“Defining true immune-tolerant” phase is challenging. Both natural killer (NK) and T cells are functionally impaired in the immune-tolerant and immune-active phases [
12]. In one study, the proportion of NK cells in the liver was significantly higher in patients in the immune-tolerant phase compared to those in the immune-clearance phase [
13]. In addition, there might be intrahepatic HBV-specific T cell activities in immune-tolerant-phase patients, even in the absence of liver inflammation [
14]. A histology study in India showed that approximately 40% of HBeAg-positive patients with persistently normal ALT had necro-inflammation and fibrosis histologic fibrosis ≥ stage 2 [
15]. In a retrospective cohort study in Korea, it was shown that the risk of developing hepatocellular carcinoma (HCC) was higher in untreated patients in the immune-tolerant phase than patients in the immune-active phase on antivirals (12.7%
vs. 6.0%,
p = 0.001) [
16]. One possible reason for the poor outcome of immune-tolerant patients in previous studies is misclassification of patients in immune clearance phase as immune-tolerant. For example, in the Korean study, the mean age of the immune-tolerant patients was 38 years and 26% of immune-tolerant patients had HBV DNA 4–7 log IU/ml, which were atypical features for immune-tolerant phase [
16]. In the Indian histology cohort, the lower range HBV DNA among HBeAg-positive patients with persistently normal ALT was only 2.78 log copies/ml, which was too low for immune-tolerant phase [
15]. Therefore, defining immune-tolerant phase is challenging, and whether a true immune-tolerant phase exists is debatable. The 2017 European Association for the Study of the Liver (EASL) Clinical Practice Guidelines renamed this phase as HBeAg-positive chronic HBV infection instead of immune-tolerant phase to avoid confusion in terminology [
11].