Lets take a moment to put in perspective the benefit to patients of the various outcomes possible after therapy of chronic HBV infections. It is important to do this to understand how goals in the industry (focusing on HBsAg loss and functional cure) are still aligned with what is in the best interest for patients,not just what is a more easily achieved therapeutic outcome.
There seems to be a notion here that sterilizing cure (elimination of cccDNA) will provide an important additional benefit for patients over functional cure (complete inactivation of cccDNA and elimination of integrated HBV DNA) . This is not the case. Agents that are designed to target cccDNA will never have any impact on integrated HBV DNA. While sterilizing cure will result in the absence of viral production (but not HBsAg) and reversal of liver disease in the absence of therapy, integrated HBV DNA will still persist, which is incredibly stable in the liver. As such, sterilizing cure is not expected to lower the risk of HCC in patients (this is driven by integrated HBV DNA) and importantly, the immunosuppressive effects of HBsAg that facilitate HBV infection and replication will still persist (HBsAg is efficiently produced by integrated HBV DNA), making vaccination impossible and potentially increasing the risk for new HBV infection (these are issues that we donât have any data on).
Functional cure (inactivation of cccDNA and elimination of integrated HBV DNA) provides the best possible patient benefit (HBsAg loss). Functional cure includes all of the benefits of sterilizing cure plus substantial reduction in HCC risk with restoration of a fully potentiated immune response against HBV. This outcome is similar to the successful and life long resolution of acute HBV infection enjoyed by ~80% of all HBV infected individuals (> 2 billion people worldwide). The primary drivers of this outcome are HBsAg loss and immunotherapy to restore immune function.
Complete cure (elimination of cccDNA and integrated HBV DNA) although it sounds great actually provides little additional benefit to patients over functional cure except for preventing reactivation with future immunosuppressive therapy for other diseases (which is a very rare event). Like functional cure, complete cure will still require HBsAg loss with immunotherapy in order to ensure the removal of integrated HBV DNA.
In setting expectations for the patient community, it is important to recognize the incredibly high efficacy barrier to sterilizing cure: HBV infection can reactivate from a single copy of cccDNA and this is facilitated in the presence of HBsAg (which turns off the bodyâs mechanism for maintaining cccDNA in an inactive state).
I agree with Thomas that the scientific investigation of cccDNA elimination will continue. However, clinical success for sterilizing cure (elimination of cccDNA) will require agents that we donât yet see on the horizon and development of detection methods for elimination of cccDNA in the liver beyond what is currently known or possible in the field. New agents and diagnostics might come from the continued research being done by researchers like Thomas. We encourage them in their efforts!
I agree with Andrew. A functional cure will give patients essentially the same benefits as having naturally cleared HBV, and importantly, it is scientifically feasible in the relatively near future! Improved therapies under development are already providing much higher functional cure rates than current therapies (for example combination therapies with NAPs that Andrew is pushing forward), and improvements are expected to continue coming as more combinations are tried. It is impossible to predict the rate of science (by definition, we are trying to figure out the unknown), but I am optimistic that the new therapies will begin to be approved within ~5 years, with a steady stream of even better ones being approved after that.
Research will continue into the cccDNA because it is the center point of HBV biology. Even after it is no longer a focus of intense research for drug discovery reasons, people will continue to look at it for scientific reasons because it is a remarkable bit of biology.
There are currently no drugs in development which have been shown to directly target integrated HBV DNA. There are several challenges here:
HBV DNA integration occurs in numerous points in most chromosomes of the human genome.
The points of integration in the linearized HBV DNA genome itself are highly diverse.
Integrated HBV DNA has the same highly diverse quasispecies composition as HBV DNA produced from viral replication. This issue makes integrated HBV DNA impossible to target efficiently with sequence dependent approaches like CRISPR Cas9 and ARCUS endonucleases.
