FIG. 1.

Immunological and viral factors that are believed to determine response to NA treatment discontinuation. (A) CD8+ T cells that are chronically overstimulated by viral antigens (e.g., HBV DNA, HBsAg) and inhibited by excessive immunosuppressive microenvironment in the liver (e.g., PD‐L1) express high levels of inhibitory receptors, such as PD‐1, TIM‐3, LAG‐3, and CTLA‐4. The rebound of HBV replication after treatment discontinuation results in a relapse of high levels of HBV‐DNA replication in those patients who cannot establish sufficient immune control due to persisting T‐cell exhaustion. (B) Patients who overcome T‐cell exhaustion during NA treatment may respond to the HBV‐DNA rebound by establishing immune control with low or undetectable levels of HBV DNA, ideally followed by HBsAg loss. Abbreviations: CTLA‐4, cytotoxic T‐lymphocyte antigen 4; LAG‐3, lymphocyte‐activation gene 3; TIM‐3, T‐cell immunoglobulin mucin family member 3.