Differential HCC risk among HBV indeterminate types at baseline and by phase transition

Background Patients with chronic hepatitis B (CHB) with indeterminate phase make up a diverse cohort with likely different outcomes. Objective We compared the hepatocellular carcinoma (HCC) risk in indeterminate CHB with different baseline types and by phase transition. Design This was a retrospective cohort study of 1986 (94.2% Asian) patients with indeterminate CHB from nine countries/regions. Patients were classified according to baseline hepatitis B e-antigen (HBeAg), alanine aminotransferase (ALT) and HBV DNA. The cumulative HCC incidence was compared. Results Based on the 2018 American Association for the Study of Liver Disease guidance, most indeterminate patients were HBeAg negative (84.9%). The 20-year HCC incidence was highest in type 1 (HBeAg positive, ALT<1×upper limit of normal (ULN), HBV DNA 20 000–10 6 IU/mL, 36.2%) and lowest in type 8 (HBeAg negative, ALT 1–2×ULN, HBV DNA<2000 IU/mL, 1.9%). The 20-year HCC incidence of those who remained indeterminate was 4.7%. Cumulative HCC incidence rates were high in patients with indeterminate CHB who transitioned to immune tolerant (15 years: 16.5%) or immune active (20 years: 13.7%) phase but low for those who transitioned to immune inactive phase (20 years: 2.5%). In multivariable analysis, compared with type 8, higher HCC risk was seen with HBeAg-positive type 1 (adjusted HR (aHR)=40.1, p<0.001), type 2 (ALT 1–2×ULN, HBV DNA≥20 000 IU/mL, aHR=25.1, p<0.001), HBeAg-negative type 9 (ALT>2×ULN, HBV DNA<2000 IU/mL, aHR=4.6, p=0.032) and type 10 (ALT<1×ULN, HBV DNA<2000 IU/mL but with moderate to severe inflammation/fibrosis, aHR=7.3, p=0.033). Similar directions in HCC risks were found in analyses based on the 2017 European Association for the Study of the Liver guideline. Conclusion Several types of indeterminate CHB had high HCC risk. These data support the potential expansion of treatment criteria for higher risk types of indeterminate CHB.