Integrated HBV DNA only efficiently produces HBsAg (as subviral particles) so the only immunological approach to targeting integrated HBV DNA efficiently involves first clearing HBsAg from the circulation so that these cells can be recognized by aspects of the immune response which broadly recognize multiple diverse species of HBsAg. This is the challenge of therapeutic vaccines currently in development, all which currently use a single HBsAg antigen.
With the understanding that HBsAg loss and functional cure requires removal or efficient reduction of integrated HBV DNA, we can begin to decipher some of clues leading to removal of integrated HBV DNA.
HBsAg loss and functional cure with approved agents like NUCs and pegIFN (while relatively rare) are accompanied during therapy by immune mediated flares of liver enzymes in the blood (where liver function remains normal) which signal the removal of infected hepatocytes (including integrated HBV DNA).
Studies with NAP-mediated HBsAg loss combined with immunotherapy have yielded very high rates of host mediated liver enzyme flares. The high rates of functional cure observed in the latest trial with NAPs are predicted by the presence of a liver enzyme flare with HBsAg at very low levels (<1 IU/mL). The functional cure established with this combination approach appears to be able efficiently reduce (or even clear) integrated HBV DNA. you can read more about this
Undoubtedly, the persistent production of subviral particles from integrated HBV DNA is the primary barrier to functional cure since we know that silencing of cccDNA with approved agents (NUCs and pegIFN) is quite common and not difficult to achieve. The best approach we know of right now is to re-awaken all of the sleeping HBsAg specific immune response present in the patient and, with HBsAg loss, allow this response to remove integrated HBV DNA.
so that these cells can be recognized by aspects of the immune response which broadly recognize multiple diverse species of HBsAg.
The best approach we know of right now is to re-awaken all of the sleeping HBsAg specific immune response present in the patient and, with HBsAg loss, allow this response to remove integrated HBV DNA.
I suppose there are further challenges: if we manage to âre-awakenâ HBsAg specific immune response - we wonât be able to control that response too well (as opposed to control we have over administered drugs - we can control both the drugâs amount and timing/frequency).
If our immune system gets re-awakened and starts killing infected hepatocytes very rapidly - it can mean a cure for some (if the number of infected hepatocytes is relatively small) or a death sentence for others (if the number of infected hepatocytes is very large). Similar to tumor lysis syndrome in oncologic patients. Please correct me if Iâm wrong!
Do we understand how many hepatocytes are infected in patients? 0.001%? 1%? 5%? 50%? It surely varies a lot by patient, and also not so easy to assess, as it requires numerous biopsies in many patients - but maybe we understand it from animal models?
Are hepatocytes with cccDNA and/or integrated HBV DNA still supporting liver functions (play role in metabolism, synthesize proteins etc.)?
Estimates on the fraction of the liver infected vary from 35-70%. We have this data from several very good biopsy studies. There is also good data to indicate that infected cells are metabolically reprogrammed by their HBV infection and subversion to the production of subviral particles (production of virus is one a small fraction of the metabolic energy devoted to supporting HBV infection in hepatocytes). It is unlikely that infected cells contribute meaningfully to normal liver function.
This likely why host (immune) mediated liver enzyme flares are not associated with changes in liver function in chronic HBV infection. The only time we see decompensation associated with liver enzyme flares is with a spike in viral replication, for instance during acute HBV infection, reactivation of HBV from the âchornic carrierâ or âinactiveâ state or with the development of resistance to older generation NUCs.
Now the route to re-activation of of HBsAg immune cells may make a difference in terms of patient safety. Using classic agents like pegIFN or thymosin alpha 1 (which generally restore naturally present immune function) with later generation NUCs like TDF always result in beneficial liver enzyme flares. Removing or reducing host regulatory control over all immune cell function (for example with agents that interfere with factors involved this these processes) can activate not only HBsAg specific responses but other immune responses normally suppressed. Agents of the latter kind have shown some interesting antiviral effects but also some cases of âbadâ liver enzyme flares where liver function is also altered.
I agree with @availlant, great questions. I thought Iâd give my perspective as well.
