Prof. Jonggi Choi: Impact of HBsAg Seroclearance on the Recurrence of Hepatocellular Carcinoma After Curative Liver Resection

Hepatitis B virus surface antigen (HBsAg) seroclearance is regarded as a realistic goal in patients with chronic hepatitis B (CHB). Previous studies consistently demonstrated the beneficial impact of HBsAg seroclearance on the risk of hepatocellular carcinoma (HCC) occurrence. However, it remained unknown regarding the impact of HBsAg seroclearance on the recurrence of HCC after curative liver resection. During this year's annual meeting of American Association for the Study of Liver Diseases (AASLD2021), Prof. Jonggi Choi - Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Liver Center, conducted a project entitled "Impact of HBsAg Seroclearance on the Recurrence of Hepatocellular Carcinoma After Curative Liver Resection" (AASLD2021, Oral 64), which studied the comparison of HCC recurrence rates 

       Hepatology Digest: What is the relevant mechanism of HBsAg serological clearance? In addition, what are the potential therapeutic targets helpful to HBsAg clearance? and /or? sero-conversion?
 
　　Dr Choi: Basically, HBsAg seroclearance is regarded as a realistic goal in the management of patients with chronic hepatitis B. HBsAg clearance is called a functional cure. The reason why we are pursuing HBsAg loss is that once HBsAg loss is achieved, we can expect better long-term outcomes, including for the development of HCC. However, the main barriers to achieving this functional cure is that there are many avenues for hepatitis B replication and HBsAg production. It could be from cccDNA in the hepatocyte, or it could be from integrated HBV DNA in the host cells. In addition, patients with hepatitis B infection usually have impaired immune responses against the hepatitis B virus. The problem is that HBsAg loss occurs very rarely in the natural history of hepatitis B infection. We have been treating with various antiviral treatments to achieve this goal, however the rate of HBsAg loss is very low with the current antiviral treatments, such as interferon or oral antiviral treatment. Recently, some studies have shown that if NUCs are stopped, it might increase the chance of HBsAg loss by the host’s immunity. However, this NUC-stopping strategy did not work well in Asian patients. This stopping strategy always carried the risk of hepatic decompensation, which is sometimes very dangerous for patients. Regarding achieving HBsAg seroclearance, we have many targets for a functional cure considering the natural life cycle of hepatitis B infection. Drugs in the pipeline today try to block these targets. Some drugs, for example, anti-Cp inhibitors, do not allow HBV to enter the hepatocyte. Some drugs block translational viral RNA. And some drugs will block capsid assembly. There is also a drug that reduces secretion of HBsAg into the blood stream. So, these are the potential therapeutic targets for achieving functional cure in patients with chronic hepatitis B.
 
　　Hepatology Digest: What indicators can predict HBsAg serological clearance? What are the similarities and differences between the spontaneous HBsAg serological clearance and those induced after antiviral therapy?
 
　　Dr Choi: Unfortunately, there has been no strong indicator to guarantee or predict HBsAg seroclearance so far. However, some studies reported that when we measure HBsAg titer in the blood, this may reflect the possibility of HBsAg seroclearance in the natural history and in patients on antiviral treatment. The lower the HBsAg titer, the higher the probability of HBsAg clearance. For your second question, last year we compared the long-term outcomes between spontaneous HBsAg loss and treatment-induced HBsAg loss. This study was published in Hepatology last year. The conclusion of our study was that there is no significant difference in the long-term prognosis, including HCC, death and liver transplantation, between these two HBsAg losses. In other words, once HBsAg loss is achieved regardless of the way, we can expect a good prognosis. Therefore, the way is not important based on our study. A following study from Hong Kong also showed consistent results to ours. In conclusion, the most important thing again is how we can achieve HBsAg loss and how we can increase the rates of HBsAg loss, regardless of the way.
 
　　Hepatology Digest: A study presented at this AASLD shows that HBsAg clearance is associated with the reduction of the relapse risk of liver cancer after radical hepatectomy. However, the risk of recurrence still exists and increases over time. What is your opinion on this? How should we deal with it?
 
　　Dr Choi: In general, when we look at the risk of recurrence after liver resection, the risk is highest shortly after the liver is sectioned, and then it goes down slowly up to two years, then the risk begins to increase gradually from that point. Unfortunately, the risk of recurrence is never going to disappear. Based on this, recurrence after liver resection can be divided into early and late recurrence, depending on the timing of recurrence. When the recurrence occurs within two years, this is usually regarded as early recurrence. This early recurrence mostly originates from residual tumor in the unresected liver, and this is basically associated with aggressive tumor biology, for example, a large size tumor, multiple tumors, tumors with vascular invasion. However, when recurrence happens after two years, then it is called late recurrence. This late recurrence is considered to be a newly developed tumor, even though it is still referred to as a recurrence. I would like to say that this would technically be a new tumor, therefore risk factors for late recurrence are shared with conventional HCC risk factors, for example, male, old age, and uncontrolled underlying liver disease. In the study presented at this AASLD 2021, we focused on late recurrence rather than early recurrence, because as I mentioned earlier, we would like to know whether there is a beneficial effect of HBsAg seroclearance in the risk of HCC recurrence after liver resection. Interestingly, the results of our study show that HBsAg loss was associated with a lower risk of HCC recurrence. The points I would like to stress coming out of our study are that first, even after liver resection for HCC, there is still a beneficial effect of HBsAg loss, which reduces recurrence. And second, you might remember a few years ago there was a debate regarding whether SVR in hepatitis C virus affects the risk of HCC recurrence. Many studies concluded that the risk of recurrence was not associated with SVR or treatment, and our study is looking at a similar context, with the only change being with hepatitis B instead of hepatitis C virus. So I would like to say that even after HCC diagnosis, once the patient has received curative treatment, they can still be a candidate for HBV cure, because, as we have shown in our study, HBsAg loss will reduce the risk of HCC recurrence.
 
　　Hepatology Digest: Could you please talk about how to improve the HBsAg serological clearance rate with the existing and future therapy?
 
　　Dr Choi: There has been a lot of effort to try to improve the rate of HBsAg seroclearance over the past decade. With existing treatment （NUC or interferon）, we are not satisfied with these options to increase the rate of functional cure. The rate of HBsAg loss by applying these two treatments is still very low, especially in Asian patients. However, there are lots of new drugs in the pipeline for functional cure of HBV. New treatments in the pipeline work on various pathways of the HBV life cycle. Some new treatments try to enhance our immunity to clear the virus. Promising studies have been reported recently, however, we still need to wait for more studies, because many questions are still unanswered. For example, which class of drugs will be more effective for a functional cure - a siRNA, CpAM, or other classes? In addition, we have no answers at to whether just one class of drugs is enough, or whether a combination of drugs is more effective to achieve functional cure. I think, together with these new treatments, the role of existing treatments should also be studied. NUCs and interferon - are they still needed for functional cure? Or, what combination will work better? These questions should be further studied in the near future.