Hi just to add to what Andrew just wrote - a Functional Cure means that there would be loss of circulating virus (HBsAg or Hep B surface antigen) and treatment would be finite (maybe a year or less?); however, the darth vader of a chronic hep b infection known as “cccDNA” would not be eliminated. A “sterilizing” or “sterile” cure - meaning a true, complete cure - is defined as the elimination of cccDNA, which is very wily and elusive. But for most of living with hep b, just knowing that we would only have to be on treatment for a limited time rather than a lifetime would be freedom. At least I would really not have to take an antiviral every day and to know my risk of liver cancer would be significantly reduced with the loss of HBsAg. If I’ve created any confusion or gotten something wrong, I know that others will chime in! Always, Joan
Yes Joan has the right of it (I love the “Darth Vader” analogy for cccDNA 
)
Sterilizing cure = removal of cccDNA
Complete cure = removal of cccDNA and integrated HBV DNA
However, HBsAg loss component of functional cure (which requires removal of integrated HBV DNA) is the key to reducing the risk of HCC. This is why functional cure is the goal of all current drugs in development.
Out of curiosity, what type of cure do we have for HCV?
Hi CNN, there is a complete cure for HCV with a pill taken daily for 8-12 weeks. The virus is completely eliminated!! Because of this breakthrough - no one thought HCV could be cured - scientists are now more hopeful and energized to find at least a “functional” cure for HBV. It may not be “sterilizing” or “complete” as defined by Andrew above, but at least we wouldn’t have take a pill for the rest of our life! AND our risk of developing serious liver diseases like liver cancer would significantly decrease. So although I would LOVE to have a complete cure like HCV, I’ll take a functional cure for now. Thanks for asking and hope others jump in! Always, Joan
Hi CNN,
Joan is absolutely correct that in HCV once daily oral therapy with the latest generation DAAs for 8-12 weeks does lead to a sustained virologic response (SVR) of HCV infection (no detectable HCV RNA in the absence of therapy) from which relapse is very rare (< 1% relapse rate 5 years after therapy). However, the term “cure” is still debated in the field since what we are really trying to “cure” by treatment is not the viral infection itself but the underlying liver disease. For HCV, the there is a clear improvement in liver disease in HCV following successful treatment but many persons achieving SVR still have progression of liver disease and or HCC, particularly if they had advanced liver disease before therapy. These issues are still evolving in the field today. Also HCV “cure” does not protect you from getting infected again.
A good reference on this is https://www.hepatitisc.uw.edu/pdf/evaluation-treatment/treatment-goals-predicting-response/core-concept/all.
For functional cure of HBV, HBsAg loss means that integrated HBV DNA has been removed from the liver (the cause of HBV-mediated HCC) and cccDNA is silent (which is the source of the bulk of inflammatory driven fibrosis and cirrhosis). Thus the functional cure of HBV is actually a better cure of overall liver disease in HBV than SVR is with HCV, with very low rates of HCC and reversal of fibrosis even when this advanced liver disease is pre-existing before treatment. Also the immune control which comes with functional cure of HBV will protect you from future HBV infection.
Hi @NeptuneJ,
Basically agree with all that has been said above, but thought your question was very timely as we have just launched a new video on this very subject. I’ve created a new topic for it here: What do we mean by Hepatitis B cure? - HBV Cure FAQs
This video is part of a series that will be released an episode at a time leading up to World Hepatitis Day this year.
Cheers,
Thomas
I really don’t like that phrase; functional cure. I suppose it makes sense because it’s not a total cure.
When I first heard the term, I thought it was a total cure. And I was excited.
One of my biggest fears is passing on the virus. Up there with HCC.
So, even though the risk is low, it’s still there.
I was reminded of this just yesterday. I had stitches in my foot, but kept bleeding so I was dripping blood everywhere and my grandchildren was cleaning it up, before I could stop them. To my horror I didn’t know whether they had been vaccinated or not. Turns out they were.
Dear Caraline,
I also do not like this term for the exact same reason: it is not patient-centric. Functional cure is really like functional remission. You have to take care of yourself to make it last.
But remember that this remission (functional cure) is a perfect remission. Your liver is not producing any virus and so it not infectious.
