Prof. Fabien Zoulim：How to achieve functional cure of chronic hepatitis B?

Editor's note: With the continuous understanding of virology, cell biology and host immunity of chronic hepatitis B virus (HBV) infection, the field of hepatitis B is developing rapidly. However, judging from the current situation, only close cooperation among different research fields can achieve the functional cure of chronic HBV infection.

To this end, the International League Against HBV (ICE-HBV) and the European Association for the Study of the Liver (EASL) jointly organized the symposium "Understanding Immunology and Virlogic Reactions in the Liver to Cure HBV Infections" during the 56th EASL Annual Meeting in 2021, aiming to share the latest progress and provide more opportunities for researchers committed to developing methods to cure persistent HBV infection.

"Hepatology Digest "has the honour to invite the moderator, one of the sponsors of ICE-HBV, a leading expert in the field of clinical viral hepatitis and antiviral treatment, Professor Fabien Zoulim of the University of Lyon, France, to look forward to the next 10 years of HBV cure.

<Hepatology Digest>: Among viral hepatitis, hepatitis C can be cured, but hepatitis B is still being explored hard. Could you please talk about the current internationally recognized ultimate therapeutic target for curing hepatitis B virus (HBV) infection, and the clinical treatment goals that are pursued or expected to be achieved in the future?

Prof. Fabien Zoulim: Hello everyone, and thank you for this invitation. This is a very important question. As you said, hepatitis C can be cured easily now with the new treatments. For hepatitis B, we have the nucleotide analogs to achieve viral suppression, but it requires lifelong therapy because of persistence of the virus in the liver. 

Now, the focus of new treatments that are emerging is to achieve a functional cure with a finite duration shorter treatment with functional cure defined by HBsAg loss that is sustained after treatment cessation. This is expected to bring about a sustained antiviral effect, improvement of liver disease, and prevention of hepatocellular carcinoma. These are very important endpoints and targets.

<Hepatology Digest>: What is the main reason that chronic hepatitis B virus (HBV) is difficult to cure? In this regard, what are the cure strategies that we have adopted or are exploring?

Prof. Fabien Zoulim: Again, a very important question. Hepatitis C virus is maintained in the infected cell just by replication. When we block replication, then the virus will fade away and be eliminated. With hepatitis B, we have two mechanisms of persistence, which explain the difficulty of curing an infection. 

One is the persistence of cccDNA, the viral genome archive, as a minichromosome in the nucleus of the infected cells. This can currently not be eliminated, so if we stop treatment, there is a relapse of viral infection coming from this cccDNA. The second mechanism is the fact that the antiviral immune responses against the HBV-infected cells are exhausted in chronically infected patients. 

Now, regarding the new strategies that are being developed, they aim to block replication much more efficiently to have an indirect effect on cccDNA, or to target cccDNA directly towards the ultimate goal of eradicating cccDNA, but this is very challenging. A third aspect is that we need to restore antiviral immune responses and stimulate the exhausted immune response. These are the main strategies that are being developed in clinical trials today.

<Hepatology Digest>: Based on the above main strategies, what is the current progress in the research and development of relevant new drugs and the exploration of new treatment options? What do you think will be the focus or trend of future research?

Prof. Fabien Zoulim: Currently, there is a lot of excitement and it is really a very dynamic field today where we have many drugs that are directed against the virus, the direct-acting antivirals, such as the capsid assembly modulators, RNA targeting strategies such as siRNA and antisense oligonucleotides. We have strategies trying to block viral egress, such as the nucleic acid polymers, as well as novel nucleoside analogs and virus entry inhibitors. These are very exciting tools to combat the virus. They are in clinical trials – phase Ib, phase IIa and even phase IIb. There are also immune modulatory strategies using TLR agonists, checkpoint inhibitors and therapeutic vaccines that are being evaluated in clinical trials. 

Now the real challenge, and what is really interesting, is that we have all the different tools to combat the virus either directly or via the immune response, but how are we going to combine all these different drugs to be more efficient and to achieve a functional cure in patients? Clinical trials are currently addressing the issues of combination treatment strategies, so we should see in the next couple of years how this will progress. There is a lot of hope in that direction.

<Hepatology Digest>: You are a recognized expert in the field of clinical viral hepatitis and antiviral therapy, and one of the initiators of the International Coalition to Eliminate HBV (ICE-HBV). Facing the WHO's goal of "eliminating viral hepatitis as a major public health threat by 2030", how do you think clinicians, researchers, and related personnel should work hard to achieve the functional cure of chronic HBV infection in the next 3 to 5 years?

Prof. Fabien Zoulim: This is a very important public health question. HBV is really a global problem with more than 250 million chronic carriers at a high risk of liver cancer. The issue of eliminating viral hepatitis as a major public health threat within the next ten years is looking to combine different approaches. 

One is to have better coverage for the vaccination to prevent new infections. That is the first thing to work out since we know it results in a decreased prevalence of HBV and a decreased incidence of HCC at the population level. 

For those who are already chronically infected, the first issue is to ensure patients know their status, so raising awareness of hepatitis B and doing screening programs to identify if people are infected or not is essential. This requires that not only doctors, but also patients and all the stakeholders are armed with knowledge and that screening efforts are at the forefront of this strategy. 

The second thing is that once people know they are carriers of the virus that they are linked to care. This is a major issue, because many people infected with HBV are living far away from hospitals and referral centers. The linkage to care is very important. And then, there is a need for an optimal clinical management of patients for a correct diagnosis, and antiviral treatment with drugs that we know are effective for those patients in need (NUC can suppress viral replication, decrease inflammation and fibrosis in the liver, and decrease (but not eliminate) the risk of HCC). 

But all of this needs a lot of resources and we need to work with Ministries of Health in each country in order to understand the significance of the problem in each location, and that resources are devoted accordingly for the management of hepatitis B. 

Obviously, the complementary approach is to support research as we have discussed, looking for better treatments that can be administered orally with a short duration of treatment providing a functional cure of 30% or more. Then we would be able to treat all carriers and provide a high rate of functional cure. That is the hope for the next ten years.