In addition to the candidates that @availlant mentioned, there are several groups attempting to target integrated HBV DNA using CRISPR technologies, though this approach is still very much in its infancy for hepatitis B. Immune modulators could technically also target cells with integrated HBV DNA, though how effective this is or could be remains unknown.
The progress in this area is slow, mostly because it is very difficult to accurately measure integrated HBV DNA in a patient and requires a liver biopsy. I have worked on the methods to do this for the last 14 years and the assays are generally very very specialised and cannot be done in diagnostic labs or even the majority of research labs.
Correct, @mantana. We do see almost 100% of the liver being infected very soon after infection (from animal model experiments) and down to 0.1-0.01% of cells having cccDNA in HBeAg-negative patients (from patient liver biopsies).
I would disagree with @availlant here or at least say that there are differing interpretations. Infected cells still produce albumin, metabolise toxins, etc. as per uninfected cells (supported by both in vitro and in vivo data). If metabolism was seriously compromised by the infection itself, then we would expect to see massive changes in LFTs and other metabolic markers in patients in the âimmune tolerantâ phase when the percentage of infected cells is very high. But these are generally normal and indistinguishable from the HBV-negative population.
I think Thomas makes some interesting points here however I offer the following counterpoints:
CRISPR does differ from ASO and siRNA in that it has the potential to modify and thus inactivate cccDNA and or integrated HBV DNA instead of degrading HBV mRNA. However, the specific targeting of the CRISPR effect is sequence dependent and thus suffers from the same limitations as ASO and siRNA; 1 or 2 point mutations will block its specific targeting. There is now excellent data showing not only that the sequence dependent mechanisms of ASO and siRNA are not playing a meaningful role in the HBsAg responses we are seeing in clincal trials but that many individuals harbour multiple point mutations to ASO and siRNA trigger sites, even simultaneously in multiple trigger sites in the case of JNJ-3989, even before they start therapy with these ASOs or siRNA. This is to be expected due to the quasispecies nature of HBV infection and of course these numerous quasispecies will also be represented in the cccDNA and integrated HBV DNA present in patients. We also know that these escape mutations become rapidly enriched in the cccDNA pool under the selection pressure of ASO and siRNA. This has been demonstrated in vitro, in vivo and in humans for several mutating viruses including influenza, HCV and HBV. The same will occur with CRISPR. We also know that CRISPR only very poorly exerts genetic modifications in condensed (heterochromatic) genomic DNA which places its ability to target inactive cccDNA in general (which is also highly condensed) into question. Of course we have to wait to for clinical data to assess the potential of CRIPSR but we should be cautious in our optimism for this approach in the face of what has been demonstrated for ASO and siRNA.
Thomas has some very good points regarding the contribution of infected hepatocytes to the reservoir of liver function and I can see where he is coming from. I come at it from a different perspective however. Recent surveillance work has shown that very powerful liver enzyme flares are indeed present in a significant proportion of immunotolerant patents which at their peak can exceed 100x the upper normal limit and persist at greater than 10x the upper normal limit for many months, all without affecting markers of liver synthetic function (bilirubin, albumin, INR) or having any other symptoms. These liver enzyme flares are a recognized signal for removal of liver cells and in these immunotolerant patients are correlated with HBV DNA reductions and HBeAg seroconversion. I would agree with Thomas that the percentage of the liver harboring infection is likely higher in these immunotolerant patients, which makes the clear evidence of striking and protracted removal of infected cells at odds with infected hepatocytes having a contribution to the reservoir of liver metabolic function which is equivalent to uninfected hepatocytes. We also have good data from the use of NUCs or NUCs + pegIFN in decompensated cirrhosis (where the reservoir of normal liver function is only a small fraction of that in a healthy person) that very strong immune mediated liver enzyme flares are not associated with changes in liver synthetic function but instead with improved liver outcomes. We also know that HBsAg loss and functional cure of HBV is associated with strong liver enzyme flares, with the extent of HBsAg decline and rates of HBsAg loss correlated with the strongest elevations in these liver enzymes (> 10x the upper normal limit). All of this reported liver enzyme flare activity (and infected cell loss) comes with no change in liver function.
