Hepatitis B will recur within a few years after clinical cure. Is there any effective clinical treatment to solve this problem?

Functional cure of chronic hepatitis B—defined as sustained HBsAg loss and undetectable HBV DNA after finite therapy—is now an attainable goal for some patients. However, an emerging clinical reality is that a considerable proportion of these patients experience viral rebound and HBsAg reversion within months to years after treatment discontinuation, even when they had stable seroclearance. This suggests that “clinical cure” does not equal complete eradication. The fundamental issue lies in the persistence of intrahepatic cccDNA and integrated HBV DNA fragments, which can serve as templates for reactivation under immune-permissive conditions. My question to the hepatology and virology community is: What are the most promising interventional strategies currently under investigation to prevent or significantly delay post-cure recurrence? Are we looking at combination approaches that include next-generation core protein allosteric modulators, therapeutic vaccines, or immune checkpoint inhibitors to restore exhausted HBV-specific T cell function? Also, from a clinical trial design perspective, how should we define “durable cure” and what duration of off-treatment follow-up is sufficient to claim non-recurrence? I would especially appreciate insights from colleagues involved in long-term follow-up cohorts and early-phase trials aiming at viral elimination rather than suppression. Thank you.