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本帖最后由 StephenW 于 2016-8-26 21:36 编辑
To my mind, the advances in understanding the HBV life cycle are key to the development of a cure. In your
newsletter issue, you reviewed a 2016 article by Hayes and colleagues that reported on our current state of HBV life
cycle knowledge. Please summarize that information for us.
DR. THIO: The important point the Hayes paper brings out is the steps that lead to the development of the covalently closed
circular DNA, or cccDNA, in the hepatocyte nucleus. This podcast isn’t the appropriate forum to discuss all of those steps in
detail, but I refer you to the newsletter to learn what some of those steps are. But I do want to hit home the point that the
cccDNA is used as the transcription template to form all of the mRNA that are used either replication or that form the various
proteins including surface antigen, e antigen, the X protein, and the core antigen. So without the cccDNA, the hepatitis B
replication and life cycle would stop.
MR. BUSKER: Keeping in mind what you just said about cccDNA, how should we define the word “cure” in regard to
hepatitis B?
DR. THIO: I think you can think of cure in two ways. The first would be what I would call a functional cure, which is what we
see in the majority of people who have natural hepatitis B recovery — people who develop surface antibody and lose
surface antigen after an acute infection. These people, for the most part, still retain cccDNA in the nucleus of some but not
all hepatocytes.
We know this because when these people become immunosuppressed either with medications or with an immune
suppressive disease such as HIV, or they are put on immunosuppressive therapy after transplant, their hepatitis B can
reactivate because cccDNA is still present in some hepatocytes.
So a functional cure would be to a point where we’re stopping replication after discontinuing medicaitons but we’re not
getting rid of that cccDNA. We are achieving that with a very small proportion of people with the currently available
therapies for hepatitis B.
The other type of cure, which I think is more difficult to achieve, is what we would call an eradication cure, which would
eliminate the cccDNA to the point where it doesn’t exist in the nuclei of any hepatocytes.
MR. BUSKER: What are the research approaches for either a functional cure or an eradication or elimination cure?
DR. THIO: In the big overview there are two basic approaches: the virological approach or the immunological approach.
The virological approach is just what it sounds like. The idea would be to attack the virus at various steps in the replication
cycle. As I mentioned, the Hayes paper talks about some of the steps toward building up to the cccDNA, and several other
steps also occur after the cccDNA is established in the nucleus. Attacking the cccDNA directly would also be one of the
virological approaches. Any of those steps could be targeted to block the replication life cycle for hepatitis B.
The current hepatitis B polymerase inhibitiors attack one of those steps, but many more steps could also be attacked.
The important thing to understand with the immunological approach is that the immune system in chronic hepatitis B is
defective in that it’s tolerant to the hepatitis B antigens. So the idea in the immunological approach would be to boost the
immune response to hepatitis B, which could be done either by boosting the general immune response or by boosting a
hepatitis B-specific immune response.
MR. BUSKER: Tell us about some of the virological approaches that are currently being investigated.
DR. THIO: On the bright side, a lot of approaches are currently being studied. Some of those will eventually fall by the
wayside, but it’s important that we understand at least what people are doing at this point.
One of the approaches would be to block the entry of the hepatitis B virus into the hepatocyte. When the hepatitis B enters
the hepatocyte, and this is reviewed in the Hayes paper, it binds to the NTCP receptor. This receptor is used as a bile acid
transport receptor, but something that also binds hepatitis B and allows it to enter.
A compound called Myrcludex B was synthesized before the receptor was identified because we knew at that point which
part of the hepatitis B virus bound to an unknown receptor. Myrcludex B was synthesized to match this pre-S1 region of
hepatitis B where this binding occurs. This compound basically blocks the binding of hepatitis B to the NTCP receptor.
Another drug, cyclosporine A, which is already available and used, also binds the NTCP receptor, and some studies have
looked at that.
In the newsletter I discuss a paper, a phase 2a clinical trial that was presented at the American Association for the Study of
Liver Diseases conference, which looked at Myrcludex B as a treatment for hepatitis B. The authors studied patients who
were HBeAg-negative and had chronic hepatitis B, all with hepatitis B DNA levels greater than 2000 and did not have
cirrhosis. They were given increasing doses of Myrcludex-B subcutaneously, from 0.5 mg to 10 mg. All of these doses were
given once daily for 12 weeks; the 10 mg group received an additional 12 weeks of treatment. They found that the response
was best in the 10 mg group. Six of eight people who received 10 mg achieved greater than a 1 log decline of hepatitis B
DNA at 12 weeks, compared to only about 21% of all the other people in the other groups. No changes in hepatitis B
surface antigen levels occurred, and the tolerability was excellent, except for three people who had some injection site
reaction.
This study is interesting because it shows you can lead to declines in hepatitis B DNA levels, but whether it will be an
important component of a cure needs to be studied. Certainly longer durations of this drug also need to be studied. That’s
one virological approach, just block the receptor.
Another approach would be to silence the mRNAs. I mentioned that the cccDNA is the transcript for making all the mRNAs.
And as probably many of you know, in other diseases people are working to silence these mRNAs so the downstream
effects of the mRNAs are no longer present. With hepatitis B, if we can silence the mRNAs, we can stop replication because
the pre-
genomic RNA can’t encapsulate, and could stop more surface antigen particles from being produced.