Best regards.
I agree with Andrew and Caraline about “Functional Cure” not being a really good term.
There was a big discussion among drug developers and hepatologists a number of years ago about what terms to use, and “functional cure” turned out to be the one that was felt to best describe the situation. It was felt to be important to use the word “cure” in the name to emphasize how much it would help patients, but because traces of HBV can remain in the body (integrated DNA, silenced or inactive cccDNA), we could not just call it a “cure”. I wish something else had come out of that discussion, but we’re stuck with that terminology at least for now.
As Andrew pointed out, a functional cure is still a great endpoint to treatment that will vastly improve the health of HBV+ people and remove the need to always take drugs. Focusing on those patient-centered goals rather than an inadequate term is what I like to do.
John.
I am CNN.
This goes out scientists in the house. What is the general feeling about or by HBV scientists on the earliest a Functional cure will be available/ can be approved for use say by FDA? I understand this is just an intelligent guess.
This is a tough question. I have been asked this several times and every day seems different. Some days I lament about the lack of research funding and how difficult this virus is to attack. Others days I look back at what we’re doing and am so excited about the progress that is accelerating as we speak.
I think it’ll likely be at least 5 years before a new therapy is available for patients that will cause a functional cure in a major fraction of people. This is dependent on many things, like how well the trial results work out, whether new breakthroughs happen, regulatory rules, etc.
Hope this is an intelligent enough guess 
TT
This is an edited post I have posted previously to the Hepatitis B Foundation Facebook page. AT present, I believe we have no single drug(such as for HCV) that will provide a cure for HBV. However, it is my belief that we have combination treatments with various existing drugs that can lead to a functional cure.
According to some researchers, especially Dr Andrew Vaillant, to achieve a functional cure, we must a)achieve very low hbvdna,cccDNA, and hence HBsAg; b) further reduction of serum HBsAg, to almost zero; c) Use an immunomodulator to restore or produce innate and adaptive immunity to maintain negative HBsAg. From the recent clinical trials, it seems to me: a) CAM (capsid inhibitor) is effective against the formation of hbvdna, like the NA. Therefore NA + a potent CAM, such as JNJ-6379, would lead to very low hbvdna, hence low cccDNA due to less refurbishment and natural loss due to liver cells turnover, resulting in lower serum HBsAg to less than 1,000 iul/ml, much faster. b) Bepirovirsen, an antisense RNAi, is a potent drug in reducing HBsAg, maybe not as potent as Replicor’s NAP. However, it may get FDA approval quicker because its mode of action is known. If serum HBsAg cannot be reduced to close to zero, a monoclonal HBsAb, such as VIR3434 and many others, even the natural HBIG can be added. c) For immunomoderator, we can try: 1) Stopping all medication - this has known to provoke an immune response; 2) Third-generation HBV vaccines, such as PreHevbrio, HEPLISAV-B, Nasalvac, and therapeutic HBV vaccines; 3) Low dosage PegINFN as suggested by Replicor. Together with the vaccines, HBIG may be used just as in an infant’s vaccination. Therefore to me, clinical studies can be conducted using the above drugs as proof of concept, leading to a larger clinical trial. Of course, we still have the hurdles of cooperation between pharmaceutical companies, ALT flares, and side effects.
Dear CNN and Stephenw,
This is a very active area of research, and there are no certainties that are solidly supported by clinical data. There are some rather promising signs, such as the data from Replicator (Andrew Vaillant’s company) and from other trials, but even the most advanced studies are only about midway through testing promising combinations. We simply cannot be sure of what will and what will not work (or in what groups of patients they will be effective) until a lot more clinical trials are done.
That being said, it is becoming clear that some combinations of drug classes are looking likely. For example, using a strong replication inhibitor (example, tenofovir), plus a suppressor of HBV protein production (example siRNAs or the NAPs), plus an immune stimulator (example, interferon alpha) is promising. The big problem right now is that we are in the early days of defining which individual drugs to use, how much of each to use, how long to treat, and which patients are most likely to benefit.