We do see evidence for reduction of liver metabolic function (decompensation) with the spread of viral infection. Liver decompensation is observed during acute HBV infection, during reactivation of HBV from the inactive state and with rebound of resistant HBV during NUC therapy.
Hello to all dear,
Sorry for the delay in replying. I was so devastated these days, I have lost my control, and fear and grief took my life. Itâs been a month since I found my Hbv status, after that, I am just trying to find something to calm me and am trying to handle it. This forum is the only place where I can be myself, talk about my problems, and ask my question to the greatest experts in the world who are at the frontline.
Dear @ThomasTu, @john.tavis, and @availlant You are very good people, you help this community with evidence-based facts and show your kindness and humanity in your efforts to research and develop a cure for us. With no language or no words, I can appreciate what you are doing. From bottom of my heart, I wish all the best for you and for your families. sorry for my silly questions sometimes but here is the only place we have. I see all of the people here as my new friends. I really hope science finds what is best for this community and I am sure about it, To finally have their normal life far from any discrimination and stigma, and fear.
I am a programmer and I know about AI. and IT. I finally find something that could be useful for this community or even for HBV. If you have any suggestions on how could IT or AI be useful please let us know? I know there are many people better than me in this forum.
Merry Christmas to all of you and wish you the best.
Just I can say, Thank you.
It is important to note that after competing NAP-based combination therapy ~78% of patients either have partial cure or functional cure (and so have a good long term prognosis in the absence of therapy). These results were achieved in the most difficult to treat patients (genotype D HBV) with a suboptimal route of administration (IV infusion) and having no patients with low HBsAg (< 1000 IU/mL) in the trial.
We expect that the rates of partial cure and functional cure will increase with the transition to SC administration, inclusion of other, more easily treated genotypes of HBV (A, B, and C) and inclusion of patients with low HBsAg.
Thanks sir.most of us in this community what we are hoping for is a functional cure.how is possible is it to get drugs that will give 95 % cure or more as with Hcv?
The issues surrounding cure of HCV are very different from those in HBV.
There is no (as far as we can tell) permanent integration of the genetic information of the virus into chromosomes for HCV (this is the case for HBV).
There is no production of viral proteins that suppress and or exhaust immune function by mechanisms that are separate from viral replication in HCV (this is the case for HBV, with HBsAg).
Blocking viral replication has the effect of stopping production of new copies of the viral genome in HCV, this is NOT the case for HBV.
So, once the issues were sorted out for getting a reasonably good inhibitor of viral replication in to the liver for HCV (the first drug to do this was a drug called sofosbuvir aka Sovaldi). the establishment of cure for HCV was achievable in > 95% of patients with a short course of therapy (initially 12 weeks, now even 8 weeks with some of the latest drugs).
The challenges of blocking viral replication AND antigen production are different for HBV. There is also the problem of dealing with an immune system which has been hamstrung by long term exposure to HBsAg.
The industry is working hard on these issues but the goal of > 95% functional cure of HBV will be much harder to achieve.
Long term outcome is very similar with partial cure compared to initiation of NUC therapy under current guidelines (when evidence of liver disease is present). With this caveat, both situations enjoy long term remission of liver disease and similarly very low rates of HCC. Patients with partial cure do have low level virema and need to take care of transmission in high risk scenarios (such as unprotected sex). Patients with partial cure can be at risk for reactivation but this just means starting NUC therapy again.
Under newly evolved guidelines in China which will see much earlier introduction of NUC therapy (before liver disease is evident), the benefit of a further reduction in the long term risk of liver cancer is likely to occur.
So it depends on when you started your NUC therapy.
Actually thereâs a cure for hbv(interferon + tdf),the cure rate is low.There is Naps with about 40% functional cure rate, thats a great progress.with my observation as time goes on the functional cure rate will still increase.
Best regards
Gods own