New targets for anti-HBV drug therapy

In patients with chronic hepatitis B virus infection, we can achieve viral suppression using NAs and IFN therapy. However, in clinical practice, although we have benefited greatly from antiviral therapy, there are many problems with the treatment, including side effects, low response rates, and incomplete clearance of cccDNA in liver cells. For new therapeutic targets, we should focus on which part of the HBV replication process?

Professor Levrero: For patients, the current suppression of viral replication is not a real problem because most patients can do this. About one-quarter of patients treated with interferon can do this and achieve a functional cure. In patients receiving NUCs, some patients can achieve viral balance, but only after a few years of treatment can inhibit viral replication. In an article we just published, we found that one-third of patients who received adefovir therapy for 5 years and achieved viral suppression can still maintain viral suppression after treatment is stopped, but these are only a few.

So, the biggest problem is how to get more patients to achieve functional healing. Of course, there are different ways to achieve this and the end result is the removal of the wild-type virus. Even if the virus is successfully suppressed for many years, the virus is still a virus, cccDNA is also lurking in the nucleus, and the virus may be reactivated. Many patients have this potential activity. After removing the drug, only wait for the treatment to start again. So the ultimate goal of treatment is to act on cccDNA.

An enterocytotic inhibitor currently under investigation has a therapeutic effect in vivo or in animal models and is about to enter the clinic. Obviously, enterocyte inhibitors do not clear the infection, but they are certainly useful in some clinical settings. Some drugs that target the core particle can inactivate it, which in turn inactivates the capsid as a carrier, ultimately affecting viral replication. We recently presented a study on EASL that showed that core nucleocapsid assembly was blocked by core particles acting on cccDNA to block core nucleus particles. This actually inhibits the cccDNA activity and thus cccDNA is no longer active.

We are still in the early stages of research. We must study in an in vivo model, and we still need to do a lot of work to identify new targets; we target the core proteins in the cytoplasm and the nucleus and the cccDNA in the nucleus, and actually target the function of the cccDNA and use Efficient methods inhibit cccDNA function. The second point is to target cccDNA in different ways. The cccDNA is like a small minichromosome. Our team and other researchers have identified the existence of the same genetic rule that governs cccDNA, such as cell chromosomes.

Our article published last year found that interferon can actually induce the recruitment of cccDNA proteins or protein complexes, especially the protein Ezh2, thereby inhibiting viral replication. When the administration of the interferon was stopped and the protein remained active, the micromitochondria maintained methylation and were inactivated. This explains why interferon is the best treatment. It is through the silencing of cccDNA to get a functional cure faster.

We have synthesized compounds that mimic the activity of interferons and have been presented to everyone at the EASL conference last year. In fact more compounds mimicking interferon activity are being developed. The most interesting part, and also the direction we are still working on, is whether the combined use of these compounds can shorten the course of interferon therapy and increase the interferon response, or whether the use of these compounds alone can continue to inhibit viral replication.

The above are two different ways to solve the problem - clearing cccDNA or silencing cccDNA. One method is biological cure that eradicates, but it is difficult to achieve because you must target all cccDNA molecules. Another method is the functional cure, that is, the inactivation of cccDNA, and we are looking for new ways to stop the treatment because these patients can get a functional cure.

Considering completeness, we also showed that capsid blockers had similar efficacy at the EASL meeting last year. The team used a cytokine approach to discover that capsid blockers inhibited approximately 50-60% of cccDNA in an in vivo model. Similarly, we must enter the body test, which means there is still a long way to go, but we can see the light at the end of the tunnel.

Question: How to treat patients who cannot achieve an effective immune response to the virus?

Prof. Levrero: The concept of functional healing of HB relies mainly on interferon and the production of cytokines in the immune system. The concept of affecting the virus and enhancing the immune response to achieve functional healing or biological eradication already exists. We already know that the immune system can control disease and reproduction. In an acquired immune response, the cell compartment has an important role in clearing infected cells. In general, the innate and acquired immune systems work together directly on cccDNA. For therapeutic vaccines, although there is a certain improvement, there is still a lot of work to do. We don't know how to translate these results into drugs that attack the virus database, but there is some hope.

One active area is trying to boost the immune response when the virus is inhibited. This has also entered clinical research. At present, we have reported that in patients with prolonged use of NUCs and viral suppression, the introduction of interferon can turn this trend into more favorable conditions. PEG-IFN is an ancient method of treatment. The disappearance of initial HBsAg is a hallmark of functional healing. Immune intervention is a big area, and when classic therapeutic vaccines have not yet emerged, simple strategies like increasing PEG-IFN seem to be the path we can follow. I was surprised that we did not consider this before, but increasing immune stimuli will allow more patients to achieve a better therapeutic effect.