Lack of Association between Early On-Treatment HBeAg-Seroclearance and Development of Hepatocellular Carcinoma or Decompensated Liver Cirrhosis

Background & Aims The association between hepatitis B virus envelope antigen (HBeAg)-seroclearance during long-term nucleos(t)ide analogue (NA) treatment and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) remains unclear. Here, we aimed to investigate the association of HBeAg-seroclearance during potent NA treatment with the development of HCC and decompensated liver cirrhosis. Methods Using a multicenter historical cohort including 2,392 non-cirrhotic adult patients with HBeAg-positive CHB who initiated NA treatment with tenofovir or entecavir, the risk of HCC and decompensated liver cirrhosis was compared between patients who achieved HBeAg-seroclearance within 36 months of NA treatment (the HBeAg-loss group) and those who did not (the HBeAg-maintained group), using inverse probability of treatment weighting. Results Over a median of 6.6 years of NA treatment, 1,077 patients achieved HBeAg-seroclearance (HBeAg-loss rate=6.0 per 100 person-years), 64 patients developed HCC (HCC incidence rate=0.39 per 100 person-years), and 46 patients developed decompensated liver cirrhosis (decompensation incidence rate=0.28 per 100 person-years). The HBeAg-loss and HBeAg-maintained groups had a similar risk of developing HCC (hazard ratio [HR]=0.89, 95% confidence interval [CI]=0.47–1.68; P=0.72), and developing decompensated liver cirrhosis (HR =0.98, 95% CI =0.48–1.81; P=0.91). Compared with delayed HBeAg-seroclearance beyond 10 years of NA treatment, the risk of HCC was comparable in those who achieved earlier HBeAg-seroclearance at any time point within 10 years, regardless of baseline age and fibrotic burden. Conclusions Early HBeAg-seroclearance during NA treatment was not associated with a reduced risk of development of HCC or decompensated liver cirrhosis in non-cirrhotic HBeAg-positive CHB patients.