Antiviral therapy lowers HCC risk in CHB patients in indeterminate phase

Patients with chronic hepatitis B (CHB) in the indeterminate phase are predisposed to advanced liver disease and hepatocellular carcinoma (HCC), as shown by a systematic review and meta-analysis.

"Although inherent heterogeneity across studies limited the evidence to support expanding treatment to all patients in the indeterminate phase, antiviral therapy may reduce the risk of HCC development in high-risk subgroups,” the investigators said.

Among the investigators, two independently searched Embase, Medline, Web of Science, and China National Knowledge Infrastructure from 1 January 2007 to 31 December 2023, and three independently assessed study eligibility and quality.

Cohort studies, cross-sectional studies, and a randomized controlled trial (RCT) were included. The RCT allowed for calculation of the incidence rate of adverse clinical outcomes, while the cross-sectional studies showed the prevalence of moderate-to-severe inflammation and different degrees of fibrosis.

Finally, generalized linear mixed-effects models and random-effects models were used to pool incidence rates and prevalence, respectively.

A total of 103 studies were included: 70 case-control (18,739 patients), 32 cohort (15,118 patients), and one RCT (160 patients). [J Hepatol 2025;82:992-1003]

HCC risk

Patients in the indeterminate CHB phase had an annual HCC incidence of 0.32 percent (95 percent confidence interval [CI], 0.21–0.48; I², 85.7 percent). Furthermore, the annual incidence rates for cirrhosis and hepatic decompensation in this population were 0.67 (95 percent CI, 0.30–1.49; I², 94.3percent) and 0.34 percent (95 percent CI, 0.17–0.69; I², 51.8 percent), respectively.

The pooled prevalence was 40.7 percent for moderate-to-severe liver inflammation, 39.7 percent for significant fibrosis, 17.9 percent for advanced fibrosis, and 7.2 percent for cirrhosis.

Notably, the use of antiviral therapy helps reduce the risk of HCC in patients in the indeterminate phase (adjusted incidence rate ratio, 0.38, 95 percent CI, 0.18–0.79; p=0.009).

“This systematic review and meta-analysis, by including the largest number of studies as of today, showed a substantial risk of HCC, cirrhosis, and hepatic decompensation among patients in the indeterminate phase of CHB,” the investigators said. 

“Despite that, with the heterogeneity of patients in the indeterminate phase, with study populations predominantly from retrospective observational studies, and marked differences in the incidence of HCC across subgroups, it is not possible to accurately determine the incidence of HCC and hepatic events,” they added.

Therefore, initiating antiviral treatment in indeterminate phase must be considered in high-risk patients. In addition, further prospective studies with structure monitoring must be conducted to improve risk stratification, according to the investigators.

Indeterminate phase

The composition of the indeterminate phase is “heterogeneous,” ranging from hepatitis B e-antigen (HBeAg)-positive patients with normal alanine transaminase (ALT) to HBeAg-negative individuals with low levels of viraemia and elevated ALT.

"The progression of the former could be triggered by hepatitis B virus (HBV) activity and ameliorated by antiviral treatment, while other factors such as metabolic dysfunction-associated steatotic liver disease might have caused the latter,” the investigators said. 

“This reinforces the need to exclude other causes of ALT elevation in indeterminate phase as antiviral treatment may have doubtful benefit if the main culprit is not viral activity from HBV,” they added.