Clinical Studies of Currently Available Drugs Continue to be a Highlight of the Conference This year’s AASLD meeting featured a number of very interesting studies and presentations. Some of these were clinical studies of currently available drugs. For example, there were studies examining the effect of long-term treatment with nucleoside (acid) analogs on the development of hepatocellular carcinoma (HCC), as well as studies finding that long-term application of nucleoside (acid) analogs reduces the risk of HCC, which is particularly important in areas with a high prevalence of hepatitis B, such as China and Southeast Asia. There have also been some excellent clinical studies on blocking mother-to-child transmission of HBV. For example, one study found that tenofovir plus classical immunoprophylaxis (hepatitis B vaccine and immunoglobulin), i.e., tenofovir treatment given to pregnant women with hepatitis B and hepatitis B immunoglobulin injections for their infants, improved the effectiveness of mother-to-child transmission interruption. This is strong evidence in support of screening pregnant women and enabling tenofovir to administer antiviral therapy to mothers with high viral loads to maximize the prevention of HBV infection in newborns. Rapid developments in the field of HBV, with a promising future for RNA-interfering drugs In addition to the clinical studies mentioned earlier, there are many exciting advances in the field of HBV with the development of new therapeutic concepts. It is still mainly in the preclinical stage, but in the coming months, these new concepts will enter clinical studies. One of these is RNA interference (RNAi) drugs targeting HBV. Two impressive studies presented at the conference showed that RNAi targeting HBV in different hosts (chimpanzees and mice) reduced serum HBsAg levels while reducing HBV DNA replication. Some of these studies have also shown fairly long-lasting effects (3 or 4 weeks), so it is conceivable how far away clinical studies are from giving patients RNAi therapy. Viral Shell Protein Inhibitors Have Very Strong Antiviral Effects In addition to RNAi, there have been some fascinating reports on new direct antiviral agents, mainly viral shell protein inhibitors, which represent a very promising class of therapeutic measures. Inhibitors of viral capsid proteins have shown very strong antiviral effects in experimental models (HBV-infected tissue culture and mouse models). This action is different from the mode of action of nucleoside (acid) analogs and interferon, so the next step could be to conduct prospective studies of viral shell protein inhibitors in combination with nucleoside (acid) analogs or interferon. The first phase IB studies have been conducted to confirm that viral capsid protein inhibitors have a favorable safety profile and can induce viral suppression. These studies have laid the foundation for phase II and beyond. In addition, many other potential targets are undergoing preclinical trials. Examples include targeting cccDNA, especially with CRISPR technology. Should immune-tolerant patients receive antiviral therapy? Whether or not to initiate antiviral therapy in immune-tolerant patients is a very important question, especially for countries and regions with high rates of mother-to-child transmission. In children, adolescents and young adults, there is a large number of immune-tolerant patients characterized by high viral loads and normal or low ALT levels, and clinical practice guidelines usually consider such patients to be ineligible for treatment. However, some studies have confirmed that liver damage also occurs in patients during the immune-tolerant phase, which is just not detectable with conventional tests (e.g., liver biopsy and pathologic analysis). Additional molecular studies would have revealed the presence of genetic damage to hepatocytes (hepatocyte clonal expansion) in some patients that could be the first step in tumorigenesis. With the continuous development of new drugs, drugs with high resistance thresholds and a very good safety profile are now available, so in this climate, the discussion among experts worldwide on the question of whether antiviral therapy should be initiated in patients with immune tolerance is becoming more and more heated, with varying opinions. The prevailing view is that treatment should be considered to be given to young patients with high viral loads and normal ALT levels, thus suppressing the virus and ultimately reducing the risk of HCC. What Fabien Zoulim’s team is working on At the end of the interview, Fabien Zoulim told us about his team’s research interests and shared the ongoing topics: ① On the clinical side, Fabien Zoulim’s team in Lyon, France, is very concerned with clinical aspects, such as following up patients, screening early patients, starting treatment early in the above immune-tolerant patients, reducing inflammation and reducing the risk of HCC. early initiation of therapy, reducing inflammation and minimizing complications. They are also interested in the clinical use of nucleoside analogues in combination with new drugs (e.g., viral capsid protein inhibitors, and siRNAs) and immune interventions (e.g., vaccine therapy), and are therefore doing clinical studies in these areas. (ii) In preclinical research (laboratory studies), mainly focusing on targeting cccDNA, the team has done a lot of work in studying the biological characteristics of cccDNA and identifying its targets, mainly including its genome and chromatin associated with it, and designing specific drugs or methods to target cccDNA. (iii) In the area of immunity, the team is very interested in the question of how HBV suppresses the intrinsic immunity of the infected hepatocytes. The team is very interested in how HBV suppresses the intrinsic immunity of infected hepatocytes, and hopes to discover specific mechanisms that can be targeted to restore the intrinsic immunity and improve the success of treatment.