So this is a long way to say that we cannot predict when licensure of a curative therapy will occur. There are too many variables in play. I’m an optimist and have speculated (and it is just a speculation), that major advances will start reaching a major fraction of the HBV+ community in 5-10 years. We will just have to keep pushing forward as hard as we can and see how things turn out. I know that this is not the most satisfying answer, but it is what the science says right now.
John.
Thank you Prof Tavis for the response.
In many combination clinical trials and studies, results always seem to be better in HBV patients with low serum HBsAg.
I am very interested to know whether the presence of serum HBsAg is responsible for the poor performance of therapeutic vaccines in HBV patients’ clinical trials?
Dear StephenW,
You have put a lot of effort into your post above but let me provide a few corrections for the the community:
-
Functional cure requires inactivation of cccDNA AND removal of integrated HBV DNA from the liver. Both of these events are required to eliminate the production of HBV subviral particles (which constitute > 99.99% of HBsAg) which normally prevent the immune control of HBV infection. Neither NUCs nor CAMs have any impact on integrated HBV DNA.
-
While there is in vitro data (in cultured cells) to show that CAMs can block the formation of cccDNA, it is also known that the viral protein that CAMs target (HBcAg) is not required for maintaining cccDNA levels in infected hepatocytes. Clinical trials with numerous CAMs have shown that that this class of compounds has no impact on cccDNA levels and does not have any impact on functional cure, even when combined with NAs (NUCs) and siRNA.
-
There is a lot of confusion regarding how siRNA (RNAi) and antisense compounds are achieving their effects. This unfortunate development is a result of ignoring the historical failures of many siRNA and antisense compounds in the clinic, the basic molecular biology of HBV (rapidly evolution of antrisense and RNAi escape mutants), how siRNA and antisense compounds work and the well known off-target effects of these classes of compounds to stimulate innate immunity. GSK has only very recently acknowledged acknowledged that the HBsAg responses from Bepirovirsen (which was initially designed as an antisense compound) are driven by these off target immunostimulatory effects (remember that unlike NAPs, HBsAg responses to bepirovirsen are only occurring in the patients with low baseline HBsAg (< 1000 IU/mL). Similarly the HBsAg response from RNAi does not include targeting subviral particles and is likely mostly due to off target immunostimulatory responses (again with stronger HBsAg reductions occurring in in patients with low baseline HBsAg). Please see Targeting Subviral Particles: A Critical Step in Achieving HBV Functional Cure but Where Are We with Current Agents in Clinical Development? - PubMed for the scientific details about these issues.
There is no question that high rates of functional cure will require three combined effects during therapy:
- Complete inactivation of cccDNA.
- HBsAg loss (not 1 log reduction from baseline or reduction to 10 IU/mL - these are well demonstrated to be futile for functional cure).
- Stimulation of a HBsAg specific T-cell response to ensure efficient clearance of integrated HBV DNA. This effect will be accompanied by transaminase flares.
For this combination approach we currently we have the following options:
- NUCs and pegIFN (both approved).
- Nothing approved but only NAPs can achieve HBsAg loss.
- PegIFN and thymosin alpha 1. Maybe also therapeutic vaccines but for any chance of success these have to include multiple variants if HBsAg in their design.
Best regards,
I think I’ve heard the same guesstimate some 10 years ago. Perhaps less complex than nuclear fission, but both a runaway goal…
Curing HBV will be definitely easier than making a fusion power plant!!
One minor clarification on the terminology in Andrew’s post. I agree with him about the need to eventually deactivate integrated HBV DNA because it can drive production of HBsAg that complicates both achieving a functional cure and defining when we’ve achieved that goal. However, what Andrew refers to is more commonly called a sterilizing or complete cure. The current formal definition of a functional cure does not include elimination/deactivation of integrated HBV DNA. It considers only durable absence of HBsAg and HBV DNA in the serum after termination of therapy. That is largely because measuring HBsAg and cccDNA can easily be done with a blood test, whereas reliably measuring integrated DNA and cccDNA requires a biopsy, which is too invasive for a routine diagnostic tool.
Everyone knows that this is just an operational definition of a functional cure that does not fully reflect the complexity of the infection in a person, but it is what we can do at this point. Lots of people around the world are working hard to find better biomarkers to define HBV cure to help solve this diagnostic limitation.
