFN than with NUCs).
Of course we have the clinical data showing better performance of pegIFN in achieving functional cure with low HBsAg but this is not widely understood as well.
However, the approach of testing HBsAg and initiating NUC + pegIFN when HBsAg is < 1000 IU/mL is one that I agree should be explored more.