It’s important to understand that because more than one mRNA is produced from the cccDNA, sometimes these surface
antigen particles are produced but don’t contain any hepatitis B DNA; these are called empty particles. These empty
particles are important because they are thought to play a role in immune tolerance. If you can decrease the number of
these empty particles, perhaps there might be a way to boost the immune system toward eliminating hepatitis B.
Other virological approaches being considered include capsid inhibitors. I’ve been mentioning that the pregenomic RNA
needs to be encapsulated, and one approach is to prevent this encapsulation with capsid inhibitors. Other approaches
include degrading the cccDNA itself, and also blocking release of hepatitis B surface antigen particles.
Those are some of the virologic approaches that are currently under development.
MR. BUSKER: What about the immunological approaches? What can you tell us about those?
DR. THIO: There are many immunologic approaches, as well. As I mentioned earlier in this podcast, you can either
stimulate the general immune system or you can stimulate the hepatitis B-specific immune system.
One of the approaches is to activate the general immune response by blocking the toll-like receptor-7 or TLR-7. TLR-7 is a
pattern recognition receptor that increases both the adaptive and the innate immune response. If you can stimulate TLR-7,
hopefully you can increase the immune response, which would allow elimination of infected hepatocytes.
One study reviewed in the newsletter looked at this TLR-7 agonist in 100 people, 84 of whom received either one or two
doses of the drug. They found no change in hepatitis B DNA, but that probably wouldn’t be expected with just one dose.
They did notice, however, an increase in a particular interferon-stimulated gene called ISG-15 mRNA, and the mRNA in the
people who received the highest doses of TLR-7 increased, suggesting that this drug was stimulating the immune system to
some degree. More studies will be needed to see whether that immune stimulation leads to a reduction in hepatitis B DNA.
The other general approach is to block the immune checkpoint markers. The important thing to understand is that in chronic
hepatitis B, these inhibitory pathways or immune checkpoint markers are up-regulated. When there is chronic stimulation by
some antigen, in this case hepatitis B, the T cells become tolerant to this by up-regulating these markers. The idea is, if you
can block these markers, perhaps you can reverse this tolerance or immune-exhausted state and allow the T cells then to
attack the infected hepatocytes.
One example reviewed in the newsletter is blocking the PD-1/PD-L1 pathway, which has been used in various cancer
chemotherapies and is now being studied with hepatitis B. In general, this study showed that patients who received this
immune checkpoint blocker along with other medications, including a therapeutic vaccine and a polymerase inhibitor, did
have some increase in their immune control of hepatitis B virus. But whether this leads to a cure for hepatitis B also needs
more study.
The other important point to know about trying to stimulate the general immune system against hepatitis B is concern that
this could lead to fulminant hepatitis. If someone has many infected hepatocytes and you unleash immune tolerance and
the T cells begin attacking the infected hepatocytes, that leads to a fulminant hepatitis. So I think up-regulating the general
immune system will be a balance between too much immune response and not enough immune response, because you
don’t want too much, which then leads to a fulminant hepatitis situation.
The other approach, if you’re not going to activate the general immune system, is to activate the hepatitis B-specific T cells.
These studies are just starting to be under development and weren’t reviewed in the newsletter, but I will just say that the
basic ideas here are either to give a therapeutic vaccine that takes parts of the hepatitis B virus that are thought to be the
most immunogenic or most likely to stimulate the immune system, and give that as a therapeutic vaccine in the hope that
you can stimulate the hepatitis B-specific T cells to attack the hepatocytes.
The other way is to engineer T cells themselves, and put them back into the patient to stimulate an immune response to
hepatitis B.
MR. BUSKER: There’s an impressive amount of research going on. How close do you think we are to developing a
cure for hepatitis B?
DR. THIO: I don’t think we’re very close. As you can tell from the papers we have discussed here and are discussed in the
newsletter, most of them are still in very early phase trials, trying to find the correct dose and trying to understand the side
effects of these various drugs. So I think we’re many, many years away from curing hepatitis B.
There are no current studies of these new agents demonstrating that they can cure hepatitis B on their own. As I mentioned
with the current polymerase inhibitors, some people can achieve this functional cure, but 5% of people actually lose surface
antigen and develop surface antibody with just a polymerase inhibitor. So we know it can be achieved, but we certainly
would want to achieve it in more people than that, and these newer drugs are a long way from being able to do either a
functional or an eradication cure.
MR. BUSKER: But are you confident that a cure is possible?
DR. THIO: Yes. As I mentioned, we can already achieve a functional cure with some of the polymerase inhibitors. It is not
very common but it is possible, so you need to believe that we should be able to achieve a functional cure in more people.
We also know that 90% to 95% adults who get infected achieve what we are aiming for: functional cure. They don’t develop
chronic hepatitis B; they develop surface antibodies, and even if they still have cccDNA present in some of their
hepatocytes, their livers do not suffer any consequences of having that cccDNA.
Because most people can naturally achieve what we would call a functional cure, I think we should be able to figure out
how to achieve this in more people who have chronic hepatitis B. An eradication cure will be more difficult, because even
people who naturally develop surface antibody and recover from hepatitis B don’t eradicate the cccDNA, but I think it will be
possible with some of the newer technologies.
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发表于 2016-8-26 21:34