Regardless of this terminology issue, either a functional or sterilizing cure would be great for HBV+ people.
John.
Hi John,
The critical part of sterilizing cure is the removal of all cccDNA in the liver (whether active or latent) so that production of virus can no longer occur. Removal of integrated HBV DNA is also part of the definition of sterilizing cure but is it not the critical feature of this definition since integrated HBV DNA is not capable of producing virus. Of course the challenges with latent cccDNA being a non-drug-able form of cccDNA persisting for a very long time in the liver make sterilizing cure very unlikely to achieve.
The coining of the term “functional cure” is several years old now and in the interim, we now know that the integration of HBV DNA is an event which occurs soon after infection and progressively increases with the duration of infection. We also know that integrated HBV DNA cannot be targeted by any direct acting antiviral and cannot be silenced by the immune mechanisms which can inactivate cccDNA. Importantly, integrated HBV DNA is fully capable of producing HBsAg in the form of HBV subviral particles. As such integrated HBV DNA is a source of a significant proportion of HBsAg and in HBeAg negative infection, provides the bulk of HBsAg.
You are quite correct that the original definition of functional cure did not mention integrated HBV DNA, but we now know that the persistent HBsAg loss in the absence of treatment (which is an important part of functional cure) cannot exist while integrated HBV DNA is present.
Functional cure of HBV infection is highly correlated not only with HBsAg loss during therapy but also with transaminase flares (which signal the removal of infected cells with cccDNA or integrated HBV DNA). Functional cure with approved agents (NUCs and pegIFN) are always associated with transaminase flares during therapy, with stronger flares correlated with higher rates of HBsAg loss and functional cure.
The reality of HBsAg loss (and functional cure) requiring removal of integrated HBV DNA and transaminase flares which signal this event were recently acknowledged at the 2022 AASLD-EASL Endpoints meeting.
All the best…
Thank you for your valuable response, it is very much appreciated.
I agree completely with your comments about CAM. I included a CAM, JNJ-6397, together with a NA, such as TDF, in the Replication Inhibition step toward a functional cure is based on two assumptions:
- A typical type II Capsid Assembly Modulator will produce rapid empty capsids without the enclosed pgRNA, and therefore will reduce the production of a mature HBV nucleocapsid with hbvdna that will be recycled to the nucleus to be converted to cccDNA.
- During liver cell turnover, a liver cell dies and another liver cell undergoes mitosis. During mitosis of an infected liver cell, some cccDNA may be lost, or the overall cccDNA pool in the liver remains constant.
A Type II CAM will not affect cccDNA directly. The Type I CAM that is supposed to interfere with the Core protein that is required for cccDNA formation has not yet been developed despite efforts by Bayer and subsequently a Chinese pharmaceutical company.
It is my understanding that with mono NA treatment, over time, usually after over 8 years, the cccDNA pool will be significantly reduced due to liver cells turnover. Together with a Type II CAM, Replication inhibition will be stronger as NA and the CAM are aimed at different targets in the Replication process. So a Type II CAM has no direct effect on cccDNA, but I assume, together will a NA, it will speed up the reduction of the cccDNA pool in the liver. I have no clear explanation why the serum HBsAg due to integrated hbdna may also be reduced.
I have read the paper you suggested, but it is way above my level of knowledge and comprehension. I heard of the problems with RNAi with off-target and splice variants. I know very little about ASO. Based on clinical trial results, for the HBsAg Reduction step, I can only suggest NAPs and Bepirovirsen. As Bepirovirsen is very much less potent than NAPs, I am hoping monoclonal HBsAb may help to reduce serum HBsAg further. Mindful of your previous comments regarding monoclonal HBsAb, I understand there is a variety of HBs MAb, there is also HBIG.
For the Immune Stimulation step, I take the clues from your research that HBsAg inhibits Adaptive immune and Innate immune functions, therefore hope the latest vaccines will be able to generate the HBV-specific B and T cells, with or without HBs MAb or HBIG.
I will not be surprised that I am wrong in all the above. I will need to study more about Interferon and its inactivation of cccDNA.
Mine was in thousands 3k around (ALT). Severe jaundice with bilirubin reaching 12 mg/dl !!!