Long-term outcomes of baseline grey-zone patients with HBeAg-negative chronic hepatitis B virus infection

The optimal management and outcomes of patients with HBeAg-negative grey-zone (GZe-) chronic HBV infection remain debatable. We assessed the outcomes and real-life management of GZe-patients and compared them to patients with typical HBeAg-negative chronic infection (CIe-).

We included all HBeAg-negative patients with baseline HBV DNA ≤20,000 IU/ml or HBV DNA >20,000 IU/ml and ALT <2x the upper limit of normal (ULN). Among patients without treatment indications in year 1, those with persistently normal ALT (≤ULN) and HBV DNA <2,000 IU/ml were defined as typical CIe-, and all others were classified as GZe-. Outcomes included treatment initiation, HBsAg loss, hepatocellular carcinoma (HCC), and liver-related events (LREs: HCC, decompensated cirrhosis, liver transplantation, or liver-related death).

In total, 1,501 patients with a mean follow-up of 6.0 ± 4.6 years were included (GZe-/CIe-baseline characteristics: 811/690; GZe-/CIe-at year 1: 719/677). Compared with CIe-patients, GZe-patients more frequently developed treatment indications after year 1 (year 5: 13.4% vs. 2.2%; log-rank, p <0.001) and were more frequently treated after year 1 (year 5: 37.6% vs. 4.6%; log-rank, p <0.001). GZe-patients, particularly those with GZe-baseline characteristics, were less likely to achieve HBsAg loss (1-/5-year: 0.1/1.0% vs. 1/3%; log-rank, p = 0.012) and more frequently developed HCC (1-/5-year: 1/3% vs. 0%; log-rank, p <0.001) and LREs (1-/5-year: 1/4% vs. 0.1%; log-rank, p <0.001).

GZe-patients represent a large proportion of patients with chronic HBV seen at tertiary centers and meet treatment indications more frequently than CIe-patients. They also have a lower probability of HBsAg loss and higher risks of HCC and LREs despite treatment initiation in most cases; therefore, their optimal management and timing of treatment initiation require further evaluation.

The outcomes of patients with grey-zone HBeAg-negative chronic HBV infection remain uncertain, hindering their optimal management and timely treatment in clinical practice. Our real-world data from a tertiary HBV center provide valuable insights to guide the management of this patient group. Grey-zone HBeAg-negative patients represent a substantial proportion of the chronic HBV population and require careful monitoring, as they are at increased risk of hepatocellular carcinoma and other liver-related events.